U.S. patent application number 10/485394 was filed with the patent office on 2004-11-18 for antiviral agent.
Invention is credited to Fuji, Masahiro, Fujishita, Toshio, Kanda, Yasuhiko, Kawasuji, Takashi, Kiyama, Ryuichi, Tada, Yukio, Takechi, Shozo.
Application Number | 20040229909 10/485394 |
Document ID | / |
Family ID | 27347328 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040229909 |
Kind Code |
A1 |
Kiyama, Ryuichi ; et
al. |
November 18, 2004 |
Antiviral agent
Abstract
The present invention provides an integrase inhibitor. The
inventors have have found the following compound of formula (I)
possessing an integrase inhibitory activity. 1 (wherein, R.sup.C
and R.sup.D taken together with the neighboring carbon atoms form a
ring which may be a condensed ring, Y is hydroxy, mercapto or
amino; Z is O, S or NH; R.sup.A is a group shown by 2 (wherein, C
ring is N-containing aromatic heterocycle) or the like)
Inventors: |
Kiyama, Ryuichi; (Osaka-shi,
JP) ; Kanda, Yasuhiko; (Osaka-shi, JP) ; Tada,
Yukio; (Osaka-shi, JP) ; Fujishita, Toshio;
(Osaka-shi, JP) ; Kawasuji, Takashi; (Osaka-shi,
JP) ; Takechi, Shozo; (Osaka-shi, JP) ; Fuji,
Masahiro; (Osaka-shi, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
27347328 |
Appl. No.: |
10/485394 |
Filed: |
January 30, 2004 |
PCT Filed: |
August 8, 2002 |
PCT NO: |
PCT/JP02/08108 |
Current U.S.
Class: |
514/317 ;
514/408 |
Current CPC
Class: |
A61K 31/351 20130101;
C07D 417/06 20130101; C07D 413/04 20130101; A61K 31/433 20130101;
A61K 31/497 20130101; C07D 403/04 20130101; C07D 413/06 20130101;
A61K 31/4439 20130101; C07D 405/04 20130101; A61K 31/4155 20130101;
C07D 409/06 20130101; A61P 43/00 20180101; A61P 31/18 20180101;
C07D 311/24 20130101; A61K 31/4178 20130101; A61P 31/12 20180101;
A61K 31/4433 20130101; A61K 31/4196 20130101; A61K 31/4245
20130101; A61K 31/4025 20130101; A61K 31/506 20130101; C07D 403/06
20130101; A61K 31/427 20130101; A61K 31/4427 20130101; A61K 31/501
20130101; A61K 31/4709 20130101; A61K 31/53 20130101; A61P 31/14
20180101; C07D 409/14 20130101; C07D 407/06 20130101; A61K 31/5377
20130101; A61K 31/422 20130101; C07D 417/04 20130101; C07D 405/06
20130101; A61K 31/513 20130101; C07D 207/38 20130101; C07D 401/04
20130101; C07D 307/46 20130101 |
Class at
Publication: |
514/317 ;
514/408 |
International
Class: |
A61K 031/445; A61K
031/40 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 10, 2001 |
JP |
2001-245071 |
Dec 5, 2001 |
JP |
2001-370860 |
Jun 28, 2002 |
JP |
2002-191483 |
Claims
1. A method for preventing or treating a viral infectious disease
in a patient, which comprises administering to the patent a
therapeutically effective amount of a compound of formula (I)
299(wherein, R.sup.C and R.sup.Dtaken together with the neighboring
carbon atoms form a ring which may be a condensed ring, Y is
hydroxy, mercapto or amino; Z is O, S or NH; R.sup.A is a group
shown by 300(wherein, C ring is N-containing aromatic heterocycle,
wherein at least one atom neighboring to the atom at the
bonding-position is non-substituted N atom; the broken line shows
the presence or absence of a bond.) or by 301(wherein, X is O, S or
NH; R.sup.B is a substituent selected from substitution group A);
at least one of the ring formed by R.sup.C and R.sup.D, C ring or
R.sup.B is substituted with a group of
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1 and Z.sup.3
are each independently a bond, optionally substituted alkylene or
optionally substituted alkenylene; Z.sup.2 is a bond, optionally
substituted alkylene, optionally substituted alkenylene,
--CH(OH)--, --S-, --SO--, --SO.sub.2, --SO.sub.2NR.sup.2--,
--NR.sup.2SO.sub.2--, --O--, --NR.sup.2--, --NR.sub.2CO--,
--CONR.sub.2--, --C(.dbd.O)--O--, --O--C(.dbd.O) or --CO--; R.sup.2
is hydrogen, optionally substituted alkyl optionally substituted
alkenyl, optionally substituted aryl or optionally substituted
heteroaryl; R.sup.1 is optionally substituted aryl optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle); the ring formed by R.sup.C and R.sup.D, C ring or
R.sup.B is optionally substituted with a non-interfering
substituent at any possition other than that where the group of
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above) locates;
substitution groupA consists of: hydrogen, halogen, alkoxycarbonyl
carboxy, alkyl, alkoxy, alkoxyalkyl nitro, hydroxy, alkenyl
alkynyl, alkylsulfonyl, optionally substituted amino, alkylthio,
alkylthioalkyl, haloalkyl haloalkoxy, haloalkoxyalkyl optionally
substituted cycloalkyl, optionally substituted cycloalkenyl
optionally substituted heterocycle, nitroso, azide, amidino,
guanidino, cyano, isocyano, mercapto, optionally substituted
carbamoyl, sulfamoyl, sulfoamino, formyl, alkyl carbonyl, alkyl
carbonyloxy, hydrazino, morpholino, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl,
optionally substituted heteroaryl alkyl, optionally substituted
aryl oxy, optionally substituted heteroaryl oxy, optionally
substituted aryl thio, optionally substituted heteroaryl thio,
optionally substituted aralkyloxy, optionally substituted
heteroaryl alkyl oxy, optionally substituted aralkylthio,
optionally substituted heteroaryl alkylthio, optionally substituted
aryl oxyalkyl, optionally substituted heteroaryl oxyalkyl,
optionally substituted aryl thioalkyl, optionally substituted
heteroaryl thioalkyl, optionally substituted arylsulfonyl,
optionally substituted heteroarylsulfonyl, optionally substituted
aralkylsulfonyl and optionally substituted heteroaryl
alkylsulfonyl), its prodrug, or a pharmaceutically acceptable salt
or solvate thereof, for use as an integrase inhibitor.
2. A method of claim 1 wherein the ring formed by R.sup.C and
R.sup.D is a 5- to 6-membered ring which may contain a hetero
atom(s) and be condensed with.
3. A method of claim 2 wherein the ring formed by R.sup.C and
R.sup.D is a 5- to 6-membered ring which may contain a hetero
atom(s) of O and/or N and be condensed with a benzene ring.
4. A method of claim 3 wherein the ring formed by R.sup.C and
R.sup.D is a 5-membered ring which contains a hetero atom(s) of
N.
5. A method of claim 3 wherein the ring formed by R.sup.C and
R.sup.D is a 6-membered ring which contains a hetero atom(s) of O
and is condensed with a benzene ring.
6. A method of claim 3 wherein the ring formed by R.sup.C and
R.sup.D is a 6-membered ring which contains a hetero atom(s) of N
and is condensed with a benzene ring.
7. A method of claim 3 wherein the ring formed by R.sup.C and
R.sup.D is a 6-membered ring which contains a hetero atom(s) of
O.
8. A method of claim 3 wherein the ring formed by R.sup.C and
R.sup.D is a 6-membered ring which contains a hetero atom(s) of
N.
9. A method of claim 1 wherein the ring formed by R.sup.C and
R.sup.D is a 6-membered carbocycle.
10. A method of claim 4 which contains as an active ingredient a
compound of formula (II-1) 302(wherein, Y, Z, C ring, Z.sup.1,
Z.sup.2, Z.sup.3, R.sup.1 and the broken line is the same as claim
1; R.sup.3, R.sup.4, R.sup.5 and R.sup.19 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
11. A method of claim 4 which contains as an active ingredient a
compound of formula (III-1) 303(wherein, X, Y, Z, R.sup.B, Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as claim 1; R.sup.5,
R.sup.6, R.sup.7 and R.sup.1.sup..sup.9 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
12-13. (Cancelled)
14. A method of claim 3 which contains as an active ingredient a
compound of formula (IV-1): 304(wherein, Y, Z, C ring and the
broken line are the same as claim 1; R.sup.8,R.sup.9 and R.sup.10
are each independently a non-interfering substituent; at least one
of R.sup.E and R.sup.F is shown by
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as claim 1) and the other is a
non-interfering substituent, or R.sup.E and R.sup.F taken together
with the neighboring carbon atoms may form a ring shown by:
305(wherein, R.sup.1.sup..sup.1 to R.sup.1.sup..sup.3 are each
independently a non-interfering substituent, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as claim 1), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
15. A method of claim 5 which contains as an active ingredient a
compound of formula(IV-2): 306(wherein, Y, Z, C ring, Z.sup.1,
Z.sup.2, Z.sup.3,R.sup.1 and the broken line are the same as claim
1; R.sup.8 to R.sup.1.sup..sup.3 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
16. A method of claim 3 which contains as an active ingredient a
compound of formula (V-1) 307(wherein, Y, Z, C ring, Z.sup.1,
Z.sup.2, Z.sup.3,R.sup.1 and the broken line are the same as claim
1; R.sup.9 and R.sup.10 are each independently a non-interfering
substituent; R.sup.E and R.sup.F are each independently a
non-interfering substituent or taken together with the neighboring
carbon atoms may form a ring shown by: 308(wherein,
R.sup.1.sup..sup.1 to R.sup.1.sup..sup.4 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
17. A method of claim 5 which contains as an active ingredient a
compound of formula (V-2): 309(wherein, Y, Z, C ring, Z.sup.1,
Z.sup.2, Z.sup.3, R.sup.1 and the broken line are the same as claim
1; R.sup.9 to R.sup.1.sup..sup.4 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
18-19. (Cancelled)
20. A method of claim 3 which contains as an active ingredient a
compound of formula(VII-1): 310(wherein, X, Y, Z, R.sup.B, Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as claim; W.sup.1 is --O
or --N(--R.sup.G)--; R.sup.G is a non-interfering substituent;
R.sup.6 and R.sup.7 are each independently a non-interfering
substituent; R.sup.E and R.sup.F are each independently a
non-interfering substituent or taken together with the neighboring
carbon atoms form a ring shown by 311(wherein, R.sup.1.sup..sup.1
to R.sup.1.sup..sup.4 are each independently a non-interfering
substituent)), its prodrug or pharmaceutically acceptable salt or
solvate thereof.
21. A method of claim 3 which contains as an active ingredient a
compound of formula(VII-2): 312(wherein, X, Y, Z, R.sup.B. Z.sup.1,
Z.sup.2,Z.sup.3 and R.sup.1 are the same as claim 1; W.sup.1 is --O
or --N(R.sup.G)--; R.sup.G is a noninterfering substituent;
R.sup.6, R.sup.7, R.sup.1.sup..sup.1 to R.sup.1.sup..sup.4 are each
independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
22. A method of claim 3 which aontains as an active ingredient a
compound of formula (VII-3): 313(wherein, X, Y, Z, R.sup.B,
Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are the same as claim 1; W is
--O or --N(--R.sup.G); R.sup.G is a non-interfering substituent;
R.sup.6 and R.sup.7 are each independently a non-interfering
substituent; R.sup.E and R.sup.F are each independently a
noninterfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
23-24. (Cancelled)
25. A method of claim 8 which contains as an active ingredient a
compound of formula (IX-1): 314(wherein, X, Y, Z, R.sup.B, Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as claim 1; R.sup.6 and
R.sup.7 are each independently a noninterfering substituent;
R.sup.F and R.sup.G are each independently a non-interfering
substituent), its prodrug or pharmaceutically acceptable salt or
its solvate thereof.
26. A method of claim 8 which contains as an active ingredient a
compound of formula (IX-2): 315(wherein, Y, Z, C ring, Z.sup.1,
Z.sup.2, Z.sup.3, R.sup.1 and the broken line are the same as claim
1; R.sup.9 and R.sup.10 are each independently a non-interfering
substituent; R.sup.F and R.sup.G are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
27-34. (Cancelled)
35. A method of claim 1, wherein the non-interfering substituents
are independently selected from hydrogen, halogen, alkoxycarbonyl
carboxy, alkyl, alkoxy, alkoxyalkyl, nitro, hydroxy, hydroxyalkyl,
alkenyl, alkynyl, alkylsulfonyl, optionally substituted amino,
alkylthio, alkylthioalkyl haloalkyl, haloalkoxy, haloalkoxyalkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl optionally substituted heterocycle, oxo, thioxo,
nitroso, azide, amidino, guanidino, cyano, isocyano, mercapto,
optionally substituted carbamoyl, sulfamoyl, sulfoamino, formyl,
alkylcarbonyl alkylcarbonyloxy, hydrazino, morpholino, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted aralkyl, optionally substituted heteroarylalkyl,
optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted arylthio, optionally
substituted heteroarylthio, optionally substituted aralkyloxy,
optionally substituted heteroarylalkyloxy, optionally substituted
aralkylthio, optionally substituted heteroarylalkylthio, optionally
substituted aryloxyalkyl optionally substituted heteroaryloxyalkyl
optionally substituted arylthioalkyl, optionally substituted
heteroarylthioalkyl optionally substituted arylsulfonyl, optionally
substituted heteroarylsulfonyl, optionally substituted
aralkylsulfonyl and optionally substituted
heteroarylalkylsulfonyl.
36-37. (Cancelled)
38. A compound of formula(I-Q):
Q--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1, its prodrug or
pharmaceutically acceptable salt or solvate thereof, wherein,
Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are the same as claim 1; Q is
shown by any one of the following formulae: 316(wherein, C ring is
the same as claim 1; Y is hydroxy; Z is O; R.sup.3, R.sup.4,
R.sup.5 and R.sup.19 are the same as claim 10), 317(wherein, X is
O; Y and Z are the same as above; R.sup.5, R.sup.6,R.sup.7 and
R.sup.19 are the same as claim 11; R.sup.B is optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted cycloalkyl, optionally substituted cycloalkenyl or
optionally substituted heterocycle), 318(wherein, X, Y, Z and
R.sup.B are the same as above; R.sup.6,R.sup.7 and
R.sup.1.sup..sup.9 are the same as claim 11), 319(wherein, C ring
is the same as claim 1; Y and Z are the same as above; R.sup.8 to
R.sup.10 are the same as claim 14; W.sup.1 is the same as claim 20;
R.sup.16 is a non-interfering substituent), 320(wherein, C ring is
the same as claim 1; Y and Z are the same as above; R.sup.8 to
R.sup.13 are the same as claim 14; W.sup.1 is the same as claim
20), 321(wherein, C ring is the same as claim 1; Y and Z are the
same as above; R.sup.9 to R.sup.4 is the same as claim 16; W.sup.1
is the same as claim 20), 322(wherein, C ring is the same as claim
1; Y and Z are the same as above; W.sup.1 is the same as claim 20;
R.sup.9 and R.sup.10 are the same as claim 14; R.sup.17 and
R.sup.18 are each independently a non-interfering substituent),
323(wherein, X, Y, Z and R.sup.B are the same as above; W.sup.1 is
the same as claim 20; R.sup.6 and R.sup.7 are the same as claim 11;
R.sup.1.sup..sup.1 to R.sup.1.sup..sup.4 are the same as claim 16),
324(wherein, X, Y, Z and R.sup.B are the same as above; W.sup.1 is
the same as claim 20; R.sup.6 and R.sup.7 are the same as claim 11;
R.sup.17 and R.sup.18 are each independently a non-interfering
substituent): 325(wherein, X, Y, Z and R.sup.B are the same as
above; R.sup.6 and R.sup.7 are the same as claim 11;
R.sup.1.sup..sup.7 and R.sup.1.sup..sup.8 are each independently a
non-interfering substituent), 326(wherein, C ring is the same as
claim 1; Y and Z are the same as above; R.sup.9 and R.sup.1 are the
same as claim 14; R.sup.1.sup..sup.7 and R.sup.18 are the same as
defined above), 327(wherein, X, Y, Z and R.sup.B are the same as
above; R.sup.5 is the same as claim 10; R.sup.6 and R.sup.7 are the
same as claim 11; R.sup.1.sup..sup.7 and R.sup.1.sup..sup.8 are the
same as defined above), 328(wherein, C ring is the same as claim 1;
Y and Z are the same as above; R.sup.5 is the same as claim 10;
R.sup.9 and R.sup.10 are the same as claim 14; R.sup.17 and
R.sup.18 are the same as defined above), 329(wherein, X, Y, Z and
R.sup.B are the same as above; R.sup.5 and R.sup.5' are the same as
claim 27; R.sup.6 and R.sup.7 are the same as claim 11),
330(wherein, C ring is the same as claim 1; Y and Z are the same as
above; R.sup.5 and R.sup.5' are the same as claim 27; R.sup.9 and
R.sup.10 are the same as claim 14): 331(wherein, X, Y, Z and
R.sup.B are the same as above; R.sup.6 and R.sup.7 are the same as
claim 11; R.sup.1.sup..sup.7 and R.sup.1.sup..sup.8 are the same as
above, the broken line(---) shows the presence or absence of a
bond), 332(wherein, C ring is the same as claim 1; Y and Z are the
same as above; R.sup.9 and R.sup.10 are the same as claim 14;
R.sup.1.sup..sup.7 and R.sup.1.sup..sup.8 are the same as above,
the broken line (---) shows the presence or absence of a bond),
333(wherein, X, Y, Z and R.sup.B are the same as above; R.sup.5,
R.sup.6 and R.sup.7 are the same as claim 11; R.sup.1.sup..sup.7
and R.sup.1.sup..sup.8 are the same as above, the broken line(---)
shows the presence or absence of a bond), 334(wherein, C ring is
the same as claim 1; Y and Z are the same as above; R.sup.5 is the
same as claim 10; R.sup.9 and R.sup.10 are the same as claim 14;
R.sup.1.sup..sup.7 and R.sup.1.sup..sup.8 are the same as above,
the broken line(---) shows the presence or absence of a bond),
335(wherein, X, Y, Z and R.sup.B are the same as above; R.sup.5,
R.sup.6 and R.sup.7 are the same as claim 11; R.sup.18 is the same
as defined above), and 336(wherein, C ring is the same as claim 1;
Y and Z are the same as above; R.sup.5 is the same as claim 10;
R.sup.9 and R.sup.10 are the same as claim 14; R.sup.18 is the same
as defined above); provided that excluded are compounds, wherein
Z.sup.1 is a bond, Z.sup.2 is --O--, Z.sup.3 is methylene, R.sup.1
is phenyl and Q is a group of the formula: 337(wherein, R.sup.8 to
R.sup.1.sup..sup.3 are hydrogens, Y is hydroxy, Z is O, W is --O--,
and C ring is quinoline-2-yl) or the formula: 338wherein, R.sup.9
and R.sup.10 are the same as above, R.sup.1.sup..sup.7 is alkyl,
R.sup.1.sup..sup.8 is hydrogen, Y is hydroxy, Z is O, C ring is
dihydropirimne).
39. A compound of claim 38, shown by formula (H-1): 339(wherein, Y
is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1
are the same as claim 1; R.sup.3,R.sup.4,R.sup.5 and
R.sup.1.sup..sup.9 are each independently a non-interfering
substituent), its prodrug or pharmaceutically acceptable salt or
solvate thereof.
40. A compound of claim 39, wherein Z.sup.1 and Z.sup.3 are each
independently a bond or alkylene; Z.sup.2 is a bond or --O--;
R.sup.1 is optionally substituted aryl or optionally substituted
heteroaryl its prodrug or pharmaceutically acceptable salt or
solvate thereof.
41. A compound of claim 39, wherein C ring is pyrimidine-4yl or
1,3,4-oxadiazole-2yl; Z.sup.1 is a bond; Z.sup.2 is -0 or alkylene;
Z.sup.3 is a bond or alkylene; R.sup.1 is aryl optionally
substituted with halogen; R.sup.3, R.sup.4 and R.sup.1.sup..sup.9
are hydrogens; R.sup.5 is alkyl, aralkyl, cycloalkyl, aryl or
alkoxy, its prodrug or pharmaceutically acceptable salt or solvate
thereof.
42. A compound of claim 38, shown by formula (III-1): 340(wherein,
X is O; Y is hydroxy; Z is O; R.sup.B is optionally substituted
aryl, optionally substituted heteroaryl optionally substituted
cycloalkyl, optionally substituted cycloalkenyl or optionally
substituted heterocycle; Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are
the same as claim 1; R.sup.5, R.sup.6, R.sup.7 and R.sup.19 are
each independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
43. A compound of claim 39 or 42, wherein, R.sup.5 is hydrogen,
alkyl, aralkyl, cycloalkyl, optionally substituted aryl, alkoxy,
alkoxyalkyl optionally substituted ammo, hydroxyalkyl, alkenyl
alkoxycarbonylalkyl or heteroarylalkyl, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
44. A compound of above 42, wherein R.sup.B is fran-2yl, its
prodrug or pharmaceutically acceptable salt or solvate thereof.
45. A compound of above 42, wherein R.sup.B is aryl or fran-2yl;
Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is alkylene; R.sup.1 is aryl
optionally substituted with halogen; R.sup.6,R.sup.7 and
R.sup.1.sup..sup.9 are hydrogens; R.sup.5 is alkyl, cycloalkyl,
alkoxy, aryl optionally substituted with alkoxy, hydroxyalkyl,
alkenyl aralkyl, alkoxycarbonylalkyl, or pyridine-2ylmethyl its
prodrug or pharmaceutically acceptable salt or solvate thereof.
46-51. (Cancelled)
52. A compound of claim 38, shown by formula (IV-2): 341(wherein, Y
is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1
are the same as claim 1; R.sup.8 to R.sup.1.sup..sup.3 are each
independently a non-interfering substituent, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
53. A compound of claim 52, wherein C ring is pyridine-2-yl,
1,2,4-triazole-3-yl or imidazole-2-yl optionally substituted with
alkyl; Z.sup.1 is a bond; Z.sup.2 is --O--; Z.sup.3 is alkylene;
R.sup.1 is aryl optionally substituted with halogen; R.sup.8 to
R.sup.1.sup..sup.3 are hydrogens, its prodrug or pharmaceutically
acceptable salt or solvate thereof.
54. A compound of claim 38, shown by formula (V-2): 342(wherein, Y
is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1
are the same as claim 1; R.sup.9 to R.sup.1.sup..sup.4 are each
independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
55. A compound of claim 52 or 54, wherein Z.sup.1 and Z.sup.3 are
each independently a bond or alkylene; Z.sup.2 is a bond or --O--;
R.sup.1 is optionally substituted aryl or optionally substituted
heteroaryl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
56. A compound of claim 54, wherein C ring is 1,3,4-oxadiazole-2y1;
Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is alkylene; R.sup.1 is aryl
optionally substituted with halogen; R.sup.9 to R.sup.1.sup..sup.4
are hydrogens, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
57-59. (Cancelled)
60. A compound of claim 38, shown by formula (VI-4): 343(wherein, X
is O; Y is hydroxy; Z is O; W.sup.2 is --O or --NH--; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as claim 1;
R.sup.6,R.sup.7,R.sup.1.sup..sup.1 to R.sup.1.sup..sup.4 are each
independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
61. A compound of claim 60, wherein R.sup.B is fran-2-yl, its
prodrug or pharmaceutically acceptable salt or solvate thereof.
62. A compound of claim 60, wherein R.sup.B is fran-2-yl; Z.sup.1
and Z.sup.3 are bonds; Z.sup.2 is alkylene; R.sup.1 is aryl
optionally substituted with halogen;
R.sup.6,R.sup.7,R.sup.1.sup..sup.1 to R.sup.1.sup..sup.4 are
hydrogens, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
63. A compound of claim 38, shown by formula (VII-5): 344(wherein,
X is O; Y is hydroxy; Z is O; W.sup.2 is --O or --NH--; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as claim 1
R.sup.6,R.sup.7, R.sup.E and R.sup.F are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
64. A compound of claim 63, wherein, R.sup.B is fran-2-yl, its
prodrug or pharmaceutically acceptable salt or solvate thereof.
65. A compound of claim 63, wherein, R.sup.B is fran-2yl; Z.sup.1
and Z.sup.3 are bonds; Z.sup.2 is alkylene; R.sup.1 is aryl
optionally substituted with halogen; R.sup.6,R.sup.7, R.sup.E and
R.sup.F are hydrogens, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
66-69. (Cancelled)
70. A compound of claim 38, shown by formula (IX-1): 345(wherein, X
is O; Y is hydroxy; Z is O; R.sup.B is optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl or optionally
substituted heterocycle; Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are
the same as claim 1; R.sup.6,R.sup.7, R.sup.F and R.sup.G are each
independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
71-72. (Cancelled)
73. A compound of claim 38, shown by formula (IX-2): 346(wherein, Y
is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1
are the same as claim 1; R.sup.9,R.sup.10, R.sup.F and R.sup.G are
each independently a non-interfering substituent, provided that
when R.sup.G is hydrogen and R.sup.F is alkyl C ring is not
dihydropirimidine), its prodrug or pharmaceutically acceptable salt
or solvate thereof.
74-89. (Cancelled)
90. A compound of claim 38, 39, 46, 52, 54, 57, 69, 73, 77, 81, 85
or 89, wherein C ring is optionally substituted pyridine-2-yl,
optionally substituted pyrimidine-4-yl, optionally substituted
1,3,4-oxadiazole-2yl, optionally substituted 1,2,4-triazole-3yl or
optionally substituted imidazole-2-yl, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
91. A compound of claim
38,(39),(46),(52),(54),(57),(69),(73),(77),(81),(8- 5) or (89),
wherein Z.sup.1 and Z.sup.3 are each independently a bond or
alkylene; Z.sup.2 is a bond or --O--; R.sup.1 is optionally
substituted aryl or optionally substituted heteroaryl its prodrug
or pharmaceutically acceptable salt or solvate thereof.
92. A compound of claim
38,(39),(46),(52),(54),(57),(69),(73),(77),(81),(8- 5) or (89),
wherein C ring is pyrimidine-4-yl or 1,3,4-oxadiazole-2-yl; Z.sup.1
is a bond; Z.sup.2 is --O or allylene; Z.sup.3 is a bond or
alkylene; R.sup.1 is aryl optionally substituted with halogen
R.sup.3,R.sup.4 and R.sup.1.sup..sup.9 are hydrogens, its prodrug
or pharmaceutically acceptable salt or solvate thereof.
93. A compound of claim
38,(39),(42),(46),(49),(52),(54),(57),(60).(63),(6-
6),(69),(70),(73),(74,(77),(78),(81),(82),(85),(86) or (89),
wherein each non-interfering substituent is independently selected
from hydrogen, halogen, alkoxycarbonyl, carboxy, alkyl, alkoxy,
alkoxy alkyl, nitro, hydroxy, alkenyl, alkynyl, alkylsulfonyl,
optionally substituted amino, alkylthio, alkylthio alkyl,
haloalkyl, haloalkoxy, haloalkoxy alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl, optionally
substituted heterocycle, oxo, thioxo, nitroso, azide, amidino,
guanidino, cyano, isocyano, mercapto, optionally substituted
carbamoyl, sulfamoyl, sulfoamino, formyl, alkyl carbonyl, alkyl
carbonyloxy, hydrazino, morpholino, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl
optionally substituted heteroaryl alkyl, optionally substituted
aryl oxy, optionally substituted heteroaryl oxy, optionally
substituted aryl thio, optionally substituted heteroaryl thio,
optionally substituted aralkyloxy, optionally substituted
heteroaryl alkyl oxy, optionally substituted aralkylthio,
optionally substituted heteroaryl alkylthio, optionally substituted
aryl oxyalkyl, optionally substituted heteroaryl oxyalkyl,
optionally substituted aryl thioalkyl, optionally substituted
heteroaryl thioalkyl, optionally substituted arylsulfonyl,
optionally substituted heteroarylsulfonyl, optionally substituted
aralkylsulfonyl and optionally substituted heteroaryl
alkylsulfonyl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
94. A compound of claim 38, (39), (42), (46), (49), (52), (54),
(57), (60). (63), (66), (69), (70), (73), (74), (77), (78), (81),
(82), (85), (86) or (89), wherein Z.sup.1, Z.sup.2 and Z.sup.3 are
not bonds at the same, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
95. A compound of claim 94, wherein R.sup.1 is phenyl optionally
substituted with halogen, Z.sup.1 is a bond, Z.sup.2 is alkylene or
--O--, Z.sup.3 is a bond or alkylene, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
96. A compound of claim 95, wherein R.sup.1 is 4-fluorophenyl, its
prodrug or pharmaceutically acceptable salt or solvate thereof.
97-99. (Cancelled)
100. A pharmaceutical composition comprising a compound of any one
of claims 38 to 99, its prodrug or pharmaceutically acceptable salt
or solvate thereof.
101-120. (Cancelled)
121. A method for preventing or treating an integrase-mediated
disease in a patient, which comprises administering to the patient
a therapeutically effective amount of a compound of formula (I):
347(wherein, R.sup.C and R.sup.Dtaken together with the neighboring
carbon atoms form a ring which may be a condensed ring, Y is
hydroxy, mercapto or amino; Z is O, S or NH; R.sup.A is a group
shown by 348(wherein, C ring is N-containing aromatic heterocycle,
wherein at least one atom neighboring to the atom at the bonding
pition is non-substituted N atom; the broken line shows the
presence or absence of a bond.) or by 349(wherein, X is O, S or NH;
R.sup.B is a substituent selected from substitution group A); at
least one of the ring formed by R.sup.C and R.sup.D, C ring or
R.sup.B is substituted with a group of
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1 and Z.sup.3
are each independently a bond, optionally substituted alkylene or
optionally substituted alkenylene; Z.sup.2 is a bond, optionally
substituted alkylene, optionally substituted alkenylene,
--CH(OH)--, --S--, --SO--,--SO.sub.2--, --SO.sub.2NR.sub.2--,
--NR.sub.2SO.sub.2--, --O--, --NR.sub.2--, --NR.sub.2CO--,
--CONR.sub.2--, --C(.dbd.O)--O--, --O--C(.dbd.O) or--CO--; R.sup.2
is hydrogen, optionally substituted alkyl optionally substituted
alkenyl, optionally substituted aryl or optionally substituted
heteroaryl; R.sup.1 is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle); the ring formed by R.sup.C and R.sup.D, C ring or
R.sup.B is optionally substituted with a non-interfering
substituent at any position other than that where the group of
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above) locates;
substitution groupA consists of: hydrogen, halogen, alkoxycarbonyl
carboxy, alkyl, alkoxy, alkoxyalkyl, nitro, hydroxy, alkenyl,
alkynyl alkylsulfonyl, optionally substituted amino, alkylthio,
alkylthioalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl optionally
substituted cycloalkyl optionally substituted cycloalkenyl,
optionally substituted heterocycle, nitroso, azide, amidino,
guanidino, cyano, isocyano, mercapto, optionally substituted
carbamoyl, sulfamoyl, sulfoamino, formyl, alkyl carbonyl, alkyl
carbonyloxy, hydrazino, morpholino, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl,
optionally substituted heteroaryl alkyl, optionally substituted
aryl oxy, optionally substituted heteroaryl oxy, optionally
substituted aryl thio, optionally substituted heteroaryl thio,
optionally substituted aralkyloxy, optionally substituted
heteroaryl alkyl oxy, optionally substituted aralkylthio,
optionally substituted heteroaryl alkylthio, optionally substituted
aryl oxyalkyl, optionally substituted heteroaryl oxyalkyl,
optionally substituted aryl thioalkyl, optionally substituted
heteroaryl thioalkyl, optionally substituted arylsulfonyl,
optionally substituted heteroarylsulfonyl, optionally substituted
aralkylsulfonyl and optionally substituted heteroaryl
alkylsulfonyl), its prodrug, or a pharmaceutically acceptable salt
or solvate thereof, for use as an integrase inhibitor.
Description
TECHNICAL FIELD
[0001] The present invention relates to an antiviral agent,
especially, a compound having an .alpha.-hydroxy-.alpha., .beta.
unsatutared keone as a partial structure, and a pharmaceutical
composition as an integrase inhibitor containing the same.
BACKGROUND ART
[0002] Among viruses, human immunodeficiency virus (HIV), a kind of
retrovirus, is known to cause acquired immunodeficiency syndrome
(AIDS). The therapeutic agent for AIDS is mainly selected from the
group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and
protease inhibitors (e.g., Indinavir), but they are proved to be
accompanied by side effects such as nephropathy and the emergence
of resistant viruses. Thus, the development of anti-HIV agents
having the other mechanism of action has been desired.
[0003] On the other hand, a combination therapy is reported to be
effective in the treatment for acquired immunodeficiency syndrome
because of the frequent emergence of the resistant mutant in
Balzarini, J. et al, Proc. Natl. Acad. Sci. USA 1996, 93,
p13152-13157. Reverse transcriptase inhibitors and protease
inhibitors are clinically used as an anti-HIV agent, however,
agents having the same mechanism of action often show the
cross-resistance or only an additional activity. Therefore,
anti-HIV agents having the other mechanism of action are
desired.
[0004] Examples of the integrase inhibitor include
1,3-dioxobutanoic acids and 1,3-propanediones described in
WO99/50245, WO99/62520, WO99/62897, WO99/62513, WO00/39086, and
WO01/00578. Another integrase inhibitor is acrylic acid derivative
described in WO01/17968. The other recently reported types are
aza-or polyazanaphthalenylcarboamide derivative described in
WO2002/30426, WO2002/30930, WO2002/30931, and WO2002/36734.
[0005] A compound having a similar structure to the present
invention compound is
N-substituted-3-carboamide-4-hydroxy-5-oxo-3-pyrroline derivative
with an anti-inflammatory effect described in Eur. J. Med.
Chemical-Chim. Ther. (1979), 14(2), 189-190. Pharmazie (1997),
52(4), 276-278 discloses
1-methyl-4-arylcarbamido-2,3-dioxopyrrolidine derivative as an
intermediate. WO92/06954 discloses pyrolizinedione derivative with
an inhibitory effect on aldose reductase. J. Med. Chemical (1976),
19(1), 172-173 discloses N-substituted-4,5-dioxopyrrolid-
ine-3-carboxyanilide derivative with anti-inflammatory effect.
Journal of Physical Chemistry A (2002), 106(11), 2497-2504
discloses pyrimidine derivative without mentioning any
pharmaceutical use.
[0006] T'ai-wan K'o Hsueh (1997), 31(3-4), 130-135 discloses
3-hydroxy-7-(phenylmethoxy)-2-(2-quinolinyl)-4H-1-benzopyrane-4-one.
Examples of a compound having a structure of
"4H-1-benzopyrane-4-one" include flavonoid derivative with anti-HIV
activity described in {circle over (1)} J. Nat. Prod. (2001),
64(4), 546-548, {circle over (2)} Anticancer Res. (2000), 20(4),
2525-2536, {circle over (3)}WO98/11889, {circle over (4)} Pharmazie
(1998), 53(8), 512-517, though the action of mechanism is not
mentioned therein.
DISCLOSURE OF INVENTION
[0007] Under the above circumstance, the development of a novel
integrase inhibitor has been desired.
[0008] The present inventors have intensively studied to find a
novel antiviral agent, the following compound (I), its prodrug, or
a pharmaceutically acceptable salt or solvate thereof, possessing
an integrase inhibitory activity; 3
[0009] (wherein, R.sup.C and R.sup.D taken together with the
neighboring carbon atoms may form a ring, and the ring may be a
condensed ring; Y is hydroxy, mercapto or amino; Z is O, S or NH;
R.sup.A is shown by 4
[0010] (wherein, C ring is N-containing aromatic heterocycle,
wherein at least one atom neighboring to the atom at the
bonding-position is N atom; the broken line shows the presence or
absence of a bond.) or by 5
[0011] (wherein, X is O, S or NH; R.sup.B is a substituent selected
from substitution group A) at least one of the ring formed by
R.sup.C and R.sup.D, C ring or R.sup.B is substituted with a group
of --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1 and
Z.sup.3 are each independently a bond, optionally substituted
alkylene or optionally substituted alkenylene; Z.sup.2 is a bond,
optionally substituted alkylene, optionally substituted alkenylene,
--CH(OH)--, --S--, --S O--, --SO.sub.2--, --SO.sub.2NR.sub.2--,
--NR.sub.2SO.sub.2--, --O--, --NR.sub.2--, --NR.sub.2CO--,
--CONR.sub.2--, --C(.dbd.O)--O--, --O--C(.dbd.O) or --CO--; R.sup.2
is hydrogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted aryl or optionally substituted
heteroaryl; R.sup.1 is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle) the ring formed by R.sup.C and R.sup.D, C ring or
R.sup.B is optionally substituted with a non-interfering
substituent at any possition other than that where the group of
--Z.sup.1--Z.sup.2--Z.sup.3 --R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above) locates;
substitution group A: hydrogen, halogen, alkoxycarbonyl, carboxy,
alkyl, alkoxy, alkoxyalkyl, nitro, hydroxy, alkenyl, alkynyl,
alkylsulfonyl, optionally substituted amino, alkylthio,
alkylthioalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkenyl,
optionally substituted heterocycle, nitroso, azide, amidino,
guanidino, cyano, isocyano, mercapto, optionally substituted
carbamoyl, sulfamoyl, sulfoamino, formyl, alkylcarbonyl,
alkylcarbonyloxy, hydrazino, morpholino, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
aralkyl, optionally substituted heteroaryl alkyl, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted aryl thio, optionally substituted
heteroarylthio, optionally substituted aralkyloxy, optionally
substituted heteroarylalkyloxy, optionally substituted aralkylthio,
optionally substituted heteroarylalkylthio, optionally substituted
aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally
substituted arylthioalkyl, optionally substituted
heteroarylthioalkyl, optionally substituted arylsulfonyl,
optionally substituted heteroarylsulfonyl, optionally substituted
aralkylsulfonyl and optionally substituted
heteroarylalkylsulfonyl.) (hereafter referred to as "the present
invention compound").
[0012] The present inventors further found that the present
invention compound and a pharmaceutical composition containing the
same are useful as antivirus agent, anti-retrovirus agent, anti-HIV
agent, anti-HTLV-1 (Human T cell leukemia virus type 1) agent,
anti-FIV (Feline immunodeficiency virus) agent, and anti-SIV
(Simian immunodeficiency virus) agent, esp., anti-HIV agent and an
integrase inhibitor, whereby to achieve the present invntion.
[0013] The present invntion provides the present invention
compound, its prodrug, a pharmaceutically acceptable salt or
solvate thereof, a pharmaceutical composition containing the same
as an active ingredient, antivirus agent, anti-HIV agent, an
integrase inhibitor, and anti-HIV mixture. These are useful as
anti-HIV agent as well as anti-AIDS agent for diseases such as
AIDS, its related clinical syndrome, e.g., AIDS related
complication ARC), persistent generalized lymphadenopath(PGL),
Kaposi sarcoma, pneumocystis carini pneumonia, sudden thrombocy
topenic purpura, AIDS related neurological symptom, for example,
AIDS dementia complications AIDS-associated encephalopathy multiple
sclerosis or tropical spastic paraparesis, and anti-HIV antibody
positive and HIV positive symptom in asymptomatic patients.
[0014] The present invntion relates to:
[0015] (1) a pharmaceutical composition containing as an active
ingredient a compound of formula (I): 6
[0016] (wherein, R.sup.C and R.sup.D taken together with the
neighboring carbon atoms form a ring which may be a condensed ring,
Y is hydroxy, mercapto or amino; Z is O, S or NH R.sup.A is a group
shown by 7
[0017] (wherein, C ring is N-containing aromatic heterocycle,
wherein at least one atom neighboring to the atom at the
bonding-position is non-substituted N atom; the broken line shows
the presence or absence of a bond.) or by 8
[0018] (wherein, X is O, S or NH; R.sup.B is a substituent selected
from substitution group A) at least one of the ring formed by
R.sup.C and R.sup.D, C ring or R.sup.B is substituted with a group
of --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1 and
Z.sup.3 are each independently a bond, optionally substituted
alkylene or optionally substituted alkenylene; Z.sup.2 is a bond,
optionally substituted alkylene, optionally substituted alkenylene,
--CH(OH)--, --S--, --S O--, --SO.sub.2--, --SO.sub.2NR.sub.2--,
--NR.sub.2SO.sub.2--, --O--, --NR.sub.2--, --NR.sub.2CO--,
--CONR.sub.2--, --C(.dbd.O)--O--, --O--C(.dbd.O) or --CO--; R.sup.2
is hydrogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted aryl or optionally substituted
heteroaryl; R.sup.1 is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle); the ring formed by R.sup.C and R.sup.D, C ring or
R.sup.B is optionally substituted with a non-interfering
substituent at any possition other than that where the group of
--Z.sup.1--Z.sup.2--Z.sup.3-- -R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above) locates;
substitution groupA consists of: hydrogen, halogen, alkoxycarbonyl,
carboxy, alkyl, alkoxy, alkoxyalkyl, nitro, hydroxy, alkenyl,
alkynyl, alkylsulfonyl, optionally substituted amino, alkylthio,
alkylthioalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkenyl,
optionally substituted heterocycle, nitroso, azide, amidino,
guanidino, cyano, isocyano, mercapto, optionally substituted
carbamoyl, sulfamoyl, sulfoamino, formyl, alkyl carbonyl, alkyl
carbonyloxy, hydrazino, morpholino, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl,
optionally substituted heteroaryl alkyl optionally substituted aryl
oxy, optionally substituted heteroaryl oxy, optionally substituted
aryl thio, optionally substituted heteroaryl thio, optionally
substituted aralkyloxy, optionally substituted heteroaryl alkyl
oxy, optionally substituted aralkylthio, optionally substituted
heteroaryl alkylthio, optionally substituted aryl oxyalkyl,
optionally substituted heteroaryl oxyalkyl, optionally substituted
aryl thioalkyl, optionally substituted heteroaryl thioalkyl,
optionally substituted arylsulfonyl, optionally substituted
heteroarylsulfonyl, optionally substituted aralkylsulfonyl and
optionally substituted heteroaryl alkylsulfonyl), its prodrug, or a
pharmaceutically acceptable salt or solvate thereof, for use as an
integrase inhibitor. In detail, the invention relates to the
following (2) to (120).
[0019] (2) A pharmaceutical composition of above (1) wherein the
ring formed by R.sup.C and R.sup.D is a 5- to 6-membered ring which
may contain a hetero atom(s) and be condensed with.
[0020] (3) A pharmaceutical composition of above (2) wherein the
ring formed by R.sup.C and R.sup.D is a 5- to 6-membered ring which
may contain a hetero atom(s) of O and/or N and be condensed with a
benzene ring.
[0021] (4) A pharmaceutical composition of above (3) wherein the
ring formed by R.sup.C and R.sup.D is a 5-membered ring which
contains a hetero atom(s) of N.
[0022] (5) A pharmaceutical composition of above (3) wherein the
ring formed by R.sup.C and R.sup.D is a 6-membered ring which
contains a hetero atom(s) of 0 and is condensed with a benzene
ring.
[0023] (6) A pharmaceutical composition of above (3) wherein the
ring formed by R c and R.sup.D is a 6-membered ring which contains
a hetero atom(s) of N and is condensed with a benzene ring.
[0024] (7) A pharmaceutical composition of above (3) wherein the
ring formed by R c and R.sup.D is a 6-membered ring which contains
a hetero atom(s) of O.
[0025] (8) A pharmaceutical composition of above (3) wherein the
ring formed by R c and R.sup.D is a 6-membered ring which contains
a hetero atom(s) of N.
[0026] (9) A pharmaceutical composition of above (1) wherein the
ring formed by R c and R.sup.D is a 6-membered carbocycle.
[0027] (10) A pharmaceutical composition of above (4) which
contains as an active ingredient a compound of formula (II-1):
9
[0028] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3, R.sup.1
and the broken line is the same as above (1); R.sup.3, R.sup.4,
R.sup.5 and R.sup.19 are each independently a non-interfering
substituent), its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0029] (11) A pharmaceutical composition of above (4) which
contains as an active ingredient a compound of formula (III-1):
10
[0030] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); R.sup.5, R.sup.6, R.sup.7 and
R.sup.19 are each independently a non-interfering substituent), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0031] (12) A pharmaceutical composition of above (3) which
contains as an active ingredient a compound of formula (II-2):
11
[0032] (wherein Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3, R.sup.1
and the broken line is the same as above (1); R.sup.3, R.sup.4 and
R.sup.19 are each independently a non-interfering substituent), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0033] (13) A pharmaceutical composition of above (3) which
contains as an active ingredient a compound of formula (III-2):
12
[0034] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 is the same as above (1); R.sup.6, R.sup.7 and R.sup.9 are
each independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0035] (14) A pharmaceutical composition of above (3) which
contains as an active ingredient a compound of formula (IV-11)
13
[0036] (wherein, Y, Z, C ring and the broken line are the same as
above (1); R.sup.8, R.sup.9 and R.sup.10 are each independently a
non-interfering substituent; at least one of R.sup.E and R.sup.F is
shown by --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1,
Z.sup.2, Z.sup.3 and R' are the same as above (1)) and the other is
a non-interfering substituent, or R.sup.E and R.sup.F taken
together with the neighboring carbon atoms may form a ring shown by
14
[0037] (wherein, R.sup.11 to R.sup.13 are each independently a
non-interfering substituent, Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1
are the same as above (1)), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0038] (15) A pharmaceutical composition of above (5) which
contains as an active ingredient a compound of formula(IV-2) 15
[0039] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3, R.sup.1
and the broken line are the same as above (1); R.sup.1 to R.sup.13
are each independently a non-interfering substituent), its prodrug
or pharmaceutically acceptable salt or solvate thereof.
[0040] (16) A pharmaceutical composition of above (3) which
contains as an active ingredient a compound of formula (V-1) 16
[0041] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3, R.sup.1
and the broken line are the same as above (1); R.sup.9 and R.sup.10
are each independently a non-interfering substituent; R.sup.E and
R.sup.F are each independently a non-interfering substituent or
taken together with the neighboring carbon atoms may form a ring
shown by 17
[0042] (wherein, R.sup.11 to R.sup.14 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0043] (17) A pharmaceutical composition of above (5) which
contains as an active ingredient a compound of formula (V-2) 18
[0044] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.31, R and
the broken line are the same as above (1); R.sup.9 to R.sup.14 are
each independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0045] (18) A pharmaceutical composition of above (3) which
contains as an active ingredient a compound of formula(VI-1) 19
[0046] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3, R.sup.1
and the broken line are the same as above (1) R.sup.9, R.sup.10 and
R.sup.15 are each independently a non-interfering substituent;
R.sup.E and R.sup.F are each independently a non-interfering
substituent or taken together with the neighboring carbon atoms may
form a ring shown by 20
[0047] (wherein, R.sup.11 to R.sup.14 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0048] (19) A pharmaceutical composition of above (6) which
contains as an active ingredient a compound of formula(VI-2):
21
[0049] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3,R.sup.1
and the broken line are the same as above (1) R.sup.9 to R.sup.15
are each independently a non-interfering substituent), its prodrug
or pharmaceutically acceptable salt or solvate thereof).
[0050] (20) A pharmaceutical composition of above (3) which
contains as an active ingredient a compound of formula(VII-1)
22
[0051] (wherein, X, Y, Z R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); W.sup.1 is --O or --N
(--R.sup.G)--; R.sup.G is a non-interfering substituent; R.sup.6
and R.sup.7 are each independently a non-interfering substituent;
R.sup.E and R.sup.F are each independently a non-interfering
substituent or taken together with the neighboring carbon atoms
form a ring shown by 23
[0052] (wherein, R.sup.11 to R.sup.14 are each independently a
non-interfering substituent)), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0053] (21) A pharmaceutical composition of above (3) which
contains as an active ingredient a compound of formula(VII-2)
24
[0054] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); W.sup.1 is --O or
--N(--R.sup.G)--; R.sup.G is a non-interfering substituent;
R.sup.6, R.sup.7, R.sup.11 to R.sup.14 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0055] (22) A pharmaceutical composition of above (3) which
contains as an active ingredient a compound of formula (VII-3):
25
[0056] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); W.sup.1 is --O or --N
(--R.sup.G)--; R.sup.G is a non-interfering substituent; R.sup.6
and R.sup.7 are each independently a non-interfering substituent;
R.sup.E and R.sup.F are each independently a non-interfering
substituent), its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0057] (23) A pharmaceutical composition of above (9) which
contains as an active ingredient a compound of formula (VIII-1)
26
[0058] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and R
are the same as above (1);R.sup.6 and R.sup.7 are each
independently a non-interfering substituent; R.sup.E and R.sup.F
are each independently a non-interfering substituent), its prodrug
or pharmaceutically acceptable salt or solvate thereof.
[0059] (24) A pharmaceutical composition of above (9) which
contains as an active ingredient a compound of formula (VIII-2)>
27
[0060] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3,R.sup.1
and the broken line are the same as above (1) R.sup.E and R.sup.F
are each independently a non-interfering substituent; R.sup.9 and
R.sup.10 are each independently a non-interfering substituent), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0061] (25) A pharmaceutical composition of above (8) which
contains as an active ingredient a compound of formula (IX-1):
28
[0062] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); R.sup.6 and R.sup.7 are each
independently a non-interfering substituent; R.sup.F and R.sup.G
are each independently a non-interfering substituent), its prodrug
or pharmaceutically acceptable salt or its solvate thereof.
[0063] (26) A pharmaceutical composition of above (8) which
contains as an active ingredient a compound of formula (IX-2):
29
[0064] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3,R.sup.1
and the broken line are the same as above (1) R.sup.9 and R.sup.10
are each independently a non-interfering substituent; R.sup.F and
R.sup.G are each independently a non-interfering substituent), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0065] (27) A pharmaceutical composition of above (4) which
contains as an active ingredient a compound of formula (X-1):
30
[0066] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); R.sup.5,R.sup.5,R.sup.6 and
R.sup.7 are each independently a non-interfering substituent), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0067] (28) A pharmaceutical composition of above (4) which
contains as an active ingredient a compound of formula(X-2): 31
[0068] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3,R.sup.1
and the broken line are the same as above (1); R.sup.5, R.sup.5',
R.sup.9 and R.sup.10 are each independently a non-interfering
substituent), its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0069] (29) A pharmaceutical composition of above (7) which
contains as an active ingredient a compound of formula(XI-1):
32
[0070] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); R.sup.6, R.sup.7, R.sup.F and
R.sup.G are each independently a non-interfering substituent; the
broken line (---) shows the presence or absence of a bond), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0071] (30) A pharmaceutical composition of above (7) which
contains as an active ingredient a compound of formula(XI-2):
33
[0072] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3,R.sup.1
and the broken line are the same as above (1) R.sup.9, R.sup.10,
R.sup.F and R.sup.G are each independently a non-interfering
substituent; the broken line(---) shows the presence or absence of
a bond), its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0073] (31) A pharmaceutical composition of above (8) which
contains as an active ingredient a compound of formula(XII-1):
34
[0074] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); R.sup.5,R.sup.1,R.sup.7, R.sup.F
and R.sup.G are each independently a non-interfering substituent;
the broken line(---) shows the presence or absence of a bond), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0075] (32) A pharmaceutical composition of above (8) which
contains as an active ingredient a compound of formula(XII-2):
35
[0076] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3,and
R.sup.1 are the same as above (1); R.sup.5,R.sup.9,R.sup.10,
R.sup.F and R.sup.G are each independently a non-interfering
substituent; the broken line(---) shows the presence or absence of
a bond), its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0077] (33) A pharmaceutical composition of above (8) which
contains as an active ingredient a compound of formula(XIII-1):
36
[0078] (wherein, X, Y, Z, R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); R.sup.5,R.sup.6,R.sup.7 and
R.sup.G are each independently a non-interfering substituent), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0079] (34) A pharmaceutical composition of above (8) which
contains as an active ingredient a compound of formula(XIII-2):
37
[0080] (wherein, Y, Z, C ring, Z.sup.1, Z.sup.2, Z.sup.3 and
R.sup.1 are the same as above (1); R.sup.5,R.sup.9, R.sup.10 and
R.sup.G are each independently a non-interfering substituent), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0081] (35) A pharmaceutical composition of any one of (1) to (34),
wherein the non-interfering substituents are independently selected
from hydrogen, halogen, alkoxycarbonyl, carboxy, alkyl, alkoxy,
alkoxyalkyl, nitro, hydroxy, hydroxyalkyl, alkenyl, alkynyl,
alkylsulfonyl, optionally substituted amino, alkylthio,
alkylthioalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkenyl,
optionally substituted heterocycle, oxo, thioxo, nitroso, azide,
amidino, guanidino, cyano, isocyano, mercapto, optionally
substituted carbamoyl, sulfamoyl, sulfoamino, formyl,
alkylcarbonyl, alkylcarbonyloxy, hydrazino, morpholino, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted aralkyl, optionally substituted heteroarylalkyl,
optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted arylthio, optionally
substituted heteroarylthio, optionally substituted aralkyloxy,
optionally substituted heteroarylalkyloxy, optionally substituted
aralkylthio, optionally substituted heteroarylalkylthio, optionally
substituted aryloxyalkyl, optionally substituted
heteroaryloxyalkyl, optionally substituted arylthioalkyl,
optionally substituted heteroarylthioalkyl, optionally substituted
arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally
substituted aralkylsulfonyl and optionally substituted
heteroarylalkylsulfonyl.
[0082] (36) A method for prevention or treatment of AIDS or
AIDS-related complication, comprising administration of a
pharmaceutical composition of any one of above (1) to (35).
[0083] (37) Use of a compound of any one of above (1) to (35) for
preparing a pharmaceutical composition as an integrase
inhibitor.
[0084] (38) A compound of formula(I-Q): Q
--Z.sup.2--Z.sup.3--R.sup.1, its prodrug or pharmaceutically
acceptable salt or solvate thereof, wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1); Q is shown by any
one of the following formulae 38
[0085] (wherein, C ring is the same as above (1); Y is hydroxy; Z
is O; R.sup.1, R.sup.4, R.sup.5 and R.sup.19 are the same as above
(10)), 39
[0086] (wherein, X is O; Y and Z are the same as above; R.sup.5,
R.sup.1,R.sup.7 and R.sup.19 are the same as above (11); R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle), 40
[0087] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.3,R.sup.4 and R.sup.19 are the same as above
(10)), 41
[0088] (wherein, X, Y, Z and R.sup.B are the same as above;
R.sup.6,R.sup.7 and R.sup.19 are the same as above (11)), 42
[0089] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.8 to R.sup.10 are the same as above (14);
W.sup.1 is the same as above (20); R.sup.16 is a non-interfering
substituent), 43
[0090] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.8 to R.sup.13 are the same as above (14);
W.sup.1 is the same as above (20)), 44
[0091] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.9 to R.sup.1.sup..sup.4 is the same as above
(16); W.sup.1 is the same as above (20)), 45
[0092] (wherein, C ring is the same as above (1); Y and Z are the
same as above; W.sup.1 is the same as above (20); R.sup.9 and
R.sup.10 are the same as above (14); R.sup.17 and R.sup.18 are each
independently a non-interfering substituent), 46
[0093] (wherein, X, Y, Z and R.sup.B are the same as above; W.sup.1
is the same as above (20); R.sup.1 and R.sup.7 are the same as
above (11); R.sup.11 to R.sup.14 are the same as above (16)),
47
[0094] (wherein, X, Y, Z and R.sup.B are the same as above; W.sup.1
is the same as above (20); R.sup.6 and R.sup.7 are the same as
above (11); R.sup.17 and R.sup.18 are each independently a
non-interfering substituent) 48
[0095] (wherein, X, Y, Z and R.sup.B are the same as above; R.sup.6
and R.sup.7 are the same as above.
[0096] (11); R.sup.17 and R.sup.18 are each independently a
non-interfering substituent), 49
[0097] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.9 and R.sup.10 are the same as above (14);
R.sup.17 and R.sup.18 are the same as defined above), 50
[0098] (wherein, X, Y, Z and R.sup.B are the same as above; R.sup.5
is the same as above (10); R.sup.6 and R.sup.7 are the same as
above (11); R.sup.17 and R.sup.18 are the same as defined above),
51
[0099] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.5 is the same as above (10); R.sup.9 and
R.sup.10 are the same as above (14); R.sup.17 and R.sup.18 are the
same as defined above), 52
[0100] (wherein, X, Y, Z and R.sup.B are the same as above; R.sup.5
and R.sup.5' are the same as above (27); R.sup.6 and R.sup.7 are
the same as above (11)), 53
[0101] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.5 and R.sup.5' are the same as above (27);
R.sup.9 and R.sup.10 are the same as above (14)) 54
[0102] (wherein, X, Y, Z and R.sup.B are the same as above; R.sup.6
and R.sup.7 are the same as above (11); R.sup.17 and R.sup.18 are
the same as above, the broken line(---) shows the presence or
absence of a bond), 55
[0103] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.9 and R.sup.10 are the same as above (14);
R.sup.17 and R.sup.18 are the same as above, the broken line(---)
shows the presence or absence of a bond), 56
[0104] (wherein, X, Y, Z and R.sup.B are the same as above;
R.sup.5, R.sup.6 and R.sup.7 are the same as above (11); R.sup.17
and R.sup.18 are the same as above, the broken line(---) shows the
presence or absence of a bond), 57
[0105] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.5 is the same as above (10); R.sup.9 and
R.sup.10 are the same as above (14); R.sup.17 and R.sup.18 are the
same as above, the broken line(---) shows the presence or absence
of a bond), 58
[0106] (wherein, X, Y, Z and R.sup.B are the same as above;
R.sup.5, R.sup.1 and R.sup.7 are the same as above (11); R.sup.18
is the same as defined above), and 59
[0107] (wherein, C ring is the same as above (1); Y and Z are the
same as above; R.sup.5 is the same as above (10); R.sup.9 and
R.sup.10 are the same as above (14); R.sup.18 is the same as
defined above);
[0108] provided that excluded are compounds, wherein Z.sup.1 is a
bond, Z.sup.2 is --O--, Z.sup.3 is methylene, R.sup.1 is phenyl,
and Q is a group of the formula: 60
[0109] (wherein, R.sup.8 to R.sup.13 are hydrogens, Y is hydroxy, Z
is O, W is --O--, and C ring is quinoline-2-yl) or the formula:
61
[0110] wherein, R.sup.9 and R.sup.10 are the same as above,
R.sup.17 is alkyl, R.sup.18 is hydrogen,Y is hydroxy, Z is O, C
ring is dihydropirimidine).
[0111] (39) A compound of above (38), shown by formula (II-1):
62
[0112] (wherein, Y is hydroxy; Z is O; C ring Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.3,R.sup.4,R.sup.5 and R.sup.9 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0113] (40) A compound of above (39), wherein Z.sup.1 and Z.sup.2
are each independently a bond or alkylene; Z.sup.2 is a bond or
--O--; R.sup.1 is optionally substituted aryl or optionally
substituted heteroaryl, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0114] (41) A compound of above (39), wherein C ring is
pyrimidine-4-yl or 1,3,4-oxadiazole-2-yl; Z.sup.1 is a bond;
Z.sup.2 is -0 or alkylene; Z.sup.3 is a bond or alkylene; R.sup.1
is aryl optionally substituted with halogen; R.sup.3, R.sup.4 and
R.sup.19 are hydrogens; R.sup.5 is alkyl, aralkyl, cycloalkyl, aryl
or alkoxy, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0115] (42) A compound of above (38), shown by formula (III-1):
63
[0116] (wherein, X is O; Y is hydroxy; Z is O; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1); R.sup.5,
R.sup.6, R.sup.7 and R.sup.19 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0117] (43) A compound of above (39) or (42), wherein, R.sup.5 is
hydrogen, alkyl, aralkyl, cycloalkyl, optionally substituted aryl,
alkoxy, alkoxyalkyl, optionally substituted amino, hydroxyalkyl,
alkenyl, alkoxycarbonylalkyl or heteroarylalkyl, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0118] (44) A compound of above (42), wherein R.sup.B is fran-2-yl,
its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0119] (45) A compound of above (42), wherein R.sup.B is aryl or
fran-2-yl; Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is alkylene;
R.sup.1 is aryl optionally substituted with halogen;
R.sup.6,R.sup.7 and R.sup.19 are hydrogens; R.sup.5 is alkyl,
cycloalkyl, alkoxy, aryl optionally substituted with alkoxy,
hydroxyalkyl, alkenyl, aralkyl, alkoxycarbonylalkyl, or
pyridine-2-ylmethyl, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0120] (46) A compound of above (38), shown by formula (II-2):
64
[0121] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1); R.sup.3,R.sup.4 and
R.sup.19 are each independently a non-interfering substituent), its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0122] (47) A compound of above (46), wherein Z.sup.1 and Z.sup.3
are each independently a bond or alkylene; Z.sup.2 is a bond or
--O--; R.sup.1 is optionally substituted aryl or optionally
substituted heteroaryl, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0123] (48) A compound of above (46), wherein C ring is
pyrimidine-4-yl or 1,3,4-oxadiazole-2-yl; Z.sup.1 is a bond;
Z.sup.2 is -0 or alkylene; Z.sup.3 is a bond or alkylene; R.sup.1
is aryl optionally substituted with halogen; R.sup.3, R.sup.4 and
R.sup.19 are hydrogens, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0124] (49) A compound of above (38) shown by formula (III-2):
65
[0125] (wherein, X is O; Y is hydroxy; Z is O; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1); R.sup.6,
R.sup.7 and R.sup.19 are each independently a non-interfering
substituent), its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0126] (50) A compound of above (49), wherein R.sup.B is fran-2-yl,
its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0127] (51) A compound of above (49), wherein R.sup.B is aryl or
fran-2-yl; Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is alkylene;
R.sup.1 is aryl optionally substituted with halogen;
R.sup.6,R.sup.7 and R.sup.19 are hydrogens, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0128] (52) A compound of above (38), shown by formula (IV-2).:
66
[0129] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1); R.sup.8 to R.sup.13
are each independently a non-interfering substituent), its prodrug
or pharmaceutically acceptable salt or solvate thereof.
[0130] (53) A compound of above (52), wherein C ring is
pyridine-2-yl, 1,2,4-triazole-3-yl or imidazole-2-yl optionally
substituted with alkyl; Z.sup.1 is a bond Z.sup.2 is --O--; Z.sup.3
is alkylene; R.sup.1 is aryl optionally substituted with halogen;
R.sup.8 to R.sup.13 are hydrogens, its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0131] (54) A compound of above (38), shown by formula (V-2):
67
[0132] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1); R.sup.9 to R.sup.14
are each independently a non-interfering substituent), its prodrug
or pharmaceutically acceptable salt or solvate thereof.
[0133] (55) A compound of above (52) or (54), wherein Z.sup.1 and
Z.sup.3 are each independently a bond or alkylene; Z.sup.2 is a
bond or --O--; R.sup.1 is optionally substituted aryl or optionally
substituted heteroaryl, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0134] (56) A compound of above (54), wherein C ring is
1,3,4-oxadiazole-2-yl; Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is
alkylene; R.sup.1 is aryl optionally substituted with halogen;
R.sup.9 to R.sup.1.sup..sup.4 are hydrogens, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0135] (57) A compound of above (38), shown by formula (VI-2):
68
[0136] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1); R.sup.9 to R.sup.15
are each independently a non-interfering substituent), its prodrug
or pharmaceutically acceptable salt or solvate thereof.
[0137] (58) A compound of above (57), wherein, R.sup.15 is hydrogen
or alkyl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0138] (59) A compound of above (57), wherein C ring is
1,3,4-oxadiazole-2-yl; Z.sup.1 and Z 3 are bonds; Z.sup.2 is
alkylene; R.sup.1 is aryl optionally substituted with halogen;
R.sup.9 to R.sup.14 are hydrogens; R.sup.15 is hydrogen or alkyl,
its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0139] (60) A compound of above (38), shown by formula (VII-4)
69
[0140] (wherein, X is O; Y is hydroxy; Z is O; W.sup.2 is --O or
--NH--; R.sup.B is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle; Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are the same as
above (1); R.sup.6,R.sup.7,R.sup.11 to R.sup.14 are each
independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0141] (61) A compound of above (60), wherein R.sup.B is fran-2-yl,
its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0142] (62) A compound of above (60), wherein R.sup.B is fran-2-yl;
Z and Z.sup.3 are bonds Z.sup.2 is alkylene; R.sup.1 is aryl
optionally substituted with halogen; R.sup.1,R.sup.7,R.sup.11 to
R.sup.14 are hydrogens, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0143] (63) A compound of above (38), shown by formula (VII-5):
70
[0144] (wherein, X is O; Y is hydroxy; Z is O; W.sup.2 is --O or
--NH--; R.sup.B is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle; Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are the same as
above (1); R.sup.6,R.sup.7, R.sup.E and R.sup.F are each
independently a non-interfering substituent), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0145] (64) A compound of above (63), wherein, R.sup.B is
fran-2-yl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0146] (65) A compound of above (63), wherein, R.sup.B is
fran-2-yl; Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is alkylene;
R.sup.1 is aryl optionally substituted with halogen;
R.sup.6,R.sup.7, R.sup.E and R.sup.F are hydrogens, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0147] (66) A compound of above (38), shown by formula (VIII-1)
71
[0148] (wherein, X is O; Y is hydroxy; Z is O; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.6,R.sup.7, R.sup.E and R.sup.F are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0149] (67) A compound of above (66), wherein R.sup.B is fran-2-yl,
its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0150] (68) A compound of above (66), wherein R.sup.B is fran-2-yl;
Z.sup.1 and Z.sup.3 are bonds Z.sup.2 is alkylene; R.sup.1 is aryl
optionally substituted with halogen; R.sup.6,R.sup.7, R.sup.E and
R.sup.F are hydrogens, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0151] (69) A compound of above (38), shown by formula (VIII-2)
72
[0152] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1); R.sup.9,R.sup.10,
R.sup.E and R.sup.F are each independently a non-interfering
substituent), its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0153] (70) A compound of above (38), shown by formula (IX-1):
73
[0154] (wherein, X is O; Y is hydroxy; Z is b; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.6,R.sup.7, R.sup.F and R.sup.G are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0155] (71) A compound of above (70), wherein, R.sup.B is
fran-2-yl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0156] (72) A compound of above (70), wherein, R.sup.B is
fran-2-yl; Z.sup.1 and Z.sup.3 are bonds; 2 is alkylene; R.sup.1 is
aryl optionally substituted with halogen; R.sup.6,R.sup.7, R.sup.F
and R.sup.G are hydrogens, its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0157] (73) A compound of above (38), shown by formula (IX-2):
74
[0158] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1); R.sup.9,R.sup.10,
R.sup.F and R.sup.G are each independently a non-interfering
substituent, provided that when R.sup.G is hydrogen and R.sup.F is
alkyl, C ring is not dihydropirimidine), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0159] (74) A compound of above (38), shown by formula (X-1):
75
[0160] (wherein, X is O; Y is hydroxy; Z is O; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.5,R.sup.5,R.sup.6 and R.sup.7 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0161] (75) A compound of above (74), wherein R.sup.B is fran-2-yl,
its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0162] (76) A compound of above (74), wherein R.sup.B is fran-2-yl;
Z.sup.1 and Z.sup.3 are bonds Z.sup.2 is alkylene; R.sup.1 is aryl
optionally substituted with halogen; R.sup.6,R.sup.7,R.sup.5 and
R.sup.5' are hydrogens, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0163] (77) A compound of above (38), shown by formula (X-2):
76
[0164] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1,
Z.sup.2,Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.5,R.sup.5', R.sup.9 and R.sup.10 are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0165] (78) A compound of above (38), shown by formula (XI-1):
77
[0166] (wherein, X is O; Y is hydroxy; Z is O; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.1,R.sup.7, R.sup.F and R.sup.G are each independently a
non-interfering substituent, the broken line(---) shows the
presence or absence of a bond), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0167] (79) A compound of above (78), wherein, R.sup.B is
fran-2-yl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0168] (80) A compound of above (78), wherein, R.sup.B is
fran-2-yl; Z.sup.1 and Z.sup.3 are bonds Z.sup.2 is alkylene;
R.sup.1 is aryl optionally substituted with halogen;
R.sup.6,R.sup.7, R.sup.F and R.sup.G are hydrogens, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0169] (81) A compound of above (38), shown by (XI-2): 78
[0170] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1); R.sup.9,R.sup.10,
R.sup.F and R.sup.G are each independently a non-interfering
substituent, the broken line(---) shows the presence or absence of
a bond), its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0171] (82) A compound of above (38), shown by (XII-1): 79
[0172] (wherein, X is O; Y is hydroxy; Z is O; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.5,R.sup.6,R.sup.7, R.sup.F and R.sup.G are each independently
a non-interfering substituent, the broken line(---) shows the
presence or absence of a bond), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0173] (83) A compound of above (82), wherein, R.sup.B is
fran-2-yl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0174] (84) A compound of above (82), wherein, R.sup.B is
fran-2-yl; Z.sup.1 and Z.sup.3 are bonds; 2 is alkylene; R.sup.1 is
aryl optionally substituted with halogen; R.sup.1,R.sup.7, R.sup.F
and R.sup.G are hydrogens, its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0175] (85) A compound of above (38), shown by formula (XII-2):
80
[0176] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.5,R.sup.9,R.sup.10, R.sup.F and R.sup.G are each
independently a non-interfering substituent, the broken line(---)
shows the presence or absence of a bond), its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0177] (86) A compound of above (38), shown by formula (XIII-1):
81
[0178] (wherein, X is O; Y is hydroxy; Z is O; R.sup.B is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle; Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.5,R.sup.6,R.sup.7 and R.sup.G are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0179] (87) A compound of above (86), wherein, R.sup.B is
fran-2-yl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0180] (88) A compound of above (86), wherein, R.sup.B is
fran-2-yl; Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is alkylene;
R.sup.1 is aryl optionally substituted with halogen; R.sup.6,
R.sup.7 and R G are hydrogens, its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0181] (89) A compound of above (38), shown by formula (XIII-2):
82
[0182] (wherein, Y is hydroxy; Z is O; C ring, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above (1);
R.sup.5,R.sup.9,R.sup.10 and R.sup.G are each independently a
non-interfering substituent), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0183] (90) A compound of above (38), (39), (46), (52), (54), (57),
(69), (73), (77), (81), (85) or (89), wherein C ring is optionally
substituted pyridine-2-yl, optionally substituted pyrimidine-4-yl,
optionally substituted 1,3,4-oxadiazole-2-yl, optionally
substituted 1,2,4-triazole-3-yl or optionally substituted
imidazole-2-yl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0184] (91) A compound of above (38), (39), (46), (52), (54), (57),
(69), (73), (77), (81), (85) or (89), wherein Z.sup.1 and Z.sup.3
are each independently a bond or alkylene; 2 is a bond or --O--;
R.sup.1 is optionally substituted aryl or optionally substituted
heteroaryl, its prodrug or pharmaceutically acceptable salt or
solvate thereof
[0185] (92) A compound of above (38), (39), (46), (52), (54), (57),
(69), (73), (77), (81), (85) or (89), wherein C ring is
pyrimidine-4-yl or 1,3,4-oxadiazole-2-yl; Z.sup.1 is a bond;
Z.sup.2 is --O or alkylene; Z.sup.3 is a bond or alkylene; R.sup.1
is aryl optionally substituted with halogen; R.sup.3,R.sup.4 and
R.sup.19 are hydrogens, its prodrug or pharmaceutically acceptable
salt or solvate thereof.
[0186] (93) A compound of above (38), (39), (42), (46), (49), (52),
(54), (57), (60), (63), (66), (69), (70), (73), (74), (77), (78),
(81), (82), (85), (86) or (89), wherein each non-interfering
substituent is independently selected from hydrogen, halogen,
alkoxycarbonyl, carboxy, alkyl, alkoxy, alkoxy alkyl, nitro
hydroxy, alkenyl, alkynyl, alkylsulfonyl, optionally substituted
amino, alkylthio, alkylthio alkyl, haloalkyl, haloalkoxy,
haloalkoxy alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkenyl, optionally substituted heterocycle, oxo,
thioxo, nitroso, azide, amidino, guanidino, cyano, isocyano,
mercapto, optionally substituted carbamoyl, sulfamoyl, sulfoamino,
formyl, alkyl carbonyl, alkyl carbonyloxy, hydrazino, morpholino,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted aralkyl, optionally substituted heteroaryl
alkyl, optionally substituted aryl oxy, optionally substituted
heteroaryl oxy, optionally substituted aryl thio, optionally
substituted heteroaryl thio, optionally substituted aralkyloxy,
optionally substituted heteroaryl alkyl oxy, optionally substituted
aralkylthio, optionally substituted heteroaryl alkylthio,
optionally substituted aryl oxyalkyl, optionally substituted
heteroaryl oxyalkyl, optionally substituted aryl thioalkyl,
optionally substituted heteroaryl thioalkyl, optionally substituted
arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally
substituted aralkylsulfonyl and optionally substituted heteroaryl
alkylsulfonyl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0187] (94) A compound of above (38), (39), (42), (46), (49), (52),
(54), (57), (60). (63), (66), (69), (70), (73), (74), (77), (78),
(81), (82), (85), (86) or (89), wherein Z.sup.1, Z.sup.2 and
Z.sup.3 are not bonds at the same, its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0188] (95) A compound of above (94), wherein R.sup.1 is phenyl
optionally substituted with halogen, Z.sup.1 is a bond, Z.sup.2 is
alkylene or --O--, Z.sup.3 is a bond or alkylene, its prodrug or
pharmaceutically acceptable salt or solvate thereof.
[0189] (96) A compound of above (95), wherein R.sup.1 is
4-fluorophenyl, its prodrug or pharmaceutically acceptable salt or
solvate thereof.
[0190] (97) A compound of the formula (I): 83
[0191] (wherein, R c and RD taken together with the neighboring
carbon atoms form 5-or 6-membered heterocycle which may contain 0
and/or N atom and be condesed with a benzene ring; Y is hydroxy,
mercapto or amino; Z is O, S or NH R.sup.A is shown of the formula:
84
[0192] (wherein, C ring is N-containing aromatic heterocycle,
wherein at least one atom neighboring to the atom at the
bonding-position is unsubstituted N atom the broken line shows the
presence or absence of a bond.) or the formula: 85
[0193] (wherein, X is O, S or NH; R.sup.B is optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl or optionally
substituted heterocycle); at least one of the ring formed by
R.sup.C and R.sup.D, C ring and R.sup.B is substituted with a group
of the formula: --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein,
Z.sup.1 and Z.sup.3 are each independently a bond, optionally
substituted alkylene or optionally substituted alkenylene; 2 is a
bond, optionally substituted alkylene, optionally substituted
alkenylene, --CH(OH)--, --S--, --SO--, --SO.sub.2--,
--SO.sub.2N(R.sup.2)--, --N(R.sup.2)SO.sub.2, --O--,
--N(R.sup.2)--, --N(R.sup.2)CO--, --CON(R.sup.2)--,
--C(.dbd.O)--O--, --O--C(.dbd.O) or --CO--; R.sup.2 is hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted aryl or optionally substituted heteroaryl;
R.sup.1 is optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted cycloalkyl, optionally
substituted cycloalkenyl or optionally substituted heterocycle);
and
[0194] the ring formed by R.sup.C and R.sup.D, C ring or R.sup.B is
optionally substituted with 1 to 3 substituents selected from
hydrogen, alkyl, aralkyl, cycloalkyl, optionally substituted aryl,
alkoxy, alkoxyalkyl, optionally substituted amino, hydroxyalkyl,
alkenyl, alkoxycarbonylalkyl, heteroarylalkyl and hydroxy, at any
position except where the above the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above) locates, its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0195] (98) A compound of above (97), wherein the ring formed by
R.sup.C and R.sup.D is.5-or 6-membered heterocycle which may
contain 0 and/or N atom and be condesed with benzene ring; Y is
hydroxy; Z is O; X is O; the ring formed by R.sup.C and R.sup.D is
optionally substituted with 1 to 3 substituents selected from
hydrogen, alkyl, aralkyl, cycloalkyl, optionally substituted aryl,
alkoxy, alkoxy alkyl, optionally substituted amino, hydroxyalkyl,
alkenyl, alkoxycarbonylalkyl and heteroaryl alkyl, and C ring and
R.sup.B are each independently optionally substituted with 1 to 3
substituents selected from alkyl, amino, halogen and hydroxy, its
prodrug or pharmaceutically acceptable salt or solvate thereof.
[0196] (99) A compound of above (97) or (98), wherein at least one
of the ring formed by R.sup.C and R.sup.D, C ring and R.sup.B is
substituted with a group of the formula: Z.sup.1--Z.sup.2--Z.sup.3
--R.sup.1 (wherein Z.sup.1 is a bond or alkylene; Z.sup.2 is
alkylene or --O--; Z.sup.3 is a bond or alkylene; R.sup.1 is
optionally substituted aryl or optionally substituted heteroaryl),
its prodrug or pharmaceutically acceptable salt or solvate
thereof.
[0197] (100) A pharmaceutical composition comprising a compound of
any one of above (38) to (99), its prodrug or pharmaceutically
acceptable salt or solvate thereof.
[0198] (101) A pharmaceutical composition of above (100) which is
an enzyme inhibitor.
[0199] (102) A pharmaceutical composition of above (100) which is a
nucleic acid-related enzyme inhibitor.
[0200] (103) A pharmaceutical composition of above (100) which is
an HIV integrase inhibitor.
[0201] (104) A pharmaceutical composition of above (100) which is
an anti-HIV agent.
[0202] (105) A pharmaceutical composition of above (100) which is a
critical prevention or treatment agent for AIDS or a AIDS-related
complication.
[0203] (106) A mixture of a pharmaceutical composition of above
(103) in combination with a reverse transcriptase inhibitor and/or
a protease inhibitor.
[0204] (107) A pharmaceutical composition of above (100) which can
enhanse the anti-HIV activity of a reverse transcriptase inhibitor
and/or a protease inhibitor.
[0205] (108) A method for prevention or treatment of AIDS or a
AIDS-related complication which comprises administration of a
compound of any one of (38) to (99).
[0206] (109) Use of a compound of any one of (38) to (99) for
preparing a pharmaceutical composition as an integrase
inhibitor.
[0207] (110) A process for preparing a compound of the formula
(111-1): 86
[0208] (wherein, X, Y, Z,R.sup.B, R.sup.5 to R.sup.7,R.sup.19,
Z.sup.1 to Z.sup.3 and R.sup.1 are the same as defined below) which
comprises reacting a compound of the formula (K): 87
[0209] (wherein, X is; Y is hydroxy; Z is O; L is a leaving group;
R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are the same as
above (1); Re and R.sup.7 are the same as above (11)) with a
compound of the formula: R.sup.5N H .sub.2(wherein, R.sup.5 is a
non-interfering substituent) and a compound of the formula:
R.sup.19CHO (wherein, R.sup.19 is a non-interfering
substituent).
[0210] (111) A process for preparing a compound of the formula
(III-1) of above (110), wherein, R.sup.B is heteroaryl; R.sup.1 and
R.sup.7 do not substitute on R.sup.B L is alkoxy; Z.sup.1 and
Z.sup.3 are bonds; Z.sup.2 is alkylene; R.sup.1 is optionally
substituted phenyl.
[0211] (112) A process for preparing a compound of the formula
(III-1) of above (110), wherein Z.sup.2 is methylene; R.sup.1 is
4-fluorophenyl.
[0212] (113) A process for preparing a compound of the formula
(111-1) of above (112), wherein the compound of the formula (K) is
4-[5-(4-fluorobenzyl)fran-2-yl]-2-hydroxy-4-oxo-2-butenoic acid
alkyl ester.
[0213] (114) A process for preparing a compound of the formula
(III-1) of above (110) to (113), wherein compounds shown of the
formula: R.sup.5N H.sub.2 and R.sup.19CHO are selected from the
following groups; compound of the formula: R.sup.5N H 2
cyclopropylamine, cyclobutylamine, cyclopentylamine, cycloleucine,
cyclohexylamine, 1-aminocyclohexan carboxylic acid,
1-ethynylcyclohexylamine, 1,2-diaminocyclohexan,
2-methylcyclohexylamine, 2,3-dimethylcyclohexylamine,
4-methylcyclohexylamine, aminomethylcyclohexan, 1,3-cyclohexan
bis(methylamine), 1-amino-6,6,7,8-tetrahydronaphthalene, 1, 2, 3,
4-tetrahydro-1-naphthylamine cyclooctylamine,
2-amino-1-propene-1,1,3-tri- carbonitril, diaminomaleonitril,
S-methylL-csteine, L-aspartic acid, L-leucine, DL-homoserine,
D-methionine, L-allylglycine, L-glutamic acid,
2-amino-1,3,4-thiadiazole, 2-amino-5-mercapto-1,3,4-thiadiazole,
2-amino-5-ethyl-1,3,4-thiadiazole,
3,5-dimethylpyrazole-1-carboamide, 5-amino-3-methylisoxazole,
3-amino-5-methylisoxazole, 2-(2-amino ethyl)-1-methylpyrrolidine,
1-(2-amino ethyl)pyrrolidine, 1-(3-amino propyl)-2-pyrolidinone,
furfurylamine, 1-aminoindan, 5-aminoindan, 1-naphthyl amine,
2-naphthyl amine, cycloheptylamine, D-tert-leucine, DL-valine,
DL-isoleucine, D-serine, guanidoacetic acid, creatine,
D-allothreonine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxy
methyl)aminomethane, DL-2-amino-3-methyl-1-butanol, L-isoleucinol,
D-leucinol, L-methioninol, DL-penicillamine, DL-cysteine,
DL-homocysteine, 1-acetyl-3-thiosemicarbazide, 1-acetyl-2-thiourea,
N-methylthiourea, ethylthiourea, allylthiourea, dithioxamide,
histamine, 3-amino-1,2,4-triazole,
3-amino-5-mercapto-1,2,4-triazole, 3-amino-5-methylthiol,
2,4-triazole, 3,5-diamino-1,2,4-triazole, 3-aminopyrazole,
3-amino-4-cyanopyrazole, 3-aminopyrazole-4-carboxylic acid,
L-prolineamide, 2-amino-2-thiazoline, 2-aminothiazole,
2-amino-5-nitrothiazole, 2-amino-4-methylthiazole, D-cycloserine,
tetrahydrofurfurylamine, 2-aminopurine, 2-aminobenzimidazole,
5-amino indole, 4-aminopyrazolo[3,4-D]pyrimidine, 6-aminoindazole,
8-azaadenine, 3,4-methylenedioxyaniline,
N-(2-aminoethyl)piperazine, nipecotamide, 4-(aminomethyl)
piperidine, 5-aminouracil, 5-azacytosine, cytosine,
5-fluorocytosine, 4-amino-2,6-dihydroxypyrimidine,
2-aminopyrimidine, 2-amino-4-chloro-6-methylpyrimidine,
2-amino-4,6-dihydroxypyrimidine,
2-amino-4-hydroxy-6-methylpyrimidine,
4-chloro-2,6-diaminopyrimidine, 2,4-diamino-6-hydroxypyrimidine,
2,4,6-triaminopyrimidine, 2-amino-4-methylpyrimidine,
2-amino-4,6-dimethylpyrimidine, 2-amino-5-nitro pyrimidine,
4-aminopyrimidine, 4,5-diaminopyrimidine, 4,5-diamino-6-hydroxy
pyrimidine, pyrazineamide, aminopyrazine, 3-aminopyrazine
E-2-carboxylic acid, 4-(2-aminoethyl)morpholine,
N-(3-aminopropyl)morpholine, nicotineamide N-oxide,
3-amino-2-chloropyridine, 5-amino-2-chloropyridine,
5-amino-2-methoxypyridine, 3-hydroxypicolineamide, 2-aminopyridine,
2-amino-3-nitropyridine, 2-amino-3-hydroxy pyridine,
2-aminonicotinic acid, 2,3-diaminopyridine,
2-amino-3-methylpyridine, 2-amino-4-methylpyridine,
2-amino-4,6-dimethylpyridine, 2-amino-5-chloropyridine,
2-amino-5-nitropyridine, 6-aminonicotinic acid,
6-aminonicotinamide, 2-amino-5-methylpyridine, 2,6-diaminopyridine,
2-amino-6-methylpyridine, 6-methylnicotinamide,
2-(aminomethyl)pyridine, 2-(2-aminoethyl)pyridine, nicotinamide,
thionicotinamide, 3-aminopyridine, 3,4-diaminopyridine,
3-(aminomethyl)pyridine, isonicotinamide, 4-aminopyridine,
4-(aminomethyl)pyridine, 3-amino-1,2,4-triazine,
3-amino-5,6-dimethyl-1,2,4-triazine, 1-(2-aminoethyl)piperidine,
3-aminoquinoline, 5-aminoquinoline, 6-aminoquinoline,
8-aminoquinoline, 5-aminoisoquinoline, nitroguanidine, cyanamide,
thiosemicarbazide, aniline, 2-aminobenzonitril, 2-fluoro aniline,
2,4-difluoroaniline, 2,4,5-trifluoroaniline,
2,4,6-trifluoroaniline, 2,5-difluoro aniline,
2-fluoro-5-methylaniline, 2,6-difluoroaniline, 2-chloroaniline,
2-chloro-4-methylaniline, 2-chloro-5-methylaniline,
2-chloro-6-methylaniline, O-nitroaniline, anisidine, O-phenetidine,
2-aminophenol, 6-amino-m-cresol, 2-amino-4-chlorophenol,
2-amino-4-methylphenol, 2-aminothiophenol, 2-(methylthio)aniline,
anthranilic acid, 2'-aminoacetophenone, 2-isopropenylaniline,
2-isopropylaniline, o-phenylene diamine, 3,4-diaminotoluene,
4,5-dimethyl-1,2-phenylenediamine, o-toluidine,
2,3-dimethylaniline, 4-methoxy-2-methylaniline,
2,4-dimethylaniline, 2,4,6-tri methylaniline, 2,5-dimethylaniline,
2-isopropyl6-methylaniline, 2,6-dimethylaniline, 2-aminobenzyl
alcohol, 2-ethylaniline, 2-ethyl-6-methylaniline,
2,6-diethylaniline, 2-aminophenetyl alcohol, 3-aminobenzonitril,
3-fluoroaniline, 3-fluoro-o-anisidine, 3-fluoro-2-methylaniline,
3,4-difluoroaniline, 3-fluoro-4-methylaniline, 3,5-difluoro
aniline, 5-fluoro-2-methylaniline, 3-chloroaniline,
3-chloro-2-methylaniline, 3-chloro-4-fluoroaniline,
3-chloro-4-methylaniline, 5-chloro-2-methylaniline, m-nitroaniline,
m-anisidine, m-phenetidine, 3-aminophenol, 3-amino-o-cresol,
3-aminothiophenol, 3-(methylthio)aniline, 3-aminobenzoic acid,
3-aminoacetophenone, 3-(1-hydroxy ethyl)aniline,
m-phenylenediamine, 2,6-diaminotoluene, 2,4-diaminotoluene,
m-toluidine, 3,4-dimethylaniline, 3,5-dimethylaniline,
2-methoxy-5-methylaniline, 3-aminobenzyl alcohol, 3-ethylaniline,
4-aminobenzonitril, 4-fluoroaniline, 4-fluoro-2-methylaniline,
4-chloroaniline, 4-chloro-2-methylaniline, p-nitroaniline,
N,N-dimethylp-phenylenediamine, p-anisidine, p-phenetidine,
4-aminophenol, 4-amino-m-cresol, 4-amino-2,5-dimethylpheno- l,
4-amino-o-cresol, 4-aminothiophenol, 4-(methylthio)aniline,
4-aminobenzoic acid, 4-aminoacetophenone, 4-tert-butylaniline,
4-isopropylaniline, p-phenylenediamine, p-toluidine,
4-aminophenylacetonitrile, 4-ethylaniline, 4-aminophenetyl alcohol,
4-propylaniline, 4-N-butylaniline, formamide, hydroxyurea,
phenylurea, cyanoacetylurea, methylurea, ethylurea, allylurea,
N-butylurea, N,N-dimethylurea, 1,1-diethylurea, phenylcarbamate,
tert-butylcarbamate, methylcarbamate, ethylcarbamate,
butylcarbamate, benzamide, 2-fluorobenzamide, salicylamide,
2-aminobenzamide, O-toluamide, 3-fluorobenzamide, 3-aminobenzamide,
m-toluamide, 4-fluorobenzamide, 4-hydroxybenzamide,
4-aminobenzamide, p-toluamide, ethyl oxamate, oxamide,
2,2,2-trifluoroacetamide, trimethylacetamide,
2,2-dichloroacetamide, 2-chloropropioneamide, lactamde,
methacrylamide, isobutylamide, urea, acetamide, cyanoacetamide,
2-bromoacetamide, fluoroacetamide, 2-chloro acetamide,
N-acetylglycineamide, acrylic amide, cinnamamide, malonamide,
propioneamide, 3-chloropropioneamide, 2-aminoisobutanoic acid,
tert-utylamine, 2-amino-2-methyl-1-propanol, tert-octylamine,
1,2-diamino-2-methylpropane, tert-amyl amine,
1,1-diethylpropargylamine, thiobenzamide, (R)-(-)-2-phenylglycinol,
thioure a, DL-.alpha.-methylbenzylamine, thioacetamide,
3-aminocrotonitril, methyl 3-aminocrotonate, ethyl
3-aminocrotonate, D-alanine, 1,2-dimethylpropylamine,
isopropylamine, 2-amino-1-methoxypropane, DL-2-amino-1-propanol,
ethyl 3-amino butylate, DL-.beta.-amino-n-butanoic acid,
1,3-dimethylbutylamine, 1,2-diaminopropane,
1-methyl-3-phenylpropylamine, 2-amino-6-methylheptane- , DL-2-amino
butanoic acid, sec-butylamine, (+/-)-2-amino-1-butanol, 3-amino
pentane, D-norvaline, D-norleucine, 2-aminoheptane, 2-aminooctane,
methylamine, benzylamine, 2-fluorobenzylamine, 2-chlorobenzylamine,
2-methoxybenzylamine, 2-methylbenzylamine, 3-fluorobenzyl amine,
3-methoxybenzylamine, 3-methylbenzylamine, m-xylylenediamine,
4-fluorobenzylamine, 4-chlorobenzylamine, 4-methoxybenzylamine,
4-methylbenzyl amine, glycine, 2,2,2-trifluoroethyl amine,
aminoacetoaldehyde dimethyl acetal, amino acetoaldehyde diethyl
acetal, 2-amino-1-phenylethanol, DL-isoserine, 1-amino-2-propanol,
3-amino-1,2-propanediol, DL-4-amino-3-hydroxybutanoic acid,
1,3-diamino-2-hydroxypropane, 2-phenylpropylamine,
DL-3-aminoisobutanoic acid, isobutylamine, 2-methylbutylamine,
2-ethylhexylamine, ethylamine, N-phenylethylenediamine,
N-acetylethylenediamine, N-isopropylethylenediam- ine,
N-methylethylenediamine, N-ethylethylenediamine,
2-(2-aminoethylamino)ethanol, diethylenediamine,
N-(n-propyl)ethylenediam- ine, N,N-dimethylethylenediamine,
N,N-diethylethylenediamine, tris(2-aminoethyl)amine,
2-methoxyethylamine, 2-(2-aminoethoxy)ethanol, ethanolamine,
phenetylamine, thyramine, 2-(4-aminophenyl)ethylamine, 2-(p-tri
l)ethylamine, taurine, propargylamine, allylamine, .beta.-alanine,
3,3-dimethylbutylamine, isoamylamine, ethylenediamine, propylamine,
N-isopropyl-1,3-propanediamine, N-methyl-1,3-propanediamine,
N-(2-aminoethyl)-1,3-propanediamine, N-propyl-1,3-propanediamine,
3,3'-diaminodipropylamine, N,N-dimethyl-1,3-propanediamine,
N,N-bis(3-aminopropyl)methylamine, N,N-diethyl-1,3-propanediamine,
3-isopropoxypropylamine, 3-ethoxypropylamine, 3-amino-1-propanol,
3-phenylpropylamine, 4-aminobutanoic acid, 1,3-diaminopropane,
4-amino-1-butanol, 4-phenylbutylamine, 5-aminovalerianic acid,
1,4-diaminobutane, N-amylamine, 5-amino-1-pentanol, 6-aminocaproic
acid, 1,5-diaminopentane, hexylamine, 6-amino-1-haxanol,
7-aminoheptanoic acid, 1,6-hexandiamine, n-heptylamine,
1,7-diaminoheptane, octylamine, 1,8-diaminooctane, nonylamine,
cyclohexane carboamide, 2,2-dimethyl-1,3-propanediamine,
2-n-propylaniline, DL-2-amino-1-pentanol, DL-2-amino-1-haxanol,
1-(3-aminopropyl)imidazole, p-xylylenediamine, 1-amino
cyclopropane-1-carboxylic acid, cyanothioacetamide,
2,4-difluorobenzylamine, 2,5-difluorobenzylamine,
2,6-difluorobenzylamine, 3,4-difluorobenzylamine,
2-methyl-3-thiosemicarb- azide, 5-amino-2-methoxyphenol,
4-sec-butylaniline, 2,3-difluoroaniline, thiophene-2-carboamide,
1-amino-1-cyclopentanemethanol, 3-methyladenine, 1-methyladenine,
4-chloro-2-fluoroaniline, 5-amino-1-ethylpyrazole,
2,3-diaminotoluene, butylamine, 4-chloro-o-phenylenediamine,
1-(trimethylsilylmethyl)urea, 2,3,4-trifluoro aniline,
2-(1-cyclohexanyl)ethylamine, 3-amino-2-butenethioamide,
2,3,6-trifluoro aniline, 1,5-diamino-2-methylpentane,
amidinothiourea, 3-ethynylaaniline,
N,N-bis(2-hydroxyethyl)ethylenediamine, 3-methoxypropylamine,
4-aminostyrene, 2-amino-6-fluorobenzonitrile,
3-amino-5-hydroxypyrazole, 2,4-diamino-6-methyl-1,3,5-triazine,
pyridine-2-carboamide, 1-aminoisoquinoline,
4-chloro-1,3-phenylenediamine, 2-chloro ethylcarbamate, amide
fumarate, acetoacetamide, N-N-butylethylenediamine,
3-butoxypropylamine, cyclopropanemethylamine, 5-aminoindazole,
2,4-diamino pyrimidine, .alpha.-ethylbenzylamine, 3-aminoisoxazole,
chlorodifluoroacetamide, 1,8-diamino-3,6-dioxaoctane,
2-sec-butylaniline, 3-chlorobenzylamine, 2-fluoro-4-methylaniline,
1-(4-fluorophenyl)ethylami- ne, 4-aminophthalonitrile, adenine,
2-chloro-4-fluoroaniline, semicarbazide,
(R)-(-)-l-cyclohexylethylamine, 5-amino-o-cresol, N,N,
2,2-tetramethyl-1,3-propanediamine, 2,2-diethoxyacetamide,
3-amino-5,5-dimethyl-2-cyclohexane-1-one, propylcarbamate,
glycolamide, 2-amino-1,3-propanediol, thiophene-2-ethylamine,
2,5-dimethyl-1,4-phenyle- nediamine,
2-amino-4-methoxy-6-methyl-1,3,5-triazine, 2-phenoxyethylamine,
4-amino-2-mercaptopyrimidine, creatinine,
2-amino-4-methoxy-6-methylpyrim- idine, 3,5-difluorobenzylamine,
(1R, 2R)-(-)-1,2-diaminocyclohexane,
(1S,2S)-(+)-1,2-diaminocyclohexan, D-asparatic acid, DL-asparatic
acid, DL-leucine, D-leucine, L-homoserine, DL-methionine,
L-methionine, DL-allylglycine, D-glutamic acid, L-leucinol,
DL-threonine, cis-1,2-diamino cyclohexane,
trans-1,2-cyclohexanediamine, L-tert-leucine, D-valine, L-valine,
D-iso leucine, L-isoleucine, DL-serine, L-serine, L-allo-threonine,
D-threonine, L-threonine, L-valinol, D-valinol, L-cysteine,
DL-cycloserine, L-cycloserine, L-asparagine,
(S)-(+)-2-phenylglycinol, (R)-(+)-1-phenylethylamine,
L-(-)-.alpha.-methylbenzylamine, DL-alanine, L-alanine, L-alaninol,
D-alaninol, D-(-)-2-aminobutanoic acid, L-.alpha.-amino-n-butanoic
acid, (R)-(-)-2-aminobutane, (S)-(+)-2-aminobutane,
(S)-(+)-2-amino-1-butanol, (R)-(-)-2-amino-1-butanol, DL-norvaline,
L-norvaline, DL-norleucine, L-norleucine,
(R)-(-)-1-amino-2-propanol, (S)-(+)-1-amino-2-propanol,
(S)-(-)-2-methylbutylamine, DL-lysine, L-lysine, DL-tert-leucine,
(S)-(+)-1-cyclohexylethylamine, ethyl thiooxamate,
2-amino-5-methylbenzyl alcohol, 2-amino-3-methylbenzyl alcohol,
3-amino-2-methylbenzyl alcohol, 3-fluoro-4-methoxyaniline,
3-amino-4-methylbenzyl alcohol, 5-methoxy-2-methylaniline,
2-amino-m-cresol, trans-1,4-diaminocyclohexan,
3-amino-5-methylpyrazole, 2,3-diaminophenol,
1-piperidinecarboamide, 6-amino-1-methyluracil,
3-fluorophenetylamine, 2-aminobenzylamine,
2-methoxy-6-methylaniline, 2-fluoro phenetylamine,
4-aminobenzylamine, 1-acetylguanidine, D-homoserine,
2-amino-5-methylthiazole, maleamine acid,
(S)-(+)-tetrahydrofurfurylamine, 2-aminobenzyl cyanide,
4-amino-2-chlorophenol, 2-amino-4,5-dicyanoimidazole,
4-amino-6-methoxypyrimidine, 2-tert-butylaniline,
2-(4-fluorophenyl)ethyl- amine, 1,3-diamino pentane,
2-amino-1-methylbenzimidazole, 5-methylfurfurylamine,
(R)-(+)-1-(p-tri l)ethylamine, (S)-(-)-1-(p-tril)ethylamine,
3-amino-1,2,4-triazole-5-carboxylic acid, muscimol,
4-ethynlaniline, 2-amino-4-methylbenzonitril,
2-amino-5-methylthio-1,3,4-thiadiazole,
1-(aminocarbonyl)-1-cyclopropanec- arboxylic acid,
cis-4-aminocyclohexan carboxylic acid,
(S)-(+)-2-(aminomethyl)pyrrolidine, 5-amino-4-nitroimidazole,
3-amino-1-propanolvinyl aether, thioethylene diamine,
isopropyldiethylene triamine, L-tert-leucinol,
N-methyl-1,2-phenylenediamine, (R)-(-)-tetrahydrofurfurylamine,
L-(-)-lactamide, (R)-(+)-lactamide,
(S)-(+)-2,2-dimethylcyclopropanecarboamide,
(1S,2R)-(-)-cis-1-amino-2-ind- anol, (1R,
2S)-(+)-cis-1-amino-2-indanol, (R)-(-)-1-aminoindane,
(S)-(+)-1-aminoindane, (R)-2-phenyl-1-propylamine,
(S)-2-phenyl-1-propylamine, D-methioninol,
(R)-2-amino-1-phenylethanol,
2-amino-4,5-dimethyl-3-furancarbonitrile, N-hexylethylene diamine,
(S)-(-)-4-amino-2-hydroxybutanoic acid,
(S)-3-amino-1,2-propanediol, (R)-3-amino-1,2-propanediol,
4-aminoindole, (R)-(-)-tert-leucinol and
2-amino-5-fluoropyridine.
[0214] compound of the formula: R.sup.19CHO
[0215] formaldehyde, ethyl 2-formyl-1-cyclopropanecarboxylate,
cyclohexancarboaldehyde, 1,2,3,6-tetrahydrobenzaldehyde,
1-methylpyrrole-2-carboaldehyde, furfural, 5-nitro-2-furaldehyde,
5-methylfurfural, 5-hydroxymethyl-2-furaldehyde,
3-(2-furyl)acrolein, benzaldehyde, 2-fluorobenzaldehyde, 2-chloro
benzaldehyde, o-anise aldehyde, salicyl aldehyde,
3-fluoro-2-hydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde,
2,5-dihydroxybenzaldehyde, o-naphthal aldehyde, o-tol aldehyde,
2,4-dimethylbenzaldehyde, mesitaldehyde, 2,5-dimethylbenzaldehyde,
3-cyanobenzaldehyde, 3-fluorobenzaldehyde, 3-chlorobenzaldehyde,
3-methoxybenzaldehyde, 3-hydroxybenzaldehyde,
3,4-dihydroxybenzaldehyde, isonaphthalaldehyde, m-tolaldehyde,
4-cyanobenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde,
4-dimethylaminobenzaldehyde, p-anisealdehyde,
imidazole-2-carboaldehyde, pyrrole-2-carboaldehyde,
2-thiophenecarboaldehyde, 3-methylthiophene-2-carboaldehyde,
5-methyl-2-thiophenecarboaldehyde, 3-thiophenecarboaldehyde,
indole-3-carboaldehyde, 2-pyridinecarboaldehyde- ,
6-methyl-2-pyridinecarboaldehyde, 3-pyridinecarboaldehyde,
4-pyridinecarboaldehyde, 4-hydroxybenzaldehyde,
terenaphthalaldehyde, cuminaldehyde, p-tolaldehyde, 4-ethyl
benzaldehyde, glyoxal, glyoxylic acid, methyl glyoxal,
trimethylacetoaldehyde, D-(-)-erythrose, 2-phenylpropionaldehyde,
methacrolein, 3-ethoxymethacrolein, alpha-methylcinnamaldehyde,
trans-2-methyl-2-butenal, 2-methyl-2-pentenal, isobutylaldehyde,
2,6-dimethyl-5-hepten-1-ol, 2-methylbutylaldehyde,
2-ethylbutylaldehyde, 2-methylpentanal, 2-ethylhaxanal,
acetoaldehyde, chloro acetoaldehyde, phenylacetoaldehyde,
phenylpropargyl aldehyde, acrolein, 3-(dimethylamino) acrolein,
trans-cinnamaldehyde, crotonaldehyde, 2,4-haxadienal,
trans,trans-2,4-heptadienal, trans,trans-2,4-nonadienal,
trans-2-hexanal, trans-2,cis-6-nonadien-1-al, trans-2-heptenal,
trans-2-octanal, trans-2-nonenal, isovaleralaldehyde,
propionaldehyde, 3-phenylpropionaldehyde,
3-(methylthio)propionaldehyde, butylaldehyde, glutaralaldehyde,
valeraldehyde, haxanal, heptalaldehyde, octanal, nonanal,
trans-2-pentenal, 2,4-dimethyl-2,6-heptadienal,
2,6-pyridinedicarboaldehyde, 2-ethylacrolein, 3-methyl-2-butenal,
2,3-difluorobenzaldehyde, 2,6-difluorobenzaldehyde,
2,4-difluorobenzaldehyde, 2,5-difluorobenzaldehyde,
3,4-difluorobenzaldehyde, 3,5-difluorobenzaldehyde, 3-furaldehyde,
3,5,5-trimethylhaxanal, 3-phenylbutylaldehyde,
2,2-dimethyl-4-pentenal, 2,4-dihydroxybenzaldehyde, cycloprop
anecarboaldehyde, 4-hydroxy-3-methylbenzaldehyde, benzo
[b]furan-2-carboaldehyde, 3,5-dihydroxybenzaldehyde,
3,4-dimethylbenzaldehyde, 2-cyanobenzaldehyde,
5-ethyl-2-furaldehyde, 2-hydroxy-3-methylbenzaldehyde,
3,3-dimethylbutylaldehyde, 5-chloro-2-thiophenecarboaldehyde,
3,4-dihydro-2H-pyrane-2-carboaldehyde, D-glyceroaldehyde,
DL-glyceroaldehyde, 3-fluoro-2-methylbenzaldehyde,
3-dimethylamino-2-methyl-2-propenal, 3,5-dimethylbenzaldehyde,
4,5-dimethyl-2-furancarboaldehyde, 4-vinylbenzaldehyde,
2,6-dimethylbenzaldehyde, 2-octanal, dimethoxyacetoaldehyde,
2-deoxy-D-ribose, 2-formyl thiazole,
5-ethyl-2-thiophenecarboaldehyde, glyoxylic acid,
4-pyridinecarboaldehyde-N-oxide, 5-norbornene-2-carboalde- hyde,
4-formylimidazole, 5-methylimidazole-4-carboaldehyde,
5-formyluracil, 2,3-thiophenedicarboaldehyde,
thiophene-2,5-dicarboaldehy- de,
2,3-o-isopropylidene-D-glyceroaldehyde,
2-hydroxy-5-methylbenzaldehyde- , 1-cyclohexane-1-carboaldehyde,
2,3-dimethylbenzaldehyde, 1-methyl-2-imidazolecarboaldehyde,
vinylbenzaldehyde, 4-fluoro-3-methylbenzaldehyde,
3-fluoro-4-methylbenzaldehyde, tetrahydrofran-3-carboaldehyde,
2-fluoro-5-formyl benzonitrile, indole-5-carboaldehyde,
4-acetylbenzaldehyde, 3-vinylbenzaldehyde and
2-fluoro-5-methylbenzaldehyde.
[0216] (115) A process for preparing a compound of the formula
(III-1) of above (110), wherein the compound of formula (K) is
4-[5-(4-fluorobenzyl)fran-2-yl]-2-hydroxy-4-oxo-2-butenoic acid
alkyl ester and compounds shown of the formula: R.sup.5N H 2 and
R.sup.19CHO are each selected from the groups of above (114).
[0217] (116) A compound of formula (III-1) prepared by the porcess
of any one of above (110) to (114).
[0218] (117) A compound of formula (III-1) prepared by the porcess
of (115).
[0219] (118) A library of compounds prepared by the process of
above (115).
[0220] (119) A pharmaceutical composition comprising as an
effective ingredient a compound of above (117).
[0221] (120) A pharmaceutical composition as an integrase inhibitor
comprising as an effective ingredient a compound of above
(117).
[0222] The present invntion is explained in detail below.
[0223] Characteristics of a compound of the formula (I) 88
[0224] (wherein, R.sup.C, R.sup.D, Y, Z and R.sup.A are the same as
defined above) includes the followings:
[0225] 1) R.sup.C and R.sup.D taken together with the neighboring
carbon atoms may form a ring, and the ring may be a condensed
ring,
[0226] 2) Y is hydroxy, mercapto or amino,
[0227] 3) Z is O, S or NH,
[0228] 4) R.sup.A is shown by the formula 89
[0229] (wherein, C ring is the same as defined above) or the
formula: 90
[0230] (wherein, X and R.sup.B are the same as defined above),
[0231] 5) C ring is N-containing aromatic heterocycle, wherein at
least one atom neighboring to the atom at the bonding-position is N
atom,
[0232] 6) X is O, S or NH,
[0233] 7) R.sup.B is a substituent selected from substitution group
A,
[0234] 8) at least one of the ring formed by R.sup.C and R.sup.D, C
ring or R.sup.B is substituted with a group of the formula:
--Z.sup.1--Z.sup.2 --Z.sup.3--R.sup.1 (wherein, Z.sup.1 and Z.sup.3
are each independently a bond, optionally substituted alkylene or
optionally substituted alkenylene; 2 is a bond, optionally
substituted alkylene, optionally substituted alkenylene,
--CH(OH)--, --S--, --SO--, --SO.sub.2--, --SO.sub.2NR.sub.2--,
--NR.sub.2SO.sub.2--, --O--, --NR.sub.2--, --NR.sub.2CO--,
--CONR.sub.2--, --C(.dbd.O)--O--, --O--C(.dbd.O) or --CO--; R.sup.2
is hydrogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted aryl or optionally substituted
heteroaryl; R.sup.1 is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle),
[0235] 9) the ring formed by R.sub.C and R.sup.D, C ring or R.sup.B
is optionally substituted with a non-interfering substituent at any
possition other than that where the group of
--Z.sup.1--Z.sup.2--Z.sup.3-- -R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 is the same as defined above) locates,
[0236] 10) substitution groupA consists of: hydrogen, halogen,
alkoxycarbonyl, carboxy, alkyl, alkoxy, alkoxyalkyl, nitro,
hydroxy, alkenyl, alkynyl, alkylsulfonyl, optionally substituted
amino, alkylthio, alkylthioalkyl, haloalkyl, haloalkoxy,
haloalkoxyalkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkenyl, optionally substituted heterocycle,
nitroso, azide, amidino, guanidino, cyano, isocyano, mercapto,
optionally substituted carbamoyl, sulfamoyl, sulfoamino, formyl,
alkylcarbonyl, alkyl carbonyloxy, hydrazino, morpholino, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted aralkyl, optionally substituted heteroaryl alkyl,
optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted arylthio, optionally
substituted heteroarylthio, optionally substituted aralkyloxy,
optionally substituted heteroarylalkyloxy, optionally substituted
aralkylthio, optionally substituted heteroaryl alkylthio,
optionally substituted aryl oxyalkyl optionally substituted
heteroaryl oxyalkyl, optionally substituted aryl thioalkyl
optionally substituted heteroaryl thioalkyl, optionally substituted
arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally
substituted aralkylsulfonyl and optionally substituted
heteroarylalkylsulfonyl,
[0237] The ring formed by R.sup.C and R.sup.D includes a 4- to
9-membered carbocycle or heterocycle, which may be condensed with
the other ring (e.g., 4- to 9-membered carbocycle or heterocycle,
or a condensed ring thereof). Preferred is a 5- to 7-membered
carbocycle or heterocycle, more preferred is 5-or 6-membered
carbocycle or heterocycle, and their condensed ring with the other
ring (e.g., 5-or 6-membered carbocycle or heterocycle). Further
preferred rings formed by R.sup.C and R.sup.D are the following
cases. The heteroaryl used below refers to a ring containing 1 to 4
hetero atom(s) (O, O or S).
[0238] 1) The ring is 5-or 6-membered one which may contain a
hetero atom(s),
[0239] 2) The ring is 5-or 6-membered heterocycle containing a
hetero atom(s),
[0240] 3) The ring is 5-or 6-membered heterocycle which may contain
O and/or N atom,
[0241] 4) The ring is 5-or 6-membered heterocycle which contains O
and/or N atom,
[0242] 5) The ring is 5-or 6-membered heterocycle which contains N
atom,
[0243] 6) The ring is 5-or 6-membered heterocycle which contains O
atom,
[0244] 7) The ring is 5-membered heterocycle which contains N
atom,
[0245] 8) The ring is 6-membered heterocycle which contains O
atom,
[0246] 9) The ring is 6-membered carbocycle, and
[0247] 10) The ring is one of above 1) to 9) which is condensed
with the other ring,
[0248] 10) The ring is heterocycle which consists of the ring of
above 1) to 9) condensed with a benzene ring.
[0249] Examples of the ring formed by R.sup.C and R.sup.D include
the followings: 91
[0250] (wherein, Z is the same as above (1))
[0251] Among the above, preferred are the folloings:
[0252] 1) The ring is 5-membered N-containing heterocycle,
[0253] 2) The ring is 6-membered O-containing heterocycle,
[0254] 3) The ring is 6-membered N-containing heterocycle,
[0255] 4) The ring is 6-membered O-containing heterocycle condensed
with benzene ring, and
[0256] 5) The ring is 6-membered N-containing heterocycle condensed
with benzene ring,
[0257] Further prferred rings are shown below 92
[0258] The ring formed by R.sup.C and R.sup.D may be substituted,
at any substitutable position of C atom or N atom constructing the
ring, with a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above.) or a
non-interfering substituent.
[0259] The compound of the formula (I) is characterized in that at
least one of the ring formed by R.sup.C and R.sup.D, C ring and
R.sup.B is substituted with a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.s- up.1 (wherein, Z.sup.1,
Z.sup.2--Z.sup.3 and R.sup.1 are the same as defined above.).
[0260] Examples of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3, and R.sup.1 are the same as defined above.) include
--R.sup.1, --CH.sub.2--R.sup.1, --CH.dbd.CH--R.sup.1,
--CH(OH)--R.sup.1,--S--R.sup.1, --SO--R.sup.1, --SO.sub.2--R.sup.1,
--SO.sub.2NH--R.sup.1, --NHSO.sub.2--R.sup.one or 1, --NH--R.sup.1,
--NHCO--R.sup.1,
--CONH--R.sup.1,--C(.dbd.O)--O--R.sup.1,--O--C(.dbd.O)---
R.sup.1,--CO--R.sup.1,--C.sub.2H.sub.4--R.sup.1,--CH.dbd.CH--CH.sub.2--R.s-
up.1,--CH(O H)--CH.sub.2--R.sup.1, --S--CH.sub.2--R.sup.1,
--SO--CH.sub.2--R.sup.1, --SO.sub.2--CH.sub.2--R.sup.1,
--SO.sub.2NH--CH.sub.2--R.sup.1, --NH SO.sub.2--CH.sub.2--R.sup.1,
--O--CH.sub.2--R.sup.1, --NH--CH.sub.2--R.sup.1,
--NHCO--CH.sub.2--R.sup.- 1,
--CONH--CH.sub.2--R.sup.1,--C(.dbd.O)--O--CH.sub.2--R.sup.1,
--O--C(.dbd.O)--CH.sub.2--R,
--CO--CH.sub.2--R.sup.1,--CH.dbd.CH--CH.dbd.- CH--R.sup.1,
--CH.dbd.CH--CH(OH)--R.sup.1, --CH.dbd.CH--S--R.sup.1,
--CH.dbd.CH--SO--R.sup.1, --CH.dbd.CH--SO.sub.2--R.sup.1,
--CH.dbd.CH--SO.sub.2NH--R.sup.1, --CH.dbd.CH--NHSO.sub.2--R.sup.1,
--CH.dbd.CH--O--R.sup.1, --CH.dbd.CH--N
H--R.sup.1,--CH.dbd.CH--NHCO--R.s-
up.1,--CH.dbd.CH--CONH--R.sup.1,--CH.dbd.CH--C(.dbd.O)--O--R.sup.1,--C
H.dbd.CH--O--C(.dbd.O)--R.sup.1,
--CH.dbd.CH--CO--R.sup.1,--CH.sub.2--CH.-
dbd.CH--R.sup.1,--CH.sub.2--CH(OH)--R.sup.1,
--CH.sub.2--S--R.sup.1,--CH.s-
ub.2--SO--R.sup.1,--CH.sub.2--SO.sub.2--R.sup.1,--CH.sub.2--SO.sub.2NH--R.-
sup.1,--CH.sub.2--NHSO.sub.2--R.sup.1, --CH.sub.2--O--R.sup.1,
--CH.sub.2--NH--R.sup.1, --CH.sub.2--NHCO--R.sup.1,
--CH.sub.2--CONH--R.sup.1, --CH.sub.2--C(.dbd.O)--O --R.sup.1,
--CH.sub.2--O--C(.dbd.O)--R.sup.1, --CH.sub.2--CO--R.sup.1,
--CH(OH)--CH.dbd.CH--R.sup.1,--S--CH.dbd.CH--R.sup.1,--SO--CH.dbd.CH--R.s-
up.1, --SO.sub.2--CH.dbd.CH--R.sup.1,
--SO.sub.2NH--CH.dbd.CH--R.sup.1, --NHSO.sub.2--CH.dbd.CH--R.sup.1,
--O--CH.dbd.CH--R.sup.1, --NH--CH.dbd.CH--R.sup.1,
--NHCO--CH.dbd.CH--R.sup.1,
--CONH--CH.dbd.CH--R.sup.1,--C(.dbd.O)--O--CH.dbd.CH--R.sup.1,
--O--C(.dbd.O)--CH.dbd.CH--R.sup.1,--CO--CH.dbd.CH--R.sup.1,--C.sub.3H.su-
b.6--R.sup.1, --CH.sub.2--CH.dbd.CH--CH.sub.2--R.sup.1,
--CH.sub.2--CH(OH)--CH.sub.2--R.sup.1,
--CH.sub.2--S--CH.sub.2--R.sup.1,
--CH.sub.2--SO--CH.sub.2--R.sup.1,
--CH.sub.2--SO.sub.2--CH.sub.2--R.sup.- 1,
--CH.sub.2--SO.sub.2NH--CH.sub.2--R.sup.1, --CH.sub.2--NHS
O.sub.2--CH.sub.2--R.sup.1, --CH.sub.2--O--CH.sub.2--R.sup.1,
--CH.sub.2--NH--CH.sub.2--R.sup.1,
--CH.sub.2--NHCO--CH.sub.2--R.sup.1,---
CH.sup.2--CONH--CH.sub.2--R.sup.1,
--CH.sub.2--C(.dbd.O)--O--CH.sub.2--R.s- up.1,
--CH.sub.2--O--C(.dbd.O)--CH.sub.2--R.sup.1,--CH.sub.2--C
O--CH.sub.2--R.sup.1, --C.sub.2H.sub.4--CH.dbd.CH--R.sup.1,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH--R.sup.1,--CH.sub.2--CH(OH)--CH.dbd.CH---
R.sup.1, --CH.sub.2--S--CH.dbd.CH--R.sup.1,
--CH.sub.2--SO--CH.dbd.CH--R.s- up.1,
--CH.sub.2--SO.sub.2--CH.dbd.CH--R.sup.1,
--CH.sub.2--SO.sub.2NH--CH- .dbd.CH--R.sup.1,
--CH.sub.2--NHSO.sub.2--CH.dbd.CH--R.sup.1,
--CH.sub.2--O--CH.dbd.CH--R.sup.1,
--CH.sub.2--NH--CH.dbd.CH--R.sup.1,
--CH.sub.2--NHCO--CH.dbd.CH--R.sup.1, --CH.sub.2--CONH
--CH.dbd.CH--R.sup.1, --CH.sub.2--C(.dbd.O)--O--CH.dbd.CH--R.sup.1,
--CH.sub.2--O--C(.dbd.O)--CH.dbd.CH--R.sup.1, --C
H.sub.2--CO--CH.dbd.CH-- -R.sup.1,
--CH.dbd.CH--C.sub.2H.sub.4--R.sup.1, --CH.dbd.CH--CH.dbd.CH--CH-
.sub.2--R.sup.1, --CH.dbd.CH--CH(OH)--CH.sub.2--R.sup.1,
--CH.dbd.CH--S--CH.sub.2--R.sup.1,
--CH.dbd.CH--SO--CH.sub.2--R.sup.1,
--CH.dbd.CH--SO.sub.2--CH.sub.2--R.sup.1,
--CH.dbd.CH--SO.sub.2NH--CH.sub-
.2--R.sup.1,--CH.dbd.CH--NHSO.sub.2--CH.sub.2--R.sup.1,
--CH.dbd.CH--O--CH.sub.2--R.sup.1,
--CH.dbd.CH--NH--CH.sub.2--R.sup.1,--C-
H.dbd.CH--NHCO--CH.sub.2--R.sup.1,
--CH.dbd.CH--CONH--CH.sub.2--R.sup.1,
--CH.dbd.CH--C(.dbd.O)--O--CH.sub.2--R.sup.1,
--CH.dbd.CH--O--C(.dbd.O)--- C H 2--R.sup.one
or--CH.dbd.CH--CO--CH.sub.2--R.sup.1 (wherein, R.sup.1 is
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, or optionally substituted heterocycle).
[0261] Preferable examples of --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1
(wherein, Z.sup.1, Z.sup.2, Z.sup.3, and R.sup.1 are the same as
defined above.) are shown below.
[0262] 1) Z.sup.1 and Z.sup.3 are bonds,
[0263] 2) Z.sup.1 and Z.sup.3 are bonds, Z.sup.2 is a bond, --CO--,
--O--, --S--, --SO.sub.2 or lower alkylene (esp.,
--CH.sub.2--,--(CH.sub.2).sub.- 2--),
[0264] 3) Z.sup.1 and Z.sup.3 are bonds, Z.sup.2 is a bond, --CO--,
--O--, --S--, --SO.sub.2 or lower alkylene (esp., --CH
.sub.2--,--(CH.sup.2).sup- .2--), R.sup.1 is optionally substituted
aryl or optionally substituted heteroaryl,
[0265] 4) Z.sup.1 and Z.sup.3 are bonds, Z.sup.2 is --S.sub.2,
--CH.sub.2 or --C.sub.2H.sub.4-, R.sup.1 is optionally substituted
aryl (esp., phenyl),
[0266] 5) Z.sup.1 is a bond or alkylene, Z.sup.3 is a bond, Z.sup.2
is optionally substituted alkylene, alkenylene or --O--, R.sup.1 is
optionally substituted aryl, optionally substituted heteroaryl or
optionally substituted cycloalkyl,
[0267] 6) Z.sup.1 is a bond or alkylene,
[0268] 7) Z.sup.1 is a bond,
[0269] 8) Z.sup.2 is a bond, alkylene, --SO.sub.2 or --O--,
[0270] 9) Z.sup.2 is a bond, alkylene or --O--,
[0271] 10) Z.sup.2 isalkyleneor--O--,
[0272] 11) Z.sup.3 is a bond or alkylene,
[0273] 12) R.sup.1 is optionally substituted cycloalkyl, optionally
substituted aryl or optionally substituted heteroaryl,
[0274] 13) R.sup.1 is optionally substituted cycloalkyl, optionally
substituted cycloalkenyl, optionally substituted heterocycle or
optionally substituted aryl,
[0275] 14) R.sup.1 is optionally substituted cycloalkyl, optionally
substituted aryl, optionally substituted heteroaryl or optionally
substituted heterocycle,
[0276] 15) R.sup.1 is optionally substituted aryl,
[0277] 16) Z.sup.1 and Z.sup.3 are bonds, Z.sup.2 is alkylene,
R.sup.1 is optionally substituted aryl,
[0278] 17) Z.sup.1 is a bond or alkylene, Z.sup.3 is a bond,
Z.sup.2 is optionally substituted alkylene, alkenylene, --S or
--O--, R.sup.1 is optionally substituted aryl, optionally
substituted heteroaryl or optionally substituted cycloalkyl,
[0279] 18) Z.sup.1 and Z.sup.3 are each independently a bond or
alkylene; Z.sup.2 is a bond or --O--R.sup.1 is optionally
substituted aryl or optionally substituted heteroaryl,
[0280] 19) Z.sup.1, Z.sup.2 and Z.sup.3 are not bonds at the same
time,
[0281] 20) R.sup.1 is phenyl optionally substituted with halogen,
Z.sup.1 is a bond, Z.sup.2 is alkylene or --O--, Z.sup.3 is a bond
or alkylene,
[0282] 21) R.sup.1 is 4-fluorophenyl, Z.sup.1 is a bond, Z.sup.2 is
alkylene or --O--, Z.sup.3 is a bond or alkylene.
[0283] Examples of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 include phenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl,
2,6-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl,
4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
4-hydroxyphenyl, 4-methoxyphenyl, 4-bromophenyl, 4-biphenyl,
benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,
2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2,4-difluorobenzyl,
2,6-difluorobenzyl, 2,5-difluorobenzyl, 3,4-difluorobenzyl,
3,6-difluorobenzyl, 4-methylbenzyl, 3-trifluoromethylbenzyl,
4-trifluoromethylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl,
4-bromobenzyl, 4-phenylbenzyl, 2-phenylethyl,
2-(2-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl,
2-(4-fluorophenyl)ethyl, 2-(2-chlorophenyl)ethyl,
2-(3-chlorophenyl)ethyl- , 2-(4-chlorophenyl)ethyl,
2-(2,4-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl,
2-(2,5-difluorophenyl)ethyl, 2-(3,4-difluorophenyl)ethyl,
2-(4-methylphenyl)ethyl, 2-(3-trifluoromethylphenyl)ethyl,
2-(4-trifluoromethylphenyl)ethyl, 2-(4-hydroxy phenyl)ethyl,
2-(4-methoxyphenyl)ethyl, 2-(4-bromophenyl)ethyl,
2-(4-biphenyl)ethyl, benzenesulfonyl, 2-fluorobenzenesulfonyl,
3-fluorobenzenesulfonyl, 4-fluorobenzenesulfonyl- ,
2-chlorobenzenesulfonyl, 3-chlorobenzenesulfonyl,
4-chlorobenzenesulfonyl, 2,4-difluorobenzenesulfonyl,
2,6-difluorobenzenesulfonyl, 2,5-difluorobenzene sulfonyl,
3,4-difluorobenzenesulfonyl, 4-methylbenzenesulfonyl,
3-trifluoromethylbenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl,
4-hydroxybenzenesulfonyl, 4-methoxybenzenesulfonyl,
4-bromobenzenesulfonyl, 4-phenylbenzenesulfonyl, phenylthio,
2-fluorophenylthio, 3-fluorophenylthio, 4-.fluorophenylthio,
2-chlorophenylthio, 3-chlorophenylthio, 4-chlorophenylthio,
2,4-difluorophenylthio, 2,6-difluorophenylthio,
2,5-difluorophenylthio, 3,4-difluorophenylthio, 4-methylphenylthio,
3-trifluoromethylphenylthio, 4-trifluoromethylphenylthio,
4-hydroxyphenylthio, 4-methoxyphenylthio, 4-bromophenylthio,
4-biphenylthio, phenoxy, 2-fluorophenoxy, 3-fluorophenoxy,
4-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy,
2,4-difluorophenoxy, 2,6-difluorophenoxy, 2,5-difluorophenoxy,
3,4-difluorophenoxy, 4-methylphenoxy, 3-trifluoromethylphenoxy,
4-trifluoromethylphenoxy, 4-hydroxy phenoxy, 4-methoxyphenoxy,
4-bromophenoxy, 4-phenylphenoxy, benzoyl, 2-fluorobenzoyl,
3-fluorobenzoyl, 4-fluorobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl,
4-chlorobenzoyl, 2,4-difluorobenzoyl, 2,6-difluorobenzoyl,
2,5-difluorobenzoyl, 3,4-difluorobenzoyl, 4-methylbenzoyl,
3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl,
4-hydroxybenzoyl, 4-methoxybenzoyl, 4-bromobenzoyl,
4-phenylbenzoyl, 2-thienyl, 3-thienyl, furfuryl, 3-furylmethyl,
(2-chlorothiophene-3-yl)me- thyl, 2-picolyl, 3-picolyl, 4-picolyl,
(2-fluoropyridine-3-yl)methyl, (2-fluoropyridine-5-yl)methyl,
(5-fluoropyridine-2-yl)methyl, benzyloxy, 4-fluorobenzyloxy,
2-phenylethyloxy, and 2-(4-fluorophenyl)ethyl oxy.
[0284] A group of the formula: 93
[0285] (wherein, C ring is N-containing aromatic heterocycle
wherein at least one atom neighboring to the atom at the
bonding-position is N atom the broken line shows the presence or
absence of a bond) means heteroaryl wherein at least one atom
neighboring to the atom at the bonding-position is non-substituted
N atom.
[0286] C ring may contain a hetero atom(s) other than the N atom
shown in the above formula. The atoms constituting C ring include
C, O, N and S. The bonds constituting C ring include a single bond
or double bond. C ring is a monocyclic ring or condensed ring
(e.g., di- to penta-cyclic condensed ring) and preferred is a
monocyclic ring or di-cyclic condensed ring, and more preferred is
a monocyclic ring.
[0287] A monocyclic heteroaryl of C ring means 5- to 8-membered
heteroaryl wherein one atom neighboring to the atom at the
bonding-position is non-substituted N atom and which may contain
further 1 to 4 of O, S and/or N atom, and preferably 5-or
6-membered heteroaryl. The examples include imidazole-2-yl,
imidazole-4-yl, pyrazole-3-yl, triazole3-yl, tetrazole-5-yl,
oxazole-2-yl, oxazole-4-yl, isoxazole-3-yl, thiazole-2-yl,
thiazole-4-yl, 1,3,4-thiadiazole-2-yl, 1,2,4-thiadiazole-5-yl,
1,2,4-thiadiazole-3-yl, 1,3,4-oxadiazole-2-yl,
1,2,4-oxadiazole-5-yl, 1,2,4-oxadiazole-3-yl, isothiazole-3-yl,
pyridine-2-yl, pyridazine-3-yl, pyradine-2-yl, pyrimidine-2-yl,
pyrimidine-4-yl, and furazan-3-yl.
[0288] Preferred is imidazole-2-yl, 1,2,4-triazole-3-yl,
tetrazole-5-yl, oxazole-2-yl, thiazole-2-yl,
1,3,4-thiadiazole-2-yl, 1,2,4-thiadiazole-5-yl,
1,2,4-thiadiazole-3-yl, 1,3,4-oxadiazole-2-yl,
1,2,4-oxadiazole-5-yl, 1,2,4-oxadiazole-3-yl, pyrimidine-2-yl, and
pyridine-2-yl, more preferred is pyridine-2-yl, pyrimidine-2-yl,
1,3,4-oxadiazole-2-yl, 1,2,4-triazole-3-yl, and imidazole-2-yl.
[0289] A condensed heteroaryl of C ring means the above monocyclic
heteroaryl which is condensed with 1 to 4 of 5- to 8-membered
aromatic carbocycle and/or with another 5- to 8-membered aromatic
heterocycle optionally containing 1 to 4 of 0, S, and/or N atom(s).
The aromatic ring to be condensed is preferably 5-or 6-membered
one, such as benzimidazole-2-yl, benzooxazole-2-yl,
quinoxaline-2-yl, cinnoline-3-yl, quinazoline-2-yl,
quinazoline-4-yl, quinoline-2-yl, phthalazine-1-yl,
isoquinoline-1-yl, isoquinoline-3-yl, purine-2-yl, purine-6-yl,
purine-8-yl, pteridine-2-yl, pteridine-4-yl, pteridine-6-yl,
pteridine-7-yl, and phenantridine-6-yl. Preferred is
benzimidazole-2-yl, benzooxazole-2-yl, quinazoline-2-yl,
purine-2-yl, purine-8-yl, pteridine-2-yl, quinoline-2-yl,
isoquinoline-1-yl, and isoquinoline-3-yl, and more preferred is
quinoline-2-yl, isoquinoline-1-yl, and isoquinoline-3-yl. More
preferred is of the formula: 94
[0290] C ring may be substituted with a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above) or a non-interfering
substituent.
[0291] R.sup.n.sub.0-1 (n is an integar more than 0) is
R.sup.n.sub.0 or R.sup.n.sub.1R.sup.n.sub.0 means "non-substituted
with R.sup.n", and R.sup.n.sub.1 means "substituted with
R.sup.n".
[0292] Preferred compounds of the formula (I) are shown below.
[0293] A compound of the formula (I): 95
[0294] (wherein, R.sup.C and R.sup.D taken together with the
neighboring carbon atoms may form 5- to 6-membered heterocycle
which may contain O and/or N atom and may be condensed with benzene
ring; Y is hydroxy, mercapto or amino; Z is O, S or NH; R.sup.A is
the formula 96
[0295] (wherein, C ring is N-containing aromatic heterocycle,
wherein at least one atom neighboring to the atom at the
bonding-position is N atom, and the broken line shows the presence
or absence of a bond) or the formula: 97
[0296] (wherein, X is O, S or NH; R.sup.B is optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl or optionally
substituted heterocycle);
[0297] at least one of the ring formed by R.sup.C and R.sup.D, C
ring or R.sup.B is substituted with a group of the formula;
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1 and Z.sup.3
are each independently a bond, optionally substituted alkylene or
optionally substituted alkenylene; Z.sup.2 is a bond, optionally
substituted alkylene, optionally substituted alkenylene,
--CH(OH)--,--S--,
--SO--,--SO.sub.2--,--SO.sub.2NR.sub.2--,--NR.sub.2SO.sub.2--,--O--,--NR.-
sub.2--,--NR.sub.2C-,--CONR.sub.2--,--C(.dbd.O)--O--,--O--C(.dbd.O)
or --CO--; R.sup.2 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted aryl or
optionally substituted heteroaryl; R.sup.1 is optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted cycloalkyl, optionally substituted cycloalkenyl or
optionally substituted heterocycle) the ring formed by R.sup.C and
R.sup.D, C ring or R.sup.B may be substituted, at any position
other than that which is substituted with the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above) locates, with 1
to 3 groups selected from hydrogen, alkyl, aralkyl, cycloalkyl,
optionally substituted aryl, alkoxy, alkoxy alkyl, optionally
substituted amino, hydroxyalkyl, alkenyl, alkoxycarbonyl alkyl,
heteroarylalkyl and hydroxy.
[0298] A compound of the above formula (I), wherein the ring formed
by R.sup.C and R.sup.D is a 5-or 6-membered heterocycle which
contains O and/or N atom and my be condensed with a benzene ring; Y
is hydroxy; Z is O; X is O; the ring formed by R.sup.C and R.sup.D
is substituted, at any possible position other than that which is
substituted with a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above), with 1 to 3 of
substituents selected from hydrogen, alkyl, aralkyl, cycloalkyl,
optionally substituted aryl, alkoxy, alkoxyalkyl, optionally
substituted amino, hydroxyalkyl, alkenyl, alkoxycarbonylalkyl and
heteroaryl alkyl, C ring and R.sup.B are each independently
substituted with 1 to 3 of substituents selected from alkyl, amino,
halogen and hydroxy.
[0299] A compound wherein at least one of the ring formed by
R.sup.C and R.sup.D, C ring or R.sup.B is substituted with a group
of the formula: --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein,
Z.sup.1 is a bond or alkylene; Z.sup.2 is alkylene or --O--;
Z.sup.3 is a bond or alkylene; R.sup.1 is optionally substituted
aryl or optionally substituted heteroaryl).
[0300] Further preferred compounds are as follows.
[0301] A compound of the formula (I-Q):
Q----Z.sup.1--Z.sup.2--Z.sup.3--R.- sup.1 (wherein, Z.sup.1,
Z.sup.2, Z.sup.3 and R.sup.1 are the same as above (1); Q is a
group of the formula 98
[0302] of the formula 99
[0303] of the formula 100
[0304] of the formula 101
[0305] of the formula 102
[0306] of the formula 103
[0307] of the formula 104
[0308] of the formula 105
[0309] of the formula 106
[0310] of the formula 107
[0311] of the formula 108
[0312] of the formula: 109
[0313] of the formula: 110
[0314] of the formula: 111
[0315] of the formula: 112
[0316] of the formula: 113
[0317] of the formula: 114
[0318] of the formula: 115
[0319] of the formula: 116
[0320] of the formula: 117
[0321] of the formula 118
[0322] or of the formula 119
[0323] Furthre preferred are the followings:
[0324] A compound of the formula: 120
[0325] A compound of the formula: 121
[0326] A compound of the formula: 122
[0327] A compound of the formula: 123
[0328] A compound of the formula: 124
[0329] (wherein, at least one of R.sup.E and R.sup.F is a group of
the formula: --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1, the other is a
non-interfering substituent or R.sup.E and R.sup.F taken together
with the neighboring carbon atoms may form a ring of the formula
125
[0330] A compound of the formula: 126
[0331] A compound of the formula: 127
[0332] (wherein, R.sup.C and R.sup.F are each independently a
non-interfering substituent or taken together with the neighboring
carbon atoms may form a ring of the formula: 128
[0333] A compound of the formula: 129
[0334] A compound of the formula: 130
[0335] (wherein, R.sup.E and R.sup.F are each independently a
non-interfering substituent or taken together with the neighboring
carbon atoms may form a ring of the formula 131
[0336] A compound of the formula: 132
[0337] A compound of the formula: 133
[0338] (wherein, R.sup.E and R.sup.F are each independently a
non-interfering substituent or taken together with the neighboring
carbon atoms may form a ring of the formula: 134
[0339] A compound of the formula: 135
[0340] A compound of the formula: 136
[0341] (wherein, R.sup.E and R.sup.F are each independently a
non-interfering substituent) A compound of the formula: 137
[0342] (wherein, R.sup.E and R.sup.F are each independently a
non-interfering substituent)
[0343] A compound of the formula: 138
[0344] (wherein, R.sup.E and R.sup.F are each independently a
non-interfering substituent)
[0345] A compound of the formula: 139
[0346] (wherein, R.sup.F and R.sup.G are each independently a
non-interfering substituent)
[0347] A compound of the formula: 140
[0348] (wherein, R.sup.F and R.sup.G are each independently a
non-interfering substituent)
[0349] A compound of the formula: 141
[0350] A compound of the formula: 142
[0351] A compound of the formula: 143
[0352] (wherein, R.sup.F and R.sup.G are each independently a
non-interfering substituent)
[0353] A compound of the formula: 144
[0354] (wherein, R.sup.F and R.sup.G are each independently a
non-interfering substituent)
[0355] A compound of the formula: 145
[0356] (wherein, R.sup.F and R.sup.G are each independently a
non-interfering substituent)
[0357] A compound of the formula: 146
[0358] (wherein, R.sup.F and R.sup.G are each independently a
non-interfering substituent)
[0359] A compound of the formula: 147
[0360] (wherein, R.sup.G is a non-interfering substituent)
[0361] A compound of the formula: 148
[0362] (wherein, R.sup.G is a non-interfering substituent)
[0363] In the above shown compounds, R.sup.6, R.sup.7 and a group
of the formula: --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 are
substituents on R.sup.B. The definition of each symbol is explained
below.
[0364] X is O, S or NH and preferred is O,
[0365] Y is hydroxy, mercapto or amino and preferred is
hydroxy,
[0366] Z is O, S or NH and preferred is O,
[0367] C ring is N-containing aromatic heterocycle, wherein at
least one atom neighboring to the atom at the bonding-position is N
atom and preferred is optionally substituted pyridine-2-yl,
optionally substituted pyrimidine-4-yl or optionally substituted
1,3,4-oxadiazole2-yl,
[0368] R.sup.B is a substituent selected from substitution group A
and preferred is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle, R.sup.1 is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl or optionally substituted
heterocycle,
[0369] Z.sup.1 and Z.sup.3 are each independently a bond,
optionally substituted alkylene or optionally substituted
alkenylene,
[0370] Z.sup.2 is a bond, optionally substituted alkylene,
optionally substituted alkenylene, --CH(OH)--, --S--, --SO--,
--SO.sub.2--, --SO.sub.2NR.sub.2--, --NR.sub.2SO.sub.2--,--,
--NR.sub.2--, --NR.sub.2CO--, --CON R.sup.2--, --C(.dbd.O)--O--,
--O--C(.dbd.O)or --CO--,
[0371] R.sup.2 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted aryl or
optionally substituted heteroaryl,
[0372] W.sup.1 is --O or --N(--R.sup.G)-,
[0373] R.sup.3 to R.sup.9 and R.sup.G are each independently a
non-interfering substituent,
[0374] R.sup.G is preferably hydrogen or alkyl.
[0375] Examples of R.sup.B include a substituent selected from
substitution group A.
[0376] substitution group A:
[0377] hydrogen, halogen, alkoxycarbonyl, carboxy, alkyl, alkoxy,
alkoxyalkyl, nitro, hydroxy, alkenyl, alkynyl, alkylsulfonyl,
optionally substituted amino, alkylthio, alkylthioalkyl, haloalkyl,
haloalkoxy, haloalkoxyalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl, optionally substituted
heterocycle, nitroso, azide, amidino, guanidino, cyano, isocyano,
mercapto, optionally substituted carbamoyl, sulfamoyl, sulfoamino,
formyl, alkylcarbonyl, alkyl carbonyloxy, hydrazino, morpholino,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted aralkyl, optionally substituted heteroaryl
alkyl-, optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted arylthio, optionally
substituted heteroarylthio, optionally substituted aralkyloxy,
optionally substituted heteroarylalkyloxy, optionally substituted
aralkylthio, optionally substituted heteroarylalkylthio, optionally
substituted aryloxyalkyl, optionally substituted
heteroaryloxyalkyl, optionally substituted arylthioalkyl,
optionally substituted heteroarylthioalkyl, optionally substituted
arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally
substituted aralkylsulfonyl and optionally substituted heteroaryl
alkylsulfonyl.
[0378] Preferred are alkoxycarbonyl, carboxy, alkyl, alkoxy,
alkoxyalkyl, hydroxy, alkenyl, alkynyl, alkylsulfonyl, optionally
substituted amino, alkylthio, alkylthioalkyl, haloalkyl,
haloalkoxy, haloalkoxyalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl, optionally substituted
heterocycle, alkylcarbonyl, alkyl carbonyloxy, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted aralkyl, optionally substituted heteroarylalkyl,
optionally substituted aryl oxy, optionally substituted heteroaryl
oxy, optionally substituted aryl thio, optionally substituted
heteroaryl thio, optionally substituted aralkyloxy, optionally
substituted heteroaryl alkyl oxy, optionally substituted
aralkylthio, optionally substituted heteroaryl alkylthio,
optionally substituted aryl oxyalkyl, optionally substituted
heteroaryl oxyalkyl, optionally substituted arylthioalkyl,
optionally substituted heteroarylthlioalkyl, optionally
substitutedarylsulfonyl, optionally substituted heteroarylsulfonyl,
optionally substituted aralkylsulfonyl, optionally substituted
heteroaryl alkylsulfonyl. More preferred are alkyl, hydroxy,
alkoxy, optionally substituted amino, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl or optionally
substituted heterocycle. Most preferred are optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl or optionally
substituted heterocycle.
[0379] Preferable R.sup.B of the above formula (III-1), (III-2),
(VII-1), (VII-2), (VII-3), (VII-4), (VII-5), (VII-1), (IX-1),
(X-1), (XI-1), (XII-1) and (XIII-1) includes optionally substituted
cycloalkyl, optionally substituted cycloalkenyl, optionally
substituted heterocycle, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted aralkyl, optionally
substituted heteroaryl alkyl, optionally substituted aryl oxy,
optionally substituted heteroaryloxy, optionally substituted
arylthio, optionally substituted heteroarylthio, optionally
substituted aralkyloxy, optionally substituted heteroaryl alkyloxy,
optionally substituted aralkylthio, optionally substituted
heteroarylalkylthio, optionally substituted aryloxyalkyl,
optionally substituted heteroaryloxyalkyl, optionally substituted
arylthioalkyl, optionally substituted heteroarylthioalkyl,
optionally substituted arylsulfonyl, optionally substituted
heteroarylsulfonyl, optionally substituted aralkylsulfonyl,
optionally substituted heteroarylalkylsulfonyl. More preferred are
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle. Most preferred
are optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl or optionally substituted heterocycle.
[0380] The ring formed by R.sup.C and R.sup.D, C ring and R.sup.B
are optionally substituted with a non-interfering substituent(s).
The substituent may locate at one or more, preferably one to five,
any substitutable positions.
[0381] The non-interfering substituent means any substituent not
interfering with the integrase inhibitory activity. The
non-interfering substituent can be selected based on the determined
integrase inhibitory activity and drug design using computer, as
well as molecular weight, an der Waals' radius, electostatic
characteristic of the substituent.
[0382] Preferred examples of the non-interfering substituent
include hydrogen, halogen, alkoxycarbonyl, carboxy, alkyl, alkoxy,
alkoxy alkyl, nitro, hydroxy, alkenyl, alkynyl, alkylsulfonyl,
optionally substituted amino, alkylthio, alkylthio alkyl,
haloalkyl, haloalkoxy, haloalkoxyalkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl, optionally
substituted heterocycle, oxo, thioxo, nitroso, azide, amidino,
guanidino, cyano, isocyano, mercapto, optionally substituted
carbamoyl, sulfamoyl, sulfoamino, formyl, alkylcarbonyl,
alkylcarbonyloxy, hydrazino, morpholino, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
aralkyl, optionally substituted heteroaryl alkyl, optionally
substituted aryl oxy, optionally substituted heteroaryl oxy,
optionally substituted aryl thio, optionally substituted heteroaryl
thio, optionally substituted aralkyloxy, optionally substituted
heteroaryl alkyl oxy, optionally substituted aralkylthio,
optionally substituted heteroaryl alkylthio, optionally substituted
aryl oxyalkyl, optionally substituted heteroaryl oxyalkyl,
optionally substituted aryl thioalkyl, optionally substituted
heteroaryl thioalkyl, optionally substituted arylsulfonyl,
optionally substituted heteroarylsulfonyl, optionally substituted
aralkylsulfonyl and optionally substituted heteroaryl
alkylsulfonyl.
[0383] More preferred non-interfering substituents include
hydrogen, halogen, alkoxycarbonyl, carboxy, alkyl, alkoxy, alkoxy
alkyl, nitro, hydroxy, alkenyl, alkynyl, alkylsulfonyl, optionally
substituted amino, alkylthio, alkylthio alkyl, haloalkyl,
haloalkoxy, haloalkoxyalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl, optionally substituted
heterocycle, oxo, thioxo, nitroso, azide, amidino, guanidino,
cyano, isocyano, mercapto, optionally substituted carbamoyl,
sulfamoyl, sulfoamino, formyl, alkylcarbonyl, alkylcarbonyloxy,
hydrazino, morpholino, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted aralkyl, optionally
substituted heteroaryl alkyl, optionally substituted aryloxy,
optionally substituted heteroaryloxy, optionally substituted
arylthio, optionally substituted heteroarylthio, optionally
substituted aralkyloxy, optionally substituted heteroaryl alkyloxy,
optionally substituted aralkylthio, optionally substituted
heteroaryl alkylthio, optionally substituted aryloxyalkyl,
optionally substituted heteroaryl oxyalkyl, optionally substituted
arylthioalkyl, optionally substituted heteroaryl thioalkyl,
optionally substituted arylsulfonyl, optionally substituted
heteroarylsulfonyl, optionally substituted aralkylsulfonyl and
optionally substituted heteroaryl alkylsulfonyl.
[0384] Most preferred non-interfering substituents include
hydrogen, halogen, alkoxycarbonyl, carboxy, alkyl, alkoxy,
alkoxyalkyl, nitro, hydroxy, alkenyl, alkynyl, alkylsulfonyl,
optionally substituted amino, alkylthio, alkylthioalkyl, haloalkyl,
haloalkoxy, haloalkoxyalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl, optionally substituted
heterocycle, oxo, thioxo, cyano, mercapto, optionally substituted
carbamoyl, formyl, alkylcarbonyl, alkylcarbonyloxy, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted aralkyl, optionally substituted heteroarylalkyl,
optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted arylthio, optionally
substituted heteroarylthio, optionally substituted aralkyloxy,
optionally substituted heteroaryl alkyloxy, optionally substituted
aralkylthio, optionally substituted heteroaryl alkylthio,
optionally substituted aryl oxyalkyl, optionally substituted
heteroaryl oxyalkyl, optionally substituted aryl thioalkyl,
optionally substituted heteroaryl thioalkyl, optionally substituted
arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally
substituted aralkylsulfonyl and optionally substituted heteroaryl
alkylsulfonyl.
[0385] Examples of non-interfering substituent on the ring formed
by R.sup.C and R.sup.D (e.g., non-interfering substituent of
R.sup.19, R.sup.E, R.sup.F, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15 and R.sup.G) are preferably hydrogen, halogen, alkyl,
aralkyl, cycloalkyl, optionally substituted aryl, alkoxy,
alkoxyalkyl, optionally substituted amino, hydroxy alkyl, alkenyl,
alkoxycarbonylalkyl, heteroarylalkyl or hydroxy.
[0386] R.sup.5 and R.sup.5' are each preferably hydrogen, alkyl,
aralkyl, cycloalkyl, optionally substituted aryl, alkoxy,
alkoxyalkyl, optionally substituted amino, hydroxy alkyl, alkenyl,
alkoxycarbonylalkyl or heteroarylalkyl.
[0387] Examples of non-interfering substituent on C ring (e.g.,
non-interfering substituent of R.sup.3, R.sup.4, R.sup.8, R.sup.9
and R.sup.1.degree. are preferably halogen, alkyl, aralkyl,
cycloalkyl, optionally substituted aryl, alkoxy, alkoxyalkyl,
optionally substituted amino, hydroxy alkyl, alkenyl,
alkoxycarbonylalkyl, heteroarylalkyl or hydroxy, and more preferred
is hydrogen, alkyl, amino, halogen or hydroxy.
[0388] Examples of non-interfering substituent on R.sup.B (e.g.,
non-interfering substituent of R.sup.6 and R.sup.7) are preferably
halogen, alkyl, aralkyl, cycloalkyl, optionally substituted aryl,
alkoxy, alkoxyalkyl, optionally substituted amino, hydroxy alkyl,
alkenyl, alkoxycarbonylalkyl, heteroarylalkyl or hydroxy, and more
preferred is hydrogen, alkyl, amino, halogen, hydroxy.
[0389] Terms used herein are explained below. Each term, by itself
or in combination with others, is defined as follows.
[0390] "alkylene" means C1 to C6 straight or branched chain
alkylene, for example, methylene, ethylene, trimethylene,
propylene, tetramethylene, ethylethylene, pentamethylene or
haxamethylene. Preferred is C1 to C4 straight alkylene, for
example, methylene, ethylene, trimethylene or tetramethylene.
[0391] "alkenylene" is C2 to C6 straight or branched chain
alkenylene derived from the above "alkylene" having one or more of
double bond, for example, vinylene, propenylene or butenylene.
Preferred is C2 to C3 straight alkenylene, for example, vinylene or
propenylene.
[0392] "alkyl" means C1 to C10 straight or branched chain alkyl,
for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl,
n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl. Preferred
is C1 to C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,
neopentyl, tert-pentyl, n-hexyl, isohexyl.
[0393] "alkenyl" means C2 to C8 straight or branched chain alkenyl
derived from the above "alkyl" having one or more double, for
example, vinyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl,
3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl.
[0394] "aryl" means monocyclic aromatic hydrocarbon group (e.g.,
phenyl) or polycyclic aromatic hydrocarbon group (e.g., 1-naphthyl,
2-naphthyl, 1-anthoryl,2-anthoryl,9-anthoryl,1-phenantryl,
2-phenantryl, 3-phenantryl, 4-phenantryl, 9-phenantryl). Preferred
is phenyl or naphthyl (e.g., 1-naphthyl, 2-naphthyl).
[0395] "heteroaryl" means monocyclic aromatic heterocyclic group
and condensed aromatic heterocyclic group.
[0396] "monocyclic aromatic heterocyclic group" means 5- to
8-membered aromatic ring which may contain 1 to 4 of O, S and/or N
atom and has a bonding radical at any substitutable position.
[0397] "condensed aromatic heterocyclic group" is a condensed ring
formed by condensing a 5- to 8-membered aromatic ring which may
contain 1 to 4 of O, S and/or N atom with a 1 to 4 of 5- to
8-membered aromatic carbocycle or the other 5- to 8-membered
aromatic heterocycle, and the condensed ring has a bonding radical
at any substitutable position.
[0398] Examples of "heteroaryl" include furyl (e.g., 2-furyl,
3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g.,
1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,
1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g.,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g.,
1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-4-yl),
tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl),
oxazolyl(e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),
isoxazolyl(e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl),
thiazolyl(e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl),
thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl,
5-isothiazolyl), pyridyl (e.g.,2-pyridyl, 3-pyridyl, 4-pyridyl),
pyridazinyl(e.g., 3-pyridazinyl, 4-pyridazinyl), pirimidinyl(e.g.,
2-pirimidinyl, 4-pirimidinyl, 5-pirimidinyl), furazanyl(e.g.,
3-furazanyl), pyradinyl(e.g., 2-pyradinyl), oxadiazolyl (e.g.,
1,3,4-oxadiazole-2-yl), benzofuryl (e.g., 2-benzo[b]furyl,3-benzo
[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl,
7-benzo[b]furyl), benzo thienyl (e.g., 2-benzo[b]thienyl,
3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo [b]thienyl,
6-benzo[b]thienyl, 7-benzo[b]thienyl), benzimidazolyl (e.g.,
1-benzo imidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl,
5-benzoimidazolyl), dibenzo furyl, benzooxazolyl, quinoxalinyl
(e.g., 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl
(e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl,
7-cinnolinyl, 8-cinnolinyl), quinazolil (e.g., 2-quinazolinyl,
4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl,
8-quinazolinyl), quinolil (e.g.,2-quinolil, 3-quinolil, 4-quinolil,
5-quinolil, 6-quinolil, 7-quinolil, 8-quinolil), phthalazinyl
(e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolil
(e.g., 1-isoquinolil, 3-isoquinolil, 4-iso quinolil, 5-isoquinolil,
6-isoquinolil, 7-isoquinolil, 8-isoquinolil), puril, pteridinyl
(e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl),
carbazolyl, phenantridinyl, acridinyl (e.g., 1-acridinyl,
2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (e.g.,
1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl,
7-indolyl), isoindolyl, phenazinyl (e.g., 1-phenazinyl,
2-phenazinyl) or phenothiadinyl (e.g., 1-phenothiadinyl,
2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl).
[0399] "cycloalkyl" means C3 to C10 cyclic saturated hydrocarbon
group, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cycloctyl. Preferred is C3 to C6
cycloalkyl, for example, cyclopentyl, cyclohexyl.
[0400] "cycloalkenyl" means C3 to C10 cyclic non-aromatic
hydrocarbon group, for example, cyclopropenyl (e.g.,
1-cyclopropenyl), cyclobutenyl (e.g., 1-cyclobutenyl),
cyclopentenyl (e.g., 1-cyclopenten-1-yl, 2-cyclopenten-1-yl,
3-cyclopenten-1-yl), cyclohexenyl (e.g., 1-cyclohexene-1-yl,
2-cyclohexene-1-yl, 3-cyclohexene-1-yl), cycloheptenyl (e.g.,
1-cycloheptenyl), cycloctenyl (e.g., 1-cycloctenyl). Preferred is
1-cyclohexene-1-yl, 2-cyclohezene-1-yl, 3-cyclohezene-1-yl.
[0401] "heterocycle" means non-aromatic heterocyclic group which
contains at least one of N, O, and S atom and has a bonding ragical
at any substitutable position, for example, 1-pyrrolinyl,
2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,
1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl,
3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidino,
3-piperidil, 4-piperidil, 1-piperazinyl, 2-piperazinyl,
2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl. The
"non-aromatic heterocyclic group" is saturated or unsaturated.
[0402] The alkyl of "alkoxy" is the same as above "alkyl", and
"alkoxy" includes for example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, tert-butoxy. Preferred is methoxy,
ethoxy.
[0403] "alkoxycarbonyl" means carbonyl substituted with the above
"alkoxy", including for example, methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,
isobutoxycarbonyl, tert-butoxycarbonyl.
[0404] "alkoxyalkyl" means the above "alkyl" substituted with the
above "alkoxy", including for example, methoxymethyl, ethoxymethyl,
n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl,
tert-butoxymethyl, methoxyethyl, ethoxyethyl, n-propoxyethyl,
isopropoxyethyl, n-butoxyethyl, isobutoxyethyl,
tert-butoxyethyl.
[0405] "alkynyl" means C2 to C8 alkynyl derived from the above
"alkyl" having one or more of triple bond, including for example,
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl.
[0406] "alkylsulfonyl" means sulfonyl substituted with the above
"alkyl", including for example, methylsulfonyl, ethylsulfonyl,
n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl,
isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,
n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl,
tert-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl,
n-heptylsulfonyl, n-octylsulfonyl, n-nonylsulfonyl,
n-desylsulfonyl.
[0407] "optionally substituted amino" is substituted or
unsubstituted amino.
[0408] "optionally substituted carbamoyl" is substituted or
unsubstituted carbamoyl.
[0409] Examples of the substituent of "optionally substituted
amino" and "optionally substituted carbamoyl" includes alkyl (e.g.,
methyl, ethyl, dimethyl), alkoxyalkyl (e.g., ethoxymethyl,
ethoxyethyl), acyl (e.g., formyl, acetyl, benzoyl, toluoyl),
aralkyl (e.g., benzyl, trityl), hydroxy.
[0410] "alkylthio" means sulfur atom substituted with the above
"alkyl", including for example, methylthio, ethylthio,
n-propylthio, isopropylthio, n-butylthio, isobutylthio,
sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio,
neopentylthio, tert-pentylthio, n-hexylthio, isohexylthio,
n-heptylthio, n-octylthio, n-nonylthio, n-desylthio. Preferred is
sulfur atom substituted with C 1 to C6 alkyl.
[0411] "alkylthioalkyl" means the above "alkyl" substituted with
the above "alkylthio", including for example, methylthiomethyl,
ethylthiomethyl, n-propylthiomethyl, isopropylthiomethyl,
n-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl,
tert-butylthiomethyl, n-pentylthiomethyl, isopentylthiomethyl,
neopentylthiomethyl, tert-pentylthiomethyl, n-hexylthiomethyl,
isohexylthiomethyl, n-heptylthiomethyl, n-octylthiomethyl,
n-nonylthiomethyl, n-desylthiomethyl, methylthioethyl, ethylthio
ethyl, n-propylthioethyl, isopropylthioethyl, n-butylthioethyl,
isobutylthioethyl, sec-butylthioethyl, tert-butylthioethyl,
n-pentylthioethyl, isopentylthioethyl, neopentylthioethyl,
tert-pentylthioethyl, n-hexylthioethyl, isohexylthioethyl,
n-heptylthioethyl, n-octylthioethyl, n-nonylthioethyl,
n-desylthioethyl. Preferred is C1 to C2 alkyl substituted with C1
to C6 alkylthio.
[0412] "haloalkyl" means the above "alkyl" substituted with one or
more of halogen. Preferred is halogenated C1 to C3 alkyl, for
example, trifluoromethyl, chloromethyl, dichloromethyl,
1,1-dichloroethyl, 2,2,2-tri chloro ethyl.
[0413] "haloalkoxy" means O substituted with the above "haloalkyl",
including for example, trifluoromethoxy, chloromethoxy,
dichloromethoxy, 1,1-dichloro ethoxy, 2,2,2-trichloroethoxy.
[0414] "haloalkoxyalkyl" means the above "alkyl" substituted with
the above "haloalkoxy", including for example,
trifluoromethoxymethyl, chloro methoxymethyl,
dichloromethoxymethyl, 1,1-dichloroethoxymethyl, 2,2,2-trichloro
ethoxymethyl, trifluoromethoxyethyl, chloromethoxyethyl,
dichloromethoxyethyl, 1,1-dichloro ethoxyethyl,
2,2,2-trichloroethoxyethy- l.
[0415] "alkylcarbonyl" means carbonyl substituted with the above
"alkyl", including for example, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaroyl, haxanoyl, octanoyl,
lauroyl.
[0416] "alkylcarbonyloxy" means O substituted with the above
"alkylcarbonyl", including for example, acetyloxy, propionyloxy,
butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaroyloxy,
haxanoyloxy, octanoyloxy, lauroyloxy.
[0417] "aralkyl" means the above "alkyl" substituted with 1 to 3 of
the above "aryl", including for example, benzyl, diphenylmethyl,
triphenylmethyl, phenetyl,1-naphthyl methyl, 2-naphthylmethyl.
[0418] "heteroarylalkyl" means the above "alkyl" substituted with 1
to 3 of the above "heteroaryl". Preferred is heteroarylalkyl having
C1 to C4 alkyl, esp., C1 or C2 alkyl, for example, furylmethyl,
thienylmethyl, pyrrolylmethyl, imidazolyl methyl, pyrazolylmethyl,
triazolylmethyl, tetrazolylmethyl, oxazolylmethyl,
isoxazolylmethyl, thiazolylmethyl, thiadiazolylmethyl,
isothiazolylmethyl, pyridyl methyl, pyridazinylmethyl,
pirimidinylmethyl, furazanylmethyl, pyrazinylmethyl,
ozadiazolylmethyl, benzofurylmethyl, benzothienylmethyl,
benzimidazolyl methyl, dibenzofurylmethyl, benzoxazolylmethyl,
quinoxalilmethyl, cinnolinylmethyl, quinazolilmethyl,
quinolilmethyl, phthalazinylmethyl, isoquinolylmethyl, purilmethyl,
pteridinylmethyl, carbazolylmethyl, phenantridinylmethyl,
acridinylmethyl, indolyl methyl, isoindolylmethyl,
phenadinylmethyl, phenothiadinylmethyl, furylethyl, thienylethyl,
pyrrolylethyl, imidazolylethyl, pyrazolylethyl, triazolylethyl,
tetrazolylethyl, oxazolylethyl, isoxazolylethyl, thiazolylethyl,
thiadiazolylethyl, isothiazolylethyl, pyridylethyl,
pyridazinylethyl, pirimidinylethyl, furazanylethyl, pyrazinylethyl,
oxadiazolylethyl, benzofurylethyl, benzothienylethyl,
benzimidazolyl ethyl, dibenzofurylethyl, benzooxazolylethyl,
quinoxalylethyl, cinnolinylethyl, quinazolilethyl, quinolilethyl,
phthalazinylethyl, isoquinolilethyl, purilethyl, pteridinylethyl,
carbazolylethyl, phenantridinylethyl, acridinylethyl, indolyl
ethyl, isoindolylethyl, phenadinylethyl or phenothiadinylethyl.
[0419] In the definitions of "aryloxy", "heteroaryloxy",
"arylthio", "heteroarylthio", "aralkyloxy", "heteroarylalkyloxy",
"aralkylthio", "heteroarylalkylthio", "aryloxyalkyl",
"heteroaryloxyalkyl", "arylthioalkyl", "heteroarylthioalkyl",
"arylsulfonyl", "heteroarylsulfonyl", "aralkylsulfonyl" and
"heteroarylalkylsulfonyl", each term of "aryl", "aralkyl",
"heteroaryl", "heteroaryl alkyl" and "alkyl" is the same as
mentioned above.
[0420] Each group of "optionally substituted alkylene", "optionally
substituted alkenylene", "optionally substituted alkyl",
"optionally substituted alkenyl", "optionally substituted aryl",
"optionally substituted heteroaryl", "optionally substituted
cycloalkyl", "optionally substituted cycloalkenyl", "optionally
substituted heterocycle", "optionally substituted aralkyl",
"optionally substituted heteroarylalkyl", "optionally substituted
aryloxy", "optionally substituted heteroaryloxy", "optionally
substituted arylthio", "optionally substituted heteroarylthio",
"optionally substituted aralkyloxy", "optionally substituted
heteroarylalkyloxy", "optionally substituted aralkylthio",
"optionally substituted heteroarylalkylthio", "optionally
substituted aryl oxyalkyl", "optionally substituted
heteroaryloxyalkyl", "optionally substituted aryl thioalkyl",
"optionally substituted heteroarylthioalkyl", "optionally
substituted arylsulfonyl", "optionally substituted
heteroarylsulfonyl", "optionally substituted aralkylsulfonyl" and
"optionally substituted heteroarylalkylsulfonyl" may have 1 to 4,
same or different substituent at any substitutable position. The
substituent is selected from those which do not interfer with the
integraseinhibitory activity, as well as tha case of above
mentioned "non-interfering substituent". Examples of the
substituent include hydroxy, carboxy, halogen (F, Cl, Br, I),
haloalkyl (e.g., CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2CCl.sub.3),
alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), alkenyl (e.g.,
vinyl), alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl),
cycloalkenyl (e.g., cyclopropenyl), alkoxy (e.g., methoxy, ethoxy,
propoxy, butoxy), alkoxycarbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl), nitro, nitroso, optionally
substituted amino (e.g., alkylamino (e.g., methylamino, ethylamino,
dimethylamino), acylamino (e.g., acetyl amino, benzoylamino),
aralkylamino (e.g., benzylamino, tritylamino), hydroxy amino),
azide, aryl (e.g., phenyl), aralkyl (e.g., benzyl), cyano,
isocyano, isocyanate, thiocyanate, isothiocyanate, mercapto,
alkylthio (e.g., methylthio), alkylsulfonyl (e.g., methanesulfonyl,
ethanesulfonyl), optionally substituted carbamoyl, sulfamoyl, acyl
(e.g., formyl, acetyl), formyloxy, haloformyl, oxazolo, thioformyl,
thiocarboxy, dithio carboxy, thiocarbamoyl, sulfino, sulfoamino,
hydrazino, azide, ureido, amidino, guanidino.
[0421] In the deifinition of R.sup.1, the substituent of
"optionally substituted aryl", "optionally substituted heteroaryl",
"optionally substituted cycloalkyl", "optionally substituted
cycloalkenyl", and "optionally substituted heterocycle" is
preferably hydroxy, carboxy, halogen (F, Cl, Br, I), haloalkyl
(e.g., CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2CCl.sub.3), alkyl (e.g.,
methyl, ethyl, isopropyl, tert-butyl), alkenyl (e.g., vinyl),
alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl),
cycloalkenyl (e.g., cyclopropenyl), alkoxy (e.g., methoxy, ethoxy,
propoxy, butoxy), alkoxycarbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl), nitro, optionally substituted
amino (e.g., alkylamino (e.g., methylamino, ethylamino,
dimethylamino), acylamino (e.g., acetyl amino, benzoylamino),
aralkylamino (e.g., benzylamino, tritylamino), hydroxy amino),
azide, aryl (e.g., phenyl), aralkyl (e.g., benzyl), cyano,
mercapto, alkylthio (e.g., methylthio), alkylsulfonyl (e.g.,
methanesulfonyl, ethanesulfonyl), optionally substituted carbamoyl,
sulfamoyl, acyl (e.g., formyl, acetyl), formyl oxy, thiocarbamoyl,
sulfoamino, hydrazino, azide, ureido, amidino, guanidino. More
preferred is alkyl, haloalkyl, halogen (e.g., F, Cl, Br), alkoxy
and further preferred is methoxy. Preferred is mono-or
disubstituted one.
[0422] In the definition of Z.sup.1, Z.sup.2 and Z.sup.3, the
substituent of "optionally substituted alkylene" and "optionally
substituted alkenylene" is preferably hydroxy, carboxy, halogen
(e.g., F, Cl, Br, I), haloalkyl (e.g., CF.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CCl.sub.3), alkyl (e.g., methyl, ethyl, isopropyl,
tert-butyl), alkenyl (e.g., vinyl), alkynyl (e.g., ethynyl),
cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl),
alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), alkoxycarbonyl
(e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl),
optionally substituted amino (e.g., alkylamino (e.g., methylamino,
ethyl amino, dimethylamino), acylamino (e.g., acetylamino,
benzoylamino), aralkylamino (e.g., benzylamino, tritylamino),
hydroxyamino), aryl (e.g., phenyl), aralkyl (e.g., benzyl), cyano,
mercapto, alkylthio (e.g., methylthio), alkylsulfonyl (e.g.,
methanesulfonyl, ethanesulfonyl), optionally substituted carbamoyl,
sulfamoyl, acyl (e.g., formyl, acetyl), formyloxy, thiocarbamoyl,
sulfoamino, hydrazino, azide, ureido, amidino, guanidino.
[0423] When a non-interfering substituent is "optionally
substituted aryl", "optionally substituted heteroaryl", "optionally
substituted cycloalkyl", "optionally substituted cycloalkenyl",
"optionally substituted heterocycle", "optionally substituted
aralkyl", "optionally substituted heteroarylalkyl", "optionally
substituted aryloxy", "optionally substituted heteroaryloxy",
"optionally substituted arylthio", "optionally substituted
heteroarylthio", "optionally substituted aralkyloxy", "optionally
substituted heteroaryl alkyloxy", "optionally substituted
aralkylthio", "optionally substituted heteroaryl alkylthio",
"optionally substituted aryl oxyalkyl", "optionally substituted
heteroaryl oxyalkyl", "optionally substituted aryl thioalkyl",
"optionally substituted heteroaryl thioalkyl", "optionally
substituted arylsulfonyl", "optionally substituted
heteroarylsulfonyl", "optionally substituted aralkylsulfonyl" or
"optionally substituted heteroaryl alkylsulfonyl", the substituent
is preferably hydroxy, carboxy, halogen (e.g., F, Cl, Br, I),
haloalkyl (e.g., CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2CCl.sub.3),
alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), alkenyl (e.g.,
vinyl), alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl),
cycloalkenyl (e.g., cyclopropenyl), alkoxy (e.g., methoxy, ethoxy,
propoxy, butoxy), alkoxycarbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl), nitro, optionally substituted
amino (e.g., alkylamino (e.g., methylamino, ethyl amino,
dimethylamino), acylamino (e.g., acetylamino, benzoylamino),
aralkylamino (e.g., benzylamino, tritylamino), hydroxyamino),
azide, aryl (e.g., phenyl), aralkyl (e.g., benzyl), cyano,
mercapto, alkylthio (e.g., methylthio), alkylsulfonyl (e.g.,
methanesulfonyl, etahnesulfonyl), optionally substituted carbamoyl,
sulfamoyl, acyl (e.g., formyl, acetyl), formyloxy, thiocarbamoyl,
sulfoamino, hydrazino, azide, ureido, amidino, guanidino. More
preferred is alkyl, haloalkyl, halogen (e.g., F, Cl, Br), alkoxy
(e.g., methoxy). Preferred is mono-or di-substituted one.
[0424] The present invention includes the above mentioned
compounds, prodrug, pharmaceutically acceptable salt and solvate
thereof, as well as all tautomers and geometrical isomers. For
example, keto/enol tautomers of the formula (I) are included in the
present invention compounds. The compounds of formula (XIII-1) and
(XIII-2) may include the following tautomers: 149
[0425] A prodrug is a derivative of a compound of the present
invention having a group which can be decomposed chemically or
metabolically, and such a prodrug is converted to a
pharmaceutically active compound of the present invention by means
of solvolysis or by placing the compound in vivo under a
physiological condition. Method for the selection and process of an
appropriate prodrug derivative are described in the literature such
as Design of Prodrugs, Elsevier and Amsterdam 1985.
[0426] It is known that HIV multiplies vigorously in a lymph node
even in the asymptomatic term. Thus a prodrug of a compound of the
present invention is preferably a lymph-directivity one. The
diseases caused by HIV include AIDS cerebrum symptom. Thus a
preferable prodrug of a compound of the present invention is a
brain-directivity one. As these lymph-directivity prodrug and
brain-directivity prodrug, the following prodrugs with high
lipophilicity are preferable.
[0427] When a compound of the present invention has a carboxyl
group, an ester derivative prepared by reacting a basal acid
compound with a suitable alcohol or an amide derivative prepared by
reacting a basal acid compound with a suitable amine is exemplified
as a prodrug. A especially preferred ester derivative as an prodrug
is methylester, ethylester, n-propylester, isopropylester,
n-butylester, isobutylester, tert-butylester, morpholinoethylester
or N, N-diethylglycolamidoester.
[0428] When a compound of the present invention has a hydroxy
group, an acyloxy derivative prepared by reacting a compound having
a hydroxyl group with a suitable acylhalide or a suitable acid
anhydride is exemplified as a prodrug. A especially preferred
acyloxy derivative as a prodrug is --O(.dbd.O)--CH.sub.3,
--OC(.dbd.O)--C.sub.2H.sub.5, --OC(.dbd.O)-(tert-Bu),
--OC(.dbd.O)--Cl.sub.5H.sub.31, --OC(.dbd.O)-(m-COONa-Ph),
--OC(.dbd.O)--CH.sub.2CH.sub.2COONa,
--O(C.dbd.O)--CH(NH.sub.2)CH.sub.3 or
--OC(.dbd.O)--CH.sub.2--N(CH.sub.3)- .sub.2.
[0429] When a compound of the present invention has an amino group,
an amide derivative prepared by reacting a compound having amino
with a suitable acid halide or a suitable acid anhydride is
exemplified as a prodrug. A especially preferred amide derivative
as a prodrug is --NHC(.dbd.O)--(CH.sub.2).sub.20CH.sub.3 or
--NHC(.dbd.O)--CH(NH.sub.2)CH- .sub.3.
[0430] For example, a prodrug can be produced by the chemical
modification of Y. For example, Y is substituted with acyl and it
is examined whether the prodrug is converted to a compound of the
present invention by means of solvolysis or by placing the compound
under a physiological condition or not. Therefore, even if Y is a
substituent except for hydroxy, mercapto or amino, a compound
converted to hydroxy, mercapto or amino by means of solvolysis or
by placing the compound under a physiological condition is
contained in prodrugs of the present invention and the present
invention. For example, a compound converted to the present
invention compound in phosphate buffer (pH7.4)-ethanol or plasma is
a compound of the present invention.
[0431] Pharmaceutically acceptable salts of a compound of the
present invention include, as basic salts, for example, alkali
metal salts such as sodium or potassium salts; alkaline-earth metal
salts such as calcium or magnesium salts; ammonium salts; aliphatic
amine salts such as trimethylamine, triethylamine,
dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or
procaine salts; aralkyl amine salts such as
N,N-dibenzylethylenediamine salts; heterocyclic aromatic amine
salts such as pyridine salts, picoline salts, quinoline salts or
isoquinoline salts; quaternary ammonium salts such as
tetramethylammonium salts, tetraethylammonium salts,
benzyltrimethylammonium salts, benzyltriethylammonium salts,
benzyltributylammonium salts, methyltrioctylammonium salts or
tetrabutylammonium salts; and basic amino acid salts such as
arginine salts or lysine salts. Acid salts include, for example,
mineral acid salts such as hydrochloride, sulfates salts, nitrate
salts, phosphates salts, carbonates salts, hydrogencarbonates or
perchlorate; organic acid salts such as acetates, propionates,
lactates, maleates, fumarates, tararic acid salts, malates,
citrates salts, or ascorbates; sulfonates such as
methanesulfonates, isethionates, benzenesulfonates, or
p-toluenesulfonates; and acidic amino acid salts such as aspartates
or glutamates.
[0432] Furthermore, various solvates of a compound of the present
invention, for example, monosolvate, disolvate, monohydrate or
dihydrate are also within the scope of the present invention.
[0433] The term "inhibit" means that a compound of the present
invention suppresses the action of integrase.
[0434] The term "pharmaceutically acceptable" means harmless with
respect to the prevention and the treatment.
BEST MODE FOR CARRYING OUT THE INVENTION
[0435] The general method for the production of a compound of the
present invention is explained below. 150
[0436] (wherein, C ring, R.sup.5, Y, Z and the broken line are the
same as above; L.sup.1 and L.sup.2 are leaving groups such as
alkoxy; H a 1 is halogen; n is an integer of 0 or more, C ring may
be substiuted with a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1(wherein Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above) and/or a non-interfering
substituent.)
[0437] Process A 1
[0438] This process is for reacting compound of the formula (A1)
with compound of the formula: R.sup.5NH.sub.2 to give compound of
the formula (B1).
[0439] Examples of compound of the formula (A1) include
heteroarylalkyl halides.
[0440] Examples of compound of the formula: R.sup.5NH.sub.2 include
alkylamine (e.g., methylamine, ethylamine, n-propylamine,
isopropylamine, n-butylamine, tert-butylamine, 2-ethylpropyl),
cycloalkylamine (e.g., cyclohexylamine), arylamine (e.g., aniline),
alkoxyamine (e.g., tert-butoxyamine), aralkylamine (e.g.,
benzylamine).
[0441] Examples of solvent include dimethylformamide, alcohol
(e.g., methanol, ethanol).
[0442] This process may be conducted in the presence of base (e.g.
sodium hydrogencarbonate, potassium carbonate).
[0443] Process B
[0444] This process is for reacting compound of the formula (B1)
with compound of the formula:
L.sup.1--C(.dbd.Y)--C(.dbd.Z)--L.sup.2 in the presence of base to
give compound of, the formula (I-A).
[0445] Examples of compound of the formula:
L.sup.1--C(.dbd.Y)--C(.dbd.Z)-- -L.sup.2 include oxalic acid
dimethyl, oxalic acid diethyl.
[0446] Examples of base include metal alcolate (e.g. sodium
methoxide, sodium ethoxide).
[0447] Examples of reaction solvent include alcohol (e.g.,
methanol, ethanol).
[0448] Compound (B1) can be prepared by the following process.
151
[0449] (wherein, C ring, n, R.sup.5 and the broken line are the
same as defined above)
[0450] Process A 2
[0451] This process is for reacting compound of the formula (A2),
in the presence of a reductant, with compound of the formula:
R.sup.5NH.sub.2 to give compound of the formula (B1).
[0452] Examples of compound of the formula (A2) include
heteroarylalkyl.
[0453] Examples of compound of the formula: R.sup.5NH.sub.2 include
amine as used in Process A1.
[0454] Examples of reductant include NaBH.sub.3CN.
[0455] Examples of reaction solvent include alcohol (e.g.,
methanol, ethanol). 152
[0456] (wherein, C ring, R.sup.5 and the broken line are the same
as above)
[0457] Process A 3
[0458] This process is for reacting compound of the formula (A3)
with compound of the formula: R.sup.5NH.sub.2 to give compound of
the formula B2).
[0459] Examples of compound of the formula (A3) include vinyl
pyrimidine (e.g., 4-vinyl-6-phenethylpyrimidine).
[0460] Examples of compound of the formula: R.sup.5NH.sub.2 include
amine as used in Process A 1.
[0461] Examples of reaction solvent include alcohol (e.g.,
methanol, ethanol). 153
[0462] (wherein, Y, Z, R.sup.5, n are the same as above; R is of
the formula: --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein,
Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are the same as above) or a
non-interfering substituent)
[0463] Process C
[0464] This process is for condesing compound of the formula (C)
with compound of the formula: R--C(.dbd.O)--NH--NH.sub.2 to give
compound of the formula (D). Y is preferably protected in
advance.
[0465] Examples of compound of the formula (C) include
2,5-dihydro-1-isopropyl-5-oxo-4-hydroxy-1H-pyrrole-3-carboxylic
acid, and examples of its protected type include
2,5-dihydro-1-isopropyl-5-oxo-4-me- thoxy-1H-pyrrole-3-carboxylic
acid.
[0466] Examples of compound of the formula:
R--C(.dbd.O)--NH--NH.sub.2 include acetyl hydrazine (e.g.,
phenylacetyl hydrazine, p-fuluorophenylacetyl hydrazine). Examples
of condensing agent include DCC (dicyclohexylcarbodiimide), WSCD
(1-ethyl-3-(3-dimethylaminopropyl)ca- rbodiimide), HOBt
(1-hydroxybenzotriazole).
[0467] Examples of reaction solvent include tetrahydrofran,
dimethylformamide.
[0468] Process D
[0469] This process is for halogenating compound of the formula
(D), followed by treating with a base, to give compound of the
formula (I-B).
[0470] Halogenation can be conducted by reacting compound of the
formula (D) with bromine or the like in the presence of
triphenylphosphine.
[0471] Examples of base include triethylamine.
[0472] Examples of reaction solvent include methylene chloride.
[0473] In Process C and D where Y is protected in advance,
deprotection of Y can be conducted by reacting trimethylsilil
chloride in the presence of NaI in acetonitrile. 154
[0474] (wherein, R.sup.5, Y, Z, n, R.sup.B and H a 1 are the same
as defined above. R.sup.B is optionally substituted with a group of
the formula: --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein,
Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are the same as above) and/or
a non-interfering substituent.)
[0475] Process E 1
[0476] This process is for reacting compound of the formula (E1)
with compound of the formula: R.sup.5NH.sub.2 to give compound of
the formula (F1), according to Process A 1.
[0477] Process F
[0478] This process is for reacting compound of the formula (F1)
with compound of the formula:
L.sup.1--C(.dbd.Y)--C(.dbd.Z)--L.sup.2 in the presence of a base to
give compound of the formula (I-C), according to Process B. 155
[0479] (wherein, R.sup.B, R.sup.5 and X are the same as defined
above)
[0480] Process E 2
[0481] This process is for reacting compound of the formula (E2)
with compound of the formula: R.sup.5NH.sub.2 to give compound of
the formula (F), according to Process A 3. 156
[0482] (wherein, n, R.sup.5, X, R.sup.B, H a 1 and Y are the same
as above; L is a leaving group)
[0483] Process G 1
[0484] This process is for reacting compound of the formula (G1)
with compound of the formula: R.sup.5NH.sub.2 to give compound of
the formula (H1), according to Process E1
[0485] Process H
[0486] This process is for reacting compound of the formula (H1)
with compound of the formula R.sup.BLi to give compound of the
formula (H1). The amino group in the formula (H1) is preferably
protected in advance.
[0487] Examples of compound of the formula (H1) include
3-alkylamino propanic acid methylmethoxyamide (e.g., 3-methylamino
propanic acid methylmethoxyamide, 3-ethyl amino propanic acid
methylmethoxyamide, 3-n-propylamino propanic acid
methylmethoxyamide, 3-n-butylamino propanic acid
methylmethoxyamide, 3-ethyl propylamino propanic acid
methylmethoxyamide, 3-tert-butylamino propanic acid
methylmethoxyamide), 3-cycloalkyl amino propanic acid
methylmethoxyamide (e.g., 3-cyclopropylaminopropanic acid
methylmethoxyamide, 3-cyclopentylaminopropanic acid
methylmethoxyamide, 3-cyclohexylaminopropanic acid
methylmethoxyamide), 3-alkoxyaminopropaanic acid methylmethoxyamide
(e.g., 3-(2-methoxyethyl amino)propanic acid methylmethoxyamide),
3-alkenyl amino propanic acid methylmethoxyamide (e.g.,
3-allylamino propanic acid methylmethoxyamide),
3-heterocyclealkylamino propanic acid methylmethoxyamide (e.g.,
3-pyrrolidil propanic acid methylmethoxyamide, 3-morpholil ethyl
propanic acid methylmethoxyamide). Examples of its protected type
include compounds wherein the amino group is protected with Boc
group (tert-butoxycarbonyl). The protection can be conducted by
reacting compound of the formula (H1) with Boc.sub.2O in an alcohol
(e.g., methanol, ethanol).
[0488] Examples of compound of the formula: R.sup.BLi include
5-(p-fluorobenzyl)fran-2-yllithium. Compound of the formula:
R.sup.BLi can be prepared by reacting compound of the formula:
R.sup.BBr with butyl lithium.
[0489] Process J
[0490] This process is for reacting compound of the formula (J)
with compound of the formula:
L.sup.1--C(.dbd.Y)--C(.dbd.Z)--L.sup.2 in the presence of a base to
give compound of the formula (I-D), according to Process B and
Process F. 157
[0491] (wherein, L, R.sup.5 and X are the same as defined
above)
[0492] Process G2
[0493] This process is for reacting compound of the formula (G2)
with compound of the formula: R.sup.5NH.sub.2 to give compound of
the formula (H2), according to Process A 3 and Process E 2. 158
[0494] (wherein, X is O; Y is hydroxy; Z is O; R.sup.6,
R.sup.7,R.sup.5 and R.sup.19 are non-interfering substituents; L is
a leaving group; R.sup.B, Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are
the same as above (1))
[0495] Process K
[0496] This process is for reacting compound of the formula (K)
with compound of the formula: R.sup.5NH.sub.2 and compound of the
formula: R.sup.19CHO to give compound of the formula (III),
according to Zhurnal Orgarncheskoi Khimii, Vol. 22, No. 8, pp.
1749-1756.
[0497] Examples of compound of the formula (K) include that
wherein, R.sup.B is optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl, or optionally substituted
heterocycle, such as 2-hydroxy-4-oxo4-aryl-2-butenic acid alkyl
ester, 2-hydroxy-4-oxo4-hetero- aryl-2-butenic acid alkyl ester,
2-hydroxy-4-oxo4-cycloalkyl-2-butenic acid alkyl ester,
2-hydroxy-4-oxo-4-cycloalkenyl-2-butenic acid alkyl ester,
2-hydroxy-4-oxo4-heterocycle-2-butenic acid alkyl ester wherein the
aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycle are
substituted with a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.s- up.1(wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as defined above). Examples
thereof include 4-(4-benzyloxybenzyl)-2-hydroxy-- 4-oxo-2-butenoic
acid methylester, 4-[4-(4-fluorobenzyloxy)benzyl]-2-hydro-
xy-4-oxo-2-butenoic acid methylester,
4-(5-benzylfran-2-yl)-2-hydroxy-4-ox- o-2-butenoic acid
methylester, 4-[5-(4-fluorobenzyl)fran-2-yl]-2-hydroxy-4-
-oxo-2-butenoic acid methylester. These compounds can be prepared
according to the method described in WO0/39086.
[0498] Examples of compound of the formula: R.sup.5NH.sub.2 include
alkylamine (e.g., methylamine, ethyl amine, n-propylamine,
isopropylamine, n-butylamine, tert-butylamine, 2-ethyl propyl),
cycloalkylamine (e.g., cyclohexylamine), arylamine (e.g., aniline),
alkoxyamine (e.g., tert-butoxyamine), aralkylamine (e.g.,
benzylamine). Compound of the formula: R.sup.5NH.sub.2 may be used
in an amount of 1 to 3 mol equivalent, preferably 1 to 2 mol
equivalent per compound of the formula (K).
[0499] Examples of compound of the formula: R.sup.19CHO include
optionally substituted arylaldehyde(e.g., benzaldehyde), optionally
substituted heteroaryl aldehyde(e.g., furfural), alkylaldehyde
(e.g., acetoaldehyde), alkenylaldehyde, cycloalkyl aldehyde (e.g.,
cyclopropylaldehyde, cyclohexylaldehyde), formaldehyde and/or
polymer thereof (formalin aqueous solution can be used.).
[0500] Compound of the formula: R.sup.19CHO can be used in an
amount of 1 to 3 mol equivalent, preferably 1 to 2 mol equivalent
per compound of the formula (K).
[0501] Examples of leaving group include alkoxy.
[0502] The reaction temperature is O.degree. C. to 100.degree. C.,
preferably room temperature to 50.degree. C., more preferably room
temperature to 30.degree. C.
[0503] Examples of reaction solvent include dioxane, ethanol,
dimethylformamide, tetrahydrofran, acetonitrile, or a mixture
thereof. Preferred is dioxane. This process may be conducted in the
presence of a base. This process is conducted for example as
follows. To a solution or suspension of compound of the formula (K)
in an organic solvent, were added compound of the formula:
R.sup.5NH.sub.2 and compound of the formula: R.sup.19CHO
succesively or simultaneously, and the mixture was stirred for
several hours (preferably, 0.5 to 24 hours, more preferably 0.5 to
5 hour) at room temperature to 50.degree. C. The reaction mixture
was added to dil. hydrochloric acid, which was extracted with an
organic solvent such as ethyl acetate, washed with saturated
saline, dried, and evaporated under reduced pressure to give
crystals of compound of the formula (III). Alternatively, addition
of an organic solvent such as methanol or aether can give the
crystal of compound of the formula (III). In case such a crystal
can not obtained, purification with silica gel chromatography gives
compound of the formula (111). In addition, the adding order of
each compound of the formula R.sup.5NH.sub.2, formula: R.sup.19CHO
and the formula (K) is optional.
[0504] In this process, the present invention compound of the
formula (III) can be readily prepared. Compound of the formula:
R.sup.5NH.sub.2 or R.sup.19CHO can be synthesized or commrcially
available.
[0505] This process can be conducted by the method used in the
combinatorial chmistry (e.g., parallel synthesis). For example, to
each well of a plate with 96 holes, are added an organic solvent
(e.g., dioxane), compound of the formula (K), compound of the
formula: R.sup.5NH.sub.2 and compound of the formula: R.sup.19CHO,
which is shaken at room temperature to 50.degree. C., then
evaporated to remove the organic solvent to give a library of
compounds of the formula (III). In this process, generation of
by-products can be controled at low level, thus the evaporation of
the used organic solvent readily give an sample for the
bioassay.
[0506] This process can be conducted as a routine work, thus useful
for preparing lots of compounds having various substituents in a
short period of time. Namely, reaction of various kinds of
compounds of the formula (K), the formula: R.sup.5NH.sub.2 and the
formula: R.sup.19CHO, each basic structure being fixed, gives
several ten to several ten thousands of compounds, from which a
compound having the most suitable substituent is selected to give a
compound of the present invention with high activity.
[0507] The library of the present invention compound can consists
of 2 or more compounds obtained by the above method. The library
means a group consisting of 2 or more compounds having a commomn
partial structure. Examples of the commomn partial structure
include a pyrrolinone structure. The pyrrolinone structure is
preferably substituted with hydroxy and a group of the formula:
--C(.dbd.O)--R.sup.B--Z.sup.1--Z.sup.- 2--Z.sup.3--R.sup.1. A
compound having such a commomn partial structure possesses an HIV
integrase inhibitory activity and a library consisting of such
compounds is useful for screening an anti-HIV agent, AIDS-treating
agent etc., as well as other medicines. In orer to obtain a
particularly useful information on Structure Activity Relationship
(SAR), the library is a group preferably consisting of 10 or more
compounds, more preferably 50 or more. The library of the present
invention comprises at least one compound of the present invention.
Thus, a compound included in the library is very useful for
screening a compound possessing a potent HIV integrase inhibitory
activity.
[0508] A preferable starting material is of the formula (K):
159
[0509] (wherein, X is O; Y is hydroxy; Z is O; R.sup.B is
heteroaryl; R.sup.B is not substituted with R.sup.1 and R.sup.7; L
is alkoxy; Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is alkylene;
R.sup.1 is optionally substituted phenyl)
[0510] A more preferable starting material of the formula (K) is a
compound wherein X is O; Y is hydroxy; Z is O; R.sup.B is
heteroaryl; R.sup.B is not substituted with R.sup.1 and R.sup.7Lis
alkoxy; Z.sup.1 and Z.sup.3 are bonds; Z.sup.2 is methylene;
R.sup.1 is 4-fluorophenyl. Further preferred is
4-[5-(4-fluorobenzyl)fran-2-yl]-2-hydroxy-4-oxo2-but- enoic acid
alkyl ester.
[0511] For use to the production of the present compound, the
following compounds of the formula: R.sup.5NH.sub.2 or R.sup.19CHO
can be selected from commercially available amine and aldehyde with
reference to molecular weight thereof. Compound of the formula:
R.sup.1NH.sub.2 can-be selected from amine shown below:
[0512] cyclopropylamine, cyclobutylamine, cyclopentylamine,
cycloroleucine, cyclohexylamine, 1-aminocyclohexan carboxylic acid,
1-etynylcyclohexylamine, 1,2-diaminocyclohexan,
2-methylcyclohexylamine, 2,3-dimethylcyclohexylamine,
4-methylcyclohexylamine, amino methylcyclohexan, 1,3-cyclohexan
bis(methylamine), 1-amino-5,6,7,8-tetrahydronaphthalene,
1,2,3,4-tetrahydro-1-naphthylamine- , cycloctylamine,
2-amino-1-propene-1,1,3-tricarbonitryl, diaminomaleonitryl,
S-methyl L-cystein, L-aspartic acid, L-leucine, DL-homoserine,
D-methionine, L-allylglycine, L-glutamic acid,
2-amino-1,3,4-thiadiazole, 2-amino-5-mercapto-1,3,4-thiadiazole,
2-amino-5-ethyl-1,3,4-thiadiazole,
3,5-dimethylpyrazole-1-carboamide, 5-amino-3-methylisoxazole,
3-amino-5-methylisoxazole, 2-(2-aminoethyl)-1-methylpyrrolidine,
1-(2-aminoethyl)pyrrolidine, 1-(3-aminopropyl)-2-pyrrolidinone,
furfurylamine, 1-amino indan, 5-aminoindan, 1-naphthylamine,
2-naphthylamine, cycloheptylamine, D-tert-leucine, DL-valine,
DL-isoleucine, D-serine, guanidoacetic acid, creatine,
D-allothreonine, 2-amino-2-methyl-1,3-propanediol,
tris(hydroxymethyl)aminomethane, DL-2-amino-3-methyl-1-nutaol,
L-isoleucinol, D-leucinol, L-methioninol, DL-penicilamine,
DL-cysteine, DL-homocysteine, 1-acetyl-3-thiosemicarbazide,
1-acetyl-2-thiourea, N-methylthiourea, ethyl thiourea,
allylthiourea, dithioxamide, histamine, 3-amino-1,2,4-triazole,
3-amino-5-mercapto-1,2,4-triazole,
3-amino-5-methylthio-1,2,4-triazole, 3,5-diamino-1,2,4-triazole,
3-aminopyrazole, 3-amino-4-cyanopyrazole,
3-aminopyrazole-4-carboxylic acid, L-prolineamide,
2-amino-2-thiazoline, 2-amino thiazole, 2-amino-5-nitrothiazole,
2-amino-4-methylthiazole, D-cyclo serine, tetra hydrofurfurylamine,
2-aminopurine, 2-aminobenzimidazole, 5-aminoindole, 4-amino
pyrazolo [3,4-D]pyrimidine, 6-aminoindazole, 8-azaadenine,
3,4-methylenedioxyaniline, N-(2-aminoethyl)piperazine,
nipecotamide, 4-(aminomethyl)piperidine, 5-aminouracil,
5-azacytosine, cytosine, 5-fluorocytosine,
4-amino-2,6-dihydroxypyrimidine, 2-amino pyrimidine,
2-amino-4-chloro-6-methylpyrimidine,
2-amino-4,6-dihydroxypyrimidine,
2-amino-4-hydroxy-6-methylpyrimidine,
4-chloro-2,6-diaminopyrimidine, 2,4-diamino-6-hydroxypyrimidine,
2,4,6-triaminopyrimidine, 2-amino-4-methylpyrimidine,
2-amino-4,6-dimethylpyrimidine, 2-amino-5-nitropyrimidine,
4-aminopyrimidine, 4,5-diaminopyrimidine,
4,5-diamino-6-hydroxypyrimidine, pyrazineamide, aminopyrazine,
3-aminopyrazine E-2-carboxylic acid, 4-(2-aminoethyl)morpholine,
N-(3-aminopropyl) morpholine, nicotinamide N-oxide,
3-amino-2-chloropyridine, 5-amino-2-chloro pyridine,
5-amino-2-methoxypyridine, 3-hydroxypicolineamide, 2-aminopyridine,
2-amino-3-nitropyridine, 2-amino-3-hydroxypyridine,
2-aminonicotinic acid, 2,3-diamino pyridine,
2-amino-3-methylpyridine, 2-amino-4-methylpyridine,
2-amino-4,6-dimethylpyridine, 2-amino-5-chloropyridine,
2-amino-5-nitropyridine, 6-aminonicotinic acid,
6-aminonicotinamide, 2-amino-5-methylpyridine, 2,6-diamino
pyridine, 2-amino-6-methylpyridine, 6-methylnicotinamide,
2-(aminomethyl)pyridine, 2-(2-aminoethyl)pyridine, nicotinamide,
thionicotinamide, 3-aminopyridine, 3,4-diaminopyridine,
3-(aminomethyl)pyridine, isonicotinamide, 4-aminopyridine,
4-(aminomethyl)pyridine, 3-amino-1,2,4-triazine,
3-amino-5,6-dimethyl-1,2,4-triazine, 1-(2-aminoethyl)piperidine,
3-aminoquinoline, 5-aminoquinoline, 6-aminoquinoline,
8-aminoquinoline, 5-aminoisoquinoline, nitroguanidine, cyanamide,
thiosemicarbazide, aniline, 2-aminobenzonitryl, 2-fluoroaniline,
2,4-difluoroaniline, 2,4,5-trifluoroaniline,
2,4,6-trifluoroaniline, 2,5-difluoroaniline,
2-fluoro-5-methylaniline, 2,6-difluoroaniline,-2-chloroaniline,
2-chloro-4-methylaniline, 2-chloro-5-methylaniline,
2-chloro-6-methylaniline, O-nitroaniline, O-anisidine,
O-phenetidine, 2-aminophenol, 6-amino-m-cresol,
2-amino-4-chlorophenol, 2-amino-4-methylphenol, 2-aminothiophenol,
2-(methylthio)aniline, anthranilic acid, 2'-aminoacetophenone,
2-isopropenylaniline, 2-isopropylaniline, o-phenylenediamine,
3,4-diaminotoluene, 4,5-dimethyl-1,2-phenylenediamine, o-toluidine,
2,3-dimethylaniline, 4-methoxy-2-methylaniline,
2,4-dimethylaniline, 2,4,6-trimethylaniline, 2,5-dimethylaniline,
2-isopropyl-6-methylaniline, 2,6-dimethylaniline, 2-aminobenzyl
alcohol, 2-ethylaniline, 2-ethyl-6-methylaniline,
2,6-diethylaniline, 2-aminophenetyl alcohol, 3-amino benzonitryl,
3-fluoroaniline, 3-fluoro-o-anisidine, 3-fluoro-2-methylaniline,
3,4-difluoroaniline, 3-fluoro-4-methylaniline, 3,5-difluoroaniline,
5-fluoro-2-methylaniline, 3-chloroaniline,
3-chloro-2-methylaniline, 3-chloro-4-fluoroaniline,
3-chloro-4-methylaniline, 5-chloro-2-methylaniline, m-nitroaniline,
m-anisidine, m-phenetidine, 3-aminophenol, 3-amino-o-cresol,
3-aminothiophenol, 3-(methylthio)aniline, 3-aminobenzoic acid,
3-amino acetophenone, 3-(1-hydroxyethyl)aniline,
m-phenylenediamine, 2,6-diaminotoluene, 2,4-diaminotoluene,
m-toluidine, 3,4-dimethylaniline, 3,5-dimethylaniline,
2-methoxy-5-methylaniline, 3-aminobenzyl alcohol, 3-ethylaniline,
4-aminobenzonitryl, 4-fluoro aniline, 4-fluoro-2-methylaniline,
4-chloroaniline, 4-chloro-2-methylaniline, p-nitro aniline,
N,N-dimethyl-p-phenylenediamine, p-anisidine, p-phenetidine,
4-amino phenol, 4-amino-m-cresol, 4-amino-2,5-dimethylphen- ol,
4-amino-o-cresol, 4-amino thiophenol, 4-(methylthio)aniline,
4-aminobenzoic acid, 4-aminoacetophenone, 4-tert-butylaniline,
4-isopropylaniline, p-phenylenediamine, p-toluidine, 4-amino
phenylacetonitrile, 4-ethylaniline, 4-aminophenetyl alcohol,
4-propylaniline, 4-N-butylaniline, formamide, hydroxyurea,
phenylurea, cyanoacetylurea, methylurea, ethylurea, arylurea,
N-butylurea, N,N-dimethylurea, 1,1-diethylurea, phenylcarbamate,
tert-butylcarbamate, methylcarbamate, ethylcarbamate,
butylcarbamate, benzamide, 2-fluorobenzamide, salicylamide,
2-aminobenzamide, O-toluamide, 3-fluorobenzamide, 3-aminobenzamide,
m-toluamide, 4-fluorobenzamide, 4-hydroxybenzamide,
4-aminobenzamide, p-toluamide, ethyl oxamate, oxamide,
2,2,2-trifluoroacetamide, trimethylacetamide,
2,2-dichloroacetamide, 2-chloropropionamide, lactamide,
methacrylamide, isobutylamide, urea, acetamide, cyano acetamide,
2-bromo acetamide, fluoroacetamide, 2-chloroacetamide,
N-acetylglycineamide, acrylamide, cinnamamide, malonamide,
propioneamide, 3-chloropropioneamide, 2-aminoisobutanoic acid,
tert-butylamine, 2-amino-2-methyl-1-propanol, tert-octylamine,
1,2-diamino-2-methylpropane, tert-amylamine,
1,1-diethylpropargylamine, thiobenzamide, (R)-(-)-2-phenylglycinol,
thiourea, DL-.alpha.-methylbenzylamine, thioacetamide,
3-aminocrotonitryl, methyl-3-aminocrotonate, ethyl
3-aminocrotonate, D-alanine, 1,2-dimethylpropylamine,
isopropylamine, 2-amino-1-methoxypropane, DL-2-amino-1-propanol,
ethyl 3-aminobutylate, DL-3-amino-n-butanoic acid,
1,3-dimethylbutylamine, 1,2-diaminopropane,
1-methyl-3-phenylpropylamine, 2-amino-6-methylhaptane,
DL-2-aminobutanoic acid, sec-butylamine, (+/-)-2-amino-1-butanol,
3-aminopentan, D-norvaline, D-norleucine, 2-aminoheptane,
2-aminooctane, methylamine, benzylamine, 2-fluorobenzylamine,
2-chlorobenzylamine, 2-methoxybenzylamine, 2-methylbenzylamine,
3-fluorobenzylamine, 3-methoxybenzylamine, 3-methylbenzylamine,
m-xylendiamine, 4-fluorobenzyl amine, 4-chlorobenzylamine,
4-methoxybenzylamine, 4-methylbenzylamine, glycine,
2,2,2-trifluoroethylamine, aminoacetoaldehyde dimethyl acetal,
aminoacetoaldehyde diethyl acetal, 2-amino-1-phenylethanol,
DL-isoserine, 1-amino-2-propanol, 3-amino-1,2-propanediol,
DL-4-amino-3-hydroxybutanoic acid, 1,3-diamino-2-hydroxypropane,
2-phenylpropylamine, DL-3-amino isobutanoic acid, isobutylamine,
2-methylbutylamine, 2-ethylhexylamine, ethylamine,
N-phenylethylenediamine, N-acetylethylenediamine,
N-isopropylethylenediamine, N-methylethylenediamine,
N-ethylethylenediamine, 2-(2-aminoethylamino)ethanol,
diethylenediamine, N-(n-propyl)ethylenediamine,
N,N-dimethylethylenediamine, N,N-diethylethylenediamine,
tris(2-aminoethyl)amine, 2-methoxyethylamine,
2-(2-aminoethoxy)ethanol, ethanolamine, phenetylamine, thyramine,
2-(4-aminophenyl)ethylamine, 2-(p-tri l)ethylamine, taurine,
propargylamine, allylamine, .beta.-alanine, 3,3-dimethylbutylamine,
isoamylamine, ethylene diamine, propylamine,
N-isopropyl-1,3-propane diamine, N-methyl-1,3-propanediamine,
N-(2-aminoethyl)-1,3-propanediamine- , N-propyl-1,3-propanediamine,
3,3'-diaminodipropylamine, N,N-dimethyl-1,3-propanediamine,
N,N-bis(3-aminopropyl)methylamine, N,N-diethyl-1,3-propanediamine,
3-isopropoxypropylamine, 3-ethoxypropylamine, 3-amino-1-propanol,
3-phenylpropylamine, 4-aminobutanoic acid, 1,3-diaminopropane,
4-amino-1-butanol, 4-phenylbutylamine, 5-aminovalerianic acid,
1,4-diaminobutane, N-amylamine, 5-amino-1-pentanol, 6-aminocaproic
acid, 1,5-diaminopentane, hexylamine, 6-amino-1-haxanol,
7-aminoheptanoic acid 1,6-hexandiamine, n-heptylamine,
1,7-diaminoheptane, octylamine, 1,8-diaminooctane, nonylamine,
cyclohexancarboamide, 2,2-dimethyl-1,3-propanediamine,
2-n-propylaniline, DL-2-amino-1-pentanol, DL-2-amino-1-haxanol,
1-(3-aminopropyl)imidazole, p-xylendiamine,
1-aminocyclopropane-1-carboxy- lic acid, cyanothioacetamide,
2,4-difluorobenzylamine, 2,5-difluorobenzyl amine,
2,6-difluorobenzylamine, 3,4-difluorobenzylamine,
2-methyl-3-thiosemicarbazide, 5-amino-2-methoxyphenol,
4-sec-butylaniline, 2,3-difluoroaniline, thiophene-2-carboamide,
1-amino-1-cyclopentanmethanol, 3-methyladenine, 1-methyladenine,
4-chloro-2-fluoroaaniline, 5-amino-1-ethylpyrazole,
2,3-diaminotoluene, butylamine, 4-chloro-o-phenylenediamine,
1-(trimethylsilylmethyl)urea, 2,3,4-trifluoroaaniline,
2-(1-cyclohexenyl)ethylamine, 3-amino-2-butenethioamide,
2,3,6-trifluoroaniline, 1,5-diamino-2-methylpentane,
amidinothiourea, 3-ethynylaniline,
N,N-bis(2-hydroxyethyl)ethylenediamine, 3-methoxypropylamine,
4-aminostyrene, 2-amino-6-fluorobenzonitryl,
3,-amino-5-hydroxypyrazole, 2,4-diamino-6-methyl-1,3,5-triazine,
pyridine-2-carboamide, 1-aminoisoquinoline,
4-chloro-1,3-phenylenediamine, 2-chloroethylcarbamate, fumaramide,
acetoamide, N-N-butylethylenediamine, 3-butoxypropylamine,
cyclopropanemethylamine, 5-aminoindazole, 2,4-diamino pyrimidine,
a-ethylbenzylamine, 3-aminoisoxazole, chlorodifluoroacetamide,
1,8-diamino-3,6-dioxaoctane, 2-sec-butylaniline,
3-chlorobenzylamine, 2-fluoro-4-methylaniline,
1-(4-fluorophenyl)ethylami- ne, 4-aminophthaloitrile, adenine,
2-chloro-4-fluoroaniline, semicarbazide,
(R)-(-)-1-cyclohexylethylamine, 5-amino-o-cresol,
N,N,2,2-tetramethyl-1,3-propanediamine, 2,2-diethoxyacetamide,
3-amino-5,5-dimethyl-2-cyclohexene-1-one, propylcarbamate,
glycolamide, 2-amino-1,3-propanediol, thiophene-2-ethylamine,
2,5-dimethyl-1,4-phenyle- nediamine,
2-amino-4-methoxy-6-methyl-1,3,5-triazine, 2-phenoxyethylamine,
4-amino-2-mercaptopyrimidine, creatinine,
2-amino-4-methoxy-6-methylpyrim- idine, 3,5-difluorobenzylamine,
(1R, 2R)-(-)-1,2-diamino cyclohexan, (1S,2S)-(+)-1,2-diamino
cyclohexan, D-aspartic acid, DL-aspartic acid, DL-leucine,
D-leucine, L-homoserine, DL-methionine, L-methionine,
DL-allylglycine, D-glutamic acid, L-leucinol, DL-threonine,
cis-1,2-diamino cyclohexan, trans-1,2-cyclohexandiamine,
L-tert-leucine, D-valine, L-valine, D-iso leucine, L-iso leucine,
DL-serine, L-serine, L-allothreonine, D-threonine, L-threonine,
L-valinol, D-valinol, L-cysteine, DL-cycloserine, L-cycloserine,
L-asparagine, (S)-(+)-2-phenylglycinol, (R)-(+)-1-phenylethylamine,
L-(-)-.alpha.-methylbenzylamine, DL-alanine, L-alanine, L-alaninol,
D-alaninol, D-(-)-2-aminobutanoic acid, L-.alpha.-amino-n-butanoic
acid, (R)-(-)-2-aminobutane, (S)-(+)-2-aminobutane,
(S)-(+)-2-amino-1-butanol, (R)-(-)-2-amino-1-butanol, DL-norvaline,
L-norvaline, DL-norleucine, L-norleucine,
(R)-(-)-1-amino-2-propaanol, (S)-(+)-1-amino-2-propanol,
(S)-(-)-2-methylbutylamine, DL-lysine, L-lysine, DL-tert-leucine,
(S)-(+)-1-cyclohexylethylamine, ethyl thiooxamate,
2-amino-5-methylbenzyl alcohol, 2-amino-3-methylbenzyl alcohol,
3-amino-2-methylbenzyl alcohol, 3-fluoro-4-methoxyaniline,
3-amino-4-methylbenzyl alcohol, 5-methoxy-2-methylaniline,
2-amino-m-cresol, trans-1,4-diaminocyclohexan,
3-amino-5-methylpyrazole, 2,3-diaminophenol,
1-piperidinecarboamide, 6-amino-1-methyluracil,
3-fluorophenetylamine, 2-aminobenzylamine,
2-methoxy-6-methylaniline, 2-fluorophenetylamine,
4-aminobenzylamine, 1-acetylguanidine, D-homoserine,
2-amino-5-methylthiazole, (S)-(+)-tetrahydrofurfurylamine, 2-amino
benzylcyanide, 4-amino-2-chlorophenol,
2-amino-4,5-dicyanoimidazole, 4-amino-6-methoxypyrimidine,
2-tert-butylaniline, 2-(4-fluorophenyl)ethyl- amine, 1,3-diamino
pentane, 2-amino-1-methylbenzimidazole, 5-methylfurfurylamine,
(R)-(+)-1-(p-tril)ethylamine, (S)-(-)-1-(p-tril)ethylamine,
3-amino-1,2,4-triazole-5-carboxylic acid, muscimol,
4-ethynylaniline, 2-amino-4-methylbenzonitryl,
2-amino-5-methylthio-1,3,4-thiadiazole,
1-(aminocarbonyl)-1-cyclopropanec- arboxylic acid, cis-4-amino
cyclohexancarboxylic acid, (S)-(+)-2-(aminomethyl)pyrrolidine,
5-amino-4-nitro imidazole, 3-amino-1-propanol vinyl aether,
thioethylenediamine, isopropyldiethylene triamine, L-tert-leucinol,
N-methyl-1,2-phenylenediamine, (R)-(-)-tetra hydrofurfurylamine,
L-(-)-lactamide, (R)-(+)-lactamide,
(S)-(+)-2,2-dimethylcyclopropanecarboamide, (1S,
2R)-(-)-cis-1-amino-2-in- danol, (1R,2S)-(+)-cis-1-amino-2-indanol,
(R)-(-)-1-aminoindane, (S)-(+)-1-aminoindane,
(R)-2-phenyl-1-propylamine, (S)-2-phenyl-1-propylamine,
D-methioninol, (R)-2-amino-1-phenylethanol,
2-amino-4,5-dimethyl-3-furancarbonitrile, N-hexylethylenediamine,
(S)-(-)-4-amino-2-hydroxybutanoic acid, (S)-3-amino-1,2-propandiol,
(R)-3-amino-1,2-propandiol, 4-aminoindole, (R)-(-)-tert-leucinol
and 2-amino-5-fluoro pyridine.
[0513] Compound of the formula: R.sup.19CHO can be selected from
aldehyde shown below. formaldehyde, ethyl
2-formyl-1-cyclopropancarboxylate, cyclohexancarboaldehyde,
1,2,3,6-tetrahydrobenzaldehyde, 1-methylpyrrole-2-carboaldehyde,
furfural, 5-nitro-2-fulaldehyde, 5-methylfurfural,
5-hydroxymethyl-2-fulaldehyde, 3-(2-furyl)acrolein, benzaldehyde,
2-fluorobenzaldehyde, 2-chlorobenzaldehyde, o-anisealdehyde,
salicylaldehyde, 3-fluoro-2-hydroxybenzaldehyde,
2,3-dihydroxybenzaldehyde, 2,5-dihydroxybenzaldehyde,
o-naphthalaldehyde, o-tolaldehyde, 2,4-dimethylbenzaldehyde,
mesitaldehyde, 2,5-dimethylbenzaldehyde, 3-cyano benzaldehyde,
3-fluorobenzaldehyde, 3-chlorobenzaldehyde, 3-methoxybenzaldehyde,
3-hydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde,
isonaphthalaldehyde, m-tolaldehyde, 4-cyanobenzaldehyde,
4-fluorobenzaldehyde, 4-chlorobenzaldehyde,
4-dimethylaminobenzaldehyde, p-anisealdehyde,
imidazole-2-carboaldehyde, pyrrole-2-carboaldehyde,
2-thiophenecarboaldehyde, 3-methylthiophene-2-carboaldehyde,
5-methyl-2-thiophenecarboaldehyde, 3-thiophenecarboaldehyde,
indole-3-carboaldehyde, 2-pyridinecarboaldehyde- ,
6-methyl-2-pyridinecarboaldehyde, 3-pyridinecarboaldehyde,
4-pyridinecarboaldehyde, 4-hydroxybenzaldehyde,
terenaphthalaldehyde, cuminaldehyde, p-tolaldehyde,
4-ethylbenzaldehyde, glyoxal, glyoxalic acid, methylglyoxal,
trimethylacetoaldehyde, D-(-)-erythrose, 2-phenylpropionaldehyde,
methacrolein, 3-ethoxy methacrolein, alpha-methylcinnamaldehyde,
trans-2-methyl-2-butenal, 2-methyl-2-pentenal, isobutylaldehyde,
2,6-dimethyl-5-hepten-1-al, 2-methylbutylaldehyde,
2-ethylbutylaldehyde, 2-methylpental, 2-ethylhaxal, acetoaldehyde,
chloroacetoaldehyde, phenylacetoaldehyde, phenylpropargylaldehyde,
acrolein, 3-(dimethylamino)acrolein, trans-cinnamaldehyde,
crotonaldehyde, 2,4-haxadienal, trans,trans-2,4-heptadienal,
trans,trans-2,4-nonadienal, trans-2-hexanal,
trans-2,cis-6-nonadien-1-al, trans-2-heptanal, trans-2-octanal,
trans-2-nonenal, isovaleraldehyde, propionaldehyde,
3-phenylpropionaldehyde, 3-(methylthio)propionaldehyde,
butylaldehyde, glutaraldehyde, valeraldehyde, haxanal,
heptaldehyde, octanal, nanal, trans-2-pentenal,
2,4-dimethyl-2,6-heptadienal, 2,6-pyridinedicarboaldehy- de,
2-ethylacrolein, 3-methyl-2-butenal, 2,3-difluoro benzaldehyde,
2,6-difluorobenzaldehyde, 2,4-difluorobenzaldehyde, 2,5-difluoro
benzaldehyde, 3,4-difluorobenzaldehyde, 3,5-difluorobenzaldehyde,
3-fulaldehyde, 3,5,5-trimethylhaxanal, 3-phenylbutylaldehyde,
2,2-dimethyl-4-pentenal, 2,4-dihydroxybenzaldehyde,
cyclopropanecarboaldehyde, 4-hydroxy-3-methylbenzaldehyde,
benzo[b]furan-2-carboaldehyde, 3,5-dihydroxybenzaldehyde,
3,4-dimethylbenzaldehyde, 2-cyanobenzaldehyde,
5-ethyl-2-fulaldehyde, 2-hydroxy-3-methylbenzaldehyde,
3,3-dimethylbutylaldehyde, 5-chloro-2-thiophenecarboaldehyde,
3,4-dihydro-2H-pyran-2-carboaldehyde, D-glyceroaldehyde,
DL-glyceroaldehyde, 3-fluoro-2-methylbenzaldehyde,
3-dimethylamino-2-methyl-2-propenal, 3,5-dimethylbenzaldehyde,
4,5-dimethyl-2-furancarboaldehyde, 4-vinylbenzaldehyde,
2,6-dimethylbenzaldehyde, 2-octynal, dimethoxyacetoaldehyde,
2-deoxy-D-ribose, 2-formyl thiazole,
5-ethyl-2-thiophenecarboaldehyde, glyoxylic acid,
4-pyridinecarboaldehyde-N-oxide, 5-norbornen-2-carboaldeh- yde,
4-formylimidazole, 5-methylimidazole-4-carboaldehyde,
5-formyluracil, 2,3-thiophenedicarboaldehyde,
thiophene-2,5-dicarboaldehyde,
2,3-o-isopropylidene-D-glyceroaldehyde,
2-hydroxy-5-methylbenzaldehyde, 1-cyclohexene-1-carboaldehyde,
2,3-dimethylbenzaldehyde, 1-methyl-2-imidazolecarboaldehyde,
vinylbenzaldehyde, 4-fluoro-3-methylbenzaldehyde,
3-fluoro-4-methylbenzaldehyde, tetrahydrofran-3-carboaldehyde,
2-fluoro-5-formyl benzonitryl, indole-5-carboaldehyde,
4-acetylbenzaldehyde, 3-vinylbenzaldehyde and
2-fluoro-5-methylbenzaldehyde. 160
[0514] (wherein, C ring, Z and Y are the same as above; benzene
ring and/or C ring of the formula (L) and/or (IV) are optionally
substituted with a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above) and/or a non-interfering
substituent.)
[0515] Process L
[0516] This process is for reacting compound of the formula (L)
with hydrogen peroxide in the presence of a base to give compound
of the formula (1-F).
[0517] Examples of compound of the formula (L) include
4-(benzyloxy)-2-(1-oxo-3-(2-pyridyl)-2-propenyl)phenol,
4-(p-fluorobenzyloxy)-2-(1-oxo-3-(2-pyridyl)-2-propenyl)phenol,
4-(phenetyloxy)-2-(1-oxo-3-(2-pyridyl)-2-propenyl)phenol,
4-(p-fluoro phenetyloxy)-2-(1-oxo-3-(2-pyridyl)-2-propenyl)phenol,
4-(phenetyl)-2-(1-oxo-3-(2-pyridyl)-2-propenyl)phenol,
4-(p-fluorophenetyl)-2-(1-oxo-3-(2-pyridyl)-2-propennyl)phenol.
[0518] Examples of base include 2N NaOH aq. solution.
[0519] Examples of hydrogen peroxide include 30% hydrogen
peroxide.
[0520] Examples of reaction solvent include alcohol (e.g.,
methanol, ethanol). 161
[0521] (wherein, Y, Z, C ring are the same as above; benzene ring
and/or C ring of the formula (M) or (I-F) is optionally substituted
with a group of the formula: --Z.sup.1--Z.sup.2--Z.sup.3--R.sup.1
(wherein, Z.sup.1, Z.sup.2, Z.sup.3 and R.sup.1 are the same as
above) and/or a non-interfering substituent.)
[0522] Process L2
[0523] This process is for reacting compound of the formula (M)
with a base to give compound of the formula (I-F). Y is preferably
protected in advance. Examples of compound of the formula (M)
include
2-(2-benzoyloxyl-oxoethyl)-3-methoxyphenyl-2-picolilate.
[0524] Examples of base include NaH.
[0525] Examples of solvent include dimethylformamide. 162
[0526] (wherein, W is --O or --N(--R.sup.15)--; L is a leaving
group such as alkoxy; Y, Z and R are the same as defined above)
[0527] Process N
[0528] This process is for reacting compound of the formula (N)
with compound of the formula: R--C(.dbd.O)--NH--NH.sub.2 in the
presence of a condensing agent to give compound of the formula (O).
Y and/or Z is preferably protected in advance. The process may be
conducted as well as Process C.
[0529] Examples of compound of the formula (N) include
3-hydroxy-4-oxo-1H-quinoline-2-carboxylic acid,
3-hydroxy-4-oxo-1-methyl-- 1H-quinoline-2-carboxylic acid,
3-hydroxy-4-oxo-4H-chromene-2-carboxylic acid. Examples of its
protected type include 2-ethoxycarbonyl-3-methoxy-1-
H-quinoline-4-one,
2-ethoxycarbonyl-3-methoxy-1-methyl-1H-quinoline-4-one,
3-benzyloxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester,
3-methoxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester. These
compounds can be prepared according to the method of J.Heterocyclic
Chem, 24, p1649, 1987.
[0530] Process M
[0531] This process is for preparing compound of the formula (I-G)
from compound of the formula (0). The process, oxadiazole ring
formation from diacylhydrazine, can be conducted by heating
diacylhydrazine together with phosphorus oxychloride or thionyl
chloride.
[0532] The reaction temperature is 50 to 100.degree. C., preferably
80 to 100.degree. C.
[0533] The process can also be conducted in the presence of
triethylamine dibromotri phenylphospholan. In this case, the
reaction temperature is 0 to 100.degree. C., preferably 0 to
30.degree. C. The reaction solvents include dichloromethane and
tetrahydrofran.
[0534] Process O
[0535] This process is for halogenating compound of the formula
(N), followed by treating with a base, to give compound of the
formula (I-G), as well as Process O. 163
[0536] (wherein, W is --O or --N(--R.sup.15)--; Y, Z and R are the
same as defined above; the benzene ring of the formula (N) or (O)
is optionally substituted with a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3--R.s- up.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above) and/or a non-interfering
substituent.
[0537] Process P
[0538] This process is for reacting compound of the formula (P)
with compound of the formula: R--C(.dbd.O)--OH in the presence of a
condensing agent to to give compound of the formula (O). Y and Z
are preferably protected in advance. The process can be conducted
as well as Process C and Process N.
[0539] Examples of compound of the formula (P) include
2-hydrazinocarbonyl-3,4-dihydroxyquinoline. Protected types thereof
include 2-hydrazinocarbonyl-3,4-dimethoxyquinoline. 164
[0540] (wherein, R.sup.6, R.sup.7, R.sup.B, R.sup.E, R.sup.F, X and
Y are the same as above; L is a leaving group; Q is a protecting
group; Y.sup.A is O, S or NH.sub.2; R.sup.X is the formula:
--Z.sup.1--Z.sup.2--Z.sup.3-- -R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above))
[0541] Process Q
[0542] This process is for reacting compound of the formula (Q-1)
with compound of the formula (Q-2) to give compound of the formula
(Q-3).
[0543] Examples of compound of the formula (Q-1) include
cyclohexenon which can be prepared by the known method
(Tetrahedron, 1997, 53, p8963).
[0544] Examples of compound of the formula (Q-2) include
furan-2-carboxylic acid halides which can be prepared by the known
method (Zhurnal Organicheskoi Khimii, Vol. 22, No. 8, pp.
1749-1756).
[0545] Examples of reaction solvent include aethers (e.g.,
tetrahydrofran, dioxane) and N,N-dimethylformamide, which can be
used by itself or in combination.
[0546] The process can be conducted in the presence of a base
(e.g., lithium bistri methylsililamide) or an acid (e.g.,
ZnCl.sub.2, TiCl.sub.4, HCl).
[0547] Process R
[0548] This process is for deprotecting compound of the formula
(Q-3) in the presence of an acid to give compound of the formula
(R-1).
[0549] Examples of acid include hydrochloric acid and sulfuric
acid.
[0550] Examples of reaction solvent include aethers (e.g.,
tetrahydrofran, dioxane), alcohols (e.g., methanol, ethanol), which
can be used by itself or in combination. 165
[0551] (wherein, R.sup.9, R.sup.10, R.sup.F, R.sup.G, R.sup.X, and
Y are the same as above Y.sup.A is O, S or NH.sub.2; R.sup.N1 and
R.sup.N2 are alkyl; Q is a protecting group)
[0552] Process S
[0553] This process is for reacting compound of the formula (S-1)
with compound of the formula (S-2) to give compound of the formula
(S-3).
[0554] Examples of compound of the formula (S-1) include pyridine
carboxylic acid which can be prepared from picoline by oxidation
with selenium dioxide and esterfication.
[0555] Examples of compound of the formula (S-2) include protected
2-hydroxyacetic acid esters.
[0556] Examples of reaction solvent include aether (e.g.,
tetrahydrofran, dioxane), N,N-dimethylformamide, which can be used
by itself or in combination.
[0557] The process can be conducted in the presence of a base
(e.g., lithium bistri methylsililamide).
[0558] Process T
[0559] This process is for reacting compound the formula (S-3) with
compound of the formula (T-1) to give compound of the formula
(T-2).
[0560] Examples of compound of the formula (T-1) include
amidines.
[0561] Examples of reaction solvent include alcohol (e.g.,
methanol, ethanol).
[0562] The process can be conducted in the presence of a base
(e.g., sodium methoxide).
[0563] Process U
[0564] This process is for deprotecting compound of the formula
(T-2) to give compound of the formula (U-1).
[0565] Examples of reaction solvent include alcohol (e.g.,
methanol, ethanol), aether (e.g., tetrahydrofran, dioxane), which
can be used by itself or in combination.
[0566] The process can be conducted in the presence of an acid
(e.g., hydrochloric acid, p-toluene sulfonic acid) or by adding
hydrogen.
[0567] Process V
[0568] This process is for reacting compound of the formula (U-1)
with a sulfurizing reagent or an amine to give compound of the
formula (V-1).
[0569] Examples of sulfurizing reagent include Lawson's reagent and
phosphorus pentasulfide.
[0570] Examples of amine include methylamine and morpholine.
[0571] Examples of reaction solvent include aromatichydrocarbon
(e.g., toluene, xylene), aether (e.g., tetrahydrofran, dioxane)
which can be used by itself or in combination. 166
[0572] (wherein, R.sup.5, R.sup.5', R.sup.6, R.sup.7,R.sup.B,
R.sup.X, L, Q, X, Y and Y.sup.A are the same as above)
[0573] Process W
[0574] This process is for reacting compound of the formula (W-1)
with compound of the formula (W-2) to give compound of the formula
(W-3).
[0575] Examples of compound of the formula (W-1) include
pyrazolones.
[0576] Examples of compound of the formula (W-2) include those
exemplified as compound of the formula (Q-2).
[0577] Examples of reaction solvent include aether (e.g.,
tetrahydrofran, dioxane), N,N-dimethylformamide, which can be used
by itself or in combination.
[0578] The process can be conducted in the presence of a base
(e.g., n-butyllithium).
[0579] Process X
[0580] This process is for deprotecting compound of the formula
(W-3) to give compound the formula (Y-1).
[0581] Examples of reaction solvent include alcohol (e.g.,
methanol, ethanol), aether (e.g., tetrahydrofran, dioxane), which
can be used by itself or in combination.
[0582] The process can be conducted in the presence of an acid
(e.g., hydrochloric acid,-toluenesulfonic acid or by adding
hydrogen.
[0583] The present invention compounds can also be prepared
according to the general oraganic synthesis method of heterocyclyl
compounds descrived in literatures e.g., (1) Alan R. Katriszly et
al., Comprehensive Heterocyclic Chemistry, (2) Alan R.Katriszly et
al., Comprehensive Heterocyclic Chemistry 11, (3) RODD'S CHEMISTRY
OF CARBON COMPOUNDS VOLUME IV HETEROCYCLIC COMPOUNDS.
[0584] Introduction of a group of the formula:
--Z.sup.1--Z.sup.2--Z.sup.3- --R.sup.1 (wherein, Z.sup.1, Z.sup.2,
Z.sup.3 and R.sup.1 are the same as above) may be conducted before
or after each of the the above processes, according to the method
of WO 00/39086. 167
[0585] (wherein, R.sup.6, R.sup.7, R.sup.B, R.sup.F, R.sup.G,
R.sup.X, L, Q. X, Y and Z are the same as above)
[0586] Process AA
[0587] This process is for reacting compound of the formula (AA-1)
with compound of the formula (AA-2) in the presence of a base to
give compound of the formula (AA-3).
[0588] Examples of compound of the formula (AA-1) include
Boc-protected pyrrolidine 2-one which can be prepared by the known
method (Tetrahedron Lett., 36, 8949-8952 (1995)).
[0589] The process can be conducted as well as Process H.
[0590] Process AB
[0591] This process is for cyclizing compound of the formula
(AA-3), optionally followed by Retroclaisen Reaction, to give
compound of the formula (AB). The cyclization can be conducted as
well as Process B.
[0592] The Retroclaisen Reaction can be conducted by treating with
a base such as LiOH in a solvent such as tetrahydrofran.
[0593] Process AC
[0594] This process is for reacting compound of the formula (AB)
with compound of the formula: R.sup.5-L (wherein L is a leaving
group) in the presence of a base to give compound of the formula
(AC). The process can be conducted according to the conventional
N-alkylation. For example, compound of the formula (AB) is reacted
with bromoethane etc. in the presence of a base such as potassium
bis(trimethylsilil)amide in a solvent such as tetrahydrofran.
168
[0595] (wherein, R.sup.6, R.sup.7, R.sup.B, R.sup.F, R.sup.G,
R.sup.N1, R.sup.X, L, Q, X, y, Y.sup.A and Z are the same as
above)
[0596] Process BA
[0597] This process is for dehydrating compound of the formula
(BA-1) to give compound of the formula (BA-2).
[0598] Examples of compound of the formula (BA-1) include
5-hydroxy-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl
ester, which can be prepared by the known method (Org. Prep.
Proced. Int., 29, 330-335 (1997)).
[0599] The process can be conducted by treating compound of the
formula (BA-1) with a catalytic amount of paradium carbon in a
solvent such as oxylene.
[0600] Process BB
[0601] This process is for protecting a reactive substituent of
compound of the formula (BA-2) to give compound of the formula
(BB).
[0602] Examples of a protecting group include alkyl and
alkoxyalkyl, which can be introduced by the conventional protection
reaction (Protective Groups in Organic Synthesis, Theodora W.
Greene).
[0603] Process BC
[0604] This process is for converting compound of the formula (BB)
into compound of the formula (BC), according to the method of
Process H and Process AA.
[0605] Process BD and BE
[0606] These processes are for deprotecting compound of the formula
(BC) to give compound of the formula (BD), followed by deprotection
to give compound the formula (BE). Depending on the reaction
conditions, both deprotections can be condcuted at the same time.
These deprotections can be conducted according to the conventional
method (Protective Groups in Organic Synthesis, Theodora W.
Greene). 169
[0607] (wherein, R, R.sup.F, R.sup.G, R.sup.N1, L, Q, X, Y, Y.sup.A
and Z are the same as above)
[0608] Process CA
[0609] This process is for reacting compound of the formula (BB)
with hydrazine to give compound of the formula (CA). The process
can be conducted by reaction with hydrazine in a solvent such as
ethanol.
[0610] Process CB
[0611] This process is for converting compound of the formula (CA)
into compound of the formula (CB) according to the methods of
Process N and Process P.
[0612] Process CC
[0613] This process is for converting compound of the formula (CB)
into compound of the formula (CC) according to the method of
Process M.
[0614] Process CD and CE
[0615] This process is for deprotecting compounds of the formula
(CC) and (CD) according to the method of Process CD and CE. 170
[0616] (wherein, R.sup.6, R.sup.7, B, R.sup.E, R.sup.F, R.sup.N1,
R.sup.X, Q, X, Y, Y.sup.A and Z are the same as above, Z A is O, S
or NH.sub.2)
[0617] Process DA
[0618] This process is for esterifing compound of the formula
(DA-1) to give compound of the formula (DA-2).
[0619] Examples of compound of the formula (DA-1) include
3-hydroxy-4-methoxypyridine-2-carboxylic acid which can be obtained
by the known method (Tetrahedron, 54, 12745-12774 (1998)). The
esterification can be conducted by the conventional method.
[0620] Process DB
[0621] This process is for protecting a reactive substituent of
compound of the formula (DA-2) to give compound of the formula
(DB). The protecting group is preferably alkyl.
[0622] The protection can be conducted according to the
conventional method (Protective Groups in Organic Synthesis,
Theodora W. Greene).
[0623] Process DC
[0624] This process is for converting compound of the formula (DB)
into compound of the formula (DC) according to Process BC.
[0625] Process DD
[0626] This process is for deprotecting compound of the formula
(DC) to give compound of the formula (DD), according to the
conventional method (Protective Groups in Organic Synthesis,
Theodora W. Greene). 171
[0627] (wherein, R.sup.5, R.sup.6, R.sup.7, R.sup.B, R.sup.G,
R.sup.N1, R.sup.X, Q, L, X, Y, Y.sup.A, Z and Z.sup.A are the same
as above, H a 1 is halogen)
[0628] Process EA
[0629] This process is for halogenating compound of the formula
(EA-1) to give compound of the formula (EA-2). Examples of compound
of the formula (EA-1) include
5-methoxy-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid
methyl ester which can be obtained by the known method
(WO92/02523). The halogenation can be conventionally conducted, for
example, compound of the formula (EA-1) is heated in phosphorus
oxychloride.
[0630] Process EB
[0631] This process is for substituting halogen of compound of the
formula (EA-2) with a group of Y.sup.A Q to give compound of the
formula (EB). Compound of the formula (EA-2) is reacted with sodium
methoxide in a solvent such as methanol.
[0632] Process EC
[0633] This process is for substituting OR.sup.N1 of compound of
the formula (EB) with a leaving group L to give compound of the
formula (EC).
[0634] Process ED
[0635] This process is for converting compound of the formula (EC)
into compound of the formula (ED) according to Process BC.
[0636] Process EF
[0637] This process is for deprotecting compound of the formula
(ED) to give compound of the formula (EF) according to the
conventional method (Protective Groups in Organic Synthesis,
Theodora W. Greene).
[0638] Use of the present invention compounds is explained
below.
[0639] The present invention compound is useful for preparing a
pharmaceutical composition such as antivirus agent. The present
invention compound, possessing a remarkable inhibitory activity on
integrase of virus, is expected to exhibit a preventing or treating
effect for diseases caused by viruses which grow at least via
production of integrase in infected animal cells, thus being useful
as an integrase inhibitor against a retro-virus (e.g., HIV-1,
HIV-2, HTLV-1, SIV, FIV) as well as an anti-HIV agent.
[0640] Further, the present invention compound can be used in
combination with other anti-HIV agents having a different action of
mechanisum such as a reverse transcriptase inhibitor and/or a
protease inhibitor. Since any of the integrase inhibitors have not
been on sale, a combination therapy of the present invention
compound with a reverse transcriptase inhibitor and/or a protease
inhibitor is very useful.
[0641] Further, the present invention compound can be used as a
combind agent for enhansing the anti-HIV acitivity of other HIV
agents, as shown in the cocktail therapy.
[0642] Further, the present invention compound can be used in gene
therapy in order to prevent a retrovirus vector derived from HIV or
MLV from spreading over non-targetd tissues. In particular, in a
case that cells infected with a vector in vitro is put back to a
body, administration of the present invention compound in advanc
can prevent an unnecessary infection in the body.
[0643] The compounds of the present invention can be administered
orally or parenterally. For oral administration, the compounds of
the present invention can be used in any form of usual
formulations, for example, solid formulations such as tablets,
powders, granules, capsules; aqueous formulations; oleaginous
suspensions; solutions such as syrup or elixir. For parenteral
administration, the compounds of the present invention can be used
as an aqueous or oleaginous suspension injection, or nose drops. In
the preparation of such formulations, conventional excipients,
binding agents, lubricants, aqueous solvents, oleaginous solvents,
emulsifying agents, suspending agents, preservatives, stabilizers,
and the like can be optionally used. Preferred is an oral agent as
an HIV-agent.
[0644] A formulation according to the present invention may be
manufactured by combining (for example, admixing) a curatively
effective amount of a compound of the present invention with a
pharmaceutically acceptable carrier or diluent. The formulation of
the present invention may be manufactured with well-known and
easily available ingredients in accordance with a known method.
[0645] In the case of manufacturing a pharmaceutical composition
according to the present invention, an active ingredient is admixed
or diluted with a carrier, or they are contained in a carrier in
the form of capsule, sacheier, paper, or another container. In the
case of functioning a carrier as a diluent, the carrier is a solid,
semi-solid, or liquid material which functions as a medium.
Accordingly, a formulation according to the present invention may
be produced in the form of tablet, pill, powder medicine, intraoral
medicine, elixir agent, suspending agent, emulsifier, dissolving
agent, syrup agent, aerosol agent (solid in liquid medium), and
ointment. Such a formulation may contain up to 10% of an active
compound. It is preferred to formulate a compound of the present
invention prior to administration.
[0646] Any suitable carrier well known to those skilled in the art
may be used for the formulation. In such formulation, a carrier is
in the form of solid, liquid, or a mixture of solid and liquid. For
instance, a compound of the present invention is dissolved into 4%
dextrose/0.5% sodium citrate aqueous solution so as to be 2 mg/ml
concentration for intravenous injection. Solid formulation includes
powder, tablet, and capsule. Solid carrier consists of one or more
of material(s) for serving also as fragrant, lubricant, dissolving
agent, suspension, binder, tablet disintegrator, capsule. A tablet
for oral administration contains a suitable excipient such as
calcium carbonate, sodium carbonate, lactose, calcium phosphate and
the like together with a disintegrator such as corn starch, alginic
acid and the like and/or a binder such as gelatin, acacia and the
like, and a lubricant such as magnesium stearate, stearic acid,
talc and the like.
[0647] In a powder medicine, a carrier is a finely pulverized solid
which is blended with finely pulverized active ingredients. In a
tablet, active ingredients are admixed with a carrier having
required binding power in a suitable ratio, and it is solidified in
a desired shape and size. Powder medicine and tablet contain about
1 to about 99% by weight of the active ingredients being novel
compounds according to the present invention. Example of suitable
solid carriers include magnesium carbonate, magnesium stearate,
talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth
gum, methyl cellulose, sodium carboxymethylcellulose, low-melting
wax, and cocoa butter.
[0648] A liquid formulation includes suspending agent, emulsifier,
syrup agent, and elixir agent. Active ingredients may be dissolved
or suspended into a pharmaceutically acceptable carrier such as
sterile water, a sterile organic solvent, a mixture thereof and the
like. Active ingredients may be dissolved frequently into a
suitable organic solvent such as propylene glycol aqueous solution.
When finely pulverized active ingredients are dispersed into
aqueous starch, sodium carboxylmethylcellulose solution, or
suitable oil, the other compositions can be prepared.
[0649] Although an appropriate dosage of the compound of the
present invention varies depending on the administration route,
age, body weight, conditions of the patient, and kind of disease,
in the case of oral administration, the daily dosage can be between
approximately 0.05-3000 mg, preferably approximately 0.1-1000 mg,
for an adult. The daily dosage can be administered in divisions. In
the case of parenteral administration, the daily dosage for an
adult can be between approximately 0.01-1000 mg, preferably
approximately 0.05-500 mg.
EXAMPLES
[0650] The production method and physical data of the synthesized
products are shown below. Reactions are usually carried out under
nitrogen atmosphere, and reaction solvents are used as dried over
molecular sieve and the like. Extracts are dried over sodium
sulfate or magnesium sulfate and the like.
[0651] A Group Compounds
[0652] Compound A-7
[0653]
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxyl-1-isopropyl-1,5-d-
ihydropyrrole-2-one 172173
[0654] (A-1) Dimethyl fumarate (30 g, 0.21 mol) was dissolved in
acetonitrile (200 ml) under heating and isopropylamine (25 g, 0.42
mol) was added thereto under ice cooling, then the mixuture was
stirred for 16 hours at room temperature. Evaporation of the
solvent and the excess isopropylamine under reduced pressure gave
dimethyl 2-isopropylaminosuccinate (42 g, yield: 100%).
NMR(CDCl.sub.3) .delta.: 1.01(3H, d, J=6.0 Hz), 1.05(3H, d, J=6.3
Hz), 2.67(1H, t, J=9.9 Hz), 2.79(1H, m), 3.69(3H, s), 3.74(3H, s),
3.68-3.75(2H, m).
[0655] (A-2) According to the method of the reference (J. Org.
Chem., 1968, 33, p2051), the above-mentioned compound A-1 (42 g,
0.21 mol) was reacted with sodium methoxide (33 g, 0.6 mol) and
dimethyl oxalate (25 g, 0.21 mol). After stirring for 16 hours at
room temperature and further refluxing under heating for 2 hours,
the solvent was evaporated. The dilute hydrochloric acid was added
to the residue, then the precipitated crystal was filtered to give
4-hydroxylisopropyl-5-oxo-2,5-dihydro-1H-pyr- role-2,3-dicarboxylic
acid dimethyl (33.6 g, yield: 65%)
[0656] NMR(CDCl.sub.3).delta.: 1.20(3H, d, J=6.9 Hz), 1.32(3H, d,
J=6.9 Hz), 3.77(3H, s), 3.85(3H, s), 4.39(1H, m), 4.78(1H, s).
[0657] (A-3) To a suspention of the above-mentioned compound A-2
(10 g, 39 mmol) in diethyl ether (200 ml), a diethyl ether solution
of diazomethane was added. After the reaction was stopped by adding
acetic acid, the reaction mixture was washed and dried. The solvent
was evaporated to give
1-isopropyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylic
acid dimethyl (10.2 g, yield: 97%).
[0658] NMR(CDCl.sub.3).delta.: 1.18(3H, d, J=6.9 Hz), 1.31(3H, d,
J=6.9 Hz), 3.77(3H, s), 3.78(3H, s), 4.36(3H, s), 4.30-4.40(1H, m),
4.76(1H, s).
[0659] (A-4) The above-mentioned compound A-3 (10.2 g, 38 mmol) was
dissolved in methyl alcohol (50 ml) and was added thereto the
aquaous sodium hydroxide solution (sodium hydroxide 8 g, water 50
ml)*The reaction mixture was refluxed for 1 hour. After the solvent
was evaporated, water (50 ml) was added to the residue. The
solution was acidified with the concentrated hydrochloric acid and
extracted with diethyl ether. The extract was washed and dried. The
solvent was evaporated and the residue was Crystallized with
diisopropylether to give
1-isopropyl-4-methoxy-5-oxo-2,5--dihydro-1H-pyrrole-3-carboxylic
acid (3.9 g, yield: 52%)
[0660] NMR(CDCl.sub.3).delta.: 1.24(6H, d, J=6.9 Hz), 3.97(2H, s),
4.38(3H, s), 4.40-4.50(1H, m).
[0661] (A-5) The above-mentioned compound A-4 (1.6 g, 8.0 mmol) was
dissolved in methylene chloride (30 ml) and to which was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.5 g, 9.8 mmol),
N,O-dimethylhydroxylamine hydrochloride (940 mg, 9.6
mmol),hydroxybenzimidazole (110 mg, 0.8 mmol) and triethylamine
(1.0 g, 9.9 mmol).The mixture was stirred for 2 hours at room
temperature. The solution was diluted with chloroform, washed and
dried. The solvent was evaporated under reduced pressure and the
residue was purified with silica gel column chromatography (ethyl
acetate) to give 1-isopropyl-4-methoxy-5-oxo-2,
dihydro-1H-pyrrole-3-carboxylic acid methoxymethylamide (1.5 g,
yield: 77%)
[0662] NMR(CDCl.sub.3).delta.: 1.22(6H, d, J=6.9 Hz), 3.30(3H, s),
3.71(3H, s), 3.98(2H, s), 4.04(3H, s), 4.40-4.50(1H, m).
[0663] (A-6) Aluminum chloride (1.36 g, 10 mmol) was suspended in
tetrahydrofuran (20 ml),to which was added sodium borohydride (650
mg, 17 mmol) under ice cooling. After the mixture was stirred for
10 minutes, (5-bromofuran-2-yl)-(4-fluorophenyl)metanone (900 mg,
3.4 mmol) was added to the mixture and refluxed for 30 minutes
under heating. After cooling, the reaction solution was poured into
the ice water and extracted with diethyl ether. The extract was
washed, dried, and evaporated to give
2-bromo-5-(4-fluorobenzyl)furan. This residue was dissolved in
tetrahydrofuran, to which was added n-butyllithium (2.5 ml, 4 mmol)
at -78.degree. C. 10 Minutes later, the compound A-5 (820 mg, 3.4
mmol) was added to the mixture and stirred for 1 hour. Water was
added to the solution and the mixture was extracted with ethyl
acetate. After the ethyl acetate solution was washed and dried, the
solvent was evaporated under reduced pressure and the residue was
purified with silica gel column chromatography(n-hexane:ethyl
acetate=2:1) to give
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-1-isopropyl-3-methoxy-1,5-dihydrop-
yrrole-2-one(80 mg, yield: 7%).
[0664] NMR(CDCl.sub.3).delta.: 1.23(6H, d, J=6.9 Hz), 4.05(2H, s),
4.08(2H, s), 4.15(3H, s), 4.40-4.50(1H, m), 6.17(1H, d, J=3.6 Hz),
6.90-7.06(2H, m), 7.20-7.26(2H, m), 7.35(1H, d, J=3.6 Hz). (A-7)
The above-mentioned compound A-6(80 mg, 0.22 mmol)was dissolved in
acetonitri(5 ml),to which was added chlorotrimethylsilane(200 mg,
1.8 mmol) and sodium iodide(270 mg, 1.8 mmol),and the mixture was
stirred for 30 minutes at room temperature. Sodium sulfite was
added to the solution, which was acidified with the 1N hydrochloric
acid aqueous solution and extracted with ethyl acetate. The extract
was washed, dried and was evaporated and the residue was
Crystallized with diethylether to give
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-isopropyl-1,5-dihydrop-
yrrole-2-one (50 mg, yield: 68%)
[0665] Melting point: 155-157.degree. C.
[0666] Elementary analysis as as C.sub.19H.sub.18FNO.sub.4
0.2H.sub.2O
[0667] Calcd. (%): C, 65.77; H, 5.35; N, 4.04; F, 5.48. Found (%):
C, 65.72; H, 5.27; N, 3.97; F, 5.26.
[0668] NMR(CDCl.sub.3).delta.: 1.23(6H, d, J=6.9 Hz), 4.08(2H, s),
4.13(2H, s), 4.50-4.60(1H, m), 6.33(1H, d, J=3.6 Hz), 7.02-7.10(2H,
m), 7.20-7.26(2H, m), 7.33(1H, d, J=3.6 Hz).
[0669] Compound A-12
[0670]
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methyl-1,5-dihyd-
ropyrrole-2-one 174
[0671] (A-8) Acrylic acid ethyl ester (2.0 g, 20 mmol) was
dissolved in ethanol(20 ml),to which was added dropwise methylamine
(20 mmol, 20% ethanol solution) under ice cooling.
Di-tert-butyldicarbonate (4.4 g, 20 mmol) was added thereto and the
mixture was warmed to room temperature. The solvent was evaporated
under reduced pressure and the residue was purified with silica gel
column chromatography (n-hexane: ethyl acetate=5:1-3:1) to give
3-(tert-butoxycarbonylmethylamino)propionic acid ethyl ester (3.1
g, yield: 66%).
[0672] NMR(CDCl.sub.3).delta.: 1.26(3H, t, J=7.2 Hz), 1.46(9H, s),
2.54(2H, t, J=7.0 Hz), 2.87(3H, s), 3.50(2H, t, J=7.0 Hz), 4.14(2H,
q, J=7.2 Hz).
[0673] (A-9) 1NLithium hydroxide aqueous solution (17.5 ml) was
added to the above-mentioned compound A-8 (4.05 g, 17.5 mmol) in
methyl alcohol (35 ml) and the mixture was stirred for 5 hours.
Methyl alcohol was evaporated under reduced pressure and the
solution was acidified with citric acid and extracted with ethyl
acetate. The extract was washed, dried and was evaporated to give
3-(tert-butoxycarbonylmethylamino)propio- nic acid (3.57 g, yield:
100%)
[0674] NMR(CD.sub.3OD) .delta.: 1.45(9H, s), 2.51(2H, t, J=7.0 Hz),
2.87(3H, s), 3.50(2H, d, J=7.0 Hz).
[0675] (A-10) The above-mentioned compound A-9 (3.82 g, 18.8 mmol)
was dissolved in a chloroform (20 ml)-acetonitrile (10 ml) solution
and to which was added O,N-dimethylhydroxylamine hydrochloride
(2.02 g, 20.7 mmol), 1-hydroxybenzotriazole (254 mg, 1.88 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.50 g, 22.6 mmol)
and triethylamine (2.09 g, 20.7 mmol) and the mixture was stirred
for 3 hours. Water was added to the solution and extracted with
chloroform. The extract was washed, dried, and evaporated under
reduced pressure and the residue was purified with silica gel
column chromatography (n-hexane: ethyl acetate=1:1-2:1) to give
[2-(methoxymethylcarbamoyl)ethyl]methylcar- bamic acid tert-butyl
ester (3.94 g, yield: 85%).
[0676] NMR(CDCl.sub.3) .delta.: 1.46(9H, s), 2.67(2H, t, J=7.0 Hz),
2.89(3H, s), 3.19(3H, s), 3.52(2H, t, J=7.0 Hz), 3.69(3H, s).
[0677] (A-11) N-butyllithium (5 mmol) was added dropwise to
2-bromo-5-(4-fluorobenzyl)furan (1.30 g, 5 mmol) in THF (10 ml) at
-78.degree. C. The above-mentioned compound A-10 (1.23 g, 5 mmol)
in THF (5 ml) was added to the mixture and stirred for 30 minutes,
then an ammonium chloride aqueous solution was added to the
solution and the solution was extracted with ethyl acetate. The
extract was washed, dried, and evaporated under reduced pressure
and the residue was purified with silica gel column chromatography
(n-hexane ethyl acetate=3:1-2:1) to give
{3-[5-(4-fluorobenzyl)furan-2-yl]-3-oxopropyl}methylcarbamic acid
tert-butyl ester (1.02 g, yield: 56%)
[0678] NMR(CDCl.sub.3) .delta.: 1.42(9H, s), 2.87(3H, s), 3.00(2H,
t, J=7.0 Hz), 3.58(2H, t, J=7.0 Hz), 4.01(2H, s), 6.10(1H, d, J=3.7
Hz), 6.98-7.05(2H, m), 7.13(1H, d, J=4.0 Hz), 7.19-7.26(2H, m). The
following compound was synthesized by the same method as above
using 3-(4-fluorobenzyl)-bromobenzene which was synthesized
according to the method of the reference (Journal of Medicinal
Chemistry, 2000, 43, 26, p4923).
{3-[3-(4-Fluorobenzyl)phenyl]-3-oxopropyl}methylcarbamic acid
tert-butyl ester
[0679] NMR(CDCl.sub.3) .delta.: 1.43(9H, s), 2.89(3H, s), 3.18(2H,
t, J=6.7 Hz), 3.61(2H, t, J=6.7 Hz), 4.01(2H, s), 6.95-7.01(2H, m),
7.11-7.16(2H, m), 7.37-7.40(2H, m), 7.81-7.82(2H, m).
[0680] (A-12) A 4Nhydrochloric acid dioxane solution (5 ml) was
added to the above-mentioned compound A-11 (1.00 g, 2.77 mmol) and
the mixture was stirred for 30 minutes. The excess hydrochloric
acid and solvent were evaporated under reduced pressure, to which
was added oxalic acid diethyl (485,mg, 3.32 mmol) in ethanol (5
ml).After sodium ethoxide (8.31 mmol, 20% ethanol solution) was
added under ice cooling, the solution was warmed to room
temperature and stirred for 1 hour. Water was added to the solution
and extracted with ethyl acetate. The extract was washed, dried and
evaporated. The precipitated crystal was washed with methyl alcohol
and dried under reduced pressure to give
4-[5-(4-fluorobenzyl)furan-2-car- bonyl]-3-hydroxy
1-methyl-1,5-dihydropyrrole-2-one (641 mg, yield:73%)
[0681] Melting point: 141-143.degree. C.
[0682] Elementary analysis as as C.sub.17H.sub.14FNO.sub.4
0.1H.sub.2O
[0683] Calcd. (%): C, 64.39; H, 4.51; N, 4.42; F, 5.99. Found (%):
C, 64.24; H, 4.29; N, 4.43; F, 5.92.
[0684] NMR(CDCl.sub.3).delta.: 3.14(3H, s), 4.07(2H, s), 4.19(2H,
s), 6.29(1H, d, J=3.7 Hz), 7.03-7.09(2H, m), 7.20-7.26(2H, m),
7.32(1H, d, J=3.7 Hz).
[0685] The following compound was synthesized by the
above-mentioned method.
[0686] (A-12-a)
4-[3-(4-Fluorobenzyl)benzoyl]-3-hydroxy-1-methyl-1,5-dihyd-
ropyrrole-2-one
[0687] Melting point:135-137.degree. C.
[0688] Elementary analysis as as Cl.sub.9H.sub.16FNO.sub.3
0.2H.sub.2O
[0689] Calcd. (%): C, 69.38; H, 5.03; N, 4.26; F, 5.78. Found (%):
C, 69.53; H, 4.83; N, 4.21; F, 5.61.
[0690] NMR(CDCl.sub.3) .delta.: 3.16(3H, s), 4.04(2H, s), 4.23(2H,
s), 6.99-7.04(2H, m), 7.13-7.18(2H, m), 7.42-7.44(2H, m), 7.56(1H,
s), 7.62-7.65(1H, m).
[0691] Compound A-17
[0692]
1-Cyclopropyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1,5--
dihydropyrrole-2-one 175176
[0693] (A-13) Sodium hydrogen carbonate(54 g, 0.64 mol) was added
to N,O-dimethylhydroxylamine hydrochloride(32 g, 0.32 mol)in
methylene chloride(1L), and the mixture was stirred for 30 minutes
at room temperature. Acryloyl chloride(30 g, 0.32 mol)in methylene
chloride was added dropwise to the solution under ice cooling and
stirred for 1 hour at room temperature. The solution was dried,
filtered and evaporated to give N-methoxy-N-methylacrylamide(34 g,
yield:92%).
[0694] NMR(CDCl.sub.3).delta.: 3.27(3H, s), 3.72(3H, s), 5.75(1H,
dd, J=10.2, 1.8 Hz), 6.43(1H, dd, J=17.1, 1.8 Hz), 6.73(1H, dd,
J=17.1, 10.2 Hz).
[0695] (A-14) The above-mentioned compound A-13(2.0 g, 17.4
mmol)and cyclopropylamine(11.0 g, 17.5 mmol) were dissolved in
ethanol(20 ml),and the mixture was refluxed forl hour under
heating. After di-tert-butyldicarbonate(4.5 g, 20 mmol) was added
to the solution under ice cooling, and the mixture was stirred for
30 minutes at room temperature. The solvent was evaporated under
reduced pressure and the residue was purified with silica gel
column chromatography(n-hexane: ethyl acetate=1:2)to give
cyclopropyl[2-(methoxymethylcarbamoyl)ethyl]car- bamic acid
tert-butyl ester(2.9 g, yield: 60%).
[0696] NMR(CDCl.sub.3).delta.: 0.58-0.65(2H, m), 0.70-0.78(2H, m),
1.46(9H, s), 2.50-2.56(1H, m), 2.68(2H, t, J=7.4 Hz), 3.18(3H, s),
3.52(2H, t, J=7.4 Hz), 3.70(3H, s).
[0697] The following compounds were synthesized by the
above-mentioned method.
[0698] Ethyl [2-(methoxymethylcarbamoyl)ethyl] carbamic Acid
Tert-Butyl Ester
[0699] NMR(CDCl.sub.3).delta.: 1.09(3H, t, J=7.0 Hz), 1.46(9H, s),
2.68(2H, t, J=6.8 Hz), 3.18(3H, s), 3.26(2H, q, J=7.0 Hz), 3.48(2H,
t, J=6.8 Hz), 3.69(3H, s).
[0700] [2-(Methoxymethylcarbamoyl)ethyl]propylcarbamic Acid
Tert-Butyl Ester
[0701] NMR(CDCl.sub.3).delta.: 0.87(3H, t, J=7.5 Hz), 1.45-1.59(2H,
m), 1.46(9H, s), 2.69(2H, s), 3.14-3.20(2H, m), 3.18(3H, s),
3.49(2H, t, J=7.1 Hz), 3.69(3H, s).
[0702] Butyl[2-(methoxymethylcarbamoyl)ethyl] Carbamic Acid
Tert-Butyl Ester
[0703] NMR(CDCl.sub.3).delta.: 0.92(3H, t, J=7.4 Hz), 1.23-1.34(2H,
m), 1.44-1.53(2H, m), 1.46(9H, s), 2.69(2H, s), 3.18(3H, s),
3.20(2H, t, J=7.5 Hz), 3.48(2H, t, J=7.1 Hz), 3.69(3H, s).
[0704] (2-Methoxyethyl)-[2-(methoxymethylcarbamoyl)ethyl]carbamic
acid tert-butyl ester
[0705] NMR(CDCl.sub.3).delta.: 1.46(9H, s), 2.71(2H, brs), 3.18(3H,
s), 3.34(3H, s), 3.42(2H, brs), 3.45(2H, brs), 3.55(2H, t, J=6.7
Hz), 3.69(3H, s).
[0706] (1-Ethylpropyl)-[2-(methoxymethylcarbamoyl)ethyl]carbamic
acid tert-butyl ester
[0707] NMR(CDCl.sub.3).delta.: 0.85(6H, t, J=7.5 Hz), 1.46(9H, s),
2.65-2.80(2H, m), 3.18(3H, s), 3.25-3.40(2H, m), 3.63(0.5H, brs),
3.69(3H, s), 3.88(0.5H, brs).
[0708] (A-15) N-butyllithium(1.55M solution, 3.3 ml, 5.1 mmol)was
added to 2-bromo-5-(4-fluorobenzyl)furan(1.3 g, 5.1 mmol)in
tetrahydrofuran(10 ml)at -78.degree. C. After the mixture was
stirred for 5 minutes, the compound A-14(1.36 g, 5 mmol)was added
and stirred for 30 minutes. A saturated ammonium chloride aqueous
solution was added to the solution and was extracted with ethyl
acetate. The extract was washed, dried, and evaporated under
reduced pressure, then the residue was purified with silica gel
column chromatography(ethyl acetate:n-hexane=4:1)to give
cyclopropyl{3-[5-(4-fluorobenzyl)furan-2-yl]-3-oxopropyl}carbamic
acid tert-butyl ester(1.12 g, yield:58%).
[0709] NMR(CDCl.sub.3).delta.: 0.55-0.62(2H, m), 0.66-0.7(2H, m),
1.44(9H, s), 2.45-2.52(1H, m), 3.00(2H, t, J=7.1 Hz), 3.60(2H, t,
J=7.1 Hz), 4.01(2H, s), 6.10(1H, d, J=3.6 Hz), 6.96-7.05(2H, m),
7.14(1H, d, J=3.6 Hz), 7.16-7.23(2H, m).
[0710] The following compounds were synthesized by the
above-mentioned method.
[0711] Ethyl{3-[5-(4-fluorobenzyl)furan-2-yl]-3-oxopropyl}carbamic
Acid Tert-Butyl Ester
[0712] NMR(CDCl.sub.3).delta.: 1.08(3H, t, J=7.1 Hz), 1.43(9H, s),
3.01(2H, t, J=6.8 Hz), 3.24(2H, q, J=7.1 Hz), 3.54(2H, t, J=6.8
Hz), 4.01(2H, s), 6.10(1H, d, J=3.6 Hz), 7.00-7.04(2H, m), 7.14(1H,
s), 7.18-7.24(2H, m).
[0713] {3-[5-(4-Fluorobenzyl)furan-2-yl]-3-oxopropyl}propylcarbamic
Acid Tert-Butyl Ester
[0714] NMR(CDCl.sub.3).delta.: 0.86(3H, t, J=7.4 Hz), 1.42-1.58(2H,
m), 1.43(9H, s), 3.01(2H, t, J=6.9 Hz), 3.14(2H, t, J=7.4 Hz),
3.54(2H, t, J=6.9 Hz), 4.01(3H, s), 6.10(1H, d, J=3.3 Hz),
6.97-7.04(2H, m), 7.14(1H, s), 7.18-7.24(2H, m).
[0715] Butyl{3-[5-(4-fluorobenzyl)furan-2-yl]-3-oxopropyl}carbamic
Acid Tert-Butyl Ester
[0716] NMR(CDCl.sub.3).delta.: 0.91(3H, t, J=7.4 Hz), 1.21-1.35(2H,
m), 1.42-1.52(2H, m), 1.43(9H, s), 3.01(2H, t, J=7.0 Hz), 3.18(2H,
t, J=7.5 Hz), 3.54(2H, t, J=7.0 Hz), 4.01(2H, s), 6.10(1H, d, J=3.3
Hz), 6.97-7.04(2H, m), 7.15(1H, s), 7.18-7.23(2H, m).
{3-[5-(4-Fluorobenzyl)fu-
ran-2-yl]-3-oxopropyl}-(2-methoxyethyl)carbamic acid tert-butyl
ester
[0717] NMR(CDCl.sub.3).delta.: 1.42(9H, s), 3.02(2H, brs), 3.32(3H,
s), 3.39(2H, brs), 3.46(2H, brs), 3.61(2H, t, J=6.9 Hz), 4.00(2H,
s), 6.09(1H, d, J=2.3 Hz), 6.98-7.05(2H, m), 7.13(1H, brs),
7.18-7.28(2H, m).
[0718]
(1-Ethylpropyl)-{3-[5-(4-fluorobenzyl)furan-2-yl]-3-oxopropyl}-carb-
amic acid tert-butyl ester
[0719] NMR(CDCl.sub.3) .delta.: 0.85(6H, brs), 1.45(9H, s),
3.02-3.11(2H, m), 3.32-3.43(2H, m), 3.63(0.5H, brs), 3.88(0.5H,
brs), 4.01(2H, s), 6.08-6.11(1H, m), 6.98-7.03(2H, m), 7.11(1H,
brs), 7.17-7.28(2H, m).
[0720] (A-16) The above-mentioned compound A-15(1.12 g, 2.9
mmol)was dissolved in a 4N hydrochloric acid/dioxane solution(4
ml)and the mixture was stirred for 30 minutes at room temperature.
The solution was poured into a sodium hydrogen carbonate solution
and extracted with ethyl acetate. The extract was washed, dried,
and evaporated under reduced pressure, then the residue was
purified with silica gel column chromatography(chloroform:methyl
alcohol=10:1)to give
3-cyclopropylamino-1-[5-(4-fluorobenzyl)furan-2-yl]propane-1-one(810
mg, yield: 98%).
[0721] NMR(CDCl.sub.3).delta.: 0.30-0.37(2H, m), 0.41-0.48(2H, m),
2.11-2.20(1H, m), 2.95-3.01(2H, m), 3.05-3.11(2H, m), 4.01(2H, s),
6.10(1H, d, J=3.6 Hz), 6.96-7.05(2H, m), 7.12(1H, d, J=3.6 Hz),
7.16-7.23(2H, m).
[0722] The following compounds were synthesized by the
above-mentioned method.
[0723] 3-Ethylamino
1-[5-(4-fluorobenzyl)furan-2-yl]propane-1-one
[0724] NMR(CDCl.sub.3).delta.: 1.48(3H, t, J=7.2 Hz), 3.04-3.18(2H,
m), 3.33-3.41(2H, m), 3.53(2H, t, J=6.6 Hz), 3.98(2H, s), 6.10(1H,
d, J=3.6 Hz), 6.97-7.04(2H, m), 7.15-7.21(2H, m), 7.23(1H, d, J=3.6
Hz), 9.57(1H, s).
[0725]
1-[5-(4-Fluorobenzyl)furan-2-yl]-3-propylaminopropane-1-one
[0726] NMR(CDCl.sub.3).delta.: 1.05(3H, t, J=7.4 Hz), 1.85-1.99(2H,
m), 2.90-3.05(2H, m), 3.29-3.40(2H, m), 3.55(2H, t, J=6.5 Hz),
3.99(2H, s), 6.12(1H, d, J=3.5 Hz), 6.98-7.06(2H, m), 7.17-7.23(2H,
m), 7.24(1H, d, J=3.5 Hz), 9.50(1H, s).
3-Butylamino-1-[5-(4-fluorobenzyl)furan-2-yl]prop- ane-1-one
[0727] NMR(CDCl.sub.3).delta.:0.95(3H, t, J=7.4 Hz), 1.37-1.51(2H,
m), 1.80-1.93(2H, m), 2.94-3.08(2H, m), 3.30-3.41(2H, m), 3.54(2H,
t, J=7.1 Hz), 3.98(2H, s), 6.10(1H, d, J=3.6 Hz), 6.96-7.05(2H, m),
7.15-7.22(2H, m), 7.25(1H, d, J=3.6 Hz), 9.51 (1H, s).
1-[5-(4-Fluorobenzyl)furan-2-yl]-
-3-(2-methoxyethylamino)propane-1-one
[0728] NMR(CDCl.sub.3).delta.: 2.86(2H, t, J=5.2 Hz), 3.05(4H, dd,
J=2.7, 2.7 Hz), 3.36(3H, s), 3.52(2H, t, J=5.2 Hz), 4.00(2H, s),
6.11(1H, d, J=3.6 Hz), 6.98-7.04(2H, m), 7.13(1H, d, J=3.4 Hz),
7.18-7.26(2H, m).
[0729]
3-(1-Ethylpropylamino)-1-[5-(4-fluorobenzyl)furan-2-yl]propane-1-on-
e
[0730] NMR(CDCl.sub.3).delta.: 0.90(6H, brs), 1.45(4H, brs),
2.90-3.15(4H, m), 4.00(2H, s), 6.12(1H, d, J=3.7 Hz), 6.95-7.08(2H,
m), 7.15(1H, d, J=3.7 Hz), 7.20-7.28(2H, m).
[0731] (A-17) The above-mentioned compound A-16(300 mg, 1 mmol)and
oxalic acid dimethyl(140 mg, 1.2 mmol)were dissolved in methyl
alcohol(2 ml),then 3N-sodium methoxide/methyl alcohol(0.7 ml, 2
mmol)was added to the mixture and stirred for 1 hour at room
temperature. The solution was poured into an ammonium chloride
aqueous solution and extracted with chloroform. The extract was
washed, dried, and evaporated under reduced pressure. The residue
was recrystallized from methyl alcohol to give
1-cyclopropyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1,5-dihydr-
opyrrole-2-one(110 mg, yield:32%).
[0732] Melting point:158-159.degree. C.
[0733] Elementary analysis as C.sub.19H.sub.16FNO.sub.4
[0734] Calcd. (%): C, 66.86; H. 4.72; N, 4.10; F, 5.57. Found (%):
C, 66.84; H, 4.62; N, 4.09; F, 5.24.
[0735] NMR(CDCl.sub.3).delta.: 0.76-0.85(2H, m), 0.90-0.98(2H, m),
2.84-2.92(1H, m), 4.07(2H, s), 4.10(2H, d, J=0.6 Hz), 6.31(1H, dt,
J=3.6, 0.6 Hz), 7.03-7.10(2H, m), 7.20-7.26(2H, m), 7.32(1H, d,
J=3.6 Hz).
[0736] The following compounds were synthesized by the
above-mentioned method.
[0737] (A-17-a)
1-Ethyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-
,5-dihydropyrrole-2-one
[0738] NMR(CDCl.sub.3).delta.: 1.23(3H, t, J=7.3 Hz), 3.58(2H, q,
J=7.3 Hz), 4.08(2H, s), 4.18(2H, s), 6.31(1H, d, J=3.6 Hz),
7.02-7.10(2H, m), 7.21-7.26(2H, m), 7.33(1H, d, J=3.6 Hz).
[0739] (A-17-b)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-propyl--
1,5-dihydropyrrole-2-one
[0740] NMR(CDCl.sub.3).delta.: 0.96(3H, t, J=7.4 Hz), 1.56-1.70(2H,
m), 3.48(2H, t, J=7.4 Hz), 4.08(2H, s), 4.16(2H, s), 6.31(1H, d,
J=3.3 Hz), 7.00-7.10(2H, m), 7.20-7.26(2H, m), 7.33(1H, d, J=3.3
Hz).
[0741] (A-17-c)
1-Butyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-
,5-dihydropyrrole-2-one
[0742] NMR(CDCl.sub.3).delta.: 0.97(3H, t, J=7.2 Hz), 1.30-1.44(2H,
m), 1.53-1.64(2H, m), 3.52(2H, t, J=7.4 Hz), 4.08(2H, s), 4.16(2H,
s), 6.31(1H, d, J=3.5 Hz), 7.01-7.10(2H, m), 7.20-7.26(2H, m),
7.33(1H, d, J=3.5 Hz).
[0743] (A-17-d)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-meth-
oxyethyl)-1,5-dihydropyrrole-2-one
[0744] Melting point:105-106.degree. C.
[0745] NMR(CDCl.sub.3).delta.: 3.35(3H, s), 3.60(2H, t, J=4.3 Hz),
3.72(2H, t, J=4.6 Hz), 4.06(2H, s), 4.40(2H, s), 6.29(1H, d, J=3.7
Hz), 7.03-7.08(2H, m), 7.21-7.24(2H, m), 7.31(1H, d, J=3.7 Hz).
[0746] (A-17-e)
1-(1-Ethylpropyl)-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-
-hydroxy-1,5-dihydropyrrole-2-one
[0747] Melting point: 140-141.degree. C.
[0748] NMR(CDCl.sub.3).delta.: 0.86(6H, t, J=7.3 Hz), 1.42-1.73(4H,
m), 4.02(2H, s), 4.06-4.15(3H, m), 6.33(1H, d, J=3.7 Hz),
7.02-7.08(2H, m), 7.20-7.27(2H, m) 7.34(1H, d, J=3.1 Hz).
[0749] Compound A-19
[0750]
1-Cyclohexyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1,5-d-
ihydropyrrole-2-one 177
[0751] (A-18)
4-[5-(4-Fluorobenzyl)furan-2-yl]-2-hydroxy-4-oxo-2-butenoic acid
methyl ester was synthesized according to the method of the
reference(WO00/39086).
[0752] (A-19) The above-mentioned compound A-18(300 mg, 1 mmol) was
dissolved in dioxane(3 ml),to which were added cyclohexylamine(200
mg, 2 mmol)and paraformaldehyde(80 mg)under ice cooling. After the
mixture was stirred for 3 hours at room temperature, the solution
was poured into a dilute hydrochloric acid-ice water and extracted
with ethyl acetate. The extract was washed, dried, and evaporated
under reduced pressure. The residue was recrystallized from diethyl
ether to give
1-cyclohexyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1,5-dihydro-
pyrrole-2-one(280 mg, yield:73%).
[0753] Melting point:41-142.degree. C.
[0754] Elementary analysis as C.sub.22H.sub.22FNO.sub.4
[0755] Calcd. (%): C, 68.92; H, 5.78; N, 3.65; F, 4.96. Found (%):
C, 68.73; H, 5.77; N, 3.60; F, 4.80.
[0756] NMR(CDCl.sub.3).delta.: 1.15-1.51(5H, m), 1.70-1.91(5H, m),
4.08(2H, s), 4.12(2H, s), 4.10-4.20(1H, m), 6.33(1H, d, J=3.6 Hz),
7.03-7.10(2H, m), 7.20-7.26(2H, m), 7.33(1H, d, J=3.6 Hz).
[0757] The following compounds were synthesized by the
above-mentioned method.
[0758] (A-19-a)
1-Cyclopentyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hyd-
roxy-1,5-dihydropyrrole-2-one
[0759] Melting point:157-159.degree. C.
[0760] Elementary analysis as C.sub.21H.sub.20FNO.sub.4
[0761] Calcd. (%): C, 68.28; H, 5.46; N, 3.79; F, 5.14. Found (%):
C, 67.94; H, 5.48; N, 3.72; F, 5.13.
[0762] NMR(CDCl.sub.3).delta.: 1.44-1.60(2H, m), 1.60-1.82(4H, m),
1.90-2.02(2H, m), 4.07(2H, s), 4.15(2H, s), 4.56-4.68(1H, m),
6.33(1H, d, J=3.6 Hz), 7.03-7.10(2H, m), 7.18-7.26(2H, m), 7.33(1H,
d, J=3.6 Hz).
[0763] (A-19-b) 4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy
1-(4-methoxyphenyl)-1,5-dihydropyrrole-2-one
[0764] Melting point:225-227.degree. C.
[0765] Elementary analysis as
C.sub.23H.sub.18FNO.sub.50.1H.sub.2O
[0766] Calcd. (%): C, 67.51; H, 4.48; N, 3.42; F, 4.64. Found (%):
C, 67.31; H, 4.46; N, 3.38; F, 4.38.
[0767] NMR(CDCl.sub.3).delta.: 3.85(3H, s), 4.10(2H, s), 4.60(2H,
s), 6.36(1H, d, J=3.6 Hz), 6.97(2Hx2, Abq, J=9.0 Hz), 7.02-7.10(2H,
m), 7.20-7.26(2H, m), 7.38(1H, d, J=3.6 Hz), 7.57(2Hx2, Abq, J=9.0
Hz).
[0768] (A-19-c) 4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy
1-(2-hydroxy 1-methylethyl)-1,5-dihydropyrrole-2-one
[0769] Melting point: 168-169.degree. C.
[0770] Elementary analysis as C.sub.19H.sub.18FNO.sub.5
[0771] Calcd. (%): C, 63.50; H, 5.05; N, 3.90; F, 5.29. Found (%):
C, 63.17; H, 4.99; N, 3.83; F, 5.13.
[0772] NMR(DMSO-d.sub.6).delta.: 1.07(3H, d, J=6.3 Hz),
3.32-3.38(2H, m), 3.89-3.96(1H, m), 4.09(2H, s), 4.27(2H, s),
4.60(1H, bs), 6.41(1H, d, J=3.6 Hz), 7.00-7.15(2H, m),
7.30-7.36(2H, m), 7.50(1H, d, J=3.6 Hz).
[0773] (A-19-d)
1-Allyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-
,5-dihydropyrrole-2-one
[0774] Melting point:95-96.5.degree. C.
[0775] Elementary analysis as C.sub.19H.sub.16FNO.sub.4
[0776] Calcd. (%): C, 66.86; H, 4.72; N, 4.10; F, 5.57. Found (%):
C, 66.69; H, 4.65; N, 4.07; F, 5.36.
[0777] NMR(CDCl.sub.3).delta.:4.05(2H, s), 4.15(2H, d, J=6.1 Hz),
4.18(2H, s), 5.24(1H, dd, J=16.7, 1.1 Hz), 5.29(1H, dd, J=10.1, 1.1
Hz), 5.81(1H, ddt, J=16.7, 10.1, 6.1 Hz), 6.31(1H, d, J=3.5 Hz),
7.00-7.08(2H, m), 7.17-7.25(2H, m), 7.32(1H, d, J=3.5 Hz).
[0778] (A-19-e)
1-Benzyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy--
1,5-dihydropyrrole-2-one
[0779] Melting point:129-130.degree. C.
[0780] Elementary analysis as C.sub.23H.sub.18FNO.sub.4
[0781] Calcd. (%): C, 70.58; H, 4.64; N, 3.58; F, 4.85. Found (%):
C, 70.42; H, 4.56; N, 3.60; F, 4.74.
[0782] NMR(CDCl.sub.3): 3.99(2H, s), 4.13(2H, s), 4.71(2H, s),
6.27(1H, d, J=3.6 Hz), 6.91-7.00(2H, m), 7.08-7.16(2H, m),
7.23-7.30(3H, m), 7.33-7.42(3H, m).
[0783] (A-19-f) 4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy
1-(2-hydroxyethyl)-1,5-dihydropyrrole-2-one
[0784] Melting point: 144-145.5.degree. C.
[0785] Elementary analysis as C.sub.18H.sub.16FNO.sub.5
[0786] Calcd. (%): C, 62.61; H, 4.67; N, 4.06; F, 5.50. Found (%):
C, 62.39; H, 4.61; N. 4.01; F, 5.42.
[0787] NMR(CDCl.sub.3): 3.68(2H, t, J=4.9 Hz), 3.89(2H, t, J=4.9
Hz), 4.07(2H, s), 4.37(2H, s), 6.29(1H, d, J=3.6 Hz), 7.01-7.10(2H,
m), 7.20-7.28(2H, m), 7.32(1H, d, J=3.6 Hz).
[0788] (A-19-g)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-hydr-
oxypropyl)-1,5-dihydropyrrole-2-one
[0789] Melting point: 172.degree. C.
[0790] Elementary analysis as C.sub.19H.sub.18NO.sub.5F
[0791] Calcd. (%) C: 65.50H: 5.05N: 3.90 F: 5.29. Found (%) C:
63.32H: 5.09N: 3.88 F: 4.94.
[0792] NMR(CDCl.sub.3).delta.: 1.27(d, 3H, J=6.0 Hz), 3.40-3.60(m,
3H), 4.07(s, 2H), 4.00-4.20(m, 1H), 4.25-4.50(m, 2H), 6.29(d, 1H,
J=3.6 Hz), 7.02-7.10(m, 2H), 7.20-7.26(m, 2H), 7.32(d, 1H, J=3.6
Hz).
[0793] (A-19-h)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-hydr-
oxybutyl)-1,5-dihydropyrrole-2-one
[0794] Melting point:132-133.degree. C.
[0795] Elementary analysis as C.sub.20H.sub.20NO.sub.5F
[0796] Calcd. (%) C: 64.34H: 5.40N: 3.75 F: 5.09. Found (%) C:
64.18H: 5.39N: 3.74 F: 4.71.
[0797] NMR(CDCl.sub.3).delta.: 1.03(t, 3H, J=7.2 Hz), 1.45-1.65(m,
2H), 3.48(dd, 1H, J=14.1 Hz, 8.1 Hz), 3.61(dd, 1H, J=14.4 Hz, 2.7
Hz), 3.75-3.90(m, 1H), 4.07(s, 2H), 4.33(d, 1H, J=18.0 Hz), 4.43(d,
1H, J=18.0 Hz), 6.29(d, 1H, J=3.6 Hz), 7.02-7.10(m, 2H),
7.20-7.28(m, 2H), 7.32(d, 1H, J=3.6 Hz).
[0798] (A-19-i)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-hydr-
oxypentyl)-1,5-dihydropyrrole-2-one
[0799] Melting point:171.degree. C.
[0800] Elementary analysis as C.sub.21H.sub.22NO.sub.5F
[0801] Calcd. (%) C: 65.11H: 5.72N: 3.62 F: 4.90. Found (%) C:
64.82H: 5.68N: 3.58 F: 4.42.
[0802] NMR(CDCl.sub.3).delta.:0.95(t, 3H, J=7.2 Hz), 1.20-140(m,
2H), 1.50-1.70(m, 2H), 3.65-3.76(m, 1H), 3.80-3.90(m, 1H), 4.07(s,
2H), 4.13(d, 1H, J=18.0 Hz), 4.31(d, 1H, J=18.0 Hz), 6.32(d, 1H,
J=3.6 Hz), 7.02-7.10(m, 2H), 7.20-7.28(m, 2H), 7.34(d, 1H, J=3.6
Hz).
[0803] (A-19-j)
1-(2,3-Dihydroxypropyl)-4-[5-(4-fluorobenzyl)furan-2-carbo-
nyl]-3-hydroxy-1,5-dihydropyrrole-2-one
[0804] Melting point:119-120.degree. C.
[0805] Elementary analysis as C.sub.19H.sub.18NO.sub.6F
[0806] Calcd. (%) C: 60.80H: 4.83N: 3.73 F: 5.06. Found (%) C:
60.56H: 4.81N: 3.70 F: 4.66.
[0807] NMR(CDCl.sub.3).delta.:3.54-3.72(m, 4H), 3.90-4.02(m, 1H),
4.07(s, 2H), 4.35(d, 1H, J=18.0 Hz), 4.43(d, 1H, J=18.0 Hz),
6.30(d, 1H, J=3.6 Hz), 7.02-7.10(m, 2H), 7.20-7.28(m, 2H), 7.34(d,
1H, J=3.6 Hz).
[0808] (A-19-k)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1,5-dihyd-
ropyrrole-2-one
[0809] Melting point: 178-179.degree. C.
[0810] Elementary analysis as C.sub.16H.sub.12NO.sub.4F
[0811] Calcd. (%) C: 63.79H: 4.01N: 4.65 F: 6.31. Found (%) C:
62.87H: 4.29N: 4.17 F: 5.92.
[0812] NMR(CDCl.sub.3).delta.: 4.05(s, 2H), 4.39(s, 2H), 6.31(d,
1H, J=3.6 Hz), 7.00-7.10(m, 2H), 7.16-7.24(m, 2H), 7.26-7.32(m,
1H), 7.35(d, 1H, J=3.6 Hz).
[0813] (A-19-1)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-morp-
holine-4-ylethyl)-1,5-dihydropyrrole-2-one
[0814] Melting point: 189-190.degree. C. (decomp.)
[0815] Elementary analysis as C.sub.22H.sub.23N.sub.2O.sub.5F
0.3H.sub.2O
[0816] Calcd. (%) C: 62.94H: 5.67N: 6.67 F: 4.53. Found (%) C:
62.91H: 5.61N: 6.64 F: 4.25.
[0817] NMR(DMSO-d6).delta.: 2.58(m), 3.55(m), 4.08(s, 2H), 4.14(s,
2H), 6.37(d,1H, J=3.6 Hz), 7.13-7.20(m, 2H), 7.30-7.35(m, 2H),
7.85(bs, 1H).
[0818] (A-19-m)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-pipe-
ridine-1-ylethyl)-1,5-dihydropyrrole-2-one
[0819] Melting point:228-232.degree. C.(decomp.)
[0820] Elementary analysis as
C.sub.23H.sub.25N.sub.2O.sub.4F.0.1H.sub.2O
[0821] Calcd. (%) C: 66.68H: 6.13N: 6.76 F: 4.59. Found (%) C:
66.55H: 6.06N: 6.76 F: 4.38.
[0822] NMR(DMSO-d.sub.6).delta.: 1.40-1.60(m, 6H), 2.40-2.80(m),
3.20-3.60(m), 3.93(s, 2H), 4.01(s, 2H), 6.19(bs, 1H), 7.11-7.20(m,
2H), 7.28-7.35(m, 2H), 8.58(bs, 1H).
[0823] (A-19-n)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-5H-furan--
2-one
[0824] Melting point:178-179.degree. C.
[0825] Elementary analysis as C.sub.16H12 NO.sub.4F
[0826] Calcd. (%) C: 63.79H: 4.01N: 4.65 F: 6.31. Found (%) C:
62.87H: 4.29N: 4.17 F: 5.92.
[0827] NMR(CDCl.sub.3).delta.: 4.06(s, 2H), 5.18(d, 2H, J=0.6 Hz),
6.35(dd, 1H, J=3.6 Hz, 0.6 Hz), 7.02-7.10(m, 2H), 7.18-7.24(m, 2H),
7.41(d, 1H, J=3.6 Hz).
[0828] (A-19-0)
4-[5-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-isoprop-
yl-5-methyl-1,5-dihydropyrrole-2-one was synthesized by using
acetaldehyde instead of paraformaldehyde.
[0829] Melting point:120-122.degree. C.
[0830] NMR(CDCl.sub.3).delta.: 1.25(3H, d, J=6.4 Hz), 1.38(3H, d,
J=6.9 Hz), 1.41(3H, d, J=6.9 Hz), 4.07(2H, d, J=2.1 Hz), 4.12(1H,
sep, J=6.9 Hz), 4.55(1H, q, J=6.4 Hz), 6.32(1H, d, J=3.6 Hz),
7.01-7.10(2H, m), 7.19-7.28(2H, m), 7.36(1H, d, J=3.6 Hz).
[0831] Compound A-29
[0832]
4-[5-(4-Fluorobenzyl)oxazole-2-carbonyl]-3-hydroxy-1-isopropyl-1,5--
dihydropyrrole-2-one(A-29-a)
[0833]
4-[5-(4-Fluorobenzyl)oxazole-2-carbonyl]-3-hydroxy-1-methyl-1,5-dih-
ydropyrrole-2-one(A-29-b) 178179
[0834] (A-20) To a solution of benzyloxycarbonylaminoacetic
acid(102.5 g, 0.49 mol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric
acid(112.7 g, 0.588 mol), hydroxybenztriazole(6.62 g, 0.049 mol)
and N,O-dimethylhydroxylamine hydrochloric acid(57.35 g, 0.588 mol)
in dichloromethane(1 L),was added triethylamine(82 ml, 0.588 mol)
and stirred for 10 minutes under water cooling, 10 minutes later,
the mixture was stirred at room temperature for 1 hour. The
solution was allowed to stand overnight at room temperature. The
mixture was evaporated under reduced pressure, to which were added
ethyl acetate(500 ml), 2N hydrochloric acid(70 ml)and water(300 ml)
and the solution was shaken and separated. The solution was washed
with water(200 ml), a saturated sodium bicarbonate aqueous
solution(100 ml)and water(100 ml), and water(200 ml) successively.
The water solution was extracted with ethyl acetate(300 ml), the
ethyl acetate was Collected, dried with magnesium sulfate and
evaporated under reduced pressure to give
[(methoxymethylcarbamoyl)methyl- ]carbamic acid benzyl ester(108.92
g, yield:88.1%).
[0835] Melting point:77-78.degree. C.
[0836] NMR(CDCl.sub.3).delta.: 3.21(3H, s), 3.72(3H, s), 4.15(2H,
d, J=4.2 Hz), 5.13(2H, s), 5.55(1H, bs), 7.30-7.40(5H, m).
[0837] (A-21) A metal sheet of magnesium(21.89 g, 900 mmol) and
diethyl ether(120 ml) were added in 2L 3 necked flask under
nitrogen atmosphere, to which was added a small amount of iodine.
After a small portion of 4-fluorobenzylbromide(112.2 ml, 900 mmol)
in diethyl ether(150 ml) was added dropwise and diluted with
diethyl ether(930 ml),the reaction mixture was Cooled with
ice-NaCl.When the reaction mixture was Come to 1.degree. C.,the
remaining 4-fluorobenzylbromide was added dropwise for 3 hours 40
minutes and the reaction mixture was stirred for 40 minutes.
[0838] The above-mentioned compound A-20(75.68 g, 300 mmol) in
tetrahydrofuran(720 ml) was added to 3L 3necked flask under
nitrogen atmosphere, then the reaction mixture was Cooled with
ice-NaCl, to which was added dropwise for 1.5 hours a diethyl ether
solution of Grignard reagent which was previously prepared. The
solution was kept from -1.degree. C. to 3.degree. C., and further
stirred for 1 hour. (the temperature of the end of the reaction was
at 3.degree. C.).The reaction mixture was poured into an ice water,
to which were added ethyl acetate(800 ml) and 2N hydrochloric
acid(600 ml) and extracted.The water solution was reextracted with
ethyl acetate(400 ml).The ethyl acetate solution was washed one
time with water(600 ml), dried with magnesium sulfate and
evaporated under reduced pressure. N-hexane and diethyl ether(2:1,
720 ml) were added to a crystal residue(130.7 g), to give crude
crystal(71.15 g, 78.7%) of A-21 which was recrystallized from
dichloromethane and n-hexane to give A-21(47.82 g, yield:52.9%).The
filtrate was purified with silica gel column
chromatography(toluene:aceto- ne=98:2) to give A-21(11.85 g,
13.1%).
[0839] Melting point:92-93.degree. C.
[0840] NMR(CDCl.sub.3).delta.: 3.71(2H, s), 4.13(2H, d, J=4.5 Hz),
5.10(2H, s), 5.43(1H, bs), 7.00-7.05(2H, m), 7.15-7.19(2H, m),
7.35(5H, bs).
[0841] (A-22) The above-mentioned compound A-21(113.88 g, 378 mmol)
was suspended in methyl alcohol(756 ml),to which were added 10%
Pd--C(7.56 g), water(76 ml) and 5N hydrochloric acid(114 ml).The
mixture was reduced under atmosphere pressure. 3Hours later, methyl
alcohol(160 ml),water(40 ml) and 10% Pd--C(3.83 g) were added to
the mixture and further reduced for 4.7 hours (6.05L, hydrogen).The
catalyst was filtered, washed with methyl alcohol and then the
solution was evaporated under reduced pressure. Diethyl ether(400
ml) was added to a crystal residue and the crystal was Crushed to
give 1-amino-3-(4-fluorophenyl)propane-2-one hydrochloride(74.67 g,
yield:97%).
[0842] Melting point:190-192.degree. C.
[0843] NMR(DMSO-d.sub.6).delta.: 3.91(2H, s), 4.01(2H, s),
7.13-7.21(2H, m), 7.22-7.28(2H, m), 8.24(2H, bs).
[0844] (A-23) The above-mentioned compound A-22(69.50 g, 341.3
mmol) was suspended to toluene(535 ml),to which was added
chloroglyoxylic acid ethyl(77 ml, 689 mmol), then the mixture was
stirred and heated at 90.degree. C. for 2 hours. The reaction
mixture was Cooled by ice, then ethyl acetate(500 ml) and water
were added to the mixture and shakend(the precipitated crystal was
not dissolved).The water layer and the precipitate were extracted 3
times with chloroform(400 ml)each chloroform solution was washed,
dried with sodium sulfate and evaporated under reduced pressure.
Diethyl ether and n-hexane(1:1, 200 ml) were added to a crystal
residue and the crystal was Crushed to give
N-[3-(4-fluorophenyl)-2-oxopropyl]-oxamic acid ethyl ester(80.0 g,
yield:87.7%).
[0845] Melting point: 126-127.degree. C.
[0846] NMR(CDCl.sub.3).delta.: 1.38(3H, t, J=7.2 Hz), 3.76(2H, s),
4.25(2H, d, J=4.8 Hz), 4.36(2H, q, J=7.2 Hz), 7.01-7.08(2H, m),
7.17-7.22(2H, m), 7.70(1H, bs).
[0847] (A-24) The above-mentioned compound A-23(74.90 g, 280 mmol)
was suspended to toluene(784 ml),to which was added phosphorus
oxychloride(144 ml, 1.545 mol),then the mixture was stirred and
heated at 120.degree. C. for 2 hours. The solution was evaporated
under reduced pressure and then the residue was dissolved in ethyl
acetate. The solution was poured into ice water, then extracted one
time with ethyl acetate and washed 2 times and dried with magnesium
sulfate. The solution was evaporated under reduced pressure to give
a crude product(70.15 g).The crude product was purified with silica
gel column chromatography(chloroform) to give
5-(4-fluorobenzyl)oxazole-2-carboxylic acid ethyl ester(66.70 g,
yield:95.6%) as a red oil.
[0848] NMR(CDCl.sub.3).delta.: 1.42(3H, t, J=7.2 Hz), 4.05(2H, s),
4.45(2H, q, J=7.2 Hz), 6.92(1H, s), 6.99-7.07(2H, m), 7.18-7.24(2H,
m).
[0849] (A-25) The above-mentioned compound A-24(54.70 g, 219.5
mmol) was dissolved in ethanol(640 ml) and the mixture was stirred
under ice cooling, to which was added dropwise 4N lithium
hydroxide(110 ml, 440 mmol)for 15 minutes and stirred for 1.5
hours. 1N hydrochloric acid(444 ml) was added dropwise for 30
minutes and then water(500 ml) was added. The mixture was stirred
for 10 minutes and the precipitated crystal was separated to give
5-(4-fluorobenzyl)oxazole-2-carboxylic acid(43.74 g,
yield:90.1%).
[0850] Melting point:84-85.degree. C.
[0851] NMR(DMSO-d6) .delta.: 4.13(2H, s), 7.12-7.21(3H, m),
7.27-7.35(2H, m).
[0852] (A-26) According to the method of the example A-20,
5-(4-fluorobenzyl)oxazole-2-carboxylic acid methoxymethylamide was
synthesized from the above-mentioned compound A-25.
[0853] NMR(CDCl.sub.3).delta.: 3.46(3H, bs), 3.83(3H, s), 4.04(2H,
s), 6.86(1H, s), 6.98-7.05(2H, m), 7.16-7.28(2H, m).
[0854] (A-27) According to the method of the example A-21,
1-[5-(4-fluorobenzyl)oxazole-2-yl]etanone was synthesized from the
above-mentioned compound A-26.
[0855] Melting point:51-52.degree. C.
[0856] NMR(CDCl.sub.3).delta.: 2.63(3H, s), 4.05(2H, s), 6.91(1H,
m), 7.00-7.06(2H, m), 7.19-7.24(2H, m).
[0857] (A-28) According to the method of the example A-18,
4-[5-(4-fluorobenzyl)oxazole-2-yl]-2-hydroxy-4-oxo-2-butenoic acid
methyl ester was synthesized from the above-mentioned compound
A-27.
[0858] Melting point: 115-116.degree. C.
[0859] NMR(CDCl.sub.3).delta.: 3.94(3H, s), 4.09(2H, s),
7.00-7.07(3H, m), 7.24-7.27(3H, m).
[0860] (A-29-a) According to the method of the example A-19,
4-[5-(4-fluorobenzyl)oxazole-2-carbonyl]-3-hydroxyl-isopropyl-1,5-dihydro-
pyrrole-2-one was synthesized from the above-mentioned compound
A-28.
[0861] Melting point:217-219.degree. C.
[0862] Elementary analysis as C.sub.18H.sub.17FN.sub.2O.sub.4
[0863] Calcd. (%): C, 62.79; H, 4.98; N, 8.14; F, 5.52. Found (%):
C, 62.31; H, 4.89; N, 8.00; F, 5.51.
[0864] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=6.9 Hz), 4.10(2H, s),
4.14(2H, s), 4.55(1H, m), 7.03-7.09(3H, m), 7.23-7.28(2H, m),
15.08(1H, bs).
[0865] According to the same method, A-29-b,
4-[5-(4-fluorobenzyl)oxazole--
2-carbonyl]-3-hydroxyl-methyl-1,5-dihydropyrrole-2-one was
synthesized.
[0866] Melting point:218-220.degree. C.
[0867] Elementary analysis as C.sub.16H.sub.13FN.sub.2O.sub.4
[0868] Calcd. (%): C, 60.76; H, 4.14; N, 8.86; F, 6.01. Found (%):
C, 60.46; H, 4.08; N, 8.78; F, 5.97.
[0869] NMR(CDCl.sub.3).delta.:3.16(3H, s), 4.14(4H, s),
7.02-7.09(3H, m), 7.22-7.28(2H, m), 15.21(1H, bs).
[0870] Compound A-33
[0871]
4-[5-(4-Fluorobenzyl)thiazole-2-carbonyl]-3-hydroxy-1-methyl-1,5-di-
hydropyrrole-2-one 180
[0872] (A-30)formic acid(2 ml) was added to acetic anhydride(4 ml)
under ice cooling and stirred at 50.degree. C. for 15 minutes. The
solution was stirred for 3 minutes under ice cooling, to which was
added sodium formate (0.91 g, 13.4 mmol) and then the mixture was
stirred at room temperature for 5 minutes.
1-Amino-3-(4-fluorophenyl)propane-2-one hydrochloride A-22(2.04 g,
10 mmol) was added to the solution and stirred at room temperature
for 40 minutes. Then water was added to the solution which was
extracted with methylene chloride. The extract was washed, dried
and evaporated under reduced pressure to give a crude crystal(1.85
g) of N-[3-(4-fluorophenyl)-2-oxopropyl]formamide.
[0873] NMR(CDCl.sub.3).delta.:3.75 (2H, s), 4.24 (2H, d, J=5.4 Hz),
6.34 (1H, br.s), 7.04 (2H, t like, J=8.7 Hz), 7.16-7.22(2H, m),
8.23 (1H, s).
[0874] (A-31) A crude crystal(1.85 g) of the above-mentioned
compound A-30 was dissolved in toluene(40 ml),to which was added
Lawesson's reagent(4.05 g, 10 mmol) and the mixture stirred at room
temperature for 15 minutes, 60.degree. C. for 15 minutes and
100.degree. C. for 1.5 hours. The solution was Cooled to room
temperature, then the insoluble matter was separated and washed
with toluene. The firtrate and the toluene solution were
concentrated under reduced pressure. The residue was purified with
silica gel column chromatography(chloroform:methyl
alcohol=1:0-49:1,n-hexane:ethyl acetate=2:1) to give
5-(4-fluorobenzyl)thiazole(1.47 g,2step yield:76%).
[0875] NMR(CDCl.sub.3).delta.:4.14 (2H, s), 7.00 (2H, t like, J=8.7
Hz), 7.14-7.20 (2H, m), 7.72 (1H, s), 8.86 (1H, s).
[0876] (A-32) A n-butyllithium-hexane solution(1.5 mmol) was added
dropwise to the above-mentioned compound A-31(290 mg, 1.5 mmol) in
tetrahydrofuran(8 ml) at -78.degree. C. and the mixture was stirred
for 20 minutes, to which was added dropwise
4-methoxy-1-methyl-5-oxo-2,5-dihy- dro-1H-pyrrole-3-carboxylic acid
methoxymethylamide(321 mg, 1.5 mmol) in tetrahydrofuran(1.5 ml)
which was synthesized according to the method of A-5 and stirred
for 55 minutes. A saturated ammonium chloride aqueous solution was
added to the solution, then extracted with ethyl acetate. The
extract was washed, dried and evaporated under reduced pressure.
The residue was Crystallized from ethyl acetate-diisopropylether to
give
4-[5-(4-fluorobenzyl)thiazole-2-carbonyl]-3-methoxy-1-methyl-1,5-dihydrop-
yrrole-2-one(226 mg, yield:44%).
[0877] NMR(CDCl.sub.3).delta.:3.12 (3H, s), 4.19 (2H, s), 4.31 (3H,
s), 4.60 (2H, s), 7.03 (2H, t, like, J=8.7 Hz), 7.17-7.23 (2H, m),
7.66 (1H, t, J=0.9 Hz).
[0878] The following compounds were synthesized by the
above-mentioned method using
1-isopropyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxy- lic
acid methoxymethylamide.
4-[5-(4-Fluorobenzyl)thiazole-2-carbonyl]-1-i-
sopropyl-3-methoxy-1,5-dihydropyrrole-2-one
[0879] NMR(CDCl.sub.3).delta.:1.28 (6H, d, J=6.6 Hz), 4.19 (2H, s),
4.29 (3H, s), 4.52 (2H, s), 4.45-4.54 (1H, m), 7.26 (2H, t, like,
J=8.7 Hz), 7.18-7.23 (2H, m), 7.68 (1H, s).
[0880] (A-33) 5N hydrochloric acid(2 ml) was added to the
above-mentioned compound A-32(219 mg, 0.63 mmol) in methyl
alcohol(10 ml), and the mixture was stirred at 50.degree. C. for 14
hours, then stirred for 30 minutes under ice cooling. The
precipitated crystal was filtered out, then washed with methyl
alcohol to give 164 mg of the crystal which was recrystallized from
methyl alcohol-ethyl acetate to give
4-[5-(4-fluorobenzyl)thiazole-2-carbonyl]-3-hydroxy-1-methyl-1,5-dihydrop-
yrrole-2-one(145 mg, yield:69%).
[0881] Melting point:230-231.degree. C.
[0882] Elementary analysis as C.sub.16H.sub.13FN.sub.2O.sub.3S
[0883] Calcd. (%): C, 57.82; H, 3.94; N, 8.43; F, 5.72; S, 9.65.
Found (%): C, 57.91; H, 3.89; N, 8.34; F, 5.71; S, 9.47.
[0884] NMR(CDCl.sub.3) (5:3.16 (3H, s), 4.11 (2H, s), 4.23 (2H, s),
7.06 (2H, t like, J=8.7 Hz), 7.20-7.25 (2H, m), 7.76 (1H, s).
[0885] The following compound was synthesized by the
above-mentioned method.
[0886]
4-[5-(4-Fluorobenzyl)thiazole-2-carbonyl]-1-isopropyl-3-hydroxy-1,5-
-dihydropyrrole-2-one
[0887] Melting point:201-202.degree. C.
[0888] Elementary analysis as C.sub.18H.sub.17FN.sub.2O.sub.3S
[0889] Calcd. (%): C, 59.99; H, 4.75; N, 7.77; F, 5.27; S, 8.90.
Found (%): C, 60.04; H, 4.70; N, 7.70; F, 5.30; S, 8.84.
[0890] NMR(CDCl.sub.3).delta.:1.26 (6H, d, J=6.6 Hz), 4.08 (2H, s),
4.24 (2H, s), 4.50-4.62 (1H, m), 7.06 (2H, t like, J=8.7 Hz),
7.20-7.26 (2H, m), 7.56 (1H, s).
[0891] Compound A-39
[0892]
4-[2-(4-Fluorobenzyl)furan-3-carbonyl]-3-hydroxy-1-methyl-1,5-dihyd-
ropyrrole-2-one 181
[0893] (A-34) To a lithium diisopropylamide solution prepared from
diisopropylamine(22.0 ml, 157 mmol) and n-butyllithium (157 mmol)
in tetrahydrofuran(150 ml),was added dropwise 3-furancarboxylic
acid (8.79 g, 78.5 mmol) in tetrahydrofuran(80 ml) at -78.degree.
C. The mixture was stirred at the same temperature for 1 hour 10
minutes, to which was added 4-fluorobenzaldehyde (10.7 g, 86.4
mmol) in tetrahydrofuran(30 ml). The temperature was warmed to
0.degree. C. for 30 minutes, then water(100 ml) was added to the
solution and the organic layer was extracted with 1N sodium
hydroxide aqueous solution. The water solution was acidified with
concentrated hydrochloric acid, then extracted with ethyl acetate.
The extract was washed, dried and evaporated under reduced pressure
to give the residue which was Crystallized from
diisopropylether-n-hexane to afford
2-[(4-fluorophenyl)hydroxymethyl]furan-3-carboxylic acid(13.5 g,
yield: 73%).
[0894] (A-35) The above-mentioned compound A-34(13.5 g, 57.2 mmol)
in acetonitrile(75 ml) was added dropwise to sodium iodide (34.3 g)
and chlorotrimethylsilane (29.1 ml) in acetonitrile (60 ml) under
ice cooling, then stirred for 15 minutes, to which was added 10%
sodium hydrogen sulfite aqueous solution(200 ml) and stirred for 15
minutes. The solution was extracted with ethyl acetate, washed and
dried, then evaporated under reduced pressure to give the residue
which was Crystallized from isopropylether-n-hexane to afford
2-(4-fluorobenzyl)furan-3-carboxylic acid(9.73 g, yield:77%).
[0895] NMR(CDCl.sub.3).delta.:4.35 (2H, s), 6.72 (1H, d, J=2.1 Hz),
6.98 (2H, t like, J=8.7 Hz), 7.22-7.28 (2H, m), 7.30 (1H, d, J=2.1
Hz).
[0896] (A-36) To a mixture of the above-mentioned compound
A-35(3.00 g, 13.6 mmol), N, O-dimethylhydroxylamine
hydrochloride(1.60 g, 16.4 mmol) and
1-hydroxy-1H-benzotriazolelhydrate (0.21 g, 1.4 mmol) in
tetrahydrofuran(40 ml), was added triethylamine(2.27 ml, 16.4 mmol)
and stirred for 10 minutes, to which was added
1-ethyl-3-(3-dimethylaminoprop- yl)carbodiimide hydrochloride(3.14
g, 16.4 mmol) and stirred overnight. Water and 2N hydrochloric
acid(10 ml) were added to the solution and extracted with ethyl
acetate. The extract was washed, dried and evaporated under reduced
pressure, then the residue was purified with silica gel column
chromatography(n-hexane:ethyl acetate=3:1) to give
2-(4-fluorobenzyl)furan-3-carboxylic acid methoxymethylamide(2.29
g, yield:64%).
[0897] NMR(CDCl.sub.3).delta.:3.33 (3H, s), 3.61 (3H, s), 4.27 (2H,
s), 6.70 (1H, d, J=1.8 Hz), 6.96 (2H, t like, J=8.7 Hz), 7.24-7.31
(3H, m).
[0898] (A-37) To the above-mentioned compound A-36 (2.29 g, 8.71
mmol) in tetrahydrofuran(40 ml), was added dropwise a
tetrahydrofuran solution of methyl magnesium bromide (26.1 mmol)
under ice cooling, and the mixture was stirred for 1 hour 10
minutes, to which was added a saturated ammonium chloride aqueous
solution and extracted with ethyl acetate. The extract was washed,
dried and evaporated under reduced pressure. The residue was
purified with silica gel column chromatography(n-hexane:ethyl
acetate=5:1) to give 1-[2-(4-fluorobenzyl)furan-3-yl]etanone (1.83
g, yield:97%).
[0899] NMR(CDCl.sub.3) .delta.:2.43 (3H, s), 4.32 (2H, s), 6.63
(1H, d, J=1.8 Hz), 6.96 (2H, t like, J=8.7 Hz), 7.24-7.39 (3H,
m).
[0900] (A-38) According to the method of the example A-18,
4-[2-(4-fluorobenzyl)furan-3-yl]-2-hydroxy-4-oxo-2-butenoic acid
methyl(557 mg, yield:79%) was synthesized by using the
above-mentioned compound A-37 (504 mg, 2.31 mmol).
[0901] Melting point:61-62.degree. C. (diisopropylether)
[0902] NMR(CDCl.sub.3).delta.:3.93 (3H, s), 4.38 (2H, s), 6.67 (1H,
d, J=2.1 Hz), 6.70 (1H, s), 6.98 (2H, t like, J=8.7 Hz), 7.23-7.29
(2H, m), 7.34 (1H, J=2.1 Hz), 15.23 (1H, br.s).
[0903] (A-39) According to the method of the example A-19,
4-[2-(4-fluorobenzyl)furan-3-carbonyl]-3-hydroxy-1-methyl-1,5-dihydropyrr-
ole-2-one (85 mg, yield:40%) was synthesized by using the
above-mentioned compound 21(203 mg, 0.67 mmol).
[0904] Melting point:171-172.degree. C.
[0905] Elementary analysis as C.sub.17H.sub.14FNO.sub.4
[0906] Calcd. (%): C, 64.76; H, 4.48; N, 4.44; F, 6.03. Found (%):
C, 64.74; H, 4.43; N, 4.41; F, 5.88.
[0907] NMR(CDCl.sub.3)(5:3.18 (3H, s), 4.30 (2H, s), 4.38 (2H, s),
6.56 (1H, d, J=2.1 Hz), 6.98 (2H, t like, J=8.7 Hz), 7.26-7.31 (2H,
m), 7.38 (1H, d, J=2.1 Hz).
[0908] According to the same method,
4-[2-(4-fluorobenzyl)furan-3-carbonyl-
]-3-hydroxy-1-isopropyl-1,5-dihydropyrrole-2-one was
synthesized.
[0909] Melting point: 180-182.degree. C.
[0910] Elementary analysis as C.sub.19H.sub.18FNO.sub.4
[0911] Calcd. (%): C, 66.46; H, 5.28; N, 4.08; F, 5.53. Found (%):
C, 66.45; H, 5.26; N, 4.08; F. 5.46.
[0912] NMR(CDCl.sub.3):1.29 (6H, d, J=6.6 Hz), 4.23 (2H, s), 4.38
(2H, s), 4.54-4.63 (1H, m), 6.61 (1H, d, J=2.1 Hz), 6.98 (2H, t
like, J=9 Hz), 7.26-7.31 (2H, m), 7.39 (1H, d, J=2.1 Hz).
[0913] Compound A-50
[0914]
4-[3-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methyl-1,5-dihyd-
ropyrrole-2-one 182183
[0915] (A-40) To a toluene(60 ml) solution of 2-furancarboxylic
acid(11.2 g, 100 mmol), were added thionyl chloride(8.76 ml, 120
mmol) and two drops of N,N-dimethylformamide, and stirred at
80.degree. C. for 4 hours. The solution was Concentrated to give a
crude product of 2-furancarboxylic acid chloride, which was used
without purification to the following reaction.
[0916] (A-41) The above-mentioned A-40 was added to
2-amino-2-methyl-1-propylalcohol(22.3 g, 250 mmol) in methylene
chloride(100 ml) under ice cooling, the mixture was stirred for 21
minutes, then water was added and the solution was extracted with
methylene chloride after salting-out. The extract was dried, then
evaporated under reduced pressure to give a crude product(18 g) of
2-furancarboxylic acid(2-hydroxy-1,1-dimethylethyl)amide. The crude
product was used without purification to the following
reaction.
[0917] (A-42) To a toluene(150 ml) solution of the above-mentioned
crude product A-41, was added thionyl chloride(9.48 ml, 130 mmol)
under ice cooling and stirred at room temperature for 1 hour 20
minutes, to which was Carefully added water(50 ml) and sodium
hydroxide(26 g) aqueous solution(100 ml) under ice cooling. The
solution was extracted with toluene, washed and dried, then
evaporated under reduced pressure. The residue was distilled under
reduced pressure to give
2-furan-2-yl-4,4-dimethyl-4,5-dihydroxazole(12.6 g, total yield of
3 steps: 76%).
[0918] Boiling point: 67-70.degree. C. (3 mmHg)
[0919] NMR(CDCl.sub.3).delta.: 1.39 (6H, s), 4.10 (2H, s),
6.47-6.50 (1H, m), 6.94 (1H, d; J=3.3 Hz), 7.53 (1H, br. s).
[0920] (A-43) To the above-mentioned compound A-42 (11.6 g, 70.3
mmol) in 1,2-dimethoxyethane(290 ml) at -60.degree. C., was added
dropwise n-butyllithium(73.8 mmol) in n-hexane and stirred for 15
minutes, to which was added dropwise 4-fluorobenzaldehyde(9.15 g,
73.8 mmol) in 1,2-dimethoxyethane(20 ml). The mixture was stirred
for 1 hour 10 minutes, then added 1N hydrochloric acid(200
ml)evaporated under reduced pressure and washed with toluene. The
water layer was alkalinized with 2N sodium hydroxide aqueous
solution(100 ml) and extracted with toluene. The extract was
washed, dried and evaporated under reduced pressure to give the
residue, purified with silica gel column
chromatography(toluene:aceto- ne=9:1) to give
[2-(4,4-dimethyl-4,5-dihydroxazole-2-yl)furan-3-yl]-(4-flu-
orophenyl)methyl alcohol(15.1 g, yield: 74%).
[0921] NMR(CDCl.sub.3).delta.: 1.35 (3H, s), 1.40 (3H, s), 4.17
(2H, s), 5.88 (1H, s) 6.13 (1H, d, J=1.8 Hz), 7.03 (2H, t like,
J=8.7 Hz), 7.37-7.43 (3H, m).
[0922] (A-44) To the above-mentioned compound A-43 (14.6 g, 50.5
mmol) in nitromethane(100 ml), added iodomethane(15.7 ml) and the
mixture was stirred at 50.degree. C. for 50 hours, to which was
added diethyl ether(400 ml) at room temperature. The solution was
stirred under ice cooling, then the precipitated crystal was
filtered to give
iodo[2-[3-[(4-fluorophenyl)hydroxy]furan-2-yl]-3,4,4-trimethyl-4,5-dihydr-
oxazole-3-ium].
[0923] Immediately, this crystal was used to the following
reaction.
[0924] (A-45) To the above-mentioned compound A-44 in methyl
alcohol(200 ml), was added 2N sodium hydroxide aqueous solution(101
ml), and the mixture was stirred at room temperature for 1 hour and
evaporated under reduced pressure. Water(150 ml) was added to the
residue, then washed with toluene. The water layer was acidified
with 2N hydrochloric acid(130 ml), and extracted with ethyl
acetate. The extract was washed, dried and evaporated under reduced
pressure to give a crude product(15.0 g) of
3-[(4-fluorophenyl)hydroxymethyl]furan-2-carboxylic acid.
[0925] NMR(CDCl.sub.3).delta.: 5.6 (2H, br, s), 6.23 (1H, s) 6.42
(1H, d, J=1.8 Hz), 7.04 (2H, t like, J=8.7 Hz), 7.37-7.43 (2H, m),
7.53 (1H, d, J=1.8 Hz).
[0926] (A-46) According to the method of A-35,
3-(4-fluorobenzyl)-2-furanc- arboxylic acid (7.72 g: total yield of
3 steps 70%) was synthesized by using the above-mentioned crude
product A-45(15.0 g).
[0927] Melting point:144.degree. C.
[0928] NMR(CDCl.sub.3).delta.: 4.18 (2H, s), 6.31 (1H, d, J=1.8
Hz), 6.99 (2H, t like, J=8.7 Hz), 7.18-7.23 (2H, m), 7.53 (1H, d,
J=1.8 Hz).
[0929] (A-47) According to the method of A-36,
3-(4-fluorobenzyl)-2-furanc- arboxylic acid methokymethylamide(1.87
g:71%) was synthesized by using the above-mentioned compound
A-46(2.20 g).
[0930] NMR(CDCl.sub.3).delta.: 3.33 (3H, s), 3.82 (3H, s), 4.11
(2H, s), 6.24 (1H, d, J=1.8 Hz), 6.96 (2H, t like, J=8.7 Hz),
7.20-7.25 (2H, m), 7.37 (1H, d, J=1.8 Hz).
[0931] (A-48) According to the method of A-37,
1-[3-(4-fluorobenzyl)furan-- 2-yl]etanone(1.99 g:96%) was
synthesized by using the above-mentioned compound A-47(2.50 g).
[0932] NMR(CDCl.sub.3).delta.: 2.51 (3H, s), 4.17 (2H, s), 6.29
(1H, d, J=1.8 Hz), 6.96 (2H, t like, J=8.7 Hz), 7.17-7.23 (2H, m),
7.39 (1H, d, J=1.8 Hz).
[0933] (A-49) According to the method of A-18,
4-[3-(4-fluorobenzyl)furan-- 2-yl]-2-hydroxy-4-oxo-2-butenoic acid
methyl(2.48 g, yield:90%) was synthesized by using the
above-mentioned compound A-48(1.98 g, 9.08 mmol).
[0934] Melting point:100-101.degree. C.
[0935] NMR(CDCl.sub.3).delta.: 3.94 (3H, s), 4.24 (2H, s), 6.36
(1H, d, J=1.5 Hz), 6.98 (2H, t like, J=8.7 Hz), 7.05 (1H, s),
7.18-7.24 (2H, m), 7.51 (1H, d, J=1.5 Hz), 14.73 (1H, br.s).
[0936] (A-50) According to the method of A-19,
4-[3-(4-fluorobenzyl)furan--
2-carbonyl]-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one(112 mg,
yield:54%) was synthesized by using above-mentioned compound 32(200
mg, 0.66 mmol).
[0937] Melting point:208-210.degree. C.
[0938] Elementary analysis as C.sub.17H.sub.14FNO.sub.4
[0939] Calcd. (%): C, 64.76; H, 4.48; N, 4.44; F, 6.03. Found (%):
C, 64.67; H, 4.38; N, 4.33; F, 5.96.
[0940] NMR(CDCl.sub.3) (5:3.18 (3H, s), 4.27 (2H, s), 4.47 (2H, s),
6.40 (1H, d, J=1.8 Hz), 6.99 (2H, t like, J=8.7 Hz), 7.20-7.26 (2H,
m), 7.58 (1H, d, J=1.8 Hz).
[0941] The following compounds were synthesized by the
above-mentioned method.
[0942] (A-50-a)
4-[3-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-isoprop-
yl-1,5-dihydropyrrole-2-one
[0943] Melting point: 197-199.degree. C.
[0944] Elementary analysis as C.sub.19H.sub.18FNO.sub.4
[0945] Calcd. (%): C, 66.46; H, 5.28; N, 4.08; F, 5.53. Found (%):
C, 66.40; H, 5.24; N, 4.04; F, 5.52.
[0946] NMR(CDCl.sub.3).delta.:1.30 (6H, d, J=7.2 Hz), 4.27 (2H, s),
4.41 (2H, s), 4.55-4.66 (1H, m), 6.41 (1H, d, J=1.5 Hz), 6.99 (2H,
t like, J=8.7 Hz), 7.20-7.26 (2H, m), 7.56 (1H, d, J=1.5 Hz).
[0947] (A-50-b)
4-[3-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-hydr-
oxyethyl)-1,5-dihydropyrrole-2-one
[0948] Melting point:195-196.degree. C.
[0949] Elementary analysis as C.sub.18H.sub.16NO.sub.5F
[0950] Calcd. (%) C: 62.61H: 4.67N: 4.06 F: 5.50 Found (%) C:
62.48H: 4.52N: 4.05 F: 5.45
[0951] NMR(DMSO-d.sub.6).delta.: 3.52(m,2H), 3.58(m,2H),
4.19(s,2H), 4.47(s,2H), 6.62(d, 1H, J=1.2 Hz), 7.05-7.15(m, 2H),
7.28-7.35(m,2H), 7.91(d, 1H, J=1.2 Hz).
[0952] (A-50-c)
4-[3-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-meth-
oxyethyl)-1,5-dihydropyrrole-2-one
[0953] Melting point:170.degree. C.
[0954] Elementary analysis as C.sub.19H.sub.18NO.sub.5F
[0955] Calcd. (%) C: 63.50H: 5.05N: 3.90 F: 5.29 Found (%) C:
63.35H: 4.93N: 3.91 F: 5.21
[0956] NMR(DMSO-d.sub.6).delta.: 3.26(s,2H), 3.52(m,2H), 3.60
(m,2H), 4.18(s,2H), 4.43(s,2H), 6.62(d,1H, J=1.2 Hz), 7.05-7.14(m,
2H), 7.28-7.35(m,2H), 7.91(d, 1H, J=1.2 Hz).
[0957] (A-50-d)
1-Ethyl-4-[3-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-
,5-dihydropyrrole-2-one
[0958] Melting point:167.degree. C.
[0959] Elementary analysis as C.sub.18H.sub.16NO.sub.4F
[0960] Calcd. (%) C: 65.65H: 4.90N: 4.25 F: 5.77 Found (%) C:
65.65H: 4.77N: 4.25 F: 5.69
[0961] NMR(DMSO-d.sub.6).delta.: 1.15(t,3H,J=7.2 Hz),
3.48(q,2H,J=7.2 Hz), 4.18(s,2H), 4.40(s,2H), 6.62(d,1H, J=1.2 Hz),
7.05-7.14(m, 2H), 7.28-7.35(m,2H), 7.90(d, 1H, J=1.2 Hz).
[0962] (A-50-e)
1-(2,3-Dihydroxypropyl)-4-[3-(4-fluorobenzyl)furan-2-carbo-
nyl]-3-hydroxy-1,5-dihydropyrrole-2-one
[0963] Melting point:208-210.degree. C.
[0964] Elementary analysis as
C.sub.19H.sub.18NO.sub.6F.0.1H.sub.2O
[0965] Calcd. (%) C: 60.51H: 4.86N: 3.71 F: 5.04 Found (%) C:
60.36H: 4.64N: 3.67 F: 4.95
[0966] NMR(DMSO-d.sub.6).delta.: 3.29-3.36(m,3H), 3.60(dd,
1H,J=14.1 Hz, 3.6 Hz), 3.72 (m, 1H), 4.19(s,2H), 4.45(d,1H,J=18.6
Hz), 4.55(d,1H,J=18.6 Hz), 4.68(m,1H), 4.98(m,1H), 6.62(d,1H, J=1.2
Hz), 7.05-7.14(m, 2H), 7.28-7.35(m,2H), 7.91(d, 1H, J=1.2 Hz).
[0967] Compound A-56
[0968]
4-[3-(4-Fluorobenzyl)-5-methylfuran-2-carbonyl]-3-hydroxy-1-methyl--
1,5-dihydropyrrole-2-one 184185
[0969] (A-51) According to the method of the reference(Tetrahedron
Lett. 1985, 26, p1777), 5-methyl-2-furoin acid(2.64 g, 20.9 mmol)
was reacted with 4-fluorobenzaldehyde(2.7 ml, 25 mmol).
[0970] (A-52) According to the method of the reference (Tetrahedron
1995, 51, p11043), the above-mentioned crude product was reacted
with trimethylsilyl chloride(10.2 ml, 80 mmol) and sodium
iodide(12.0 g, 80 mmol).
[0971] (A-53) According to the method of the example A-36, the
above-mentioned crude product was reacted with
N,O-dimethylhydroxylamine hydrochloride(2.05 g, 21 mmol) to give
3-(4-fluorobenzyl)-5-methyl-2-furo- inacid methoxymethylamide (3.38
g, yield: 58%).
[0972] (A-54) According to the method of the example A-37, the
above-mentioned compound A-53(3.35 g, 12.1 mmol) was reacted with
1M methylmagnesium bromide(24 ml, 24 mmol) to give
1-[3-(4-fluorobenzyl)-5-m- ethylfuran-2-yl]etanone(2.44 g, yield:
87%).
[0973] NMR(CDCl.sub.3).delta.: 2.30(3H, d, J=0.6 Hz), 2.46(3H, s),
4.12(2H, s), 5.92(1H, s), 6.93-6.99(2H, m), 7.17-7.22(2H, m).
[0974] The following compounds were synthesized by the
above-mentioned method.
[0975] 1-[3,5-Bis(4-fluorobenzyl)-5-methylfuran-2-yl] etanone
[0976] NMR(CDCl.sub.3).delta.: 2.45(3H, s), 3.92(2H, s), 4.11(2H,
s), 5.90(1H, s), 6.92-7.03(4H, m), 7.15-7.20(4H, m).
[0977] 1-[5-Tert-butyl-3-(4-fluorobenzyl)furan-2-yl]etanone
[0978] NMR(CDCl.sub.3).delta.: 1.28(9H, s), 2.47(3H, s), 4.13(2H,
s), 5.90(1H, s), 6.93-6.99(2H, m), 7.19-7.24(2H, m).
[0979] 1-[3-(4-Fluorobenzyl)-5-p-tolylfuran-2-yl]etanone
[0980] NMR(CDCl.sub.3).delta.: 2.37(3H, s), 2.58(3H, s), 4.21(2H,
s), 6.47(1H, s), 6.95-7.01(2H, m), 7.20-7.27(4H, m), 7.60(2H, d,
J=8.1 Hz). 1-[3-(4-Fluorobenzyl)-4,5-dimethylfuran-2-yl]etanone
[0981] NMR(CDCl.sub.3).delta.: 1.82(3H, s), 2.26(3H, s), 2.45(3H,
s), 4.13(2H, s), 6.89-6.95(2H, m), 7.15-7.20(2H, m).
[0982] (A-55) According to the method of the example A-38, the
above-mentioned compound A-54 was reacted to give
4-[3-(4-fluorobenzyl)-5-
-methylfuran-2-yl]-2-hydroxy-4-oxo-2-butenoic acid methyl
ester.
[0983] NMR(CDCl.sub.3).delta.: 2.35(3H, d, J=0.6 Hz), 3.94(3H, s),
4.19(2H, s), 6.01(1H, s), 6.95-7.01(2H, m), 7.00(1H, s),
7.19-7.23(2H, m).
[0984] The following compounds were synthesized by the
above-mentioned method.
[0985]
4-[3,5-Bis(4-fluorobenzyl)-5-methylfuran-2-yl]-2-hydroxy-4-oxo-2-bu-
tenoic Acid Methyl Ester
[0986] NMR(CDCl.sub.3).delta.: 3.93(3H, s), 3.95(2H, s), 4.17(2H,
s), 5.96(1H, s), 6.93-7.04(4H, m), 6.97(1H, s), 7.15-7.21(4H, m),
14.84(1H, brs).
[0987]
4-[5-Tert-butyl-3-(4-fluorobenzyl)furan-2-yl]-2-hydroxy-4-oxo-2-but-
enoic Acid Methyl Ester
[0988] NMR(CDCl.sub.3).delta.: 1.30(9H, s), 3.94(3H, s), 4.20(2H,
s), 5.99(1H, s), 6.96-7.02(2H, m), 6.96(1H, s), 7.20-7.25(2H,
m).
[0989]
4-[3-(4-Fluorobenzyl)-5-p-tolylfuran-2-yl]-2-hydroxy-4-oxo-2-buteno-
ic Acid Methyl Ester
[0990] NMR(CDCl.sub.3).delta.: 2.39(3H, s), 3.96(3H, s), 4.27(2H,
s), 6.54(1H, s), 6.98-7.03(2H, m), 7.11(1H, s), 7.22-7.28(4H, m),
7.63(2H, d, J=8.1 Hz).
[0991]
4-[3-(4-Fluorobenzyl)-4,5-dimethylfuran-2-yl]-2-hydroxy-4-oxo-2-but-
enoic Acid Methyl Ester
[0992] NMR(CDCl.sub.3).delta.: 1.84(3H, s), 2.31(3H, s), 3.93(3H,
s), 4.20(2H, s), 6.91-6.97(2H, m), 7.01(1H, s), 7.15-7.20(2H, m),
14.88(1H, brs).
[0993] (A-56) According to the method of the example A-39, the
above-mentioned compound A-55 was reacted to give
4-[3-(4-fluorobenzyl)-5-
-methylfuran-2-carbonyl]-3-hydroxy-l-methyl-1,5-dihydropyrrole-2-one.
[0994] Melting point:154-156.degree. C.
[0995] Elementary analysis as C.sub.18H.sub.16FNO.sub.4
[0996] Calcd. (%): C, 65.65; H, 4.90; N, 4.25; F, 5.77. Found (%):
C, 65.30; H, 4.83; N, 4.05; F, 5.59.
[0997] NMR(CDCl.sub.3).delta.: 2.37(3H, s), 3.18(3H, s), 4.22(2H,
s), 4.43(2H, s), 6.05(1H, s), 6.96-7.01(2H, m), 7.20-7.26(2H,
m).
[0998] The following compounds were synthesized by the
above-mentioned method.
[0999] (A-56-a)
4-[3-(4-Fluorobenzyl)-5-methylfuran-2-carbonyl]-3-hydroxy--
1-isopropyl-1,5-dihydropyrrole-2-one
[1000] Melting point:125-127.degree. C.
[1001] Elementary analysis as C.sub.20H.sub.20FNO.sub.4
[1002] Calcd. (%): C, 67.22; H, 5.64; N, 3.92; F, 5.32. Found (%):
C, 67.95; H, 5.64; N, 3.86; F, 5.64.
[1003] NMR(CDCl.sub.3).delta.: 1.30(6H, d, J=6.7 Hz), 2.38(3H, d,
J=0.9 Hz), 4.22(2H, s), 4.38(2H, s), 4.59(1H, sec, J=6.7 Hz),
6.05(1H, d, J=0.9 Hz), 6.95-7.01(2H, m), 7.20-7.24(2H, m).
[1004] (A-56-b)
4-[3,5-Bis(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-me-
thyl-1,5-dihydropyrrole-2-one
[1005] Melting point: 157-160.degree. C.
[1006] Elementary analysis as C.sub.24H.sub.19F.sub.2NO.sub.4
0.2H.sub.2O
[1007] Calcd. (%): C, 67.51; H, 4.55; N, 3.28; F, 8.90. Found (%):
C, 67.45; H, 4.52; N, 3.21; F, 8.61.
[1008] NMR(CDCl.sub.3).delta.:3.10(3H, s), 3.98(2H, s), 4.09(2H,
s), 4.20(2H, s), 6.08(1H, s), 6.95-7.08(4H, m), 7.17-7.24(4H,
m).
[1009] (A-56-c)
4-[3,5-Bis(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-is-
opropyl-1,5-dihydropyrrole-2-one
[1010] Melting point:159-161.degree. C.
[1011] Elementary analysis as C.sub.26H.sub.23F.sub.2NO.sub.4
[1012] Calcd. (%): C, 69.17; H, 5.14; N, 3.10; F, 8.42. Found (%):
C, 68.94; H, 5.22; N, 3.06; F, 8.07.
[1013] NMR(CDCl.sub.3).delta.: 1.20(6H, d, J=6.7 Hz), 3.98(2H, s),
4.07(2H, s), 4.21(2H, s), 4.54(1H, sec, J=6.7 Hz), 6.18(1H, d,
J=0.9 Hz), 6.96-7.08(4H, m), 7.18-7.24(4H, m).
[1014] (A-56-d)
4-[5-Tert-butyl-3-(4-fluorobenzyl)furan-2-carbonyl]-3-hydr-
oxy-1-methyl-1,5-dihydropyrrole-2-one
[1015] Melting point:179-181.degree. C.
[1016] Elementary analysis as C.sub.21H.sub.22FNO.sub.4
[1017] Calcd. (%): C, 67.91; H, 5.97; N, 3.77; F, 5.12. Found (%):
C, 67.51; H, 5.88; N, 3.62; F, 4.96.
[1018] NMR(CDCl.sub.3).delta.:1.31(9H, s), 3.19(3H, s), 4.22(2H,
s), 4.43(2H, s), 6.02(1H, s), 6.96-7.02(2H, m), 7.21-7.26(2H,
m).
[1019] (A-56-e)
4-[3-(4-Fluorobenzyl)-5-p-tolylfuran-2-carbonyl]-3-hydroxy-
-1-methyl-1,5-dihydropyrrole-2-one
[1020] Melting point:242-245.degree. C.
[1021] Elementary analysis as
C.sub.24H.sub.20FNO.sub.4.0.1H.sub.2O
[1022] Calcd. (%): C, 70.79; H, 5.00; N, 3.44; F, 4.67. Found (%):
C, 70.50; H, 5.17; N, 3.41; F, 4.58.
[1023] NMR(CDCl.sub.3).delta.: 2.41(3H, s), 3.23(3H, s), 4.30(2H,
s), 4.57(2H, s), 6.58(1H, s), 6.98-7.04(2H, m), 7.25-7.30(4H, m),
7.54(2H, d, J=8.1 Hz).
[1024] (A-56-f)
4-[3-(4-Fluorobenzyl)-4,5-dimethylfuran-2-carbonyl]-3-hydr-
oxy-1-methyl-1,5-dihydropyrrole-2-one
[1025] Melting point:202-204.degree. C.
[1026] Elementary analysis as C.sub.19H.sub.18FNO.sub.4
0.2H.sub.2O
[1027] Calcd. (%): C, 66.46; H, 5.28; N, 4.08; F, 5.53. Found (%):
C, 66.46; H, 5.20; N, 4.00; F, 5.44.
[1028] NMR(CDCl.sub.3).delta.: 1.87(3H, s), 2.32(3H, s), 3.18(3H,
s), 4.22(2H, s), 4.43(2H, s), 6.91-6.97(2H, m); 7.17-7.22(2H,
m).
[1029] (A-56-g)
4-[5-Tert-butyl-3-(4-fluorobenzyl)furan-2-carbonyl]-1-ethy-
l-3-hydroxy-1,5-dihydropyrrole-2-one
[1030] Melting point: 141-143.degree. C.
[1031] Elementary analysis as C.sub.22H.sub.24FNO.sub.4
[1032] Calcd. (%): C, 68.56; H, 6.28; N, 3.63; F, 4.93. Found (%):
C, 68.54; H, 6.36; N, 3.63; F, 4.87.
[1033] NMR(CDCl.sub.3).delta.: 1.21(3H, t, J=7.4 Hz), 1.31(9H, s),
3.65(2H, q, J=7.2 Hz), 4.22(2H, s), 4.44(2H, s), 6.02(1H, s),
6.96-7.02(2H, m), 7.21-7.26(2H, m).
[1034] (A-56-h)
4-[5-Tert-butyl-3-(4-fluorobenzyl)furan-2-carbonyl]-3-hydr-
oxy-1-isopropyl-1,5-dihydropyrrole-2-one
[1035] Melting point:146-147.degree. C.
[1036] Elementary analysis as C.sub.23H.sub.26FNO.sub.4
[1037] Calcd. (%): C, 69.16; H, 6.56; N, 3.51; F, 4.76. Found (%):
C, 69.11; H, 6.62; N, 3.50; F, 4.77.
[1038] NMR(CDCl.sub.3).delta.: 1.30(6H, d, J=6.6 Hz), 1.32(9H, s),
4.22(2H, s), 4.40(2H, s), 4.59(1H, seq, J=6.6 Hz), 6.03(1H, s),
6.96-7.02(2H, m), 7.21-7.26(2H, m).
[1039] (A-56-i)
4-[5-Tert-butyl-3-(4-fluorobenzyl)furan-2-carbonyl]-1-cycl-
opropyl-3-hydroxy-1,5-dihydropyrrole-2-one
[1040] Melting point:148-150.degree. C.
[1041] Elementary analysis as C.sub.23H.sub.24FNO.sub.4
0.1H.sub.2O
[1042] Calcd. (%): C, 69.19; H, 6.11; N, 3.51; F, 4.76. Found (%):
C, 68.82; H, 6.17; N, 3.73; F, 4.61.
[1043] NMR(CDCl.sub.3).delta.: 0.83-0.99(4H, m), 1.32(9H, s),
2.92-3.00(1H, m), 4.21(2H, s), 4.36(2H, s), 6.02(1H, s),
6.96-7.02(2H, m), 7.21-7.25(2H, m).
[1044] Compound A-61
[1045]
4-[3-(4-Fluorobenzyl)thiophene-2-carbonyl]-3-hydroxy-1-methyl-1,5-d-
ihydropyrrole-2-one 186
[1046] (A-57) According to the method of the reference(Tetrahedron
Lett. 1985, 26, p1777), 2-thiophenecarboxylic acid(3.84 g, 30 mmol)
was reacted with 4-fluorobenzylbromide(5.6 ml, 45 mmol).
[1047] (A-58) According to the example A-36, the above-mentioned
crude product A-57 was reacted with N, O-dimethylhydroxylamine
hydrochloride(2.93 g, 30 mmol).
[1048] (A-59) According to the example A-37, the above-mentioned
crude product A-58 was reacted with 1M methylmagnesium bromide(30
ml, 30 mmol) to give 1-[3-(4-fluorobenzyl) thiophene-2-yl]
etanone(3.47 g, yield: 49%).
[1049] NMR(CDCl.sub.3).delta.: 2.55(3H, s), 4.36(2H, s), 6.86(1H,
d, J=4.9 Hz), 6.93-6.99(2H, m), 7.15-7.20(2H, m), 7.41(1H, d, J=5.2
Hz).
[1050] (A-60) According to the example A-38, the above-mentioned
crude product A-59 was reacted to give
4-[3-(4-fluorobenzyl)thiophene-2-yl]-2-h- ydroxy-4-oxo-2-butenoic
acid methyl ester.
[1051] NMR(CDCl.sub.3).delta.: 3.93(3H, s), 4.42(2H, s), 6.83(1H,
s), 6.91(1H, d, J=4.9 Hz), 6.95-7.01(2H, m), 7.16-7.21(2H, m),
7.55(1H, d, J=5.2 Hz).
[1052] (A-61) According to the example A-39, the above-mentioned
crude product A-60 was reacted to give
4-[3-(4-fluorobenzyl)thiophene-2-carbony-
l]-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one.
[1053] Melting point: 181-183.degree. C.
[1054] Elementary analysis as C.sub.17H.sub.14FNO.sub.3S
[1055] Calcd. (%): C, 61.62; H, 4.26; N, 4.23; F, 5.73. Found (%):
C, 61.34; H, 4.35; N, 3.99; F, 5.59.
[1056] NMR(CDCl.sub.3).delta.: 3.19(3H, s), 4.42(4H, s), 6.96(1H,
d, J=5.1 Hz), 6.95-7.01(2H, m), 7.18-7.22(2H, m), 7.58(1H, d, J=4.8
Hz).
[1057] The following compound was synthesized by the
above-mentioned method.
[1058]
4-[3-(4-Fluorobenzyl)thiophene-2-carbonyl]-3-hydroxy-1-isopropyl-1,-
5-dihydropyrrole-2-one
[1059] Melting point:174-175.degree. C.
[1060] Elementary analysis as C.sub.19H.sub.18FNO.sub.3S
0.1H.sub.2O
[1061] Calcd. (%): C, 63.18; H, 5.08; N, 3.88; F, 5.26. Found (%):
C, 62.93; H, 5.03; N, 3.78; F, 5.08.
[1062] NMR(CDCl.sub.3).delta.:1.31(6H, d, J=6.7 Hz), 4.34(2H, s),
4.42(2H, s), 4.60(1H, sec, J=6.7 Hz), 6.96(1H, d, J=5.2 Hz),
6.95-7.01(2H, m), 7.18-7.22(2H, m), 7.58(1H, d, H=4.9 Hz).
[1063] Compound A-69
[1064]
4-[5-(4-Fluorobenzyl)-2-methyloxazole-4-carbonyl]-3-hydroxy-1-methy-
l-1,5-dihydropyrrole-2-one 187188
[1065] (A-62) According to the method of the reference(Org. Synth.
Col. VII, 1990, p359), 4-fluorophenylacetyl chloride(27.6 g, 160
mmol) was reacted with meldrum's acid in the presence of pyridine,
then reacted with methyl alcohol to give
4-(4-fluorophenyl)-3-oxobutanoic acid methyl ester1(28.9 g,
yield:86%).
[1066] NMR(CDCl.sub.3).delta.: 3.47(2H, s), 3.72(3H, s), 3.81(2H,
s), 7.00-7.06(2H, m), 7.15-7.20(2H, m).
[1067] (A-63) According to the method of the reference(Org. Synth.
1992, 70, p93), the above-mentioned compound A-62(4.20 g, 20 mmol)
was reacted with 4-acetamidebenzenesulfonyl azide in the presence
of triethylamine to give 2-diazo-4-(4-fluorophenyl)-3-oxobutanoic
acid methyl ester 2a(3.67 g, yield:78%).
[1068] NMR(CDCl.sub.3).delta.: 3.85(3H, s), 4.16(2H, s),
6.97-7.03(2H, m), 7.23-7.28(2H, m).
[1069] According to the method of the reference(J. Org. Chem. 1962,
27, p1717), 2-diazo-5-(4-fluorophenyl)-3-oxopentanoic acid methyl
ester was prepared from the known compound
5-(4-fluorophenyl)-3-oxopentanoic acid methyl ester.
[1070] NMR(CDCl.sub.3).delta.:2.93(2H, t, J=7.5 Hz), 3.13-3.18(2H,
m), 3.83(3H, s), 6.93-6.99(2H, m), 7.17-7.21(2H, m).
[1071] (A-64) According to the method of the reference(Synthesis,
1993, p793), the above-mentioned compound A-63(2.92 g, 12.4 mmol)
was reacted with acetonitrile in the presence of boron trifluoride
to give 5-(4-fluorobenzyl)-2-methyloxazole-4-carboxylic acid methyl
ester(1.72 g, yield:56%).
[1072] NMR(CDCl.sub.3).delta.: 2.43(3H, s), 3.93(3H, s), 4.31(2H,
s), 6.97-7.02(2H, m), 7.23-7.28(2H, m).
[1073] The following compound was synthesized by the
above-mentioned method.
[1074] 5-[2-(4-Fluorophenyl)ethyl]-2-methyloxazole-4-carboxylic
Acid Methyl Ester
[1075] NMR(CDCl.sub.3).delta.: 2.44(3H,s), 2.95(2H, t, J=7.8 Hz),
3.27(2H, dd, J=6.9, 8.7 Hz), 3.87(3H, s), 6.94-6.99(2H, m),
7.12-7.17(2H, m).
[1076] (A-65) The above-mentioned compound A-64(1.70 g, 6.82 mmol)
washedydrolyzed to give
5-(4-fluorobenzyl)-2-methyloxazole-4-carboxylic acid(l.27 g,
yield:79%).
[1077] NMR(CDCl.sub.3).delta.: 2.31(3H, s), 4.29(2H, s),
6.90-6.96(2H, m), 7.22-7.26(2H, m).
[1078] The following compound was synthesized by the
above-mentioned method.
[1079] 5-[2-(4-Fluorophenyl)ethyl]-2-methyloxazole-4-carboxylic
Acid
[1080] NMR(CDCl.sub.3).delta.: 2.49(3H,s), 2.97(2H, t, J=8.0 Hz),
3.30(2H, dd, J=6.9, 8.7 Hz), 6.94-7.00(2H, m), 7.12-7.17(2H,
m).
[1081] (A-66) According to the method of the example A-36, the
above-mentioned compound A-65(1.25 g, 5.31 mmol) was reacted with
N,O-dimethylhydroxylamine hydrochloride(1.53 g, 8.0 mmol) to give
5-(4-fluorobenzyl)-2-methyloxazole-4-carboxylic acid
methoxymethylamide (1.30 g, yield:88%).
[1082] NMR(CDCl.sub.3).delta.: 2.40(3H, s), 3.43(3H, s), 3.80(3H,
s), 4.22(2H, s), 6.95-7.01(2H, m), 7.28-7.33(2H, m).
[1083] The following compound was synthesized by the
above-mentioned method.
[1084] 5-[2-(4-Fluorophenyl)ethyl]-2-methyloxazole-4-carboxylic
acid methoxymethylamide 5b
[1085] NMR(CDCl.sub.3).delta.:2.42(3H,s), 2.94(2H, t, J=8.1 Hz),
3.20(2H, dd, J=6.8, 8.9 Hz), 3.37(3H, s), 3.76(3H, s),
6.92-6.98(2H, m), 7.13-7.18(2H, m).
[1086] (A-67) According to the method of the example A-37, the
above-mentioned compound A-66(1.28 g, 4.6 mmol) was reacted with 1M
methylmagnesium bromide(9.2 ml, 9.2 mmol)to give
1-[5-(4-fluorobenzyl)-2-- methyloxazole-4-yl] etanone A-7(0.89 g,
yield:83%).
[1087] NMR(CDCl.sub.3).delta.: 2.42(3H, s), 2.54(3H, s), 4.30(2H,
s), 6.95-7.01(2H, m), 7.24-7.29(2H, m).
[1088] The following compound was synthesized by the
above-mentioned method.
[1089]
1-{5-[2-(4-Fluorophenyl)ethyl]-2-methyloxazole-4-yl}etanone
[1090] NMR(CDCl.sub.3).delta.: 2.43(3H,s), 2.49(3H, s), 2.93(2H, t,
J=8.0 Hz), 3.27(2H, dd, J=7.1, 8.9 Hz), 6.93-6.99(2H, m),
7.12-7.17(2H, m).
[1091] (A-68) According to the method of the example A-38, the
above-mentioned compound A-67 was reacted to give
4-[5-(4-fluorobenzyl)-2-
-methyloxazole4-carbonyl]-2-hydroxy4-oxo2-butenoic
acidmethylester.
[1092] NMR(CDCl.sub.3).delta.: 2.44(3H, s), 3.92(3H, s), 4.36(2H,
s), 6.97-7.03(2H, m), 7.19(1H, s), 7.25-7.30(2H, m), 14.82(1H,
brs).
[1093] The following compound was synthesized by the
above-mentioned method.
[1094]
4-{5-[2-(4-Fluorophenyl)ethyl]-2-methyloxazole-4-carbonyl}-2-hydrox-
y-4-oxo-2-butenoic Acid Methyl Ester
[1095] NMR(CDCl.sub.3).delta.: 2.45(3H,s), 2.97(2H, t, J=7.8 Hz),
3.33(2H, dd, J=6.8, 8.9 Hz), 3.91(3H, s), 6.94-7.00(2H, m),
7.13-7.19(2H, m), 7.14(1H,s), 14.70(1H, brs).
[1096] (A-69) According to the method of the example A-39, the
above-mentioned compound A-68 was reacted to give
4-[5-(4-fluorobenzyl)-2-
-methyloxazole-4-carbonyl]-3-hydroxyl-methyl-1,5-dihydropyrrole-2-one.
[1097] Melting point: 170.degree. C.
[1098] Elementary analysis as C.sub.17H.sub.15FN.sub.2O.sub.4
[1099] Calcd. (%): C, 61.82; H, 4.58; N, 8.48; F, 5.75. Found (%):
C, 61.66; H, 4.57; N, 8.45; F, 5.64.
[1100] NMR(CDCl.sub.3).delta.: 2.56(3H, s), 3.15(3H, s), 4.15(2H,
d, J=0.6 Hz), 4.41(2H, s), 6.97-7.03(2H, m), 7.26-7.31(2H, m),
15.08(1H, brs).
[1101] The following compound was synthesized by the
above-mentioned method.
[1102]
4-[5-(4-Fluorobenzyl)-2-methyloxazole-4-carbonyl]-3-hydroxy-1-isopr-
opyl-1,5-dihydropyrrole-2-one
[1103] Negative ESIMS m/Z.sup.357 (M-H).sup.-
[1104] Positive ESIMS m/Z.sup.359 (M+H).sup.+
[1105] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=5.3 Hz), 2.57(3H, s),
4.08(2H, s), 4.14(2H, s), 4.54(1H, sec, J=6.6 Hz), 6.97-7.02(2H,
m), 7.27-7.32(2H, m), 15.03(1H, brs).
[1106]
4-{5-[2-(4-Fluorophenyl)ethyl]-2-methyloxazole-4-carbonyl}-3-hydrox-
y-1-methyl 1,5-dihydropyrrole-2-one
[1107] Melting point:184-185.degree. C.
[1108] Elementary analysis as C.sub.18H.sub.17FN.sub.2O.sub.4
[1109] Calcd. (%): C, 62.79; H, 4.98; N, 8.14; F, 5.52. Found (%):
C, 62.57; H, 4.91; N, 8.03; F, 5.37.
[1110] NMR(CDCl.sub.3).delta.: 2.56(3H, s), 2.98(2H, t, J=7.2 Hz),
3.14(3H, s), 3.38(2H, dd, J=6.9, 8.7 Hz), 4.07(2H, s),
6.94-7.00(2H, m), 7.15-7.19(2H, m), 15.11(1H, brs).
[1111] Compound A-73
[1112]
4-[2-(4-Fluorobenzyl)-1H-imidazole-4-carbonyl]-3-hydroxy-1-isopropy-
l-1,5-dihydropyrrole-2-one 189
[1113] (A-70) According to the method of the reference(J. Org.
Chem. 1987, 52, p2714), (5-methylisoxazole-4-yl)amine
hydrochloride(16.15 g, 120 mmol) was reacted with
4-fluorophenylacetyl chloride(20.8 g, 120 mmol) in the presence of
triethylamine to give 2-(4-fluorophenyl)-N-(5-methylisoxa-
zole-4-yl)acetamide (22.55 g, yield: 80%).
[1114] NMR(CDCl.sub.3).delta.: 2.28(3H, s), 3.69(3H, s), 6.71(1H,
brs), 7.06-7.20(2H, m), 7.26-7.32(2H, m), 8.46(1H, s).
[1115] (A-71) The above-mentioned compound A-70 was reduced by
hydrogenation, then treated with sodium hydroxideto give
1-[2-(4-fluorobenzyl)-1H-imidazole-4-yl]etanone (yield:82%).
[1116] NMR(CDCl.sub.3).delta.: 2.45(3H, s), 4.12(2H, s),
6.96-7.01(2H, m), 7.19-7.23(2H, m), 7.64(1H, s).
[1117] (A-72) The above-mentioned compound A-71 was protected with
a BOC group, then according to the method of the example A-38,
2-(4-fluorobenzyl)-4-(3-hydroxy-3-methoxycarbonylacryloyl)imidazole-4-car-
boxylic acid tert-butyl ester was synthesized.
[1118] NMR(CDCl.sub.3).delta.: 1.55(9H, s), 3.93(3H, s), 4.41(2H,
s), 6.94-7.00(2H, m), 7.17(1H, s), 7.19-7.23(2H, m), 8.06(1H,
s).
[1119] (A-73) A-72 was reacted according to the method of exammple
A-39 to give a mixture comprising a de-protected product. The
mixture was deprotected by using trifluoroacetic acid to give
4-[2-(4-fluorobenzyl)-1-
H-imidazole-4-carbonyl]-3-hydroxy-1-isopropyl-1,5-dihydropyrrole-2-one.
[1120] Melting point:220.degree. C.
[1121] Elementary analysis as C.sub.18H.sub.18FN.sub.3O.sub.3
0.2H.sub.2O
[1122] Calcd. (%): C, 62.31; H, 5.35; N, 12.11; F, 5.48. Found (%):
C, 62.13; H, 5.07; N, 11.94; F, 5.57.
[1123] NMR(CDCl.sub.3).delta.:1.24(6H, d, J=6.7 Hz), 4.05(2H, s),
4.12(2H, s), 4.52(1H, sec, J=6.7 Hz), 6.98-7.03(2H, m),
7.24-7.29(2H, m), 7.64(1H, s).
[1124] Compound A-78-a 190
[1125] (A-74-a, A-74-b) To a dimethylformamide solution(30 ml) of
1H-imidazole-4-carboaldehyde(2.88 g, 30 mmol), potassium
tert-butoxide(3.7 g, 33 mmol) and 4-fluorobenzylbromide(3.74 ml, 30
mmol) were added under ice cooling, then, the mixture was stirred
for 1 hour. The solution was added a saturated ammonium chloride
aqueous solution and extracted with ethyl acetate, washed with
water and brine, dried and evaporated under reduced pressure. The
residue was purified with silica gel column chromatography to give
1-(4-fluorobenzyl)-1H-imidazole-4-carbo- aldehyde A-74-a(2.7 g,
yield:44%); NMR(CDCl.sub.3).delta.: 5.18(2H, s), 7.06-7.18(2H, m),
7.20-7.23(2H, m), 7.60(1H, d, J=1.1 Hz), 7.62(1H, s), 9.87(1H, s)
and 3-(4-fluorobenzyl)-3H-imidazole-4-carboaldehyde A-74-b (2.95 g,
yield:48%);
[1126] NMR(CDCl.sub.3).delta.: 5.49(2H, s), 7.00-7.06(2H, m),
7.21-7.24(2H, m), 7.72(1H, s), 7.84(1H, s), 9.75(1H, d, J=0.9
Hz).
[1127] (A-75-a) To a tetrahydrofuran solution(30 ml) of the
above-mentioned compound A-74-a(2.7 g, 13.2 mmol), was added
dropwise 1M methylmagnesium bromide(16 ml, 16 mmol) under ice
cooling at room temperature, the mixture was stirred for 1.5 hours,
then was added dropwise 1M methylmagnesium bromide(16 ml, 16 mmol).
The solution was stirred for 1.5 hours, then was added a saturated
ammonium chloride aqueous solution and extracted with ethyl
acetate, washed with water and brine. The solution was dried and
evaporated under reduced pressure. The residue was purified with
silica gel column chromatography to give
1-[1-(4-fluorobenzyl)-1H-imidazole-4-yl]ethanol(2.75 g, yield:
95%).
[1128] NMR(CDCl.sub.3).delta.: 1.50(3H, d, J=6.4 Hz), 3.04(1H,
brs), 4.86(1H, q, J=6.6 Hz), 5.03(2H, s), 6.76(1H, s),
7.01-7.08(2H, m), 7.13-7.17(2H, m), 7.47(1H, d, J=1.3 Hz).
[1129] (A-75-b) The following compound was synthesized by the
above-mentioned method from the compound A-74-b.
[1130] 1-[3-(4-Fluorobenzyl)-3H-imidazole-4-yl]ethanol.
[1131] NMR(DMSO-d.sub.6).delta.: 1.36(3H, d, J=6.7 Hz), 4.55(1H,
m), 5.18(1H, q, J=6.1 Hz), 5.25(2H, s), 6.81(1H, t, J=0.9 Hz),
7.17-7.22(4H, m), 7.65(1H, d, J=1.2 Hz).
[1132] (A-76-a) To a tetrahydrofuran solution(60 ml) of the
above-mentioned compound A-75-a(2.48 g, 11.3 mmol), was added
manganese dioxide(9.56 g, 110 mmol) at room temperature, then the
mixture was stirred for 2.5 hours. The solution was filtered by
celite, then evaporated under reduced pressure and the residue was
recrystallized with diisopropylether-ethyl acetate to give
1-[1-(4-fluorobenzyl)-1H-imidazole- -4-yl]etanone(1.77 g,
yield:72%).
[1133] NMR(CDCl.sub.3).delta.: 2.55(3H, s), 5.12(2H, s),
7.05-7.10(2H, m), 7.16-7.21(2H, m), 7.54-7.56(2H, m).
[1134] (A-76-b) The following compound was synthesized by the
above-mentioned method from the compound A-75-b.
[1135] 1-[3-(4-Fluorobenzyl)-3H-imidazole-4-yl]etanone.
[1136] NMR(CDCl.sub.3).delta.: 2.55(3H, s), 5.49(2H, s),
6.99-7.04(2H, m), 7.15-7.20(2H, m), 7.64(1H, s), 7.82(1H, s).
[1137] (A-77-a) According to the method of the above-mentioned
example A-39,
4-[1-(4-fluorobenzyl)-1H-imidazole-4-carbonyl]-2-hydroxy-4-oxo-2-bu-
tenoic acid methyl ester was synthesized from the compound
A-76-a.
[1138] NMR(DMSO-d.sub.6).delta.: 3.65(3H, s), 5.18(2H, s),
7.12-7.18(2H, m), 7.32-7.37(2H, m), 7.54(1H, brs), 7.67(1H,
brs).
[1139] (A-77-b) The following compound was synthesized by the
above-mentioned method from the compound A-76-b.
[1140]
4-[3-(4-Fluorobenzyl)-3H-imidazole-4-carbonyl]-2-hydroxy-4-oxo-2-bu-
tenoic Acid Methyl Ester
[1141] NMR(CDCl.sub.3).delta.: 3.71(3H, s), 5.43(2H, s), 6.46(1H,
s), 6.81-6.87(2H, m), 7.06-7.10(2H, m), 7.52(1H, s), 7.65(1H,
s).
[1142] (A-78-a) According to the method of the above-mentioned
example A-39,
4-[1-(4-fluorobenzyl)-1H-imidazole-4-carbonyl]-3-hydroxy-1-isopropy-
l-1,5-dihydropyrrole-2-one was synthesized from the compound
A-77-a.
[1143] Melting point:224-226.degree. C.
[1144] Elementary analysis as C.sub.18H.sub.18FN.sub.3O.sub.3
[1145] Calcd. (%): C, 62.97; H, 5.28; N, 12.24; F, 5.53. Found (%):
C, 62.57; H, 5.15; N, 12.02; F, 5.27.
[1146] NMR(DMSO-d.sub.6).delta.: 1.18(6H, d, J=6.7 Hz), 3.97(2H,
s), 4.25(1H, sec, J=6.7 Hz), 5.37(2H, s), 7.21-7.27(2H, m),
7.47-7.52(2H, m), 8.17(1H, s), 8.48(1H, s).
[1147] (A-78-b) The following compound was synthesized by the
above-mentioned method from the compound A-77-b.
[1148]
4-[3-(4-Fluorobenzyl)-3H-imidazole-4-carbonyl]-3-hydroxy-1-isopropy-
l-1,5-dihydropyrrole-2-one
[1149] Melting point:156-159.degree. C.
[1150] Negative ESIMS m/z 342 (M-H).sup.-
[1151] Positive ESIMS m/z 344 (M+H).sup.+
[1152] NMR(DMSO-d.sub.8)d: 1.17(6H, d, J=6.7 Hz), 4.02(2H, s),
4.21(1H, sec, J=6.7 Hz), 5.55(2H, s), 7.03(2H, brt), 7.21-7.25(2H,
m), 7.90(1H, brs), 8.11(1H, brs).
[1153] Compound A-84
[1154]
4-[5-(4-Fluorobenzyl)-1H-pyrrole-2-carbonyl]-3-hydroxy-1-methyl-1,5-
-dihydropyrrole-2-one 191
[1155] (A-79) According to the method of the reference(J. Org.
Chem., 1983, 48, p3214), 1-benzenesulfonyl 1H-pyrrole(J. Org.
Chem., 1999, 64, p3379)(45.0 g, 217 mmol) was reacted with
4-fluorobenzoyl chloride(103 g, 651 mmol) in the presence of boron
trifluoride-diethyl ether complex(80.1 ml, 651 mmol) in methylene
chloride(360 ml) to give
2-(4-fluorophenyl)-N-(5-methylisoxazole-4-yl)acetamide(22.55 g,
yield:80%). The residue was Crystallized(diisopropylether-n-hexane)
to give
(1-benzenesulfonyl1H-pyrrole-2-yl)-(4-fluorophenyl)metanone(33 g,
yield:46%).
[1156] NMR(CDCl.sub.3).delta.: 6.36(1H, dd, J=3.3, 3.6 Hz),
6.70(1H, dd, J=1.5, 3.6 Hz), 7.08-7.15(2H, m), 7.55-7.70(3H, m),
7.78(1H, dd, J=1.5, 3.3 Hz), 7.80-7.89(2H, m), 8.00-8.14(2H,
m).
[1157] (A-80) According to the method of the reference(Synth.
Comm., 1990, 20, p1647), the above-mentioned compound A-79(32.5 g,
98.7 mmol) was reduced by borane tert-butylamine complex(51.5 g,
0.59 mol) in the presence of aluminum chloride(39.5 g, 0.30 mol) in
methylene chloride(150 ml). The residue was purified with column
chromatography(ethyl acetate:n-hexane=1:4-1:3) to give
1-benzenesulfonyl-2-(4-fluorobenzyl)-1H- -pyrrole(26.9 g,
yield:86%).
[1158] NMR(CDCl.sub.3).delta.:4.05(2H, s), 5.81(1H, dd, J=1.5, 3.3
Hz), 6.21(1H, t, J=1.5 Hz), 6.81-7.01(4H, m), 7.34(1H, dd, J=1.5,
3.3 Hz), 7.37-7.44(2H, m), 7.52-7.61(3H, m).
[1159] (A-81) To a methyl alcohol(400 ml) solution of the
above-mentioned compound A-80(26.9 g, 86.5 mmol), was added 5N
sodium hydroxide aqueous solution 85 ml, and the reaction mixture
was stirred for 6 hours under refluxing. The solution was Cooled at
room temperature, to which was added 2N hydrochloric acid 185 ml,
then extracted with ethyl acetate. The extract was washed with
saturated NaCl aqueous solution, dried, then evaporated under
reduced pressure. The residue was purified with column
chromatography(ethyl acetate:n-hexane=1:3)to give
2-(4-fluorobenzyl)-1H-p- yrrole(14.5 g, yield:97%).
[1160] NMR(CDCl.sub.3).delta.: 3.95(2H, s), 5.97(1H, s), 6.15(1H,
dd, J=2.7, 5.7 Hz), 6.68(1H, dd, J=2.7, 4.2 Hz), 6.94-7.02(2H, m),
7.12-7.19(2H, m), 7.82(1H, brs).
[1161] (A-82) To phosphorus oxychloride(7.33 ml, 78.6 mmol) at room
temperature, was added dropwise DMA(12.5 ml)for 20 minutes under
stirring, to which was added dropwise a DMA(12.5 ml) solution of
the above-mentioned compound A-81(12.5 g, 71.3 mmol) at room
temperature. The solution was stirred at 50.degree. C. for 3 hours,
to which was added 5N sodium hydroxide aqueous solution 86 ml under
ice-water cooling, to which was added 6N hydrochloric acid 30 ml
and extracted with ethyl acetate. The extract was washed with
water, and saturated NaCl aqueous solution, dried, then evaporated
under reduced pressure. The residue was Crystallized with
diisopropylether 40 ml and filtered out, then washed with
diisopropylether, dried to give
1-[5-(4-fluorobenzyl)-1H-pyrrole-2-y- l]etanone(5.65 g, yield:36%).
The filtrate was Concentrated under reduced pressure, then the
residue was purified with column chromatography(ethyl
acetate:n-hexane=1:3-1:2)and recrystallized(diisopropylether) to
give 1-[5-(4-fluorobenzyl)-1H-pyrrole-2-yl]etanone(3.85 g,
yield:25%).
[1162] NMR(CDCl.sub.3).delta.: 3.37(3H, s), 3.96(2H, s),
6.00-6.04(1H, m), 6.82-6.86(1H, m), 6.96-7.05(2H, m), 7.12-7.18(2H,
m), 9.11(1H, brs).
[1163] (A-83) According to the method of the above-mentioned
example A-18,
4-[5-(4-fluorobenzyl)-1H-pyrrole-2-yl]-2-hydroxy-4-oxo-2-butenoic
acid methyl ester was synthesized from the above-mentioned compound
A-82.
[1164] NMR(CDCl.sub.3).delta.: 3.92(3H, s), 4.00(2H, s),
6.10-6.13(1H, m), 6.75(1H, s), 6.97-7.06(3H, m), 7.12-7.19(2H, m),
9.09(1H, brs).
[1165] (A-84) According to the method of the above-mentioned
example A-19,
4-[5-(4-fluorobenzyl)-1H-pyrrole-2-carbony-l]-3-hydroxy-1-methyl-1,5-dihy-
dropyrrole-2-one was synthesized from the above-mentioned compound
A-83.
[1166] NMR(DMSO-d.sub.6): 3.00(3H, s), 3.95(2H, s), 4.22(2H, s),
5.97-6.03(1H, m), 7.06-7.16(3H, m), 7.26-7.34(2H, m), 12.00(1H,
brs).
[1167] Melting point:221-223.degree. C.
[1168] Elementary analysis as C.sub.17H.sub.15FN.sub.2O.sub.3
[1169] Calcd. (%): C, 64.96; H, 4.81; N, 8.91; F, 6.04. Found (%):
C, 64.87; H, 4.68; N, 8.80; F, 6.10.
[1170] The following compound was synthesized by the
above-mentioned method.
[1171]
4-[5-(4-Fluorobenzyl)-1H-pyrrole-2-carbonyl]-3-hydroxy-1-isopropyl--
1,5-dihydropyrrole-2-one
[1172] NMR(DMSO-d.sub.6).delta.: 1.20(6H, d, J=6.9 Hz), 3.95(2H,
s), 4.17(2H, s), 4.19-4.31(1H, m), 5.99-6.03(1H, m), 7.07-7.18(3H,
m), 7.27-7.35(2H, m), 11.96(1H, brs).
[1173] Melting point:222-224.degree. C.
[1174] Elementary analysis as C.sub.19H.sub.19FN.sub.2O.sub.3
[1175] Calcd. (%): C, 66.66; H, 5.59; N, 8.18; F, 5.55. Found (%):
C, 66.66; H, 5.49; N, 8.12; F, 5.62.
[1176] Compound A-89
[1177]
4-[4-(4-Fluorobenzyl)-1H-pyrrole-3-carbonyl]-3-hydroxy-1-methyl-1,5-
-dihydropyrrole-2-one 192
[1178] (A-85) According to the method of the reference(J. Org.
Chem., 1983, 48, p3214), 1-benzenesulfonyl-1H-pyrrole(J. Org.
Chem., 1999, 64, p3379) was reacted with 4-fluorobenzoyl
chloride(2.88 ml, 26.5 mmol) in the presence of aluminum
chloride(3.25 g, 26.5 mmol) in methylene chloride(40 ml) to give a
crude ketone(9.15 g) which was reduced by borane tert-butylamine
complex(11.6 g, 133 mmol) in the presence of aluminum chloride(8.88
g, 66.6 mmol) in methylene chloride(200 ml) according to the method
of the reference(Synth. Comm., 1990, 20, p1647). The residue was
purified with column chromatography(ethyl acetate:n-hexane=1:4-1:3)
to give 1-benzenesulfonyl-3-(4-fluorobenzyl)-1H- -pyrrole(4.66 g,
yield:61%).
[1179] NMR(CDCl.sub.3).delta.: 3.70(2H, s), 6.10(1H, dd, J=1.5, 3.0
Hz), 6.86-7.12(6H, m), 7.46-7.64(3H, m), 7.80-7.85(2H, m).
[1180] (A-86) To a methylene chloride(35 ml) suspension of aluminum
chloride(4.33 g, 32.5 mmol) at room temperature, was added dropwise
a methylene chloride(5 ml) solution of acetic anhydride(1.66 g,
16.3 mmol)for 15 minutes under stirring, to which a methylene
chloride(10 ml) solution of the above-mentioned compound A-85(4.66
g, 14.8 mmol) was added dropwise under ice cooling. The solution
was stirred for 1 hour under ice cooling, then for 30 minutes at
room temperature, to which was added ice water and extracted with
ethyl acetate. The extract was washed with a saturated sodium
hydrogen carbonate aqueous solution and a saturated NaCl aqueous
solution, then dried and evaporated under reduced pressure. The
residue was Crystallized by diisopropyl ether and n-hexane and
filtered out. The filtrate was evaporated under reduced pressure,
then the residue was purified with column chromatography(ethyl
acetate:n-hexane=1:3-1:2) and crystallized with(diisopropyl
ether-n-hexane) to give
1-[1-benzenesulfonyl-4-(4-fluorobenzyl)-1H-pyrrol-
e-3-yl]etanone(3.57 g, yield:68%).
[1181] NMR(CDCl.sub.3).delta.: 2.39(3H, s), 3.98(2H, s), 6.66-6.89
(1H, m), 6.91-7.15(4H, m), 7.52-7.89(6H, m).
[1182] (A-87) According to the method of the above-mentioned
example A-18,
4-[1-benzenesulfonyl-4-(4-fluorobenzyl)-1H-pyrrole-3-yl]-2-hydroxy-4-oxo--
2-butenoic acid methyl ester was synthesized from the
above-mentioned compound A-86.
[1183] NMR(CDCl.sub.3).delta.:3.93(3H, s), 4.03(2H, s),
6.72-6.74(1H, m), 6.93-7.15(4H, m), 7.53-7.92(6H, m).
[1184] (A-88) According to the method of the above-mentioned
example A-19,
4-[1-benzenesulfonyl-4-(4-fluorobenzyl)-1H-pyrrole-3-carbonyl]-3-hydroxy--
1-methyl-1,5-dihydropyrrole-2-one was synthesized from the
above-mentioned compound A-87.
[1185] NMR(DMSO-d.sub.6)d: 2.99(3H, s), 3.90(2H, s), 4.02(2H, s),
7.00-7.21(6H, m), 7.63-7.82(3H, m), 7.97-8.14 (3H, m).
[1186] The following compound was synthesized by the
above-mentioned method.
[1187]
4-[1-Benzenesulfonyl-4-(4-fluorobenzyl)-1H-pyrrole-3-carbonyl]-3-hy-
droxy-1-isopropyl-1,5-dihydropyrrole-2-one
[1188] NMR(DMSO-d.sub.6).delta.: 1.18(6H, d, J=6.7 Hz), 3.90(2H,
s), 3.97(2H, s), 4.16-4.31(1H, m), 7.05-7.15(6H, m), 7.63-7.82(5H,
m), 8.13(2H, brs).
[1189] (A-89) According to the method of the reference(J. Org.
Chem., 1983, 48, p3214), the protected NH group of the pyrrole ring
of the above-mentioned compound A-88 was deprotected by hydrolysis
to give
4-[4-(4-fluorobenzyl)-1H-pyrrole-3-carbonyl]-3-hydroxy-1-methyl-1,5-dihyd-
ropyrrole-2-one.
[1190] NMR(DMSO-d.sub.6).delta.: 2.99(3H, s), 4.02(2H, s), 4.19(2H,
s), 6.54(1H, s), 7.00-7.27(4H, m), 7.62(1H, s), 11.41(1H, brs).
[1191] Melting point:265-267.degree. C.
[1192] Elementary analysis as C.sub.17H.sub.15FN.sub.2O.sub.3
0.1H.sub.2O
[1193] Calcd. (%): C, 64.59; H, 4.85; N, 8.86; F, 6.01. Found (%):
C, 64.54; H, 4.72; N, 8.82; F, 5.89.
[1194] The following compound was synthesized by the
above-mentioned method.
4-[4-(4-Fluorobenzyl)-1H-pyrrole-3-carbonyl]-3-hydroxy-1-isopropy-
l-1,5-dihydropyrrole-2-one
[1195] NMR(DMSO-d.sub.6).delta.: 1.20(6H, d, J=6.7 Hz), 4.02(2H,
s), 4.14(2H, s), 4.18-4.32(1H, m), 6.56(1H, s), 7.00-7.26(4H, m),
7.68(1H, s), 11.39(1H, brs).
[1196] Melting point:255-258.degree. C.
[1197] Elementary analysis as C.sub.1 gH,.sub.9FN.sub.2O.sub.3
0.2H.sub.2O
[1198] Calcd. (%): C, 65.96; H, 5.65; N, 8.10; F, 5.49. Found (%):
C, 66.06; H, 5.45; N, 8.01; F, 5.42. Compound A-92
[1199]
4-[1-(4-Fluorobenzyl)-1H-pyrrole-2-carbonyl]-3-hydroxy-1-methyl-1,5-
-dihydropyrrole-2-one 193
[1200] (A-90) Sodium hydride(5 g, 12.5 mmol) was washed with
n-hexane, then dried and suspend in dimethylformamide 100 ml, to
which were added 2-acetylpyrrole(10.9 g, 10 mmol) and
4-fluorobenzyl bromide(20 g, 10.6 mmol) under ice cooling. Then the
mixture was stirred at room temperature for 1 hour and added to an
ammonium chloride solution. The solution was extracted with ethyl
ether, then washed, dried and evaporated under reduced pressure.
The residue was purified with column chromatography(ethyl
acetate:n-hexane=1:10) to give the objective compound 21;4 g(yield
99%).
[1201] NMR(CDCl.sub.3).delta.: 2.41(s, 3H), 5.53(s, 2H), 6.20(dd,
1H, J=3.9 Hz, 2.4 Hz), 6.90(m, 1H), 6.92-7.02(m, 3H), 7.07-7.12(m,
2H).
[1202] (A-91) To a tetrahydrofuran 40 ml solution of the
above-mentioned compound A-90(4.35 g, 20 mmol), lithium hexamethyl
disilazide(1N tetrahydrofuran solution, 24 ml) was added dropwise
at -78.degree. C. 10 Minutes later, oxalic acid dimethyl(2.83 g, 24
mmol) was added thereto and stirred at 0.degree. C. for 30 minutes.
The solution was added to ice water and acidified with hydrochloric
acid, then extracted with ethyl acetate, washed, dried and
evaporated under reduced pressure. The residue was Crystallized
with n-hexane to give the objective compound 5.7 g(yield 94%).
[1203] NMR(CDCl.sub.3).delta.: 3.90(s, 3H), 5.60(s, 2H), 6.28(dd,
1H, J=3.9 Hz, 2.4 Hz), 6.84(s, 1H), 6.95-6.99(m, 3H), 7.07-7.16(m,
3H).
[1204] (A-92) To a dioxane 50 ml solution of the above-mentioned
compound A-91(1.0 g, 3.3 mmol), methylamine(40% methyl alcohol
solution) and paraformaldehyde 300 mg were added at room
temperature for 1 hour under stirring. The solvent was evaporated
under reduced pressure, to which was added an ammonium chloride
solution and extracted with chloroform, washed, dried and
evaporated under reduced pressure. The residue was Crystallized by
isopropyl alcohol to give 4-[1-(4-fluorobenzyl)-1H-pyrrol-
e-2-carbonyl]-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one 720
mg(yield 69%).
[1205] Melting point:150-151.degree. C.
[1206] Elementary analysis as C.sub.17H.sub.15N.sub.2O.sub.3F
[1207] Calcd. (%) C: 64.96H: 4.81N: 8.91 F: 6.04 Found (%) C:
65.81H: 4.68N: 8.74 F: 5.85
[1208] NMR(CDCl.sub.3).delta.:3.15(s,3H), 4.32(s,2H), 5.60(s,2H),
6.31(dd, 1H,J=4.2 Hz, 2.4 Hz), 6.91(dd,1H,J=4.2 Hz, 1.5 Hz),
6.96-7.16(m,5H).
[1209] The following compound was synthesized by the
above-mentioned method.
[1210]
4-[1-(4-Fluorobenzyl)-1H-pyrrole-2-carbonyl]-3-hydroxy-1-isopropyl--
1,5-dihydropyrrole-2-one
[1211] Melting point:132.degree. C.
[1212] Elementary analysis as C.sub.19H.sub.19N.sub.2O.sub.3F
[1213] Calcd. (%) C: 66.66H: 5.59N: 8.18 F: 5.55 Found (%) C:
66.46H: 5.48N: 8.14 F: 5.47
[1214] NMR(CDCl.sub.3).delta.: 1.28(d,6H,J=6.6 Hz), 4.25(s,2H),
4.57(m,1H), 5.61(s,2H), 6.32(dd,1H,J=4.2 Hz, 2.4 Hz),
6.95-7.14(m,6H).
[1215] Compound A-98
[1216]
4-[5-(4-Fluorobenzyl)oxazole-4-carbonyl]-3-hydroxy-1-methyl-1,5-dih-
ydropyrrole-2-one 194
[1217] (A-93) To a tetrahydrofuran solution(20 ml) of potassium
t-butoxide(3.4 g, 30 mmol), isocyanoacetic acid ethylester(3.4 g,
30 mmol) was added dropwise thereto under ice cooling. 10 minutes
later, 4-phenylacetic acid chloride(5 g, 29 mmol) was added
dropwise under ice cooling and stirred for 1 hour. The solution was
added to the ammonium chloride solution and extracted with ethyl
acetate, then washed, dried and evaporated under reduced pressure.
The residue was purified with column chromatography(ethyl
acetate:n-hexane=1:2) to give the objective compound 4.8
g(yield65%).
[1218] NMR(CDCl.sub.3).delta.:1.42(t,3H,J=7.1 Hz), 4.37(s,2H),
3.92(q,2H,J=7.1 Hz), 6.95-7.03(m,2H), 7.23-7.29(m,2H),
7.76(s,1H).
[1219] (A-94) To an ethanol 30 ml solution of the above-mentioned
compound A-93(4.8 g, 19.3 mmol), 1N lithium hydroxide solution 20
ml was added at room temperature for 1 hour under stirring, then
the mixture was evaporated under reduced pressure and acidified
with 1N hydrochloric acid. The solution was extracted with ethyl
acetate, then washed, dried and evaporated under reduced pressure.
The residue was Crystallized with isopropyl alcohol to give the
objective compound 3.9 g(yield91%).
[1220] NMR(DMSO-d.sub.6).delta.: 4.38(s,2H), 7.11-7.18(m,2H),
7.28-7.31(m,2H), 8.34(s,1H), 13.20(bs, 1H).
[1221] (A-95) According to the method of the above-mentioned
example A-20, 5-(4-fluorobenzyl) oxazole-4-carboxylic acid
methoxymethylamide 4.4 g(yield 95%) was synthesized from the
above-mentioned compound A-94(3.9 g, 17.6 mmol).
[1222] NMR(CDCl.sub.3).delta.: 3.42(s,3H), 3.83(s,3H), 4.28(s,2H),
6.95-7.01(m,2H), 7.25-7.34(m,2H), 7.72(s, 1H).
[1223] (A-96) According to the method of the above-mentioned
example A-21, 1-[5-(4-fluorobenzyl)oxazole-4-yl]etanone3.5
g(yield96%)was synthesized from the above-mentioned compound
A-95(4.4 g, 16.7 mmol).
[1224] NMR(CDCl.sub.3).delta.: 2.59(s,3H), 4.36(s,2H),
6.95-7.01(m,2H), 7.25-7.34(m,2H), 7.71(s,1H).
[1225] (A-97) According to the method of the above-mentioned
example A-18,
4-[5-(4-fluorobenzyl)oxazole-4-yl]-2-hydroxy-4-oxo-2-butenoic acid
methylester5.37 g(yield 90%) was synthesized from the
above-mentioned compound A-96(4.3 g, 19.6 mmol).
[1226] NMR(CDCl.sub.3).delta.:3.93(s,3H), 4.43(s,2H),
6.95-7.04(m,2H), 7.26(s, 1H), 7.25-7.31(m,2H), 7.77(s, 1H).
[1227] (A-98) According to the method of the above-mentioned
example A-19,
4-[5-(4-fluorobenzyl)oxazole-4-carbonyl]-3-hydroxy-1-methyl-1,5-dihydropy-
rrole-2-one 760 mg(yield 67%) was synthesized from the
above-mentioned compound A-97(lg, 3.3 mmol).
[1228] NMR(CDCl.sub.3).delta.: 3.93(s,3H), 4.14(s,2H), 4.49(s,2H),
6.95-7.04(m,2H), 7.25-7.31(m,2H), 8.14(s, 1H).
[1229] Melting point:257.degree. C.
[1230] Elementary analysis as
C.sub.16H.sub.13N.sub.2O.sub.4F.0.2HCl
[1231] Calcd. (%) C: 59.39H: 4.11N: 8.66 F: 5.87Cl: 2.19 Found (%)
C: 59.51H: 4.01N: 8.65 F: 5.69Cl: 2.12
[1232] The following compound was synthesized by the
above-mentioned method.
[1233]
4-[5-(4-Fluorobenzyl)oxazole-4-carbonyl]-3-hydroxy-1-isopropyl-1,5--
dihydropyrrole-2-one
[1234] NMR(CDCl.sub.3).delta.: 3.93(s,3H), 4.14(s,2H), 4.49(s,2H),
6.95-7.04(m,2H), 7.25-7.31(m,2H), 8.14(s,1H).
[1235] Melting point:193.degree. C.
[1236] Elementary analysis as C.sub.18H.sub.17N.sub.2O.sub.4F
[1237] Calcd. (%) C: 62.79H: 4.98N: 8.14 F: 5.52 Found (%) C:
62.73H: 4.91N: 8.14 F: 5.42
[1238] Compound A-102
[1239]
4-[1-(4-Fluorobenzyl)-1H-pyrazole-4-carbonyl]-3-hydroxy-1-isopropyl-
-1,5-dihydropyrrole-2-one 195
[1240] (A-99) To a N,N-dimethylformamide solution(20 ml) of
4-bromopyrazole(5.0 g, 34.0 mmol) at 0.degree. C., sodium
hydride(60%)(2.04 g, 51.0 mmol) was added, then the mixture was
stirred for 20 minutes, to which was added 4-fluorobenzyl
bromide(5.1 ml, 40.8 mmol) at room temperature for 1 hour. The
solution was poured into ice water, then extracted with ether,
washed, dried and evaporated under reduced pressure. The residue
was purified with silica gel column chromatography(n-hexane/ethyl
acetate=8/1) to give 4-bromol-(4-fluorobenzyl)-1H-pyrazole(7.42 g,
yield:86%).
[1241] (A-100) A mixture of the above-mentioned compound A-99(1.28
g, 5.00 mmol), acetic acid palladium (34 mg, 0.150 mmol),
1,3-diphenylphosphinopr- opane (136 mg, 0.330 mmol),
butylvinylether(3.24 ml,25.0 mmol) and potassium carbonate (829 mg,
6.00 mmol) in a solution of N,N-dimethylformamide(12.5 ml) and
water(3 ml) was reacted in a shield tube at 100.degree. C. for 24
hours. The solution was Cooled, then poured into 5% hydrochloric
acid and stirred for 30 minutes, to which was added a saturated
sodium bicarbonate aqueous solution, extracted with ethyl acetate,
washed, dried, and evaporated under reduced pressure. The residue
was purified with silica gel column chromatography(n-hexane/ethyl
acetate=2/1) to give
1-[1-(4-fluorobenzyl)-1H-pyrazole-4-yl]etanone(555 mg,
yield:51%).
[1242] NMR(CDCl.sub.3).delta.:2.41(3H, s), 5.28(2H, s),
7.01-7.09(2H, m), 7.21-7.28(2H, m), 7.85(1H, s), 7.93(1H, s).
[1243] (A-101) According to the method of the above-mentioned
example A-18,
4-[1-(4-fluorobenzyl)-1H-pyrazole-4-yl]-2-hydroxy-4-oxo-2-butenoic
acid methyl(1.08 g, yield:77%) was synthesized from the
above-mentioned compound A-100(1.00 g, 4.59 mmol).
[1244] NMR(CDCl.sub.3).delta.:3.92(3H, s), 5.31(2H, s), 6.67(1H,
s), 7.03-7.12(2H, m), 7.23-7.28(2H, m), 7.94(1H, s), 8.02(1H,
s).
[1245] (A-102) According to the method of the above-mentioned
example A-19,
4-[1-(4-fluorobenzyl)-1H-pyrazole-4-carbonyl]-3-hydroxy-1-isopropyl-
-1,5-dihydropyrrole-2-one(122 mg, yield:36%) was synthesized from
the above-mentioned compound A-101(304 mg, 1.00 mmol).
[1246] Melting point:129.5-131.degree. C.
[1247] Elementary analysis as C.sub.18H.sub.18FN.sub.3O.sub.3
[1248] Calcd. (%): C, 62.97; H, 5.28; N, 12.24; F, 5.53. Found (%):
C, 62.96; H, 5.22; N, 12.22; F, 5.49.
[1249] NMR(CDCl.sub.3).delta.:1.30(6H, d, J=6.7 Hz), 4.22(2H, s),
4.56(1H, sep, J=6.7 Hz), 5.33(2H, s), 7.03-7.12(2H, m),
7.23-7.31(2H, m), 7.97(1H, s), 8.05(1H, s).
[1250] The following compound was synthesized by the
above-mentioned method.
[1251] (4-1)
4-[1-(4-Fluorobenzyl)-1H-pyrazole-4-carbonyl]-3-hydroxy-1-met-
hyl-1,5-dihydropyrrole-2-one
[1252] Melting point: 150-151.degree. C.
[1253] Elementary analysis as C.sub.16H.sub.14FN.sub.3O.sub.3
[1254] Calcd. (%): C, 60.95; H, 4.48; N, 13.33; F, 6.03. Found (%):
C, 60.73; H, 4.38; N, 13.25; F, 6.00.
[1255] NMR(CDCl.sub.3).delta.:3.18(3H, s), 4.29(2H, s), 5.33(2H,
s), 7.03-7.13(2H, m), 7.24-7.31(2H, m), 7.92(1H, s), 8.01(1H,
s).
[1256] Compound A-107
[1257]
4-[2-(4-Fluorobenzyl)oxazole-5-carbonyl]-3-hydroxy-1-isopropyl-1,5--
dihydropyrrole-2-one 196
[1258] (A-103) To a dioxane solution(30 ml) of
2-(4-fluorobenzyl)oxazole-5- -carboxylic acid ethyl(10 g, 40.1
mmol) which was prepared according to the method of the
reference(J. Chem. Soc.,Perkin Trans. 1, 1997, p2673), 1N lithium
hydroxide aqueous solution(48 ml, 48.0 mmol) was added for 3
minutes at 0.degree. C. The mixture was stirred at room temperature
for 30 minutes, then 1N hydrochloric acid(55 ml, 55.0 mmol) was
added and extracted with ethyl acetate, washed, dried and
evaporated under reduced pressure. The residue was Crystallized
using diisopropyl ether and hexane to give
2-(4-fluorobenzyl)oxazole-5-carboxylic acid(8.50 g, yield:95%).
[1259] NMR(CDCl.sub.3).delta.:4.19(2H. s), 7.00-7.08(2H, m),
7.25-7.34(2H, m), 7.80(1H, s).
[1260] The following compound was synthesized by the
above-mentioned method using 2-(4-fluorobenzyl)oxazole-4-carboxylic
acid ethyl which was prepared according to the method of the
reference(J. Org. Chem., 1996, 61, p1761).
[1261] NMR(CDCl.sub.3).delta.:4.21(2H, s), 6.97-7.06(2H, m),
7.25-7.33(2H, m), 8.24(1H, s).
[1262] (A-104) According to the method of the above-mentioned
example A-20, 2-(4-fluorobenzyl)oxazole-5-carboxylic acid
methoxymethylamide (955 mg, yield:76%) was synthesized from the
above-mentioned compound A-103(1.0 g, 4.70 mmol).
[1263] NMR(CDCl.sub.3).delta.:3.33(3H, s), 3.74(3H, s), 4.16(2H,
s), 6.97-7.06(2H, m), 7.25-7.34(2H, m), 7.60(1H, s).
[1264] The following compound was synthesized by the
above-mentioned method.
[1265] 2-(4-Fluorobenzyl)oxazole-4-carboxylic acid
methoxymethylamide
[1266] NMR(CDCl.sub.3).delta.:3.37(3H, s), 3.73(3H, s), 4.14(2H,
s), 6.96-7.05(2H, m), 7.25-7.33(2H, m), 8.08(1H, s).
[1267] (A-105) According to the method of the above-mentioned
example A-21, 1-[2-(4-fluorobenzyl)oxazole-5-yl]etanone(7)(730 mg,
yield:92%) was synthesized from the above-mentioned compound
A-104(950 mg, 3.60 mmol).
[1268] NMR(CDCl.sub.3).delta.:2.46(3H, s), 4.16(2H, s),
6.69-7.08(2H, m), 7.25-7.33(2H, m), 7.68(1H, s).
[1269] The following compound was synthesized by the
above-mentioned method.
[1270] 1-[2-(4-Fuorobenzyl)oxazole-4-yl]etanone
[1271] NMR(CDCl.sub.3).delta.:2.51(3H, s), 4.12(2H, s),
6.98-7.06(2H, m), 7.24-7.31(2H, m), 8.11(1H, s).
[1272] (A-106) According to the method of the above-mentioned
example A-18,
4-[2-(4-fluorobenzyl)oxazole-5-yl]-2-hydroxy-4-oxo-2-butenoic acid
methyl(1.43 g, yield:86%) was synthesized from the above-mentioned
compound A-105(1.20 g, 5.48 mmol).
[1273] NMR(CDCl.sub.3).delta.:3.94(3H, s), 4.19(2H, s), 6.80(1H,
s), 7.00-7.09(2H, m), 7.26-7.34(2H, m), 7.83(1H, s).
[1274] The following compound was synthesized by the
above-mentioned method.
[1275]
4-[2-(4-Fluorobenzyl)oxazole-4-yl]-2-hydroxy-4-oxo-2-butenoic Acid
Methyl
[1276] (A-107) According to the method of the above-mentioned
example A-19,
4-[2-(4-fluorobenzyl)oxazole-5-carbonyl]-3-hydroxy-1-isopropyl-1,5--
dihydropyrrole-2-one(256 mg, yield:75%) was synthesized from the
above-mentioned compound (8)(305 mg, 1.00 mmol).
[1277] Melting point:174-178.degree. C.
[1278] Elementary analysis as C.sub.18H.sub.17FN.sub.2O.sub.4
[1279] Calcd. (%): C, 62.79; H, 4.98; N, 8.14; F, 5.52. Found (%):
C, 62.41; H, 4.89; N, 7.98; F, 5.33.
[1280] NMR(CDCl.sub.3).delta.:1.25(6H, d, J=6.8 Hz), 4.10(2H, s),
4.23(2H, s), 4.54(1H, sep, J=6.8 Hz), 7.03-7.12(2H, m),
7.28-7.35(2H, m), 7.95(1H, s).
[1281] The following compound was synthesized by the
above-mentioned method.
4-[2-(4-Fluorobenzyl)oxazole-4-carbonyl]-3-hydroxy-1-isopropyl-1,-
5-dihydropyrrole-2-one
[1282] Melting point: 154-155.degree. C.
[1283] NMR(CDCl.sub.3).delta.:1.26(6H, d, J=6.8 Hz), 4.05(2H, s),
4.22(2H, s), 4.54(1H, sep, J=6.8 Hz), 7.03-7.12(2H, m),
7.25-7.32(2H, m), 8.27(1H, s).
[1284] Compound A-111
[1285]
4-[5-(4-Fluorobenzyl)thiophene-2-carbonyl]-3-hydroxy-1-isopropyl-1,-
5-dihydropyrrole-2-one 197
[1286] (A-108) To a tetrahydrofuran solution(25 ml) of
2-(2-methyl[1,3]dioxolane-2-yl)thiophene(2.0 g, 11.8 mmol) at
-78.degree. C., 1.55M n-butyllithium-hexane solution(9.1 ml,14.1
mmol) was added dropwise for 10 minutes. The mixture was stirred at
-78.degree. C. for 1 hour, then a tetrahydrofuran solution(5 ml) of
p-fluorobenzaldehyde(2.2 g, 17.7 mmol) was added and stirred for 15
minutes, to which was added a saturated ammonium chloride aqueous
solution. The solution was extracted with ethyl acetate, washed,
dried and evaporated. The residue was purified with silica gel
column chromatography(n-hexane/ethyl acetate=3/1) to give
(4-fluorophenyl)-[5-(2-methyl[1,3]dioxolane-2-yl)thi-
ophene-2-yl]methyl alcohol(3.20 g, yield: 92%).
[1287] (A-109) To an acetonitrile solution(30 ml) of sodium
iodide(7.85 g,52.4 mmol), chlorotrimethylsilane(6.7 ml,52.4 mmol)
was added at 0.degree. C., to which an acetonitrile solution(10 ml)
of the above-mentioned compound A-108(3.08 g, 10.5 mmol) was added
and stirred for 1 hour. The saturated sodium bicarbonate and 0.5M
sodium thiosulfate aqueous solution were added to the reaction
mixture and extracted with ethyl acetate, washed, dried and
evaporated under reduced pressure. The residue was purified with
silica gel column chromatography(n-hexane/ethyl acetate=3/1) to
give 1-[5-(4-fluorobenzyl)thiophene-2-yl]etanone (1.34 g,
yield:55%).
[1288] NMR(CDCl.sub.3).delta.:2.50(3H, s), 4.13(2H, s), 6.81(1H, d,
J=3.8 Hz), 6.97-7.05(2H, m), 7.16-7.24(2H, m), 7.53(1H, d, J=3.8
Hz).
[1289] (A-110) According to the method of the above-mentioned
example A-18,
(4-[5-(4-fluorobenzyl)thiophene-2-yl]-2-hydroxy-4-oxo-2-butenoic
acid methyl(127 g, yield: 76%) was synthesized from the
above-mentioned compound A-109(1.23 g,5.26 mmol).
[1290] NMR(CDCl.sub.3).delta.:3.93(3H, s), 4.17(2H, s), 6.85(1H,
s), 6.88(1H, d, J=3.9 Hz), 6.98-7.07(2H, m), 7.17-7.24(2H, m),
7.69(1H, d, J=3.9 Hz).
[1291] (A-111) According to the method of the above-mentioned
example A-19,
4-[5-(4-fluorobenzyl)thiophene-2-carbonyl]-3-hydroxy-1-isopropyl-1,-
5-dihydropyrrole-2-one(181 mg, yield:50%) was synthesized from the
above-mentioned compound A-110(320 mg,1.00 mmol).
[1292] Melting point:138-139.degree. C.
[1293] NMR(CDCl.sub.3).delta.:1.30(6H, d, J=6.8 Hz), 4.19(2H, s),
4.28(2H, s), 4.58(1H, sep, J=6.8 Hz), 6.91(1H, d, J=3.9 Hz),
7.00-7.07(2H, m), 7.19-7.25(2H, m), 7.64(1H, d, J=3.9 Hz).
[1294] Compound A-115
[1295]
4-[2-(4-Fluorobenzyl)-2H-pyrazole-3-carbonyl]-3-hydroxy-1-methyl-1,-
5-dihydropyrrole-2-one 198
[1296] (A-112) To a dimethylformamide (57 ml) suspension of sodium
hydride(purity 60%, 3.23 g, 80.7 mmol), the dimethylformamide(5 ml)
solution of pyrazole(5.00 g, 73.4 mmol) was added dropwise. The
mixture was stirred at room temperature for 1 hour, then to which
was added a dimethylformamide(5 ml) solution of
4-fluorobenzylbromide(14.6 g, 77.1 mmol) and stirred for 1 hour.
The mixture was poured into ice water, extracted with ethyl
acetate, washed, dried and evaporated under reduced pressure to
give a crude product of 1-(4-fluorobenzyl)-1H-pyrazole(14.2 g,
yield: 100%).
[1297] NMR(CDCl.sub.3).delta.: 5.29(2H, s), 6.29(1H, dd, J=1.8 Hz,
2.1 Hz), 7.00-7.05(2H, m), 7.17-7.21(2H, m), 7.38(1H, d, J=2.1 Hz),
7.55(1H, d, J=1.8 Hz).
[1298] (A-113) To a solution of tetrahydrofuran(35 ml)-diethyl
ether(23 ml) of the above-mentioned compound A-112(2.00 g, 11.4
mol), n-butyllithium(7.90 ml, 12.5 mmol, 1.59M hexane solution) was
added at -78.degree. C., then the mixture was stirred for 1.5
hours, to which was added acetic anhydride(2.32 g, 22.7 mmol). The
mixture was stirred for 1 hour under ice cooling, then sodium
hydrogen carbonate aqueous solution was added and extracted with
ethyl acetate, washed, dried and evaporated under reduced pressure.
The residue was purified with silica gel column
chromatography(n-hexane:ethyl acetate=4:1) to give
1-[2-(4-fluorobenzyl)-2H-pyrazole-3-yl]etanone(700 mg,
yield:28%).
[1299] NMR(CDCl.sub.3).delta.:4.50(3H, s), 5.71(2H, s), 6.87(1H, d,
J=2.1 Hz), 6.95-7.00(2H, m), 7.24-7.29(2H, m), 7.55(1H, d, J=2.1
Hz).
[1300] (A-114) To a tetrahydrofuran solution(8 ml) of the
above-mentioned compound A-113(1.00 g, 4.58 mmol), lithium
hexamethyldisilazane(5.50 ml, 5.50 mmol, 1.0M tetrahydrofuran
solution) was added dropwise at -78.degree. C. for 10 minutes under
stirring, to which was added oxalic acid diethyl(804 mg, 5.50
mmol). The mixture was stirred at 0.degree. C. for 1 hour, then
ammonium chloride aqueous solution was added, then extracted with
ethyl acetate, washed, dried and evaporated under reduced pressure.
The crystal was washed with isopropyl ether to give
4-[2-(4-fluorobenzyl)-2H-pyrazole-3-yl]-2-hydroxy-4-oxo-2-butenoic
acid ethyl ester(754 mg, yield:52%).
[1301] NMR(CDCl.sub.3).delta.: 1.40(3H, q, J=6.9 Hz), 4.39(2H, q,
J=6.9 Hz), 5.78(2H, s), 6.82(1H, s), 6.96-7.01(3H, m),
7.24-7.29(2H, m), 7.61(1H, d, J=2.1 Hz), 14.24(1H, br).
[1302] (A115) To a dioxane(13 ml) solution of the above-mentioned
compound A-114(318 mg, 1.00 mmol), methylamine(2.20 mmol, 40%
ethanol solution) and paraformaldehyde(90 mg) were added. The
mixture was stirred for 1 hour at room temperature and diluted with
ammonium chloride aqueous solution and chloroform. An insoluble
product was filtered out, then the filtrate was extracted with
chloroform, washed, dried and evaporated under reduced pressure.
The crude crystal was recrystallized by acetone-isopropylether to
give 4-[2-(4-fluorobenzyl)-2H-pyrazole-3-carbon-
yl]-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one(161 mg,
yield:51%).
[1303] Melting point:179-181.degree. C.
[1304] Elementary analysis as C.sub.16H.sub.14FN.sub.2O.sub.3
[1305] Calcd. (%): C, 60.95; H, 4.48; N, 13.33; F, 6.03. Found (%):
C, 60.86; H, 4.24; N, 13.28; F, 5.78.
[1306] NMR(CDCl.sub.3).delta.: 3.17(3H, s), 4.28(2H, s), 5.77(2H,
s), 6.82(1H, d, J=2.2 Hz), 6.98(2H, t, J=8.7 Hz), 7.24-7.29(2H, m),
7.63(1H, d, J=2.2 Hz).
[1307] The following compound was synthesized by the
above-mentioned method.
[1308]
4-[2-(4-Fluorobenzyl)-2H-pyrazole-3-carbonyl]-3-hydroxy-1-isopropyl-
-1,5-dihydropyrrole-2-one (199 mg, yield:58%)
[1309] Melting point: 170-171.degree. C.
[1310] Elementary analysis as C.sub.18H.sub.18FN.sub.3O.sub.3
[1311] Calcd. (%): C, 62.97; H, 5.28; N, 12.24; F, 5.58. Found (%):
C, 62.95; H, 5.00; N, 12.25; F, 5.59.
[1312] NMR(CDCl.sub.3).delta.:1.29(6H, d, J=6.9 Hz), 4.20(2H, s),
4.51-4.60(1H, m), 5.77(2H, s), 6.88(1H, d, J=2.1 Hz), 6.96-7.02(2H,
m), 7.25-7.30(2H, m), 7.65(1H, d, J=2.1 Hz)
[1313] Compound A-124
[1314]
4-[5-(4-Fluorobenzyl)furan-3-carbonyl]-3-hydroxy-1-methyl-1,5-dihyd-
ropyrrole-2-one 199200
[1315] (A-116) To a diethylformamide(0.5 ml)-methylene chloride(200
ml) solution of furan-3-carboxylic acid(20.0 g, 178 mmol), oxalyl
chloride(24.9 g, 196 mmol) was added dropwise. The mixture was
stirred at room temperature for 1 hour and was evaporated under
reduced pressure. The residue was dissolved into methylene
chloride(200 ml), to which were added N,O-dimethylhydroxylamine
hydrochloride (20.8 g, 214 mmol) and triethylamine (43.2 g, 427
mmol) at 0.degree. C. The mixture was stirred at room temperature
for 30 minutes, then was added water, which was extracted with
chloroform, washed, dried and evaporated under reduced pressure to
give a crude product of furan-3-carboxylic acid
methoxymethylamide(31.3 g).
[1316] NMR(CDCl.sub.3).delta.:3.34(3H, s), 3.72(3H, s),
6.87-6.88(1H, in), 7.42-7.43(1H, m), 8.03-8.04(1H, m).
[1317] (A-117) To a tetrahydrofuran(300 ml) solution of the
above-mentioned crude product A-116(31.3 g), methyl
magnesiumbromide(214 ml, 214 mmol, 1M tetrahydrofuran solution) was
added at -50.degree. C. The mixture was stirred at 0.degree. C. for
2 hours, to which was added methyl magnesiumbromide(70 ml, 70 mmol,
1M tetrahydrofuran solution) and was stirred for 0.2 hours. 2N
Hydrochloric acid(2001m) was added to the mixture, which was
extracted with diethyl ether and washed, dried and evaporated under
reduced pressure to give 3-acetylfuran (15.9 g, yield:81%).
[1318] NMR(CDCl.sub.3).delta.: 2.45(3H, s), 6.77-6.78(1H, m),
7.44-7.45(1H, m), 8.02-8.03(1H, m).
[1319] (A-118) A mixture of the above-mentioned compound A-117(15.9
g, 144 mmol), p-toluenesulfonic acid mono hydrate(1.69 g, 8.90
mmol) and ethylene glycol(55.2 g, 890 mmol) was refluxed in
benzene(500 ml)for 16 hours removing the produced water. Then,
sodium hydrogen carbonate aqueous solution was added to the
mixture, which was extracted with ethyl acetate, washed, dried and
evaporated under reduced pressure to give
2-furan-3-yl-2-methyl[1,3]-dioxolane(20.9 g, yield:94%).
[1320] NMR(CDCl.sub.3).delta.: 1.67(3H, s), 3.89-4.05(4H, m),
6.36-6.37(1H, m), 7.36-7.37(1H, m), 7.41-7.42(1H, m).
[1321] (A-119) To a tetrahydrofuran(200 ml) solution of the
above-mentioned compound A-118(19.8 g, 128 mmol),
n-butyllithium(90.0 ml, 141 mmol, 1.59M hexane solution) was added
at -78.degree. C. and the mixture was stirred at 0.degree. C. for
30 minutes. Then chloro trimethylsilane(15.3 g, 141 mmol) was added
at -78.degree. C., which was stirred at 0.degree. C. for 30
minutes, to which was added ammonium chloride aqueous solution and
extracted with diethyl ether, washed, dried and evaporated under
reduced pressure to give trimethyl[3-(2-methyl[1,3]d-
ioxolane-2-yl)furan-2-yl] silane(26 g, yield:92%).
[1322] NMR(CDCl.sub.3).delta.:0.30(9H, s), 1.63(3H, s),
3.81-4.02(4H, m), 6.39(1H, d, J=1.8 Hz), 7.51(1H, d, J=1.8 Hz).
[1323] (A-120) To a tetrahydrofuran(130 ml) solution of the
above-mentioned compound A-119(26.7 g, 118 mmol), n-butyllithium(89
ml, 142 mmol, 1.59M hexanesolution) was added at -78.degree. C. and
the mixture was stirred at 0.degree. C. for 30 minutes, to which
was added a tetrahydrofuran(60 ml) solution of
p-fluorobenzaldehyde(17.6 g, 142 mmol) at -78.degree. C. To the
mixture was added ammonium chloride aqueous solution at room
temperature, then extracted with diethyl ether, washed, dried and
evaporated under reduced pressure. The residue was purified with
silica gel column chromatography(n-hexane:ethyl acetate=4:1) to
give
(4-fluorophenyl)-[4-(2-methyl[1,3]dioxolane-2-yl)-5-trimethylsilanylfuran-
-2-yl]methyl alcohol(18.3 g, yield:49%).
[1324] NMR(CDCl.sub.3).delta.: 0.29(9H, S), 1.57(3H, s),
3.78-3.99(4H, m), 5.76(1H, m), 6.02(1H, s), 7.03-7.09(2H, m),
7.41-7.46(2H, m).
[1325] (A-121) Tetrabutylammonium fluoride(8 ml, 8 mmol, 1M
tetrahydrofuran solution) was added to the above-mentioned compound
A-120(762 mg, 2.17 mmol) in tetrahydrofuran(8 ml), then the mixture
was stirred at 60.degree. C. for 30 minutes. The solution was
diluted with diethyl ether, which was washed with 1N hydrochloric
acid, water and saturated NaCl aqueous solution, successively, then
dried and evaporated under reduced pressure to give
(4-fluorophenyl)-[4-(2-methyl[1,3] dioxolane-2-yl)furan-2-yl]methyl
alcohol(561 mg, yield:93%).
[1326] NMR(CDCl.sub.3).delta.:1.61(3H, s), 3.86-4.03(4H, m),
5.76(1H, s), 6.06-6.07(1H, m), 7.04-7.09(2H, m), 7.37-7.44(3H,
m).
[1327] (A-122) A mixture of sodium iodide(1.90 g, 12.7 mmol) and
chlorotrimethylsilane(1.39 g, 12.7 mmol) in acetonitrile(7 ml) was
stirred at room temperature for 15 minutes, to which was added the
above-mentioned compound A-121(709 mg, 2.55 mmol) at 0.degree. C.,
then the mixture was stirred at room temperature for 30 minutes.
Water and 1N sodium hydroxide aqueous solution were added thereto
successively, which was extracted with diethyl ether, washed, dried
and evaporated under reduced pressure. The residue was purified
with silica gel column chromatography(n-hexane:ethyl acetate=4:1)
to give 3-acetyl-5-(4-fluorobenzyl)furan(307 mg, yield:55%).
[1328] NMR(CDCl.sub.3).delta.:2.39(3H, s), 3.93(2H, s), 6.36(1H, d,
J=0.9 Hz), 6.79-7.03(2H, m), 7.16-7.21(2H, m), 7.26(1H, d, J=0.9
Hz).
[1329] (A-123) Lithium hexamethyldisilazane(4.30 ml, 4.30 mmol, 1M
tetrahydrofuran solution) was added to the above-mentioned compound
A-122(773 mg, 3.54 mmol) in tetrahydrofuran(15 ml) at -78.degree.
C., then the mixture was stirred for 10 minutes. Oxalic acid
diethyl(621 mg, 4.25 mmol) was added at -30.degree. C., which was
stirred for 30 minutes, to which was added water and 1N
hydrochloric acid. The mixture was extracted with ethyl acetate,
washed, dried and evaporated under reduced pressure. The crude
crystal was washed with diisopropyl ether to give
4-[5-(4-fluorobenzyl)furan-3-yl]-2-hydroxy-4-oxo-2-butenoic acid
ethyl ester(689 mg, yield:61%).
[1330] NMR(CDCl.sub.3).delta.:1.39(3H, t, J=7.2 Hz), 3.96(2H, s),
4.37(2H, q, J=7.2 Hz), 6.40(1H, d, J=0.9 Hz), 6.62(1H, s),
6.99-7.04(2H, m), 7.17-7.22(2H, m), 8.03(1H, d, J=0.9 Hz).
[1331] (A-124) To a dioxane(8 ml) solution of the above-mentioned
compound A-123(200 mg, 0.628 mmol), methylamine(1.38 mmol, 30%
ethanol solution) and paraformaldehyde(57 mg) were added
successively. The mixture was stirred at room temperature for 30
minutes, then diluted with ammonium chloride aqueous solution and
chloroform. The insoluble product was filtered off, then the
filtrate was extracted with chloroform, washed with 1N hydrochloric
acid, water and saturated NaCl aqueous solution successively. The
mixture was evaporated under reduced pressure, then the residue was
Crystallized by acetone-diisopropyl ether to give
4-[5-(4-fluorobenzyl)furan-3-carbonyl]-3-hydroxy-1-methyl-1,5-dihydropyrr-
ole-2-one(56 mg, yield:28%).
[1332] Melting point:158-160.degree. C.
[1333] Elementary analysis as C.sub.17H.sub.14FNO.sub.4
[1334] Calcd. (%): C, 64.76; H, 4.48; N, 4.44; F, 6.03. Found (%):
C, 64.54; H, 4.48; N, 4.41; F, 6.03.
[1335] NMR(CDCl.sub.3).delta.: 3.17(3H, s), 3.98(2H, s), 4.24(2H,
s), 6.43(1H, s), 6.99-7.05(2H, m), 7.18-7.23(2H, m), 7.98(1H,
s).
[1336] The following compound was synthesized by the
above-mentioned method.
4-[5-(4-Fluorobenzyl)furan-3-carbonyl]-3-hydroxy-1-isopropyl-1,5--
dihydropyrrole-2-one(87 mg, yield:43%)
[1337] Melting point:162-164.degree. C.
[1338] Elementary analysis as C.sub.19H.sub.18FNO.sub.4
[1339] Calcd. (%): C, 66.46; H, 5.28; N, 4.08; F, 5.53. Found (%):
C, 66.42; H, 5.30; N, 3.96; F, 5.53.
[1340] NMR(CDCl.sub.3).delta.: 1.29(6H, d, J=6.9 Hz), 3.98(2H, s),
4.17(2H, s), 4.51-4.60(1H, m), 6.46(1H, d, J=0.9 Hz), 6.98-7.04(2H,
m), 7.18-7.23(2H, m), 8.03(1H, d, J=0.9 Hz).
[1341] Compound A-130
[1342]
4-[4-(4-Fluorobenzyl)oxazole-2-carbonyl]-3-hydroxy-1-methyl-1,5-dih-
ydropyrrole-2-one 201
[1343] (A-125) To a methylene chloride(100 ml) solution of
4-fluorophenylacetic acid(10.0 g, 64.9 mmol) and
dimethylformamide(0.5 ml), oxalyl chloride(9.06 g, 71.4 mmol) was
added dropwise at room temperature and the mixture was stirred for
1 hour, which was evaporated under reduced pressure. The residue
was distilled to give (4-fluorophenyl)acetyl chloride(8.44 g,
yield:75%).
[1344] Boiling point:80.degree. C./15 mmHg
[1345] (A-126) N,N-Nitrosomethylurea(10.1 g, 97.8 mmol) was added
to 50% potassium hydroxide aqueous solution(40 ml)-diethyl
ether(250 ml), then the yellow ether layer was added to the
above-mentioned compound A-125(8.44 g, 48.9 mmol) in diethyl
ether(80 ml) under ice cooling. The mixture was stirred at
0.degree. C. for 15 minutes and at room temperature for 15 minutes.
The solution was Cooled at -30.degree. C., to which was added 48%
hydrogen bromide(50 ml), then which was stirred at -30.degree. C.
for 30 minutes and at room temperature for 30 minutes. To the
solution was added water, then which was extracted with diethyl
ether, washed, dried and evaporated under reduced pressure to give
1-bromo-3-(4-fluorophenyl)propane-2-one(6.52 g, yield: 58%).
[1346] NMR(CDCl.sub.3).delta.:3.91(2H, s), 3.94(2H, s),
7.01-7.07(2H, m), 7.18-7.22(2H, m).
[1347] (A-127) A solution mixture of the above-mentioned compound
A-126(6.52 g, 28.2 mmol) and 2-methylacrylamide(5.28 g, 62.1 mmol)
in tetrahydrofuran(100 ml) was stirred for 3 days at 100.degree. C.
To the solution was added water and extracted with ethyl acetate,
washed, dried and evaporated under reduced pressure. The residue
was purified with silica gel column chromatography(chloroform) to
give 4-(4-fluorobenzyl)-2-isopropenyloxazole(5.68 g,
yield:93%).
[1348] NMR(CDCl.sub.3).delta.:2.15-2.16(3H, m), 3.86(2H, s),
5.35-5.36(1H, m), 5.91-5.92(1H, m), 6.97-7.03(2H, m), 7.15-7.16(1H,
m), 7.22-7.24(2H, m).
[1349] (A-128) To a dioxane(110 ml)-water(110 ml) solution of the
above-mentioned compound A-127(5.68 g, 26.1 mmol), 5% osmium
tetroxide(0.44 ml) and sodium periodic acid(11.2 g, 52.5 mmol) were
added at room temperature for 20 minutes under stirring. The
solution was diluted with water, then extracted with ethyl acetate,
washed, dried and evaporated under reduced pressure. The residue
was purified with silica gel column chromatography(n-hexane:ethyl
acetate=4:1) to give 1-[4-(4-fluorobenzyl)oxazole-2-yl]etanone(2.26
g, yield:40%).
[1350] NMR(CDCl.sub.3).delta.: 2.65(3H, m), 3.92(2H, s),
6.99-7.05(2H, m), 7.22-7.24(2H, m), 7.43(1H, m).
[1351] (A-129) To a tetrahydrofuran(2.5 ml) solution of the
above-mentioned compound A-128(110 mg, 0.50 mmol), lithium
hexamethyldisilazane(0.60 mmol, 1M tetrahydrofuran solution) was
added dropwise at -78.degree. C., then the mixture was stirred for
30 minutes, to which was added a tetrahydrofuran(1 ml) solution of
imidazole-1-yloxoethyl acetate ester(101mg, 0.60 mmol) which was
synthesized according to the method of the reference (J. Org.
Chem., 1981, 46, 211-213). The mixture was stirred at -78.degree.
C. for 1 hour, to which was added 2N hydrochloric acid-ice water,
which was extracted with diethyl ether, washed, dried and
evaporated under reduced pressure to give
4-[4-(4-fluorobenzyl)oxazole-2-yl]-2-hydroxy-4-oxo-2-butenoic acid
ethyl ester(152 mg, yield:95%).
[1352] NMR(CDCl.sub.3).delta.:1.41(3H, t, J=7.2 Hz), 3.95(2H, s),
4.40(2H, q, J=7.2 Hz), 6.99-7.05(2H, m), 7.22-7.26(3H, m),
7.51-7.52(1H, m).
[1353] (A-130) To a dioxane(8 ml) solution of the above-mentioned
compound A-129(199 mg, 0.623 mmol), methylamine(1.37 mmol, 40%
ethanol solution) and paraformaldehyde(56 mg) were added, then the
mixture was stirred at room temperature for 1 hour. The solution
was diluted with ammonium chloride aqueous solution and chloroform,
succesively. The insoluble product was filtered out, then the
filtrate was extracted with chloroform. The extract was washed with
1Nhydrochloric acid, water and saturated NaCl aqueous solution,
successively. The solvent was evaporated under reduced pressure,
then the residue was Crystallized by isopropyl alcohol to give
4-[4-(4-fluorobenzyl)oxazole-2-carbonyl]-3-hydroxy-1-meth-
yl-1,5-dihydropyrrole-2-one(36 mg, yield: 18%).
[1354] Melting point:209-210.degree. C.
[1355] Elementary analysis as C.sub.16H.sub.13FN.sub.2O.sub.4
[1356] Calcd. (%): C, 60.76; H, 4.14; N, 8.86; F, 6.01. Found (%):
C, 60.63; H, 4.13; N, 8.64; F, 5.91.
[1357] NMR(CDCl.sub.3).delta.: 3.16(3H, s), 3.99(2H, s), 4.14(2H,
s), 7.02-7.08(2H, m), 7.23-7.27(2H, m), 7.67(1H, s).
[1358] The following compound was synthesized by the
above-mentioned method.
[1359]
4-[4-(4-Fluorobenzyl)oxazole-2-carbonyl]-3-hydroxy-1-isopropyl-1,5--
dihydropyrrole-2-one(48 mg, yield:29%)
[1360] Melting point:184.5-185.5.degree. C.
[1361] Elementary analysis as C.sub.18H.sub.17FN.sub.2O.sub.4
[1362] Calcd. (%): C, 62.79; H, 4.98; N, 8.14; F, 5.52. Found (%):
C, 62.70; H, 4.78; N, 8.26; F, 5.43.
[1363] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=6.6 Hz), 3.99(2H, s),
4.10(2H, s), 4.51-4.60(1H, m), 7.02-7.08(2H, m), 7.22-7.27(2H, m),
7.68(1H, m).
[1364] Compound A-137
[1365]
4-[4-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methyl-1,5-dihyd-
ropyrrole-2-one 202
[1366] (A-131) 2-Acetylfuran(11.0 g, 100 mmol) and bromine(32.0 g,
200 mmol) were successively added dropwise to aluminum
chloride(33.3 g, 250 mmol) at room temperature, then the mixture
was stirred for 10 minutes. The solution was poured into ice-37%
hydrochloric acid, then which was extracted with diethyl ether,
washed, dried and evaporated under reduced pressure. The residue
was purified with silica gel chromatography(n-hexane:ethyl
acetate=4:1) to give 2-acetyl-4,5-dibromofuran(20.9 g,
yield:78%).
[1367] NMR(CDCl.sub.3).delta.: 2.46(3H, s), 7.17(1H, s).
[1368] (A-132) The above-mentioned compound A-131(7.00 g, 26.1
mmol) in diethyl ether(3.5L) was irradiated at 0.degree. C. for 2
hours, then which was evaporated under reduced pressure. The
residue was purified with silica gel chromatography(n-hexane:ethyl
acetate=9:1) to give 2-acetyl-4-bromofuran(2.03 g, yield:41%).
[1369] NMR(CDCl.sub.3).delta.: 2.47(3H, s), 7.18(1H, d, J=0.6 Hz),
7.59(1H, d, J=0.6 Hz).
[1370] (A-133) A mixture of the above-mentioned compound A-132(1.80
g, 9.52 mmol)ethylene glycol(3.00 g, 47.6 mmol) and
p-toluenesulfonic acid(91 mg, 0.475 mmol) in benzene(100 ml) was
refluxed for 5 hours removing the produced water. The solution was
diluted with diethyl ether, then washed with water, saturated NaCl
aqueous solution, successively. The mixture was dried and
evaporated under reduced pressure. The residue was purified with
silica gel column chromatography(n-hexane:ethyl acetate=9:1) to
give 2-(4-bromofuran-2-yl)-2-methyl[1,3] dioxolane(1.96 g, yield:
88%).
[1371] NMR(CDCl.sub.3).delta.: 1.70(3H, s), 3.95-4.08(4H, m),
6.38(1H, d, J=0.9 Hz), 7.37(1H, d, J=0.9 Hz).
[1372] (A-134) To a tetrahydrofuran(30 ml) solution of the
above-mentioned compound A-133(1.50 g, 6.44 mmol),
n-butyllithium(4.45 ml, 7.08 mmol, 1.59M hexane solution) was added
dropwise at -78.degree. C. The mixture was stirred at -78.degree.
C. for 10 minutes, then to which was added a tetrahydrofuran(8 ml)
solution of p-fluorobenzaldehyde(959 mg, 7.73 mmol) and stirred for
1.5 hours. To the solution was added ammonium chloride aqueous
solution, then extracted with ethyl acetate, washed, dried and
evaporated under reduced pressure. The residue was purified with
silica gel chromatography(n-hexane:ethyl acetate=2:1) to give
(4-fluorophenyl)-[5-(2-methyl[1,3]dioxolane-2-yl)furan-3-yl]methyl
alcohol(939 mg, yield:53%).
[1373] NMR(CDCl.sub.3).delta.:1.69(3H, s), 3.98-4.04(4H, m),
5.72(1H, s), 6.25(1H, d, J=0.9 Hz), 7.02-7.05(2H, m), 7.22(1H, d,
J=0.9 Hz), 7.35-7.40(2H, m).
[1374] (A-135) To an acetonitrile(20 ml) solution of sodium
iodide(2.35 g, 15.7 mmol) and chlorotrimethylsilane(1.71 g, 15.7
mmol) was added, then which was stirred at room temperature for 15
minutes. To the mixture was added an acetonitrile(20 ml) solution
of the above-mentioned compound A-134(876 mg, 3.15 mmol) under ice
cooling, which was stirred for 30 minutes, to which was added 1N
sodium hydroxide aqueous solution, then extracted with diethyl
ether. The extract was washed, dried and evaporated under reduced
pressure. The residue was purified with silica gel
chromatography(n-hexane:ethyl acetate=4:1) to give
1-[4-(4-fluorobenzyl)furan-2-yl]etanone(299 mg, yield:44%).
[1375] NMR(CDCl.sub.3).delta.:2.43(3H, s), 3.77(2H, s),
6.97-7.02(3H, m), 7.13-7.18(2H, m), 7.35(1H, d, J=0.9 Hz).
[1376] (A-136) To a tetrahydrofuran(10 ml) solution of the
above-mentioned compound A-135(299 mg, 1.37 mmol), lithium
hexamethyldisilazane(1.64 ml, 1.64 mmol, 1M tetrahydrofuran
solution) was added dropwise at -78.degree. C., then the mixture
was stirred at -78.degree. C. for 10 minutes. Oxalic acid
diethyl(240 mg, 1.64 mmol) was added at -30.degree. C. and was
stirred for 1 hour, to which was added ammonium chloride aqueous
solution and extracted with ethyl acetate. The extract was washed,
dried and evaporated with reduced pressure to give
4-[4-(4-fluorobenzyl)furan-2-yl]- -2-hydroxy-4-oxo-2-butenoic acid
ethyl ester(436 mg, yield: 100%).
[1377] NMR(CDCl.sub.3).delta.:1.40(3H, t, J=6.9 Hz), 3.80(2H, s),
4.38(2H, q, J=6.9 Hz), 6.88(1H, d, J=1.4 Hz), 6.99-7.04(2H, m),
7.14-7.19(3H, m), 7.44(1H, br).
[1378] (A-137) To a dioxane(8 ml) solution of the above-mentioned
compound A-136(200 mg, 0.628 mmol), methylamine(1.38 mmol, 40%
ethanol solution) and paraformaldehyde(57 mg) were added
successively at room temperature and the mixture was stirred for 1
hour. The solution was diluted with ammonium chloride aqueous
solution and chloroform, then insoluble product was filtered out,
and the filtrate was extracted with chloroform. The extract was
washed with 1N hydrochloric acid, water, saturated NaCl aqueous
solution, successively, which was evaporated under reduced
pressure. The residue was Crystallized with isopropyl alcohol to
give
4-[4-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methyl-1,5-dihydropyrr-
ole-2-one(72 mg, yield: 36%).
[1379] Melting point: 143-145.degree. C.
[1380] Elementary analysis as C.sub.17H.sub.14FNO.sub.4
[1381] Calcd. (%): C, 64.76; H, 4.48; N, 4.44; F, 6.03. Found (%):
C, 64.56; H, 4.59; N, 4.35; F, 5.95.
[1382] NMR(CDCl.sub.3).delta.:3.17(3H, s), 3.81(2H, s), 4.42(2H,
s), 6.99-7.04(2H, m), 7.14-7.19(2H, m), 7.22(1H, s), 7.43(1H,
s).
[1383] The following compound was synthesized by the
above-mentioned method.
[1384]
4-[4-(4-Fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-isopropyl-1,5-di-
hydropyrrole-2-one(26 mgyield:36%)
[1385] Melting point: 148-150.degree. C.
[1386] Elementary analysis as C.sub.1 gH,.sub.8FNO.sub.4
[1387] Calcd. (%): C, 66.46; H, 5.28; N, 4.08; F, 5.53. Found (%):
C, 66.11; H, 5.23; N, 4.10; F, 5.37.
[1388] NMR(CDCl.sub.3).delta.:1.29(6H, d, J=6.6 Hz), 3.81(2H, s),
4.36(2H, s), 4.54-4.63(1H, m), 6.98-7.04(2H, m), 7.14-7.19(2H, m),
7.23(1H, br), 7.44(1H, d, J=0.9 Hz).
[1389] Compound A-141
[1390]
3-Hydroxy-1-isopropyl-4-[5-(2-methoxybenzyl)furan-2-carbonyl]-1,5-d-
ihydropyrrole-2-one 203
[1391] (A-138) To a tetrahydrofuran solution (25 ml) of
2-(2-methyl[1,3]dioxolane-2-yl)furan(2.50 g, 16.2 mmol), 1.58M
n-butyllithium-hexane solution(11.3 ml, 17.9 mmol) was added
dropwise for 10 minutes at -78.degree. C., then the solution was
stirred for 1 hour at -30.degree. C. A tetrahydrofuran solution(20
ml) of o-isopropoxybenzaldehyde(2.06 g, 18.7 mmol) was added at
-78.degree. C. and the reaction mixture was stirred at 0.degree. C.
for 20 minutes, to which was added saturated ammonium chloride
aqueous solution, which was extracted with ethyl acetate. The
extract was washed, dried and evaporated, then the residue was
purified with silica gel column chromatography(n-hexane/ethyl
acetate=3/1) to give (2-methoxyphenyl)-[5-(2-methyl [1,3]
dioxolane-2-yl)furan-2-yl]methyl alcohol (3.97 g, yield:77%).
[1392] (A-139) To an acetonitrile solution(40 ml) of sodium
iodide(4.65 g,31.1 mmol), chlorotrimethylsilane(3.90 ml,31.1 mmol)
was added at 0.degree. C., to which was added an acetonitrile
solution(20 ml) of the above-mentioned compound A-138(3.95 g, 12.5
mmol). To the reaction mixture were added saturated sodium
bicarbonate and 0.5M sodium thiosulfate aqueous solution, then
which was extracted with ethyl acetate. The extract was washed,
dried and evaporated under reduced pressure. The residue was
purified with silica gel column chromatography(n-hexane/ethyl
acetate=8/1) to give 1-[5-(2-methoxybenzyl)furan-2-yl]etanone(1.82
g, yield: 57%).
[1393] NMR(CDCl.sub.3).delta.:2.43(3H, s), 3.82(3H, s), 4.04(2H,
s), 6.05(1H, d, J=3.6 Hz), 6.87-6.94(2H, m), 7.08(1H, d, J=3.6 Hz),
7.15(1H, dd, J=7.4, 1.7 Hz), 7.25(1H, td, J=7.8, 1.4 Hz).
[1394] The following compounds were synthesized by the
above-mentioned method.
[1395] 1-(5-Benzo[1,3] dioxol-4-ylmethylfuran-2-yl)etanone
[1396] NMR(CDCl.sub.3).delta.:2.43(3H, s), 4.01(2H, s), 5.96(2H,
s), 6.15(1H, d, J=3.6 Hz), 6.68-6.81(3H, m), 7.10(1H, d, J=3.6 Hz).
1-(5-Naphthalene-1-ylmethylfuran-2-yl)etanone
[1397] NMR(CDCl.sub.3).delta.:2.43(3H, s), 4.49(2H, s), 5.94(1H, d,
J=3.5 Hz), 7.05(1H, d, J=3.5 Hz), 7.36-7.53(4H, m), 7.81(1H, d,
J=8.1 Hz), 7.85-7.90(1H, m), 7.93-7.98(1H, m).
1-[5-(2-Isopropoxybenzyl)furan-2-yl] etanone
[1398] NMR(CDCl.sub.3).delta.:1.29(6H, d, J=6.1 Hz), 2.42(3H, s),
4.02(2H, s), 4.55(1H, sep, J=6.1 Hz), 6.07(1H, d, J=3.5 Hz),
6.84-6.91(2H, m), 7.09(1H, d, J=3.5 Hz), 7.14-7.25(2H, m).
1-[5-(3-Isopropoxybenzyl)furan-2- -yl]etanone
[1399] NMR(CDCl.sub.3).delta.:1.32(6H, d, J=6.0 Hz), 2.43(3H, s),
4.00(2H, s), 4.53(1H, sep, J=6.0 Hz), 6.12(1H, dd, J=4.0, 0.9 Hz),
6.75-6.83(3H, m), 7.10(1H, d, J=4.0 Hz). 7.17-7.24(1H,m).
[1400] 1-[5-(4-Fluoro-2-methoxybenzyl)furan-2-yl] etanone
[1401] NMR(CDCl.sub.3).delta.:2.42(3H, s), 3.80(3H, s), 3.98(2H,
s), 6.04(1H, d, J=3.6 Hz), 6.58-6.64(2H, m), 7.06-7.12(2H, m).
[1402] 1-[5-(4-Fluoro-3-methoxybenzyl)furan-2-yl]etanone
[1403] NMR(CDCl.sub.3).delta.:2.44(3H, s), 3.87(3H, s), 4.00(2H,
s), 6.12(1H, d, J=3.6 Hz), 6.76(1H, ddd, J=8.1, 4.1, 2.1 Hz),
6.85(1H, dd, J=8.3, 2.1 Hz), 7.02(1H, dd, J=11.0, 8.1 Hz), 7.11(1H,
d, J=3.6 Hz).
[1404] 1-[5-(4-Fluoro-2-isopropoxybenzyl)furan-2-yl]etanone
[1405] NMR(CDCl.sub.3).delta.:1.29(6H, d, J=6.0 Hz), 2.42(3H, s),
3.96(2H, s), 4.49(1H, sep, J=6.0 Hz), 6.04-6.06(1H, m),
6.54-6.62(2H, m), 7.07-7.13(2H, m).
1-(5-Benzylfuran-2-yl)etanone
[1406] NMR(CDCl.sub.3).delta.:2.43(3H, s), 4.04(2H, s), 6.10(1H, d,
J=3.5 Hz), 7.09(1H, d, J=3.5 Hz),. 7.23-7.36(4H, m).
[1407]
1-[5-(2-[1,3]Dioxolane-2-yl-4-fluorobenzyl)furan-2-yl]etanone
[1408] NMR(CDCl.sub.3).delta.:2.43(3H, s), 3.98-4.16(4H, m),
4.17(2H, s),.5.91(1H, s), 6.02(1H, d, J=3.5 Hz), 7.01(1H, td,
J=8.4, 2.9 Hz), 7.08(1H, d, J=3.5 Hz), 7.17(1H, dd, J=5.6, 2.9 Hz),
7.33(1H, dd, J=9.6, 2.9 Hz).
[1409] 1-[5-(2-[1,3]Dioxolane-2-ylbenzyl)furan-2-yl] etanone
[1410] NMR(CDCl.sub.3).delta.:2.43(3H, s), 3.99-4.16(2H, m),
4.22(2H, s), 5.93(1H, s), 6.01(1H, d, J=3.4 Hz), 7.08(1H, d, J=3.4
Hz), 7.18-7.22(1H, m), 7.29-7.34(2H, m), 7.58-7.62(1H, m)
[1411] (A-140) According to the method of the above-mentioned
example A-18,
2-hydroxy-4-[5-(2-methoxybenzyl)furan-2-yl]-4-oxo-2-butenoic acid
methyl(977 mg, yield:88%) was synthesized from the above-mentioned
compound A-139(810 mg,3.52 mmol).
[1412] NMR(CDCl.sub.3).delta.:3.83(3H, s), 3.93(3H, s), 4.07(2H,
s), 6.15(1H, d, J=3.6 Hz), 6.88(1H, s), 6.89-6.95(2H, m), 7.16(1H,
dd, J=7.5, 1.8 Hz)7.23-7.30(2H, m).
[1413] The following compounds were synthesized by the
above-mentioned method.
[1414] 4-(5-Benzo[1,3]
dioxol-4-ylmethylfuran-2-yl)-2-hydroxy-4-oxo-2-bute- noic acid
methyl
[1415] NMR(CDCl.sub.3).delta.:3.93(3H, s), 4.04(2H, s), 5.97(2H,
s), 6.25(1H, d, J=3.6 Hz), 6.67-6.84(3H, m), 6.89(1H, s), 7.27(1H,
d, J=3.6 Hz).
[1416]
2-Hydroxy-4-(5-naphthalene-1-ylmethylfuran-2-yl)-4-oxo-2-butenoic
acid methyl
[1417] NMR(CDCl.sub.3).delta.:3.93(3H, s), 4.53(2H, s), 6.05(1H, d,
J=3.6 Hz), 6.88(1H, s), 7.22(1H, d, J=3.6 Hz), 7.36-7.55(1H, m),
7.80-7.97(3H, m).
[1418]
2-Hydroxy-4-[5-(2-isopropoxybenzyl)furan-2-yl]-4-oxo-2-butenoic
acid methyl
[1419] NMR(CDCl.sub.3).delta.:1.29(6H, d, J=6.1 Hz), 3.93(3H, s),
4.06(2H, s), 4.57(1H, sep, J=6.1 Hz), 6.17(1H, d, J=3.9 Hz),
6.85-6.92(3H, m), 7.15-7.28(3H, m).
[1420]
2-Hydroxy-4-[5-(3-isopropoxybenzyl)furan-2-yl]-4-oxo-2-butenoic
acid methyl
[1421] NMR(CDCl.sub.3).delta.:1.33(6H, d, J=6.0 Hz), 3.93(3H, s),
4.03(2H, s), 4.54(1H, sep, J=6.0 Hz), 6.22(1H, d, J=3.6 Hz),
6.76-6.82(3H, m), 6.88(1H, s), 7.20-7.26(1H, m), 7.27(1H, d, J=3.6
Hz).
[1422]
4-[5-(4-Fluoro-2-methoxybenzyl)furan-2-yl]-2-hydroxy-4-oxo-2-buteno-
ic acid methyl
[1423] NMR(CDCl.sub.3).delta.:3.82(3H, s), 3.93(3H, s), 4.02(2H,
s), 6.14(1H, d, J=3.3 Hz), 6.60-6.66(2H, m), 6.88(1H, s),
7.07-7.14(1H, m), 7.26(1H, d, J=3.3 Hz).
[1424]
4-[5-(4-Fluoro-3-methoxybenzyl)furan-2-yl]-2-hydroxy-4-oxo-2-buteno-
ic acid methyl
[1425] NMR(CDCl.sub.3).delta.:3.88(3H, s), 3.93(3H, s), 4.03(2H,
s), 6.22(1H, d, J=3.5 Hz), 6.77(1H, ddd, J=8.3, 4.1, 1.9 Hz),
6.84-6.88(1H, m), 6.87(1H, s), 7.03(1H, dd, J=11.1, 8.3 Hz),
7.28(1H, d, J=3.5 Hz).
[1426]
4-[5-(4-Fluoro-2-isopropoxybenzyl)furan-2-yl]-2-hydroxy-4-oxo-2-but-
enoic acid methyl
[1427] NMR(CDCl.sub.3).delta.:1.30(6H, d, J=6.0 Hz), 3.93(3H, s),
4.00(2H, s), 4.50(1H, sep, J=6.0 Hz), 6.15(1H, d, J=3.5 Hz),
6.55-6.62(2H, m), 6.87(1H, s), 7.08-7.14(1H, m), 7.26(1H, d, J=3.5
Hz).
[1428] 4-(5-Benzylfuran-2-yl)-2-hydroxy-4-oxo-2-butenoic acid
methyl
[1429] NMR(CDCl.sub.3).delta.:3.93(3H, s), 4.08(2H, s), 6.20(1H, d,
J=3.6 Hz), 6.88(1H, s), 7.23-7.37(5H, m).
[1430] (A-141) According to the method of the above-mentioned
example A-19,
3-hydroxy-1-isopropyl-4-[5-(2-methoxybenzyl)furan-2-carbonyl]-1,5-d-
ihydropyrrole-2-one (168 mg, yield:47%) was synthesized from the
above-mentioned compound A-140(316 mg, 1.00 mmol).
[1431] Melting point:123-124.degree. C.
[1432] Elementary analysis as C.sub.20H.sub.21NO.sub.5
[1433] Calcd. (%): C, 67.59; H, 5.96; N, 3.94. Found (%): C, 67.36;
H, 5.94; N, 3.88.
[1434] NMR(CDCl.sub.3).delta.:1.24(6H, d, J=6.8 Hz), 3.81(3H, s),
4.09(2H, s), 4.15(2H, s), 4.55(1H, sep, J=6.8 Hz), 6.30(1H, d,
J=3.6 Hz), 6.89-6.98(2H, m), 7.19-7.34(3H, m).
[1435] The following compounds were synthesized by the
above-mentioned method.
[1436] (A-141-a) 4-(5-Benzo[1,3]
dioxyl-4-ylmethylfuran-2-carbonyl)-3-hydr-
oxy-1-isopropyl-1,5-dihydropyrrole-2-one
[1437] Melting point: 130-132.degree. C.
[1438] NMR(CDCl.sub.3).delta.:1.25(6H, d, J=6.8 Hz), 4.06(2H, s),
4.20(2H, s), 4.56(1H, sep, J=6.8 Hz), 5.96(2H, s), 6.36(1H, d,
J=3.6 Hz), 6.72-6.87(3H, m), 7.34(1H, d, J=3.6 Hz).
[1439] (A-141-b) 4-(5-Benzo[1,3]
dioxyl-4-ylmethylfuran-2-carbonyl)-3-hydr-
oxy-1-methyl-1,5-dihydropyrrole-2-one
[1440] Melting point:169-1.70.degree. C.
[1441] NMR(CDCl.sub.3).delta.:3.14(3H, s), 4.06(2H, s), 4.23(2H,
s), 5.97(2H, s), 6.34(1H, d, J=3.6 Hz), 6.68-6.74(1H, m),
6.77-6.87(2H, m), 7.33(1H, d, J=3.6 Hz).
[1442] (A-141-c)
3-Hydroxy-1-isopropyl-4-(5-naphthalene-1-ylmethylfuran-2--
carbonyl)-1,5-dihydropyrrole-2-one
[1443] Melting point:165-166.5.degree. C.
[1444] NMR(CDCl.sub.3)(:1.14(6H, d, J=6.8 Hz), 3.92(2H, s),
4.47(1H, sep, J=6.8 Hz), 4.55(2H, s), 6.37(1H, d, J=3.8 Hz),
7.33(1H, d, J=3.8 Hz), 7.43-7.56(4H, m), 7.83-7.96(3H, m).
[1445] (A-141-d)
3-Hydroxy-4-[5-(2-isopropoxybenzyl)furan-2-carbonyl]-1-is-
opropyl-1,5-dihydropyrrole-2-one
[1446] NMR(CDCl.sub.3).delta.:1.22(6H, d, J=3.6 Hz), 1.24(6H, d,
J=3.3 Hz), 4.06(2H, s), 4.11(2H, s), 4.50-4.61(2H, m), 6.32(1H, d,
J=3.5 Hz), 6.87-6.95(2H, m), 7.21-7.30(2H, m), 7.34(1H, d, J=3.5
Hz).
[1447] (A-141-e)
3-Hydroxy-4-[5-(3-isopropoxybenzyl)furan-2-carbonyl]-1-is-
opropyl-1,5-dihydropyrrole-2-one
[1448] Melting point:98-99.degree. C.
[1449] Elementary analysis as C.sub.22H.sub.25NO.sub.5
[1450] Calcd. (%): C, 68.91; H, 6.57; N, 3.65. Found (%): C, 68.74;
H, 6.49; N, 3.65.
[1451] NMR(CDCl.sub.3).delta.:1.24(6H, d, J=6.9 Hz), 1.32(6H, d,
J=6.0 Hz), 4.04(2H, s), 4.18(2H, s), 4.48-4.63(2H, m), 6.35(1H, d,
J=3.8 Hz), 6.77-6.84(3H, m), 7.22-7.29(1H, m), 7.33(1H, d, J=3.8
Hz).
[1452] (A-141-f)
4-[5-(4-Fluoro-2-methoxybenzyl)furan-2-carbonyl]-3-hydrox-
y-1-isopropyl-1,5-dihydropyrrole-2-one
[1453] Melting point:112-113.degree. C.
[1454] Elementary analysis as C.sub.20H.sub.20FNO.sub.5
[1455] Calcd. (%): C, 64.34; H, 5.40; N, 3.75; F, 5.09. Found (%):
C, 64.24; H, 5.45; N, 3.69; F, 4.97.
[1456] NMR(CDCl.sub.3).delta.:1.25(6H, d, J=6.8 Hz), 3.80(3H, s),
4.04(2H, s), 4.15(2H, s), 4.56(1H, sep, J=6.8 Hz), 6.28(1H, d,
J=3.8 Hz), 6.62-6.70(2H, m), 7.13-7.19(1H, m), 7.33(1H, d, J=3.8
Hz).
[1457] (A-141-g)
4-[5-(4-Fluoro-2-methoxybenzyl)furan-2-carbonyl]-3-hydrox-
y-1-methyl-1,5-dihydropyrrole-2-one
[1458] Melting point:134-135.degree. C.
[1459] Elementary analysis as C.sub.18H.sub.16FNO.sub.5
[1460] Calcd. (%): C, 62.61; H, 4.67; N, 4.06; F, 5.50. Found (%):
C, 62.36; H, 4.64; N, 3.73; F, 5.43.
[1461] NMR(CDCl.sub.3).delta.:3.13(3H, s), 3.82(3H, s), 4.04(2H,
s), 4.18(2H, s), 6.25(1H, d, J=3.6 Hz), 6.63-6.70(2H, m),
7.10-7.16(1H, m), 7.32(1H, d, J=3.6 Hz).
[1462] (A-141-h)
4-[5-(4-Fluoro-3-methoxybenzyl)furan-2-carbonyl]-3-hydrox-
y-1-isopropyl-1,5-dihydropyrrole-2-one
[1463] Melting point:160-161.degree. C.
[1464] Elementary analysis as C.sub.20H.sub.20FNO.sub.5
[1465] Calcd. (%): C, 64.34; H, 5.40; N, 3.75; F, 5.09. Found (%):
C, 64.12; H, 5.42; N, 3.68; F, 5.04.
[1466] NMR(CDCl.sub.3).delta.:1.24(6H, d, J=6.7 Hz), 3.87(3H, s),
4.06(2H, s), 4.15(2H, s), 4.55(1H, sep, J=6.7 Hz), 6.33(1H, d,
J=3.6 Hz), 6.77-6.85(2H, m), 7.06(1H, dd, J=11.1, 8.1 Hz), 7.33(1H,
d, J=3.6 Hz).
[1467] (A-141-i)
4-[5-(4-Fluoro-3-methoxybenzyl)furan-2-carbonyl]-3-hydrox-
y-1-methyl-1,5-dihydropyrrole-2-one
[1468] Melting point: 164-166.degree. C.
[1469] Elementary analysis as C.sub.18H.sub.16FNO.sub.5
[1470] Calcd. (%): C, 62.61; H, 4.67; N, 4.06; F, 5.50. Found (%):
C, 62.36; H, 4.61; N, 3.87; F, 5.38.
[1471] NMR(CDCl.sub.3).delta.:3.13(3H, s), 3.89(3H, s), 4.05(2H,
s), 4.21(2H, s), 6.30(1H, d, J=3.6 Hz), 6.78(1H, ddd, J=8.2, 4.1,
2.2 Hz), 6.84(1H, dd, J=8.0, 2,2 Hz), 7.06(1H, dd, J=11.1, 8.2 Hz),
7.32(1H, d, J=3.6 Hz).
[1472] (A-141-j)
4-[5-(4-Fluoro-2-isopropoxybenzyl)furan-2-carbonyl]-3-hyd-
roxy-1-isopropyl-1,5-dihydropyrrole-2-one
[1473] Melting point:98-100.degree. C.
[1474] Elementary analysis as C.sub.22H.sub.24FNO.sub.5
[1475] Calcd. (%): C, 65.82; H, 6.03; N, 3.49; F, 4.73. Found (%):
C, 65.68; H, 5.98; N, 3.49; F, 4.65.
[1476] NMR(CDCl.sub.3).delta.:1.23(6H, d, J=6.9 Hz), 1,25(6H, d,
J=6.3 Hz), 4.02(2H, s), 4.11(2H, s),4.42-4.62(2H, m), 6.29(1H, d,
J=3.6 Hz), 6.60-6.67(2H, m), 7.14-7.20(1H, m), 7.34(1H, d, J=3.6
Hz).
[1477] (A-141-k)
4-[5-(4-Fluoro-2-isopropoxybenzyl)furan-2-carbonyl]-3-hyd-
roxy-1-methyl-1,5-dihydropyrrole-2-one
[1478] Melting point:126-129.degree. C.
[1479] NMR(CDCl.sub.3).delta.:1.26(6H, d, J=6.1 Hz), 3.12(3H, s),
4.01(2H, s), 4.15(2H, s), 4.49(1H, sep, J=6.1 Hz), 6.26(1H, d,
J=3.3 Hz), 6.60-6.67(2H, m), 7.11-7.17(1H, m), 7.32(1H, d, J=3.3
Hz).
[1480] (A-141-l)
4-(5-Benzylfuran-2-carbonyl)-3-hydroxy-1-isopropyl-1,5-di-
hydropyrrole-2-one
[1481] Melting point:162-163.degree. C.
[1482] Elementary analysis as C.sub.19H.sub.19NO.sub.4
[1483] Calcd. (%): C, 70.14; H, 5.89; N, 4.31. Found (%): C, 70.11;
H, 5.81; N, 4.31.
[1484] NMR(CDCl.sub.3).delta.:1.23(6H, d, J=6.8 Hz), 4.10(2H, s),
4.14(2H, s), 4.55(1H, sep, J=6.8 Hz), 6.34-6.36(1H, m),
7.25-7.31(2H, m), 7.32-7.40(3H, m).
[1485] (A-141--m)
4-(5-Benzylfuran-2-carbonyl)-3-hydroxy-1-methyl-1,5-dihy-
dropyrrole-2-one
[1486] Melting point:116-118.degree. C.
[1487] NMR(CDCl.sub.3).delta.:3.12(3H, s), 4.10(2H, s), 4.18(2H,
s), 6.32(1H, d, J=3.6 Hz), 7.24-7.29(2H, m), 7.31-7.41(3H, m).
[1488] Compound A-145
[1489]
5-Fluoro-2-[5-(4-hydroxy-1-isopropyl-5-oxo-2,5-dihydro-1H-pyrrole-3-
-carbonyl)furan-2-ylmethyl]benzamide 204
[1490] (A-142) According to the method of the above-mentioned
example A-18, a crude product(2.78 g) of
4-[5-(2-[1,3]dioxolane-2-yl-4-fluorobenz-
yl)furan-2-yl]-2-hydroxy-4-oxo-2-butenoic acid methyl was
synthesized from the above-mentioned compound; 1-[5-(2-[1,3]
dioxolane-2-yl-4-fluorobenzyl- )furan-2-yl]ethane(2.03 g, 7.00
mmol).
[1491] NMR(CDCl.sub.3).delta.:3.93(3H, s), 4.02-4.15(4H, m),
4.21(2H, s), 5.92(1H, s), 6.12(1H, d, J=3.6 Hz), 6.88(1H, s),
7.03(1H, td, J=8.3, 2.8 Hz), 7.18(1H, dd, J=8.3, 5.6 Hz), 7.26(1H,
d, J=3.6 Hz), 7.34(1H, dd, J=9.8, 2.8 Hz).
[1492] The following compound was synthesized by the
above-mentioned method.
[1493]
4-[5-(2-[1,3]Dioxolane-2-ylbenzyl)furan-2-yl]-2-hydroxy-4-oxo-2-but-
enoic acid methyl
[1494] NMR(CDCl.sub.3).delta.:3.93(3H, s), 4.00-4.17(4H, m),
4.26(2H, s), 5.94(1H, s), 6.12(1H, d, J=3.8 Hz), 6.89(1H, s),
7.18-7.22(1H, m), 7.26(1H, d, J=3.8 Hz), 7.31-7.35(2H, m),
7.58-7.62(1H, m).
[1495] (A-143) To a methyl alcohol(3 ml)-ether(10 ml) solution of a
crude product(1.51 g) of 4-[5-(2-[1,3]
dioxolane-2-yl-4-fluorobenzyl)furan-2-ca-
rbonyl]-3-hydroxy-1-isopropyl-1,5-dihydropyrrole-2-one which was
produced from the above-mentioned compound A-142(1.39 g), an ether
solution of diazomethane was added at 0.degree. C. until the foam
disappeared. According to the method of the above-mentioned example
A-19, the reaction mixture was stirred for 10 minutes, then which
was evaporated under reduced pressure. The residue was purified
with silica gel column chromatography(n-hexane/ethyl acetate=1/l)
to give 4-[5-(2-[1,3]
dioxolane-2-yl-4-fluorobenzyl)furan-2-carbonyl]-1-isopropyl-3-methoxy-1,5-
-dihydropyrrole-2-one (880 mg, yield: 59% (from 2-9)).
[1496] NMR(CDCl.sub.3).delta.:1.23(6H, d, J=6.8 Hz), 4.00-4.15(4H,
m), 4.07(2H, s), 4.16(3H, s), 4.21(2H, s), 4.45(1H, sep, J=6.8 Hz),
5.91(1H, s), 6.09(1H, dd, J=3.6, 0.9 Hz), 7.02(1H, td, J=8.3, 2,7
Hz), 7.20(1H, dd, J=8.3, 5.4 Hz), 7.30-7.37(1H, m), 7.33(1H, d,
J=3.6 Hz).
[1497] The following compound was synthesized by the
above-mentioned method.
[1498]
4-[5-(2-[1,3]Dioxolane-2-ylbenzyl)furan-2-carbonyl]-1-isopropyl-3-m-
ethoxy-1,5-dihydropyrrole-2-one
[1499] NMR(CDCl.sub.3).delta.:1.22(6H, d, J=6.7 Hz), 3.99-4.16(4H,
m), 4.08(2H, s), 4.15(3H, s), 4.26(2H, s), 4.45(1H, sep, J=6.7 Hz),
5.93(1H, s), 6.10(1H, d, J=3.9 Hz), 7.22-7.27(1H, m), 7.31-7.36(3H,
m), 7.59-7.63(1H, m)
[1500] (A-144) To a tetrahydrofuran(10 ml)-methyl alcohol(10 ml)
solution of the above-mentioned compound A-143(880 mg, 2.05 mmol),
2N hydrochloric acid(1.0 ml) was added at 50.degree. C., then the
reaction mixture was stirred for 3 hours, to which was added a
saturated sodium bicarbonate aqueous solution under cooling. The
mixture was extracted with ethyl acetate, washed, dried and
evaporated under reduced pressure to give a crude product(764 mg,
yield:97%) of 5-fluoro-2-[5-(1-isopropyl-4-methoxy--
5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)furan-2-ylmethyl]benzaldehyde,
which was dissolved into dioxane(10 ml)-methyl alcohol(5 ml), then
2-methyl-2-butene(2.1 ml,19.8 mmol) was added thereto. Sodium
chlorite(538 mg,5.94 mmol) was added to the reaction mixture at
0.degree. C., to which was added a sodium dihydrogen phosphate
dihydrate(929 mg, 5.94 mmol) aqueous solution(10 ml)for 5 minutes.
The reaction mixture was stirred at the same temperature for 1
hour, then 2N hydrochloric acid was added and the mixture was
extracted with ethyl acetate. The extract was washed, dried and
evaporated under reduced pressure to give
5-fluoro-2-[5-(1-isopropyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbo-
nyl)furan-2-ylmethyl]benzoic acid (609 mg, yield:77%).
[1501] NMR(CDCl.sub.3).delta.:1.23(6H, d, J=6.7 Hz), 4.08(2H, s),
4.11(3H, s), 4.46(1H, sep, J=6.7 Hz), 4.52(2H, s), 6.15(1H, d,
J=3.3 Hz), 7.20-7.27(1H, m), 7.30-7.36(2H, m), 7.78(1H, dd, J=9.3,
2.7 Hz).
[1502] The following compound was synthesized by the
above-mentioned method.
2-[5-(1-Isopropyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbon-
yl)furan-2-ylmethyl]benzoic Acid
[1503] NMR(CDCl.sub.3).delta.:1.23(6H, d, J=6.8 Hz), 4.03-4.16(4H,
m), 4.08(2H, s), 4.10(3H, s), 4.45(1H, sep, J=6.8 Hz), 4.56(2H, s),
6.15(1H, d, J=3.6 Hz), 7.32(1H, d, J=3.6 Hz), 7.34-7.42(2H, m),
7.54(1H, td, J=7.5, 1.5 Hz), 8.11(1H, dd, J=7.2, 1.2 Hz).
[1504] (A-145) To a N,N-dimethylformamide solution(5 ml) of the
above-mentioned compound A-144(300 mg,0.748 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(215 mg,
1.12 mmol), 1-hydroxy-1H-benzotriazole monohydrate(127 mg, 0.898
mmol) and ammonium chloride(60 mg, 1.12 mmol), triethylamine(0.16
ml, 1.12 mmol) was added at 0.degree. C., then the reaction mixture
was stirred for overnight at room temperature. 2N Hydrochloric acid
was added to the solution, which was extracted with ethyl acetate.
The extract was washed, dried and evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography(chloroform/methyl alcohol=40/1) to give
5-fluoro-2-[5-(1-isopropyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-3--
carbonyl)furan-2-ylmethyl]benzamide(82 mg, yield:27%) from which
compound(82 mg, 0.205 mmol),
5-fluoro-2-[5-(4-hydroxy-1-isopropyl-5-oxo-2-
,5-dihydro-1H-pyrrole-3-carbonyl)furan-2-ylmethyl]benzamide(39 mg,
yield:49%) was produced according to the synthetic method of
compound(16).
[1505] Melting point:215-218.degree. C.
[1506] Elementary analysis as C.sub.20H.sub.19FN.sub.2O.sub.5
[1507] Calcd. (%): C, 62.17; H, 4.96; N, 7.25; F, 4.92. Found (%):
C, 62.14; H, 5.03; N, 7.18; F, 4.92.
[1508] NMR(DMSO).delta.:1.19(6H, d, J=6.6 Hz), 4.10(2H, s),
4.25(1H, sep, J=6.6 Hz), 4.31(2H, s), 6.29(1H, d, J=3.5 Hz),
7.23-7.31(2H, m), 7.35-7.40(2H, m), 7.52(1H, s), 7.55(1H, d, J=3.5
Hz), 7.90(1H, s).
[1509] The following compound was synthesized by the
above-mentioned method.
[1510]
2-[5-(4-Hydroxy-1-isopropyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl-
)furan-2-ylmethyl]benzamide
[1511] Melting point:195-197.degree. C.
[1512] NMR(CDCl.sub.3).delta.:1.26(6H, d, J=7.0 Hz), 4.20(2H, s),
4.41(2H, s), 4.56(1H, sep, J=7.0 Hz), 5.60(1H, br s), 5.83(1H, br
s), 6.35(1H, d, J=3.9 Hz), 7.31-7.39(3H, m), 7.43-7.50(1H, m),
7.53-7.58(1H, m).
[1513] Compound A-146
[1514]
5-Fluoro-2-[5-(4-hydroxy-1-isopropyl-5-oxo-2,5-dihydro-1H-pyrrole-3-
-carbonyl)furan-2-ylmethyl]benzoic Acid Methyl 205
[1515] (A-146) To a methyl alcohol(2 ml)-ether(4 ml) solution of
the above-mentioned compound,
5-fluoro-2-[5-(1-isopropyl-4-methoxy-5-oxo-2,5--
dihydro-1H-pyrrole-3-carboxy)furan-2-ylmethyl]benzoic acid, an
ether solution of diazomethane was added at 0.degree. C., until the
foam disappeared. The reaction mixture was stirred for 10 minutes,
then which was evaporated under reduced pressure. The residue was
purified with silica gel column chromatography(n-hexane/ethyl
acetate=2/1-1/1) to give
5-fluoro-2-[5-(1-isopropyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbo-
nyl)furan-2-ylmethyl]benzoic acid methyl(187 mg, yield:60%) from
which compound(187 mg, 0.451 mmol),
5-fluoro-2-[5-(4-hydroxy-1-isopropyl-5-oxo--
2,5-dihydro-1H-pyrrole-3-carbonyl)furan-2-ylmethyl]benzoic acid
methyl(121 mg, yield:70%) was produced according to the synthetic
method of the compound(16).
[1516] Melting point:110-111.degree. C.
[1517] Elementary analysis as C.sub.21H.sub.20FNO.sub.6
[1518] Calcd. (%): C, 62.84; H, 5.02; N, 3.49; F, 4.73. Found (%):
C, 62.99; H, 5.15; N, 3.43; F, 4.66.
[1519] NMR(CDCl.sub.3).delta.:1.25(6H, d, J=6.8 Hz), 3.87(3H, s),
4.14(2H, s), 4.50(2H, s), 4.56(1H, sep, J=6.8 Hz), 6.30(1H, d,
J=3.4 Hz), 7.20-7.29(1H, m), 7.31-7.37(1H, m), 7.33(1H, d, J=3.4
Hz), 7.72(1H, dd, J=9.1, 2.7 Hz).
[1520] Compound A-152
[1521]
4-[5-Cyclohexyl-3-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-met-
hyl-1,5-dihydropyrrole-2-one 206207
[1522] (A-(147) To a tetrahydrofuran solution(14 ml) of
diisopropylamine(1.54 ml, 1 mmol) under dry ice cooling, 1.58M
n-butyllithium(7.0 ml, 11 mmol) was added, then the reaction
mixture was stirred for 30 minutes, to which was added dropwise a
tetrahydrofuran solution(7 ml) of the above-mentioned compound
A-46(1.10 g, 5.0 mmol) for 10 minutes. The reaction mixture was
stirred for 1 hour, then to which was added cyclohexanone(0.62 ml,
6.0 mmol) and stirred for 30 minutes. 2N Hydrochloric acid was
added to the reaction mixture, then which was extracted 2 times
with ethyl acetate. The organic layer was washed with 2N
hydrochloric acid and brine, successively, then dried with
anhydrosodium sulfate, which was evaporated to give a crude
product(1.8 g) of
3-(4-fluorobenzyl)-5-(1-hydroxycyclohexyl)-2-furoin acid.
[1523] (A-148) According to the method of A-35, a crude product(1.6
g) of 5-cyclohexyl-3-(4-fluorobenzyl)-2-furoin acid was synthesized
from the above-mentioned crude product A-147.
[1524] (A-149) According to the method of A-36,
5-cyclohexyl-3-(4-fluorobe- nzyl)-2-furoin acid
methoxymethylamide(1.05 g, total yield of 3 process:61%) was
synthesized from the above-mentioned product A-148.
[1525] NMR(CDCl.sub.3).delta.: 1.1-2.1(10H, m), 2.5-2.6(1H, m),
3.32(3H, s), 3.84(3H, s), 4.08(2H, s), 5.83(1H, d, J=0.9 Hz),
6.93-6.98(2H, m), 7.21-7.25(2H, m).
[1526] (A-150) According to the method of A-37,
1-[5-cyclohexyl-3-(4-fluor- obenzyl)furan-2-yl]etanone(860 mg,
yield:99%) was synthesized from the above-mentioned compound
A-149(1.0 g, 2.9 mmol).
[1527] NMR(CDCl.sub.3).delta.:1.2-2.1(10H, m), 2.46(3H, s),
2.5-2.7(1H, m), 4.13(2H, s), 5.89(1H, s), 6.93-6.98(2H, m),
7.18-7.22(2H, m).
[1528] (A-151) According to the method of A-18,
4-[5-cyclohexyl-3-(4-fluor-
obenzyl)furan-2-yl]-2-hydroxy-4-oxo-2-butenoic acid methyl
ester(709 mg, yield:65%) was synthesized from the above-mentioned
compound A-150(850 mg, 2.83 mmol).
[1529] NMR(CDCl.sub.3).delta.: 1.1-2.1(10H, m), 2.64(1H, m),
3.94(3H, s), 4.20(2H, s), 5.97(1H, s), 6.95-7.01(2H, m), 6.98(1H,
s), 7.19-7:24(2H, m).
[1530] (A-152) According to the method of A-19,
4-[5-cyclohexyl-3-(4-fluor-
obenzyl)furan-2-carbonyl]-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one(102
mg, yield: 34%) was synthesized from the above-mentioned compound
A-151(290 mg, 0.75 mmol).
[1531] Melting point:175-176.degree. C.
[1532] Elementary analysis as C.sub.23H.sub.24FNO.sub.4
[1533] Calcd. (%): C, 69.51; H, 6.09; N, 3.52; F, 4.78. Found (%):
C, 69.45; H, 6.11; N, 3.57; F, 4.69.
[1534] NMR(CDCl.sub.3).delta.:1.20-2.05(10H, m), 2.65(1H,
m),3.20(3H, s), 4.22(2H, s), 4.42(2H, s), 6.02(1H, s),
6.96-7.02(2H, m), 7.21-7.25(2H, m).
[1535] Compound A-158
[1536]
4-[3-(4-Fluorobenzyl)-5-(1-methoxy-1-methylethyl)furan-2-carbonyl]--
3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one 208209
[1537] (A-153) To a tetrahydrofuran solution(28 ml) of
diisopropylamine(3.1 ml, 22 mmol) under dry ice cooling, 1.58M
n-butyllithium(14 ml, 22 mmol) was added, then the reaction mixture
was stirred for 30 minutes, to which was added dropwise a
tetrahydrofuran solution(7 ml) of the above-mentioned compound
A-46(2.2 g, 10 mmol)for 10 minutes. The reaction mixture was
stirred for 1 hour, then to which was added acetone(1 ml) and
stirred for 30 minutes. 2N Hydrochloric acid was added to the
reaction mixture, then which was extracted 2 times with ethyl
acetate. The organic layer was washed with 2N hydrochloric acid and
brine, successively, then dried with anhydrosodium sulfate, which
was evaporated to give a crude product(3.07 g) of
3-(4-fluorobenzyl)-5-(1-hyd- roxy-1-methylethyl)-2-furoin acid.
[1538] (A-154) According to the method of A-36,
3-(4-fluorobenzyl)-5-(1-hy- droxy-1-methyl ethyl)-2-furoin acid
methoxymethylamide(1.97 g, total yield of 2 process:61%)was
synthesized from the above-mentioned crude product A-153.
[1539] NMR(CDCl.sub.3)(d: 1.56(6H, s), 3.31(3H, s), 3.84(3H, s),
4.07(2H, s), 6.06(1H, s), 6.93-6.99(2H, m), 7.21-7.25(2H, m).
[1540] (A-155) To a N,N-dimethylformamide solution(8 ml) of the
above-mentioned compound A-154(964 mg, 3.0 mmol), 60% sodium
hydride(144 mg, 3.6 mmol) and iodomethane(0.28 ml, 4.5 mmol) were
successively added under ice cooling, then the reaction mixture was
stirred at room temperature for 3 hours, to which was added water
and 2N hydrochloric acid, successively. The reaction mixture was
extracted 2 times with ethyl acetate, then the organic layer was
washed with water and brine, successively, which was dried with
anhydro magnesium sulfate. The reaction mixture was evaporated,
then the crude product was treated with silica gel column
chromatography to give 3-(4-fluorobenzyl)-5-(1-methoxy
1-methylethyl)-2-furoin acid methoxymethylamide (774 mg,
yield:77%).
[1541] NMR(CDCl.sub.3).delta.: 1.50(6H, s), 3.07 (3H, s), 3.32(3H,
s), 3.87(3H, s), 4.09(2H, s), 6.09(1H, s), 6.94-7.00(2H, m),
7.21-7.26(2H, m).
[1542] (A-156) According to the method of A-37,
1-[3-(4-fluorobenzyl)-5-(1-
-methoxy-1-methylethyl)furan-2-yl]etanone(624 mg, yield:95%) was
synthesized from the above-mentioned A-155(760 mg, 2.27 mmol).
[1543] NMR(CDCl.sub.3).delta.: 1.52(6H, s), 2.51(3H, s), 3.10(3H,
s), 4.15(2H, s), 6.15(1H, s), 6.94-7.00(2H, m), 7.18-7.23(2H,
m).
[1544] (A-157) According to the method of A-18, a crude product(822
mg) of
4-[3-(4-fluorobenzyl)-5-(1-methoxy-1-methylethyl)furan-2-yl]-2-hydroxy-4--
oxo-2-butenoic acid methyl ester was synthesized from the
above-mentioned compound A-156(620 mg, 2.10 mmol).
[1545] NMR(CDCl.sub.3).delta.: 1.54(6H, s), 3.11(3H, s), 3.94(3H,
s), 4.22(2H, s), 6.22(1H, s), 6.97-7.02(2H, m), 7.01(1H, s),
7.20-7.24(2H, m).
[1546] (A-158) According to the method of A-19,
4-[3-(4-fluorobenzyl)-5-(1-
-methoxy-1-methylethyl)furan-2-carbonyl]-3-hydroxy-1-methyl-1,5-dihydropyr-
role-2-one(143 mg, yield:34%) was synthesized from the
above-mentioned crude product A-157(410 mg, 1.09 mmol).
[1547] Melting point: 144-145.degree. C.
[1548] Elementary analysis as C.sub.21H.sub.22FNO.sub.5
[1549] Calcd. (%): C, 65.11; H, 5.72; N, 3.62; F, 4.90. Found (%):
C, 65.00; H, 5.63; N, 3.62; F, 4.67.
[1550] NMR(CDCl.sub.3).delta.:1.54(6H, s), 3.09(3H, s), 3.19(3H,
s), 4.24(2H, s), 4.45(2H, d, J=0.6 Hz), 6.25(1H, s), 6.97-7.03(2H,
m), 7.21-7.26(2H, m).
1-Ethyl-4-[3-(4-fluorobenzyl)-5-(1-methoxy-1-methylethy-
l)furan-2-carbonyl]-3-hydroxy-1,5-dihydropyrrole-2-one(187 mg,
yield:47%) was synthesized from the above-mentioned crude product
A-157(376 mg, 11.0 mmol).
[1551] Melting point:146-148.degree. C.
[1552] Elementary analysis as C.sub.22H.sub.24FNO.sub.5
[1553] Calcd. (%): C, 65.82; H, 6.03; N, 3.49; F, 4.73. Found (%):
C, 65.78; H, 6.00; N, 3.45; F, 4.55.
[1554] NMR(CDCl.sub.3).delta.: 1.27(3H, t, J=7.2 Hz), 1.54(6H, s),
3.09(3H, s), 3.65(2H, q, J=7.2 Hz), 4.24(2H, s), 4.45(2H, s),
6.24(1H, s), 6.97-7.02(2H, m), 7.21-7.25(2H, m).
[1555] Compound A-164
[1556] 1-Ethyl-4-[3-(4-fluorobenzyl)-5-methane
sulfonylfuran-2-carbonyl]-3- -hydroxy-1,5-dihydropyrrole-2-one
210211
[1557] (A-159) To a tetrahydrofuran solution(30 ml) of
diisopropylamine(3.4 ml, 24 mmol) under dry ice cooling, 1.58M
n-butyllithium(15 ml, 24 mmol) was added, then the reaction mixture
was stirred for 30 minutes, to which was added dropwise a
tetrahydrofuran solution(10 ml) of the above-mentioned compound
A-46(2.2 g, 10 mmol)for 10 minutes. The reaction mixture was
stirred for 1 hour, then to which was added dimethyl disulfide(0.9
ml, 10 mmol) and stirred for 30 minutes. 2N Hydrochloric acid was
added to the reaction mixture, then which was extracted 2 times
with ethyl acetate. The organic layer was washed with 2N
hydrochloric acid and brine, successively, then dried with
anhydrosodium sulfate, which was evaporated to give a crude
product(2.82 g) of 3-(4-fluorobenzyl)-5-methylsulfanil-2-furoin
acid.
[1558] (A-160) According to the method of A-36,
3-(4-fluorobenzyl)-5-methy- lsulfanil-2-furoin acid
methoxymethylamide (3.14 g) was synthesized from the
above-mentioned crude product A-159.
[1559] (A-161) According to the method of A-37,
1-[3-(4-fluorobenzyl)-5-me- thylsulfanilfuran-2-yl]etanone(2.44 g)
was synthesized from the above-mentioned crude product A-160.
[1560] (A-162) To a methylene chloride solution(6 ml) of the
above-mentioned crude product A-161(1.06 g, 4 mmol) under ice
cooling, a methylene chloride solution(8 ml) of 80%
m-chloroperbenzoic acid(1.73 g, 8 mmol) was added dropwise for 10
minutes, then the reaction mixture was stirred for 30 minutes, to
which was added 80% m-chloroperbenzoic acid(863 mg, 4 mmol). The
reaction mixture was stirred for 2 hours, then the crystal was
filtered out. The filtrate was evaporated, then the residue was
dissolved in ethyl acetate, which was washed 3 times with saturated
sodium hydrogen carbonate aqueous solution and 1 time with brine,
which was then dried with anhydro magnesium sulfate. The reaction
mixture was evaporated to give a crude product, which was treated
with silica gel column chromatography to give
1-[3-(4-fluorobenzyl)-5-methanes- ulfonylfuran-2-yl]etanone(942 mg,
total yield of 4 process:64%).
[1561] NMR(CDCl.sub.3).delta.:2.59(3H, s), 3.19(3H, s), 4.17(2H,
s), 6.95(1H, s), 6.97-7.03(2H, m), 7.17-7.21(2H, m).
[1562] (A-163) According to the method of A-18, a crude product(213
mg) of 4-[3-(4-fluorobenzyl)-5-methane
sulfonylfuran-2-yl]-2-hydroxy-4-oxo-2-but- enoic acid ethyl ester
was synthesized from the above-mentioned compound A-162(148 mg, 0.5
mmol).
[1563] NMR(CDCl.sub.3).delta.: 1.42(3H, t, J=7.1 Hz), 3.21(3H, s),
4.25(2H, s), 4.43(2H, q, J=7.2 Hz), 6.99-7.05(2H, m), 6.99(1H, s),
7.05(1H, s), 7.18-7.23(2H, m).
[1564] (A-164) According to the method of A-19,
1-ethyl-4-[3-(4-fluorobenz-
yl)-5-methanesulfonylfuran-2-carbonyl]-3-hydroxy-1,5-dihydropyrrole-2-one(-
69 mg yield:34%) was synthesized from the above-mentioned crude
product 15(213 mg, 0.5 mmol).
[1565] Melting point:154-157.degree. C.
[1566] Elementary analysis as C.sub.19H.sub.19FNO.sub.6S
[1567] Calcd. (%): C, 56.01; H, 4.45; N, 3.44; F, 4.66; S, 7.87.
Found (%): C, 55.77; H, 4.36; N, 3.39; F, 4.43; S, 7.69.
[1568] NMR(CDCl.sub.3).delta.: 1.28(3H, t, J=7.1 Hz), 3.19(3H, s),
3.65(2H, q, J=7.2 Hz), 4.27(2H, s), 4.48(2H, s), 7.00-7.05(2H, m),
7.02(1H, s), 7.20-7.25(2H, m).
[1569] Compound A-171
[1570]
4-[3-(4-Fluorobenzyl)-5-(1,1-dioxotetrahydrothiopyran-4-yl)furan-2--
carbonyl]-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one 212213
[1571] (A-165) To a tetrahydrofuran solution(30 ml) of
diisopropylamine(3.08 ml, 22 mmol) under dry ice cooling, 1.57M
n-butyllithium(14 ml, 22 mmol) was added, then the reaction mixture
was stirred for 30 minutes, to which was added dropwise a
tetrahydrofuran solution(10 ml) of the above-mentioned compound
A-46(2.2 g, 10 mmol)for 10 minutes. The reaction mixture was
stirred for 1hour, then to which was added
tetrahydrothiopyran-4-one(1.39 g, 12 mmol) and stirred for 30
minutes. 2N Hydrochloric acid was added to the reaction mixture,
then which was extracted 2 times with ethyl acetate. The organic
layer was washed with 2N hydrochloric acid and brine, successively,
then dried with anhydrosodium sulfate, which was evaporated to give
a crude product(3.95 g) of
3-(4-fluorobenzyl)-5-(4-hydroxytetrahydrothiopyran-4-yl)-2-furoin
acid.
[1572] (A-166) According to the method of A-36,
3-(4-fluorobenzyl)-5-(4-hy- droxytetrahydrothiopyran-4-yl)-2-furoin
acid methoxymethylamide(2.97 g, total yield of 2process:78%) was
synthesized from the above-mentioned compound A-165.
[1573] NMR(CDCl.sub.3).delta.: 2.15-2.19(4H, m), 2.43-2.51(2H, m),
3.00-3.09(2H, m), 3.31(3H, s), 3.83(3H, s), 4:07(2H, s), 6.07(1H,
s), 6.93-6.99(2H, m), 7.19-7.24(2H, m).
[1574] (A-167) To a methylene chloride solution(20 ml) of the
above-mentioned crude product A-166(2.86 g, 7.54 mmol) under ice
cooling, a methylene chloride solution(20 ml) of 80%
m-chloroperbenzoic acid(3.11 g, 18 mmol) was added dropwise for 15
minutes, then the reaction mixture was stirred for 2 hours, to
which was added 80% m-chloroperbenzoic acid(650 mg, 3.77 mmol). The
reaction mixture was stirred for 1 hour, then the crystal was
filtered out. The filtrate was evaporated, then the residue was
dissolved in ethyl acetate, which was washed 3 times with saturated
sodium hydrogen carbonate aqueous solution and 1 time with brine,
which was then dried with anhydro magnesium sulfate. The reaction
mixture was evaporated to give a crude product, which was
crystallized with diisopropyl ether-acetone to give
3-(4-fluorobenzyl)-5-(4-hydroxy-1,-
1-dioxotetrahydrothiopyran-4-yl)-2-furoin acid methoxymethylamide
(2.63 g, yield:85%).
[1575] NMR(CDCl.sub.3).delta.:2.30-2.37(2H, m), 2.51-2.61(2H, m),
2.88-2.94(2H, m), 3.30(3H, s), 3.46(2H, dt, J=3.3, 13.5 Hz),
3.81(3H, s), 4.03(2H, s), 6.12(1H, s), 6.94-6.99(2H, m),
7.17-7.22(2H, m).
[1576] (A-168) According to the method of A-35,
3-(4-fluorobenzyl)-5-(1,1-- dioxotetrahydrothiopyran-4-yl)-2-furoin
acid methoxymethylamide(l.53 g, yield: 97%) was synthesized from
the above-mentioned compound A-167(1.65 g, 4.0 mmol).
[1577] NMR(CDCl.sub.3).delta.: 2.29-2.43(4H, m), 2.90-3.16(5H, m),
3.32(3H, s), 3.81(3H, s), 4.07(2H, s), 5.95(1H, s), 6.94-7.00(2H,
m), 7.19-7.24(2H, m).
[1578] (A-169) According to the method of A-37,
1-[3-(4-fluorobenzyl)-5-(1-
,1-dioxotetrahydrothiopyran-4-yl)furan-2-yl]etanone(1.14 g,
yield:92%) was synthesized from the above-mentioned compound
A-168(1.40 g, 3.54 mmol).
[1579] NMR(CDCl.sub.3).delta.: 2.31-2.43(4H, m), 2.47(3H, s),
2.91-3.17(5H, m), 4.13(2H, s), 6.00(1H, s), 6.94-7.00(2H, m),
7.16-7.21(2H, m).
[1580] (A-170) According to the method of A-18,
4-[3-(4-fluorobenzyl)-5-(1-
,1-dioxotetrahydrothiopyran-4-yl)furan-2-yl]-2-hydroxy-4-oxo-2-butenoic
acid ethyl ester(286 mg, yield:66%) was synthesized from the
above-mentioned compound A-169(350 mg, 1.0 mmol).
[1581] NMR(CDCl.sub.3).delta.: 2.28-2.48(4H, m), 2.94-3.18(5H, m),
3.95(3H, s), 4.20(2H, s), 6.07(1H, s), 6.94(1H, s), 6.97-7.02(2H,
m), 7.18-7.23(2H, m).
[1582] (A-171) According to the method of A-19,
4-[3-(4-fluorobenzyl)-5-(1-
,1-dioxotetrahydrothiopyran-4-yl)furan-2-carbonyl]-3-hydroxy-1-methyl-1,5--
dihydropyrrole-2-one(69 mg, yield:34%) was synthesized from the
above-mentioned compound A-170(175 mg, 0.4 mmol).
[1583] Melting point:200-203.degree. C.
[1584] Elementary analysis as C.sub.22H.sub.22FNO.sub.6S
[1585] Calcd. (%): C, 59.05; H, 4.96; N, 3.13; F, 4.25; S, 7.17.
Found (%): C, 58.67; H, 4.85; N, 2.95; F, 4.06; S, 7.05.
[1586] NMR(CDCl.sub.3).delta.: 2.29-2.45(4H, m), 2.93-3.15(5H, m),
3.20(3H, s), 4.23(2H, s), 4.40(2H, s), 6.12(1H, s), 6.97-7.03(2H,
m), 7.19-7.24(2H, m).
[1587] According to the same method,
1-ethyl-4-[3-(4-fluorobenzyl)-5-(1,1--
dioxotetrahydrothiopyran-4-yl)furan-2-carbonyl]-3-hydroxy-1,5-dihydropyrro-
le-2-one(55 mg, yield:52%) was synthesized from the above-mentioned
compound A-170(100 mg, 0.23 mmol).
[1588] Melting point:213-216.degree. C.
[1589] Elementary analysis as C.sub.23H.sub.24FNOeS 0.2H.sub.2O
[1590] Calcd. (%): C, 59.39; H, 5.29; N. 3.01; F, 4.08; S, 6.89.
Found (%): C, 59.22; H, 5.20; N, 2.91; F, 3.95; S, 6.76.
[1591] NMR(CDCl.sub.3).delta.: 1.29(3H, t, J=7.2 Hz), 2.35-2.43(4H,
m), 2.95-3.19(5H, m), 3.65(2H, q, J=7.2 Hz), 4.23(2H, s), 4.40(2H,
s), 6.12(1H, s), 6.97-7.03(2H, m), 7.19-7.24(2H, m).
[1592] Compound A-178
[1593]
4-[3-(4-Fluorobenzyl)-5-(morpholine-4-carbonyl)furan-2-carbonyl]-3--
hydroxy-1-methyl-1,5-dihydropyrrole-2-one 214215
[1594] (A-172) To a tetrahydrofuran(75 ml) solution of
diisopropylamine(8.41 ml, 60 mmol) in nitrogen gas under dry ice
acetone cooling(-70.degree. C.), n-butyllithium-hexane
solution(1.58M)(38 ml, 60 mmol) was added dropwise(LDA
preparation)for 20 minutes, then the reaction mixture was stirred
for 30 minutes, to which was added dropwise a tetrahydrofuran(35
ml) solution of 3-(4-fluorobenzyl)furan-2-carboxylic
acid(A-46)(5.505 g, 25 mmol)for 20 minutes. The reaction mixture
was stirred for 1 hour, then a tetrahydrofuran(25 ml) solution of
carbonic acid di-t-butyl ester(19.3 g, 88.4 mmol) was added dropwis
for 15 minutes, which was stirred for 1.5 hours. The reaction
mixture was stirred for 15 minutes under ice cooling, then
water(100 ml) was added dropwise and stirred for 20 minutes. The
reaction mixture was extracted with diethyl ether(300 ml)-water(200
ml), then the ether layer was extracted 4 times with 2N sodium
hydroxide(15 ml) and water(50 ml). The alkali layer was cooled with
ice, to which was added 2N hydrochloric acid(105 ml), then which
was extracted with ethyl acetate(300 ml), washed with water(100 ml)
and dried with magnesium sulfate. The reaction mixture was
evaporated under reduced pressure to give a crude product of
3-(4-fluorobenzyl)furan-2,5-dicarboxylic acid-5-tert-butyl
ester(A-172) (7.70 g, yield:96.1%).
[1595] (A-173) A mixture of
3-(4-fluorobenzyl)furan-2,5-dicarboxylic acid 5-tert-butyl
ester(A-172)(7.70 g, 24.04 mmol), N,O-dimethylhydroxylamine
hydrochloric acid(2.93 g, 30 mmol) and hydroxybenztriazole(4.05 g,
30 mmol) was suspended in dichloromethane(250 ml) at room
temperature, to which were added triethylamine(4.25 ml, 30.5 mmol)
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric
acid(5.75 g, 30 mmol), successivly. The reaction mixture was
stirred, then allowed to stand overnight at room temperature, to
which was added ethyl acetate, then dichloromethane was evaporated
under reduced pressure. To the ethyl acetate solution, ice water
and saturated sodium bicarbonate aqeous solution(80 ml) were added,
and the mixture was extracted, washed and dried with magnesium
sulfate. The reaction mixture was evaporated under reduced
pressure, then the residue was purified with silica gel column
chromatography(n-hexane:acetone=19:1) to give
4-(4-fluorobenzyl)-5-(metho- xymethylcarbamoyl)furan-2-carboxylic
acid tert-butyl ester(3.901 g, yield:44.6%)from the n-hexane
eluent.
[1596] Melting point:103-107.degree. C.
[1597] NMR(CDCl.sub.3).delta.: 1.55(9H, s), 3.33(3H, s), 3.93(3H,
s), 4.09(2H, s), 6.83(1H, s), 6.94-7.01(2H, m), 7.20-7.25(2H,
m).
[1598] (A-174) To a tetrahydrofuran(40 ml) solution of the
above-mentioned compound A-173(3.80 g, 10.46 mmol) in nitrogen gas
under dry ice acetone cooling(-30.degree. C.), methylmagnesium
bromide tetrahydrofuran solution(1M)(15.7 ml, 15.7 mmol) was added
dropwise for 10 minutes, then the reaction mixture was stirred for
40 minutes, to which was added dropwise methylmagnesium bromide
tetrahydrofuran solution(1M)(18.8 ml, 18.-8 mmol). The reaction
mixture was stirred for 1.5 hours, then the reaction mixture was
poured into ice water, to which was added ethyl acetate and 2N
hydrochloric acid(17.3 ml, 34.5 mmol), then extracted. The extract
was washed with water, then dried with magnesium sulfate, which was
evaporated under reduced pressure. N-hexane(8 ml) was added to the
crystalline residue(3.375 g) under ice cooling to give a
crystalline colorless powder of
5-acetyl-4-(4-fluorobenzyl)furan-2-carboxylic acid tert-butyl
ester(2.906 g, yield:87.3%). The filtrate was purified with silica
gel column chromatography(n-hexane:acetone=24:1) to give A-174(200
mg, yield:6.0%) which was similary treated with n-hexane.
[1599] Melting point: 102-103.degree. C.
[1600] NMR(CDCl.sub.3).delta.: 1.56(9H, s), 2.58(3H, s), 4.16(2H,
s), 6.83(1H, s), 6.95-7.01(2H, m), 7.16-7.21(2H, m).
[1601] (A-175) To a dichloromethane(20 ml) solution of the
above-mentioned compound A-174(1.273 g, 4.0 mmol) at room
temperature, trifluoroacetic acid(12 ml) was added. The reaction
mixture was stirred for 1.5 hours, then evaporated under reduced
pressure. Toluene was added to the residue and evaporated. This
operation was done for 2 times. N-hexane was added to the
crystalline residue to give a colorless powder of
5-acetyl-4-(4-fluorobenzyl)furan-2-carboxylic acid(1.004 g,
yield:95.7%).
[1602] Melting point:143-144.degree. C.
[1603] NMR(CDCl.sub.3).delta.: 2.61(3H, s), 4.18(2H, s),
6.96-7.02(2H, m), 7.07(1H, s), 7.17-7.22(2H, m).
[1604] (A-176) To a dichloromethane(10 ml) suspension of the
above-mentioned compound A-175(262 mg, 1.0 mmol) and
hydroxybenztriazole(162 mg, 1.2 mmol) at room temperature,
morpholine(0.105 ml, 1.2 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)carbo- diimide hydrochloric
acid(230 mg, 1.2 mmol) were added. The reaction mixture was stirred
for 3 hours, then evaporated under reduced pressure. Ice water and
ethyl acetate were added to the residue(776 mg), which was washed
with 2N hydrochloric acid(0.5 ml, 1 mmol), saturated sodium
bicarbonate aqueous solution and water, successively. The reaction
mixture was dried with magnesium sulfate, then evaporated under
reduced pressure to give a yellow green oil of
1-[3-(4-fluorobenzyl)-5-(morpholin-
e-4-carbonyl)furan-2-yl]etanone(343 mg, 103%).
[1605] NMR(CDCl.sub.3).delta.: 2.53(3H, s), 3.70-3.85(8H, m),
4.16(2H, s), 6.81(1H, s), 6.94-7.00(2H, m), 7.17-7.22(2H, m).
5-Acetyl-4-(4-fluorobenz- yl)furan-2-carboxylic acid
diethylamide(yield:91.8%) was synthesized, by the above-mentioned
method.
[1606] Melting point:74-75.degree. C.
[1607] NMR(CDCl.sub.3).delta.: 1.15-1.40(6H, m), 2.53(3H, s),
3.40-3.65(4H, m), 4.16(2H, s), 6.85(1H, s), 6.94-6.99(2H, m),
7.18-7.22(2H, m).
[1608] (A-177) According to the method of A-18, a yellow crystal of
4-[3-(4-fluorobenzyl)-5-(morpholine-4-carbonyl)furan-2-yl]-2-hydroxy-4-ox-
o-2-butenoic acid methyl ester(407 mg, yield:97.6%) was synthesized
from the above-mentioned compound A-176(343 mg, 1.0 mmol).
[1609] Melting point:143-146.degree. C.
[1610] NMR(CDCl.sub.3).delta.: 3.73-3.83(8H, m), 3.95(3H, s),
4.23(2H, s), 6.84(1H, s), 6.97-7.03(3H, m), 7.18-7.25(2H, m).
[1611] A yellow powder crystal of
4-[5-diethylcarbamoyl-3-(4-fluorobenzyl)-
furan-2-yl]-2-hydroxy-4-oxo-2-butenoic acid methyl
ester(yield:93.1%) was synthesized, by the above-mentioned
method.
[1612] Melting point: 128-130.degree. C.
[1613] NMR(CDCl.sub.3).delta.: 1.15-1.45(6H, m), 3.45-3.65(4H, m),
3.94(3H, s), 4.23(2H, s), 6.91(1H, s), 6.96-7.03(3H, m),
7.19-7.24(2H, m).
[1614] (A-178) According to the method of A-19, a yellow crystal of
4-[3-(4-fluorobenzyl)-5-(morpholine-4-carbonyl)furan-2-carbonyl]-3-hydrox-
y-1-methyl-1,5-dihydropyrrole-2-one(237 mg, yield:57.5%) was
synthesized from the above-mentioned compound A-177(401 mg, 0.961
mmol).
[1615] Melting point:209-211.degree. C.(dec)
[1616] Elementary analysis as C.sub.22H2,FN.sub.2O.sub.6
[1617] Calcd. (%): C, 61.68; H. 4.94; N, 6.54; F, 4.43. Found (%):
C, 61.33; H, 4.92; N, 6.36; F, 4.34.
[1618] NMR(CDCl.sub.3).delta.: 3.19(3H, s), 3.75(8H, bs), 4.27(2H,
s), 4.47(2H, s), 6.69(1H, s), 6.98-7.03(2H, m), 7.20-7.25(2H,
m).
[1619] (A-178-a) An ocher prism crystal of
4-(4-fluorobenzyl)-5-(4-hydroxy-
-l-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)furan-2-carboxylic
acid diethylamide(yield: 36.5%) was synthesized, by the
above-mentioned method.
[1620] Melting point:122-123.degree. C.
[1621] Elementary analysis as C.sub.22H.sub.23FN.sub.2O.sub.5
[1622] Calcd. (%): C, 63.76; H, 5.59; N, 6.76; F, 4.58. Found (%):
C, 63.63; H, 5.58; N, 6.61; F, 4.44.
[1623] NMR(CDCl.sub.3).delta.: 1.25(6H, t, J=6.9 Hz), 3.18(3H, s),
3.53(4H, q, J=6.9 Hz), 4.27(2H, s), 4.51(2H, s), 6.64(1H, s),
6.97-7.03(2H, m), 7.20-7.27(2H, m).
[1624] Compound A-184
[1625]
2-(4-Fluorobenzyl)-5-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrro-
le-3-carbonyl)furan-3-carboxylic acid ethylamide 216
[1626] (A-179) To an ethanol(40 ml) solution of the above-mentioned
compound A-35(3.55 g, 16.1 mmol), conc-sulfuric acid(0.1 ml) was
added, then dehydration was performed for 9 hours under refluxing.
The reaction mixture was allowed to stand overnight at room
temperature, then evaporated. The residue was dissolved to ethyl
acetate, which was washed with saturated sodium hydrogen carbonate
solution, dried and evaporated under reduced pressure to give a
crude product of 2-(4-fluorobenzyl)furan- -3-carboxylic acid ethyl
ester(4.18 g, yield: 100%).
[1627] NMR(CDCl.sub.3).delta.: 1.35(3H, t, J=7.2 Hz), 4.31(2H, q,
J=7.2 Hz), 4.32(2H, s), 6.67(1H, d, J=2.1 Hz), 6.94-7.00(2H, m),
7.22-7.27(3H, m).
[1628] (A-180) Aluminum chloride(11.2 g, 84 mmol) was added to
methylene chloride(30 ml), then a methylene chloride solution(5 ml)
of the above-mentioned compound A-179(4.18 g, 16.8 mmol) was added
thereto under ice cooling. The reaction mixture was stirred for 30
minutes, to which was added acetyl chloride(6.6 g, 84 mmol), then
which was stirred at room temperature for 15 minutes. The reaction
mixture was poured into ice water, which was extracted with
methylene chloride, washed with 1N hydrochloric acid and saturated
sodium hydrogen carbonate aqeous solution, successively. The
reaction mixture was dried, then which was evaporated under reduced
pressure to give a crude product of
5-acetyl-2-(4-fluorobenzyl)furan-3-carboxylic acid ethyl ester(4.54
g, yield:93%).
[1629] NMR(CDCl.sub.3).delta.: 1.37(3H, t, J=7.2 Hz), 2.44(3H, s),
4.35(2H, q, J=7.2 Hz), 4.38(2H, s), 6.94-7.00(2H, m), 7.26-7.31(2H,
m), 7.41(1H, s).
[1630] (A-181) According to the method of the example A-18,
5-(3-ethoxycarbonyl-3-hydroxyacryloyl)-2-(4-fluorobenzyl)furan-3-carboxyl-
ic acid ethyl ester(1.1 g, yield:82%) was synthesized from the
above-mentioned compound A-180(1.0 g, 3.44 mmol).
[1631] NMR(CDCl.sub.3).delta.:1.38(3H, t, J=7.2 Hz), 1.41(3H, t,
J=7.2 Hz), 4.35(2H, q, J=7.2 Hz), 4.39(2H, q, J=7.2 Hz), 4.41(2H,
s), 6.84(1H, s), 6.97-7.03(2H, m), 7.26-7.31(2H, m), 7.57(1H,
s).
[1632] (A-182) According to the method of the example A-19,
2-(4-fluorobenzyl)-5-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-c-
arbonyl)furan-3-carboxylic acid ethyl ester(850 mg, yield:86%) was
synthesized from the above-mentioned compound A-181(1.0 g, 2.56
mmol).
[1633] Melting point:172-173.degree. C.
[1634] Elementary analysis as C.sub.20H.sub.18FNO.sub.6
[1635] Calcd. (%): C, 62.01; H, 4.68; N, 3.62; F, 4.90. Found (%):
C, 61.95; H, 4.45; N, 3.60; F, 4.73.
[1636] NMR(CDCl.sub.3).delta.:1.40(3H, t, J=7.2 Hz), 3.10(3H, s),
4.02(2H, s), 4.38(2H, q, J=7.2 Hz), 4.45(2H, s), 7.03-7.10(2H, m),
7.26-7.31(2H, m), 7.61(1H, s).
[1637] (A-183) To a dioxane(20 ml) solution of the above-mentioned
compound A-182(500 mg, 1.29 mmol), 1N lithium hydroxide solution(3
ml) was added at 50.degree. C. for 30 minutes, then the reaction
mixture was concentrated, diluted with water, which was acidified
with hydrochloric acid. The reaction mixture was extracted with
chloroform, washed, dried and evaporated under reduced pressure to
give a crude product(420 mg, yield:91%), which was crystallized
from methyl alcohol to give
2-(4-fluorobenzyl)-5-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-c-
arbonyl)furan-3-carboxylic acid.
[1638] Melting point:255-258.degree. C.(decomp.)
[1639] Elementary analysis as C.sub.18H.sub.14FNO.sub.6
[1640] Calcd. (%): C, 60.17; H, 3.93; N, 3.90; F, 5.29. Found (%):
C, 59.86; H, 3.86; N, 3.80; F, 5.04.
[1641] NMR(DMSO-d.sub.6) d: 2.99(3H, s), 4.09(2H, s), 4.42(2H, s),
7.13-7.19(2H, m), 7.29-7.34(2H, m), 7.85(1H, s), 13.22(1H, bs).
[1642] (A-184) To a DMF(5 ml) solution of the above-mentioned
compound A-183(359 mg, 1 mmol), HOBt(13.5 mg, 0.1 mmol) and
WSCD(575 mg, 3 mmol) in ethylamine(2 mol/l in THF, 1.5 ml, 3 mmol)
was added under ice cooling. The reaction mixture was stirred at
room temperature for 20 hours, then water was added to stop the
reaction, which was extracted with chloroform, washed with water,
dried and evaporated under reduced pressure. The crystalline
residue was recrystallized from isopropyl alcohol to give
2-(4-fluorobenzyl)-5-(4-hydroxy-1-methyl-5-oxo-2,5-dihydr-
o-1H-pyrrole-3-carbonyl)furan-3-carboxylic acid ethylamide(91 mg,
yield:24%).
[1643] Melting point: 169-170.degree. C.
[1644] Elementary analysis as C.sub.20H.sub.19O.sub.5FN.sub.2
[1645] Calcd. (%) C: 62.17H: 4.96 F: 4.92N: 7.25 Found (%) C:
62.05H: 4.89 F: 4.75N: 7.22 .sup.1H-NMR(CDCl.sub.3).delta.:
1.26(3H, t, J=7.2 Hz), 3.10(3H, s), 3.40-3.53(2H, m), 4.01(2H, s),
4.49(2H, s), 5.93(1H, bs), 7.03-7.08(2H, m), 7.25-7.33(2H, m),
7.41(1H, s).
[1646] The following compound was synthesized by the
above-mentioned method.
[1647] (A-184-a)
2-(4-Fluorobenzyl)-5-(4-hydroxy-1-methyl-5-oxo-2,5-dihydr-
o-1H-pyrrole-3-carbonyl)furan-3-carboxylic acid benzylamide
[1648] Melting point:181-184.degree. C.
[1649] Elementary analysis as C.sub.21H.sub.21O.sub.5FN.sub.2
[1650] Calcd. (%) C: 66.96H: 4.72 F: 4.24N: 6.25 Found (%) C:
66.63H: 4.64 F: 4.06N: 6.12
[1651] .sup.1H-NMR(CDCl.sub.3).delta.: 3.9(3H, s), 4.00(2H, s),
4.51(2H, s), 4.62(2H, d, J=5.5 Hz), 6.28(1H, bs), 7.02-7.08(2H, m),
7.26-7.42(8H, m).
[1652] B Group Compound
[1653] Compound B-6
[1654]
3-Hydroxy-1-isopropyl-4-(6-phenethylpyrimidine-4-yl)-1,5-dihydropyr-
role-2-one 217
[1655] (B-1) According to the method of the reference (WO01/17968),
4-methyl-6-phenethylpyrimidine was synthesized.
[1656] (B-2) To a THF(100 ml) solution of the above-mentioned
compound B-1(19.8 g, 100 mmol) at -78.degree. C., n-butyllithium
solution(100 mmol) was added dropwise, then a THF(50 ml) solution
of 2-(trimethylsilyl)ethoxymethyl chloride(16.7 g, 100 mmol) was
added thereto. The reaction mixture was stirred at 0.degree. C. for
30 minutes, to which was added ammonium chloride aqueous solution,
then extracted with ethyl acetate. The extract was washed, dried
and evaporated to give a 9:1 mixture(32.7 g, yield: 100%) of
4-phenethyl-6-[2-(2-trimethylsilany- lethoxy)ethyl]pyrimidine and
4-methyl-6-[2-phenyl-1-(2-trimethylsilanyleth-
oxymethyl)ethyl]pyrimidine.
[1657]
(4-phenethyl-6-[2-(2-trimethylsilanylethoxy)ethyl]pyrimidine)
[1658] NMR(CDCl.sub.3).delta.: -0.03(9H, s), 0.89(2H, dd, J=8.0,
8.0 Hz), 2.95(2H, t, J=6.5 Hz), 3.04(4H, s), 3.50(2H, dd, J=8.0,
8.0 Hz), 3.75(2H, t, J=6.5 Hz), 7.03(1H, d, J=1.2 Hz),
7.18-7.31(5H, m), 9.05(1H, d, J=1.2 Hz).
[1659] (B-3) To a 1,4-dioxane(50 ml) solution of the
above-mentioned compound B-2(32.7 g, 100 mmol), 5N-hydrochloric
acid aqueous solution(100 ml) was added, then the reaction mixture
was stirred at 60.degree. C. for 1 hour, to which was added sodium
carbonate until the solution became alkali, then extracted with
ethyl acetate. The extract was washed, dried, and evaporated to
give a crude mixture product(23.6 g) of
2-(6-phenethylpyrimidine-4-yl)ethanol and
2-(6-methylpyrimidine-4-yl)-3-p- henylpropane-1-ol.
[1660] NMR(CDCl.sub.3).delta.: 2.94(2H, t, J=5.5 Hz), 3.06(4H, s),
4.00(2H, t, J=5.5 Hz), 6.97(1H, d, J=1.2 Hz), 7.16-7.31(5H, m),
9.05(1H, d, J=1.2 Hz).
[1661] (B-4) To a chloroform(100 ml) solution of the
above-mentioned crude product B-3(23.6 g), pyridine(15.8 g, 200
mmol) was added, to which was added trifluoromethanesulfonic acid
anhydride(28.2 g, 100 mmol) under ice cooling. The reaction mixture
was stirred for 10 minutes, then sodium hydrogen carbonate aqueous
solution(100 ml) was added thereto and chloroform was evaporated
under reduced pressure. 1,4-Dioxane(50 ml) was added to the
residue, then was added 5N-sodium hydroxide aqueous solution(50 ml)
under ice cooling. The reaction mixture was stirred for 30 minutes,
which was extracted with diethyl ether. The extract was washed,
dried and evaporated under reduced pressure, then the residue was
purified with silica gel column chromatography(n-hexane ethyl
acetate=5:1-1:1) to give 4-phenethyl-6-vinylpyrimidine(3.7 g,
yield:18%).
[1662] NMR(CDCl.sub.3).delta.: 3.07(4H, s), 5.67(1H, dd, J=10.7,
1.2 Hz), 6.42(1H, dd, J=17.4, 1.2 Hz), 6.68(1H, dd, J=10.4, 17.4
Hz), 7.03(1H, d, J=1.2 Hz), 7.17-7.32(5H, m), 9.09(1H, d, J=1.2
Hz).
[1663] (B-5) To an ethanol(3 ml) solution of the above-mentioned
compound B-4(316 mg, 1.5 mmol), acetic acid(90 mg, 1.5 mmol) and
isopropylamine(266 mg, 4.5 mmol) were added, then the reaction
mixture was refluxed for 3 hours. Sodium hydrogen carbonate aqueous
solution was added thereto, then extracted with chloroform. The
extract was washed, dried and evaporated under reduced pressure,
then the residue was purified with silica gel column
chromatography(chloroform:methyl alcohol=9:1) to give
isopropyl[2-(6-phenethylpyrimidine-4-yl)ethyl]amine(- 309 mg,
yield: 76%).
[1664] NMR(CDCl.sub.3).delta.: 1.07(6H, d, J=6.3 Hz), 2.85-3.06(9H,
m), 6.96(1H, d, J=1.2 Hz), 7.16-7.31(5H, m), 9.05(1H, d, J=1.2
Hz).
[1665] The following compounds were synthesized by the
above-mentioned method.
[1666] Methyl [2-(6-phenethylpyrimidine-4-yl)ethyl]amine
[1667] NMR(CDCl.sub.3).delta.: 2.45(3H, s), 2.86-3.04(4H, m),
3.06(4H, s), 6.94(1H, d, J=1.2 Hz), 7.16-7.31(5H, m), 9.05(1H, d,
J=1.2 Hz).
[1668] Benzyl [2-(6-phenethylpyrimidine-4-yl)ethyl]amine
[1669] NMR(CDCl.sub.3).delta.:2.90-3.05(8H, m), 3.84(2H, s),
6.93(1H, d, J=0.9 Hz), 7.15-7.33(5H, m), 9.03(1H, d, J=1.3 Hz).
[1670]
(1-Ethylpropyl)-[2-(6-phenethylpyrimidine-4-yl)ethyl]amine
[1671] NMR(CDCl.sub.3).delta.:0.87(6H, t, J=7.5 Hz), 1.45(4H, dq,
J=7.6, 7.0 Hz), 2.44(1H, tt, J=6.1, 5.8 Hz), 2.89-3.06(8H, m),
6.99(1H, d, J=1.2 Hz), 7.17-7.31(5H, m), 9.04(1H, d, J=1.2 Hz).
[1672] Cyclohexyl[2-(6-phenethylpyrimidine-4-yl)ethyl]amine
[1673] NMR(CDCl.sub.3).delta.: 1.07-1.28(6H, m), 1.60-1.91(4H, m),
2.48(1H, m), 2.90(2H, t, J=6.7 Hz), 3.01-3.06(6H, m), 6.96(1H, d,
J=1.2 Hz), 7.16-7.31(5H, m), 9.05(1H, d, J=1.2 Hz).
[1674] [2-(6-Phenethylpyrimidine-4-yl)ethyl]phenylamine
[1675] NMR(CDCl.sub.3).delta.: 2.97-3.05(6H, m), 3.53(2H, t, J=6.4
Hz), 6.65(2H, d, J=7.3 Hz), 6.75(1H, t, J=7.3 Hz), 6.92(1H, d,
J=0.9 Hz), 7.14-7.30(7H, m), 9.08(1H, d, J=1.2 Hz).
[1676] Tert-butyl[2-(6-phenethylpyrimidine-4-yl)ethyl]amine
[1677] NMR(CDCl.sub.3).delta.:1.19(9H, s), 2.99-3.06(8H, m),
6.97(1H, d, J=1.2 Hz), 7.16-7.31(5H, m), 9.04(1H, d, J=1.2 Hz).
[1678] O-tert-butyl
N-[2-(6-phenethylpyrimidine-4-yl)ethyl]hydroxylamine
[1679] NMR(CDCl.sub.3).delta.:1.20(9H, s), 2.95(2H, brs), 3.04(4H,
s), 3.27(2H, brs), 6.99(1H, d, J=1.2 Hz), 7.16-7.31(5H, m),
9.04(1H, d, J=1.2 Hz).
[1680] (B-6) To an ethanol(1.5 ml) solution of the above-mentioned
compound B-5(269 mg, 1 mmol), oxalic acid diethyl(175 mg, 1.2 mmol)
and sodium ethoxide(4.5 mmol, 20% ethanol solution) were added,
then the reaction mixture was heated at 60.degree. C. for 5 hours.
Ammonium chloride aqueous solution was added to the solution, which
was extracted with chloroform. The extract was washed, dried and
evaporated under reduced pressure. The precipitated crystal was
washed with methyl alcohol, which was dried with reduced pressure
to give
3-hydroxy-1-isopropyl-4-(6-phenethylpyrimidine-4-yl)-1,5-dihydropyrrole-2-
-one(209 mg, yield:65%).
[1681] Melting point:229-231.degree. C.
[1682] Elementary analysis as C.sub.19H.sub.21N.sub.3O.sub.2
0.2H20
[1683] Calcd. (%): C, 69.79; H, 6.60; N, 12.85. Found (%): C,
69.85; H, 6.46; N, 12.83.
[1684] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=6.7 Hz), 3.09(4H, s),
4.05(2H, s), 4.57(1H, qq, J=6.9, 6.7 Hz), 6.93(1H, s),
7.18-7.32(5H, m), 9.02(1H, s).
[1685] The following compounds were synthesized by the
above-mentioned method. 03-6-a)
3-Hydroxy-1-methyl-4-(6-phenethylpyrimidine-4-yl)-1,5-dih-
ydropyrrole-2-one Melting point:211-213.degree. C.
[1686] Elementary analysis as C.sub.17H.sub.17N.sub.3O.sub.2
[1687] Calcd. (%): C, 69.14; H, 5.80; N, 14.23. Found (%): C,
69.09; H, 5.61; N, 14.23.
[1688] NMR(CDCl.sub.3).delta.:3.09(4H, s), 3.16(3H, s), 4.07(2H,
s), 6.79(1H, s), 7.16-7.29(5H, m), 9.01(1H, s).
[1689] (B-6-b)
1-Benzyl-3-hydroxy-4-(6-phenethylpyrimidine-4-yl)-1,5-dihyd-
ropyrrole-2-one
[1690] Melting point:222-223.degree. C.
[1691] Elementary analysis as C.sub.23H.sub.21N.sub.3O.sub.2
0.3H20
[1692] Calcd. (%): C, 73.31; H, 5.78; N, 11.15. Found (%): C,
73.37; H, 5.49; N, 11.19.
[1693] NMR(CDCl.sub.3).delta.: 3.05(4H, s), 3.93(3H, s), 4.73(2H,
s), 6.70(1H, s), 7.13-7.39(10H, m), 9.00(1H, s).
[1694] (B-6-c)
1-(1-Ethylpropyl)-3-hydroxy-4-(6-phenethylpyrimidine-4-yl)--
1,5-dihydropyrrole-2-one
[1695] Melting point:182-183.degree. C.
[1696] Elementary analysis as C.sub.21H.sub.25N.sub.3O.sub.2
[1697] Calcd. (%): C, 71.77; H, 7.17; N, 11.96. Found (%): C,
71.69; H, 7.13; N, 11.90.
[1698] NMR(CDCl.sub.3).delta.: 0.88(6H, t, J=7.3 Hz), 1.48-1.74(4H,
m), 3.10(4H, s), 3.96(2H, s), 4.10(1H, m), 6.94(1H, s),
7.19-7.33(5H, m), 9.06(1H, s).
[1699] (B-6-d)
1-Cyclohexyl-3-hydroxy-4-(6-phenethylpyrimidine-4-yl)-1,5-d-
ihydropyrrole-2-one
[1700] Melting point:248-250.degree. C.
[1701] Elementary analysis as C.sub.22H.sub.25N.sub.3O.sub.2
0.1H.sub.2O
[1702] Calcd. (%): C, 72.34; H, 6.95; N, 11.50. Found (%): C,
72.28; H, 6.92; N, 11.55.
[1703] NMR(CDCl.sub.3).delta.: 1.41-1.51(4H, m), 1.71-1.88(6H, m),
3.10(4H, s), 4.07(2H, s), 4.15(1H, m), 6.92(1H, s), 7.18-7.32(5H,
m), 9.03(1H, s).
[1704] (B-6-e)
1-Hydroxy-4-(6-phenethylpyrimidine-4-yl)-1-phenyl-1,5-dihyd-
ropyrrole-2-one
[1705] Melting point:253-255.degree. C.
[1706] Elementary analysis as C.sub.22H.sub.19N.sub.3O.sub.2
0.1H.sub.2O
[1707] Calcd. (%): C, 73.56; H, 5.39; N, 11.70. Found (%): C,
73.37; H, 5.16; N, 11.65.
[1708] NMR(CDCl.sub.3).delta.: 3.13(4H, s), 4.56(2H, s), 6.98(1H,
s), 7.18-7.33(6H, m), 7.44(2H, t, J=7.6 Hz), 7.81(2H, d, J=7.6 Hz),
9.08(1H, s).
[1709] (B-6-f)
1-Tert-butyl-3-hydroxy-4-(6-phenethylpyrimidine-4-yl)-1,5-d-
ihydropyrrole-2-one
[1710] Melting point:199-200.degree. C.
[1711] Elementary analysis as C.sub.20H.sub.23N.sub.302
[1712] Calcd. (%): C, 71.19; H, 6.87; N, 12.45. Found (%): C,
70.84; H, 6.81; N, 12.30.
[1713] NMR(CDCl.sub.3).delta.: 1.53(9H, s), 3.09(4H, s), 4.16(2H,
s), 7.03(1H, s), 7.19-7.32(5H, m), 9.03(1H, s).
[1714] (B-6-g)
1-Tert-butoxy-3-hydroxy-4-(6-phenethylpyrimidine-4-yl)-1,5--
dihydropyrrole-2-one
[1715] Melting point:230-232.degree. C.
[1716] Elementary analysis as C.sub.20H.sub.23N.sub.3O.sub.2
0.1H20
[1717] Calcd. (%): C, 67.62; H, 6.58; N, 11.83. Found (%): C,
67.51; H, 6.42; N, 11.83.
[1718] NMR(CDCl.sub.3).delta.: 1.39(9H, s), 3.10(4H, s), 4.27(2H,
s), 6.76(1H, s), 7.17-7.32(5H, m), 9.02(1H, s).
[1719] Compound B-9
[1720]
4-[5-(4-Fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-hydroxy-1-isopropyl-
-1,5-dihydropyrrole-2-one 218
[1721] (B-7) To a THF(10 ml) solution of
4-hydroxy-1-isopropyl-5-oxo-2,5-d- ihydro-1H-pyrrole-3-carboxylic
acid A-4(995 mg, 5 mmol), (4-fluorophenyl) acetic acid hydrazide
(924 mg, 5.5 mmol), 1-hydroxybenzotriazole(67 mg, 0.5 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(931 mg, 6 mmol) were
added, then the reaction mixture was stirred for 2 hours. The
reaction was stopped with water, which was extracted with ethyl
acetate. The extract was washed, dried and evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography(n-hexane:ethyl acetate=1:4-0:1) to give
1-isopropyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrro- le-3-carboxylic
acid N'-[2-(4-fluorophenyl)acetyl]hydrazide(1.46 g, yield:84%).
[1722] Melting point: 157-158.degree. C.
[1723] NMR(CDCl.sub.3).delta.: 1.21(6H, d, J=6.9 Hz), 3.63(2H, s),
3.94(2H, s), 4.36-4.45(4H, m), 7.00-7.08(2H, m), 7.26-7.32(2H, m),
8.38(1H, s), 9.26(1H, s).
[1724] (B-8) To a methylene chloride(3 ml) solution of
triphenylphosphine (629 mg, 2.4 mmol), bromine(2.4 mmol, 1M
methylene chloride solution) was added dropwise under ice cooling,
then the reaction mixture was stirred at room temperature for 30
minutes, to which triethylamine(506 mg, 5 mmol) and the
above-mentioned compound B-7(699 mg, 2 mmol) were added at room
temperature, successively. The reaction mixture was warmed, then
the reaction was stopped with water, which was extracted with
chloroform. The extract was washed, dried and evaporated under
reduced pressure. The residue was purified with silica gel column
chromatography(n-hexane:ethyl acetate=1:1-1:3) to give
4-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-1--
isopropyl-3-methoxy-1,5-dihydropyrrole-2-one(595 mg,
yield:90%).
[1725] NMR(CDCl.sub.3).delta.:1.24(6H, d, J=6.7 Hz), 4.16(2H, s),
4.22(2H, s), 4.30(3H, s), 4.46(1H, qq, J=6.7 Hz), 7.00-7.08(2H, m),
7.27-7.34(2H, m).
[1726] (B-9) To an acetonitrile solution(5 ml) of the
above-mentioned compound B-8(550 mg, 1.66 mmol), sodium iodide(1.99
g, 13.3 mmol) was added, to which was added
chlorotrimethylsilane(1.44 g, 13.3 mmol) under ice cooling. The
reaction mixture was stirred at 50.degree. C. for 2 hours, to which
were added water and 10% sodium sulfite aqueous solution(2 ml),
successively. The precipitated crystal was washed with water and
ethyl acetate, successively, then dried under reduced pressure to
give
4-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-hydroxy-1-isoprop-
yl-1,5-dihydropyrrole-2-one(441 mg, yield:84%).
[1727] Melting point: 204-206.degree. C.
[1728] Elementary analysis as C.sub.16H.sub.16N.sub.3O.sub.3
[1729] Calcd. (%): C, 60.56; H, 5.08; N, 13.24; F, 5.99. Found (%):
C, 60.43; H, 4.93; N, 13.14; F, 5.93.
[1730] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=6.7 Hz), 4.22(2H, s),
4.24(2H, s), 4.50(1H, qq, J=6.7 Hz), 6.99-7.07(2H, m),
7.26-7.34(2H, m).
[1731] Compound B-12
[1732]
4-(6-Benzyloxypyrimidine-4-yl)-3-hydroxy-1-methyl-1,5-dihydropyrrol-
e-2-one 219
[1733] (B-10) To a dimethylformamide(5 ml) solution of sodium
hydride(192 mg, 8 mmol), a dimethylformamide(3 ml) solution of
benzyl alcohol was added for 30 minutes, to which was added for 10
minutes 4-chloro-6-methylpyrimidine(1.03 g, 8 mmol) which was
synthesized according to the method of the reference(WO01/17968).
The reaction was quenched by adding ammonium chloride aqueous
solution, then the reaction mixture was extracted with diethyl
ether. The extract was washed, dried and evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography(n-hexane:ethyl acetate=3: 1-2:1) to give
4-benzyloxy-6-methylpyrimidine(1.49 g, yield:93%).
[1734] NMR(CDCl.sub.3).delta.: 2.45(3H, s), 5.42(2H, s), 6.64(1H,
s), 7.36-7.43(5H, m), 8.69(1H, s).
[1735] (B-11) To a tetrahydrofuran(10 ml) solution of the
above-mentioned compound B-10(601 mg, 3 mmol), oxalic acid
diethyl(2.2 g, 15 mmol) and potassium tert-butoxide(672 mg, 6 mmol)
were added at 60.degree. C. for 30 minutes, successively. The
reaction was quenched by adding ammonium chloride aqueous solution,
then extracted with ethyl acetate. The extract was washed, dried
and evaporated under reduced pressure. The precipitated crystal was
washed with n-hexane, then dried under reduced pressure to give
3-(6-benzyloxypyrimidine-4-yl)-2-hydroxyacrylic acid ethyl
ester(694 mg, yield:77%).
[1736] Melting point: 136-137.degree. C.
[1737] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.2 Hz), 4.36(2H, q,
J=7.2 Hz), 5.46(2H, s), 6.42(1H, s), 6.57(1H, s), 7.35-7.46(5H, m),
8.69(1H, s).
[1738] (B-12) To a dioxane(1 ml) solution of the above-mentioned
compound B-11(100 mg, 0.33 mmol), paraformaldehyde(50 mg, 1.65
mmol) and methylamine(0.66 mmol. 30% ethanolsolution) were added at
room temperature forlhour, successively. The reaction was quenched
by adding ammonium chloride aqueous solution, then the reaction
mixture was extracted with ethyl acetate. The extract was washed,
dried and evaporated under reduced pressure. The precipitated
crystal was washed with diethyl ether, then dried under reduced
pressure to give
4-(6-benzyloxypyrimidine-4-yl)-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-on-
e(83 mg, yield:85%).
[1739] Melting point:203-204.degree. C.
[1740] Elementary analysis as C.sub.16H.sub.15N.sub.3O.sub.3
0.1H.sub.2O
[1741] Calcd. (%): C, 64.25; H, 5.12; N, 14.05. Found (%): C,
64.09; H, 4.94; N, 13.99.
[1742] NMR(CDCl.sub.3).delta.: 1.15(3H, s), 4.07(2H, s), 5.47(2H,
s), 6.47(1H, s), 7.30-7.48(5H, m), 8.72(1H, s).
[1743] The following compounds were synthesized by the
above-mentioned method.
[1744] (B-12-a)
4-(6-Benzyloxypyrimidine-4-yl)-3-hydroxy-1-isopropyl-1,5-d-
ihydropyrrole-2-one
[1745] Melting point:177-178.degree. C.
[1746] Elementary analysis as C.sub.18H.sub.19N.sub.3O.sub.3
0.1H.sub.2O
[1747] Calcd. (%): C, 66.08; H, 5.92; N, 12.84. Found (%): C,
65.99; H, 5.80; N, 12.68.
[1748] NMR(CDCl.sub.3).delta.:1.26(6H, d, J=6.7 Hz), 4.04(2H, s),
4.56(1H, sept), 5.47(2H, s), 6.55(1H, s), 7.30-7.47(5H, m),
8.72(1H, s).
[1749] (B-12-b)
4-[6-(4-Fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-1-methy-
l-1,5-dihydropyrrole-2-one
[1750] H-NMR(CDCl.sub.3).delta.:3.15(s,3H), 4.08(s,2H), 5.43(s,2H),
6.47(d,1H, J=1.2 Hz), 7.05-7.15(m, 2H), 7.40-7.50(m,2H), 8.71(d,
1H, J=1.2 Hz).
[1751] Melting point:232-234.degree. C.
[1752] Elementary analysis as C.sub.16H.sub.14N.sub.3O.sub.3F
[1753] Calcd. (%) C: 60.95H: 4.48N: 13.33 F: 6.03 Found (%) C:
60.89H: 4.36N: 13.27 F: 6.14
[1754] (B-12-c)
4-[6-(4-Fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-1-isopr-
opyl-1,5-dihydropyrrole-2-one
[1755] H-NMR(CDCl.sub.3).delta.: 1.26(d,6H,J=6.9 Hz), 4.05(s,2H),
4.55(m,1H), 5.43(s,2H), 6.50(d,1H, J=1.2 Hz), 7.05-7.15(m, 2H),
7.40-7.50(m,2H), 8.71(d, 1H, J=1.2 Hz).
[1756] Melting point:191.degree. C.
[1757] Elementary analysis as
C.sub.18H.sub.18N.sub.3O.sub.3F.0.3H.sub.2O
[1758] Calcd. (%) C: 61.99H: 5.38N: 12.05 F: 5.45 Found (%) C:
61.87H: 5.11N: 12.05 F: 5.35
[1759] (B-12-d)
4-[6-(2-Fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-1-methy-
l-1,5-dihydropyrrole-2-one
[1760] H-NMR(CDCl.sub.3).delta.: 3.15(s,3H), 4.07(s,2H),
5.53(s,2H), 6.48(d,1H, J=1.2 Hz), 7.10-7.20(m, 2H), 7.34(m,1H),
7.48(m,1H), 8.72(d, 1H, J=1.2 Hz).
[1761] Melting point:215-217.degree. C.
[1762] Elementary analysis as C.sub.16H.sub.14N.sub.303F
0.3H.sub.2O
[1763] Calcd. (%) C: 59.92H: 4.59N: 13.10 F: 5.92 Found (%) C:
60.10H: 4.51N: 13.05 F: 5.64
[1764] (B-12-e)
4-[6-(2-Fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-1-isopr-
opyl-1,5-dihydropyrrole-2-one
[1765] H-NMR(CDCl.sub.3).delta.: 1.26(d,6H,J=6.9 Hz), 4.06(s,2H),
4.55(m,1H), 5.54(s,2H), 6.63(d,1H, J=1.2 Hz), 7.05-7.20(m, 2H),
7.35(m,1H), 7.48(m,1H), 8.72(d, 1H, J=1.2 Hz).
[1766] Melting point:170-171.degree. C.
[1767] Elementary analysis as C.sub.18H.sub.18N.sub.303F
[1768] Calcd. (%) C: 62.97H: 5.28N: 12.24 F: 5.53 Found (%) C:
62.94H: 5.33N: 12.21 F: 5.31
[1769] (B-12-f)
3-Hydroxy-4-[6-(3-isopropylbenzyloxy)pyrimidine-4-yl]-1-me-
thyl-1,5-dihydropyrrole-2-one
[1770] H-NMR(CDCl.sub.3).delta.: 1.27(d,6H,J=6.6 Hz), 2.93(m,1H),
3.15(s,3H), 4.08(s,2H), 5.45(s,2H), 6.48(d,1H, J=1.2 Hz),
7.20-7.36(m, 4H), 8.73(d, 1H, J=1.2 Hz).
[1771] Melting point: 149-150.degree. C.
[1772] Elementary analysis as Cl.sub.9H.sub.21N.sub.3O.sub.3
[1773] Calcd. (%) C: 67.24H: 6.24N: 12.38 Found (%) C: 67.17H:
6.08N: 12.38 (B1-12-g)
3-Hydroxy-4-[6-(3-isopropylbenzyloxy)pyrimidine-4-yl]-1-i-
sopropyl-1,5-dihydropyrrole-2-one
H-NMR(CDCl.sub.3).delta.:1.26(d,6H,J=6.6 Hz), 1.27(d,6H,J=6.9 Hz),
2.93(m,1H), 4.05(s,3H), 4.56(m,1H), 5.45(s,2H), 6.58(d,1H, J=1.2
Hz), 7.20-7.36(m, 4H), 8.73(d, 1H, J=1.2 Hz).
[1774] Melting point:191.degree. C.
[1775] Elementary analysis as C.sub.21H.sub.25N.sub.3O.sub.3
[1776] Calcd. (%) C: 68.64H: 6.86N: 11.44 Found (%) C: 68.63H:
6.64N: 11.38
[1777] (B-12-h)
1-Ethyl-4-[6-(4-fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-
-1,5-dihydropyrrole-2-one
[1778] H-NMR(CDCl.sub.3).delta.: 1.24(t,3H,J=7.2 Hz),
3.61(q,2H,J=7.2H), 4.10(s,2H), 5.43(s,2H), 6.57(d,1H, J=1.2 Hz),
7.05-7.11(m, 2H), 7.40-7.46(m,2H), 8.70(d, 1H, J=1.2 Hz).
[1779] Melting point:171-173.degree. C.
[1780] Elementary analysis as C.sub.17H.sub.16N.sub.3O.sub.3F
[1781] Calcd. (%) C: 62.00H: 4.90N: 12.76 F: 5.77 Found (%) C:
61.97H: 4.83N: 12.69 F: 5.77 (B-12-i)
4-[6-(4-Fluorobenzyloxy)pyrimidine-4-yl]-3--
hydroxy-1-propyl-1,5-dihydropyrrole-2-one
[1782] H-NMR(CDCl.sub.3).delta.: 0.95(t,3H,J=7.5 Hz), 1.65(m,2H),
3.51(t,2H,J=7.5H), 4.08(s,2H), 5.43(s,2H), 6.52(d,1H, J=1.2 Hz),
7.05-7.11(m, 2H), 7.40-7.45(m,2H), 8.71(d, 1H, J=1.2 Hz).
[1783] Melting point: 159-160.degree. C.
[1784] Elementary analysis as C.sub.1sH.sub.18N.sub.3O.sub.3F
[1785] Calcd. (%) C: 62.97H: 5.28N: 12.24 F: 5.53 Found (%) C:
63.00H: 5.24N: 12.21 F: 5.65
[1786] (B-12-j)
4-[6-(4-Fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-1-(2-hy-
droxyethyl)-1,5-dihydropyrrole-2-one
[1787] H-NMR(DMSO-d.sub.6).delta.: 3.50(m,2H), 3.59(m,2H),
4.29(s,2H), 4.85(bs,2H), 5.42(s,2H), 7.19-7.28(m, 3H),
7.50-7.58(m,2H), 8.75(m, 1H).
[1788] Melting point: 178-180.degree. C.
[1789] Elementary analysis as C.sub.17H.sub.6N.sub.3O.sub.4F
[1790] Calcd. (%) C: 59.13H: 4.67N: 12.17 F: 5.50 Found (%) C:
59.07H: 4.64N: 12.07 F: 5.55
[1791] (B-12-k)
4-[6-(4-Fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-1-(2-me-
thoxyethyl)-1,5-dihydropyrrole-2-one
[1792] H-NMR(CDCl.sub.3).delta.: 3.35(s,3H), 3.59(t,2H,J=4.8 Hz),
3.72(t,2H,J=4.8 Hz), 4.23(s,2H), 5.43(s,2H), 6.48(d,1H, J=1.2 Hz),
7.05-7.11(m, 2H), 7.40-7.46(m,2H), 8.71(d, 1H, J=1.2 Hz).
[1793] Melting point:153-154.degree. C.
[1794] Elementary analysis as C.sub.18H.sub.18N.sub.3O.sub.4F
[1795] Calcd. (%) C: 60.16H: 5.05N: 11.69 F: 5.29 Found (%) C:
60.17H: 5.01N: 11.64 F: 5.37
[1796] (B-12-1)
4-[6-(4-Fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-1,5-dih-
ydropyrrole-2-one
[1797] H-NMR(DMSO-d.sub.6) (: 4.11(s,2H), 5.42(s,2H), 7.18-7.28(m,
3H), 7.50-7.56(m,2H), 8.73(s,1H), 8.76(m, 1H).
[1798] Melting point: 194-196.degree. C.
[1799] Elementary analysis as C.sub.15H.sub.12N.sub.3O.sub.3F
[1800] Calcd. (%) C: 59.80H: 4.01N: 13.95 F: 6.31 Found (%) C:
59.53H: 4.00N: 13.83 F: 6.21
[1801] (B-12-m)
4-[6-(4-Fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-1-(4-me-
thoxybenzyl)-1,5-dihydropyrrole-2-one
[1802] H-NMR(CDCl.sub.3).delta.: 3.80(s,3H), 3.91(s,2H),
4.66(s,2H), 5.40(s,2H), 6.38(d,1H, J=1.2 Hz), 6.87 and
7.20(ABq,2Hx2,J=8.4 Hz), 7.02-7.09(m, 2H), 7.37-7.41(m,2H), 8.69(d,
1H, J=1.2 Hz).
[1803] Melting point:227-228.degree. C.
[1804] Elementary analysis as C.sub.23H.sub.20N.sub.3O.sub.4F.
0.1H.sub.2O
[1805] Calcd. (%) C: 65.27H: 4.81N: 9.93 F: 4.49 Found (%) C:
65.06H: 4.52N: 9.94 F: 4.43
[1806] (B-12-n)
1-Allyl-4-[6-(4-fluorobenzyloxy)pyrimidine-4-yl]-3-hydroxy-
-1,5-dihydropyrrole-2-one
[1807] H-NMR(CDCl.sub.3).delta.: 4.05(s,2H), 4.16(m,2H),
5.20-5.23(m,1H), 5.26(m,1H), 5.43(s,2H), 5.75-5.90(m,1H),
6.48(d,1H, J=1.2 Hz), 7.04-7.10(m, 2H), 7.37-7.44(m,2H), 8.71(d,
1H, J=1.2 Hz).
[1808] Melting point:167-168.degree. C.
[1809] Elementary analysis as C.sub.18H.sub.16N.sub.3O.sub.3F
[1810] Calcd. (%) C: 63.34H: 4.72N: 12.31 F: 5.57 Found (%) C:
63.43H: 4.59N: 12.37 F: 5.62
[1811] (B-12-o)
3-Hydroxy-4-[6-(2-isopropylbenzyloxy)-pyrimidine-4-yl]-1-m-
ethyl-1,5-dihydropyrrole-2-one
[1812] Melting point:240-241.degree. C.
[1813] Elementary analysis as C.sub.19H.sub.2,N.sub.3O.sub.3
[1814] Calcd. (%): C, 67.24; H, 6.24; N, 12.38. Found (%): C,
67.03; H, 6.07; N, 12.31.
[1815] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=6.7 Hz), 3.15(3H, s),
3.22(1H, m), 4.08(2H, s), 5.52(2H, s), 6.42(1H, s), 7.19-7.23(1H,
m), 7.37-7.42(3H, m), 8.73(1H, s).
[1816] Compound B-14
[1817]
4-{6-[2-(4-Fluorophenyl)ethyl]pyrimidine-4-yl}-3-hydroxy-1-methyl-1-
,5-dihydropyrrole-2-one 220
[1818] (B-13) According to the method of the reference
(WO01/17968),
3-{6-[2-(4-fluorophenyl)ethyl]pyrimidine-4-yl}-2-hydroxyacrylic
acid ethyl ester was synthesized.
[1819] Melting point: 139-141.degree. C.
[1820] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.3 Hz), 3.04(4H, s),
4.37(2H, q, J=7.3 Hz), 6.39(1H, s), 6.86(1H, s), 6.93-6.99(2H, m),
7.10-7.18(2H, m), 8.95(1H, s).
[1821] (B-14) To a dioxane(2 ml) solution of the above-mentioned
compound B-13(100 mg, 0.33 mmol), paraformaldehyde(20 mg, 0.66
mmol) and methylamine(0.66 mmol. 30% ethanol solution) were added,
successively at room temperature for 2 hours. The reaction was
quenched with ammonium chloride aqueous solution, then the reaction
mixture was extracted with ethyl acetate. The extract was washed,
dried and evaporated under reduced pressure. The precipitated
crystal was washed with methyl alcohol and dried under reduced
pressure to give 4-{6-[2-(4-fluorophenyl)ethyl]pyrimi-
dine-4-yl}-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one(72 mg,
yield:72%).
[1822] Melting point:225-228.degree. C.
[1823] Elementary analysis as C.sub.17H.sub.16FN.sub.3O.sub.2
[1824] Calcd. (%): C, 65.17; H, 5.15; N, 13.41; F, 6.06. Found (%):
C, 65.03; H, 5.31; N, 13.37; F, 5.93.
[1825] NMR(CDCl) d: 3.06(3H, s), 3.16(2H, s), 4.08(2H, s), 6.78(1H,
s), 6.94-7.00(2H, m), 7.10-7.15(2H, m), 9.01(1H, d, J=1.2 Hz).
[1826] The following compound was synthesized by the
above-mentioned method.
[1827] (B-14-a)
4-{6-[2-(4-Fluorophenyl)ethyl]pyrimidine-4-yl}-3-hydroxy-1-
-isopropyl-1,5-dihydropyrrole-2-one
[1828] Melting point:225-228.degree. C.
[1829] Elementary analysis as Cl.sub.9H.sub.20FN.sub.3O.sub.2
[1830] Calcd. (%): C, 66.85; H, 5.91; N, 12.31; F, 5.57. Found (%):
C, 66.61; H, 6.10; N, 12.25; F, 5.43.
[1831] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=6.7 Hz), 3.06(4H, s),
4.05(2H, s), 4.57(1H, sept), 6.89(1H, d, J=1.2 Hz), 6.91-6.99(2H,
m), 7.00-7.16(2H, m), 9.02(1H, d, H=1.2 Hz).
[1832] Compound 16
[1833]
4-{6-[1-(4-Fluorobenzyl)-2-(4-fluorophenyl)ethyl]pyrimidine-4-yl}-3-
-hydroxy-1-methyl-1,5-dihydropyrrole-2-one 221
[1834] (B-15) According to the method of the reference
(WO01/17968),
3-{6-[1-(4-fluorobenzyl)-2-(4-fluorophenyl)ethyl]pyrimidine-4-yl}-2-hydro-
xyacrylic acid ethyl ester was synthesized.
[1835] Melting point: 132-133.degree. C.
[1836] NMR(CDCl.sub.3).delta.: 1.36(3H, t, J=7.0 Hz), 2.95-3.15(5H,
m), 4.33(2H, q, J=7.0 Hz), 6.22(1H, s), 6.42(1H, d, J=1.4 Hz),
6.85-7.00(8H, m), 8.97(1H, s).
[1837] (B-16) To a dioxane(2 ml) solution of the above-mentioned
compound B-15(100 mg, 0.24 mmol), paraformaldehyde(14 mg, 0.48
mmol) and methylamine(0.48 mmol. 30% ethanol solution) were added
successively at room temperature for 2 hours. The reaction was
quenched with ammonium chloride aqueous solution, then the reaction
mixture was extracted with ethyl acetate. The extract was washed,
dried and evaporated under reduced pressure. The precipitated
crystal was washed with diethyl ether, which was dried to give
4-{6-[1-(4-fluorobenzyl)-2-(4-fluorophenyl)ethyl]pyrimi-
dine-4-yl}-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one(60 mg,
yield:59%).
[1838] Melting point: 162-164.degree. C.
[1839] Elementary analysis as C.sub.24H.sub.21F.sub.2N.sub.3O.sub.2
0.2H.sub.2O
[1840] Calcd. (%): C, 67.82; H, 5.07; N, 9.89; F, 8.94. Found (%):
C, 67.82; H, 5.09; N, 9.87; F, 8.79.
[1841] NMR(CDCl.sub.3).delta.: 2.99-3.15(8H, m), 3.89(2H, s),
6.28(1H, s), 6.85-6.99(8H, m), 9.04(1H, s).
[1842] The following compound was synthesized by the
above-mentioned method.
[1843] (B-16-a)
4-{6-[1-(4-Fluorobenzyl)-2-(4-fluorophenyl)ethyl]pyrimidin-
e-4-yl}-3-hydroxy-1-isopropyl-1,5-dihydropyrrole-2-one
[1844] Melting point:181-183.degree. C.
[1845] Elementary analysis as
C.sub.26H.sub.2rF.sub.2N.sub.3O.sub.2
[1846] Calcd. (%): C, 69.47; H, 5.61; N, 9.35; F, 8.45. Found (%):
C, 69.49; H, 5.65; N, 9.32; F, 8.32.
[1847] NMR(CDCl.sub.3).delta.: 1.23(6H, d, J=6.7 Hz), 3.00-3.20(5H,
m), 3.87(2H, s), 4.53(1H, sept), 6.42(1H, s), 6.86-7.00(8H, m),
9.05(1H, s).
[1848] Compound B-19
[1849]
3-Hydroxy-1-methyl-4-(6-phenoxypyrimidine-4-yl)-1,5-dihydropyrrole--
2-one 222
[1850] (B-17) According to the synthetic method of (B-10),
4-methyl-6-phenoxypyrimidine was synthesized.
[1851] NMR(CDCl.sub.3).delta.: 2.50(3H, s), 6.72(1H, s),
7.13-7.17(2H, m), 7.25-7.31(1H, m), 7.42-7.47(2H, m), 8.68(1H,
s).
[1852] (B-18) According to the synthetic method of (B-11),
2-hydroxy-3-(6-phenoxy pyrimidine-4-yl)acrylic acid ethyl ester was
synthesized from the above-mentioned compound (B-17).
[1853] NMR(CDCl.sub.3).delta.: 1.40(3H, t, J=7.0 Hz), 4.37(2H, q,
J=7.0 Hz), 6.46(1H, s), 6.64(1H, s), 7.14-7.18(2H, m),
7.29-7.34(1H, m), 7.44-7.49(2H, m), 8.69(1H, s).
[1854] (B-19) According to the synthetic method of (B-12),
3-hydroxy-1-methyl-4-(6-phenoxy
pyrimidine-4-yl)-1,5-dihydropyrrole-2-one was synthesized from the
above-mentioned compound (B-18).
[1855] Melting point:235-236.degree. C.
[1856] Elementary analysis as C.sub.15H.sub.13N.sub.3O.sub.3
0.3H20
[1857] Calcd. (%): C, 62.41; H, 4.75; N, 14.56. Found (%): C,
62.48; H, 4.41; N, 14.49.
[1858] NMR(DMSO-d.sub.6).delta.: 3.02(3H, s), 4.20(2H, s),
7.21-7.32(3H, m), 7.39(1H, d, J=1.0 Hz), 7.44-7.49(2H, m), 8.67(1H,
d, J=1.0 Hz).
[1859] Compound B-22
[1860]
N-[6-(4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-yl)pyrimidi-
ne-4-yl]-benzenesulfoneamide 223
[1861] (B-20) To a DMSO(2 ml) solution of
4-chloro-6-methylpyrimidine(128 mg, 1 mmol) which was synthesized
according to the method of the reference (WOO1/17968),
benzenesulfone amide(236 mg, 1.5 mmol) and potassium carbonate(207
mg, 1.5 mmol) were added, successively. The reaction mixture was
heated at 120.degree. C. for 3 hours. The reaction was quenched
with ammonium chloride aqueous solution, then the reaction mixture
was extracted with chloroform. The extract was dried and evaporated
under reduced pressure. The precipitated crystal was washed with
ethyl acetate and diethyl ether, successively, which was dried to
give N-(6-methylpyrimidine-4-yl)benzenesulfoneamide(151 mg,
yield:61%).
[1862] Melting point: 188-189.degree. C.
[1863] NMR(CDCl.sub.3).delta.: 2.45(3H, s), 7.11(1H,
s),7.45-7.63(3H, m), 7.92-7.95(2H, m), 8.71(1H, s).
[1864] (B-21) According to the synthetic method of (B-ll),
3-(6-benzenesulfonylaminopyrimidine-4-yl)-2-hydroxyacrylic acid
ethyl ester was synthesized from the above-mentioned compound
(B-20).
[1865] Melting point: 205-208.degree. C.
[1866] NMR(CDCl.sub.3).delta.:1.40(3H, t, J=7.0 Hz), 4.37(2H, q,
J=7.0 Hz), 6.44(1H, s), 7.08(1H, s), 7.52-7.67(3H, m),
7.93-8.00(2H, m), 8.84(1H, s), 10.82(1H, bs), 13.81(1H, bs),
8.69(1H, s).
[1867] (B-22) According to the synthetic method of (B-12),
N-[6-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-yl)-pyrimidine-4--
yl]-benzenesulfoneamide was synthesized from the above-mentioned
compound (B-21).
[1868] Melting point:>300.degree. C.
[1869] Elementary analysis as C.sub.15H.sub.14N.sub.4O.sub.4S
0.9H.sub.2O
[1870] Calcd. (%): C, 49.69; H, 4.39; N, 15.45; S, 8.84. Found (%):
C, 49.67; H, 4.17; N, 15.32; S, 8.82.
[1871] NMR(DMSO-d.sub.6).delta.: 3.00(3H, s), 4.12(2H, s),
7.54-7.65(3H, m), 7.69(1H, s), 7.90(2H, m), 8.53(1H, s).
[1872] The following compound was synthesized by the
above-mentioned method.
[1873] (B-22-a)
N-[6-(4-Hydroxy-1-isopropyl-5-oxo-2,5-dihydro-1H-pyrrole-3-
-yl)pyrimidine-4-yl]benzenesulfoneamide
[1874] Melting point:255-260.degree. C.
[1875] Elementary analysis as Cl.sub.7H.sub.18N.sub.4O.sub.4S
0.5H.sub.2O
[1876] Calcd. (%): C, 53.25; H, 4.99; N, 14.61; S. 8.36. Found (%):
C, 53.55; H, 4.72; N, 14.61; S, 8.09.
[1877] NMR(DMSO-d.sub.6) .delta.: 1.18(6H, d, J=6.7 Hz), 4.05(2H,
s), 4.25(1H, m),. 7.52-7.62(4H, m), 7.89-7.92(2H, m), 8.48(1H,
s).
[1878] Compound B-25
[1879]
3-Hydroxy-1-methyl-4-(5-phenoxypyridine-2-yl)-1,5-dihydropyrrole-2--
one 224
[1880] (3-23) According to the method of the reference (J. Am.
Chem. Soc. 1997,119(43),10539-10540), 2-methyl-5-phenoxypyridine
was synthesized using 6-methylpyridine-3-ol and iodobenzene.
[1881] NMR(CDCl.sub.3).delta.:2.54(3H, s), 6.67-7.01(2H, m),
7.09-7.15(2H, m), 7.21-7.24(1H, m), 7.31-7.38(2H, m), 8.30(1H, d,
J=2.7 Hz).
[1882] The following compound was synthesized by the
above-mentioned method.
[1883] 5-(4-Fluorophenoxy)-2-methylpyridine
[1884] NMR(CDCl.sub.3).delta.: 2.54(3H, s), 6.94-7.07(4H, m),
7.11(1H, d, J=8.4 Hz), 7.18(1H, dd, J=2.8, 5.6 Hz), 8.26(1H, d,
J=2.8 Hz).
[1885] (B-24) According to the method of the reference
(WO01/17968), 2-hydroxy-3-(5-phenoxy pyridine-2-yl)acrylic acid
ethyl ester was synthesized using the above-mentioned compound
B-23.
[1886] Melting point: 73-75.degree. C.
[1887] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.0 Hz), 4.36(2H, q,
J=7.0 Hz), 6.58(1H, s), 7.04-7.08(2H, m), 7.17-7.22(2H, m),
7.35-7.43(3H, m), 8.24(1H, d, J=2.7 Hz).
[1888] The following compound was synthesized by the
above-mentioned method.
[1889] 3-[5-(4-Fluorophenoxy)pyridine-2-yl]-2-hydroxyacrylic acid
ethyl ester
[1890] Melting point:99-101.degree. C.
[1891] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.0 Hz), 4.36(2H, q,
J=7.0 Hz), 6.58(1H, s), 7.01-7.13(4H, m), 7.21(1H, d, J=8.9 Hz),
7.33(1H, dd, J=2.7, 8.5 Hz), 8.22(1H, d, J=2.7 Hz).
[1892] (B-25) According to the synthetic method of (B-12),
3-hydroxy-1-methyl-4-(5-phenoxypyridine-2-yl)-1,5-dihydropyrrole-2-one
was synthesized from the above-mentioned compound (13-24).
[1893] Melting point:200-202.degree. C.
[1894] Elementary analysis as C.sub.16H1.sub.4N.sub.2O.sub.3
0.2H20
[1895] Calcd. (%): C, 67.22; H, 5.08; N, 9.80. Found (%): C, 67.22;
H, 4.97; N, 9.74.
[1896] NMR(CDCl.sub.3).delta.: 3.15(3H, s), 4.15(2H, s),
7.03-7.07(2H, m), 7.15-7.22(2H, m), 7.36-7.43(3H, m), 8.32(1H, d,
J=2.3 Hz).
[1897] The following compounds were synthesized by the
above-mentioned method.
[1898] (B-25-a)
3-Hydroxy-1-isopropyl-4-(5-phenoxypyridine-2-yl)-1,5-dihyd-
ropyrrole-2-one
[1899] Melting point:181-183.degree. C.
[1900] Elementary analysis as C.sub.18H.sub.18N.sub.2O.sub.3
0.2H.sub.2O
[1901] Calcd. (%): C, 68.86; H, 5.91; N, 8.92. Found (%): C, 68.65;
H, 5.65; N, 8.89.
[1902] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=6.7 Hz), 4.12(2H, s),
4.57(1H, sept), 7.02-7.07(2H, m), 7.17-7.28(2H, m), 7.37-7.43(3H,
m), 8.32(1H, dd, J=0.6, 2.7 Hz).
[1903] (B-25-b)
4-[5-(4-Fluorophenoxy)pyridine-2-yl]-3-hydroxy-1-methyl-1,-
5-dihydropyrrole-2-one
[1904] Melting point:229-230.degree. C.
[1905] Elementary analysis as C.sub.16H,sFN.sub.2O.sub.3
[1906] Calcd. (%): C, 64.00; H, 4.36; N, 9.33; F, 6.33. Found (%):
C, 63.90; H, 4.27; N, 9.32; F, 6.13.
[1907] NMR(CDCl.sub.3).delta.: 3.15(3H, s), 4.16(2H, s),
7.01-7.13(4H, m), 7.19(1H, d, J=8.9 Hz), 7.35(1H, dd, J=2.7, 8.5
Hz), 8.30(1H, d, J=2.7 Hz).
[1908] (B-25-c)
4-[5-(4-Fluorophenoxy)pyridine-2-yl]-3-hydroxy-1-isopropyl-
-1,5-dihydropyrrole-2-one
[1909] Melting point: 178-179.degree. C.
[1910] Elementary analysis as C.sub.18H.sub.17FN.sub.203
[1911] Calcd. (%): C, 65.84; H, 5.22; N, 8.49; F, 5.79. Found (%):
C, 65.63; H, 5.14; N, 8.49; F, 5.58.
[1912] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=7.0 Hz), 4.12(2H, s),
4.56(1H, sept), 7.00-7.13(4H, m), 7.27(1H, d, J=8.9 Hz), 7.35(1H,
dd, J=2.7, 8.8 Hz), 8.30(1H, dd, J=0.6, 2.7 Hz).
[1913] Compound B-29
[1914]
4-[5-(4-Fluorobenzyl)-pyridine-2-yl]-3-hydroxy-1-methyl-1,5-dihydro-
pyrrole-2-one 225
[1915] (B-26) To a methylene chloride(100 ml) solution of
5-hydroxy-2-methylpyridine(10.9 g, 100 mmol) and pyridine(12.2 ml,
150 mmol), trifluoromethanesulfonic acid anhydride(18.5 ml, 120
mmol) was added dropwise under ice cooling, then the reaction
mixture was stirred for 1.5 hours, to which were added methyl
alcohol(2 ml) and saturated sodium hydrogen carbonate aqueous
solution(150 ml), successively. Then the reaction mixture was
extracted with methylene chloride. The extract was washed, dried
and evaporated under reduced pressure. The residue was purified
with silica gel column chromatography(n-hexane:ethyl
acetate=9:1-4:1) to give
2-methyl-5-(trifluoromethanesulfonyloxy)pyridine- (23.0 g, yield:
95%).
[1916] (B-27) To a tetrahydrofuran(130 ml) solution of the
above-mentioned compound B-26(10.4 g, 43.2 mmol),
4-fluorobenzylzinc bromide in tetrahydrofuran (65 mmol) synthesized
according to the method of the reference(J. Org. Chem., 1994, 59,
p2671) and tetrakis(triphenylphosphine- )palladium(2.4 g) were
added, then the reaction mixture was refluxed for 5 hours. The
reaction mixture was evaporated under reduced pressure, to which
were added water and ethyl acetate, then insoluble product was
filtered with celite. The filtrate was extracted with ethyl
acetate, then washed with water. The ethyl acetate solution was
extracted with 1N hydrochloric acid, then the hydrochloric acid
extract was alkalized with 2N sodium hydroxide aqueous solution.
The alkali solution was extracted with ethyl acetate, then washed,
dried and evaporated. The residue was purified with silica gel
column chromatography(n-hexane:ethyl acetate=2:1) to give
5-(4-fluorobenzyl)-2-methylpyridine(5.42 g, yield:62%).
[1917] NMR(CDCl.sub.3).delta.:2.53 (3H, s), 3.91 (2H, s), 6.96 (2H,
t like, J=8.7 Hz), 7.06-7.15 (3H, m), 7.34 (1H, dd, J=8.1 Hz, 1.5
Hz), 7.36 (1H, d, J=1.5 Hz).
[1918] (B-28) To a tetrahydrofuran(30 ml) solution of the
above-mentioned compound B-27(2.88 g, 14.3 mmol), n-butyllithium
solution(15.7 mmol) was added dropwise at -78.degree. C., and
oxalic acid diethyl(6.27 g, 42.9 mmol) was added thereto, then the
reaction mixture was stirred for 30 minutes, then stirred at
0.degree. C. for 30 minutes. The reaction was quenched with
ammonium chloride aqueous solution, extracted with ethyl acetate.
The extract was washed, dried and evaporated under reduced
pressure. The precipitated crystal was washed with n-hexane, which
was dried to give
3-[5-(4-fluorobenzyl)pyridine-2-yl]-2-hydroxyacrylic acid ethyl
ester(2.72 g, yield:63%).
[1919] Melting point: 94-96.degree. C.
[1920] Elementary analysis as C.sub.17H.sub.16FNO.sub.3
[1921] Calcd. (%): C, 67.76; H, 5.35; N, 4.65; F, 6.31. Found (%):
C, 67.83; H, 5.21; N, 4.63; F, 6.13.
[1922] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.1 Hz), 3.96(2H, s),
4.36(2H, q, J=7.1 Hz), 6.56(1H, s), 6.98-7.04(2H, m), 7.11-7.18(3H,
m), 7.51(1H, dd, J=2.0, 8.3 Hz), 8.29(1H, d, J=2.0 Hz).
[1923] (B-29) To a dioxane (7.5 ml) solution of the above-mentioned
compound B-28 (151 mg, 0.50 mmol), paraformaldehyde (40 mg, 11.0
mmol) and methylamine (11.0 mmol. 40% methyl alcohol solution) were
added, successively, then the reaction mixture was stirred at room
temperature for 2 hours. The solvent was evaporated in vaccum and
an ammonium chloride aqueous solution, water and chloroform were
added thereto, followed by filtration. The filtrate was washed,
dried and evaporated in vaccum. The precipitated crystal was
recrystallized from 2-propyl alcohol and dried in vaccum to give
4-[5-(4-fluorobenzyl)-pyridine2-yl]-3-hydroxy-
-1-methyl-1,5-dihydropyrrole-2-one (55 mg, yield: 37%) Melting
point: 204-206.degree. C.
[1924] Elementary analysis as C.sub.17H.sub.15FN.sub.2O.sub.2
[1925] Calcd. (%): C, 68.45; H, 5.07; N, 9.39; F, 6.37. Found (%):
C, 68.14; H, 5.14; N, 9.09; F, 6.00.
[1926] NMR(CDCl.sub.3).delta.:3.14(3H, s), 3.97(2H, s), 4.12(2H,
s), 6.98-7.16(5H, m), 7.53(1H, dd, J=2.1, 8.2 Hz), 8.37(1H, d,
J=1.5 Hz).
[1927] The following compounds were prepared as well as above.
[1928] (B-29-a)
4-[5-(4-fluorobenzyl)-pyridine2-yl]-3-hydroxyl-isopropyl-1-
,5-dihydro-pyrrole-2-one
[1929] Melting point: 162-164.degree. C.
[1930] Elementary analysis as C.sub.19H.sub.1 gFN.sub.2O.sub.2
[1931] Calcd. (%): C, 69.92; H, 5.87; N, 8.58; F, 5.82. Found (%):
C, 69.77; H, 5.81; N, 8.57; F, 5.58.
[1932] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=6.7 Hz), 3.98(2H, s),
4.08(2H, s), 4.57(1H, sept, J=6.7 Hz), 6.98-7.16(5H, m), 7.53(1H,
dd, J=2.4, 8.2 Hz), 8.37-8.38 (1H, m).
[1933] (B-29-b)
4-[5-(4-fluorobenzyl)-pyridine2-yl]-3-hydroxyl-(2-hydroxye-
thyl)-1,5-dihydropyrrole2-one
[1934] Melting point: 202-204.degree. C.
[1935] Elementary analysis as C.sub.18H.sub.17FN.sub.2O.sub.3
[1936] Calcd. (%):.C, 65.84; H, 5.22; N, 8.53; F, 5.79. Found (%):
C, 60.49; H, 4.89; N, 7.66; F, 5.09.
[1937] NMR(CDCl.sub.3).delta.:3.70(2H, t, J=5.1 Hz), 3.90(2H, t,
J=5.0 Hz), 3.98(2H, s), 4.27(2H, s), 6.98-7.04(3H, m),
7.11-7.16(2H, m), 7.53(1H, dd, J=1.9, 8.9 Hz), 8.37(1H, d, J=1.9
Hz).
[1938] (B-29-c) 4-[5-(4-fluorobenzyl)-pyridine2-yl]-3-hydroxy
1-(2-methoxyethyl)-1,5-dihydropyrrole2-one
[1939] Melting point: 202-204.degree. C.
[1940] Elementary analysis as C.sub.20H.sub.23FN.sub.203
[1941] Calcd. (%): C, 67.02; H, 6.47; N, 7.82; F, 5.30. Found (%)
C, 66.23; H, 5.52; N,. 8.02; F, 5.33.
[1942] NMR(CDCl.sub.3).delta.: 3.35(3H, s), 3.60(2H, t, J=4.9 Hz),
3.73(2H, t, J=4.9 Hz), 3.97(2H, s), 4.26(2H, s), 6.98-7.05(3H, m),
7.11-7.15(2H, m), 7.52(1H, dd, J=2.3, 8.1 Hz), 8.37(1H, d, J=1.4
Hz).
[1943] (B-29-d)
4-[5-(4-fluorobenzyl)-pyridine-2-yl]-3-hydroxy-1-(4-methox-
ybenzyl)-1,5-dihydropyrrole-2-one
[1944] Melting point: 164-166.degree. C.
[1945] Elementary analysis as C.sub.24H.sub.2,FN.sub.2O.sub.3
[1946] Calcd. (%) C, 71.27; H, 5.23; N, 6.93; F, 4.70. Found (%) C,
70.28; H, 5.15; N, 6.93; F, 4.38.
[1947] NMR(CDCl.sub.3).delta.: 3.79(3H, s), 3.94(2H, s), 3.96(2H,
s), 4.66(2H, s), 6.85-6.89(2H, m), 6.96-7.02(3H, m), 7.08-7.13(2H,
m), 7.20-7.25(2H, m), 7.46(1H, dd, J=2.2, 8.0 Hz), 8.34(1H, d,
J=2.3 Hz).
[1948] Compound B-34
[1949]
4-{4-[2-(4-fluorophenyl)ethyl]pyridine-2-yl}-3-hydroxy-1-methyl-1,5-
-dihydropyrrole-2-one 226
[1950] (B-30) To a solution of diisopropylamine (5.06 g, 50 mmol)
in THF (20 ml) was added a n-butyllithium solution (50 mmol) at
0.degree. C. After stirring for 5 minutes, a solution of
2,4-dimethylpyridine (5.35 g, 50 mmol) in THF (10 ml) was added
dropwise thereto at -78.degree. C. The mixture was stirred at
-78.degree. C. for 30 minutes, warmed to 10.degree. C., and
4-fluorobenzaldehyde (6.8 g, 55 mmol) was added thereto, wherby the
temperature rose to 35.degree. C. After stirring for 10 minutes, an
ammonium chloride aqueous solution was added to terminate the
reaction, followed by extraction with ethyl acetate. The extract
was washed, dried, and evaporated under reduced pressure. The
residue was purified with silica gel column chromatography using
ethyl acetate to give
1-(4-fluorophenyl)-2-(2-methylpyridine4-yl)ethanol (6.2 g, yield:
54%).
[1951] (B-31) To a solutuion of the above-mentioned compound B-30
(6.15 g, 26.6 mmol) triethylamine (4.03 g, 39.9 mmol), and
dimethylaminopyridine (200 mg, 1.6 mmol) in THF (20 ml), was added
dropwise acetic anhydride (4.07 g, 36 mmol) under ice cooling.
After stirring for 45 minutes, ice water was added to treminate the
reaction, followed by extraction with ethyl acetate. The extract
was washed, dried, and evaporated under reduced pressure, to give
acetic acid 1-(4-fluorophenyl)-2-(2-methylpyrid-
ine-4-yl)ethylester (7.25 g, yield: 99%).
[1952] (B-32) To a solutuion of the above-mentioned compound B-31
(7.25 g, 26.5 mmol) in ethanol (250 ml), were added triethylamine
(5.37 g, 53 mmol) and 10% palladium carbon (1 g) and the mixture
was stirred under hydrogen atomospher at room temperature. After
removing palladium carbon, the solvent was evaporated under reduced
pressure and the residue was purified with silica gel column
chromatography (ethyl acetate) to give
4-[2-(4-fluorophenyl)ethyl]-2-methylpyridine (5.23 g, yield:
92%).
[1953] NMR(CDCl.sub.3).delta.: 2.52(3H, s), 2.90-3.00(4H, m),
6.88(1H, dd, J=5.5, 1.2 Hz), 6.90-7.00(3H, m), 7.04-7.14(2H, m),
8.37(1H, d, J=5.1 Hz).
[1954] (B-33) To a solutuion of isopropylamine (1.01 g, 10 mmol) in
THF (10 ml), was added a n-butyllithium solution (10 mmol) under
ice-cooling. After stirring the mixture for 5 minutes, a solution
of B-32 (2.15 g, 10 mmol) in THF (5 ml) was added dropwise at
-78.degree. C., then the mixture was stirred for 20 minutes and
oxalic acid diethyl (5.84 g, 40 mmol) was added dropwise with
stirring for 45 minutes. The mixture was further stirred at room
temperature for 1 hour, then an ammonium chloride aqueous solution
was added to terminate the reaction, followed by extraction with
ethyl acetate. The extract was washed, dried, and evaporated under
reduced pressure. The residue was purified with silica gel column
chromatography (ethyl acetate) to give 3-{4-[2-(4-fluorophenyl-
)ethyl]pyridine-2-yl}-2-hydroxyacrylic acid ethylester (224 mg,
yield: 11%).
[1955] Melting point: 129-130.degree. C.
[1956] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=6.9 Hz), 2.92(4H, s),
4.36(2H, q, J=6.9), 6.48(1H, s), 5.47(2H, s), 6.90-7.04(3H, m),
7.04-7.14(2H, m), 8.25(1H, d, J=5.1 Hz).
[1957] Elementary analysis as C.sub.18H.sub.1sNFO3
[1958] Calcd. (%) C, 68.56; H, 5.75; N, 4.44; F, 6.02. Found (%):
C, 68.85; H, 5.55; N, 4.57; F, 5.93.
[1959] (B-34) To a solution of the above-mentioned compound B-33
(200 mg, 0.635 mmol) and 95% paraformaldehyde (52 mg, 1.73 mmol) in
dioxane (3 ml), was added a 30% methylamine ethanol solution (250,u
1) at room temperature and the mixture was stirred for 2 hours 30
minutes. An ammonium chloride aqueous solutionwas added thereto to
terminate the reaction, which was extracted with ethyl acetate. The
extract was washed, dried, and evaporated under reduced pressure.
The precipitated crystal was washed with diethyl ether to give
4-{4-[2-(4-fluorophenyl)ethyl]pyrid-
ine-2-yl}-3-hydroxy-l-methyl-1,5-dihydropyrrole-2-one (108 mg,
yield: 55%)
[1960] Melting point: 167-168.degree. C.
[1961] NMR(CDCl.sub.3).delta.: 2.92(4H, s), 3.15(3H, s), 4.07(2H,
s), 6.74(1H, s), 6.93(1H, dd, J=5.7, 2.1 Hz), 6.98(2H, t, J=8.4
Hz), 7.08-7.14(2H, m), 8.33(1H, d, J=6.7 Hz).
[1962] Elementary analysis as C.sub.18H.sub.17N.sub.2FO.sub.2
[1963] Calcd. (%): C, 69.22; H, 5.49; N, 8.97; F, 6.08. Found (%):
C, 69.08; H, 5.39; N, 8.58; F, 6.00.
[1964] The following compound was prepared as well as above.
[1965] (B1-34-a)
4-{4-[2-(4-fluorophenyl)ethyl]pyridine-2-yl}-3-hydroxy-1--
isopropyl-1,5-dihydropyrrole-2-one
[1966] Melting point: 167-168.degree. C.
[1967] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=6.6 Hz), 2.93(4H, s),
4.03(2H, s), 4.58(1H, m), 6.82(1H, s), 6.93(1H, dd, J=6.0, 1.5 Hz),
6.98(2H, t, J=8.7 Hz), 7.05-7.14(2H, m), 8.35(1H, d, J=6.0 Hz).
[1968] Elementary analysis as C.sub.20H.sub.21N.sub.2FO.sub.2
[1969] Calcd. (%): C, 70.57; H, 6.22; N. 8.23; F, 5.58. Found (%):
C, 70.10; H, 6.10; N, 8.11; F, 5.50.
[1970] Compound B-38
[1971]
4-[5-(4-fluorobenzyloxy)-pyridine-2-yl]-3-hydroxy-1-methyl-1,5-dihy-
dropyrrole-2-one 227
[1972] (B-35) According to the reference (J. Med.
Chem.20,1258,1977), 5-(4-fluorobenzyloxy)-pyridine-2-carboaldehyde
was synthesized.
[1973] (B-36) To a THF (50 ml) solution containing
(dimethoxyphosphoryl)-(-
2,2,2-trichloro-1,1-dimethylethoxycarbonyloxy)-acetic acid methyl
ester (1.91 g, 4.76 mmol) prepared according to the reference
(Tetrahedron Lett. 25, 3529, 1984), lithium bistrimethylsilylamine
(1M-THF solution, 5.62 mmol) was added at -78.degree. C. and the
mixture was stirred for 30 minutes. The above-mentioned compound
B-35 (1 g, 4.3 mmol) was slowly added thereto and the mixture was
stirred for 15 minutes, warmed to 0.degree. C., and further stirred
for 30 minutes. An ammonium chloride aqueous solution was added to
terminate the reaction, which was extracted with ethyl acetate. The
extract was washed, dried, and evaporated under reduced pressure.
The residue was purified with silica gel column chromatography
(ethyl acetatehexane=1:1) to give 3-[5-(4-fluorobenzyloxy)-
-pyridine-2-yl]-2-(2,2,2-trichloro-1,1-dimethylethoxycarbonyloxy)-acrylic
acid methyl ester (1.096 g, 50%)
[1974] (B-37) To a solutuion of the above-mentioned compound B-36
(1.2 g, 2.36 mmol) in methyl alcohol (25 ml), 28% sodium methoxide
(910 mg, 4.72 mmol) was added at 0.degree. C. and the mixture was
at room temperature for 1 hour. An ammonium chloride aqueous
solution was added to terminate the reaction, which was extracted
with ethyl acetate. The extract was washed, dried, and evaporated
under reduced pressure. The residue was purified with silica gel
column chromatography (ethyl acetate) to give
3-[5-(4-fluorobenzyloxy)-pyridine2-yl]-2-hydroxyacrylic acid methyl
ester (233 mg, yield: 32%)
[1975] Melting point: 131-132.degree. C.
[1976] NMR(CDCl.sub.3).delta.: 3.89(3H, s), 5.10(2H, s), 6.56(1H,
s), 7.10(2H, t, J=8.4 Hz), 7.18(1H, d, J=8.4 Hz), 7.33(1H, dd,
J=8.4,2.7 Hz), 7.36-7.45(2H, m), 8.13(1H, d, J=2.7 Hz).
[1977] Elementary analysis as C.sub.16H.sub.14NFO.sub.4
[1978] Calcd. (%) C, 60.36; H, 4.65; N, 4.62; F, 6.26. Found (%) C,
60.63; H, 4.57; N, 4.66; F, 6.06.
[1979] (B-38) To a solutuion of the above-mentioned compound B-37
(150 mg, 0.495 mmol) and 95% paraformaldehyde (40 mg, 1.33 mmol) in
dioxane (5 ml), was added a 30% methylamine--ethanol solution (150u
1) and the mixture was stirred at room temperature for 5 hours. An
ammonium chloride aqueous solution was added to terminate the
reaction, followed by extraction with ethyl acetate stirred. The
extract was washed, dried, and evaporated under reduced pressure.
The precipitated crystal was washed with diethyl ether to give
4-[5-(4-fluorobenzyloxy)-pyridine-2-yl]-3-hydr-
oxyl-methyl-1,5-dihydropyrrole-2-one (70 mg, yield: 45%)
[1980] Melting point: 210-211.degree. C.
[1981] NMR(CDCl.sub.3).delta.: 3.14(3H, s), 4.11(2H, s), 5.10(2H,
s), 7.10(2H, t, J=8.7 Hz), 7.11(1H, d, J=8.4 Hz), 7.32(1H, dd,
J=9.0, 3.0 Hz), 7.41(2H, dd, J=8.7, 5.4 Hz), 8.29(1H, d, J=3.0
Hz).
[1982] Elementary analysis as C.sub.17H.sub.15N.sub.2FO.sub.3
[1983] Calcd. (%): C, 64.96; H, 4.81; N, 8.91; F, 6.04. Found (%):
C, 64.68; H, 4.77; N, 8.78; F, 5.81.
[1984] The following compound was prepared as well as above.
[1985] (B-38-a) 4-[5-(4-fluorobenzyloxy)-pyridine-2-yl]-3-hydroxy
1-isopropyl-1,5-dihydropyrrole-2-one
[1986] Melting point: 195-196.degree. C.
[1987] NMR(CDCl.sub.3).delta.:1.26(6H, d, J=6.6), 4.09(2H, s),
4.56(1H, m), 5.10(2H, s), 7.10(2H, t, J=8.7 Hz), 7.20(1H, d, J=8.7
Hz), 7.32(1H, dd, J=8.7, 3.0 Hz), 7.41(2H, dd, J=8.4, 5.4 Hz),
8.30(1H, d, J=3.0 Hz).
[1988] Elementary analysis as C.sub.9H.sub.19N.sub.2FO.sub.3
[1989] Calcd. (%): C, 66.66; H. 5.59; N, 8.18; F, 5.55. Found (%):
C, 66.46; H, 5.61; N, 8.20; F, 5.54.
[1990] Compound B-42
[1991]
4-[5-(4-fluorophenylsulfanil)-pyridine-2-yl]-3-hydroxy-1-methyl-i,5-
-dihydropyrrol-2-one 228
[1992] (B-39) Using 6-methylpyridine-3-ol, with reference to J.
Org. Chem. 1967,32,1607, 5-bromo-2-methylpyridine was
synthesized.
[1993] NMR(CDCl.sub.3).delta.: 2.51(3H, s), 7.05(1H, d, J=8.3 Hz),
7.68(1H, d, J=2.5, 8.3 Hz), 8.55(1H, d, J=2.3 Hz).
[1994] (B-40) To a solutuion of the above-mentioned compound B-39
(6.0 g, 35 mmol) in tetrahydrofuran (100 ml), was added
n-butyllithium (35 mmol) at -78.degree. C., then
4-fluorophenyldisulphide (8.9 g, 35 mmol) synthesized according to
Tetrahedron Lett. 1990,31,5007 was added thereto and the mixture
was stirred for 30 minutes. Water was added to terminate the
reaction, followed by extraction with ethyl acetate. The extract
was washed, dried, and evaporated under reduced pressure. The
residue was purified with silica gel column chromatography
(n-hexaneethyl acetate=6:1) to give
5-(4-fluorophenylsulfanil)-2-methylpyridine (2.8 g, yield: 34%)
[1995] NMR(CDCl.sub.3).delta.: 2.54(3H, s), 6.98-7.04(2H, m),
7.09(1H, d, J=8.1 Hz), 7.31-7.36(2H, m), 7.49(1H, dd, J=2.3, 8.1
Hz), 8.46(1H, d, 2.3 Hz).
[1996] (B-41) Using the above-mentioned compound B-40, according to
the method of (B-11),
3-[5-(4-fluorophenylsulfinyl)-pyridine-2-yl]-2-hydroxya- crylic
acid ethyl ester was synthesized.
[1997] Melting point: 96-98.degree. C.
[1998] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.0 Hz), 4.36(2H, q,
J=7.0 Hz), 6.54(1H, s), 7.06-7.13(3H, m), 7.42-7.46(2H, m),
7.55(1H, dd, J=2.4, 8.5 Hz), 8.32(1H, d, J=2.4 Hz).
[1999] (B-42) Using the above-mentioned compound B-41, according to
the method of (B-12),
4-[5-(4-fluorophenylsulfinyl)-pyridine-2-yl]-3-hydroxy--
1-methyl-1,5-dihydropyrrole-2-one was synthesized.
[2000] Melting point: 210-212.degree. C.
[2001] Elementary analysis as C.sub.16H.sub.13FN.sub.2O.sub.2S
[2002] Calcd. (%): C, 60.75; H, 4.14; N, 8.86; F, 6.01; S, 10.14.
Found (%) C, 60.44; H, 4.01; N, 8.66; F, 5.75; S, 9.97.
[2003] NMR(CDCl.sub.3).delta.:1.14(3H, s), 4.11(2H, s),
7.02-7.11(3H, m), 7.41-7.46(2H, m), 7.58(1H, dd, J=2.3, 8.2 Hz),
8.38(1H, d, J=1.6 Hz).
[2004] The following compound was prepared as well as above.
[2005] (B-42-a)
4-[5-(4-fluorophenylsulfinyl)-pyridine-2-yl]-3-hydroxy-1-i-
sopropyl-1,5-dihydropyrrole-2-one
[2006] Melting point: 163-164.degree. C.
[2007] Elementary analysis as C.sub.18H.sub.17FN.sub.2O.sub.2S
[2008] Calcd. (%): C, 62.77; H, 4.98; N, 8.13; F, 5.52; S, 9.31.
Found (%): C, 62.62; H, 4.74; N, 7.98; F, 5.28; S, 9.10.
[2009] NMR(CDCl.sub.3).delta.:1.27(6H, d, J=6.9 Hz), 4.08(2H, s),
4.56(1H, sept), 7.05-7.11(2H, m), 7.13(1H, dd, J=0.6, 8.3 Hz),
7.39-7.45(2H, m), 7.59(1H, dd, J=2.3, 8.4 Hz), 8.38(1H, dd, J=0.6,
2.3 Hz).
[2010] Compound B-44
[2011]
4-[5-(4-fluorobenzenesulfinyl)-pyridine-2-yl]-3-hydroxy-1-methyl-1,-
5-dihydropyrrole-2-one 229
[2012] (B-43) To a solution of B-41 (640 mg, 2 mmol) in chloroform
(6 ml), was added mCPBA (690 mg, 4 mmol) under ice-cooling. After
30 minutes stirring, a saturated sodium hydrogen carbonate aqueous
solution was added to terminate the reaction, which was extracted
with chloroform. The extract was washed and dried, then the solvent
was evaporated under reduced pressure. The residue was purified
with silica gel column chromatography (n-hexaneethyl acetate=4:1)
to give
3-[5-(4-fluorobenzenesulfinyl)-pyridine-2-yl]-2-hydroxyacrylic acid
ethyl ester (400 mg, yield: 60%)
[2013] Melting point: 148-150.degree. C.
[2014] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.2 Hz), 4.36(2H, q,
J=7.2 Hz), 6.58(1H, s), 7.20-7.26(2H, m), 7.29(1H, d, J=8.4 Hz),
7.66-7.71(2H, m), 7.93(1H, dd, J=2.3, 8.4 Hz), 8.64(1H, d, J=2.3
Hz).
[2015] (B-44) Using the above-mentioned compound B-43, according to
the method of B-12, 4-[5-(4-fluorobenzene
sulfinyl)-pyridine-2-yl]-3-hydroxy--
1-methyl-1,5-dihydropyrrole-2-one was synthesized.
[2016] Melting point: 228-230.degree. C.
[2017] Elementary analysis as C.sub.16H.sub.13FN.sub.203S
[2018] Calcd. (%): C, 57.82; H, 3.94; N, 8.43; F, 5.72; S, 9.65.
Found (%): C, 57.56; H, 3.74; N, 8.20; F, 5.52; S, 9.49.
[2019] NMR(CDCl.sub.3).delta.: 3.16(3H, s), 4.16(2H, s),
7.19-7.26(2H, m), 7.30(1H, dd, J=0.9, 8.5 Hz), 7.66-7.71(2H, m),
8.02(1H, dd, J=2.4, 8.5 Hz), 8.67(1H, dd, J=0.9, 2.4 Hz).
[2020] The following compound was prepared as well as above.
[2021] (B-44-a)
4-[5-(4-fluorobenzenesulfinyl)-pyridine-2-yl]-3-hydroxy-1--
isopropyl-1,5-dihydropyrrole-2-one
[2022] Melting point: 205-207.degree. C.
[2023] Elementary analysis as C.sub.18H.sub.17FN.sub.2O.sub.3S
[2024] Calcd. (%): C, 59.99; H, 4.75; N, 7.77; F, 5.27; S, 8.90.
Found (%): C, 59.75; H, 4.57; N, 7.58; F, 5.08; S, 8.84.
[2025] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=7.0 Hz), 4.12(2H, s),
4.56(1H, sept), 7.19-7.26(2H, m), 7.38(1H, d, J=8.5 Hz),
7.65-7.71(2H, m), 8.01(1H, dd, J=2.4, 8.5 Hz), 8.67(1H, dd, J=0.9,
2.4 Hz).
[2026] Compound B-55
[2027]
4-[5-(4-fluorobenzyl)-pyrimidine-2-yl]-3-hydroxy-1-methyl-1,5-dihyd-
ropyrrole-2-one 230231
[2028] (B-45) According to J.Org.Chem. vol. 64, No.3, (1999), p992,
experimental(25), using 4-fluorobenzylbromide and di-t-butyl
malonate, 2-(4-fluorobenzyl)-malonic acid t-butyl ester was
synthesized.
[2029] NMR(CDCl.sub.3).delta.: 1.41(18H, s), 3.09(2H, d, J=7.9 Hz),
3.42(1H, t, J=7.9 Hz), 6.93-6.98(2H, m), 7.15-7.19(2H, m).
[2030] (B-46) To a solution of the above-mentioned compound B-45
(16.4 g, 50.6 mmol) in dichloromethane(15 ml), trifluoroacetic
acid(15 ml) was added and the mixture was stirred at room
temperature for 1 hour. The solvent was evaporated under reduced
pressure and the residue was recrystallized with ethylether and
n-hexane to give 2-(4-fluorobenzyl)malonic acid (8.90 g, yield:
83%)
[2031] NMR(CDCl.sub.3).delta.: 3.13(2H, d, J=7.6 Hz), 3.60(1H, t,
J=7.8 Hz), 6.95-7.01(2H, m), 7.22-7.27(2H, m).
[2032] (B-47) According to Collection Czechoslov.Chem.Commun.
vol.32 (1967), p3792-3793, using the above-mentioned compound B-46,
3-dimethylamino-2-(4-fluorobenzyl)-propenalwas synthesized.
[2033] (B-48) To a solution of the above-mentioned compound B-47
(1.42 g, 7.5 mmol) and actoamide hydrochloride (1.42 g, 15 mmol) in
methyl alcohol (5 ml), was added a solution of sodium methylate in
methyl alcohol (15 ml) and the mixture was refluxed for 4 hours. An
ammonium chloride aqueous solution was added thereto, which was
extracted with ethyl acetate. The extract was washed and dried,
then the solvent was evaporated. The residue was purified with
silica gel column chromatography (n-hexane: ethyl acetate=1:2-1:3)
to give 5-(4-fluorobenzyl)-2-methylpyrimidine (956 mg, yield:
69%)
[2034] NMR(CDCl.sub.3).delta.: 2.71(3H, s), 3.90(2H, s),
6.97-7.03(2H, m), 7.12-7.15(2H, m), 8.46(2H, s).
[2035] (B-49) To a solution of the above-mentioned compound B-48
(3.01 g, 15 mmol) in pyridine (22 ml), was added selenium dioxide
(11.0 g, 99 mmol) and the mixture was refluxed for 17.5 hours.
Chloroform and water were added thereto, followed by
celite-filtration. The filtrate was washed and dried, then the
solvent was evaporated to give crude
5-(4-fluorobenzyl)-pyrimidine-2-carboxylic acid (3.57 g)
[2036] NMR(CDCl.sub.3).delta.: 4.07(2H, s), 6.99-7.06(2H, m),
7.13-7.18(2H, m), 8.83(2H, s).
[2037] (B-50) To a solution of the above-mentioned crude product
B-49 (3.57 g) in tetrahydrofuran (43 ml), was addd a solution of
diazomethane in ethylether (30 mmol) and the mixture was stirred at
0.degree. C. for 10 minutes. The solution was warmed to room
temperature and stirred for 10 minutes. Acetic acid was added
thereto under ice-cooling, which was neutralized with a sodium
hydrogen carbonate aqueous solution, then extracted with ethyl
acetate. The extract was washed and dried, then the solvent was
evaporated. The residue was purified with silica gel column
chromatography (n-hexane: ethyl acetate=2:3) to give
5-(4-fluorobenzyl)-pyrimidine-2-carboxylic acid methyl ester (1.98
g, yield: 54%)
[2038] NMR(CDCl.sub.3).delta.: 4.05(2H, s), 4.07(3H, s),
7.01-7.06(2H, m), 7.12-7.17(2H, m), 8.75(2H, s).
[2039] (B-51) To a solution of the above-mentioned compound B-50
(1.98 g, 8.04 mmol) in tetrahydrofuran (26 ml) and t-butanol (13
ml), was added at -30.degree. C. sodium borohydride (338 mg, 8.04
mmol), then the mixture was warmed to room temperature and stirred
for 4 hours. An ammonium chloride aqueous solution was added to
terminate the reaction, followed by extraction with ethyl acetate.
The extract was washed and dried, then the solvent was evaporated
under reduced pressure. The residue was purified with silica gel
column chromatography (n-hexane: ethyl acetate=1:2) to give
[5-(4-fluorobenzyl)-pyrimidine-2-yl]-methyl alcohol (470 mg, yield:
27%)
[2040] NMR(CDCl.sub.3).delta.: 4.05(2H, s), 4.07(3H, s),
7.01-7.06(2H, m), 7.12-7.17(2H, m), 8.75(2H, s).
[2041] (B-52) To a solution of oxalyl chloride (281 ul, 3.23 mmol)
in methylene chloride (5 ml),was added dropwise a solution of
dimethylsulfoxide (457 ul, 6.45 mmol) in methylene chloride (1 ml)
at -78.degree. C. with stirring for 10 minutes. A solution of the
above-mentioned compound B-51 (470 mg, 2.15 mmol) in methylene
chloride (1.5 ml) was added dropwise thereto with stirring for 30
minutes. Triethylamine (1.79 ml, 12.9 mmol) was added dropwise to
the mixture, which was warmed to 0.degree. C. and stirred for 30
minutes. The solution was diluted with chloroform, washed, and
dried, then the solvent was evaporated under reduced pressure. The
residue was purified with silica gel column chromatography
(n-hexane:ethyl acetate=1:2) to give
5-(4-fluorobenzyl)-pyrimidine-2-carboaldehyde (337 mg, yield:
72%)
[2042] NMR(CDCl.sub.3).delta.: 4.08(2H, s), 7.01-7.07(2H, m),
7.15-7.20(2H, m), 8.81(2H, s), 10.09(1H, s).
[2043] (B-53) To a solution of lithiumbis(trimethylsilyl)amide
solution (1.87 ml), was added dropwise at -78.degree. C. a
tetrahydrofuran (2 ml) solution containing
(dimethoxyphosphoryl)-(2,2,2-trichloro-1,1-dimethylet-
hoxycarbonyloxy)-acetic acid methyl ester (688 mg, 1.71 mmol)
prepared according to Tetrahedron Lett.25,3529,1984, and the
mixture was stirred for 10 minutes. A solution of the
above-mentioned compound B-52 (337 mg, 1.56 mmol) in
tetrahydrofuran (2 ml) was added threto and the mixture was stirred
for 5 minutes, which was warmed to 0.degree. C. and stirred for 30
minutes. An ammonium chloride aqueous solution was added to
terminate the reaction, followed by extraction with ethyl acetate.
The extract was washed, dried, and evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography (n-hexane ethyl acetate=2:1) to give
3-[5-(4-fluorobenzyl)-pyrimidine-2-yl]-2-(2,2,2-tric-
hloro-1,1-dimethylethoxycarbonyloxy)-acrylic acid methyl ester (500
mg, yield: 66%)
[2044] NMR(CDCl.sub.3).delta.:1.98(6H, s), 3.76(2H, s), 3.94(3H,
s), 6.88(1H, s), 6.99-7.04(2H, m), 7.10-7.16(2H, m), 8.52(2H,
s).
[2045] (B-54) To a solution of the above-mentioned compound B-53
(380 mg, 0.77 mmol) in methyl alcohol (12 ml), a solution of sodium
methlate in methanol (376ul) was added under ice-cooling, which was
warmed to room temperature and stirred for 30 minutes.
Triethylamine (1.79 ml, 12.9 mmol) was added dropwise and the
mixture was warmed to 0.degree. C. and stirred for 30 minutes. An
ammonium chloride aqueous solution was added to terminate the
reaction, followed by extraction with ethyl acetate. The extract
was washed, dried, and the solvent was evaporated under reduced
pressure. The precipitated crystal was washed with diusopropylether
and dried under reduced pressure to give
3-[5-(4-fluorobenzyl)-pyrimidine-2-y- l]-2-hydroxyacrylic acid
methylester (129 mg, yield: 58%)
[2046] Melting point: 132-134.degree. C.
[2047] Elementary analysis as C.sub.15H13FN.sub.2O.sub.3
[2048] Calcd. (%): C, 62.50; H, 4.55; N, 9.72; F, 6.59. Found (%):
C, 60.81; H, 4.55; N, 9.69; F, 6.42.
[2049] NMR(CDCl.sub.3).delta.: 3.91(3H, s), 3.97(2H, s), 6.75(1H,
s), 7.01-7.06(2H, m), 7.13-7.18(2H, m), 8.54(2H, s).
[2050] According to the method of (B-55) (13-12),
4-[5-(4-fluorobenzyl)-py-
rimidine-2-yl]-3-hydroxyl-methyl-1,5-dihydropyrrole-2-one was
obtained.
[2051] Melting point: 163-165.degree. C.
[2052] Elementary analysis as C.sub.16H.sub.14FN.sub.3O.sub.2
[2053] Calcd. (%): C, 64.21; H, 4.71; N, 14.04; F, 6.35. Found (%):
C, 63.05; H, 4.82; N, 13.48; F, 6.07.
[2054] NMR(CDCl.sub.3).delta.: 3.16(3H, s), 3.97(2H, s), 4.22(2H,
s), 7.01-7.06(2H, m), 7.13-7.18(2H, m), 8.53(2H, s).
[2055] The following compound was prepared as well as above.
[2056] (B-55-a)
4-[5-(4-fluorobenzyl)-pyrimidine-2-yl]-3-hydroxy-1-isoprop-
yl-1,5-dihydropyrrole-2-one
[2057] Melting point: 155-157.degree. C.
[2058] Elementary analysis as C.sub.18H.sub.18FN.sub.3O.sub.2
[2059] Calcd. (%) C, 66.04; H, 5.54; N, 12.84; F, 5.80. Found (%):
C, 65.09; H, 5.44; N, 12.35; F, 5.67.
[2060] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=6.7 Hz), 3.97(2H, s),
4.19(2H, s), 4.58(1H, sept, J=6.9 Hz), 7.01-7.06(2H, m),
7.13-7.17(2H, m), 8.53(2H, s).
[2061] Compound B-59
[2062]
3-hydroxy-1-methyl-4-(5-phenoxypyrimidine-2-yl)-1,5-dihydropyrrole--
2-one 232
[2063] (B-56) According to J. Med. Chem. 1980,23,1016,
3-dimethylamino-2-phenoxypropenal was synthesized.
[2064] NMR(CDCl.sub.3).delta.: 3.10(6H, s), 6.57(1H, s),
6.93-6.99(3H, m), 7.24-7.30(2H, m), 8.83(1H, s).
[2065] The following compound was prepared as well as above.
[2066] 3-dimethylamino-2-(4-fluorophenoxy)-propenal
[2067] NMR(CDCl.sub.3).delta.: 3.11(6H, s), 6.57(1H, s),
6.86-6.98(4H, m), 8.81(1H, s).
[2068] (B-57) To a solution of the above-mentioned compound B-56
(17.9 g, 97 mmol) and acetoamidine hydrochloride (17.7 g, 187 mmol)
in methyl alcohol (200 ml), was added sodium methoxide (562 mmol)
and the mixture was refluxed for 3 hours. Ammonium chloride (20 g)
was added thereto at room temperature the mixture was stirred 1 for
hours. The solvent was evaporated under reduced pressure and to the
residue was added chloroform (200 ml), then insoluble products were
filtered off. The solvent was evaporated and the residue was
purified with silica gel column chromatography (ethyl acetate) to
give 2-methyl-5-phenoxypyrimidine (13.2 g, yield: 76%)
[2069] NMR(CDCl.sub.3).delta.: 2.73(3H, s), 7.01-7.05(2H, m),
7.16-7.21(1H, m), 7.36-7.42(2H, m), 8.40(2H, s).
[2070] The following compound was prepared as well as above.
[2071] 5-(4-fluorophenoxy)-2-methylpyrimidine
[2072] NMR(CDCl.sub.3).delta.: 2.72(3H, s),.6.99-7.12(4H, m),
8.37(2H, s).
[2073] (B-58) Using the above-mentioned compound B-57, according to
the method of (B-11),
2-hydroxy-3-(5-phenoxypyrimidine-2-yl)-acrylic acid ethyl ester was
synthesized.
[2074] Melting point: 52-53.degree. C.
[2075] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.3 Hz), 4.37(2H, q,
J=7.3 Hz), 6.78(1H, s), 7.07-7.11(2H, m), 7.24-7.28(1H, m),
7.41-7.46(2H, m), 8.47(2H, s).
[2076] The following compound was prepared as well as above.
[2077] 3-[5-(4-fluorophenoxy)-pyrimidine-2-yl]-2-hydroxy-acrylic
acid ethyl ester
[2078] Melting point: 92-93.degree. C.
[2079] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.3 Hz), 4.37(2H, q,
J=7.3 Hz), 6.78(1H, s), 7.05-7.16(4H, m), 8.44(2H, s).
[2080] (B-59) Using the above-mentioned compound B-58, according to
(B-12),
3-hydroxy-1-methyl-4-(5-phenoxypyrimidine-2-yl)-1,5-dihydropyrrol-
e-2-one was synthesized.
[2081] Melting point: 207-208.degree. C.
[2082] Elementary analysis as C.sub.15H.sub.13N.sub.3O.sub.3
[2083] Calcd. (%): C, 63.60; H, 4.63; N, 14.83. Found (%): C,
63.53; H, 4.47; N, 14.82.
[2084] NMR(CDCl.sub.3).delta.:3.17(3H, s), 4.23(2H, s),
7.07-7.10(2H, m), 7.22-7.27(1H, m), 7.41-7.46(2H, m), 8.47(2H,
s).
[2085] The following compound was prepared as well as above.
[2086] (B-59-a) 3-hydroxy
1-isopropyl-4-(5-phenoxypyrimidine-2-yl)-1,5-dih-
ydropyrrole-2-one
[2087] Melting point: 164-165.degree. C.
[2088] Elementary analysis as C.sub.17H.sub.17N.sub.3O.sub.3
0.2H.sub.2O
[2089] Calcd. (%): C, 64.83; H, 5.57; N, 13.34. Found (%): C,
64.98; H, 5.48; N, 13.22.
[2090] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=7.0 Hz), 4.20(2H, s),
4.59(1H, sept), 7.05-7.10(2H, m), 7.22-7.27(1H, m), 7.40-7.47(2H,
m), 8.47(2H, s).
[2091] (B-59-b)
4-[5-(4-fluorophenoxy)-pyrimidine-2-yl]-3-hydroxy-1-methyl-
-1,5-dihydropyrrole-2-one
[2092] Melting point: 230-232.degree. C.
[2093] Elementary analysis as C.sub.15H.sub.12FN.sub.3O.sub.3
[2094] Calcd. (%) C, 59.80; H, 4.01; N, 13.95; F, 6.31. Found (%):
C, 59.60; H, 3.89; N, 13.81; F, 6.05.
[2095] NMR(CDCl.sub.3) .delta.: 3.17(3H, s), 4.22(2H, s),
7.04-7.16(4H, m), 8.44(2H, s).
[2096] (B-59-c)
4-[5-(4-fluorophenoxy)-pyrimidine-2-yl]-3-hydroxy-1-isopro-
pyl-1,5-dihydropyrrole-2-one
[2097] Melting point: 165-166.degree. C.
[2098] Elementary analysis as C.sub.17H.sub.16FN.sub.3O.sub.3
[2099] Calcd. (%): C, 62.00; H, 4.90; N, 12.76; F, 5.77. Found (%):
C, 62.00; H, 4.91; N, 12.71; F, 5.51.
[2100] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=7.0 Hz), 4.19(2H, s),
4.59(1H, m), 7.04-7.16(4H, m), 8.45(2H, s).
[2101] Compound B-64
[2102]
4-(4-benzyloxypyrimidine-2-yl)-3-hydroxy-1-methyl-1,5-dihydropyrrol-
e-2-one 233
[2103] (B-60) To a solution of 3-ethoxyacrylic acid ethyl ester
(12.95 g, 89.82 mmol) and acetoamidine hydrochloride (25.44 g,
269.1 mmol) in ethanol(130 ml), was added potassium carbonate
(37.23 g, 269.4 mmol) and the mixture was refluxed for 2.5 hours.
After filtrating, the solvent was evaporated under reduced pressure
and the precipitated crystals were washed with chloroform and dried
under reduced pressure to give crude
2-methyl-3H-pyrimidine-4-one.
[2104] (B-61) To the crude above-mentioned compound B-60, was added
phosphorus oxychloride (60 ml) and the mixture was stirred at
80.degree. C. for 1.5 hours. The solvent was evaporated under
reduced pressure and to the residue was added ice (120 g), then the
mixture was neutralized with a 5N sodium hydroxide aqueous solution
and extracted with ethyl acetate. The extract was washed and dried,
then the solvent was evaporated under reduced pressure. The residue
was diluted with ethyl acetate and diethyl ether, and a 4N
hydrochloric acid ethyl acetate solution (20 ml) was added thereto.
The precipitated crystals were washed with ethyl acetate and dried
under reduced pressure to give 4-chloro-2-methylpyrimidine
hydrochloride (8.08 g, yield: 55%)
[2105] NMR(DMSO-d.sub.6).delta.: 2.62(3H, s), 7.55(1H, d, J=5.7
Hz), 8.69(1H, d, J=5.7 Hz).
[2106] (B-62) To a solution of sodium hydride (973 mg, 24.3 mmol)
in dimethylformamide (10 ml) was added benzylalcohol(2.50 ml, 24.2
mmol) under ice-cooling and the mixture was stirred at room
temperature for 30 minutes. The above-mentioned compound B-xx (2.02
g, 12.2 mmol) was added thereto under ice-cooling, and the mixture
was stirred at room temperature for 1 hour. Water was added to
terminate the reaction, and the mixture was extracted with ethyl
acetate. The extract was washed, dried, and evaporated under
reduced pressure, then the residue was purified with silica gel
column chromatography (n-hexane: ethyl acetate=5:1) to give
4-benzyloxy-2-methylpyrimidine (2.45 g, yield: 100%).
[2107] NMR(CDCl.sub.3).delta.: 2.64(3H, s), 5.42(2H, s), 6.58(1H,
d, J=5.9 Hz), 7.29-7.48(5H, m), 8.33(1H, d, J=5.9 Hz).
[2108] The following compound was prepared as well as above.
[2109] 4-(4-fluorobenzyloxy)-2-methylpyrimidine
[2110] NMR(CDCl.sub.3).delta.: 2.63(3H, s), 5.38(2H, s), 6.57(1H,
d, J=5.7 Hz), 7.07(2H, m), 7.43(2H, m), 8.34(1H, d, J=5.7 Hz).
[2111] (B-63) To a solution of the above-mentioned compound B-62
(1.00 g, 4.99 mmol) in tetrahydrofuran (20 ml), were added oxalic
acid diethyl (3.40 ml, 25.0 mmol) and potassium tert-butoxide (1.12
g, 9.98 mmol) under ice-cooling and the mixture was stirred at
50.degree. C. for 45 minutes. An ammonium chloride aqueous solution
was added to terminate the reaction, followed by extraction with
ethyl acetate. The extract was washed and dried, then the solvent
was evaporated under reduced pressure. The precipitated
crystalswere recrystallized from ethyl acetate/n-hexane to give
3-(4-benzyloxypyrimidine-2-yl)-2-hydroxyacrylic acid ethyl ester
(911 mg, yield: 61%)
[2112] Melting point: 124-126.degree. C.
[2113] Elementary analysis as Cl.sub.6H.sub.16N.sub.2O.sub.4
0.1H.sub.2O
[2114] Calcd. (%) C, 63.61; H, 5.40; N, 9.27. Found (%): C, 63.51;
H, 5.21; N, 9.13.
[2115] NMR(CDCl.sub.3).delta.: 1.40(3H, t, J=7.2 Hz), 4.38(2H, q,
J=7.2 Hz), 5.45(2H, s), 6.57(1H, d, J=6.0 Hz), 6.60(1H, s),
7.34-7.48(5H, m), 8.29(1H, d, J=6.0 Hz).
[2116] The following compound was prepared as well as above.
3-[4-(4-fluorobenzyloxy)pyrimidine-2-yl]-2-hydroxyacrylic acid
ethyl ester
[2117] Melting point: 150-151.degree. C.
[2118] Elementary analysis as C.sub.15H.sub.15FN.sub.2O.sub.4
[2119] Calcd. (%): C, 60.37; H, 4.75; N, 8.80; F, 5.97. Found (%):
C, 60.28; H, 4.61; N, 8.78; F, 5.81.
[2120] NMR(CDCl.sub.3).delta.: 1.41(3H, t, J=7.5 Hz), 4.38(2H, q,
J=7.5 Hz), 5.42(2H, s), 6.57(1H, d, J=5.9 Hz), 6.60(1H, s),
7.08(2H, m), 7.43(2H, m), 8.29(1H, d, J=5.9 Hz).
[2121] (B-64) To a solution of the above-mentioned compound B-63
(150 mg, 0.50 mmol) in dioxane (7.5 ml), were added
paraformaldehyde (80.5 mg, 2.01 mmol) and methylamine (2.00 mmol,
40% methyl alcohol solution) and the mixture was stirred at room
temperature for 18 hours. An ammonium chloride aqueous solution was
added to terminate the reaction, followed by extraction with
chloroform. The extract was washed and dried, then the solvent was
evaporated under reduced pressure. The precipitated crystals were
recrystallized from methyl alcohol to give
4-(4-benzyloxypyrimidine--
2-yl)-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one (86.0 mg, yield:
58%)
[2122] Melting point: 222-224.degree. C.
[2123] Elementary analysis as C.sub.16H.sub.15N.sub.3O.sub.3
0.1CH.sub.3OH 0.2H.sub.2O
[2124] Calcd. (%): C, 63.59; H, 5.24; N, 13.82. Found (%): C,
63.58; H, 5.03; N, 13.75.
[2125] NMR(CDCl.sub.3).delta.: 3.17(3H, s), 4.21(2H, s), 5.44(2H,
s), 6.59(1H, d, J=5.9 Hz), 7.33-7.47(5H, m), 8.34(1H, d, J=5.9
Hz).
[2126] The following compound was prepared as well as above.
[2127] (B-64-a)
4-(4-benzyloxypyrimidine-2-yl)-3-hydroxy-1-isopropyl-1,5-d-
ihydropyrrole-2-one
[2128] Melting point: 155-157.degree. C.
[2129] Elementary analysis as C.sub.18H.sub.19N.sub.3O.sub.3
0.3H.sub.2O
[2130] Calcd. (%): C, 65.36; H, 5.97; N, 12.70. Found (%): C,
65.31; H, 5.84; N, 12.62.
[2131] NMR(CDCl.sub.3).delta.: 1.29(6H, d, J=6.6 Hz), 4.15(2H, s),
4.60(1H, sept), 5.45(2H, s), 6.60(1H, d, J=6.0 Hz), 7.35-7.48(5H,
m), 8.36(1H, d, J=6.0 Hz).
[2132] (B-64-b)
4-[4-(4-fluorobenzyloxy)pyrimidine-2-yl]-3-hydroxy-1-methy-
l-1,5-dihydropyrrole-2-one
[2133] Melting point: 227-230.degree. C.
[2134] Elementary analysis as C.sub.16H.sub.14FN.sub.3O.sub.3
[2135] Calcd. (%): C, 60.95; H, 4.48; N, 13.33; F, 6.03. Found (%):
C, 60.82; H, 4.30; N, 13.12; F, 5.78.
[2136] NMR(CDCl.sub.3).delta.: 3.18(3H, s), 4.21(2H, s), 5.40(2H,
s), 6.58(1H, d, J=6.2 Hz), 7.09(2H, m), 7.42(2H, m), 8.35(1H, d,
J=6.2 Hz).
[2137] (B-64-c)
4-[4-(4-fluorobenzyloxy)pyrimidine-2-yl]-3-hydroxy-1-isopr-
opyl-1,5-dihydropyrrole-2-one
[2138] Melting point: 148-149.degree. C.
[2139] Elementary analysis as C.sub.18H.sub.18FN30.sub.3
0.3H.sub.2O
[2140] Calcd. (%): C, 61.99; H, 5.38; N, 12.05; F, 5.45. Found (%):
C, 61.95; H, 5.17; N, 11.78; F, 5.23.
[2141] NMR(CDCl.sub.3).delta.:1.29(6H, d, J=6.6 Hz), 4.16(2H, s),
4.60(1H, sept), 5.41(2H, s), 6.59(1H, d, J=6.0 Hz), 7.09(2H, m),
7.43(2H, m), 8.37(1H, d, J=6.0 Hz).
[2142] Compound B-68
[2143]
4-[5-(4-fluorobenzyloxy)pyrimidine-2-yl]-3-hydroxy-1-methyl-1,5-dih-
ydropyrrole-2-one 234
[2144] (B-65) According to the method described in US 5010193,
2-methylpyrimidine-5-ol was synthesized.
[2145] (B-66) To a solution of the above-mentioned compound B-65
(640 mg, 5.81 mmol) and potassium carbonate (1.20 g, 8.68 mmol) in
acetone (20 ml), was added 4-fluorobenzyl bromide(1.10 ml, 8.83
mmol) and the mixture was stirred at room temperature for 15 hours.
After filtrating, the solvent was evaporated under reduced
pressure, then the residue was purifiedwith silica gel column
chromatography (n-hexane:ethyl acetate=1:1) to give
5-(4-fluorobenzyloxy)-2-methylpyrimidine (758 mg, yield: 60%)
[2146] NMR(CDCl.sub.3).delta.: 2.68(3H, s), 5.09(2H, s), 7.10(2H,
m), 7.40(2H, m), 8.36(2H, s).
[2147] (B-67) To a solution of the above-mentioned compound B-66
(699 mg, 3.20 mmol) and 18-crown-6 (94.0 mg, 0.355 mmol) in
tetrahydrofuran (15 ml), were added oxalic acid diethyl (4.35 ml,
32.0 mmol) and potassium tert-butoxide (1.44 g, 12.8 mmol) and the
mixture was stirred at 60.degree. C. for 1 hour. An ammonium
chloride aqueous solutionwas added to terminate the reaction,
followed by extraction with ethyl acetate. The extract was washed
and dried, then the solvent was evaporated under reduced pressure.
The residue was subjected to silica gel column chromatography with
ethyl acetate, giving the elution comprising the objective
compound, from which the solvent was evaporated under reduced
pressure. The precipitated crystals were recrystallized from
isopropyl alcohol to give
3-[5-(4-fluorobenzyloxy)pyrimidine-2-yl]-2-hydroxyacrylic acid
ethyl ester (530 mg, yield: 52%)
[2148] Melting point: 134-135.degree. C.
[2149] Elementary analysis as C.sub.16H.sub.15FN.sub.2O.sub.4
[2150] Calcd. (%): C, 60.37; H, 4.75; N, 8.80; F, 5.97. Found (%):
C, 59.95; H, 4.66; N, 8.68; F, 5.70.
[2151] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.1 Hz), 4.36(2H, q,
J=7.1 Hz), 5.15(2H, s), 6.75(1H, s), 7.12(2H, m), 7.41(2H, m),
8.45(2H, s), 12.74(1H, brs).
[2152] (B-68) To a solution of the above-mentioned compound B-67
(151 mg, 0.474 mmol) in dioxane (7.5 ml), were added
paraformaldehyde (75.7 mg, 1.89 mmol) and methylamine (3.86 mmol.
30% ethanol solution) and the mixture was stirred at room
temperature for 22 hours. An ammonium chloride aqueous solution was
added to terminate the reaction, followed by extraction with
chloroform. The extract was washed and dried, then the solvent was
evaporated under reduced pressure. The precipitated crystals were
recrystallized from isopropyl alcohol to give
4-[5-(4-fluorobenzyloxy)pyrimidine-2-yl]-3-hydroxy-1-methyl-1,5-dihydropy-
rrole-2-one (104 mg, yield: 70%)
[2153] Melting point: 185-187.degree. C.
[2154] Elementary analysis as C.sub.16H.sub.14FN.sub.3O.sub.3
[2155] Calcd. (%): C, 60.95; H, 4.48; N, 13.33; F, 6.03. Found (%):
C, 60.82; H, 4.44; N, 13.20; F, 5.78.
[2156] NMR(CDCl.sub.3).delta.: 3.15(3H, s), 4.20(2H, s), 5.16(2H,
s), 7.12(2H, m), 7.42(2H, m), 8.44(2H, s), 10.53(1H, brs).
[2157] The following compound was prepared as well as above.
[2158] (B-68-a)
4-[5-(4-fluorobenzyloxy)pyrimidine-2-yl]-3-hydroxy-1-isopr-
opyl-1,5-dihydropyrrole-2-one
[2159] Melting point: 219-221.degree. C.
[2160] Elementary analysis as C.sub.18H.sub.18FN.sub.3O.sub.3
[2161] Calcd. (%): C, 62.97; H, 5.28; N, 12.24; F, 5.53. Found (%):
C, 62.71; H, 4.85; N, 12.10; F, 5.36.
[2162] NMR(CDCl.sub.3).delta.:1.27(6H, d, J=6.9 Hz), 4.17(2H, s),
4.58(1H, m), 5.16(2H, s), 7.12(2H, m), 7.42(2H, m), 8.44(2H, s),
10.43(1H, brs).
[2163] Compound B-73
[2164]
4-{5-[2-(4-fluorophenyl)ethyl]pyrimidine-2-yl}-3-hydroxy-1-methyl-1-
,5-dihydropyrrole-2-one 235
[2165] (B-69) According to J. Org. Chem. 1993, 58, 1696-1701,
1-fluoro-4-(4-methoxy-3-butenyl)benzene was synthesized.
[2166] (B-70) To dimethylformamide (3.35 ml, 43.3 mmol), was added
dropwise phosphorus oxychloride (4.00 ml, 42.9 mmol) under
ice-cooling and the mixture was stirred at 50.degree. C. for 45
minutes. The mixture was diluted with chloroform (6 ml), to which
was added at 75.degree. C. a solution of the above-mentioned
compound B-69 (2.60 g, 14.4 mmol) in chloroform (3 ml) and the
mixture was refluxed for 5 hours. The reaction mixture was added
dropwise to a solution of potassium carbonate (40 g) in
water-toluene-ethanol (10:9:1, 80 ml), and the mixture was stirred
for 1 hour. After filtrating, the filtrate was extracted with
chloroform, washed, and dried, then the solvent was evaporated
under reduced pressure to give crude
2-dimethylaminomethylene-4-(4-fluorophenyl)butylaldehyde.
[2167] (B-71) To a solution of the above-mentioned crude compound
B-70 in methyl alcohol (15 ml), were added acetoamidine
hydrochloride (2.61 g, 27.6 mmol) and sodium methoxide (83 mmol,
28% methyl alcoholsolution) and the mixture was refluxed for 3
hours. An ammonium chloride aqueous solution was added to terminate
the reaction, followed by extraction with chloroform. The extract
was washed and dried, then the solvent was evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography (n-hexane:ethyl acetate=5:1) to give
5-[2-(4-fluorophenyl)ethyl]-2-methylpyrimidine (764 mg, yield:
25%)
[2168] NMR(CDCl.sub.3).delta.:2.70(3H, s), 2.88(4H, m), 6.97(2H,
m), 7.06(2H, m), 8.37(2H, s).
[2169] (B-72) To a solution of the above-mentioned compound B-71
(759 mg, 3.51 mmol) in tetrahydrofuran (15 ml), were added oxalic
acid diethyl (2.40 ml, 17.7 mmol) and potassium tert-butoxide (787
mg, 7.01 mmol) under ice-cooling, and the mixture was stirred at
50.degree. C. for 2.5 hours and refluxed for 1.5 hours. An ammonium
chloride aqueous solution was added to terminate the reaction,
followed by extraction with ethyl acetate. The extract was washed
and dried, then the solvent was evaporated under reduced pressure.
The precipitated crystalswere recrystallized from ethyl
acetate-isopropyl ether to
3-{5-[2-(4-fluorophenyl)ethyl]pyrimidine-2-yl}-2-hydroxyacrylic
acid ethyl ester (704 mg, yield: 63%).
[2170] Melting point: 133-134.degree. C.
[2171] Elementary analysis as C.sub.17H.sub.17FN.sub.2O.sub.3
[2172] Calcd. (%): C, 64.55; H, 5.42; N, 8.86; F, 6.01. Found (%):
C, 64.38; H, 5.35; N, 8.73; F, 6.06.
[2173] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.2 Hz), 2.93(4H, s),
4.37(2H, q, J=7.2 Hz), 6.74(1H, s), 6.98(2H, m), 7.07(2H, m),
8.44(2H, s), 13.25(1H, brs).
[2174] (B-73) To a solution of the above-mentioned compound B-72
(152 mg, 0.481 mmol) in dioxane (7.5 ml), were
addedparaformaldehyde(76.9 mg, 1.92 mmol) andmethylamine(1.93 mmol.
30% ethanol solution) and the mixture was stirred at room
temperature for 14 hours. An ammonium chloride aqueous solution was
added to terminate the reaction, followed by extraction with
chloroform. The extract was washed and dried, then the solvent was
evaporated under reduced pressure. The precipitated crystalswere
recrystallized from isopropyl alcohol to give
4-{5-[2-(4-fluorophenyl)eth-
yl]pyrimidine-2-yl}-3-hydroxy-1-methyl-1,5-dihydropyrrole-2-one
(86.9 mg, yield: 58%)
[2175] Melting point: 158-160.degree. C.
[2176] Elementary analysis as C.sub.17H.sub.17FN.sub.3O.sub.2
[2177] Calcd. (%): C, 65.17; H, 5.15; N, 13.41; F, 6.06. Found (%):
C, 65.10; H, 5.17; N, 13.19; F, 6.06.
[2178] NMR(CDCl.sub.3).delta.:2.93(4H, s), 3.16(3H, s), 4.21(2H,
s), 6.98(2H, m), 7.07(2H, m), 8.41(2H, s).
[2179] The following compound was prepared as well as above.
[2180] (B-73-a)
4-{5-[2-(4-fluorophenyl)ethyl]pyrimidine-2-yl}-3-hydroxy-1-
-isopropyl-1,5-dihydropyrrole-2-one
[2181] Melting point: 143-144.degree. C.
[2182] Elementary analysis as C.sub.19H.sub.20FN.sub.3O.sub.2
[2183] Calcd. (%): C, 66.85; H, 5.91; N, 12.31; F, 5.57. Found (%):
C, 66.71; H, 5.87; N, 12.18; F, 5.57.
[2184] NMR(CDCl.sub.3).delta.: 1.27(6H, d, J=6.9 Hz), 2.93(4H, s),
4.18(2H, s), 4.58(1H, sept), 6.98(2H, m), 7.07(2H, m), 8.41(2H,
s).
[2185] Compound B-79
[2186]
3-hydroxy-1-methyl-4-(4-phenethylpyrimidine-2-yl)-1,5-dihydropyrrol-
e-2-one 236
[2187] (B-74) A solution of 4-phenylbutan-2-one (74 g, 500 mmol)
and N,N-dimethylformamidedimethylacetal (60 g, 500 mmol) in DMF (50
ml) was refluxed for 3 hours. The solvent was evaporated under
reduced pressure and the oily residue was purified with silica gel
column chromatography (ethyl acetatehexane=1:1) to give
1-dimethylamino-5-phenylpent-1-en-3-one (23.1 lg, yield:27.6%).
[2188] (B-75) To a solution of the above-mentioned compound B-74
(23.11 g, 113.7 mmol) and acetoamidine hydrochloride (12.89 g,
227.4 mmol) in methyl alcohol (50 ml), was added sodium methoxide
(3N-methyl alcohol solution, 564 mmol) and the mixture was refluxed
for 6 hours. The methyl alcohol was evaporated under reduced
pressure, to which was added water to terminate the reaction. After
adding hydrochloric acid and an ammonium chloride aqueous solution
for neutrization, the mixture was extracted with ethyl acetate,
which was washed and dried. The solvent was evaporated under
reduced pressure and the residue was purified with silica gel
column chromatography (ethyl acetate) to give
2-methyl-4-phenethylpyrimidine.
[2189] NMR(CDCl.sub.3).delta.: 2.73(3H, s), 3.03(4H, s), 6.87(1H,
d, J=5.1 Hz), 7.14-7.32(5H, m), 8.47(1H, d, J=5.1 Hz).
[2190] (B-76) To a solution of the above-mentioned compound B-75 (1
g, 5 mmol) and oxalic acid diethyl (3.68 g, 25 mmol) in THF (15
ml), was added at room temperature potassium tert-butoxide (2.24 g,
20 mmol) and the mixture was stirred at 80.degree. C. for 2 hours
30 minutes. An ammonium chloride aqueous solution was added to
terminate the reaction, then the mixture was extracted with ethyl
acetate. The extract was washed and dried, and the solvent was
evaporated under reduced pressure. The residue was purified with
silica gel column chromatography (hexaneethyl acetate=1:1) to give
3-{2-(2-ethoxycarbonyl-2-hydroxyvinyl)-3-methyl-2,3--
dihydropyridine-4-yl}-2-hydroxy-4-phenyl-2-butenoic acid ethyl
ester (520 mg, 26%).
[2191] (B-77) To a solution of the above-mentioned compound B-76
(628 mg, 1.58 mmol) in methylalcohol (20 ml) and water (5 ml), was
added lithium hydroxide (1N-aqueous solution, 1.6 mmol) and the
mixture was stirred at 60.degree. C. for 1.5 hours. Methylalcohol
was evaporated under reduced pressure and water was added thereto,
then the mixture was washed with chloroform. Citric acid was added
to the aqueous layer, which was extracted with ethyl acetate. The
extract was washed and dried, then the solvent was evaporated under
reduced pressure to give
2-hydroxy-3-(4-phenethylpyrimidine-2-yl)-acrylic acid (510 mg,
99%)
[2192] (B-78) To the above-mentioned compound B-77 (510 mg, 1.9
mmol) was added a hydrochloric acid/methyl alcohol solution (8 ml)
and the mixture was stirred at room temperature for 2.5 hours. The
solvent was evaporated under reduced pressure and the residue was
added to a sodium hydrogen carbonate aqueous solution, which was
extracted with ethyl acetate. The extract was washed and dried,
then the solvent was, evaporated under reduced pressure to give
2-hydroxy-3-(4-phenethylpyrimidine-2-yl)-acrylic acid methyl ester
(511 mg, 94%)
[2193] NMR(CDCl.sub.3).delta.:3.09(4H, s), 3.93(3H, s), 6.76(1H,
s), 6.90(1H, d, J=5.4 Hz), 7.15-7.35(5H, m), 8.55(1H, d, J=5.4 Hz),
13.8(1H, bs).
[2194] (B-79) To a solution of the above-mentioned compound B-78
(230 mg, 0.8195 mmol) and 95% paraformaldehyde (51 mg, 1.7 mmol) in
dioxane (5 ml), was added a 30% methylamine/ethanol solution(170,u
1), and the mixture was stirred at room temperature for 2.5 hours.
An ammonium chloride aqueous solution was added to terminate the
reaction, then the mixture was extracted with ethyl. The extract
was washed and dried, and the solvent was evaporated under reduced
pressure. The precipitated crystals were recrystallized from
ethanol to give 3-hydroxy-1-methyl-4-(4-
-phenethylpyrimidine-2-yl)-1,5-dihydropyrrole-2-one (120 mg, yield:
50%)
[2195] Melting point: 118-119.degree. C.
[2196] NMR(CDCl.sub.3).delta.: 3.10(4H, s), 3.17(3H, s), 4.24(2H,
s), 6.90(1H, d, J=6.0 Hz), 7.20-7.35(5H, m), 8.52(1H, d, J=5.2
Hz).
[2197] Elementary analysis as C.sub.17H,.sub.7N.sub.3O.sub.2
[2198] Calcd. (%) C, 69.14; H, 5.80; N, 14.32. Found (%): C, 69.04;
H, 5.54; N, 14.18.
[2199] The following compound was prepared as well as above.
[2200] (B-79-a)
3-hydroxy-1-isopropyl-4-(4-phenethylpyrimidine-2-yl)-1,5-d-
ihydropyrrole-2-one
[2201] Melting point 126-127.degree. C.
[2202] NMR(CDCl.sub.3).delta.: 1.29(6H, d, J=6.6 Hz), 3.00-3.15(4H,
m), 4.20(2H, s), 4.60(1H, sept), 6.90(1H, d, J=5.4 Hz),
7.15-7.35(5H, m), 8.53(1H, d, J=5.1 Hz).
[2203] Elementary analysis as Cl.sub.9H.sub.21N.sub.3O.sub.3
[2204] Calcd. (%): C, 70.57; H, 6.55; N, 12.99. Found (%) C, 70.39;
H, 6.55; N, 12.93.
[2205] Compound B-84
[2206]
3-hydroxy-1-methyl-4-(6-phenoxypyridazine-3-yl)-1,5-dihydropyrrole--
2-one 237
[2207] (B-80) According to the method of J. Chem. Soc. 1947,239,
6-methyl-2H-pyridazine-3-one was synthesized.
[2208] NMR(CDCl.sub.3).delta.: 2.34(3H, s), 6.92(1H, d, J=9.7 Hz),
7.16(1H, d, J=9.5 Hz), 11.97(1H, bs).
[2209] (B-81) Using the above-mentioned compound (B-80), according
to the method of WO 01/17968, 3-chloro-6-methylpyridazine was
synthesized.
[2210] NMR(CDCl.sub.3).delta.:2.72(3H, s), 7.32(1H, d, J=8.9 Hz),
7.42(1H, d, J=8.9 Hz).
[2211] (B-82) Using the above-mentioned compound B-81, according to
the method of (B-10), 3-methyl-6-phenoxypyridazine was
synthesized.
[2212] NMR(CDCl.sub.3).delta.:2.66(3H, s), 7.07(1H, d, J=8.9 Hz),
7.17-7.25(3H, m), 7.34(1H, d, J=8.9 Hz), 7.37-7.43(2H, m).
[2213] The following compound was prepared as well as above.
[2214] 3-(4-fluorophenoxy)-6-methylpyridazine
[2215] NMR(CDCl.sub.3).delta.:2.65(3H, s), 7.05-7.19(5H, m),
7.34(1H, d, J=8.9 Hz).
[2216] (B-83) Using the above-mentioned compound B-82, according to
the method of (B-11)
[2217] 2-hydroxy-3-(6-phenoxypyridazine-3-yl)-acrylic acid ethyl
ester was synthesized.
[2218] Melting point: 127-128.degree. C.
[2219] NMR(CDCl.sub.3).delta.:1.39(3H, t, J=7.2 Hz), 4.36(2H, q,
J=7.2 Hz), 6.47(1H, s), 7.19-7.32(4H, m), 7.41-7.49(3H, m).
[2220] The following compound was prepared as well as above.
3-[6-(4-fluorophenoxy)-pyridazine-3-yl]-2-hydroxyacrylic acid ethyl
ester
[2221] Melting point: 164-165.degree. C.
[2222] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.0 Hz), 4.36(2H, q,
J=7.0 Hz), 6.48(1H, s), 7.11-7.26(5H, m), 7.44(1H, dd, J=0.6, 9.1
Hz).
[2223] (B-84) Using the above-mentioned compound B-83, according to
the method of (B-12)
3-hydroxy-1-methyl-4-(6-phenoxypyridazine-3-yl)-1,5-dihy-
dropyrrole-2-one was synthesized.
[2224] Melting point: 220-225.degree. C.
[2225] Elementary analysis as C.sub.15H.sub.13N.sub.303
[2226] Calcd. (%) C, 63.60; H, 4.63; N, 14.83. Found (%): C, 63.49;
H, 4.36; N, 14.54.
[2227] NMR(CDCl.sub.3).delta.: 3.17(3H, s), 4.29(2H, s),
7.20-7.30(4H, m), 7.42-7.48(2H, m), 7.85(1H, d, J=9.5 Hz).
[2228] The following compound was prepared as well as above.
[2229] (B-84-a)
3-hydroxy-1-isopropyl-4-(6-phenoxypyridazine-3-yl)-1,5-dih-
ydropyrrole-2-one
[2230] Melting point: 203-205.degree. C.
[2231] Elementary analysis as C.sub.17H.sub.17N.sub.3O.sub.3
0.1H.sub.2O
[2232] Calcd. (%): C, 65.21; H, 5.54; N, 13.42. Found (%): C,
65.17; H, 5.22; N, 13.17.
[2233] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=6.7 Hz), 4.31(2H, s),
4.53(1H, sept), 7.20-7.29(4H, m), 7.41-7.47(2H, m), 8.03(1H, d,
J=9.2 Hz).
[2234] (B-84-b)
4-[6-(4-fluorophenoxy)-pyridazine-3-yl]-3-hydroxy-1-methyl-
-1,5-dihydropyrrole-2-one
[2235] Melting point: 240-243.degree. C.
[2236] Elementary analysis as C.sub.15H.sub.12FN.sub.3O.sub.3
0.2H20
[2237] Calcd. (%) C, 59.09; H, 4.10; N, 13.78; F, 6.23. Found (%)
C, 59.06; H, 3.70; N, 13.72; F, 6.02.
[2238] NMR(CDCl.sub.3).delta.: 3.17(3H, s), 4.30(2H, s),
7.09-7.27(5H, m), 7.94(1H, d, J=9.2 Hz).
[2239] (B-84-c)
4-[6-(4-fluorophenoxy)-pyridazine-3-yl]-3-hydroxy-1-isopro-
pyl-1,5-dihydropyrrole-2-one
[2240] Melting point: 204-206.degree. C.
[2241] Elementary analysis as C.sub.17H.sub.16FN.sub.3O.sub.3
[2242] Calcd. (%): C, 62.00; H, 4.90; N, 12.76; F, 5.77. Found (%):
C, 61.95; H, 4.61; N, 12.67; F, 5.58.
[2243] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=6.7 Hz), 4.31(2H, s),
4.50(1H, m), 7.09-7.23(5H, m), 8.06(1H, d, J=9.2 Hz).
[2244] Compound B-90
[2245]
3-hydroxy-1-methyl-4-(5-phenethylpyridazine-3-yl)-1,5-dihydropyrrol-
e-2-one 238
[2246] (B-85) To a solution of diisopropylamine (11.5 ml, 82.1
mmol) in tetrahydrofuran (100 ml), was added dropwise a n-butyl
lithium solution (79.5 mmol) under ice-cooling and the mixture was
stirred for 20 minutes. Acetone (5.85 ml, 79.7 mmol) was added
dropwise thereto at -78.degree. C. and th mixture was stirred for
30 minutes. A solution of 2-oxo-4-phenylbutanoic acid ethyl ester
(15.0 g, 72.7 mmol) in tetrahydrofuran (50 ml) was added dropwise
thereto and the mixture was stirred for 1 hour. An ammonium
chloride aqueous solution was added to terminate the reaction, then
the mixture was extracted with ethyl acetate. The extract was
washed and dried, and the solvent was evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography (n-hexane:ethyl acetate=5:1-2:1) to give
2-hydroxy-4-oxo-2-phenethylpentanoic acid ethyl ester (16.7 g,
yield: 87%)
[2247] NMR(CDCl.sub.3).delta.:1.29(3H, t, J=7.2 Hz), 1.96(2H, m),
2.16(3H, s), 2.49(1H, m), 2.79(1H, m), 2.88(1H, d, J=17.4 Hz),
3.07(1H, d, J=17.4 Hz), 3.81(1H, brs), 4.23(2H, q, J=7.2 Hz),
7.13-7.31(5H, m).
[2248] (B-86) To a solution of the above-mentioned compound B-85
(16.7 g, 63.2 mmol) in 95% ethanol (35 ml), was added
hydrazine-hydrate (4.70 ml, 95.0 mmol) and the mixture was refluxed
for 2 hours. The solvent was evaporated under reduced pressure,
then the precipitated crystals were washed with water and dried
under reduced pressure to give
6-methyl-4-phenethyl-2H-pyridazine-3-one (8.71 g, yield: 64%).
[2249] NMR(CDCl.sub.3).delta.: 2.25(3H, s), 2.92(4H, m), 6.82(1H,
s), 7.16-7.33(5H, m), 11.03(1H, brs).
[2250] (B-87) To a solution of the above-mentioned compound B-86
(4.29 g, 20.0 mmol), was added phosphorus oxychloride (10 ml) and
the mixture was stirred at 80.degree. C. for 30 minutes. The
solvent was evaporated and to the residue was added ice (40 g),
then the mixture was neutrazied with a 5N sodium hydroxide aqueous
solution and extracted with ethyl acetate. The extract was washed
and dried, then the solvent was evaporated under reduced pressure
to give crude 3-chloro-6-methyl-4-phenethylpyridazine.
[2251] (B-88) A suspension of the above-mentioned crude compound
B-87, 28% aqueous ammonia (4 g), and 10% palladium-carbon (0.80 g)
in 95% ethanol (400 ml) was stirred in hydrogen atomospher at 4 atm
at room temperature for 30 minutes. The reaction mixture was
filtered and the solvent was evaporated under reduced pressure. The
residue was extracted with ethyl acetate and the extract was washed
and dried, then the solvent was evaporated under reduced pressure.
The residue was purified with silica gel column chromatography
(ethyl acetate) to give 3-methyl-5-phenethylpyr- idazine (3.49 g,
yield: 88%).
[2252] NMR(CDCl.sub.3).delta.: 2.66(3H, s), 2.93(4H, m), 7.05(1H,
d, J=2.3 Hz), 7.10-7.33(5H, m), 8.84(1H, d, J=2.3 Hz).
[2253] (B-89) To a solution of the above-mentioned compound B-88
(3.00 g, 15.1 mmol) in tetrahydrofuran (60 ml), was added dropwise
a n-butyl lithium solution (16.7 mmol) at -78.degree. C. Oxalic
acid diethyl (6.20 ml, 45.6 mmol) was added thereto and the mixture
was stirred for 1 hour, to which was added an ammonium chloride
aqueous solution under ice-cooling to terminate the reaction,
followed by extraction with ethyl acetate. The extract washed and
dried, then the solvent was evaporated under reduced pressure. The
residue was subjected to silica gel column chromatography and the
portion eluted with ethyl acetate was evaporated under reduced
pressure. The precipitated crystals were recrystallized from ethyl
acetate-isopropylether-n-hexane to give
2-hydroxy-3-(5-phenethylpyridazine-3-yl)-acrylic acid ethylester
(954 mg, yield: 21%) Melting point: 94-95.degree. C.
[2254] Elementary analysis as C.sub.17H.sub.18N.sub.2O.sub.3
[2255] Calcd. (%): C, 68.44; H, 6.08; N, 9.39. Found (%) C, 68.35;
H, 5.88; N, 9.36.
[2256] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.1 Hz), 2.88-3.02(4H,
m), 4.35(2H, q, J=7.1 Hz), 6.02(1H, s), 7.00(1H, s), 7.10-7.16(2H,
m), 7.21-7.35(3H, m), 8.31(1H, s).
[2257] (B-90) To a solution of the above-mentioned compound B-89
(149 mg, 0.50 mmol) in dioxane (7.5 ml), were added
paraformaldehyde (79.8 mg, 2.00 mmol) and methylamine (2.01 mmol.
40% methyl alcohol solution)and the mixture was stirred at room
temperature for 3.5 hours. An ammonium chloride aqueous solution
was added thereto to terminate the reaction, and the mixture was
extracted with chloroform. The extractwas washed and dried, then
the solvent was evaporated under reduced pressure. The precipitated
crystals were recrystallized from ethanol to give
3-hydroxy-1-methyl-4-(5-phenethylpyridazine-3-yl)-1,5-dihydropyrrole-2-on-
e (119 mg, yield: 81%)
[2258] Melting point: 203-205.degree. C.
[2259] Elementary analysis as C.sub.17H.sub.17N30.sub.2
[2260] Calcd. (%): C, 69.14; H, 5.80; N, 14.23. Found (%): C,
68.76; H, 5.68; N, 14.04.
[2261] NMR(CDCl.sub.3).delta.: 2.99(4H, s), 3.17(3H, s), 4.15(2H,
s), 7.11-7.18(3H, m), 7.21-7.37(3H, m), 8.62(1H, d, J=1.5 Hz).
[2262] The following compound was prepared as well as above.
[2263] (B-90-a)
3-hydroxy-1-isopropyl-4-(5-phenethylpyridazine-3-yl)-1,5-d-
ihydropyrrole-2-one
[2264] Melting point: 182-184.degree. C.
[2265] Elementary analysis as C.sub.19H.sub.21N.sub.3O.sub.2
0.1C.sub.3H.sub.7OH
[2266] Calcd. (%): C, 70.37; H, 6.67; N, 12.76. Found (%) C, 70.06;
H, 6.40; N, 12.64.
[2267] NMR(CDCl.sub.3).delta.:1.29(6H, d, J=6.9 Hz), 3.00(4H, s),
4.17(2H, s), 4.57(1H, m), 7.12-7.17(2H, m), 7.21-7.37(5H, m),
8.67(1H, d, J=2.1 Hz).
[2268] Compound B-95
[2269]
3-hydroxy-1-methyl-4-(5-phenoxypyrazine-2-yl)-1,5-dihydropyrrole-2--
one 239
[2270] (B-91) According to the method of J. Am. Chem. Soc.
1952,74,1580, 5-methyl-1H-pyrazine-2-one was synthesized.
[2271] NMR(CDCl.sub.3).delta.: 2.34(3H, s), 7.08(1H, s), 8.21(1H,
s).
[2272] (B-92) Using the above-mentioned compound B-91, according to
WO 01/17968, 2-chloro-5-methyl pyrazine was synthesized.
[2273] NMR(CDCl.sub.3).delta.: 2.56(3H, s), 8.24(1H, s), 8.49(1H,
s).
[2274] (B-93) Using the above-mentioned compound B-92, according to
the method of (B-10), 2-methyl-5-phenoxypyrazine was
synthesized.
[2275] NMR(CDCl.sub.3).delta.: 2.51(3H, s), 7.12-7.26(3H, m),
7.39-7.44(2H, m), 7.98(1H, s), 8.31(1H, s).
[2276] The following compound was prepared as well as above.
[2277] 2-(4-fluorophenoxy)-5-methylpyrazine
[2278] NMR(CDCl.sub.3).delta.: 2.51(3H, s), 7.09-7.12(4H, m),
7.95(1H, s), 8.32(1H, s).
[2279] (B-94) Using the above-mentioned compound B-93, according to
the method of (B-11) 2-hydroxy-3-(5-phenoxypyrazine-2-yl)-acrylic
acid ethyl ester was synthesized.
[2280] Melting point: 128-129.degree. C.
[2281] NMR(CDCl.sub.3).delta.: 1.40(3H, t, J=7.0 Hz), 4.37(2H, q,
J=7.0 Hz), 6.63(1H, s), 7.16-7.19(2H, m), 7.26-7.31(1H, m),
7.43-7.48(2H, m), 8.13(1H, d, J=1.5 Hz), 8.29(1H, d, J=1.2 Hz).
[2282] The following compound was prepared as well as above.
[2283] 3-[5-(4-fluorophenoxy)-pyrazine-2-yl]-2-hydroxyacrylic acid
ethyl ester
[2284] Melting point: 139-140.degree. C.
[2285] NMR(CDCl.sub.3).delta.: 1.40(3H, t, J=7.0 Hz), 4.37(2H, q,
J=7.0 Hz), 6.63(1H, s), 7.12-7.14(4H, m), 8.11(1H, d, J=1.1 Hz),
8.30(1H, d, J=0.9 Hz).
[2286] (B-95) Using the above-mentioned compound B-94, according to
the method of (B-12)
3-hydroxy-1-methyl-4-(5-phenoxypyrazine-2-yl)-1,5-dihydr-
opyrrole-2-one was synthesized.
[2287] Melting point: 233-235.degree. C.
[2288] Elementary analysis as C.sub.15H.sub.13N.sub.3O.sub.3
0.3H.sub.2O
[2289] Calcd. (%): C, 62.41; H, 4.75; N, 14.56. Found (%) C, 62.52;
H, 4.48; N, 14.61.
[2290] NMR(CDCl.sub.3).delta.: 3.16(3H, s), 4.19(2H, s),
7.16-7.18(2H, m), 7.25-7.31(1H, m), 7.42-7.48(2H, m), 8.27(1H, d,
J=1.2 Hz), 8.35(1H, d, J=1.5 Hz).
[2291] The following compound was prepared as well as above.
[2292] (B-95-a)
3-hydroxy-1-isopropyl-4-(5-phenoxypyrazine-2-yl)-1,5-dihyd-
ropyrrole-2-one
[2293] Melting point: 216-217.degree. C.
[2294] Elementary analysis as C.sub.17H.sub.17N303
[2295] Calcd. (%): C, 65.58; H, 5.50; N, 13.50. Found (%):.C,
65.27; H, 5.35; N, 13.47.
[2296] NMR(CDCl.sub.3).delta.: 1.29(6H, d, J=7.0 Hz), 4.17(2H, s),
4.51(1H, sept), 7.15-7.20(2H, m), 7.24-7.30(1H, m), 7.41-7.47(2H,
m), 8.34(1H, d, J=1.5 Hz),.8.40(1H, d, J=1.2 Hz), 8.78(1H, bs).
[2297] (B-95-b)
4-[5-(4-fluorophenoxy)-pyrazine-2-yl]-3-hydroxy-1-methyl-1-
,5-dihydropyrrole-2-one
[2298] Melting point: 237-238.degree. C.
[2299] Elementary analysis as C.sub.15H.sub.12FN.sub.3O.sub.3
0.1H.sub.2O
[2300] Calcd. (%): C, 59.44; H, 4.06; N, 13.86; F, 6.27. Found (%):
C, 59.34; H, 4.01; N, 13.95; F, 6.31.
[2301] NMR(CDCl.sub.3).delta.: 3.16(3H, s), 4.19(2H, s),
7.11-7.15(4H, m), 8.26(1H, d, J=0.9 Hz), 8.36(1H, d, J=0.9 Hz),
8.93(1H, bs).
[2302] (B-95-c)
4-[5-(4-fluorophenoxy)-pyrazine-2-yl]-3-hydroxy-1-isopropy- l
1,5-dihydropyrrole-2-one
[2303] Melting point: 227-229.degree. C.
[2304] Elementary analysis as C.sub.17H.sub.16FN.sub.3O.sub.3
[2305] Calcd. (%): C, 62.00; H, 4.90; N, 12.76; F, 5.77. Found (%):
C, 62.05; H, 4.81; N, 12.75; F, 5.72.
[2306] NMR(CDCl.sub.3).delta.: 1.29(6H, d, J=6.7 Hz), 4.17(2H, s),
4.51(1H, sept), 7.09-7.16(4H, m), 8.35(1H, s), 8.40(1H, s),
8.69(1H, bs).
[2307] Compound B-106
[2308]
4-[5-(4-fluorobenzyl)-pyrazine-2-yl]-3-hydroxy-1-methyl-1,5-dihydro-
pyrrole-2-one 240241
[2309] (B-96) To a solution of 5-methyl-2-pyrazine carboxylic acid
(25 g, 180 mmol), HOBt (4.9 g, 36 mmol), and
N,O-dimethylhydroxyamine hydrochloride (21 g, 220 mmol) in
methylene chloride (100 ml) and chloroform (400 ml), were added
triethylamine (30 ml, 220 mmol) and WSCD (41 g, 220 mmol) and the
mixture was stirred at room temperature for 2 hours. The solution
was washed and dried, then the solvent was evaporated undr reduced
pressure to give crude 5-methylpyrazine-2-carboxylic acid
methoxymethylamide (30.5 g)
[2310] NMR(CDCl.sub.3).delta.:2.63(3H, s), 3.41(3H, s), 3.75(3H,
s), 8.47(1H, s), 8.82(1H, s).
[2311] (B-97) To a solution of the above-mentioned crude product
B-96 (16.3 g, 90 mmol) in tetrahydrofuran (220 ml), was added
dropwise 4-fluorophenylmagnesium bromide (99 ml) at -40.degree. C.
and the mixture was stirred at -20.degree. C. for 30 minutes. An
ammonium chloride aqueous solution was added to terminate the
reaction, which was extracted with ethyl acetate. The extract was
washed and dried, then the solvent was evaporated under reduced
pressure. The precipitated crystals were washed with n-hexane and
dried to give 4-fluorophenyl-5-methylpyrazine-2-- yl-metanone (16.8
g, yield: 86%).
[2312] NMR(CDCl.sub.3).delta.: 2.70(3H, s), 7.15-7.21(2H, m),
8.16-8.20(2H, m), 8.54(1H, s), 9.17(1H, s).
[2313] (B-98) To a solution of the above-mentioned compound B-97
(16.8 g, 78 mmol) in chloroform(250 ml), was added
m-chloroperbenzoic acid (22.7 g, 86 mmol) and the mixture was
stirred at room temperature overnight. Sodium hydrogen carbonate
was added thereto to alkalify the solution and the mixture washed
and dried, then the solvent was evaporated under reduced pressure.
The precipitated crystals were washed with diisopropylether and
dried under reduced pressure to give
(4-fluorophenyl)-(5-methyl-4-oxypyrazine-2-yl)-metanone (15.8 g,
yield: 88%)
[2314] NMR(CDCl.sub.3).delta.: 2.56(3H, s), 7.14-7.22(2H, m),
8.18-8.24(2H, m), 8.53(1H, s), 8.77(1H, s).
[2315] (B-99) A solution of the above-mentioned compound B-98 (15.8
g, 78 mmol) in acetic anhydride (160 ml) was stirred at 135.degree.
C. for 3 hours, which was cooled to room temperature, then water
(500 ml) was added thereto with stirring overnight. The reaction
solution was extracted with ethyl acetate, then the extract was
washed and dried. The solvent was evaporated under reduced pressure
and the residue was purified with silica gel column chromatography
(n-hexane:ethyl acetate=3:1) to give acetic acid
5-(4-fluorobenzoyl)-pyrazine-2-ylmethyl ester (8.0 g, yield:
43%).
[2316] NMR(CDCl.sub.3).delta.: 2.22(3H, s), 5.37(2H, s),
7.16-7.22(2H, m), 8.17-8.22(2H, m), 8.72(1H, s), 9.24(1H, s).
[2317] (B-100) To a solution of the above-mentioned compound B-99
(8.0 g, 29 mmol) in methyl alcohol (60 ml), was added sodium
borohydrate (491 mg, 11.7 mmol) under ice-cooling and the mixture
was stirred for 2 hours, which was warmed to room temperature,
followed by stirring for 30 minutes. An ammonium chloride aqueous
solution was added to terminate the reaction, and the mixture was
extracted with ethyl acetate. The extract was washed and dried,
then the solvent was evaporated under reduced pressure to give
crude acetic acid
[2318] 5-[(4-fluorophenyl)-hydroxymethyl]-pyrazine-2-ylmethyl ester
(8.0 g)
[2319] NMR(CDCl.sub.3).delta.: 2.15(3H, s), 5.25(2H, s), 5.87(1H,
s), 7.02-7.08(2H, m), 8.34-8.39(2H, m), 8.53(1H, s), 8.58(1H,
s).
[2320] (B-101) To a solution of the above-mentioned crude product
B-100 (8.0 g) in trifluoroacetic acid(200 ml), was added
triethylsilane(40 ml, 250 mmol)under ice-cooling and the mixture
was stirred at room temperature for 4 days. The solvent was
evaporated under reduced pressure and an aqueous solution of sodium
hydrogen carbonate was added to neutrize the solution, which was
extracted with ethyl acetate. The extract was washed and dried,
then the solvent was evaporated under reduced pressure and the
residue was purified with silica gel column chromatography
(n-hexane:ethyl acetate=1:1) to give acetic acid
5-(4-fluorobenzyl)-pyrazine-2-ylmethyl ester (4.5 g, yield:
60%)
[2321] NMR(CDCl.sub.3).delta.: 2.15(3H, s), 4.14(2H, s), 5.22(2H,
s), 6.97-7.03(2H, m), 7.20-7.25(2H, m), 8.43(1H, s), 8.57(1H,
s).
[2322] (B-102) To a solution of the above-mentioned compound B-101
(4.5 g, 17.3 mmol) in methyl alcohol (50 ml), was added a 2N sodium
hydroxide aqueous solution (26 ml) and the mixture was stirred at
room temperature for 1 hour. Hydrochloric acid and an ammonium
chloride aqueous solution were added to neutrize the reaction
solution, which was extracted with ethyl acetate. The extract was
washed and dried, then the solvent was evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography (n-hexane: ethyl acetate=1:2) to give
[5-(4-fluorobenzyl)-pyrazine-2-yl]-methyl alcohol (3.1 g, yield:
82%)
[2323] NMR(CDCl.sub.3).delta.: 3.15(1H, brs), 4.14(2H, s), 4.79(2H,
s), 6.97-7.02(2H, m), 7.19-7.24(2H, m), 8.39(1H, s), 8.55(1H,
s).
[2324] (B-103) To a solution of the above-mentioned compound B-102
(3.0 g, 13.7 mmol) in chloroform (90 ml), was added manganese
dioxide (12.0 g, 137 mmol) and the mixture was refluxed for 3
hours. The reaction mixture was filtered with celite and the
solvent was evaporated under reduced pressure to give crude
5-(4-fluorobenzyl)-pyrazine-2-carboaldehyde (2.46 g)
[2325] NMR(CDCl.sub.3) .delta.: 4.25(2H, s), 7.00-7.06(2H, m),
7.23-7.28(2H, m), 8.60(1H, s), 9.09(1H, s), 10:11(1H, s).
[2326] (B-104) (03-105) --78C cool To a lithium
bis(trimethylsilyl)amide solution (13.6 ml), was added dropwise a
tetrahydrofuran (15 ml) solution containing
(dimethoxyphosphoryl)-(2,2,2-trichloro-1,1-dimethylethoxycarbo-
nyloxy)-acetic acid methyl ester (5.03 g, 12.5 mmol) synthesized
according to Tetrahedron Lett.25, 3529, 1984) and the mixture was
stirred for 10 minutes. A solution of the above-mentioned compound
B-103 (337 mg, 1.56 mmol) in tetrahydrofuran (2 ml) was added
thereto and the mixture was stirred for 10 minutes, which was
warmed to 0.degree. C. and stirred for 20 minutes. An ammonium
chloride aqueous solution was added to terminate the reaction and
the mixture was extracted with ethyl acetate. The extract was
washed and dried, then the solvent was evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography (n-hexane:ethyl acetate=2:1-1:2) to give
3-[5-(4-fluorobenzyl)-pyrazine-2-yl]-2-(2,2,2-trichloro-1,1-dimethylethox-
ycarbonyloxy)-acrylic acid methyl ester (3.46 g, yield: 62%) and
3-[5-(4-fluorobenzyl)-pyrazine-2-yl]-2-hydroxy acrylic acid methyl
ester (0.70 g, yield: 21%).
3-[5-(4-fluorobenzyl)-pyrazine-2-yl]-2-(2,2,2-trich-
loro-1,1-dimethylethoxycarbonyloxy)-acrylic acid methyl ester.
[2327] NMR(CDCl.sub.3).delta.: 1.98(6H, s), 3.76(2H, s), 4.15(3H,
s), 6.93(1H, s), 6.98-7.04(2H, m), 7.20-7.25(2H, m),.8.42(1H, d,
J=1.5 Hz), 8.69(1H, d, J=1.5 Hz).
3-[5-(4-fluorobenzyl)-pyrazine-2-yl]-2-hydroxyacry- lic acid methyl
ester
[2328] Melting point: 122-123.degree. C.
[2329] Elementary analysis as C.sub.15H.sub.3FN.sub.2O.sub.3
[2330] Calcd. (%): C, 62.50; H, 4.55; N, 9.72; F, 6.59. Found (%):
C, 62.45; H, 4.35; N, 9.72; F, 6.45.
[2331] NMR(CDCl.sub.3).delta.:3.91(3H, s), 4.16(2H, s), 6.64(1H,
s), 6.99-7.05(2H, m), 7.22-7.25(2H, m), 8.28(1H, s), 8.50(1H,
s).
[2332] (B-106) Using the above-mentioned compound B-105, by a
similar method to (B-12),
4-[5-(4-fluorobenzyl)-pyrazine-2-yl]-3-hydroxy-1-methyl-
-1,5-dihydropyrrole-2-one was obtained.
[2333] Melting point: 223-225.degree. C.
[2334] Elementary analysis as C.sub.16H.sub.14FN.sub.3O.sub.2
[2335] Calcd. (%): C, 64.21; H, 4.71; N, 14.04; F, 6.35. Found (%):
C, 63.65; H, 4.31; N, 13.89; F, 6.19; Cl, 0.82.
[2336] NMR(CDCl.sub.3).delta.: 3.16(3H, s), 4.16(2H, s), 4.21(2H,
s), 6.98-7.04(2H, m), 7.21-7.27(2H, m), 8.35(1H, s), 8.60(1H,
s).
[2337] The following compound was prepared as well as above.
[2338] (B-106-a)
4-[5-(4-fluorobenzyl)-pyrazine-2-yl]-3-hydroxy-1-isopropy-
l-1,5-dihydropyrrole-2-one
[2339] Melting point: 207-209.degree. C.
[2340] Elementary analysis as C.sub.18H.sub.18FN.sub.3O.sub.2
[2341] Calcd. (%) C, 66.04; H, 5.54; N, 12.84; F, 5.80. Found (%):
C, 65.25; H, 5.38; N, 12.46; F, 5.51.
[2342] NMR(CDCl.sub.3).delta.: 1.29(6H, d, J=6.9 Hz), 4.16(2H, s),
4.18(2H, s), 4.55(1H, sept, J=6.9 Hz), 6.98-7.04(2H, m),
7.21-7.26(2H, m), 8.34(1H, s), 8.74(1H, s).
[2343] Compound B-110
[2344]
4-[4-(4-fluorobenzyloxy)-[1,3,5]triazine-2-yl]-3-hydroxy-1-methyl-1-
,5-dihydropyrrole-2-one 242
[2345] (B-107) According to Synthesis 1981,907,
2-chloro-4-methyl[1,3,5]tr- iazine was synthesized.
[2346] NMR(CDCl.sub.3).delta.:2.71(3H, s), 8.92(1H, s).
[2347] (B-108) To a solution of calcium carbonate (7.8 g, 57 mmol)
in 4-fluorobenzyl alcohol (15 ml), was added the above-mentioned
compound (B-107) (7.4 g, 57 mmol) and the mixture was stirred at
90.degree. C. for 3 hours. Water was added to terminate the
reaction, which was extracted with ethyl acetate. The extract was
washed and dried, then the solvent was evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography (n-hexane:ethyl acetate=3:1-1:1) to give
2-(4-fluorobenzyloxy)-4-methyl[1,3,5]triazine (3.3 g, yield:
26%)
[2348] NMR(CDCl.sub.3).delta.: 2.60(3H, s), 5.44(2H, s),
7.32-7.36(2H, m), 7.43-7.48(2H, m), 8.77(1H, s).
[2349] (B-109) Using the above-mentioned compound B-108, according
to the method of (B-11)
3-[4-(4-fluorobenzyloxy)-[1,3,5]triazine-2-yl]-2-hydroxy- acrylic
acid ethyl ester was synthesized.
[2350] Melting point: 142-143.degree. C.
[2351] NMR(CDCl.sub.3).delta.: 1.40(3H, t, J=7.0 Hz), 4.38(2H, q,
J=7.0 Hz), 5.47(2H, s), 6.54(1H, s), 7.05-7.11(2H, m),
7.44-7.48(2H, m), 8.80(1H, s).
[2352] (B-110) Using the above-mentioned compound B-109, according
to the method of (B-12)
4-[4-(4-fluorobenzyloxy)-[1,3,5]triazine-2-yl]-3-hydroxy-
-1-methyl-1,5-dihydropyrrole-2-one was synthesized.
[2353] Melting point: 169-171.degree. C.
[2354] Elementary analysis as C.sub.15H.sub.13FN.sub.4O.sub.3
0.3H.sub.2O
[2355] Calcd. (%): C, 56.00; H, 4.26; N, 17.42; F, 5.91. Found (%):
C, 55.92; H, 3.89; N, 17.58; F, 5.62.
[2356] NMR(CDCl.sub.3).delta.: 3.17(3H, s), 4.20(2H, s), 5.47(2H,
s), 7.05-7.11(2H, m), 7.44-7.48(2H, m), 8.82(1H, s).
[2357] The following compound was prepared as well as above.
[2358] (B-110-a)
4-[4-(4-fluorobenzyloxy)-[1,3,5]triazine-2-yl]-3-hydroxy--
1-isopropyl-1,5-dihydropyrrole-2-one
[2359] Melting point: 105-106.degree. C.
[2360] Elementary analysis as C.sub.17H.sub.17FN.sub.4O.sub.3
[2361] Calcd. (%) C, 59.30; H, 4.98; N, 16.27; F, 5.52. Found (%)
C, 59.12; H, 4.68; N, 16.29; F, 5.36.
[2362] NMR(CDCl.sub.3).delta.:1.27(6H, d, J=6.7 Hz), 4.15(2H, s),
4.57(1H, sept), 5.48(2H, s), 7.03-7.11(2H, m), 7.44-7.48(2H, m),
8.82(1H, s).
[2363] Compound B-112
[2364]
4-{5-[2-(4-fluorophenyl)ethyl]-thiazole-2-yl}-3-hydroxy-1-methyl
1,5-dihydropyrrole-2-one 243
[2365] (B-111) According to WO 01/17968,
3-{5-[2-(4-fluorophenyl)ethyl]-th- iazole-2-yl}-2-hydroxyacrylic
acid ethyl ester was synthesized.
[2366] Melting point: 146-148.degree. C.
[2367] Elementary analysis as C.sub.16H.sub.16FNO.sub.3S
[2368] Calcd. (%): C, 59.80; H, 5.02; N, 4.36; F, 5.91; S, 9.98.
Found (%): C, 59.85; H, 4.90; N, 4.32; F, 5.82; S, 10.03.
[2369] NMR(CDCl.sub.3).delta.: 1.38(3H, t, J=7.1 Hz), 2.95(2H, t,
J=7.5 Hz), 3.14(2H, t, J=7.5 Hz), 4.36(2H, q, J=7.1 Hz), 6.69(1H,
s), 6.95-7.01(2H, m), 7.09-7.14(2H, m), 7.41(1H, s).
[2370] (B-112) Using the above-mentioned compound B-ill, by a
similar method to (B-12),
4-{5-[2-(4-fluorophenyl)ethyl]-thiazole-2-yl}-3-hydroxy-
-1-methyl-1,5-dihydropyrrole-2-one was obtained.
[2371] Melting point: 214-216.degree. C.
[2372] Elementary analysis as C.sub.16H.sub.15FN.sub.2O.sub.2S
[2373] Calcd. (%) C, 60.36; H, 4.75; N, 8.80; F, 5.97; S, 10.07.
Found (%): C, 59.98; H, 4.59; N, 8.59; F, 5.77; S, 9.95.
[2374] NMR(CDCl.sub.3).delta.: 2.93(2H, t, J=7.6 Hz), 2.98(3H, s),
3.15(2H, t, J=7.4 Hz), 4.21(2H, s), 7.07-7.12(2H, m), 7.25-7.29(2H,
m), 7.48(1H, s).
[2375] The following compound was prepared as well as above.
[2376] (B-112-a)
4-{5-[2-(4-fluorophenyl)ethyl]-thiazole-2-yl}-3-hydroxy-1-
-isopropyl-1,5-dihydropyrrole-2-one
[2377] Melting point: 208-210.degree. C.
[2378] Elementary analysis as C.sub.18H.sub.19FN.sub.2O.sub.2S
[2379] Calcd. (%): C, 62.41; H, 5.53; N, 8.09; F, 5.48; S, 9.26.
Found (%) C, 62.21; H, 5.51; N, 8.02; F, 5.39; S, 9.24.
[2380] NMR(CDCl.sub.3).delta.: 1.28(6H, d, J=6.7 Hz), 2.96(2H, t,
J=7.4 Hz), 3.16(2H, t, J=7.4 Hz), 4.23(2H, s), 4.53(1H, sept, J=6.7
Hz), 6.95-7.00(2H, m), 7.10-7.14(2H, m), 7.41(1H, s).
[2381] Compound B-117
[2382]
4-[5-(4-fluorobenzyl)-thiazole-2-yl]-3-hydroxy-1-methyl-1,5-dihydro-
pyrrole-2-one 244
[2383] (B-113) According to J. Org. Chem. 1993, 58, 1696-1701,
3-(4-fluorophenyl)-propionic aldehyde was synthesized.
[2384] (B-114) To a solution of the above-mentioned compound B-113
(4.6 g, 30 mmol). in acetonitrile (120 ml), tetrabutylammonium
tribromide (14.5 g, 30 mmol) was added and the mixture was stirred
at room temperature for 30 minutes. The solvent was evaporated
under reduced pressure and water was added thereto, which was
extracted with diethyl ether. The extract was washed and dried,
then the solvent was evaporated under reduced pressure to give
crude 2-bromo-3-(4-fluorophenyl)-propionic aldehyde (6.0 g)
[2385] NMR(CDCl.sub.3).delta.:3.14(1H, dd, J=7.8, 14.8 Hz),
3.46(1H, dd, J=6.6, 14.8 Hz), 4.41(1H, dt, J=2.4, 6.7 Hz),
6.98-7.04(2H, m), 7.17-7.21(2H, m), 9.49(1H, s).
[2386] (B-115) To a solution of the above-mentioned crude product
B-114 (6.0 g) in acetonitrile (60 ml), was added thioacetoamide
(3.9 g, 52 mmol) and the mixture was refluxed for 1 hour. A sodium
hydrogen carbonate aqueous solution was added to neutrize the
solution, which was extracted with diethyl ether. The extract was
washed and dried, then the solvent was evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography (n-hexane: ethyl acetate=3:1) to give
5-(4-fluorobenzyl)-2-methylthiazole (3.8 g, yield: 71%)
[2387] NMR(CDCl.sub.3).delta.: 2.64(3H, s), 4.06(2H, s),
6.96-7.02(2H, m), 7.15-7.20(2H, m), 7.32(1H, s).
[2388] (B-116) Using the above-mentioned compound B-115, by a
similar method to (B-11),
3-[5-(4-fluorobenzyl)-thiazole-2-yl]-2-hydroxyacrylic acid ethyl
ester was obtained.
[2389] Melting point: 160-162.degree. C.
[2390] Elementary analysis as C.sub.15H.sub.14FNO.sub.3S
[2391] Calcd. (%): C, 58.62; H, 4.59; N, 4.56; F, 6.18; S, 10.43.
Found (%): C, 58.84; H, 4.32; N, 4.76; F, 6.45; S, 10.90.
[2392] NMR(CDCl.sub.3).delta.: 1.38(3H, t, J=7.1 Hz), 4.13(2H, s),
4.35(2H, q, J=7.1 Hz), 6.68(1H, s), 7.00-7.05(2H, m), 7.17-7.21(2H,
m), 7.48(1H, s).
[2393] (B-117) Using the above-mentioned compound B-116, by a
similar method to (B-12),
4-[5-(4-fluorobenzyl)-thiazole-2-yl]-3-hydroxy-1-methyl-
-1,5-dihydropyrrole-2-one was obtained.
[2394] Melting point: 222-224.degree. C.
[2395] Elementary analysis as C.sub.15H.sub.13FN.sub.2O.sub.2S
[2396] Calcd. (%): C, 59.20; H,. 4.31; N, 9.20; F, 6.24; S, 10.54.
Found (%): C, 57.01; H, 4.08; N, 8.68; F, 5.91; S, 10.06.
[2397] NMR(CDCl.sub.3).delta.: 2.98(3H, s), 4.19(2H, s), 4.22(2H,
s), 7.11-7.17(2H, m), 7.30-7.35(2H, m), 7.60(1H, s).
[2398] The following compound was prepared as well as above.
[2399] (B-117-a)
4-[5-(4-fluorobenzyl)-thiazole-2-yl]-3-hydroxy-1-isopropy-
l-1,5-dihydropyrrole-2-one
[2400] Melting point: 212-214.degree. C.
[2401] Elementary analysis as C.sub.17H.sub.17FN.sub.2O.sub.2S
[2402] Calcd. (%) C, 61.43; H, 5.16; N, 8.43; F, 5.72; S, 9.65.
Found (%): C, 61.17; H, 5.06; N, 8.30; F, 5.62; S, 9.58.
[2403] NMR(CDCl.sub.3).delta.: 1.26(6H, d, J=6.7 Hz), 4.16(2H, s),
4.22(2H, s), 4.51(1H, sept, J=6.7 Hz), 6.98-7.03(2H, m),
7.17-7.22(2H, m), 7.53(1H, s).
[2404] C Group Compound
[2405] Compound C-8
[2406]
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-4H-1-benzopyrane-4-
-one 245246
[2407] (C-1) To a suspension of 60% sodium hydride (3.61 g, 90.3
mmol) in dimethylformamide (50 ml), was added dropwise a solution
of 2-bromophenol (15.1 g, 87.3 mmol) in dimethylformamide (50 ml)
under ice-cooling and the mixture was stirred at the same
temperature for 40 minutes. Chloromethyl methyl ether (7.29 ml,
96.0 mmol) was added dropwise thereto, and the mixture was stirred
for 45 minutes. Water was added to terminate the reaction, which
was extracted with ethyl acetate. The extract was washed and dried,
then the solvent was evaporated under reduced pressure. The residue
was distilled under reduced pressure to give
1-bromo-2-methoxymethoxybenzene (17.7 g, yield 94%)
[2408] boiling point: 67-68.degree. C. (0.7 mmHg)
[2409] (C-2) To a solution of the above-mentioned compound C-1
(14.9 g, 68.7 mmol) in tetrahydrofuran (250 ml), was added dropwise
an n-butyl lithium solution (1.55N, 46.5 ml, 72.1 mmol) at
-78.degree. C. The mixture was stirred at the same temperature for
20 minutes and a solution of zinc chloride in diethylether (1.0N,
72.1 ml, 72.1 mmol) was added dropwise thereto, which was stirred
for 30 minutes. Chlorobenzyloxyacetyl (13.0 ml, 82.4 mmol) and
tetrakistriphenylphosphine palladium (1.59 g, 1.4 mmol) were added
thereto and the mixture was stirred for 2 hours with cooling to
room temperature. After adding dilute hydrochloric acid, the
mixture was extracted with ethyl acetate, washed and dried, then
the solvent was evaporated under reduced pressure and the residue
was purified with silica gel column chromatography (ethyl
acetate:n-hexane=1:9-1:3) to give
2-benzyloxy-1-(2-methoxymethoxyphenyl)e- tanone (10.2 g, yield:
52%).
[2410] NMR(CDCl.sub.3).delta.:3.43(3H, s), 4.69(2H, s), 4.73(2H, s)
5.22(2H, s), 7.05-7.18(2H, m), 7.27-7.49(6H, m), 7.86(1H, dd,
J=1.8, 7.8 Hz).
[2411] (C-3) To a solution of the above-mentioned compound C-2
(10.2 g, 35.7 mmol) in methyl alcohol (100 ml), was added 2N
hydrochloric acid (25 ml) and the mixture was stirred at 50.degree.
C. for 4 hours 30 minutes. Water(100 ml) was added thereto, and the
mixture was extracted with ethyl acetate, washed and dried, then
the solvent was evaporated under reduced pressure and the residue
was purified with silica gel column chromatography (ethyl
acetate:n-hexane=1:4) to give
2-benzyloxy-l-(2-hydroxyphenyl)etanone (7.89 g, yield 91%)
[2412] NMR(CDCl.sub.3).delta.: 4.70(2H, s), 4.77(2H, s),
6.83-6.90(1H, m), 7.00(1H, dd, J=1.2, 8.4 Hz), 7.28-7.51(6H, m),
7.63(1H, dd, J=1.5, 8.1 Hz), 11.9(1H,s).
[2413] (C-4) To a solution of the above-mentioned compound C-3
(7.64 g, 31.6 mmol) in pyridine (76 ml), was added ethyl chloro
glyoxylic acetate (5.29 ml, 47.4 mmol) under ice-cooling. The
mixture was stirred for 20 minutes while allowing to be at room
temperature, then further stirred at 100.degree. C. for 37 hours.
Water (5 ml) was added thereto and the mixture was stirred at room
temperature for 15 minutes and evaporated under reduced pressure,
to which was added 1N hydrochloric acid, followed by extraction
with ethyl acetate. The extract was washed and dried, then the
solvent was evaporated under reduced pressure. The residue was
purifiedwith silica gel column chromatography (ethyl acetate:
n-hexane=1:3) to give 3-benzyloxy4-oxo-4H-chromene-2-carboxylic
acid ethyl ester (3.48 g, yield: 34%)
[2414] NMR(CDCl.sub.3).delta.: 1.36(3H, t, J=7.2 Hz), 4.40(2H, q,
J=7.2 Hz), 5.28(2H, s), 7.30-7.76(8H, m), 8.23-8.27(1H, m).
[2415] (C-5) To the above-mentioned compound C-4 (1.73 g, 5.34
mmol) in ethanol (16 ml),was added 2N sodium hydroxide aqueous
solution (3 ml) and the mixture was stirred at room temperature for
1 hour. The mixture was concentrated under reduced pressure and 2N
hydrochloric acid (3.2 ml) and water were added thereto, which was
extracted with ethyl acetate, washed, and dried. The solvent was
evaporated under reduced pressure and the residue was crystallized
from ethyl acetate/n-hexane to give
3-benzyloxy-4-oxo-4H-chromene-2-carboxylic acid (1.24 g, yield:
79%)
[2416] Melting point: 145-146.degree. C.
[2417] NMR(CDCl.sub.3).delta.: 5.63(2H, s), 7.36-7.52(6H, m),
7.62-7.66(1H, m), 7.75-7.82(1H, m), 8.25(1H, dd, J=2.1, 7.8
Hz).
[2418] (C-6) To a solution of the above-mentioned compound C-5 (157
mg, 0.53 mmol) in methylene chloride (3 ml), were added
oxalylchloride (50,u 1, 0.69 mmol) and dimethylformamide (2 .mu.l)
under ice-cooling and the mixture was stirred for 20 minutes while
allowing to be at room temperature. The solution was concentrated
under reduced pressure to give crude
3-benzyloxy-4-oxo-4H-chromene-2-carboxylic acid chloride.
[2419] (C-7) To a solution of the above-mentioned compound C-6 in
chloroform(1 ml), were added dichlorobis(acetonitrile)palladium(II)
(12 mg, 0.046 mmol) and trimethylzinc compound (250 mg) prepared
below at room temperature and the mixture was stirred at the same
temperature for 5 minutes and at 50.degree. C. for 20 minutes.
Water was added thereto and the mixture was extracted with ethyl
acetate, washed and dried. The solvent was evaporated and the
residue was purified with silica gel column chromatography (ethyl
acetate: n-hexane=1:4). Crystallization from ethyl acetate/n-hexane
gave 3-benzyloxy-2-[5-(4-fluorobenzyl)furan-2-carb- onyl]
chromene-4-one (82 mg, yield: 21%)
[2420] Melting point: 158.degree. C.
[2421] NMR(CDCl.sub.3).delta.: 4.02(2H, s), 5.24(2H, s),
6.96-7.76(13H, m), 8.30 (1H, dd, J=1.5, 8.1 Hz).
[2422] (C-8) To a solution of the above-mentioned compound C-7 (79
mg, 0.17 mmol) in ethanol (2 ml) and tetrahydrofuran (6 ml), was
added 10% palladium-carbon (20 mg) and the mixture was stirred at
room temperature for 10 minutes under hydrogen atomospher. Aftre
filtrating off the palladium-carbon, the filtrate was concentrated
under reduced pressure and the residue was crystallized from
tetrahydrofuran/methyl alcohol to give
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-4H-1-benzopyrane-4--
one (45 mg, yield: 71%)
[2423] Melting point: 226-227.degree. C.
[2424] Elementary analysis as C.sub.21H.sub.13FO.sub.5
[2425] Calcd. (%): C, 69.23; H, 3.60; F, 5.21. Found (%): C, 69.00;
H, 3.53; F, 5.15.
[2426] NMR(CDCl.sub.3).delta.:4.14(2H, s), 6.32(1H, d, J=3.6 Hz),
7.01-7.79(7H, m), 7.90(1H, d, J=3.6 Hz), 8.30 (1H, dd, J=1.5, 8.1
Hz), 11.86(1H, s).
[2427] (C-9) To a solution of bromofuran(500 mg, 1.96 mmol) in
tetrahydrofuran(250 ml), was added dropwise a n-butyl lithium
solution (1.55N, 1.3 ml, 2.02 mmol) at -78.degree. C. and the
mixture was stirred for 5 minutes. To the mixture was added
dropwise a solution of trimethyltin chloride (423 mg, 2.06 mmol) in
tetrahydrofuran (0.5 ml) and the mixture was stirred at -78.degree.
C. for 30 minutes and further stirred with warming to room
temperature. Water was added thereto and the mixture was extracted
with ethyl acetate, washed, and dried. The solvent was evaporated
under reduced pressure to give the crude trimethyltin compound.
[2428] NMR(CDCl.sub.3).delta.:0.20-0.40(9H, m), 3.98(2H, s),
5.92-5.96(1H, m), 6.46-6.50(1H, m), 6.94-7.22(4H, m).
[2429] Compound C-12
[2430]
6-[(4-fluorobenzyl)oxy]-3-hydroxy(2-pyridine-2-yl)-4H-1-benzopyrane-
-4-one 247
[2431] (C-10) To a suspension of 2', 5'-dihydroxyacetophenone (23.1
g, 152 mmol) and powder potassium carbonate (23.1 g, 167 mmol) in
acetonitrile (400 ml), was added 4-fluorobenzylbromide (18.9 ml,
152 mmol) at room temperature and the mixture was refluxed for 3
hours. The solution cooled to room temperature was filtered and the
obtained solid products were washed with ethyl acetate. The
filtrate and the ethyl acetate solution after washing were combined
and concentrated under reduced pressure, to which was added an
ammonium chloride aqueous solution, followed by extraction with
ethyl acetate. The extract was washed and dried, then active carbon
(10 g) was added thereto, followed by filtration and concentration
under reduced pressure. The residue was crystallized from methyl
alcohol (100 ml) to give 1-[5-(4-fluorobenzyloxy)-2-hydroxyphenyl]-
etanone (30.3 g, yield: 77%).
[2432] Melting point: 88-89.degree. C.
[2433] NMR(CDCl.sub.3).delta.: 2.60(3H, s), 5.00(2H, s),
6.90-7.45(7H, m), 11.87(1H, s).
[2434] (C-11) To a solution of the above-mentioned compound
C-10(470 mg, 1.81 mmol)in ethanol (14 ml), were added
pyridine-2-aldehyde (202 mg, 1.90 mmol), and a 50% sodium hydroxide
aqueous solution (0.490 ml) and the mixture was stirred at room
temperature for 43 hours. The solution was neutrized with 2N
hydrochloric acid, which was extracted with ethyl acetate. The
extract was washed and dried, then the solvent was evaporated under
reduced pressure. The residue was purified with silica gel column
chromatography (ethyl acetate:n-hexane=1:4) and crystallized from
methyl alcohol/diisopropylether to give
1-[5-(4-fluorobenzyloxy)-2-h- ydroxyphenyl]-3-pyridine-2-yl
propenone (157 mg, yield 25%)
[2435] Melting point: 118.degree. C.
[2436] NMR(CDCl.sub.3).delta.:5.04(2H, s), 6.96-7.89(11H, m),
8.20(1H, d, J=15.3 Hz), 8.70-8.75(1H, m).
[2437] (C-12) To a suspension of the above-mentioned compound C-11
(155 mg, 0.44 mmol) in methyl alcohol (7.5 ml), were added 2N
sodium hydroxide aqueous solution (0.89 ml) and 30% hydrogen
peroxide solution (0.151 ml) and the mixture was stirred at room
temperature for 30 minutes. The solution was neutrized with 2N
hydrochloric acid, to which was added water and methyl alcohol. The
precipitated crystals were filtered off. The crude crystals were
washd with water, dried, and crystallized from methyl alcohol to
give 6-[(4-fluorobenzyl)oxy]-3-hydroxy(2-pyridine-2-yl)-
-4H-1-benzopyrane-4-one (31 mg, yield: 19%).
[2438] Melting point: 204-205.degree. C.
[2439] Elementary analysis as C.sub.19H.sub.18FNO.sub.4
[2440] Calcd. (%): C, 69.42; H, 3.88; N, 3.86; F, 5.23. Found (%):
C, 69.39; H, 3.81; N, 3.86; F, 5.01.
[2441] NMR(CDCl.sub.3).delta.:5.13(2H, s), 7.05-7.54(7H, m),
7.76(1H, d, J=3.0 Hz), 8.00 (1H, dd, J=1.5, 8.1 Hz), 8.11-8.17(1H,
m), 8.62-8.63(1H, m), 13.02(1H, brs).
[2442] Compound C-22
[2443]
5-[(4-fluorobenzyl)oxy]-3-hydroxy(2-pyridine-2-yl)-4H-1-benzopyrane-
-4-one 248249
[2444] (C-13) To a suspension of 2', 6'-dihydroxyacetophenone (5.0
g, 32.9 mmol) and powder potassium carbonate (10.0 g, 72.4 mmol) in
dimethylformamide (30 ml), was added iodomethane (7.1 ml, 114 mmol)
at room temperature and the mixture was stirred at the same
temperature overnight. To the solution was added 2N hydrochloric
acid (45 ml) and water (45 ml) and the precipitated crystals were
filtered off. The crude crystals were washed with water and dried,
then crystallized from ethyl acetate/n-hexane to give
1-(2,6-dimethoxyphenyl)etanone (4.2 g, yield: 71%)
[2445] Melting point: 69.degree. C.
[2446] NMR(CDCl.sub.3).delta.:2.48(3H, s), 3.81(6H, s), 6.55(2H, d,
J=8.1 Hz), 7.26(1H, t, J=8.1 Hz).
[2447] (C-14) To a solution of the above-mentioned compound C-13
(4.0 g, 22.2 mmol) in tetrahydrofuran (40 ml), was added
phenyltrimethylammoniumt- ribromide (8.34 g, 22.2 mmol) over 10
minutes at room temperature and the mixture was stirred at the same
temperature for 1 hour. Water was added thereto, and the mixture
was extracted with ethyl acetate, washed, and dried, then the
solvent was evaporated under reduced pressure. The residue was
purified with silica gel column chromatography (ethyl
acetate:n-hexane=1:4). After allowing to stand at room temperature,
the obtained solid residue was washed with diisopropylether to give
2-bromo-1-(2,6-dimethoxyphenyl)etanone (4.22 g, yield: 70%).
[2448] Melting point: 78-82.degree. C.
[2449] NMR(CDCl.sub.3).delta.: 3.82(6H, s), 4.38(2H, s), 6.57(2H,
d, J=8.4 Hz), 7.32(1H, t, J=8.4 Hz).
[2450] (C-15) A suspension of benzoic acid (1.13 g, 9.3 mmol) and
powder potassium carbonate (0.91 g, 6.56 mmol) in dimethylformamide
(30 ml) was stirred at 90.degree. C. for 1 hour and cooled to room
temperature. The above-mentioned compound C-14 (2.0 g, 7.7 mmol)
was added thereto and the mixture was stirred at 100.degree. C. for
30 minutes. To the solution cooled to room temperature, was added
water (120 ml), then the precipitated crystals were filtered off,
washed with water, and dried to give benzoic acid
2-(2,6-dimethoxyphenyl)-2-oxoethyl ester (2.0 g, yield: 86%)
[2451] NMR(CDCl.sub.3).delta.: 3.82(6H, s), 5.25(2H, s), 6.58(2H,
d, J=8.4 Hz), 7.33(1H, t, J=8.4 Hz), 7.41-7.61(3H, m),
8.06-8.12(2H, m).
[2452] (C-16) To a solution of the above-mentioned compound C-15
(1.5 g, 4.99 mmol) in methylene chloride (250 ml), was added
dropwise a tribromoborane-methylene chloride solution (1.0N, 4.99
ml, 4.99 mmol) at -78.degree. C. and the mixture was stirred at the
same temperature for 15 minutes. To the solution was added water,
which was extracted with ethyl acetate, washed, and dried. The
solvent was evaporated under reduced pressure. After allowing to
stand at room temperature, the obtained solid residue was washed
with diisopropylether to give benzoic acid
2-(2-hydroxy-6-methoxyphenyl)-2-oxoethyl ester(1.14 g, yield:
80%).
[2453] NMR(CDCl.sub.3).delta.: 3.97(3H, s), 5.51(2H, s), 6.43(1H,
d, J=8.1 Hz), 6.61(1H, dd, J=1.2, 8.4 Hz), 7.37-7.63(4H, m),
8.13-8.19(2H, m), 12.76(1H, s).
[2454] (C-17) To a solution of the above-mentioned compound C-18
(1.14 g, 3.98 mmol) in dimethylformamide (15 ml), were added
picolyl chloride hydrochloride (0.92 g, 5.18 mmol) and
triethylamine (1.36 ml, 9.75 mmol) under ice-cooling and the
mixture was stirred at room temperature for 30 minutes. Water was
added thereto, and the mixture was extracted with ethyl acetate,
washed, and dried, then the solvent was evaporated under reduced
pressure. The residue was purified with silica gel column
chromatography (ethyl acetate:n-hexane=1:2-1:1) to give
pyridine-2-carboxylic acid 2-(2-benzoyloxyacetyl)-3-methoxyphenyl
ester (1.17 g, yield: 75%)
[2455] NMR(CDCl.sub.3).delta.:3.90(3H, s), 5.34(2H, s), 6.90(1H, d,
J=8.4 Hz), 6.99(1H, d, J=7.5 Hz), 7.35-7.58(5H, m), 7.88(1H, dt,
J=1.8, 7.8 Hz), 7.95-8.01(2H, m), 8.26(1H, d, J=7.8 Hz),
8.80-8.85(1H, m).
[2456] (C-18) To a solution of the above-mentioned compound C-17
(805 mg, 2.06 mmol) in dimethylformamide (8 ml), was added 60%
sodium hydride (205 mg, 5.15 mmol) under ice-cooling and the
mixture was stirred at 55.degree. C. for 15 minutes. After cooling,
the solution was poured into 2N hydrochloric acid (2.6 ml) and ice
water, then the mixture was extracted with ethyl acetate. The
extract was washed and dried, then the solvent was evaporated under
reduced pressure. The residue was dissolved into acetic acid (6
ml), to which was added sulfuric acid(0.16 ml)and the mixture was
stirred at 60.degree. C. for 2 hours. After cooling, the solution
was poured into ice water, which was neutrized with a saturated
sodium hydrogen carbonate aqueous solution. The mixture was
extracted with ethyl acetate and chloroform, washed, and dried. The
residue was purified with silica gel column chromatography
(chloroform:methyl alcohol=20:1) to give
3-hydroxy-5-methoxy-2-pyridine-2-ylchromene-4-one (234 mg, yield:
42%)
[2457] NMR(CDCl.sub.3).delta.:4.02(3H, s), 6.77(1H, d, J=8.1 Hz),
7.11(1H, d, J=8.1 Hz), 7.40(1H, ddd, J=1.2, 5.1, 7.5 Hz), 7.56(1H,
t, J=8.1 Hz), 7.97(1H, dt, J=1.8, 8.1 Hz), 8.07-8.12(1H, m),
8.61-8.66(1H, m), 12.48(1H, brs).
[2458] (C-19) To a suspension of the above-mentioned compound C-18
(234 mg, 0.87 mmol) and powder potassium carbonate (240 mg, 1.74
mmol) in dimethylformamide (7 ml), was added chlorobenzoyl (0.20
ml, 1.74 mmol) at room temperature and the mixture was stirred at
115.degree. C. for 10 minutes. To the solution cooled to room
temperature, was added water, and the mixture was extracted ethyl
acetate. The extract was washed and dried, then the solvent was
evaporated under reduced pressure. The residue was purified with
silica gel column chromatography (chloroform:methyl alcohol=20:1)
to give benzoic acid
5-methoxy-4-oxo-2-pyridine-2-yl-4H-chromene-3-yl ester (213 mg,
yield: 66%)
[2459] NMR(CDCl.sub.3).delta.: 3.98(3H, s), 6.84(1H, d, J=7.8 Hz),
7.21(1H, dd, J=0.9, 8.4 Hz), 7.33-7.67(5H, m), 7.80(1H, dt, J=1.8,
7.8 Hz), 7.91-7.96(1H, m), 8.17-8.23(1H, m), 8.69-8.73(1H, m).
[2460] (C-20) To a solution of the above-mentioned compound C-19
(213 mg, 0.57 mmol) in methylene chloride (10 ml), was added
dropwise a solution of boron tribromide in methylene chloride
(1.0N, 0.685 ml, 0.685 mmol) at -78.degree. C. and the mixture was
stirred at the same temperature for 10 minutes. Water was added
thereto and the mixture was extracted with ethyl acetate, washed,
and dried. The solvent was evaporated under reduced pressure and
the residue was purified with silica gel column chromatography
(ethyl acetate:n-hexane=1:1) to give benzoic acid
5-hydroxy-4-oxo-2-pyridine-2-yl-4H-chromene-3-yl ester (66 mg,
yield: 32%)
[2461] NMR(CDCl.sub.3).delta.: 6.87(1H, d, J=8.4 Hz), 7.10(1H, d,
J=8.7 Hz), 7.35-7.70(5H, m), 7.84(1H, dt, J=1.8, 7.8 Hz), 7.98(1H,
d, J=8.1 Hz), 8.18-8.24(1H, m), 8.61-8.66(1H, m), 12.04(1H, s).
[2462] (C-21) To a suspension of the above-mentioned compound C-20
(91 mg, 0.25 mmol) and powder potassium carbonate (53 mg, 0.38
mmol) in dimethylformamide (2 ml), was added 4-fluorobenzylbromide
(40,ul, 0.32 mmol) at room temperature and the mixture was stirred
for 3 hours. Water was added thereto and and the mixture was
extracted with ethyl acetate, washed, and dried. The solvent was
evaporated under reduced pressure and the residue was purified with
silica gel column chromatography (ethyl acetate:n-hexane=1:1-1:2)
to give benzoic acid 5-(4-fluorobenzyloxy)-4-ox-
o-2-pyridine-2-yl-4H-chromene-3-yl ester (108 mg)
[2463] (C-22) To a suspension of the above-mentioned compound C-21
(105 mg, 0.23 mmol) in ethanol (5 ml), was added 2N sodium
hydroxide aqueous solution (0.124 ml) at 60.degree. C. and the
mixture was stirred for 25 minutes. After cooling, the reaction
mixture was neutrized with 2N hydrochloric acid. The precipitated
crystals were filtered off, washed with water and ethanol and
dried. The crude crystals were crystallized from methyl alcohol to
give 5-[(4-fluorobenzyl)oxy]-3-hydroxy(2-pyridine--
2-yl)-4H-1-benzopyrane-4-one (30 mg, yield 33%)
[2464] Melting point: 213.degree. C.
[2465] Elementary analysis as C.sub.21H.sub.14FNO.sub.4
0.1H.sub.2O
[2466] Calcd. (%): C, 69.08; H, 3.92; N, 3.84; F, 5.20 Found (%):
C, 68.98; H, 3.81; N, 3.85; F, 5.01.
[2467] NMR(CDCl.sub.3).delta.: 5.24(1H, s), 6.82(1H, d, J=8.1 Hz),
7.06-7.17(3H, m), 7.38-7.44(1H, m), 7.55(1H, t, J=8.1 Hz),
7.70-7.78(2H, m),7.98(1H, dt, J=1.8, 8.1 Hz), 8.10(1H, d, J=8.1
Hz), 8.6-2-8.67(1H, m), 12.79(1H, brs).
[2468] Compound C-26
[2469]
2-[5-(4-fluorobenzyl)-[1,3,4]-oxadiazole-2-yl]-3-hydroxy-4H-1-benzo-
pyrane-4-one 250
[2470] (C-23) To a solution of compound C-4 (1.73 g, 5.34 mmol) in
methyl alcohol (16 ml),was added a 2N sodium hydroxide aqueous
solution (3 ml) and the mixture was stirred at room temperature for
1 hour. The solution was neutrized with 2N hydrochloric acid, to
which was added water, and the mixture was extracted with ethyl
acetate. The extract was washed and dried, then the solvent was
evaporated under reduced pressure to give crude
3-benzyloxybenzyloxy-4-oxo-4H-chromene-2-carboxylic acid (48
mg)
[2471] (C-24) To a solution of the above-mentioned compound C-23(48
mg) in diglyme (1 ml), were added oxalylchloride(14 .mu.l, 0.16
mmol)and dimethylformamide(2 .mu.l) under ice-cooling. The mixture
was cooled to room temperature with stirring for 30 minutes to give
a crude 3-benzyloxy-4-oxo-4H-chromene-2-carboxylic acid chloride
solution.
[2472] (C-25) To the above-mentioned solution of (C-24), were added
a tetrazole (25 mg, 0.14 mmol)mentioned below and pyridine(47,ul,
0.58 mmol) and the mixture was stirred at room temperature for 30
minutes and at 130.degree. C. for 15 minutes. After cooling, water
was added thereto, then the precipitated crystals were filtered
off, washed with water, and dried to give
3-benzyloxy-2-[5-(4-fluorobenzyl)-[1,3,4]-oxadiazole-2-yl]c-
hromene-4-one(37 mg, yield:62%).
[2473] NMR(CDCl.sub.3).delta.: 4.23(2H, s), 5.36(2H, s),
6.98-7.78(12H, m), 8.25-8.30(1H, m).
[2474] (C-26) To a solution of compound C-25(34 mg, 0.079 mmol)in
ethanol (2 ml) and tetrahydrofuran(4 ml), was added 10%
palladium-carbon(8 mg) and the mixture was stirred under hydrogen
atmosphere at room temperature for 10 minutes. After removing the
palladium-carbon by filtration, the solution was evaporated under
reduced pressure. The residue was crystallized from methyl alcohol
to give 2-[5-(4-fluorobenzyl)-[1,3,4]-ox-
adiazole-2-yl]-3-hydroxy-4H-1-benzopyrane-4-one (19 mg, yield:
70%).
[2475] Melting point:221.degree. C.
[2476] Elementary analysis as C.sub.18H.sub.11FN.sub.2O.sub.4
[2477] Calcd. (%): C, 63.91; H, 3.28; N, 8.28; F, 5.62. Found (%):
C, 63.84; H, 3.23; N, 8.18; F, 5.48.
[2478] NMR(CDCl.sub.3).delta.: 4.36(2H, s), 7.04-7.13(2H, m),
7.34-7.60(5H, m), 8.13(1H, brs), 8.29(1H, dd, J=1.2, 7.8 Hz).
[2479] (C-27) To a solution of 4-fluorobenzylcyanide(7.5 g, 55.5
mmol)in dimethylformamide(75 ml), were added ammonium chloride(5.9
g, 111.0 mmol) and sodium azide(7.2 g, 111.0 mmol)at room
temperature and the mixture was stirred at 130.degree. C. for 3
hours. The mixture was cooled to room temperature and water was
added thereto, followed by extraction with ethyl acetate. The
extract was washed and dried, and then the solvent was evaporated
under reduced pressure. The residue was washed with
diisopropylether/n-hexane and dried to give
5-(4-fluorobenzyl)-2H-tetrazo- le (5.45 g, yield:55%).
[2480] Melting point: 158-159.degree. C.
[2481] NMR(CDCl.sub.3).delta.:4.29(2H, s), 7.13-7.36(4H, m).
[2482] Compound C-31a and C-31b
[2483]
6-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(1H-[1,2,4]triazole-3-yl)-4H-1--
benzopyrane-4-one and
6-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(1-methyl-1H-imi-
dazole-2-yl)-4H-1-benzopyrane-4-one 251
[2484] (C-28) To a suspension of 60% sodium hydride(0.45 g, 11.3
mmol)in dimethylformamide(25 ml), was added dropwise a solution of
C-10(2.64 g, 10.2 mmol) in dimethylformamide(25 ml) under
ice-cooling and the mixture was stirred at the same temperature for
20 minutes. Chloromethyl methyl ether(0.93 ml, 12.3 mmol)was added
dropwise thereto and the mixture was stirred for 5 minutes, and
further 25 minutes while warming to room temperature. Water was
added thereto and the mixture was extracted with ethyl acetate,
washed, and dried. The solvent was evaporated under reduced
pressure and the residue was purified with silica gel column
chromatography(ethyl acetate:n-hexane=1:5-1:3)to give
1-[5-(4-fluorobenzyloxy)-2-methoxymethoxyphenyl] etanone(2.93 g,
yield: 95%).
[2485] NMR(CDCl.sub.3).delta.: 2.65(311, s), 3.51(3H, s), 5.01(2H,
s), 5.22(2H, s), 7.03-7.16(4H, m), 7.33-7.42(3H, m).
[2486] (C-29a) To a solution of the above-mentioned compound
C-28(304 mg, 11.0 mmol) and 1H-[1,2,4]triazole-2-aldehyde(145 mg,
1.5 mmol)in dioxane(4 ml)and 99% ethanol(6 ml), was added a 1N
sodium hydroxide aqueous solution(2 ml)and the mixture was refluxed
for 3 hours 20 minutes. An ammonium chloride aqueous solution was
added thereto and the mixture was extracted with ethyl acetate,
washed, and dried. The solvent was evaporated under reduced
pressure and the residue was purified with silica gel column
chromatography(methyl alcohol:chloroform=3:97). Crystallization
from ethyl acetate and diusopropylether gave
1-[5-(4-fluorobenzyloxy)-2-methoxymethoxyphenyl]-3-(1H-[1,2,4]triazole-3--
yl)propenone (260 mg, yield: 68%).
[2487] Melting point:114-116.degree. C.
[2488] NMR(CDCl.sub.3).delta.:3.47(3H, s), 5.01(2H, s), 5.19(2H,
s), 7.02-7.27(5H, m), 7.37-7.43(2H, m), 7.61(1H, d, J=15.6 Hz),
7.88(1H, d, J=15.6 Hz), 8.32(1H, br.s).
[2489] (C-29b) Using the above-mentioned compound C-28 (304 mg, 1.0
mmol) and 1-methyl-2-imidazole-2-aldehyde(166 mg, 1.5 mmol),
according to the method of C-29a, crude
1-[5-(4-fluorobenzyloxy)-2-methoxymethoxyphenyl]-3-
-(1-methyl-1H-imidazole-2-yl)propenone(434 mg)was obtained, which
was used in the next reaction without purification.
[2490] (C-30a) To a solution of the above-mentioned compound
C-29a(202 mg, 0.527 mmol)in methyl alcohol(6 ml), was added 2N
hydrochloric acid(1.5 ml) and the mixture was stirred at 50.degree.
C. for 3 hours 20 minute. A sodium hydrogen carbonate aqueous
solution was added thereto and the mixture was extracted with ethyl
acetate, washed and dried. The solvent was evaporated under reduced
pressure to give crude crystals of
1-[5-(4-fluorobenzyloxy)-2-hydroxyphenyl]-3-(1H-[1,2,4]triazole-3-yl)prop-
enone (183 mg).
[2491] (C-30b) Using the above-mentioned compound C-29b (434 mg),
according to the method of C-30a, crude crystals of
1-[5-(4-fluorobenzyloxy)-2-hydroxyphenyl]-3-(1-methyl-1H-imidazole-2-yl)p-
ropenone(355 mg) was obtained, which was used in the next reaction
without purification.
[2492] (C-31a) To a suspension of the above-mentioned compound
C-30a(180 mg, 0.53 mmol)in methyl alcohol(8 ml), were added a 2N
sodium hydroxide aqueous solution(1.06 ml)and 30% hydrogen peroxide
solution(0.18 ml)and the mixture were stirred at room temperature
for 1 hour. A 2N hydrochloric acid(1.06 ml)was added thereto and
the mixture was stirred for 2 hours 20 minutes. The precipitated
crystals were filtered off and washed with water to give crude
crystals(121 mg). Recrystallization from dimethylformamide/water
gave 6-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(1H-[1,2-
,4]triazole-3-yl)-4H-1-benzopyrane-4-one(110 mg yield:59%).
[2493] Melting point:277.degree. C. (comp.)
[2494] Elementary analysis as C.sub.18H.sub.12FN.sub.3O.sub.4
0.4H.sub.2O
[2495] Calcd. (%): C, 59.97; H, 3.58; N, 11.66; F, 5.27. Found (%):
C, 59.91; H, 3.63; N, 11.60; F, 5.13.
[2496] NMR(DMSO-d.sub.6).delta.:5.23(2H, s), 7.22-7.28(2H, m),
7.48-7.59(5H, m), 7.69(1H, d, J=9.3 Hz), 8.79(1H, br.s).
[2497] (C-31b) Using the above-mentioned compound C-30b(355 mg),
according to C-31a,
6-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(1-methyl-1H-imidazole-2-yl-
)-4H-1-benzopyrane-4-one(169 mg, total yield of 3
processes:47%).
[2498] Melting point:239-242.degree. C. (methylene chloride/methyl
alcohol).
[2499] Elementary analysis as C.sub.20H.sub.15FN.sub.2O.sub.4
[2500] Calcd. (%): C, 65.57; H, 4.13; N, 7.65; F, 5.19. Found (%):
C, 65.64; H, 4.08; N, 7.65; F, 5.09.
[2501] NMR(CDCl.sub.3).delta.:4.16(3H, s), 5.11(2H, s), 7.04(1H, d,
J=0.9 Hz), 7.06-7.12(2H, m), 7.21(1H, d, J=0.9 Hz), 7.31(1H, dd,
J=3.0, 9.3 Hz), 7.39-7.46(3H, m), 7.75(1H, d, J=3.0 Hz).
[2502] Compound C-35 and C-36
[2503]
6-[(4-fluorobenzyl)oxy]-3-hydroxy-4H-1-benzopyrane-4-one-2-carboxyl-
ate ethyl ester and
6-[(4-fluorobenzyl)oxy]-3-hydroxy-4H-1-benzopyrane-4-o-
ne-2-carboxylic acid 252
[2504] (C-32) To a solution of bromo hydroquinon (10.0 g, 52.9
mmol) in DMF(50 ml), was added 60% sodium hydride (4.44 g, 111.1
mmol) under ice-cooling and the mixture was stirred at room
temperature for 30 minutes. Chloromethyl methyl ether(8.44 ml,
111.1 mmol) was added dropwise thereto under ice-cooling and the
mixture was stirred at room temperature for 30 minutes. Water and
2N hydrochloric acid were added thereto and the mixture was
extracted with ethyl acetate. The extract was washed with water and
saturated brine, washed, and dried. The solvent was evaporated
under reduced pressure and the residue was purified with column
chromatography(ethyl acetate:n-hexane=1:19-1:9)to give
2-bromo-1,4-bismethoxymethylbenzene(11.4 g, yield:83%).
[2505] NMR(CDCl.sub.3).delta.: 3.47(3H, s), 3.52(3H, s), 5.10(2H,
s), 5.17(2H, s), 6.93(1H, dd, J=2.7, 9.0 Hz), 7.07(1H, d, J=9.0
Hz), 7.27(1H, d, J=2.7 Hz).
[2506] (C-33) To a solution of the above-mentioned compound
C-32(2.0 g, 7.22 mmol)in tetrahydrofuran(40 ml), was added dropwise
a n-butyl lithium-hexane solution(1.55N, 4.7 ml, 7.22 mmol)at
-78.degree. C. and the mixture was stirred at the same temperature
for 15 minutes. A zincchloride-tetrahydrofuran solution(I.3N, 5.6
ml, 7.22 mmol)was added dropwise and the mixture was stirred for 30
minutes. To the solution were added chloro(benzyloxy)acetyl(1.25
ml, 7.94 mmol)and tetrakistriphenylphosphine palladium (0.83 g,
0.72 mmol) and the mixture was stirred for 1.5 hours under cooling
to room temperature. Water and 2N hydrochloric acid were added
thereto and the mixture was extracted with ethyl acetate, water and
a sodium hydrogen carbonate aqueous solution, After washing with
saturated brine, the mixture was dried and evaporated under reduced
pressure. The residue was purified with column chromatography(ethyl
acetate:n-hexane=1:9-1:3) to give a crude ketone(845 mg), which was
dissolved into methyl alcohol 10 ml and 2N hydrochloric acid 3.0 ml
was added thereto. The mixture was stirred at 60.degree. C. for 2
hours 30 minutes. After allowing to stand for cooling, water was
added thereto, then the precipitated crystals were filtered off,
washed with water, and dried to give
2-benzyloxyl-(2,5-dihydroxyphenyl)etanone(3- 76 mg, yield:20%).
[2507] NMR(CDCl.sub.3).delta.: 4.69(2H, s), 4.71(2H, s), 6.88-7.42
(8H, m), 11.5(1H,s).
[2508] (C-34) To a solution of the above-mentioned compound C-33
(370 mg, 1.43 mmol) in pyridine(6 ml), was added ethyl
chloroglyoxylacetate (0.57 ml, 5.10 mmol) under ice-cooling and the
mixture was stirred for 1 hour under cooling to room temperature
and further stirred for 1 hour 30 minutes at 100.degree. C. After
cooling, water and 2N hydrochloric acid were added thereto and the
mixture was extracted with ethyl acetate. The extract was washed
with water, a sodium hydrogen carbonateaqueous solution, and
saturated brine, and dried. The solvent was evaporated under
reduced pressure and the residue was purified with column
chromatography(ethyl acetate:n-hexane=1:2)to give
3,6-dihydroxy-4H-1-benz- opyrane-4-one-2-carboxylate ethyl
ester(109 mg, yield:22%).
[2509] NMR(CDCl.sub.3).delta.:1.36(3H, t, J=6.9 Hz), 4.40(2H, q,
J=6.9 Hz), 5.25(2H, s), 7.18(1H, brs), 7.30-7.76(7H, m), 7.83(1H,
d, J=3.0 Hz).
[2510] (C-35) To a solution of the above-mentioned compound
C-34(120 mg, 0.35 mmol) in methyl alcohol(6 ml) and
tetrahydrofuran(2 ml), was added 10% palladium-carbon (15 mg)under
1 atm hydrogen atomospher. The mixture was stirred at room
temperature for 1 hour and filtered, then the solvent was
evaporated under reduced pressure to give a residue(93 mg). The
residue(33 mg)was dissolved in DMF 1 ml, and 60% sodium hydride(12
mg, 0.30 mmol) was added thereto under ice-cooling. The mixture was
stirred at room temperature for 30 minutes and at 50.degree. C. for
30 minutes, then 4-fluorobenzylbromide (12 .mu.l, 96.3 .mu.mol)was
added dropwise under ice-cooling.
[2511] The mixture was stirred at room temperature for 1 hour 30
minutes, then water and 2N hydrochloric acid were added thereto.
The precipitated crystals were filtered off, washed with water, and
dried. The crude crystals were recrystallized from
chloroform/methyl alcohol to give
6-[(4-fluorobenzyl)oxy]-3-hydroxy-4H-1-benzopyrane-4-one-2-carboxylate
ethyl ester(33 mg, yield:70%).
[2512] NMR(CDCl.sub.3).delta.: 1.49(3H, t, J=7.2 Hz), 4.54(2H, q,
J=7.2 Hz), 5.11(2H, s), 7.06-7.13(2H, m), 7.37-7.53(4H, m),
7.66(1H, d, J=3.0 Hz), 9.43(1H, s).
[2513] Melting point: 190-192.degree. C.
[2514] Elementary analysis as C.sub.19H.sub.15FO.sub.6
0.1H.sub.2O
[2515] Calcd. (%): C, 63.37; H, 4.25; F, 5.28. Found (%): C, 63.31;
H, 4.18; F, 5.43.
[2516] (C-36) To a solution of the above-mentioned compound C-35(31
mg, 86.5 .mu.mol)in DMSO(1.5 ml), was added a 2N sodium hydroxide
aqueous solution 108 .mu.l and the mixture was stirred at room
temperature for 1 hour. 2N hydrochloric acid and water were added
thereto and the precipitated crystals were filtered off, washed
with water, and dried. The crude crystals were recrystallized from
diisopropylether and methyl alcohol to give
6-[(4-fluorobenzyl)oxy]-3-hydroxy-4H-1-benzopyrane-4-one--
2-carboxylic acid(18 mg, yield:62%).
[2517] NMR(DMSO-d.sub.6).delta.:5.21(2H, s), 7.21-7.67(7H, m).
[2518] Melting point:219-220.degree. C.
[2519] Elementary analysis as Cl.sub.9H.sub.15FO.sub.6
1.3H.sub.2O
[2520] Calcd. (%): C, 57.73; H, 3.88; F, 5.37. Found (%): C, 57.75;
H, 3.90; F, 5.11.
[2521] Compound C-39
[2522]
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3--
yl)-4H-1-benzopyrane-4-one 253
[2523] (C-37) To a suspension of 2',6'-dihydroxyacetophenone(5.0 g,
32.9 mmol)and powder potassium carbonate (9.1 g, 65.7 mmol)in
DMF(30 ml), was added 4-fluorobenzyl bromide(4.1 ml, 32.9
mmol)under ice-cooling and the mixture was stirred at room
temperature for 4 hour. Water 30 ml and 2N hydrochloric acid 60 ml
were added thereto and the precipitated crystals were filtered off,
washed with water, methyl alcohol, and diisopropylether, and dried
to give 1-[2-(4-fluorobenzyloxy)-6-hydroxyphe- nyl]etanone(5.52 g,
yield:65%).
[2524] NMR(CDCl.sub.3).delta.: 2.59(3H, s), 5.09(2H, s), 6.45(1H,
d, J=8.4 Hz), 6.60(1H, d, J=8.4 Hz), 7.07-7.45(5H, m), 13.24(1H,
s).
[2525] (C-38) To a solution of the above-mentioned compound
C-37(1.0 g, 3.84 mmol)and 2-methyl 2H-[1,2,4]triazole-3-carboxylate
ethyl ester (J. Am. Chem. Soc., 1972, 94, p5894, Heterocycles,
1990, 31, p1629)(1.2 g, 7.68 mmol) in DMF(20 ml), was added
potassium tert-butoxide(1.72 mg, 15.4 mmol)under ice-cooling and
the mixture was stirred at room temperature for 20 minutes. After
ice-cooling the mixture, 2N hydrochloric acid 7.5 ml and water 33
ml were added thereto and the precipitated crystals were filtered
off, washed with water, and dried. The obtained crystals were
suspended to a mixture of tetrahydrofuran(15 ml)and methyl
alcohol(6 ml), then a solution of concentrated hydrochloric acid
1.3 ml in methyl alcohol(15 ml) was added thereto at room
temperature and the mixture was stirred at 60.degree. C. for 40
minutes. After allowing to stand the mixture for cooling, 2N sodium
hydroxide 7.7 ml and water 125 ml were added thereto, then the
precipitated crystals were filtered off, washed with water, and
dried to give 5-[(4-fluorobenzyl)oxy]-2-(2-methyl-2H-[1,2-
,4]triazole-3-yl)-4H-1-benzopyrane-4-one(1.16 g yield:86%).
[2526] NMR(CDCl.sub.3).delta.: 4.29(3H, s), 5.25(2H, s), 6.92(1H,
d, J=8.11 Hz), 7.04(1H, s), 7.07-7.14(2H, m), 7.56-7.65(5H, m),
7.99(1H, s).
[2527] According to the method mentioned above, the following
compounds were prepared.
[2528] (C-38a)
5-[(4-fluorobenzyl)oxy]-2-(1-methyl-11H-[1,2,4]triazole-3-y-
l)-4H-1-benzopyrane-4-one
[2529] NMR(DMSO-d.sub.6).delta.: 4.00(3H, s), 5.25(2H, s), 6.75(1H,
s), 7.12(1H, d, J=8.1 Hz), 7.21-7.29(3H, m), 7.65-7.76(3H, m),
8.72(1H, s).
[2530] (C-38b)
5-[(4-fluorobenzyl)oxy]-2-(5-methyl-1H-[1,2,4]triazole-3-yl-
)-4H-1-benzopyrane-4-one
[2531] NMR(DMSO-d.sub.6).delta.: 2.45(3H, s), 5.25(2H, s), 6.72(1H,
s), 7.11(1H, d, J=8.1 Hz), 7.21-7.29(3H, m), 7.65-7.76(3H, m).
[2532] (C-38c)
5-[(4-fluorobenzyl)oxy]-2-(1H-[1,2,4]triazole-3-yl)-4H-1-be-
nzopyrane-4-one
[2533] NMR(DMSO-d.sub.6).delta.: 5.26(2H, s), 6.79(1H, s), 7.12(1H,
d, J=8.4 Hz), 7.21-7.29(3H, m), 7.66-7.77(3H, m), 8.78(1H, s).
[2534] (C-38d)
5-[(4-fluorobenzyl)oxy]-2-(pyrimidine-2-yl)-4H-1-benzopyran-
e-4-one
[2535] NMR(CDCl.sub.3).delta.: 5.25(2H, s), 6.89(1H, s), 7.12(1H,
d, J=8.4 Hz), 7.07-7.14(2H, m), 7.31-7.43(3H, m), 7.51(1H, s),
7.56-7.66(3H, m), 8.95(2H, d, J=4.8 Hz).
[2536] (C-39) To a solution of the above-mentioned compound
C-38(500 mg, 1.42 mmol)in methylene chloride(25 ml), was added,
under ice-cooling, an acetone solution containing dimethyldioxylane
(0.076N, 18.7 ml, 1.42 mmol) prepared by the method mentioned in
Chem. Ber., 1991, 124, p2377) and the mixture was stirred at room
temperature for 28 hours. The solvent was evaporated under reduced
pressure and the residue was dissolved in methylene chloride 25 ml,
and p-toluenesulfonic acid 1 hydrate (325 mg, 1.87 mmol)was added
thereto under ice-cooling and the mixture was stirred at room
temperature for 1 hour. The solvent was evaporated under reduced
pressure and the residue was suspended in methyl alcohol 25 ml, to
which were added 2N sodium hydroxide 0.8 ml, saturated sodium
hydrogen carbonate aqueous solution 4.0 ml, and water 20 ml under
ice-cooling. The precipitated crystals were filtered off, washed
with water, and dried to give
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3-y-
l)-4H-1-benzopyrane-4-one(280 mg, yield:54%).
[2537] NMR(CDCl.sub.3).delta.: 3.97(3H, s), 5.29(2H, s), 7.10(1H,
d, J=8.1 Hz), 7.20-7.30(3H, m), 7.70-7.77(5H, m), 8.21(1H, s),
10.12(1H, brs).
[2538] Melting point:215-216.degree. C.
[2539] The following compounds were prepared according to the
method mentioned above.
[2540] (C-39a)
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(1-methyl-1H-[1,2,4]tri-
azole-3-yl)-4H-1-benzopyrane-4-one
[2541] NMR(DMSO-d.sub.6).delta.: 4.01(3H, s), 5.27(2H, s), 7.06(1H,
d, J=8.1 Hz), 7.17-7.30(3H, m), 7.66-7.77(3H, m), 8.78(1H, s),
9.56(1H, brs).
[2542] Melting point:264-266.degree. C.
[2543] (C-39b)
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(5-methyl-1H-[1,2,4]tri-
azole-3-yl)-4H-1-benzopyrane-4-one
[2544] NMR(DMSO-d.sub.6).delta.: 2.47(3H, s), 5.27(2H, s), 7.05(1H,
d, J=8.4 Hz), 7.17-7.30(3H, m), 7.66-7.77(3H, m).
[2545] Melting point:289-292.degree. C.
[2546] (C-39c)
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(1H-[1,2,4]triazole-3-y-
l)-4H-1-benzopyran-4-one
[2547] NMR(DMSO-d.sub.6).delta.: 5.28(2H, s), 7.07(1H, d, J=7.8
Hz), 7.20-7.30(3H, m), 7.68-7.78(3H, m), 8.66(1H, brs).
[2548] Melting point:254-256.degree. C.
[2549] (C-39d)
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(pyrimidine-2-yl)-4H-1--
benzopyrane-4-one
[2550] NMR(CDCl.sub.3).delta.:5.28(2H, s), 7.05(1H, d, J=8.1 Hz),
7.22-7.31(3H, m), 7.65-7.80(4H, m), 9.10(2H, d, J=5.7 Hz),
11.96(1H, brs).
[2551] Melting point:252-254.degree. C.
[2552] Compound C-41
[2553]
3-hydroxy-2-(5-phenoxypyrimidine-2-yl)-4H-1-benzopyrane-4-one
254
[2554] (C-40) According to the method of compound C-38,
2'-hydroxyacetophenone (150 mg, 1.10 mmol)and
5-phenoxypyrimidine-2-carbo- xylic acid(380 mg, 1.65 mmol)were
subjected to cyclization reaction to give
2-(5-phenoxypyrimidine-2-yl)-4H-1-benzopyrane-4-one(296 mg,
yield:85%).
[2555] NMR(CDCl.sub.3).delta.: 7.12-7.75(9H, m), 8.24-8.28(1H, m),
8.63(2H, s).
[2556] (C-41) According to the method of compound C-39, the
above-mentioned compound C-40(150 mg, 0.42 mmol) was oxidized with
dimethyldioxylane to give
3-hydroxy-2-(5-phenoxypyrimidine-2-yl)-4H-1-ben- zopyrane-4-one(32
mg, yield:20%).
[2557] NMR(CDCl.sub.3).delta.: 7.14-7.72(8H, m), 8.31-8.35(1H, m),
8.68(2H, s), 11.63(1H, s).
[2558] Melting point:212.degree. C.
[2559] Compound C-48
[2560]
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3--
yl)-4H-1-benzopyrane-4-one-7-carboxylic Acid Dimethylamide
255256
[2561] (C-42) To a suspension of
2',4',6'-trihydroxyacetophenone(18.6 g, 100 mmol)and powder
potassium carbonate(20.7 g, 150 mmol)in DMF(140 ml), was added
4-fluorobenzyl bromide(13.7 ml, 110 mmol) under ice-cooling and the
mixture was stirred at room temperature for 1 hour 15 minutes.
Water and 2N hydrochloric acid were added tereto and the mixture
was extracted with ethyl acetate. The extract was washed with water
and saturated brine, and dried, then the solvent was evaporated
under reduced pressure. The residue was purified with column
chromatography(ethyl acetate:n-hexane=1:3-1:2) to give crude
crystals, which were washed with diisopropylether to give
1-[2-(4-fluorobenzyloxy)-4,6-dihydroxyphenyl]eta- none(2.62 g,
yield:10%).
[2562] NMR(CDCl.sub.3).delta.: 2.45(3H, s), 5.13(2H, s), 5.88(1H,
d, J=1.5 Hz), 6.07(1H, d, J=1.5 Hz), 7.21-7.28(2H, m),
7.54-7.61(2H, m), 10.59(1H, brs), 13.81(1H, s).
[2563] (C-43) According to the method of compound C-38, the
above-mentioned compound C-42(2.05 g, 7.42 mmol)and
2-methyl-2H-[1,2,4]triazole-3-carboxylate ethyl ester(2.30 g, 14.8
mmol)were subjected to cyclization reaction to give
5-[(4-fluorobenzyl)oxy]-7-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H-
-1-benzopyrane-4-one(0.90 g, yield:33%).
[2564] NMR(DMSO-d.sub.6).delta.: 4.21(3H, s), 5.19(2H, s),
6.52-6.67(3H, m), 7.21-7.29(2H, m), 7.63-7.70(2H, m), 8.14(1H, s),
11.1(1H, brs).
[2565] (C-44) To a suspension of the above-mentioned compound
C-43(0.90 g, 2.45 mmol)and triethylamine(1.02 ml, 7.35 mmol) in
methylene chloride(140 ml), was added anhydrous
trifluoromethanesulfonic acid(0.62 ml, 3.68 mmol)under ice-cooling
and the mixture was stirred for 40 minutes. Ice water was added
thereto and the mixture was extracted with ethyl acetate. The
extract was washed with water and saturated brine, and dried, then
the solvent was evaporated under reduced pressure. The residue was
purified with column chromatography (ethyl
acetate:n-hexane=1:1-2:1) to give trifluoromethanesulfonic acid
5-[(4-fluorobenzyl)oxy]-2-(2-methyl-2H-
-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one-7-yl ester(1.13 g,
yield:93%).
[2566] NMR(CDCl.sub.3).delta.: 4.28(3H, s), 5.26(2H, s), 6.81(1H,
d, J=2.4 Hz), 7.05-7.16(4H, m), 7.56-7.62(2H, m), 8.01(1H, s).
[2567] (C-45) To a suspension of the above-mentioned compound
C-44(1.06 g, 2.12 mmol), acetic acid palladium(II)(48 mg, 0.21
mmol) and 1,3-bis(diphenylphosphino)propane(109 mg, 0.27 mmol)in
DMSO (30 ml), were added at room temperature triethylamine(3.0 ml,
15.1 mmol), and methyl alcohol(10 ml) successively, and the mixture
was stirred under added 1 atm CO atomospher at 70.degree. C. for 55
minutes. After cooling, 2N hydrochloric acid 10 ml and water 70 ml
were added thereto, and the precipitated crystals were filtered
off, washed with water, and dried. The crude crystals were
recrystallized from ethyl acetate/methyl alcohol to give
5-[(4-fluorobenzyl)oxy]-2-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H-1-
-benzopyrane-4-one-7-carboxylate methyl ester(486 mg,
yield:56%).
[2568] NMR(CDCl.sub.3).delta.: 4.00(3H, s), 4.32(3H, s), 5.30(2H,
s), 7.08-7.15(2H, m), 7.10(1H, s), 7.56(1H, d, J=1.5 Hz),
7.61-7.67(2H, m), 7.77(1H, d, J=1.5 Hz), 8.00(1H, s).
[2569] (C-46) To a solution of the above-mentioned compound
C-45(325 mg, 0.79 mmol) in DMSO(16 ml), was added 2N sodium
hydroxide aqueous solution 437 .mu.l and the mixture was stirred at
room temperature for 2 hours. To the solution were added 2N
hydrochloric acid and water, then the precipitated crystals were
filtered, washed with water, and dried to give
5-[(4-fluorobenzyl)oxy]-2-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H-1-benzopy-
rane-4-one-7-carboxylic acid(300 mg, yield:86%).
[2570] NMR(DMSO-d.sub.6).delta.: 4.29(3H, s), 5.35(2H, s), 6.86(1H,
d, J=1.2 Hz), 7.23-7.31(2H, m), 7.57(1H, s), 7.68-7.77(2H, m),
7.83(1H, s), 8.18(1H, d, J=1.2 Hz).
[2571] (C-47) To a solution of the above-mentioned compound
C-46(140 mg, 0.35 mmol)in DMF(7 ml), were added at room temperature
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg,
0.40 mmol) and 1-hydroxybenzotriazole (55 mg, 0.35 mmol) and the
mixture was stirred for 10 minutes. A 2N dimethylamine THF solution
(195 .mu.l, 0.40 mmol) was added thereto, and the mixture was
stirred for 40 minutes. To the solution were added 2N hydrochloric
acid and ice water, and the mixture was extracted with ethyl
acetate. The extract was washed with water and saturated brine and
dried, then the solvent was evaporated under reduced pressure. The
residue was purified with column chromatography(chloroform:methyl
alcohol=50:1-20:1)to give
5-[(4-fluorobenzyl)oxy]-2-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H-1-benzopy-
rane-4-one-7-carboxylic acid dimethylamide(104 mg, yield:90%).
[2572] NMR(CDCl.sub.3).delta.:2.93(3H, s), 3.14(3H, s), 4.28(3H,
s), 5.27(2H, s), 6.91(1H, d, J=1.5 Hz), 7.06(1H, s), 7.07-7.14(2H,
m), 7.15(1H, d, J=1.5 Hz), 7.57-7.63(2H, m), 8.00(1H, s).
[2573] (C-48) According to the method of compound C-39, the
above-mentioned compound C-47(103 mg, 0.24 mmol) was oxidized with
dimethyldioxylane to give
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2-
H-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one-7-carboxylic acid
dimethylamide(15 mg, yield:14%).
[2574] NMR(DMSO-d.sub.6).delta.: 2.90(3H, s), 3.02(3H, s), 4.00(3H,
s), 5.33(2H, s), 7.05(1H, s), 7.23-7.31(3H, m), 7.70-7.76(2H, m),
8.21(1H, s), 10.22(1H, brs).
[2575] Melting point:227-229.degree. C.
[2576] The following compounds were prepared according to the
method above.
[2577] (C-48a)
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]tri-
azole-3-yl)-4H-1-benzopyrane-4-one-7-carboxylate methyl ester
[2578] NMR(DMSO-d.sub.6).delta.: 3.94(3H, s), 4.02(3H, s), 5.39(2H,
s), 7.24-7.32(2H, m), 7.51(1H, s), 7.72-7.82(3H, m), 8.24(1H, s),
10.36(1H, brs).
[2579] Melting point:253-255.degree. C.
[2580] (C-48b)
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]tri-
azole-3-yl)-4H-1-benzopyrane-4-one-7-carboxylic acid
[2581] NMR(DMSO-d.sub.6).delta.: 4.01(3H, s), 5.38(2H, s),
7.24-7.32(2H, m), 7.51(1H, s), 7.69(1H, s), 7.74-7.82(2H, m),
8.23(1H, s), 10.34(1H, brs).
[2582] Melting point:280-282.degree. C.
[2583] Compound C-53
[2584]
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3--
yl)-4H-1-benzopyrane-4-one-8-carboxylate methyl ester 257
[2585] (C-49) To a solution of compound C-37(10.0 g, 38.4 mmol)in
methylene chloride(150 ml), was added phenyltrimethylammonium
tribromide(14.4 g, 384 mmol) under ice-cooling and the mixture was
stirred for 2 hours 20 minutes. A 10% sodium hydrogen sulfate
aqueous solution was added thereto and methylene chloride was
evaporated under reduced pressure, to which was added water,
followed by extraction with ethyl acetate. The extract was washed
with water and saturated brine, and dried, then the solvent was
evaporated under reduced pressure. The residue was crystallized
from diusopropylether/ethyl acetate to give
1-[3-bromo-6-.(4-fluorobenzyloxy)-2-hydroxyphenyl]etanone(9.88 g,
yield:76%).
[2586] NMR(CDCl.sub.3).delta.: 2.60(3H, s), 5.09(2H, s), 6.42(1H,
d, J=9.0 Hz), 7.07-7.14(2H, m), 7.37-7.43(2H, m), 7.60(1H, d, J=9.0
Hz), 14.02(1H, s).
[2587] (C-50) According to the method of compound C-38, cyclization
using as starting materials the above-mentioned compound C-49(150
mg, 11.8 mmol)and 2-methyl-2H-[1,2,4]triazole-3-carboxylate ethyl
ester(3.66 g, 23.6 mmol) gave
8-bromo-5-[(4-fluorobenzyl)oxy]-2-(2-methyl-2H-[1,2,4]tri-
azole-3-yl)-4H-1-benzopyrane-4-one(296 mg, yield:85%).
[2588] NMR(CDCl.sub.3).delta.: 4.46(3H, s), 5.23(2H, s), 6.85(1H,
d, J=9.0 Hz), 7.06-7.14(2H, m), 7.18(1H, s), 7.55-7.62(2H, m),
7.81(1H, d, J=9.0 Hz), 7.99(1H, s).
[2589] (C-51) According to the method of compound C-39, the
above-mentioned compound C-50(1.0 g, 0.42 mmol) as a starting
material was oxydized with dimethyldioxysilane to give crude
substituted 3-hydroxybenzopyranone(550 mg). The obtained compound
was dissolved to DMF(15 ml) and 60% sodium hydride (54 mg, 1.35
mmol) was added thereto under ice-cooling. The mixture was stirred
at room temperature for 15 minutes and chloromethyl methyl ether(93
.mu.l, 1.35 mmol) was added dropwise under ice-cooling, and the
mixture was stirred at room temperature for 30 minutes. To the
solution was added ice water, and the mixture was extracted with
ethyl acetate. The extract was washed with water and saturated
brine, dried, then the solvent was evaporated under reduced
pressure. The residue was purified with column chromatography(ethyl
acetate:n-hexane=1:2)to give 8-bromo-5-[(4-fluoroben-
zyl)oxy]-3-methoxymethoxy-2-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H-1-benzop-
yrane-4-one(119 mg, yield:13%).
[2590] NMR(CDCl.sub.3).delta.: 3.05(3H, s), 4.11(3H, s), 5.22(2H,
s), 5.25(2H, s), 6.80(1H, d, J=9.0 Hz), 7.07-7.14(2H, m),
7.56-7.61(2H, m), 7.80(1H, d, J=9.0 Hz), 8.11(1H, s).
[2591] (C-52) To a suspension of the above-mentioned compound
C-51(100 mg, 0.20 mmol), acetic acid palladium(II)(4.6 mg, 0.02
mmol) and 1,3-bis(diphenylphosphino)propane(10.5 mg, 0.025 mmol)in
DMF(3 ml), wre added at room temperature triethylamine(0.28 ml,
2.04 mmol)and methyl alcohol(1.0 ml) successively, then the mixture
was stirred under 1 atm CO atomospher at 70.degree. C. for 18
hours. After cooling, water 6 ml was added thereto, and the
precipitated crystals were filtered off, washed with water, and
dried. The crude crystals were purified with column
chromatography(ethyl acetate:n-hexane=1:2-1:3) to give
5-[(4-fluorobenzyl)oxy]-3-methoxymethoxy-2-(2-methyl-2H-[1,2,4]triazole-3-
-yl)-4H-1-benzopyrane-4-one-8-carboxylate methyl ester(53 mg,
yield:55%).
[2592] NMR(CDCl.sub.3).delta.: 3.03(3H, s), 3.90(3H, s), 4.11(3H,
s), 5.22(2H, s), 5.33(2H, s), 6.91(1H, d, J=9.0 Hz), 7.09-7.15(2H,
m), 7.57-7.63(2H, m), 8.09(1H, s), 8.25(1H, d, J=9.0 Hz).
[2593] (C-53) To a suspension of the above-mentioned compound C-52
in tetrahydrofuran(1 ml) and methyl alcohol(1 ml), was added a
solution of concentrated hydrochloric acid 36 .mu.l in methyl
alcohol(0.5 ml) at room temperature, and the mixture was stirred at
50.degree. C. for 10 minutes. The mixture was ice-cooled, and
saturated sodium hydrogen carbonate aqueous solution 0.5 ml and
water 2 ml were added thereto, then the precipitated crystals were
filtered off, washed with water, and dried to give
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3-y-
l)-4H-1-benzopyrane-4-one-8-carboxylate methyl ester(38 mg,
yield:84%).
[2594] NMR(CDCl.sub.3).delta.: 3.93(3H, s), 4.48(3H, s), 5.32(2H,
s), 6.90(1H, d, J=9.0 Hz), 7.09-7.15(2H, m), 7.66-7.72(2H, m),
8.05(1H, s), 8.25(1H, d, J=9.0 Hz), 10.94(1H, brs).
[2595] Melting point:236-237.degree. C.
[2596] Elementary analysis as C.sub.21H.sub.16FN.sub.3O.sub.6
0.1H.sub.2O
[2597] Calcd. (%): C, 59.05; H, 3.82; N, 9.84; F, 4.45. Found (%):
C, 58.92; H, 3.78; N, 9.62; F, 4.45.
[2598] The following compound was prepared as well as above.
[2599] (C-53a)
8-bromo-5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1-
,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one
[2600] NMR(CDCl.sub.3).delta.: 4.53(3H, s), 5.24(2H, s), 6.81(1H,
d, J=9.0 Hz), 7.08-7.14(2H, m), 7.65-7.70(2H, m), 7.82(1H, d, J=9.0
Hz), 8.06(1H, s), 10.86(1H, brs).
[2601] Melting point:220-223.degree. C.
[2602] Compound C-57
[2603]
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3--
yl)-4H-1-benzopyrane-4-one-7-carboxylic acid amide 258
[2604] (C-54) To a solution of compound C-48a (520 mg, 1.22 mmol)
in DMF(10.4 ml), were added dropwise triethylamine (0.77 ml, 5.52
mmol) and chloromethyl methyl ether(0.28 ml, 3.69 mmol) at room
temperature and the mixture was stirred for 1 hour 30 minute. Water
15 ml was added thereto and the precipitated crystals were filtered
off and dried to give
5-[(4-fluorobenzyl)oxy]-3-methoxymethoxy-2-(2-methyl-2H-[1,2,4]triazole-3-
-yl)-4H-1-benzopyrane-4-one-7-carboxylate methyl ester(543 mg,
yield:95%).
[2605] NMR(CDCl.sub.3).delta.: 2.99(3H, s), 3.97(3H, s), 4.03(3H,
s), 5.20(2H, s), 5.31(2H, s), 7.08-7.16(2H, m), 7.52(1H, d, J=1.2
Hz), 7.60-7.67(2H, m), 7.78(1H, d, J=1.2 Hz), 8.10(1H, s).
[2606] (C-55) To a solution of the above-mentioned compound
C-54(100 mg, 0.21 mmol) in DMSO(4 ml), was added a 2N sodium
hydroxide aqueous solution 128 .mu.l and the mixture was stirred at
room temperature for 30 minutes. 2N hydrochloric acid and water
were added thereto and the mixture was extracted with ethyl
acetate. The extract was washed with water and saturated brine and
dried, then the solvent was evaporated under reduced pressure. To
the residue were added methyl alcohol(2 ml)and diisopropylether(4
ml)and the precipitated crystals were filtered off, washed with
isopropylether, and dried to give 5-[(4-fluorobenzyl)oxy]-3-m-
ethoxymethoxy-2-(2-methyl2H-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one-7-
-carboxylic acid(78 g, yield:80%).
[2607] NMR(DMSO-d.sub.6).delta.: 2.91(3H, s), 3.99(3H, s), 5.08(2H,
s), 5.37(2H, s), 7.24-7.33(2H, m), 7.55(1H, s), 7.65-7.76(3H, m),
8.25(1H, s).
[2608] (C-56) To a solution of the above-mentioned compound
C-55(140 mg, 0.16 mmol)in DMF(3 ml), were added at room temperature
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg,
0.20 mmol) and 1-hydroxybenzotriazole (25 mg, 0.16 mmol) and the
mixture was stirred for 10 minutes. To the mixture were added
ammonium chloride (26 mg, 0.49 mmol) and triethylamine (92 .mu.l,
0.66 mmol) and the mixture was stirred for 45 hours. Water was
added thereto and the mixture was extracted with ethyl acetate. The
extract was washed with water and saturated brine, and dried, then
the solvent was evaporated under reduced pressure. The residue was
purified column chromatography(chloroform:methy- l alcohol=20:
1-15:1)to give 5-[(4-fluorobenzyl)oxy]-3-methoxymethoxy-2-(2-
-methyl-2H-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one-7-carboxylic
acid amide(62 mg, yield:83%).
[2609] NMR(DMSO-d6).delta.: 2.89(3H, s), 3.98(3H, s), 5.07(2H, s),
5.35(2H, s), 7.25-7.33(2H, m), 7.56(1H, s), 7.68-7.75(3H, m),
8.25(1H, s), 8.27(1H, brs).
[2610] The following compound was prepared as well as above.
[2611] (C-56a)
5-[(4-fluorobenzyl)oxy]-3-methoxymethoxy-2-(2-methyl-2H-[1,-
2,4]triazole-3-yl)-4H-1-benzopyrane-4-one-7-carboxylic acid
methoxymethylamide
[2612] NMR(CDCl.sub.3).delta.: 2.99(3H, s), 3.38(3H, s), 3.50(3H,
s), 4.03(3H, s), 5.20(2H, s), 5.29(2H, s), 7.07-7.15(2H, m),
7.17(1H, d, J=1.2 Hz), 7.43(1H, d, J=1.2 Hz), 7.57-7.64(2H, m),
8.10(1H, s).
[2613] (C-57) According to the method of compound C-53, the
above-mentioned compound C-56(61 mg, 0.13 mmol) as a starting
material was deprotected to give
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H--
[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one-7-carboxylic acid
amide(37 mg, yield:67%).
[2614] NMR(DMSO-d.sub.6).delta.: 4.00(3H, s), 5.35(2H, s),
7.23-7.33(2H, m), 7.52(1H, s), 7.70-7.83(4H, m), 8.22(1H, s),
8.26(1H, brs), 10.28(1H, brs).
[2615] Melting point:257-258.degree. C.
[2616] The following compound was prepared as well as above.
[2617] (C-57a)
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]tri-
azole-3-yl)-4H-1-benzopyrane-4-one-7-carboxylic acid
methoxymethylamide
[2618] NMR(CDCl.sub.3).delta.: 3.40(3H, s), 3.51(3H, s), 4.31(3H,
s), 5.28(2H, s), 7.07-7.28(3H, m), 7.40(1H, s), 7.63-7.72(2H, m),
8.06(1H, s), 10.07(1H, brs).
[2619] Melting point:220-221.degree. C.
[2620] Compound C-60
[2621]
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3--
yl)-4H-1-benzopyrane-4-one-8-carboxylic Acid Dimethylamide 259
[2622] (C-58) According to the method of compound C-55, compound
C-52(120 mg, 0.26 mmol)as a starting material was hydrolyzed at the
ester miety to give
5-[(4-fluorobenzyl)oxy]-3-methoxymethoxy-2-(2-methyl-2H-[1,2,4]triaz-
ole-3-yl)-4H-1-benzopyrane-4-one-8-carboxylic acid(57 mg,
yield:49%).
[2623] NMR(CDCl.sub.3).delta.: 3.05(3H, s), 4.09(3H, s), 5.23(2H,
s), 5.32(2H, s), 6.90(1H, d, J=9.0 Hz), 7.08-7.17(2H, m),
7.56-7.64(2H, m), 8.14(1H, s), 8.27(1H, d, J=9.0 Hz).
[2624] (C-59) According to the method of compound C-56, the
above-mentioned compound C-58(56 mg, 0.12 mmol)as a starting
material was subjected to amidation to give
5-[(4-fluorobenzyl)oxy]-3-methoxymethoxy-2-
-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one-8-carboxylic
acid dimethylamide(52 mg, yield:88%).
[2625] NMR(CDCl.sub.3).delta.: 3.00(3H, s), 3.01(3H, s), 3.11(3H,
s), 4.01(3H, s), 5.21(2H, s), 5.29(2H, s), 6.92(1H, d, J=8.7 Hz),
7.07-7.17(2H, m), 7.55-7.64(3H, m), 8.06(1H, s).
[2626] (C-60) According to the method of compound C-53, the
above-mentioned compound C-59(51 mg, 0.11 mmol)as a starting
material was deprotected to give
5-[(4-fluorobenzyl)oxy]-3-hydroxy-2-(2-methyl-2H-[1,2-
,4]triazole-3-yl)-4H-1-benzopyrane-4-one-8-carboxylic acid
dimethylamide(34 mg, yield:74%).
[2627] NMR(CDCl.sub.3).delta.: 2.95(3H, s), 3.16(3H, s), 4.21(3H,
s), 5.27(2H, s), 6.91(1H, d, J=8.7 Hz), 7.07-7.16(2H, m), 7.53(1H,
d, J=8.7 Hz), 7.64-7.72(2H, m), 8.06(1H, s), 10.41(1H, brs).
[2628] Melting point:246-247.degree. C.
[2629] Compound C-63
[2630]
5-[2-(4-fluorophenyl)ethoxy]-3-hydroxy-2-(2-methyl-2H-[1,2,4]triazo-
le-3-yl)-4H-1-benzopyrane-4-one 260
[2631] (C-61) According to the method of compound C-38,
2',6'-dihydroxyacetophenone (1.0 g, 6.57 mmol) and
2-methyl-2H-[1,2,4]triazole-3-carboxylate ethyl ester(2.0 g, 12.9
mmol)as starting materials, were subjected to cyclization to give
5-hydroxy-2-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one(1.1-
3 g, yield:71%).
[2632] NMR(CDCl.sub.3).delta.: 4.32(3H, s), 6.89(1H, dd, J=0.9, 8.4
Hz), 6.98(1H, dd, J=0.9, 8.4 Hz), 7.14(1H, s), 7.61(1H, t, J=8.4
Hz), 8.00(1H, s), 12.34(1H, s).
[2633] (C-62) To a suspension of the above-mentioned compound
C-62(500 mg, 2.06 mmol), 2-(4-fluorophenyl)ethanol(0.52 ml, 4.16
mmol), and triphenylphosphine (1.08 g, 4.12 mmol)in
tetrahydrofuran(10 ml), was added azodicarboxylic acid
diisopropyl(0.81 ml, 4.11 mmol)under ice-cooling and the mixture
was stirred at room temperature for 2 hours. To the solution were
added water and ethyl acetate, and the precipitated crystals were
filtered off, washed with water and ethyl acetate, and dried to
give 5-[2-(4-fluorophenyl)ethoxy]-2-(2-methyl-2H-[1,2,4]triazole-
-3-yl)-4H-1-benzopyrane-4-one(523 mg, yield:70%). The filtrate was
extracted with ethyl acetate, and the extract was washed with
saturated brine and water, and dried, then the solvent was
evaporated under reduced pressure. To the residue was added ethyl
acetate and the precipitated crystals were filtered off, washed
with diisopropylether, and dried to give
5-[2-(4-fluorophenyl)ethoxy]-2-(2-methyl2H-[1,2,4]triazole-3-yl)-4H--
1-benzopyrane-4-one (122 mg, yield:16%).
[2634] NMR(CDCl.sub.3).delta.: 3.23(2H, t, J=6.6 Hz), 4.25(2H, t,
J=6.6 Hz), 4.28(3H, s), 6.82(1H, d, J=7.5 Hz), 6.07-7.09(4H, m),
7.40-7.60(3H, m), 7.99(1H, s).
[2635] (C-63) According to the method of compoundC-39, the
above-mentioned compound C-62(200 mg, 0.55 mmol)as a starting
material was oxidized with dimethyldioxylane to give
5-[2-(4-fluorophenyl)ethoxy]-3-hydroxy-2-(2-met-
hyl-2H-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one(86 mg,
yield:41%).
[2636] NMR(CDCl.sub.3).delta.: 3.24(2H, t, J=6.3 Hz), 4.26(2H, t,
J=6.3 Hz), 4.29(3H, s), 6.75(1H, d, J=8.1 Hz), 6.97-7.08(3H, m),
7.44-7.58(3H, m), 8.05(1H, s), 9.72(1H, brs).
[2637] Melting point:215-217.degree. C.
[2638] Compound C-66
[2639]
5-[-2-(4-fluorophenyl)ethyl]-3-hydroxy-2-(2-methyl2H-[1,2,4]triazol-
e-3-yl)-4H-1-benzopyrane-4-one 261
[2640] (C-64) To a solution of compound C-61(500 mg, 2.06 mmol) and
triethylamine(1.15 ml, 8.25 mmol) in methylene chloride(10 ml), was
added anhydrous trifluoromethanesulfonic acid (0.69 ml, 4.10
mmol)under ice-cooling and the mixture was stirred for 1 hour 30
minutes. To the solution was added ice water and the mixture was
extracted with ethyl acetate. The extract was washed with saturated
brine and dried, and the solvent was evaporated under reduced
pressure. The residue was purified with column chromatography(ethyl
acetate:n-hexane=1:1) and recrystallized from acetone/hexaneto give
trifluoromethanesulfonic acid
2-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one-5-yl
ester(495 mg, yield:64%).
[2641] NMR(CDCl.sub.3).delta.: 4.31(3H, s), 7.14(1H, s), 7.31(1H,
d, J=7.8 Hz), 7.63(1H, dd, J=0.9, 8.7 Hz), 7.77-7.83(1H, m),
8.02(1H, s).
[2642] (C-65) To a suspension of zinc(310 mg, 4.74 mmol) in
tetrahydrofuran(2.0 ml), was added chlorotrimethylsilane(25 .mu.l,
0.27 mmol) at room temperature for 5 minutes. To the mixture was
added a tetrahydrofuran(2.0 ml)solution containing
1-fluoro-4-(2-iodoethyl)benzen- e(1.0 g, 4.0 mmol), synthesized
from 2-(4-fluorophenyl)ethanol according to the method of J. Org.
Chem., 1979, 44, p1247, and the mixture was stirred at 40.degree.
C. for 4 hour and allowed to stand at room temperature overnight.
To a solution of compound C-64(417 mg, 1.11 mmol)in
tetrahydrofuran(8.3 ml), were added HMPA(1.0 ml),
tetrakistriphenylphosphine palladium(64 mg, 0.06 mmol) and the
above-mentioned alkylzinc solution(2.8 ml)at 60.degree. C. for 2.5
hour. After cooling, water was added thereto, and the mixture was
extracted with ethyl acetate. The extract was washed with saturated
brine, and dried, then the solvent was evaporated under reduced
pressure. The residue was purified with column chromatography(ethyl
acetate:n-hexane=1:1) and recrystallized from ethyl acetate/hexane
to give
5-[2-(4-fluorophenyl)ethyl]-2-(2-methyl-2H-[1,2,4]triazole-3-yl)-4H--
1-benzopyrane-4-one(256 mg, yield:66%).
[2643] NMR(CDCl.sub.3).delta.: 2.90(2H, t, J=8.1 Hz), 3.55(2H, t,
J=8.1 Hz), 4.32(3H, s), 6.93-7.02(2H, m), 7.09-7.14(3H, m),
7.22-7.29(2H, m), 7.41(1H, dd, J=1.2, 8.4 Hz), 7.57(1H, dd, J=7.5,
8.4 Hz), 8.01(1H, s).
[2644] (C-66) According to the method of compound C-39, the
above-mentioned compound C-65(200 mg, 0.57 mmol) was oxidized with
dimethyldioxylane to give
5-[2-(4-fluorophenyl)ethyl]-3-hydroxy-2-(2-meth-
yl-2H-[1,2,4]triazole-3-yl)-4H-1-benzopyrane-4-one(99 mg,
yield:47%).
[2645] NMR(CDCl.sub.3).delta.: 2.91(2H, t, J=8.1 Hz), 3.57(2H, t,
J=8.1 Hz), 4.36(3H, s), 6.93-7.02(2H, m), 7.10(1H, dd, J=1.2, 7.5
Hz), 7.28-7.36(2H, m), 7.38(1H, dd, J=1.2, 8.7 Hz), 7.56(1H, dd,
J=7.5, 8.7 Hz), 8.07(1H, s), 10.15(1H, brs).
[2646] Melting point: 192-193.degree. C.
[2647] Compound C-69
[2648]
3-hydroxy-2-[1-(4-fluorobenzyl)-1H-[1,2,4]triazole-3-yl]-4H-1-benzo-
pyrane-4-one 262
[2649] (C-67) To a suspension of 1H-[1,2,4]triazole-3-carboxylate
ethyl ester(Farmako, 1997, 52, p429)(1.0 g, 7.09 mmol)in ethanol(25
ml), were added 20% sodium ethoxide ethanol solution 3.3 ml and
4-fluorobenzylbromide(0.93 ml, 7.46 mmol) under ice-cooling and the
mixture was stirred for 1.5 hour, Further, the mixture was stirred
at room temperature for 30 minutes and at 80.degree. C. for 40
minutes. After cooling, water was added to the solution and the
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine and dried, then the solvent was evaporated
under reduced pressure. The residue was purified with silica gel
column chromatography(ethyl acetate :n-hexane=1:1-1:3)to give
1-(4-fluorobenzyl)-1H-[1,2,4]triazole-3-carboxy- late ethyl
ester(754 mg, yield:42%).
[2650] NMR(CDCl.sub.3).delta.:1.44(3H, t, J=7.2 Hz), 4.48(2H, t,
J=7.2 Hz), 5.39(2H, s), 7.00-7.13(2H, m), 7.25-7.34(2H, m),
8.08(1H, s).
[2651] (C-68) According to the method of compound C-38,
2'-hydroxyacetophenone(145 mg, 1.07 mmol)and the above-mentioned
compound C-67(533 mg, 2.14 mmol)as starting materials were
subjected to cyclization to give
2-[1-(4-fluorobenzyl)-1H-[1,2,4]triazole-3-yl]-4H-1-b-
enzopyrane-4-one(205 mg, yield:60%).
[2652] NMR(CDCl.sub.3) .delta.: 5.43(2H, s), 7.07-7.16(2H, m),
7.31-7.47(3H, m), 7.64-7.75(2H, m), 8.14(1H, s), 8.22-8.27(1H,
m).
[2653] (C-69) According to the method of compound C-39, the
above-mentioned compound C-68(204 mg, 0.63 mmol)as a starting
material was oxidized with dimethyldioxylane to give
3-hydroxy-2-[1-(4-fluorobenzy-
l)-1H-[1,2,4]triazole-3-yl]-4H-1-benzopyrane-4-one(137 mg,
yield:64%).
[2654] NMR(CDCl.sub.3).delta.: 5.49(2H, s), 7.09-7.18(2H, m),
7.34-7.46(3H, m), 7.63-7.75(2H, m), 8.22(1H, s), 8.30-8.36(1H, m),
9.45(1H, brs).
[2655] Melting point:260-262.degree. C.
[2656] Compound C-71
[2657] 3-hydroxy-4H-1-benzopyrane-4-one-2-carboxylic acid
4-fluorobenzylamide 263
[2658] (C-70) To a solution of compound C-5(200 mg, 0.68 mmol) in
DMF(4 ml), were added at room temperature
1-ethyl-3-(3-dimethylaminopropyl)carb- odiimide hydrochloride (155
mg, 0.81 mmol), 4-fluorobenzylamine (85 .mu.l, 0.74 mmol) and
1-hydroxybenzotriazole (10 mg, 0.07 mmol) and the mixture was
stirred at room temperature for 3 hour. To the solution was added
water and 2N hydrochloric acid and the mixture was extracted with
ethyl acetate. The extract was washed with a saturated sodium
hydrogen carbonate aqueous solution and saturated brine, and dried.
The solvent was evaporated under reduced pressure, to which was
added diisopropylether(6 ml) and hexane(3 ml), then the
precipitated crystals were filtered off, washed with
diisopropylether, and dried to give
3-benzyloxy-4-oxo-4H-chromene-2-carboxylic acid
4-fluorobenzylamide(231 mg, yield:85%).
[2659] NMR(DMSO-d.sub.6).delta.: 4.45(2H, d, J=6.0 Hz), 5.15(2H,
s), 7.07-7.16(2H, m), 7.30-7.46(7H, m), 7.51-7.58(1H, m),
7.70-7.76(1H, m), 7.84-7.91(1H, m), 8.14(1H, d, J=7.8 Hz), 9.33(1H,
d, J=6.0 Hz).
[2660] (C-71) According to the method of compound C-8, the
above-mentioned compound C-70(120 mg, 0.30 mmol)as a starting
material was deprotected to give
3-hydroxy-4H-1-benzopyrane-4-one-2-carboxylic acid
4-fluorobenzylamide(62 mg, yield:67%).
[2661] NMR(CDCl.sub.3).delta.: 4.67(2H, d, J=6.0 Hz), 7.04-7.14(2H,
m), 7.34-7.49(4H, m), 7.67-7.75(1H, m), 7.84-7.91(1H, m), 8.28(1H,
dd, J=1.5, 8.1 Hz), 10.72(1H, brs).
[2662] Melting point:235-236.degree. C.
[2663] D Group Compound
[2664] Compound D-5
[2665]
2-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-hydroxy-1H-quinolin-
e-4-one 264265
[2666] (D-1a, D-1b) To a solution of
2-ethoxycarbonyl3-methoxy1H-quinoline- 4-one(1.236 g, 5 mmol),
synthesized according to J.Heterocyclic Chem, 24, p1649, 1987, in
dimethylformamide(10 ml), was added potassium carbonate(691 mg, 5
mmol)and the mixture was stirred at room temperature for 5 minutes.
Iodomethane(0.63 ml, 10.1 mmol) was added thereto, and the mixture
was stirred for 2 hours. To the mixture was poured ice water, which
was extracted with ethyl acetate 3 times. The extract was washed
and dried, then the solvent was evaporated under reduced pressure.
The residue was purified with silica gel column
chromatography(lober column B, toluene:acetone=24:1) to give
2-ethoxycarbonyl-3,4-dimethoxyquinoline(- 890 mg, yield:34.1%)and
2-ethoxycarbonyl-3-methoxy-1-methylquinoline-4-one- (1.583 g,
yield: 60.6%).
[2667] D-1a: Oily Product
[2668] NMR(CDCl.sub.3).delta.:1.47(3H, t, J=7.2 Hz), 3.98(3H, s),
4.22(3H, s), 4.54(2H, q, J=7.2 Hz), 7.54-7.59(1H, m), 7.65-7.70(1H,
m), 8.09-8.15(2H, m).
[2669] D-1b: Melting point:103.degree. C.
[2670] NMR(CDCl.sub.3).delta.:1.46(3H, t, J=7.2 Hz), 3.72(3H, s),
3.97(3H, s), 4.53(2H, q, J=7.2 Hz), 7.40(1H, m), 7.47(1H, d, J=8.7
Hz), 7.70(1H, m), 8.52(1H, m).
[2671] (D-2) To a solution of the above-mentioned compound D-1a(885
mg, 3.39 mmol)in ethanol(4.5 ml), was added hydrazine hydrate(0.34
ml, 7.0 mmol)and the mixture was stirred for 30 minutes and allowed
to stand at room temperature overnight. The mixture was stirred at
90.degree. C. for 4 hour and water was added thereto, then the
mixture was concentrated under reduced pressure and extracted with
ethyl acetate. The extract was washed and dried, then the solvent
was evaporated under reduced pressure to give
3,4-dimethoxyquinolinecarboxylic acid hydrazide (832 mg,
yield:99.3%).
[2672] NMR(CDCl.sub.3).delta.:2.79(3H, bs), 4.02(3H, s), 4.24(3H,
s), 7.55-7.60(1H, m), 7.65-7.71(1H, m), 8.02(1H, d, J=8.4 Hz),
8.14(1H, d, J=7.8 Hz).
[2673] (D-3) To a solution of the above-mentioned compound D-2(826
mg, 3.34 mmol)and 4-fluorophenylacetic acid(592 mg, 3.84 mmol)in
tetrahydrofuran(10 ml), were added 1-hydroxybenztriazole(90 mg,
0.67 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
hydrochloric acid(768 mg, 4 mmol)and the mixture was stirred for 6
hours. To the solution was added ice water and the mixture was
extracted with ethyl acetate, washed, dried, and concentrated under
reduced pressure. Diethyl ether was added thereto and the
precipitated crystals were filtered off to give
3,4-dimethoxyquinoline-2-carboxylic acid N-[2-(4-fluorophenyl)ace-
tyl]hydrazide (968 mg, yield:75.6%).
[2674] Melting point:172-173.degree. C.
[2675] NMR(CDCl.sub.3).delta.:3.73(2H, s), 3.99(3H, s), 4.23(3H,
s), 7.02-7.08(2H, m), 7.33-7.38(2H, m), 7.55-7.60(1H, m),
7.65-7.70(1H, m), 8.04(1H, d, J=8.4 Hz), 8.12(1H, d, J=8.4 Hz),
8.83(1H, bs), 10.35(1H, bs).
[2676] (D-4) To a solution of triphenylphosphine (738 mg, 2.81
mmol)in methylene chloride(15 ml), was added a solution of
bromine(0.144 ml, 2.81 mmol)in methylene chloride(2 ml)under
ice-cooling, and the mixture was stirred at room temperature for 30
minutes. After ice-cooling, a solution of triethylamine(0.82 ml,
5.87 mmol)in methylene chloride(2 ml)was added dropwise, followed
by adding the above-mentioned compound D-3(769 mg, 2.0lmmol), and
the mixture was stirred for 1 hour 20 minutes. After further
stirring at room temperature for 15 minutes, the solution was
poured into ice water, and the mixture was extracted with
chloroform. The extract was washed and dried, and the solvent was
evaporated under reduced pressure. The residue was purified with
silica gel column chromatography (lober column B,
toluene:acetone=7:1) to give
2-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3,4-dimethoxyquinoline(615
mg, yield: 83.9%).
[2677] Melting point: 126.degree. C.
[2678] NMR(CDCl.sub.3).delta.: 3.99(3H, s), 4.27(3H, s), 4.36(2H,
s), 7.02-7.08(2H, m), 7.36-7.41(2H, m), 7.57-7.63(1H, m),
7.68-7.74(1H, m), 8.12-8.19(2H, m).
[2679] (D-5) To a solution of sodium iodide(4.12 g, 27.5 mmol)in
acetonitrile(116 ml), was added trimethylchlorosilane(3.49 ml, 27.5
mmol)and the mixture was stirred for 20 minutes, followed by adding
the above-mentioned compoundD-4(628 mg, 1.72 mmol). After stirring
for 40 minutes, the mixture was refluxed for 2 hours. The reaction
mixture was poured into ice water, which was stirred at room
temperature for 1 hour. The precipitated yellow crystals were
filtered off and the obtained crude crystals(532 mg,
yield:91.7%)were dissolved into dimethylformamide(100 ml)under
heating. The mixture was filtered and concentrated to the volume of
30 ml, to which was added water (20 ml) and the mixture was allowed
to stand at room temperature overnight. The precipitated crystals
were filtered off to give
2-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-hydr-
oxy-1H-quinoline-4-one(505 mg, yield:87%).
[2680] Melting point:>300.degree. C.
[2681] Elementary analysis as C.sub.18H.sub.12FN.sub.3O.sub.3
[2682] Calcd. (%): C, 64.09; H, 3.59; N, 12.46; F, 5.63. Found (%):
C, 64.05; H, 3.49; N, 12.54; F, 5.46.
[2683] NMR(DMSO-d).delta.: 4.46(2H, s), 7.19-7.31(3H, m),
7.43-7.48(2H, m), 7.61-7.67(1H, m), 7.88(1H, d, J=8.7 Hz), 8.13(1H,
dd, J=1.2, 8.4 Hz).
[2684] Compound D-9
[2685]
2-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-hydroxy-1-methyl-1H-
-quinoline-4-one 266
[2686] (D-6) To a solution of D-1b(1.21 g, 4.63 mmol)in
ethanol(15.3 ml), was added a 1N sodium hydroxide aqueous
solution(15.3 ml, 15.3 mmol), and the mixture was refluxed for 2
hours. After ice-cooling, water (25 ml) and a 1N hydrochloric acid
aqueous solution(18.5 ml, 18.5 mmol)were added to make the pH 1 to
2, and the precipitated crystals were filtered off and washed with
water to give 3-methoxy-1-methyl-4-oxo-1,4-dihydroquinoli-
ne-2-carboxylic acid(1.122 g, yield: 100%).
[2687] Melting point: 155-156.degree. C.(decomp.)
[2688] NMR(DMSO-d.sub.6).delta.: 3.76(3H, s), 3.78(3H, s),
7.41-7.46(1H, m), 7.78-7.80(2H, m), 8.24-8.27(1H, m).
[2689] (D-7) To a solution of the above-mentioned compound D-7(997
mg, 4.28 mmol) and 4-fluorophenylacetic acid hydrazide(1.08 g, 6.41
mmol)in dimethylformamide(17 ml), were added
1-hydroxybenztriazole(866 mg, 6.41 mmol)and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric
acid(1.23 g, 6.41 mmol)and the mixture was stirred for 3 hours.
4-Fluorophenylacetic acid hydrazide (1.08 g, 6.41 mmol)was added
thereto and the mixture was allowed to stand at room temperature
overnight. To the solution was added ice water and the precipitated
crystals were filtered off, washed with water to give
3-methoxy-1-methyl-4-oxo-1,4-dihy- droquinoline-2-carboxylic acid
N'-[2-(4-fluorophenyl)acetyl]hydrazide (969 mg, yield:59%).
[2690] Melting point: 140-142-(solid)-212-213.degree. C.
[2691] NMR(CDCl.sub.3).delta.: 3.75(2H, s), 3.77(3H, s), 3.79(3H,
s), 7.03-7.08(2H, m), 7.26-7.47(5H, m), 8.17(1H, dd, J=1.2, 8.4
Hz), 8.44(1H, bs), 10.73(1H, bs).
[2692] (D-8) To a solution of triphenylphosphine(929 mg, 3.54
mmol)in methylene chloride(35 ml)was added a solution of
bromine(0.182 ml, 3.54 mmol) in methylene chloride(2 ml) under
ice-cooling, and the mixture was stirred at room temperature for 30
minutes. After ice-cooling, a solution of triethylamine(1.03 ml,
7.37 mmol)in methylene chloride(2 ml) was added dropwise, and the
above-mentioned compound D-7(905 mg, 2.36 mmol)was added thereto,
and the mixture was stirred for 1 hour 30 minutes. The solution was
poured into ice water, which was extracted with chloroform, and
then the precipitated unreacted materials were filtered off. The
extract was washed and dried, and then the solvent was evaporated
under reduced pressure. The residue was purified with silica gel
column chromatography(lober column B, toluene:acetone=6:1)to give
2-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-methoxy-1-methyl-1H-quino-
line-4-one(527 mg, yield:55.1%).
[2693] Melting point:156-157.degree. C.
[2694] NMR(CDCl.sub.3).delta.: 3.60(3H, s), 3.84(3H, s), 4.33(2H,
s), 7.04-7.10(2H, m), 7.32-7.36(2H, m), 7.40-7.46(1H, m), 7.51(1H,
d, J=8.7 Hz), 7.71-7.77(1H, m), 8.53(1H, dd, J=1.5, 8.1 Hz).
[2695] (D-9) To a solution of sodium iodide(1.62 g, 10.8 mmol)in
acetonitrile(90 ml), was added trimethylchlorosilane(1.36 ml, 10.7
mmol)at room temperature and the mixture was stirred for 30
minutes. The above-mentioned compound D-8(490 mg, 1.34 mmol)was
added thereto and the mixture was stirred for 30 minutes and
refluxed for 2 hours. After cooling, the reaction mixture was
poured to ice water and the mixture was stirred at room temperature
for 1 hour. The precipitated yellow crystals were filtered off as
crude crystals(412 mg, yield:87.5%). The crystals were dissolved to
methylene chloride, which was filtered with a millipore filter, and
then the methylene chloride was concentrated in water bath while
adding methyl alcohol thereto. After ice-cooling, the precipitated
crystals were filtered off and washed with methyl alcohol to give
2-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-hydroxy-1-methyl-1H-quino-
line-4-one(360 mg, yield: 76.4%).
[2696] Melting point:222.degree. C.
[2697] Elementary analysis as C.sub.19H.sub.14FN.sub.3O.sub.3
[2698] Calcd. (%): C, 64.95; H, 4.02; N, 11.96; F, 5.41. Found (%):
C, 64.96; H, 3.91; N, 11.96; F, 5.23.
[2699] NMR(CDCl.sub.3).delta.:3.78(3H, s), 4.35(2H, s),
7.04-7.10(2H, m), 7.35-7.45(3H, m), 7.57(1H, d, J=8.7 Hz),
7.73-7.78(1H, m), 8.47-8.50(1H, m).
[2700] E Group Compound
[2701] Compound E-8
[2702] 2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxypyrane-4-one
267268
[2703] (E-2) Hydroxymethyl product (E-1) (2.2 g, 15.5 mm) was
dissolved in acetone (33 ml). To the solution, were added potassium
carbonate (6.4 g, 46 mm) and benzylbromide (3.2 g, 18.7 mm) and the
mixture was refluxed under heating for 3 hours. After evaporating
acetone, water was added thereto. The mixture was extracted with
ethyl acetate, washed with water, dried with sodium sulfate, and
then concentrated under reduced pressure. The residue was isolated
and purified with silica gel column chromatography (ethyl acetate:
n-hexane=3:1) to give compound E-2 as oily product (1.4 g, yield:
39%).
[2704] .sup.1H-NMR(CDCl.sub.3)64.32(s,2H), 5.21(s,2H), 6.40(d,J=5.4
Hz, 1H), 7.37-7.38(m, 5H), 7.69(d,J=6.0 Hz,1H)
[2705] (E-3) Oxalylchloride (1.64 g, 13 mm) was dissolved in
methylene chloride (15 ml) and the solution cooled to -78.degree.
C. To this solution, was added dropwise a solution of
dimethylsulfoxide (2.1 g, 26.9 mm) in methylene chloride (10 ml).
After stirring at -78.degree. C. for 15 minutes, a solution which
alcohol product (E-2) (1.5 g, 6.5 mm) was dissolved in methylene
chloride (10 ml) was added thereto. After 30 minutes, triethylamine
(5.3 g, 42 mm) was added thereto and the mixture stirred for 15
minutes. After warming to room temperature, ice water was added
thereto and the mixture was extracted with ethyl acetate, washed
with water, dried with sodium sulfate, and then concentrated under
reduced pressure. The residue was isolated and purified with silica
gel column chromatography (ethyl acetate: n-hexane=1:1) to give
compound E-3 as oily product (1.39 g, yield: 93%).
[2706] .sup.1H-NMR(CDCl.sub.3)(5.52(s,2H), 6.50(d,J=5.4 Hz,1H),
7.36(s,5H), 7.75(d,J=5.7 Hz, 1H), 9.88(s, 1H)
[2707] (E-5) 2-Furan-2-yl-[1.3]dioxolane (920 mg, 6.6 mm) was
dissolved in dried tetrahydrofuran (20 ml), and the solution cooled
to -78.degree. C. To this solution, was added dropwise a solution
of 1.57 mol/l n-butyl lithium-hexane solution (5.4 ml, 8.5 mm).
After 15 minutes, a solution of .gamma.-pyrone product (E-3) (1.5
g, 6.5 mm) in tetrahydrofuran (15 ml) was added thereto. After 30
minutes, the mixture was-warmed to 0.degree. C. After saturated
ammonium chloride aqueous solution was added thereto, the mixture
was extracted with ethyl acetate, washed with water, and then
concentrated under reduced pressure. The obtained residue was
dissolved in methyl alcohol (10 ml). 6N hydrochloric acid (2 ml)
was added thereto and the mixture was stirred at room temperature
for 1 hour. The mixture was neutralized with sodium hydrogen
carbonate, extracted with ethyl acetate, washed with water, dried
with sodium sulfate, and then concentrated under reduced pressure.
The residue was purified with silica gel column chromatography
(ethyl acetate: n-hexane=1:1) to give compound E-5 as oily product
(730 mg, yield: 35%).
[2708] .sup.1H-NMR(CDCl.sub.3)(5.22(d, J=11.1 Hz, 1H), 5.27(d,
J=11.1 Hz, 1H), 5.90(s,1H), 6.42(d, J=5.7 Hz, 1H),6.44(d, J=3.6 Hz,
1H),7.17(d, J=3.6 Hz, 1H),7.35-7.38(m,5H), 7.66(d, J=5.7 Hz, 1H),
9.58(s,1H)
[2709] (E-6) Oxalylchloride (570 mg, 4.5 mm) was dissolved in
methylene chloride (10 ml) and the solution was cooled to
-78.degree. C. A solution which dimethyl sulfoxide (700 mg, 9 mm)
was dissolved in methylene chloride (5 ml) was added dropwise and
the mixture was stirred for 15 minutes. A solution of alcohol
product (E-5) (730 mg, 2.2 mm) in methylene chloride (10 ml) was
added. After stirring for 30 minutes, triethylamine (1.8 g, 18 mm)
was added dropwise thereto. After 15 minutes, the mixture was put
to be 0.degree. C. and a saline solution was added thereto. The
mixture was extracted with ethyl acetate, washed with water, dried
with sodium sulfate, and then concentrated under reduced pressure.
The residue was purified with silica gel column chromatography
(ethyl acetate: n-hexane=2:1) to give product E-6 as oily product
(610 mg, yield: 84%).
[2710] .sup.1H-NMR(d6-DMSO).delta. 5.19(s,2H),6.66(d,J=5.7 Hz,
1H),7.20-7.27(m,5H), 7.64(d,J=3.6 Hz, 1H), 7.71(d,J=3.9 Hz, 1H),
8.29(d,J=5.7 Hz, 1H), 9.79(s,1H)
[2711] (E-7) Aldehyde product (E-6) (550 mg, 1.7 mm) was dissolved
in dried tetrahydrofuran (22 ml) and a solution of 1 mol/l
parafluorophenyl magnesium bromide in tetrahydrofuran (1.6 ml, 1.7
mm) were added thereto under ice-cooling. After stirring at room
temperature for 15 minutes, ammonium chloride aqueous solution was
added thereto. The mixture was extracted with ethyl acetate, washed
with water, dried with sodium sulfate, and then concentrated under
reduced pressure. The residue was purified with silica gel column
chromatography (ethyl acetate: n-hexane=1:1) to give compound E-7
as oily product (413 mg, yield: 58%).
[2712] .sup.1H-NMR(d6-DMSO).delta. 5.06(s,2H), 5.82(s,1H),
6.53(d,J=3.6 Hz,1H), 6.58(d,J=5.4 Hz,1H), 7.13-7.25(m,7H),
7.40-7.45(m,2H), 7.50(d,J=3.6 Hz,1H), 8.20(d,J=5.7 Hz,1H)
[2713] (E-8) Alcohol product (E-7)(290 mg, 0.7 mm) was dissolved in
trifluoroacetic acid (6 ml) and triethylsilane (0.7 ml) added
thereto under ice-cooling. After 30 minutes, the mixture was
stirred at room temperature for 30 minutes. After concentrating
under reduced pressure, the mixture was neutralized with sodium
hydrogen carbonate, extracted with ethyl acetate, washed with
water, dried with sodium sulfate, and then concentrated under
reduced pressure. The residue was dissolved in acetone, treated
with active carbon, and then recrystallized with ethyl
acetate/isopropylether to give compound E-8 as pale yellow crystal
(83 mg, yield: 39%) of mp157-9.
[2714] .sup.1H-NMR(d6-DMSO).delta. 4.15(s,1H), 6.50(d,J=3.9 Hz,1H),
6.51(d,J=5.4 Hz,1H), 7.15-7.21(m,2H), 7.32-7.37(m,2H), 7.70(d,J=3.6
Hz,1H), 8.22(d,J=5.7 Hz,1H), 10.77(brs,1H)
[2715] Elementary analysis
as(C.sub.17H.sub.11FO.sub.5/0.3H.sub.2O)
[2716] Calcd. (%) C:63.87H:3.66 F:5.94 Found (%) C:63.85H:3.27
F:6.27
[2717] m/Z.sup.313[M-H]-, m/z315[M+H]+, m/z359[M+2Na-H]+
[2718] IR(nujol)(cm.sup.-1)3400, 1646, 1608
[2719] Compound E-16
[2720]
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-6-methylpyrane-4-o-
ne 269
[2721] (E-10) Kojic acid product E-9 (14.2 g, 0.1 mol) was
dissolved in thionyl chloride (24 g) and the solution was stirred
at room temperature. After 10 minutes, solid content was washed
with hexane to give white crystal (16.5 g, yield: 100%).
[2722] .sup.1H-NMR(CDCl.sub.3).delta.: 4.36(s,2H), 6.58(s,1H),
7.89(s,1H).
[2723] (E-11) The above-mentioned compound E-10 (16.5 g, 0.1
mol).was suspended in water (400 ml). Zinc powder (13 g, 0.2 mol)
and concentrated hydrochloric acid (10 ml) were added thereto and
the mixture was stirred at 75.degree. C. for 1 hour. After cooling,
zinc powder was removed by suction filtration and the filtrate was
extracted with chloroform. After washing and drying, the solvent
was evaporated under reduced pressure and the residue was
crystallized with ether to give the compound (10.4 g, yield:
82%).
[2724] .sup.1H-NMR(CDCl.sub.3).delta.: 2.31(s,3H), 6.28(s,1H),
6.61(bs, 1H), 7.79(s,1H).
[2725] (E-12) The above-mentioned compound E-11 (10.4 g, 82 mmol)
was dissolved in methyl alcohol (54 ml). Sodium hydroxide solution
(sodium hydroxide (4.2 g) was dissolved in water (11 ml)) and 37%
formaldehyde solution (17 ml) were added thereto and the mixture
was stirred at room temperature for 25 hours. Methyl alcohol was
evaporated under reduced pressure. The solution was acidified with
concentrated hydrochloric acid and then sodium sulfate was added
thereto. The mixture was diluted with tetrahydrofuran. To the
solution, was added molecular sieve and the mixture was dried and
filtered. The solvent was evaporated under reduced pressure and the
residue was crystallized with chloroform to give the compound (8.1
g, yield: 64%).
[2726] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.26(s,3H), 4.39(s, 2H),
5.36(bs,1H), 6.22(s, 1H), 8.91(bs,1H).
[2727] (E-13) The above-mentioned compound E-12 (7.0 g, 45 mmol)
was dissolved in acetone (150 ml). Potassium carbonate (20 g, 145
mmol) and benzyl bromide (9.6 g, 56 mmol) were added thereto and
the mixture was refluxed for 16 hours. After cooling, acetone was
evaporated under reduced pressure and the residue was extracted
with ethyl acetate. After washing and drying, the solvent was
evaporated under reduced pressure and the residue was crystallized
with ether to give the compound (8.5 g, yield: 76%).
[2728] .sup.1H-NMR(CDCl.sub.3).delta.: 2.26(s,3H), 4.28(s,2H),
5.21(s,2H), 6.21(s,1H), 7.38(m,5H).
[2729] (E-14) Oxalylchloride (8.6 g, 67 mmol) was dissolved in
methylene chloride (80 ml). To the solution, was added dropwise a
solution of dimethyl sulfoxide (10.5 g, 135 mmol) in methylene
chloride (50 ml) at -78.degree. C. After 15 minutes, a solution of
the above-mentioned compound E-13 (8.3 g, 34 mmol) in methylene
chloride (50 ml) was added dropwise thereto at -78.degree. C. and
the mixture was stirred at the same temperature for 30 minutes.
Triethylamine (27 g, 270 mmol) was added thereto and warmed to room
temperature. Water was added thereto and the mixture was extracted
with chloroform. After washing and drying, the solvent was
evaporated under reduced pressure and the residue was crystallized
with isopropylether to give the compound (7.4 g, yield: 90%).
[2730] .sup.1H-NMR(CDCl.sub.3).delta.: 2.32(s,3H), 5.49(s,2H),
6.30(s,1H), 7.35(m,5H), 9.84(s,1H).
[2731] (E-15) To a solution of 2-(4-fluorobenzyl)furanlithium salt
synthesized as the synthetic method of A-6 in tetrahydrofuran (5
mmol), added a solution of the above-mentioned compound E-14 (1.22
g, 5 mmol) in tetrahydrofuran at -78.degree. C. The mixture was
stirred at the same temperature for 30 minutes. The solution was
added to ammonium chloride solution and extracted with ethyl
acetate. After washing and drying, the solvent was evaporated under
reduced pressure and the residue was dissolved in chloroform (30
ml). To the solution, was added manganese dioxide (20 g) and the
mixture was stirred at 60.degree. C. for 15 minutes. The solution
was filtered and the filtrate was dried and evaporated under
reduced pressure. The residue was purified with column
chromatography (ethyl acetate: n-hexane=1:1) to give the compound
(1.15 g, yield: 55%).
[2732] .sup.1H-NMR(CDCl.sub.3).delta.:2.29(s,3H), 4.00(s,2H),
5.21(s,2H), 6.13(d,1H, J=3.9 Hz), 6.30(d, 1H, J=0.6 Hz),
6.98-7.04(m, 2H), 7.14(d, 1H, J=3.6 Hz), 7.15-7.24(m,7H).
[2733] (E-16) The above-mentioned compound E-15 (3.78 g, 9.0 mmol)
was dissolved in trifluoroacetic acid (30 ml) and the mixture was
stirred at room temperature for 30 minutes. The solvent was
evaporated under reduced pressure. Ice water was added thereto and
extracted with ethyl acetate. After washing and drying, the solvent
evaporated under reduced pressure and the residue was
recrystallized with methyl alcohol to give compound (1.8 g, yield:
62%).
[2734] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.36(s,3H), 4.15(s,2H),
6.41(s,1H), 6.52(d,1H, J=3.6 Hz), 7.14-7.22(m, 2H),
7.30-7.38(m,2H), 7.63(d, 1H, J=3.6 Hz).
[2735] Melting point:173-175.degree. C.
[2736] Elementary analysis as C.sub.18H.sub.13O.sub.5F
[2737] Calcd. (%) C: 65.85H: 3.99 F: 5.79 Found (%) C:65.64H:3.96
F:5.69
[2738] Compound E-24
[2739]
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-6-hydroxymethylpyr-
ane-4-one 270271
[2740] (E-17) To a solution of kojic acid compound E-9 (44.9 g, 316
mmol) in DMF (400 ml), were added imidazole (45.1 g, 663 mmol) and
then chlorotert-butyldimethylsilane (100 g, 663 mmol) under
ice-cooling. The mixture was warmed to room temperature and stirred
for 30 minutes. Water was added thereto to stop the reaction and
the mixture was extracted with diethyl ether. After washing with
water and drying, the solvent was evaporated under reduced pressure
to give 5-(tert-butyldimethylsilanyloxy-
)-2-(tert-butyldimethylsilanyloxymethyl)-pyrane-4-one.
[2741] .sup.1H-NMR(CDCl.sub.8).delta.: 0.11(6H, s), 0.23(6H, s),
0.93(9H, s), 0.96(9H, s), 4.45(2H, s), 6.45(s,1H), 7.62(s,1H).
[2742] (E-18) To the above-mentioned compound E-17, was added 30%
fomic acid-chloroform solution (300 ml) and the mixture was stirred
for 1 hour. Water (300 ml) was added thereto, extracted with
chloroform, washed with water and dried. The solvent was evaporated
under reduced pressure and precipitated crystal was washed with
n-hexane to give
2-(tert-butyldimethylsilanyloxymethyl)-5-hydroxypyrane-4-one (76.22
g, yield: 94%).
[2743] Melting point: 121-122.degree. C.
[2744] .sup.1H-NMR(CDCl.sub.3).delta.:0.12(6H, s), 0.93(9H, s),
4.49(2H, s), 6.50(1H, bs), 6.57(s,1H), 7.80(s, 1H).
[2745] (E-19) To a solution of the above-mentioned compound E-18
(76.22 g, 297 mmol) in methyl alcohol (500 ml), were added sodium
hydroxide solution (5N-aqueous solution, 59.4 ml, 297 mmol) and 37%
formaldehyde aqueous solution (72.3 g, 891 mmol) under ice-cooling.
Then the mixture was warmed to room temperature and stirred for 5
hours. Saturated ammonium chloride aqueous solution was added
thereto to stop the reaction and methyl alcohol was evaporated
under reduced pressure. The solution was extracted with chloroform,
washed with water and dried. The precipitated crystal was washed
with n-hexane to give
6-(tert-butyldimethylsilanyloxymethyl)-3-hydroxy2-hydroxymethylpyrane-4-o-
ne (74.47 g, yield: 88%).
[2746] Melting point: 133-134.degree. C.
[2747] .sup.1H-NMR(CDCl.sub.3).delta.: 0.12(6H, s), 0.94(9H, s),
4.53(2H, s), 4.70(2H, s), 6.56(1H, bs), 6.57(1H, s).
[2748] (E-20) The above-mentioned compound E-19 (74.47 g, 260 mmol)
was dissolved in acetone (350 ml). Potassium carbonate (35.9 g, 260
mmol) and benzyl bromide (44.5 g, 260 mmol) were added thereto and
the mixture was refluxed for 2 hours. After cooling, acetone was
evaporated under reduced pressure and the residue was extracted
with ethyl acetate. After washing and drying, the solvent was
evaporated under reduced pressure and the precipitated crystal was
washed with n-hexane to give
3-benzyloxy-6-(tert-butyl-dimethylsilanyloxymethyl)-2-hydroxymethylpyrane-
-4-one (89.08 g, yield: 91%).
[2749] Melting point:87-90.degree. C.
[2750] .sup.1H-NMR(CDCl.sub.3).delta.: 0.11(6H, s), 0.93(9H, s),
4.26(2H, s), 4.46(2H, s), 5.22(2H, s), 6.51(1H, s), 7.38(5H,
s).
[2751] (E-21) To a solution of the above-mentioned compound E-20
(89.08 g, 237 mmol) in chloroform (400 ml), was added manganese
dioxide (103 g, 1.18 mmol). The mixture was refluxed under heating
for 2 hours. Manganese dioxide was filtered and dried. The solvent
was evaporated under reduced pressure to give
3-benzyloxy6-(tert-butyl-dimethylsilanyloxymethyl)-4-oxo-
-4H-pyrane-2-carboaldehyde (87.7 g, yield: 99%).
[2752] .sup.1H-NMR(CDCl.sub.3).delta.: 0.11(6H, s), 0.93(9H, s),
4.51(2H, s), 5.51(2H, s), 6.63(1H, s), 7.36(s,1H), 9.84(1H, s).
[2753] (E-22) With using the above-mentioned compound E-21 (34.8 g,
93 mmol) according to the synthetic method of E-15,
3-benzyloxy-6-(tert-buty-
ldimethylsilanyloxymethyl)-2-[5-(4-fluorobenzyl)furan-2-carbonyl]-pyrane-4-
-one (34.0 g, yield: 67%) was given.
[2754] .sup.1H-NMR(CDCl.sub.3).delta.:0.11(6H, s), 0.93(9H, s),
4.00(2H, s), 4.47(2H, s), 5.23(2H, s), 6.13(1H, d, J=3.7 Hz),
6.59(1H, s), 6.99-7.04(2H, m), 7.14-7.23(8H, m).
[2755] (E-23) The above-mentioned compound E-22 (34.0 g, 62 mmol)
was dissolved in dioxane (300 ml). 3N-hydrochloric acid aqueous
solution (150 ml) was added thereto. After stirring for 30 minutes,
the mixture was extracted with ethyl acetate, washed and dried. The
solvent was evaporated under reduced pressure. The precipitated
crystal was washed with diethyl ether to give
3-benzyloxy-2-[5-(4-fluorobenzyl)furan-2-carbo-
nyl]-6-hydroxymethylpyrane-4-one (26.2 g, yield: 97%).
[2756] Melting point: 104-106.degree. C.
[2757] .sup.1H-NMR(CDCl.sub.3).delta.: 3.99(2H, s), 4.48(2H, s),
5.21(2H, s), 6.12(1H, d, J=3.7 Hz), 6.58(1H, s), 6.98-7.04(2H, m),
7.12-7.22(8H, m).
[2758] (E-24) With using the above-mentioned compound E-23
according to the synthetic method of E-16,
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hy-
droxy-6-hydroxymethylpyrane-4-one was synthesized.
[2759] Melting point: 193-195.degree. C.
[2760] Elementary analysis as C.sub.18H.sub.31O.sub.6F
[2761] Calcd. (%) C: 62.79H: 3.81 F: 5.52 Found (%) C: 62.73H: 3.75
F: 5.32
[2762] .sup.1H-NMR(CD.sub.3OD).delta.: 4.13(2H, s), 4.55(2H, s),
6.44(1H, d, J=3.7 Hz), 6.57(1H, s), 7.03-7.09(2H, m), 7.30-7.35(2H,
m), 7.86(1H, d, J=3.7 Hz).
[2763] Compound E-26
[2764]
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-6-methoxymethylpyr-
ane-4-one 272
[2765] (E-25) To a solution of compound E-23 (217 mg, 0.5 mmol) in
THF (1 ml), added diazomethane ether solution under ice-cooling and
then silica gel (100 mg). Acetic acid was added thereto to stop the
reaction. The solvent was evaporated under reduced pressure and the
residue was purified with silica gel column chromatography (ethyl
acetate: n-hexane=1:1) to give
3-benzyloxy2-[5-(4-fluorobenzyl)furan-2-carbonyl]-6-
-methoxymethylpyrane-4-one (118 mg, yield: 53%).
[2766] .sup.1H-NMR(CDCl.sub.3).delta.: 3.44(3H, s), 4.00(2H, s),
4.24(2H, s), 5.23(2H, s), 6.13(1H, d, J=3.6 Hz), 6.54(1H, s),
6.98-7.04(2H, m), 7.16-7.26(8H, m).
[2767] (E-26) With using the above-mentioned compound E-25
according to the synthetic method of E-16,
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hy-
droxy-6-methoxymethylpyrane-4-one was synthesized.
[2768] Melting point: 147-148
[2769] Elementary analysis as C,.sub.9H.sub.15O.sub.6F
[2770] Calcd. (%) C: 63.69H: 4.22 F: 5.30 Found (%) C: 63.72H: 4.27
F: 5.14
[2771] .sup.1H-NMR(CDCl.sub.3).delta.: 3.47(3H, s), 4.11(2H, s),
4.36(2H, s), 6.26(1H, d, J=3.7 Hz), 6.50(1H, s), 7.01-7.07(2H, m),
7.22-7.26(2H, m), 7.76(1H, d, J=3.7 Hz).
[2772] Compound E-28
[2773]
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyrane-2--
carboxylic Acid 273
[2774] (E-27) To a solution of compound E-23 (10 g, 10 mmol) in
acetone (100 ml), added dropwise 8N-Jones reagent aqueous
solution(CrO.sub.3--H.s- ub.2SO.sub.4, 13.8 ml, 110 mmol) under
ice-cooling for 30 minutes and the mixture was warmed to room
temperature. After stirring for 1 hour, isopropylalcohol was added
thereto to stop the reaction and the insoluble product was
filtered. Water was added thereto and the mixture was extracted
with ethyl acetate, washed and dried. The solvent was evaporated
under reduced pressure to give 5-benzyloxy-6-[5-(4-fluorobenzy-
l)furan-2-carbonyl]-4-oxo-4H-pyrane-2-carboxylic acid (8.29 g,
yield: 80%).
[2775] .sup.1H-NMR(DMSO-D.sub.6).delta.: 4.14(2H, s), 5.12(2H, s),
6.51(1H, d, J=3.4 Hz), 7.09-7.35(10H, m).
[2776] (E-28) With using the above-mentioned compound E-27
according to the synthetic method of E-16,
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hy-
droxy-4-oxo-4H-pyrane-2-carboxylic acid was synthesized.
[2777] Melting point:>200.degree. C. decomp.
[2778] .sup.1H-NMR(DMSO-D.sub.6).delta.: 4.17(2H, s), 6.59(1H, d,
J=3.4 Hz), 7.03(1H, s), 7.15-7.21(2H, m), 7.32-7.37(2H, m),
8.04(1H, d, J=3.4 Hz).
[2779] Compound E-30
[2780]
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyrane-2--
carboxylate Methyl Ester 274
[2781] (E-29) To a solution of compound E-27 (400 mg, 0.89 mmol) in
THF (3 ml), was added trimethylsilyldiazomethane (2.0 mol/l in THF,
0.53 ml, 1.07 mmol). Acetic acid was added thereto to stop the
reaction. The solvent was evaporated under reduced pressure and the
residue was purified with silica gel column chromatography (ethyl
acetate: n-hexane=3:1) to give
5-benzyloxy-6-[5-(4-fluorobenzyl)furan-2-carbonyl]--
4-oxo-4H-pyrane-2-carboxylate methyl ester (320 mg, yield:78%).
[2782] .sup.1H-NMR(CDCl.sub.3).delta.: 3.95(3H, s), 4.02(2H, s),
5.29(2H, s), 6.16(1H, d, J=3.8 Hz), 6.98-7.04(2H, m), 7.17-7.34(9H,
m).
[2783] (E-30) With using the above-mentioned compound E-29
according to the synthetic method of E-16,
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hy-
droxy-4-oxo-4H-pyrane-2-carboxylate methyl ester was
synthesized.
[2784] Melting point:174-176.degree. C.
[2785] Elementary analysis as C.sub.19H.sub.13O.sub.7F
[2786] Calcd. (%) C: 61.30H: 3.52 F: 5.10 Found (%) C: 61.30H: 3.52
F: 4.97
[2787] .sup.1H-NMR(CDCl.sub.3).delta.: 4.03(3H, s), 4.13(2H, s),
6.32(1H, d, J=3.7 Hz), 7.01-7.07(2H, m), 7.21-7.28(3H, m), 8.23(1H,
d, J=3.7 Hz).
[2788] Compound E-32
[2789]
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyrane-2--
carboxylate benzylamide 275
[2790] (E-31) To a solution of compound E-27 (224 mg, 0.5 mmol),
HOBt (7 mg, 0.05 mmol) and WSCD (115 mg, 0.6 mmol) in DMF (3 ml),
was added benzylamine (4 mg, 0.6 mmol) at room temperature. After
stirring 20 hours, water was added thereto to stop the reaction.
The mixture was extracted with ethyl acetate, washed with water and
dried. The solvent was evaporated under reduced pressure and the
residue was purified with silica gel column chromatography (ethyl
acetate: n-hexane=2:1) to give
5-benzyloxy-6-[5-(4-fluorobenzyl)furan-2-carbonyl]-4-oxo-4H-pyrane-2-carb-
oxylate benzylamide (112 mg, yield:42%).
[2791] .sup.1H-NMR(CDCl.sub.3).delta.: 3.92(2H, s), 4.56(2H, d,
J=5.8 Hz), 5.24(2H, s), 6.12(1H, d, J=3.7 Hz), 6.97-7.35(16H,
m).
[2792] (E-32) Using the above-mentioned compound E-31 according to
the synthetic method of E-16,
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydrox-
y-4-oxo-4H-pyrane-2-carboxylate benzylamide was synthesized.
[2793] Melting point: 195-197.degree. C.
[2794] Elementary analysis as
C.sub.25H.sub.18O.sub.5F.sub.1N.sub.1
[2795] Calcd. (%) C: 67.11H: 4.06 F: 4.25N: 3.13 Found (%) C:
65.21H: 4.06 F: 4.07N: 3.04
[2796] .sup.1H-NMR(CDCl.sub.3).delta.: 3.72(2H, s), 4.63(2H, d,
J=5.8 Hz), 6.14(1H, d, J=3.7 Hz), 6.99-7.35(10H, m), 7.70(1H, d,
J=3.7 Hz), 11.54(1H, bs).
[2797] According to the same method, the following compounds were
synthesized.
[2798] (E-32-a)
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H--
pyrane-2-carboxylate methyl amide
[2799] Melting point:231-232.degree. C.
[2800] Elementary analysis as C.sub.19H.sub.14NO.sub.6F
[2801] Calcd. (%) C: 61.46H: 3.80N: 3.77 F: 5.12 Found (%) C:
61.26H: 3.76N: 3.71 F: 5.02
[2802] .sup.1H-NMR(CDCl.sub.3).delta.: 2.97(d, 3H, J=4.8 Hz),
4.14(s, 2H), 6.35(d, 1H, J=3.6 Hz), 6.87(1H, bs), 7.03-7.09(m, 2H),
7.15(s, 1H), 7.19-7.27(m,2H), 7.87(d, 1H, J=3.6 Hz).
[2803] (E-32-b)
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H--
pyrane-2-carboxylate ethyl amide
[2804] Melting point:217-219.degree. C.
[2805] Elementary analysis as
C.sub.20H.sub.16O.sub.5F.sub.1N.sub.1
[2806] Calcd. (%) C: 62.34H: 4.19 F: 4.93N: 3.63 Found (%) C:
62.46H: 4.15 F: 4.79N: 3.56
[2807] .sup.1H-NMR(CDCl.sub.3).delta.: 1.25(3H, t, J=7.3 Hz),
3.46(2H, m), 4.13(2H, s), 6.32(1H, d, J=3.7 Hz), 6.78(1H, bs),
7.03-7.09(2H, m), 7.14(1H, s), 7.21-7.26(2H, m), 7.88(1H, d, J=4.0
Hz), 11.30(1H, bs).
[2808] (E-32-c)
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H--
pyrane-2-carboxylate isopropylamide
[2809] Melting point:208-210.degree. C.
[2810] Elementary analysis as
C.sub.21H.sub.18O.sub.6F.sub.1N.sub.1
[2811] Calcd. (%) C: 63.16H: 4.54 F: 4.76N: 3.51 Found (%) C:
63.19H: 4.54 F: 4.55N: 3.40
[2812] .sup.1H-NMR(CDCl.sub.3).delta.: 1.29(6H, d, J=6.7 Hz),
4.12(2H, s), 4.26(1H, m), 6.29(1H, d, J=3.7 Hz), 6.49(1H, d, J=7.9
Hz), 7.02-7.09(2H, m), 7.13(1H, s), 7.21-7.27(2H, m), 7.89(1H, d,
J=3.7 Hz), 11.32(1H, bs).
[2813] (E-32-d)
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H--
pyrane-2-carboxylate phenylamide
[2814] Melting point:263-266.degree. C.
[2815] .sup.1H-NMR(DMSO-D.sub.6).delta.: 4.17(2H, s), 6.58(1H, d,
J=3.7 Hz), 7.14-7.21(3H, m), 7.32-7.42(5H, m); 7.72(2H, d, J=7.6
Hz), 7.98(1H, d, J=3.7 Hz), 10.5(1H, s), 11.00(1H, bs).
[2816] (E-32-e)
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H--
pyrane-2-carboxylic acid(2-methoxyethyl)-amide
[2817] Melting point: 177-179.degree. C.
[2818] Elementary analysis as
C.sub.21H.sub.18O.sub.7F.sub.1N.sub.1
[2819] Calcd. (%) C: 60.72H: 4.37 F: 4.57N: 3.37 Found (%) C:
60.94H: 4.30 F: 4.44N: 3.31 .sup.1H-NMR(CDCl.sub.3).delta.:3.36(3H,
s), 3.53-3.56(2H, m), 3.61-3.65(2H, m), 4.17(1H, s), 6.28(1H, d,
J=3.7 Hz), 7.02-7.08(2H, m), 7.15(1H, bs), 7.19-7.27(2H, m),
7.81(1H, d, J=3.7 Hz), 11.65(1H, bs).
[2820] (E-32-f)
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H--
pyrane-2-carboxylate amide
[2821] Melting point:259-262.degree. C.
[2822] .sup.1H-NMR(DMSO-D.sub.6).delta.: 4.16(2H, s), 6.57(1H, d,
J=3.7 Hz), 7.11(1H, s), 7.15-7.20(2H, m), 7.32-7.37(2H, m),
7.97(1H, d, J=3.7 Hz), 8.13(1H, bs), 8.29(1H, bs), 10.92(1H,
bs).
[2823] (E-32-g)
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-6-(piperi-
dine-1-carbonyl)-pyrane-4-one
[2824] Melting point: 146-148.degree. C.
[2825] Elementary analysis as
C.sub.23H.sub.20O.sub.6F.sub.1N.sub.1
[2826] Calcd. (%) C: 64.94H: 4.74 F: 4.47N: 3.29 Found (%) C:
64.87H: 4.82 F: 4.30N: 3.17
[2827] .sup.1H-NMR(CDCl.sub.3).delta.: 1.50-1.80(6H, m),
3.40-3.75(4H, m), 4.10(2H, s), 6.27(1H, d, J=3.7 Hz), 6.57(1H, s),
7.01-7.06(2H, m), 7.21-7.26(2H, m), 7.80(1H, d, J=3.7 Hz),
11.82(1H, bs).
[2828] (E-32-h)
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-44H-
-pyrane-2-carboxylate dimethylamide
[2829] Melting point: 182-183.degree. C.
[2830] Elementary analysis as C.sub.20H.sub.16NO.sub.6F
[2831] Calcd. (%) C: 62.34H: 4.19N: 3.63 F: 4.93 Found (%) C:
62.19H: 4.16N: 3.64 F: 4.73
[2832] .sup.1H-NMR(CDCl.sub.3).delta.: 3.13(m, 6H), 4.10(s, 2H),
6.28(d, 1H, J=3.6 Hz), 6.63(s, 1H), 7.00-7.07(m, 2H),
7.06-7.27(m,2H), 7.83(d, 1H, J=3.6 Hz), 11.81(s, 1H).
[2833] (E-32-i)
({6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4-
H-pyrane-2-carbonyl}amino)ethyl acetate ester
[2834] Melting point:150-151.degree. C.
[2835] Elementary analysis as
C.sub.22H.sub.18NO.sub.8F.0.2H.sub.2O
[2836] Calcd. (%) C: 59.12H: 4.15N: 3.13 F: 4.25 Found (%) C:
58.87H: 4.00N: 3.15 F: 4.13
[2837] .sup.1H-NMR(CDCl.sub.3).delta.: 1.32(t, 3H, J=7.2 Hz),
4.14(m, 4H), 7.27(q, 2H, J=7.2 Hz), 6.34(d, 1H, J=3.6 Hz),
7.01-7.07(m, 2H), 7.19-7.26(m,3H), 7.85(d, 1H, J=3.6 Hz).
[2838] Compound E-37
[2839]
N-{6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyraan-
e-2-yl-methyl}-acetoamide 276
[2840] (E-33) To a solution of compound E-23 (434 mg, 1 mmol) in
methylene chloride (4 ml), were added diisopropylethylamine (142
mg, 1.1 mmol) and then methanesulfonylchloride (126 mg, 1.1 mmol)
under ice-cooling. After stirring for 10 minutes, water was added
thereto to stop the reaction. The mixture was extracted with
chloroform, washed and dried to give methanesulfonic acid
5-benzyloxy6-[5-(4-fluorobenzyl)furan-2-carbonyl]-4--
oxo-4H-pyrane-2-yl-methylester (521 mg, yield:100%).
[2841] .sup.1H-NMR(CDCl.sub.3).delta.: 3.09(3H, s), 3.99(2H, s),
4.99(2H, s), 5.22(2H, s), 6.15(1H, d, J=3.6 Hz), 6.59(1H, s),
6.98-7.04(2H, m), 7.16-7.23(8H, m).
[2842] (E-34) To a solution of the above-mentioned compound E-33
(256 mg, 0.5 mmol) in DMF (3 ml), was added sodium azide (49 mg,
0.75 mmol) and the mixture was stirred for 1 hour. Water was added
thereto to stop the reaction and the mixture was extracted with
ethyl acetate, washed and dried to give
6-azidemethyl-3-benzyloxy-2-[5-(4-fluorobenzyl)furan-2-carb-
onyl]-pyrane-4-one (228 mg, yield: 99%).
[2843] .sup.1H-NMR(CDCl.sub.3).delta.: 3.99(2H, s), 4.19(2H, s),
5.22(2H, s), 6.15(1H, d, J=3.6 Hz), 6.50(1H, s), 6.98-7.04(2H, m),
7.15-7.26(8H, m).
[2844] (E-35,36) To a solution of the above-mentioned compound E-34
(228 mg, 0.5 mmol) in THF (3 ml), were added water (0.3 ml) and
then triphenylphosphine (292 mg, 1 mmol). After stirring at room
temperature for 30 minutes, 4N-HCl/dioxane solution (0.25 ml) was
added thereto and the solvent was evaporated under reduced
pressure. To the mixture, were added methylene chloride (3 ml) and
then acetic anhydride (102 mg, 1 mmol) under ice-cooling. To the
mixture, was added triethylamine (101mg, 1 mmol) at the same
temperature. Water was added thereto to stop the reaction. The
mixture was extracted with chloroform, washed and dried. The
solvent was evaporated under reduced pressure and the residue was
purified with silica gel column chromatography (ethyl acetate) to
give
N-{5-benzyloxy-6-[5-(4-fluorobenzyl)furan-2-carbonyl]-4-oxo-4H-pyrane-2-y-
lmethyl}-acetoamide (177 mg, yield: 74%).
[2845] 1H-NMR(CDCl.sub.3).delta.: 1.98(3H, s), 3.99(2H, s),
4.24(2H, d, J=6.1 Hz), 5.16(2H, s), 6.13(1H, d, J=3.7 Hz), 6.33(1H,
s), 6.82(1H, bs), 6.98-7.05(2H, m), 7.15-7.35(8H, m).
[2846] (E-37) Using the above-mentioned compound E-36 (170 mg, 0.36
mmol) according to the synthetic method of E-16,
N-{6-[5-(4-fluorobenzyl)furan--
2-carbonyl]-5-hydroxy-4-oxo-4H-pyrane-2-yl-methyl}-acetoamide(110
mg, 80%) was synthesized.
[2847] Melting point:263-265.degree. C.
[2848] .sup.1H-NMR(DMSO-D.sub.6).delta.: 1.90(3H, s), 4.16(2H, s),
4.25(2H, d, J=5.6 Hz), 6.39(1H, s), 6.52(1H, d, J=3.8 Hz),
7.14-7.20(2H, m), 7.32-7.36(2H, m), 7.66(1H, d, J=3.4 Hz), 8.53(1H,
t, J=5.6 Hz).
[2849] According to the same method, the following compounds were
synthesized.
[2850] (E-37-a)
N-{6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo--
4H-pyrane-2-ylmethyl}-3-methylbutylamide
.sup.1H-NMR(CDCl.sub.3).delta.: 0.94(6H, d, J=4.2 Hz),
2.10-2.18(3H, m), 4.10(2H, s), 4.23(2H, d, J=6.1), 6.22(1H, bs),
6.29(1H, d, J=4.0 Hz), 6.37(1H, s), 7.01-7.08(2H, m), 7.22-7.26(2H,
m), 7.78(1H, d, J=3.7 Hz), 11.90(1H, s).
[2851] (E-37-b)
N-{6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo--
4H-pyrane-2-ylmethyl}-2-methoxyacetoamide
[2852] .sup.1H-NMR(CDCl.sub.3).delta.:3.44(3H, s), 3.97(2H, s),
4.11(2H, s), 4.45(2H, d, J=6.4), 6.43(1H, s), 7.01-7.08(3H, m),
7.22-7.26(2H, m), 7.75(1H, d, J=3.7 Hz), 11.88(1H, s).
[2853] (E-37-c)
N-{6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo--
4H-pyrane-2-ylmethyl}-benzamide
[2854] .sup.1H-NMR(DMSO-d.sub.6): 4.12(2H, s), 4.49(2H, d, J=5.8),
6.34(1H, d, J=3.7 Hz), 6.48(1H, s), 7.14-7.20(2H, m), 7.29-7.33(2H,
m), 7.47-7.60(3H, m), 7.64(1H, d, J=3.7 Hz), 7.88-7.91(2H, m),
9.18(1H, t, J=5.5 Hz), 10.83(1H, s).
[2855] (E-37-d)
N-{6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo--
4H-pyrane-2-ylmethyl}-benzenesulfone amide
[2856] .sup.1H-NMR(DMSO-d.sub.6).delta.: 4.09(2H, d, J=5.8 Hz),
4.17(2H, s), 6.42(1H, s), 6.52(1H, d, J=3.7 Hz), 7.15-7.21(2H, m),
7.33-7.38(2H, m), 7.47-7.60(3H, m), 7.70(1H, d, J=3.7 Hz),
7.75-7.78(2H, m), 8.54(1H, t, J=5.5 Hz), 10.81(1H, bs).
[2857] Compound E-40
[2858]
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyrane-2--
carboaldehyde O-methyloxime 277
[2859] (E-38) To a solution of alcohol E-23 (1.00 g, 2.31 mmol) in
chloroform (40 ml), was added manganese dioxide (4.02 g, 46.2 mmol)
and the mixture was refluxed for 4 hours under heating. The
insoluble product was separated with filtrate and the concentrated
residue was dissolved in a solution of chloroform (40 ml) under
reduced pressure. Manganese dioxide (4.02 g, 46.2 mmol) was added
thereto and the mixture was refluxed for 2 hours under heating. The
insoluble product was separated with filtrate. The concentrated
residue under reduced pressure was purified with silica gel column
chromatography (toluene: acetone=2:1) and crystallized from
acetone-diisopropylether to give
5-benzyloxy6-[5-(4-fluorobenzyl)furan-2-carbonyl]-4-oxo-4H-pyrane-2-carbo-
aldehyde (364 mg, yield: 36%).
[2860] Melting point:69-72.degree. C.
[2861] NMR(CDCl.sub.3).delta.:4.01 (2H, s), 5.29 (2H, s), 6.17 (1H,
d, J=3.6 Hz), 7.01 (2H, t like, J=8.7 Hz), 7.06 (1H, s), 7.16-7.30
(8H, m), 9.67 (1H, s).
[2862] (E-39) To a solution of the above-mentioned compound E-38
(150 mg, 0.346 mmol) in ethanol (5 ml)-water (1 ml), were added
sodium acetate (85 mg) and hydrochloric acid O-methylhydroxylamine
(35 mg) and the mixture was stirred at 80.degree. C. for 5 hours.
Water was added thereto and extracted with ethyl acetate. The
extract was washed and dried. The solvent was evaporated under
reduced pressure. The residue was purified with lobey column (size
B) (toluene: ethyl acetate=5:1) and crystallized from ethyl
acetate-diisopropylether to give 5-benzyloxy6-[5-(4-fluorobenz-
yl)furan-2-carbonyl]-4-oxo-4H-pyrane-2-carboaldehyde O-methyloxime
(103 mg, yield: 64%).
[2863] Melting point:116-117.degree. C.
[2864] NMR(CDCl.sub.3).delta.: 4.01 (2H, s), 4.02 (3H, s), 5.27
(2H, s), 6.14 (1H, d, J=3.6 Hz), 6.69 (1H, s), 7.00 (2H, t like,
J=8.7 Hz), 7.15-7.30 (7H, m), 7.73 (1H, s).
[2865] (E-40) The above-mentioned compound E-39 (132 mg, 0.286
mmol) was dissolved in trifluoroacetic acid (1 ml) and the solution
was stirred at room temperature for 35 minutes. The residue that
trifluoroacetic acid was evaporated under reduced pressure was
dissolved in chloroform, washed with water twice and dried. The
solvent was evaporated under reduced pressure. The residue was
crystallized from tetrahydrofuran-diisopropylet- her to give
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyra-
ne-2-carboaldehyde O-methyloxime (100 mg, yield:94%).
[2866] Melting point: 180-182.degree. C.
[2867] NMR(CDCl.sub.3).delta.: 4.10 (3H, s), 4.12 (2H, s), 6.26
(1H, d, J=3.6 Hz), 6.54 (1H, s), 7.04 (2H, t like, J=8.7 Hz),
7.23-7.28 (2H, m), 7.80 (1H, s), 8.19 (1H, d, J=3.6 Hz), 11.97 (1H,
br. s).
[2868] Compound E-43
[2869]
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyrane-2--
carbonitrile 278
[2870] (E-41) To a solution of compound E-38 (264 mg, 0.611 mmol)
in ethanol (5 ml)-water (1 ml), were added sodium acetate (150 mg)
and hydroxylamine hydrochloride (51 mg) and the mixture was stirred
at room temperature overnight. To a solution, water was added and
the mixture was extracted with ethyl acetate. The extract was
washed and dried. The solvent was evaporated under reduced pressure
to give rude crystal (250 mg) of
5-benzyloxy6-[5-(4-fluorobenzyl)furan-2-carbonyl]-4-oxo-4H-pyrane--
2-carboaldehyde oxime. This was used for the next reaction without
purifying.
[2871] (E-42) To a solution of imidazole (250 mg) in methylene
chloride (5 ml), was added thionyl chloride (0.067 ml) under
ice-cooling and the mixture was stirred for 15 minutes. To the
solution, was added a suspension of the above-mentioned compound
E-41 (250 mg) in methylene chloride (10 ml) and the mixture was
stirred under warming to room temperature for 51 minutes. Water was
added to the solution and the mixture was extracted with
chloroform. The extract was washed and dried. The solvent was
evaporated under reduced pressure and the residue was purified with
silica gel column chromatography (toluene: ethyl acetate=10:1) to
give 5-benzyloxy-6-[5-(4-fluorobenzyl)furan-2-carbonyl]--
4-oxo-4H-pyrane-2-carbonitrile (195 mg, 0.2 total yield of process:
74%).
[2872] NMR(CDCl.sub.3).delta.: 4.00 (2H, s), 5.26 (2H, s), 6.18
(1H, d, J=3.6 Hz), 6.95 (1H, s), 7.02 (2H, t like, J=8.7 Hz),
7.13-7.28 (8H, m).
[2873] (E-43) The above-mentioned compound E-42 (195 mg, 0.454
mmol) was dissolved in trifluoroacetic acid (2 ml) and the mixture
was stirred at room temperature for 35 minutes. The residue which
trifluoroacetic acid was evaporated under reduced pressure was
dissolved in chloroform, washed with water twice and dried. The
solvent was evaporated under reduced pressure. The residue was
crystallized from tetrahydrofuran-diisopropylet- her to give
6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyra-
ne-2-carbonitrile (98 mg, yield: 64%).
[2874] Melting point: 190-194.degree. C. (decomp.)
[2875] NMR(CDCl.sub.3).delta.: 4.12 (3H, s), 6.35 (1H, d, J=3.9
Hz), 6.95 (1H, s), 7.05 (2H, t like, J=8.7 Hz), 7.23-7.29 (2H, m),
7.67 (1H, d, J=3.9 Hz), 12.15 (1H, br. s).
[2876] Compound E-45
[2877]
3-[6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyrane-
-2-yl]ethyl Acrylate 279
[2878] (E-44) To a suspension of 60% sodium hydride (20 mg, 0.5
mmol) in tetrahydrofuran (2 ml), was added diethylphosphonoethyl
acetate (0.119 ml) and the mixture was stirred at room temperature
for 10 minutes. To the solution, was added a solution of compound
E-38 (220 mg, 0.506 mmol) in tetrahydrofuran (3 ml) under
ice-cooling and the mixture was stirred for 35 minutes. The
solution added ammonium chloride aqueous solution was extracted
with ethyl acetate. The extract was washed and dried. The solvent
was evaporated under reduced pressure and the residue was purified
with lober column (size B) (toluene: ethyl acetate=5:1) to give
3-[-5-benzyloxy[6-[5-(4-fluorobenzyl)furan-2-carbonyl]-4-oxo-4H-pyrane-2--
yl]ethyl acrylate (149 mg, yield: 58%).
[2879] Melting point: 104-106.degree. C.
[2880] NMR(CDCl.sub.3).delta.: 1.31 (3H, t, J=7.2 Hz), 4.00 (2H,
s), 4.26 (2H, q, J=7.2 Hz), 5.25 (2H, s), 6.16 (1H, d, J=3.6 Hz),
6.56 (1H, d, J=15.3 Hz), 6.57 (1H, s), 7.00 (2H, t like, J=8.7 Hz),
7.13-7.29 (9H, m).
[2881] (E-45) The above-mentioned compound E-44 (149 mg, 0.297
mmol) was dissolved in trifluoroacetic acid (1 ml) and the mixture
was stirred at room temperature for 35 minutes. The residue which
trifluoroacetic acid was evaporated under reduced pressure was
dissolved, washed with water twice and dried. The solvent was
evaporated under reduced pressure. The residue was crystallized
from tetrahydrofuran-diisopropylether
3-[6-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-hydroxy-4-oxo-4H-pyrane-2-yl]-
ethyl acrylate (99 mg, yield: 81%).
[2882] Melting point:205-207.degree. C.
[2883] NMR(CDCl.sub.3).delta.: 1.33 (3H, t, J=6.9 Hz), 4.17 (2H,
s), 4.30 (2H, q, J=6.9 Hz), 6.32 (1H, d, J=3.6 Hz), 6.62 (1H, s),
6.83 (1H, d, J=15.6 Hz), 7.04 (2H, t like, J=8.7 Hz), 7.23-7.27
(2H, m), 7.30 (1H, d, J=15.6 Hz), 7.62 (1H, d, J=3.6 Hz), 11.85
(1H, br.s).
[2884] Compound E-50
[2885]
5-bromo2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxypyrane-4-one
280
[2886] (E-47) To a solution of 3-bromo-5-hydroxypyrane-4-one E-46
(10.0 g, 52.4 mmol) synthesized according to the method described
in reference (Heterocycles, 1992, 34, p1803) in methyl alcohol (40
ml), was added sodium hydroxide (2.61 g, 65.3 mmol) aqueous
solution (12 ml) and the mixture was stirred for 5 minutes. 37%
formaldehyde aqueous solution (10.6 ml, 131 mmol) was added
dropwise thereto over 40 minutes and the mixture was stirred
overnight. After removing formaldehyde and methyl alcohol under
reduced pressure, methyl alcohol (40 ml) and chlorobenzyl (7.2 ml,
62.9 mmol) were added to the residue and the mixture was stirred at
60.degree. C. for 2 hours. After cooling, the mixture was
neutralized with 2M hydrochloric acid and methyl alcohol was
evaporated under reduced pressure. The water layer was extracted
with ethyl acetate. The extract was washed and dried. The solvent
was evaporated under reduced pressure to give crude product (12.2
g). To a solution of the obtained crude product (12.2 g) and
2,2,6,6-tetramethylpiperidine-1-oxyl, free radical (613 mg, 3.92
mmoli in ethyl acetate (80 ml), was added 1.0M sodium hydrogen
carbonate aqueous solution (80 ml, 80 mmol). 10% sodium hyochlorite
aqueous solution (58 ml, 78.5 mmol) was added dropwise thereto for
50 minutes with stirring hard under about 5.degree. C. The water
layer was divided, acidified with 2M hydrochloric acid and then
extracted with ethyl acetate. The extract was washed and dried. The
solvent was evaporated under reduced pressure to give
3-benzyloxy-5-bromo-4-oxo-4H-pyrane-2-carboxylic acid (6.26 g,
yield: 37%).
[2887] (E-48) To a solution of the above-mentioned compound E-47
(685 mg, 2.11 mmol) in dimethylformamide (5 ml), were added
1,8-diazabicyclo[5,4,0]-7-undecen (0,35 ml 2.32 mmol) and
iodomethane (0.13 ml, 2.53 mmol) and the mixture was stirred at
room temperature for 3 hours. Water was added to the solution and
the mixture was extracted with ethyl acetate. The extract was
washed and dried. The solvent was evaporated under reduced pressure
to give 3-benzyloxy-5-bromo-4-oxo-4H-py- rane-2-carboxylate methyl
ester (643 mg, yield: 90%).
[2888] NMR(CDCl.sub.3).delta.:3.89(3H, s), 5.32(2H, s),
7.32-7.40(2H, m), 7.44-7.49(2H, m), 8.11(1H, s).
[2889] (E-49) A solution of 2-bromo-5-(4-fluorobenzyl)furan (181
mg, 0.708 mmol) in tetrahydrofuran (5 ml) was cooled to -78.degree.
C. 1.57M butyllithiumhexane solution (0.45 ml, 0.649 mmol) was
added dropwise thereto. After stirring at the same temperature for
10 minutes, a solution of compound E-48 (200 mg, 0.59 mmol) in
tetrahydrofuran (2 ml) was added thereto and the mixture was
stirred for 80 minutes. The saturated ammonium chloride aqueous
solution was added thereto and the mixture was extracted with ethyl
acetate. The extract was washed and dried. The solvent was
evaporated under reduced pressure and the residue was purified with
silica gel column chromatography (n-hexane/ethyl acetate=3/1) to
give 3-benzyloxy-5-bromo-2-[5-(4-fluorobenzyl)furan2-carb-
onyl]pyrane-4-one (109 mg, yield: 38%).
[2890] NMR(CDCl.sub.3).delta.:3.99(2H, s), 5.24(2H, s), 6.14(1H, d,
J=3.6 Hz), 6.97-7.05(2H, m), 7.13-7.21(3H, m), 7.21-7.26(5H, m),
8.11(1H, s).
[2891] (E-50) The above-mentioned compound E-49 (100 mg, 0.207
mmol) was dissolved in trifluoroacetic acid (2 ml) and the mixture
was stirred for 1 hour. The solvent was evaporated under reduced
pressure. Water was added to the residue and the mixture was
extracted with ethyl acetate. The extract was washed and dried. The
solvent was evaporated under reduced pressure and the obtained
solid was recrystallized with the acetone-methyl alcohol mixture to
give 5-bromo-2-[5-(4-fluorobenzyl)furan-
-2-carbonyl]-3-hydroxypyrane-4-one (61 mg, yield: 75%).
[2892] Melting point: 191-192.degree. C.
[2893] Elementary analysis as C.sub.17H.sub.10BrFO.sub.5
[2894] Calcd. (%): C, 51.93; H, 2.56; Br, 20.32; F, 4.83. Found
(%): C, 52.12; H, 2.55; Br, 20.37; F, 4.66.
[2895] NMR(CDCl.sub.3).delta.:4.11(2H, s), 6.28(1H, d, J=3.7 Hz),
7.01-7.09(2H, m), 7.21-7.29(2H, m), 7.64(1H, d, J=3.7 Hz), 8.16(1H,
s), 11.92(1H, s).
[2896] Compound E-52
[2897]
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-5-phenylpyrane-4-o-
ne 281
[2898] (E-51) To a solution of compound E-49 (250 mg, 0.518 mmol),
phenylboronic acid (76 mg, 0.622 mmol) and
tetrakistriphenylphosphine palladium (30 mg, 0.0259 mmol) in
dimethoxyethane (4 ml) ethanol (1 ml), was added 2M sodium
carbonate aqueous solution (0.93 ml, 1.86 mmol) and the mixture was
fluxed under heating for 1 hour. After cooling, the saturated
ammonium chloride aqueous solution was added thereto and the
mixture was extracted with ethyl acetate. The extract was washed
and dried. The solvent was evaporated under reduced pressure. The
residue was purified with silica gel column chromatography
(n-hexane/ethyl acetate=3/1) to give
3-benzyloxy-2-[5-(4-fluorobenzyl)furan-2-carbonyl]-5-
-phenylpyrane-4-one(67 mg, yield: 27%).
[2899] NMR(CDCl.sub.3).delta.:4.02(2H, s), 5.25(2H, s), 6.15(1H, d,
J=3.6 Hz), 6.97-7.05(2H, m), 7.17-7.38(7H, m), 7.41-7.50(4H, m),
7.52-7.58(2H, m), 7.92(1H, s).
[2900] (E-52) According to the same method of example E-16,
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-5-phenylpyrane-4-one(28
mg, yield: 51%) was synthesized from the above-mentioned compound
E-51 (67 mg, 0.140 mmol).
[2901] Melting point: 199-201.degree. C.
[2902] NMR(CDCl.sub.3).delta.:4.12(2H, s), 6.27(1H, d, J=3.6 Hz),
7.01-7.09(2H, m), 7.22-7.28(2H, m), 7.40-7.50(3H, m), 7.53-7.58(2H,
m), 7.69(1H, d, J=3.6 Hz), 7.98(1H, s), 11.68(1H, s).
[2903] F Group Compound
[2904] Compound F-4
[2905]
3-[5-(4-fluorobenzyl)furan-2-carbonyl]-2-hydroxy-2-cyclohexene-1-on-
e 282
[2906] (F-3) To a lithiumbistrimethylsilylamide solution prepared
from hexamethyldisilazane (0.23 ml) and n-butyllithium (1.1 mmol)
in tetrahydrofuran (3 ml), was added dropwise a solution of
2-(tert-butyldimethylsilyloxy)-2-cyclohexene-1-one (F-1)(226 mg,
1.0 mmol) synthesized according to the method described in
reference (Tetrahedron, 1997, 53, p8963) in tetrahydrofuran (2 ml)
under cooling at -78.degree. C. After stirring at the same
temperature for 19 minutes, a solution of
5-(4-fluorobenzyl)furan-2-carboxylate chloride
(F-2)(WO-00039086,example 120) (120 mg, 0.5 mmol) in
tetrahydrofuran (1 ml) was added dropwise thereto. After stirring
for 1 hour, the mixture was warmed to 0.degree. C. over 20 minutes.
The ammonium chloride aqueous solution was added to the solution
and the mixture was extracted with ethyl acetate. The extract was
washed and dried. The solvent was evaporated under reduced pressure
and the residue was purified with silica gel column chromatography
(n-hexane: ethyl acetate=10:1-5:1) to give
2-(tert-butyldimethylsilyloxy)-6-[5-(4-fluorobenzyl)furan-2-carbonyl-
]-2-cyclohexene-1-one(189 mg, yield:88%).
[2907] (F-4) To a solution of the above-mentioned compound F-3 (172
mg, 0.40 mmol) in tetrahydrofuran (1 ml)-methyl alcohol (4 ml), was
added 2n-hydrochloric acid (1 ml) and the mixture was stirred at
room temperature for 15 minutes and then at 50.degree. C. for 1
hour. Ice water was added to the solution and the mixture was
extracted with ethyl acetate. The extract was washed and dried. The
solvent was evaporated under reduced pressure and the residue was
crystallized from ethyl acetate diisopropylether to give
3-[5-(4-fluorobenzyl)furan-2-carbonyl]-2-
-hydroxy-2-cyclohexene-1-one (85 mg, yield: 68%).
[2908] Melting point: 133-134.degree. C.
[2909] Elementary analysis as C.sub.18H.sub.15FO.sub.4
[2910] Calcd. (%): C, 68.78; H, 4.81; F, 6.04. Found (%): C, 68.56;
H, 54.77; F, 5.90.
[2911] NMR(CDCl.sub.3).delta.:2.02-2.10 (2H, m), 2.61 (2H, t like,
J=7 Hz), 2.87 (2H, t, J=6.0 Hz), 4.06 (2H, s), 6.22 (1H, J=3.6 Hz),
7.03 (2H, t like, J=9 Hz), 7.23 (2H, dd, J=8.3 Hz, 5.3 Hz), 7.30
(1H, d, J=3.6 Hz), 13.26 (1H, br.s). There was the mixture of three
kinds of tautomers in CDCl.sub.3 and the data of compound F-4,
which had the highest presence ratio (70%), was shown.
[2912] G Group Compound
[2913] Compound G-7
[2914]
6-[5-(4-fluorobenzyl)pyridine-2-yl]-5-hydroxy2-methyl-1H-pyrimidine-
-4-one 283
[2915] (G-1) 5-hydroxy-2-methylpyridine (10.9 g, 100 mmol) and
pyridine (12.2 ml, 150 mmol) was dissolved in methylene chloride
(100 ml) and trifluoromethanesulfonic acid anhydride (18.5 ml, 120
mmol) was added dropwise thereto under ice-cooling. After stirring
at the same temperature for 1.5 hours, methyl alcohol (2 ml) and
then the saturated sodium hydrogen carbonate aqueous solution (150
ml) were added thereto and the mixture was extracted with methylene
chloride. The extract was washed and dried. The solvent was
evaporated under reduced pressure and the residue was purified with
silica gel column chromatography (n-hexane: ethyl acetate=9:1-4:1)
to give 2-methyl-5-(trifluoromethanesulfonyloxy)py- ridine (23.0 g,
yield: 95%).
[2916] (G-2) To a solution of the above-mentioned compound G-1
(10.4 g, 43.2 mmol) in tetrahydrofuran (130 ml), were added
4-fluorobenzyl bromidezinc-tetrahydrofuran solution (65 mmol)
synthesized according to the method described in reference (J. Org.
Chem., 1994, 59, p2671) and tetrakis(triphenylphosphine)palladium
(2.4 g) and the mixture was refluxed under heating for 5 hours. The
solvent was evaporated under reduced pressure. Water and ethyl
acetate was added to the residue and the insoluble product was
filtrated with celite. The filtration was extracted with ethyl
acetate and the residue was washed with water. The obtained
solution of ethyl acetate was extracted with 1n-hydrochloric acid.
The hydrochloric acid extract turned alkaline with 2n-sodium
hydroxide aqueous solution. The solution was extracted with ethyl
acetate, washed and dried. The residue which the solvent was
evaporated was purified with silica gel column chromatography
(n-hexane: ethyl acetate=2:1) to give
5-(4-fluorobenzyl)-2-methylpyridine (5.42 g, yield: 62%).
[2917] NMR(CDCl.sub.3).delta.:2.53 (3H, s), 3.91 (2H, s), 6.96 (2H,
t like, J=8.7 Hz), 7.06-7.15 (3H, m), 7.34 (1H, dd, J=8.1 Hz, 1.5
Hz), 7.36 (1H, d, J=1.5 Hz).
[2918] (G-3) To a solution of the above-mentioned compound G-2
(4.64 g, 22.9 mmol) in pyridine (40 ml), was added selenium dioxide
(15.3 g, 138 mmol) and the mixture was refluxed under heating for
36 hours. Water and chloroform were added to the residue, which
pyridine was evaporated under reduced pressure. The insoluble
product was separated with filtrate. The filtration was extracted
with chloroform and the extract was washed and dried. The solvent
was evaporated under reduced pressure. The residue was dissolved in
toluene (50 ml) and the solution was treated with active carbon (4
g). The solvent was evaporated under reduced pressure to give crude
product (5.6 g) of 5-(4-fluorobenzyl)pyridine-2-carboxylic
acid.
[2919] Furthermore, using 5-(4-fluorophenyloxy)-2-methylpyridine
synthesized according to the method described in reference
(JP1979-125681), 5-(4-fluorophenyloxy)pyridine-2-carboxylic acid
was synthesized according to the same method.
[2920] (G-4) To a solution of the above-mentioned crude product G-3
(5.6 g) in methyl alcohol (50 ml), was added dropwise thionyl
chloride (8.36 ml, 115 mmol) under ice-cooling. After adding
dropwise, the mixture was refluxed under heating for 4 hours. Water
and ethyl acetate were added thereto under ice-cooling. Sodium
hydrogen carbonate (14 g) was added gradually at the same
temperature and the mixture was extracted with ethyl acetate. The
extract was washed and dried. The solvent was evaporated under
reduced pressure and the residue was purified with silica gel
column chromatography (n-hexane: acetone=2:1) to give
5-(4-fluorobenzyl)pyridine-2-carboxylate methyl (3.40 g, 2 total
yield of process: 60%).
[2921] NMR(CDCl.sub.3).delta.:4.00(3H, s), 4.04 (2H, s), 7.01 (2H,
t like, J=8.7 Hz), 7.10-7.16 (2H, m), 7.58 (1H, dd, J=7.8 Hz, 2.4
Hz), 8.06 (1H, d, J=7.8 Hz), 8.62 (1H, d, J=2.4 Hz). According to
the same method, 5-(4-fluorophenyloxy)pyridine-2-carboxylate methyl
was synthesized.
[2922] NMR(CDCl.sub.3).delta.:4.00 (3H, s), 7.03-7.16 (4H,m), 7.25
(1H, dd, J=8.7 Hz, 2.4 Hz), 8.10 (1H, dd, J=8.7 Hz), 8.47 (1H, d,
J=2.4 Hz).
[2923] (G-5) To a solution of benzyloxyethyl acetate (521 mg, 2.7
mmol) in tetrahydrofuran (10 ml), was added dropwise
lithium(bistrimethylsilyl)ami- detetrahydrofuran solution (2.7
mmol) at -78.degree. C. After stirring at the same temperature for
25 minutes, a solution of the above-mentioned compound G-4 (328 mg,
1.34 mmol) in tetrahydrofuran (5 ml) was added dropwise thereto and
the mixture was stirred for 32 minutes. To the solution, was added
saturated ammonium chloride aqueous solution and the mixture was
extracted with ethyl acetate. The extract was washed and dried. The
solvent was evaporated under reduced pressure and the residue was
purified with silica gel column chromatography (n-hexane:
acetone=3:1) to give
2-benzyloxy-3-[5-(4-fluorobenzyl)pyridine-2-yl]-3-ox- o ethyl
propionate (315 mg, yield: 58%). According to the same method,
2-benzyloxy-3-[5-(4-fluorophenyloxy)pyridine-2-yl]-3-oxo ethyl
propionate was synthesized.
[2924] Furthermore, using
[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-carboxyl- ate ethyl
synthesized according to the method described in reference
(Carbohydr. Res., 1994, 254, p91),
2-benzyloxy-3-[5-(4-fluorobenzyl)-[1,3- ,4]oxadiazole-2-yl]-3-oxo
ethyl propionate was synthesized.
[2925] (G-6) The above-mentioned compound G-5 (315 mg, 0.77 mmol)
and acetoamidine hydrochloride (293 mg, 3.1 mmol) were dissolved in
a solution of methyl alcohol (6 ml). 28% sodium methoxide-methyl
alcohol solution (0.47 ml) was added thereto and the mixture was
refluxed under heating for 2 hours 25 minutes. To the solution,
which cooled to room temperature, was added the saturated ammonium
chloride aqueous solution and the mixture was extracted with ethyl
acetate. The extract was washed and dried. The solvent was
evaporated under reduced pressure and the residue was crystallized
from ethyl acetate isopropylether to give
5-benzyloxy-6-[5-(4-fluorobenzyl)pyridine-2-yl]-2-methyl-1H-pyrimidine-4--
one (164 mg, yield: 53%).
[2926] NMR(CDCl.sub.3).delta.:2.57 (3H, s), 4.01 (2H, s), 5.20 (2H,
s), 7.01 (2H, t like, J=8.7 Hz), 7.10-7.18 (2H, m), 7.20-7.27 (5H,
m), 7.49 (1H, dd, J=8.1 Hz, 2.1 Hz), 7.88 (1H, d, J=8.1 Hz), 8.64
(1H, d, J=2.1 Hz).
[2927] The following compound was prepared as well as above.
[2928]
5-benzyloxy-6-[5-(4-fluorophenyloxy)pyridine-2-yl]-2-methyl-1H-pyri-
midine-4-one
[2929] NMR(CDCl.sub.3).delta.: 2.59 (3H, s), 5.21 (2H, s),
7.00-7.14 (4H, m), 7.21-7.31 (6H, m), 7.93 (1H, d, J=9.0 Hz), 8.49
(1H, d, J=2.7 Hz).
[2930]
5-benzyloxy-6-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-2-methyl--
1H-pyrimidine-4-one
[2931] NMR(CDCl.sub.3).delta.: 2.55 (3H, s), 4.23 (2H, s), 5.36
(2H, s), 7.23-7.40 (6H, m),12.61 (1H, br.s).
[2932] (G-7) To a solution of the above-mentioned compound G-6 (102
mg, 0.25 mmol) in tetrahydrofuran (2 ml)-methyl alcohol (2 ml), was
added 10% palladium-carbon (13 mg) and the mixture was stirred
under hydrogen atmosphere at room temperature for 10 minutes.
Chloroform (8 ml) and methyl alcohol (3 ml) was added to the
solution. The precipitated crystal was dissolved in the solution
and catalyst was separated with filtrate. The solvent was
evaporated under reduced pressure and the crystalline residue was
recrystallized from N,N-dimethylformamide to give
6-[5-(4-fluorobenzyl)pyridine-2-yl]-5-hydroxy-2-methyl-1H-pyrimidine-4-on-
e (47 mg, yield-59%).
[2933] Melting point:>300.degree. C.
[2934] Elementary analysis as C.sub.17H.sub.14FN.sub.3O.sub.2
[2935] Calcd. (%): C, 65.59; H, 4.53; N, 13.50; F, 6.10. Found (%):
C, 65.57; H, 4.44; N, 13.50; F, 5.82.
[2936] NMR(ODMSO-d.sub.6)d :2.27 (3H, s), 4.07 (3H, s), 7.15 (2H, t
like J=9 Hz), 7.30-7.38 (2H, m), 7.93 (1H, dd, J=1.8 Hz, 8.1 Hz),
8.23 (1H, d, J=8.1 Hz), 8.59 (1H, d, J=1.8 Hz), 12.41 (1H, br.s),
13.82 (1H, br.s).
[2937] The following compound was prepared as well as above.
[2938]
6-[5-(4-fluorophenyloxy)pyridine-2-yl]-5-hydroxy-2-methyl-1H-pyrimi-
dine-4-one (G-7-a)
[2939] Melting point:255-256.degree. C.
[2940] Elementary analysis as C.sub.16H.sub.12FN.sub.3O.sub.3
0.5H.sub.2O
[2941] Calcd. (%): C, 59.63; H, 4.07; N, 13.04; F, 5.89. Found (%):
C, 59.71; H, 4.04; N, 12.93; F, 5.74.
[2942] NMR(DMSO-d.sub.6).delta.:2.28 (3H, s), 7.22-7.36 (4H, m),
7.68 (1H, dd, J=3 Hz, 9 Hz), 8.29 (1H, d, J=9 Hz), 8.47 (1H, d, J=3
Hz), 12.43 (1H, br.s), 13.23 (1H, br.s).
6-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-5--
hydroxy-2-methyl-1H-pyrimidine-4-one (G-7-b)
[2943] Melting point:283-286.degree. C.
[2944] Elementary analysis as C.sub.14H.sub.11FN.sub.4O.sub.3
[2945] Calcd. (%): C, 55.63; H, 3.67; N, 18.54; F, 6.29. Found (%):
C, 55.61; H, 3.69; N, 18.36; F, 5.99.
[2946] NMR(DMSO-d.sub.6).delta.:2.25 (3H, s), 4.37 (2H, s), 7.20
(2H, t like J=9 Hz), 7.36-7.42 (2H, m).
[2947] H Group Compound
[2948] Compound H-7
[2949]
3-hydroxy-1-isopropyl-4-(6-phenethylpyrimidine-4-yl)-1,5-dihydropyr-
role-2-one 284
[2950] (H-1) According to the method described in reference
(Tetrahedron 1997,53(15),5617),
4-benzyloxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrazole-3-c- arboxylate
ethyl ester was synthesized.
[2951] Melting point:131-133.degree. C.
[2952] NMR(CDCl.sub.3).delta.: 1.39(3H, t, J=7.0 Hz), 3.58(3H, s),
4.40(2H, q, J=7.0 Hz), 5.03(2H, s), 7.33-7.39(5H, m).
[2953] (H-2) To a solution of sodium hydride (856 mg, 21.4 mmol)
and dimethylformamide (25 ml), was added the above-mentioned
compound H-1 (4.93 g, 17.8 mmol) and the mixture was stirred for 30
minutes. Chloromethoxymethylbenzene (3.35 g, 21.4 mmol) was added
thereto under ice-cooling and the mixture was warmed to room
temperature and stirred for 30 minutes. The ammonium chloride
aqueous solution was added thereto to stop the reaction and the
mixture was extracted with diethyl ether. The extract was washed
and dried. The solvent was evaporated under reduced pressure to
give 4-benzyloxy-2-benzyloxymethyl-1-methyl-5-oxo-2,5-
-dihydro-1H-pyrazole-3-carboxylate ethyl ester (6.68 g, yield:
95%).
[2954] NMR(CDCl.sub.3).delta.: 1.40(3H, t, J=7.0 Hz), 3.67(3H, s),
4.42(2H, q, J=7.0 Hz), 4.73(2H, s), 5.05(2H, s), 5.33(2H, s),
7.26-7.44(10H, m).
[2955] (H-3) To a solution of the above-mentioned compound H-2
(6.68 g, 16.8 mmol) in methyl alcohol (50 ml), was added 1N-lithium
hydroxide aqueous solution (25.3 ml, 25.3 mmol). The mixture was
warmed to 60.degree. C. and stirred for 2 hours. Methyl alcohol was
evaporated under reduced pressure and the water layer was washed
with diethyl ether. The aqueous solution was acidified with citric
acid and the mixture was extracted with ethyl acetate. The extract
was washed and dried and the solvent was evaporated to give
4-benzyloxy-2-benzyloxymethyl-1-methyl-5-o-
xo-2,5-dihydro-1H-pyrazole-3-carboxylic acid (5.28 g, yield:
85%).
[2956] NMR(DMSO-d.sub.8).delta.: 3.63(3H, s), 4.77(2H, s), 4.98(2H,
s),.5.34(2H, s), 7.25-7.38(10H, m).
[2957] (H-4) A solution of the above-mentioned product H-3 (5.28 g,
14.3 mmol),1-hydroxybenzotriazole (189 mg, 1.4
mmol),1-ethyl-3-(3-dimethylamin- opropyl)carbodiimidehydrochloride
(3.3 g, 17.2 mmol),N, O-dimethylhydroxyamine (1.68 g, 17.2 mmol)
and triethylamine (1.74 g, 17.2 mmol) in dimethylformamide (50 ml)
was stirred at room temperature for 3 hours. Water was added
thereto to stop the reaction and the mixture was extracted with
ethyl acetate. The extract was washed and dried. The solvent was
evaporated under reduced pressure and the residue was purified with
silica gel column chromatography (n-hexane-ethyl acetate=1:1-1:2)
to give 4-benzyloxy-2-benzyloxymethyl-1-methyl-5-oxo-2,5-
-dihydro-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide (3.89
g, yield: 66%).
[2958] NMR(CDCl.sub.3).delta.: 3.37(3H, s), 3.63(3H, s), 3.76(3H,
s), 4.75(2H, s), 5.12(2H, s), 5.32(2H, s), 7.26-7.37(10H, m).
[2959] (H-5) To a solution of 2-bromo-5-(4-fluorobenzyl)furan (2.41
g, 9.45 mmol) synthesized according to the method of example A-6 in
THF (60 ml), were added n-butyllithium (9.45 mmol) at -78.degree.
C. and then a solution of the above-mentioned compound H-4 (3.89 g,
9.45 mmol) in THF(10 ml). The ammonium chloride aqueous solution
was added thereto to stop the reaction and the mixture was
extracted with ethyl acetate. The extract was washed and dried. The
solvent was evaporated under reduced pressure and the residue was
purified with silica gel column chromatography (n-hexane-ethyl
acetate=3:1-1:2) to give
4-benzyloxy-1-benzyloxymethyl-5-[5-(4-fluorobenzyl)furan-2-carbonyl]-2-me-
thyl-1,2-dihydropyrazole-3-one (2.36 g, yield: 47%).
[2960] NMR(CDCl.sub.3).delta.: 3.67(3H, s), 4.07(2H, s), 4.76(2H,
s), 5.10(2H, s), 5.37(2H, s), 6.10(1H, d, J=3.6 Hz), 6.97-7.03(2H,
m), 7.21-7.36(10H, m), 7.45-7.48(2H, m), 7.69(1H, d, J=3.4 Hz).
[2961] (H-6) To a solution of the above-mentioned compound H-5
(2.36 g, 4.48 mmol) in dioxane (205 ml), was added 6N hydrochloric
acid aqueous solution (20 ml) and the mixture was stirred at room
temperature for 1 hour. The solvent was evaporated under reduced
pressure and the residue was purified with silica gel column
chromatography (n-hexane-ethyl acetate=1:1-0:1) to give
4-benzyloxy-5-[5-(4-fluorobenzyl)furan-2-carbony-
l]-2-methyl1,2-dihydropyrazole-3-one (1.56 g, yield:86%).
[2962] NMR(CDCl.sub.3).delta.: 3.61(3H, s), 4.06(2H, s), 5.09(2H,
s), 6.11(1H, d, J=3.7 Hz), 7.98-7.03(2H, m), 7.21-7.42(7H, m),
7.71(1H, d, J=3.1 Hz).
[2963] (H-7) To a solution of the above-mentioned compound H-6 (837
mg, 2.1 mmol) in acetic acid (10 ml), was added 47% hydrogen
bromide aqueous solution (10 ml) and the mixture was stirred at
50.degree. C. for 1 hour. The solvent was evaporated under reduced
pressure and the residue was dissolved in ethyl acetate, washed
with water and dried. The precipitated crystal obtained by
evaporating solvent under reduced pressure was washed with
n-hexane-ethyl acetate (2:1) to give
3-hydroxy-1-isopropyl-4-(6-phen-
ethylpyrimidine-4-yl)-1,5-dihydropyrrole-2-one (476 mg, yield:
72%).
[2964] Melting point: 156-159.degree. C.
[2965] Elementary analysis as Cr.sub.6H.sub.13FN.sub.2O.sub.4
[2966] Calcd. (%): C, 60.76; H, 4.14; N, 8.86; F, 6.01. Found (%):
C, 60.94; H, 4.16; N, 8.66; F, 5.86.
[2967] NMR(CDCl.sub.3).delta.: 3.77(3H, s), 4.09(2H, s), 6.21(1H,
d, J=3.7 Hz), 6.99-7.05(2H, m), 7.26-7.32(2H, m), 8.00(1H, d, J=3.7
Hz).
[2968] Compound H-13
[2969]
5-[5-(4-fluorobenzyl)furan-2-carbonyl]-4-hydroxy-1,2-dimethyl-1,2-d-
ihydropyrazole-3-one 285
[2970] (H-8) According to the method described in reference
(Tetrahedron 1997,53(15),5617),
4-methoxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrazole-3-car- boxylate
ethyl ester was synthesized.
[2971] Melting point: 99-100.degree. C.
[2972] NMR(CDCl.sub.3).delta.: 1.37(3H, t, J=7.0 Hz), 3.67(3H, s),
3.84(3H, s), 4.38(2H, q, J=7.0 Hz).
[2973] (H-9) Using the above-mentioned compound H-8 and iodo
methane according to the synthetic method of (H-2),
4-methoxy-1,2-dimethyl-5-oxo--
2,5-dihydro-1H-pyrazole-3-carboxylate ethyl ester was
synthesized.
[2974] NMR(CDCl.sub.3).delta.:1.41(3H, t, J=7.0 Hz), 3.68(3H, s),
3.87(3H, s), 4.09(3H, s), 4.41(2H, q, J=7.0 Hz).
[2975] (H-10) Using the above-mentioned compound H-9 according to
the synthetic method of (H-3), the crude product of
4-methoxy-1,2-dimethyl-5-- oxo-2,5-dihydro-1H-pyrazole-3-carboxylic
acid was synthesized.
[2976] (H-11) Using the above-mentioned crude product H-10
according to the synthetic method of (H-4),
4-methoxy-1,2-dimethyl-5-oxo-2,5-dihydro-1- H-pyrazole-3-carboxylic
acid methoxy-methyl-amide was synthesized.
[2977] NMR(CDCl.sub.3).delta.: 3.39(3H, s), 3.63(3H, s), 3.77(3H,
s), 3.83(3H, s), 4.07(3H, s).
[2978] (H-12) Using the above-mentioned product H-11 according to
the synthetic method of (H-5),
5-[5-(4-fluorobenzyl)furan-2-carbonyl]-4-metho-
xy-1,2-dimethyl-1,2-dihydropyrazole-3-one was synthesized.
[2979] Melting point:111-113.degree. C.
[2980] NMR(CDCl.sub.3).delta.: 3.69(3H, s), 3.89(3H, s), 4.06(2H,
s), 4.11(3H, s), 6.09(1H, d, J=3.7 Hz), 6.97-7.03(2H, m),
7.21-7.26(2H, m), 7.66(1H, d, J=3.7 Hz).
[2981] (H-13) The above-mentioned compound H-12 (750 mg, 2.18 mmol)
and pyridinehydrochloride (7.5 g) were heated to 1500C for 12
minutes. Water was added thereto to stop the reaction and the
mixture was extracted with ethyl acetate. The extract was washed
and dried. The solvent was evaporated under reduced pressure and
the precipitated crystal was recrystallized with n-hexane-ethyl
acetate (2:1) to give
(5-[5-(4-fluorobenzyl)furan-2-carbonyl]-4-hydroxy-1,2-dimethyl-1,2-dihydr-
opyrazole-3-one (250 mg, yield: 35%).
[2982] Melting point: 110-111.degree. C.
[2983] Elementary analysis as C.sub.17H.sub.15FN.sub.2O.sub.4
[2984] Calcd. (%): C, 61.82; H, 4.58; N, 8.48; F, 5.75. Found (%):
C, 61.82; H, 4.46; N, 8.41; F, 5.64.
[2985] NMR(CDCl.sub.3).delta.: 3.68(3H, s), 3.92(3H, s), 4.06(2H,
s), 6.12(1H, d, J=3.4 Hz), 6.97-7.03(2H, m), 7.21-7.26(2H, m),
7.71(1H, d, J=3.7 Hz).
[2986] I Group Compound
[2987] Compound 1-3
[2988]
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-5,6-dihydro-1H-pyr-
idine-2-one
[2989] Compound I-4
[2990]
1-ethyl4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-5,6-dihydro-
-1H-pyridinee-2-one 286
[2991] (I-1) Aluminum chloride (2.96 g, 22.2 mmol) was suspended in
tetrahydrofuran (30 ml) and sodium borohydride (1.41 g, 37.3 mmol)
was added thereto under ice-cooling. After stirring for 10 minutes,
(5-bromofuran-2-yl)-(4-fluorophenyl)metanone (2.00 g, 7.43 mmol)
was added thereto and the mixture was refluxed under heating for 20
minutes. After cooling, water (60 ml) was added dropwise to the
solution and the mixture was extracted with diethyl ether. The
extract was washed and dried. The solvent was evaporated under
reduced pressure to give 2-bromo-5-(4-fluorobenzyl)furan. This
residue was dissolved in tetrahydrofuran (40 ml) and n-butyllithium
(5.20 ml, 8.16 mmol) was added dropwise at -78.degree. C. After 5
minutes, 2-oxo pyrrolidine-1-carboxyli- c acid tert-butylester
(2.76 g, 14.9 mmol) in tetrahydrofuran (5 ml) known by reference
(Tetrahedron Lett., 36, 8949-8952 (1995)) was added thereto and the
mixture was stirred for 2 hours. The saturated ammonium chloride
aqueous solution was added to the solution to stop the reaction and
the mixture was extracted with ethyl acetate. The extract was
washed and dried. The solvent was evaporated under reduced pressure
and the residue was purified with silica gel column chromatography
(n-hexane:ethyl acetate=3:1) to give
{4-[5-(4-fluorobenzyl)furan-2-yl]-4-oxobutyl}carbami- c acid
tert-butylester (1.95 g, yield: 73%).
[2992] NMR(CDCl.sub.3).delta.: 1.42(9H, s), 1.89(2H, m), 2.81(2H,
t, J=7.2 Hz), 3.19(2H, m), 4.01(2H, s), 4.64(1H, brs), 6.09(1H, d,
J=3.5 Hz), 7.01(2H, m), 7.10(1H, d, J=3.5 Hz), 7.21(2H, m).
[2993] (I-2) To a solution of the above-mentioned compound I-1 (900
mg, 2.49 mmol) and dimethyl oxalate (881 mg, 7.46 mmol) in toluene
(20 ml), was added sodiumm ethoxide (5.00 mmol, 28% methyl alcohol
solution) and the mixture was stirred at room temperature for 4
hours. 5N hydrochloric acid (5 mV) was added to the solution to
stop the reaction and the mixture was extracted with ethyl
acetate-tetrahydrofuran. The extract was washed and dried and the
solvent was evaporated under reduced pressure to give the crude
product of 3-(4-fluorophenyl)-2-hydroxy-3-[5-(5-hydroxy-6--
oxo-1,2,3,6-tetrahydropyridine-4-carbonyl)furan-2-yl]propenoic acid
methylester.
[2994] (I-3) To a solution of the crude product of the
above-mentioned compound I-2 in tetrahydrofuran (50 ml), was added
1N lithium hydroxide aqueous solution (20 ml) at 60.degree. C. and
the mixture was stirred for 2 hours. 5N hydrochloric acid (4 ml)
was added to the solution to stop the reaction and the mixture was
extracted with ethyl acetate. The extract was washed and dried. The
solvent was evaporated under reduced pressure. The obtained
precipitated crystal was recrystallized with methyl alcohol to give
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-5-
,6-dihydro-1H-pyridine-2-one (138 mg, yield: 18%).
[2995] Melting point: 166-168.degree. C.
[2996] Elementary analysis as C.sub.17H.sub.14FNO.sub.4
[2997] Calcd. (%): C, 64.76; H, 4.48; N, 4.44; F, 6.03. Found (%):
C, 64.51; H, 4.55; N, 4.41; F, 5.88.
[2998] NMR(CDCl.sub.3).delta.: 2.96(2H, t, J=6.8 Hz), 3.46(2H, dt,
J=2.9, 6.8 Hz), 4.05(2H, s), 6.22(1H, d, J=3.5 Hz), 6.57(1H, brs),
7.03(2H, m), 7.21(2H, m), 7.29(1H, d, J=3.5 Hz), 14.75(1H,
brs).
[2999] (I-4) To a solution of the above-mentioned compound I-3 (336
mg, 1.07 mmol) and bromoethane (0.320 ml, 4.29 mmol) in
tetrahydrofuran (27 ml), was added a solution of
potassiumbis(trimethylsilyl)amide (2.70 mmol, 0.5Mtoluenesolution)
and the mixture was refluxed under heating for 2.5 hours. 2N
hydrochloric acid (30 ml) was added to the solution to stop the
reaction and the mixture was extracted with ethyl acetate. The
extract was washed and dried. The solvent was evaporated under
reduced pressure and the residue was purified with silica gel
column chromatography (chloroform:methyl alcohol=50:1) to give
1-ethyl-4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-5,6-dihydro-1H-p-
yridine-2-one (184 mg, yield: 50%).
[3000] NMR(CDCl.sub.3).delta.: 1.21(3H, t, J=7.2 Hz), 2.92(2H, t,
J=6.8 Hz), 3.56(2H, t, J=6.8 Hz), 3.56(2H, q, J=7.2 Hz), 4.04(2H,
s), 6.21(1H, d, J=3.3 Hz), 7.03(2H, m), 7.21(2H, m), 7.26(1H, d,
J=3.3 Hz), 14.51(1H, brs).
[3001] The following compound was prepared as well as above.
[3002] (I-4-a)
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methyl-5-
,6-dihydro-1H-pyridine-2-one
[3003] NMR(CDCl.sub.3).delta.: 2.94(2H, t, J=6.6 Hz), 3.11(3H, s),
3.46(2H, t, J=6.6 Hz), 4.04(2H, s), 6.21(1H, d, J=3.3 Hz), 7.03(2H,
m), 7.21(2H, m), 7.26(1H, d, J=3.3 Hz), 14.55(1H, brs).
[3004] (I-4-b)
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-(2-metho-
xyethyl)-5,6-dihydro-1H-pyridine2-one
[3005] NMR(CDCl.sub.3).delta.: 2.91(2H, t, J=6.6 Hz), 3.55(2H, t,
J=6.6 Hz), 3.61(3H, s), 3.56-3.70(4H, m), 4.04(2H, s), 6.20(1H, d,
J=4.5 Hz), 7.02(2H, m), 7.21(2H, m), 7.26(1H, d, J=4.5 Hz),
14.64(1H, brs).
[3006] (I-4-c)
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxyl-(2-hydrox-
yethyl)-5,6-dihydro-1H-pyridine-2-one
[3007] NMR(CDCl.sub.3).delta.:2.95(2H, t, J=6.6 Hz), 3.56(2H, t,
J=6.6 Hz), 3.66(2H, t, J=4.8 Hz), 3.86(2H, t, J=4.8 Hz), 4.04(2H,
s), 6.21(1H, d, J=3.3 Hz), 7.02(2H, m), 7.21(2H, m), 7.26(1H, d,
J=3.3 Hz), 14.71(1H, brs).
[3008] J Group Compound
[3009] Compound J-4
[3010]
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methyl-1H-pyridi-
ne-2-one 287
[3011] (J-1) A suspension of
5-hydroxy-6-oxo-1,2,3,6-tetrahydropyridine-4-- carboxylate ethyl
ester (5.32 g, 28.7 mmol) known by reference (Org. Prep. Proced.
Int., 29, 330-335 (1997)) and 10% palladium carbon (1.18 g) in
xylene (100 ml) was refluxed under heating for 21 hours. The
solution was diluted with chloroformmethyl alcohol and palladium
carbon was removed with filtrate. The solvent was evaporated under
reduced pressure to give a crude product of
3-hydroxy-2-oxo-1,2-dihydropyridine-4-carboxylate ethyl ester.
[3012] (J-2) To a solution of crude product of the above-mentioned
compound J-1 and potassium carbonate (20.28 g, 143.8 mmol) in
dimethylformamide (90 ml), was added iodomethane (7.20 ml, 116
mmol) under ice-cooling and the mixture was stirred at 50.degree.
C. for 3 hours. 1N hydrochloric acid (135 ml) was added to the
solution to stop the reaction and the mixture was extracted with
ethyl acetate. The extract was washed and dried and the solvent was
evaporated under reduced pressure to give
3-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxyla- te ethyl
ester (2.69 g, yield:44%).
[3013] NMR(CDCl.sub.3) .delta.: 1.39(3H, t, J=7.2 Hz), 3.57(3H, s),
4.01(3H, s), 4.36(2H, q, J=7.2 Hz), 6.33(1H, d, J=6.9 Hz), 7.07(1H,
d, J=6.9 Hz).
[3014] (J-3) Aluminum chloride (4.84 g, 36.3 mmol) was suspended in
tetrahydrofuran (50 ml) and sodium borohydride (2.28 g, 60.3 mmol)
was added thereto under ice-cooling. After stirring for 10 minutes,
(5-bromofuran-2-yl)-(4-fluorophenyl)metanone (3.25 g, 12.1 mmol)
was added thereto and the mixture was refluxed under heating for 20
minutes. After cooling, water (100 ml) was added dropwise to the
solution and the mixture was extracted with diethyl ether. The
extract was washed and dried and the solvent was evaporated under
reduced pressure to give 2-bromo-5-(4-fluorobenzyl)furan. This
residue was dissolved in tetrahydrofuran (50 ml) and n-butyllithium
(8.00 ml, 12.6 mmol) was added dropwise thereto at -78.degree. C.
After 10 minutes, the above-mentioned compound J-2 (2.55 g, 12.1
mmol) in tetrahydrofuran (25 ml) was added thereto and the mixture
was stirred for 1 hour. The saturated ammonium chloride aqueous
solution was added to the solution to stop the reaction and the
mixture was extracted with ethyl acetate. The extract was washed
and dried. The solvent was evaporated under reduced pressure and
the residue was diluted with methyl alcohol (50 ml). 1N lithium
hydroxide aqueous solution (25 ml) was added thereto and the
mixture was stirred at room temperature for 1 hour. 1N hydrochloric
acid (20 ml) was added to the solution to stop the reaction and the
mixture was extracted with ethyl acetate. The extract was washed
and dried. The solvent was evaporated under reduced pressure and
the residue was purified with silica gel column chromatography
(n-hexane:ethyl acetate=1:2) to give
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-methoxy-1-methyl-1H-pyridine-2-o-
ne (1.09 g, yield: 27%).
[3015] NMR(CDCl.sub.3).delta.: 3.60(3H, s), 3.90(3H, s), 4.04(2H,
s), 6.11(1H, d, J=6.9 Hz), 6.12(1H, d, J=3.3 Hz), 7.02(2H, m),
7.05(1H, d, J=3.3 Hz), 7.12(1H, d, J=6.9 Hz), 7.23(2H, m).
[3016] (J-4) To a solution of the above-mentioned compound J-3 (518
mg, 1.52 mmol) in methylene chloride (25 ml), was added boron
tribromide (4.50 mmol, 1.0Mmethylene chloride solution) at
-78.degree. C. and the mixture was stirred for 1.5 hours. Water (15
ml) was added to the solution to stop the reaction and the mixture
was extracted with ethyl acetate. The extract was washed and dried.
The solvent was evaporated under reduced pressure. The precipitated
crystal was recrystallized with ethanol to give
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methyl-
-1H-pyridine-2-one (279 mg, yield: 56%).
[3017] Melting point:145-147.degree. C.
[3018] Elementary analysis as C.sub.18H.sub.14FNO.sub.4
[3019] Calcd. (%): C, 66.05; H, 4.31; N, 4.28; F, 5.80. Found (%):
C, 65.87; H, 4.32; N, 4.13; F, 5.58.
[3020] NMR(CDCl.sub.3).delta.:3.63(3H, s), 4.07(2H, s), 6.20(1H, d,
J=3.9 Hz), 6.57(1H, d, J=7.2 Hz), 6.83(1H, d, J=7.2 Hz), 7.03(2H,
m), 7.24(2H, m), 7.29(1H, d, J=3.9 Hz), 9.94(1H, brs).
[3021] Compound J-7
[3022]
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methoxymethyl-1H-
-pyridine-2-one 288
[3023] (J-5) To a solution of the above-mentioned compound J-1
(3.66 g, 20 mmol) in dimethylformamide (80 ml), was added sodium
hydride (2.40 g, 60 mmol) under ice-cooling and the mixture was
stirred for 20 minutes. Chloromethylmethylether (4.56 ml, 60 mmol)
was added dropwise thereto. Then, the mixture was warmed to room
temperature and stirred for 1 hour. To a mixture of ethyl acetate
and sodium hydrogen carbonate aqueous solution, was added the
solution under ice-cooling and the mixture was extracted with ethyl
acetate. The extract was washed and dried. The solvent was
evaporated and the residue was purified with silica gel column
chromatography (n-hexane-ethyl acetate=3:1) to give
3-methoxymethoxy-1-methoxymethyl-2-oxo-1,2-dihydropyridine-4-carboxylate
ethyl ester (1.47 g, yield: 26%).
[3024] NMR(CDCl.sub.3).delta.: 1.31(3H, t, J=7.1 Hz), 3.31(3H, s),
3.48(3H, s), 4.30(2H, q, J=7.1 Hz), 5.25(2H, s), 5.32(2H, s),
6.32(1H, d, J=7.3 Hz), 7.12(1H, d, J=7.3 Hz).
[3025] (J-6) Aluminum chloride (3.25 g, 24.4 mmol) was suspended in
tetrahydrofuran (22 ml) and sodium borohydride (1.54 g, 40.7 mmol)
was added thereto under ice-cooling. After stirring for 10 minutes,
(5-bromofuran-2-yl)-(4-fluorophenyl)metanone (2.19 g, 8.13 mmol)
was added thereto and the mixture was refluxed under heating for 30
minutes. After cooling, water (40 ml) was added dropwise to the
solution and the mixture was extracted with diethyl ether. The
extract was washed and dried. The solvent was evaporated under
reduced pressure to give the crude purified product (2.22 g) of
2-bromo-5-(4-fluorobenzyl)furan. This residue was dissolved in
tetrahydrofuran (30 ml) and n-butyllithium(5.18 ml, 8.13 mmol) was
added dropwise thereto at -78.degree. C. After stirring for 10
minutes, a solution of the above-mentioned compound J-5 (1.47 g,
5.42 mmol) in tetrahydrofuran (3 ml) was added thereto and the
mixture was stirred for 90 minutes. Ammonium chloride aqueous
solution and water were added to the solution at -78.degree. C. and
the mixture was extracted with ethyl acetate. The extract was
washed and dried. The solvent was evaporated under reduced pressure
and the residue was purified with silica gel column chromatography
(ethyl acetate from n-hexane-ethyl acetate=3:1) to give
4-[5-(4-fluorobenzyl)furan-2-carbonyl-
]-3-methoxymethoxy-1-methoxymethyl-1H-pyridine-2-one (735 mg,
yield: 34%).
[3026] NMR(CDCl.sub.3).delta.: 3.25(3H, s), 3.43(3H, s), 4.05(2H,
s), 5.25(2H, s), 5.35(2H, s), 6.16(1H, d, J=3.4 Hz), 6.20(1H, d,
J=7.0 Hz), 6.98-7.04(2H, m), 7.11(1H, d, J=3.7 Hz), 7.20-7.29(3H,
m).
[3027] (J-7) To a solution of the above-mentioned compound J-6 (141
mg, 0.35 mmol) in ethanol (5 ml), was added 3n-hydrochloric acid (5
ml) and the mixture was stirred for 1 hour. The solution was
neutralized with sodium hydroxide aqueous solution and sodium
hydrogen carbonate aqueous solution and the mixture was extracted
with ethyl acetate. The extract was washed and dried. The solvent
was evaporated under reduced pressure. The obtained precipitated
crystal was recrystallized with diisopropylether and ethanol and
dried under reduced pressure to give
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1-methoxymethyl-1H-pyrid-
ine-2-one (52 mg, yield: 42%).
[3028] Melting point:128-130.degree. C.
[3029] Elementary analysis as Cl.sub.9H.sub.16FNO.sub.5
[3030] Calcd. (%): C, 63.86; H, 4.51; N, 3.92; F, 5.32. Found (%):
C, 63.35; H, 4.43; N, 3.79; F, 5.07.
[3031] NMR(CDCl.sub.3).delta.: 3.42(3H, s), 4.08(2H, s), 5.38(2H,
s), 6.21(1H, d, J=3.7 Hz), 6.64(1H, d, J=7.6 Hz), 6.95(1H, d, J=7.6
Hz), 7.01-7.06(2H, m), 7.22-7.27(2H, m), 7.32(1H, d, J=3.7 Hz).
[3032] Compound J-8
[3033]
4-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1H-pyridine-2-one
289
[3034] (J-8) To a solution of the above-mentioned compound J-6 (685
mg, 1.71 mmol) in methylene chloride (15 ml), was added boron
tribromide methylene chloride solution (5.13 ml) at -78.degree. C.
The mixture was stirred for 90 minutes, warmed to 0.degree. C. and
then stirred for 20 minutes. Water was added to the solution under
ice-cooling and the mixture was extracted with ethyl acetate. The
extract was washed and dried. The solvent was evaporated. The
obtained precipitated crystal was washed with chloroform,
recrystallized with ethanol and dried under reduced pressure to
give 4-[5-(4-fluorobenzyl)furan-2
carbonyl]-3-hydroxy-1H-pyridine-2-one (301 mg, yield: 56%).
[3035] Melting point:229-231.degree. C.
[3036] Elementary analysis as C.sub.17H.sub.12FNO.sub.4
[3037] Calcd. (%): C, 65.18; H, 3.86; N, 4.47; F, 6.06. Found (%):
C, 63.80; H, 3.75; N, 4.37; F, 5.77; Cl, 0.87.
[3038] NMR(DMSO-d6).delta.: 4.15(2H, s), 6.14(1H, d, J=6.7 Hz),
6.44(1H, d, J=3.7 Hz), 6.97(1H, d, J=6.7 Hz), 7.19-7.25(3H, m),
7.35-7.40(2H, m), 9.76(1H, brs), 11.98(1H, brs).
[3039] K Group Compound
[3040] Compound K-4
[3041]
4-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-hydroxy-1-methyl-1H-
-pyridine-2-one 290
[3042] (K-1) To a solution of compound J-2 (1.00 g, 4.73 mmol) in
ethanol (5 ml), was added hydrazine monohydrate (1 ml) and the
mixture was refluxed under heating for 1 hour. The solvent was
evaporated under reduced pressure to give crude product of
3-methoxy-1-methyl-2-oxo-1,2-di- hydropyridine-4-carboxylic acid
hydrazide.
[3043] (K-2) To a suspension of crude product of the
above-mentioned compound K-1,4-fluorophenylacetic acid (1.12 g,
7.12 mmol) and 1-hydroxybenzotriazole (132 mg, 0.977 mmol) in
dimethylformamide (10 ml), was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (1.36 g,
7.09 mmol) and the mixture was stirred at room temperature for 20
hours. Water (20 ml) was added to the solution to stop the reaction
and the mixture was extracted with chloroform. The extract was
washed and dried. The solvent was evaporated under reduced pressure
and the residue was purified with silica gel column chromatography
(chloroform) to give
3-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid
N'-[2-(4-fluorophenyl) acetyl]-hydrazide (919 mg, yield: 58%)
[3044] NMR(CDCl.sub.3).delta.: 3.57(3H, s), 3.66(3H, s), 4.22(2H,
s), 6.72(1H, d, J=7.2 Hz), 7.04(2H, m), 7.12(1H, d, J=7.2 Hz),
7.30(2H, m).
[3045] (K-3) To the above-mentioned compound K-2 (916 mg, 2.75
mmol), was added polyphosphoric acid (18 g) and the mixture was
stirred at 150.degree. C. for 1 hour. Ice water (50 g) was added to
the solution and the obtained precipitated crystal was washed with
water and recrystallized with ethanol to give
4-[5-(4-fluorobenzyl)-[1,3,4]oxadiazo-
le-2-yl]-3-methoxy-1-methyl-1H-pyridine-2-one (498 mg, yield:
58%).
[3046] NMR(CDCl.sub.3).delta.: 3.59(3H, s), 4.01(3H, s), 4.28(2H,
s), 6.69(1H, d, J=7.2 Hz), 7.05(2H, m), 7.13(1H, d, J=7.2 Hz),
7.35(2H, m).
[3047] (K-4) To a solution of the above-mentioned compound K-3 (261
mg, 0.828 mmol) in methylene chloride (25 ml), was added boron
tribromide (2.40 mmol, 1.0M methylene chloride solution) under
ice-cooling and the mixture was stirred for 75 minutes. Water (10
ml) was added to the solution to stop the reaction and the mixture
was extracted with chloroform. The extract was washed and dried.
The solvent was evaporated under reduced pressure. The obtained
precipitated crystal was recrystallized with chloroformmethyl
alcohol to give
4-[5-(4-fluorobenzyl)-[1,3,4]oxadiazole-2-yl]-3-hydroxy-1-methyl-1H-pyrid-
ine-2-one (200 mg, yield: 80%).
[3048] Melting point:216-218.degree. C.
[3049] Elementary analysis as
C.sub.15H.sub.12FN.sub.3O.sub.3(CHCl.sub.3).- sub.0.04
[3050] Calcd. (%): C, 59.02; H, 3.97; N, 13.73; Cl, 1.39; F, 6.21.
Found (%): C, 59.10; H, 3.92; N, 13.68; Cl, 1.20; F, 6.13.
[3051] NMR(DMSO-d.sub.6).delta.: 3.52(3H, s), 4.37(2H, s), 6.56(1H,
d, J=7.5 Hz), 7.19(2H, m), 7.27(1H, d, J=7.5 Hz), 7.41(2H, m),
10.37(1H, brs).
[3052] L Group Compound
[3053] Compound L-4
[3054]
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1H-pyridine-4-one
291
[3055] (L-1) To a solution of
3-hydroxy-4-methoxypyridine-2-carboxylic acid (2.85 g, 16.8 mmol)
in ethanol (60 ml) known by reference (Tetrahedron, 54, 12745-12774
(1998)), was added strong sulfuric acid (1 ml) and the mixture was
refluxed under heating for 75 hours. The solvent was evaporated
under reduced pressure. Water (60 ml) and potassium carbonate (1.6
g) were added the obtained residue to neutralize and the mixture
was extracted with chloroform. The extract was washed and dried.
The solvent was evaporated under reduced pressure to give
3-hydroxy-4-methoxypyridine-2-carboxylate ethyl ester (2.06 g,
yield: 62%).
[3056] NMR(CDCl.sub.3).delta.: 1.49(3H, t, J=7.2 Hz), 3.97(3H, s),
4.54(2H, q, J=7.2 Hz), 6.94(1H, d, J=5.1 Hz), 8.19(1H, d, J=5.1
Hz), 11.01(1H, brs).
[3057] (L-2) To a solution the above-mentioned compound L-1 (2.05
g, 10.4 mmol) and potassium carbonate (2.85 g, 20.6 mmol) in
dimethylformamide (40 ml), was added dimethyl sulfate (1.45 ml,
15.3 mmol) and the mixture was stirred at 80.degree. C. for 2
hours. 1N hydrochloric acid (30 ml) and water (50 ml) were added to
the solution to stop the reaction and the mixture was extracted
with ethyl acetate. The extract was washed and dried. The solvent
was evaporated under reduced pressure and the residue was purified
with silica gel column chromatography (n-hexane:ethyl acetate=1:1)
to give 3,4-dimethoxypyridine-2-carboxylate ethyl ester (1.08 g,
yield: 49%).
[3058] NMR(CDCl.sub.3).delta.: 1.43(3H, t, J=7.2 Hz), 3.93(3H, s),
3.95(3H, s), 4.45(2H, q, J=7.2 Hz), 6.95(1H, d, J=5.4 Hz), 8.32(1H,
d, J=5.4 Hz).
[3059] (L-3) Aluminum chloride (3.06 g, 22.9 mmol) was suspended in
tetrahydrofuran (30 ml). Sodium borohydride (1.45 g, 38.3 mmol) was
added thereto under ice-cooling. The mixture was stirred for 10
minutes. (5-bromofuran-2-yl)-(4-fluorophenyl)metanone (2.05 g, 7.62
mmol) was added thereto and the mixture was refluxed under heating
for 20 minutes. After cooling, water (60 ml) was added dropwise to
the solution and the mixture was extracted with diethyl ether. The
extract was washed and dried. The solvent was evaporated under
reduced pressure to give 2-bromo-5-(4-fluorobenzyl)furan. This
residue was dissolved in tetrahydrofuran (35 ml). n-butyllithium
(4.90 ml, 7.64 mmol) was added dropwise thereto at -78.degree. C.
After 10 minutes, tetrahydrofuran (15 ml) of the above-mentioned
compound L-2 (1.07 g, 5.07 mmol) was added thereto and the mixture
was stirred for 1 hour. The saturated ammonium chloride aqueous
solution was added to the solution to stop the reaction and the
mixture was extracted with ethyl acetate. The extract was washed
and dried. The solvent was evaporated under reduced pressure and
the residue was purified with silica gel column chromatography
(n-hexane:ethyl acetate=1:1) to give
(3,4-dimethoxypyridine-2-yl)-[5-(4-f-
luorobenzyl)furan-2-yl]metanone (1.53 g, yield: 90%).
[3060] NMR(CDCl.sub.3).delta.: 3.90(3H, s), 3.96(3H, s), 4.05(2H,
s), 6.09(1H, d, J=3.5 Hz), 6.95(1H, d, J=5.6 Hz), 7.00(2H, m),
7.03(1H, d, J=3.5 Hz), 7.22(2H, m), 8.28(1H, d, J=5.6 Hz).
[3061] (L-4) To a suspention of the above-mentioned compound L-3
(1.48 g, 4.34 mmol) and sodium iodide (5.22 g, 34.8 mmol) in
acetonitrile (30 ml), was added chlorotrimethylsilane (4.40 ml,
34.7 mmol) and the mixture was refluxed under heating for 3 hours.
Water (30 ml) and 10% sodium hydrogen sulfate aqueous solution (30
ml) were added to the solution to stop the reaction and the mixture
was extracted with ethyl acetate. The extract was washed and dried.
The solvent was evaporated under reduced pressure and the residue
was purified with silica gel column chromatography. The solvent was
evaporated from the fraction of the obtained product by eluting
with ethyl acetate under reduced pressure and the obtained
precipitated crystal was crystallized with toluene to give
2-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-1H-pyridine-4-one
(448 mg, yield: 33%).
[3062] NMR(CD.sub.3OD).delta.: 4.10(2H, s), 6.35(1H, d, J=3.6 Hz),
6.69(1H, d, J=5.9 Hz), 7.05(2H, m), 7.32(2H, m), 7.81(1H, d, J=5.9
Hz), 7.84(1H, brs).
[3063] M Group Compound
[3064] Compound M-6
[3065]
5-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-2-methyl-1H-pyridi-
ne-4-one 292
[3066] (M-1) According to the method described in WO92/02523,
5-methoxy-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate methyl
ester was synthesized.
[3067] (M-2) A solution of the above-mentioned compound M-1 (980
mg, 5.0 mmol) in phosphorus oxychloride (5 ml) was refluxed under
heating for 30 minutes. The solvent was evaporated from the
solution under reduced pressure and the residue was neutralized
with sodium hydroxideaqueous solution. The mixture was extracted
with ethyl acetate and the extract was washed and dried. The
solvent was evaporated to give crude product (738 mg) of
4-chloro-5-methoxy-6-methyl-nicotinate methylester.
[3068] NMR(CDCl.sub.3).delta.: 2.61(3H, s), 3.88(3H, s), 3.96(3H,
s), 8.71(1H, s).
[3069] (M-3) To a solution of the above-mentioned crude product M-2
(738 mg) in methyl alcohol (5 ml), was added sodium methylate
methyl alcohol solution (2.49 ml) under ice-cooling. After stirring
at room temperature for 2 hours, the mixture was warmed to 500C and
stirred for 2 hours. The solution was neutralized with ammonium
chloride aqueous solution. Methyl alcohol was evaporated under
reduced pressure and the residue was extracted with ethyl acetate.
The extract was washed and dried. The solvent was evaporated to
give crude product (609 mg) of 4,5-dimethoxy-6-methyl-nicotinate
methylester.
[3070] NMR(CDCl.sub.3).delta.: 2.53(3H, s), 3.85(3H, s), 3.92(3H,
s), 4.02(3H, s), 8.61(1H, s).
[3071] (M-4) A solution of the above-mentioned crude product M-3
(449 mg) in sodium hydroxide (10 ml) was refluxed under heating for
1 hour. The solution was neutralized with hydrochloric acid and the
solvent was evaporated under reduced pressure. To a solution of the
residue in methylene chloride (10 ml), were added
N,O-dimethylhydroxyamine hydrochloride (249 mg, 2.56 mmol) and
1-hydroxybenztriazole (58 mg, 0.43 mmol). Triethylamine (357 ul,
2.56 mmol) and 1-ethyl3-(3-dimethylaminopro-
pyl)carbodiimidehydrochloride (491 mg, 2.56 mmol) were added
thereto under ice-cooling and the mixture was warmed and stirred
for 2 hours. The ammonium chloride aqueous solution was added to
the solution and the mixture was extracted with chloroform. The
extract was washed and dried. The solvent was evaporated under
reduced pressure and the residue was purified with silica gel
column chromatography (n-hexane-ethyl acetate=1:1) to give
4,5,N-trimethoxy-6,N-dimethyl-nicotinamide (449 mg, yield:
80%).
[3072] NMR(CDCl.sub.3).delta.: 2.51(3H, s), 3.34(3H, brs), 3.52(3H,
brs), 3.83(3H, s), 4.00(3H, s), 8.13(1H, s).
[3073] (M-5) Aluminum chloride (2.02 g, 15.0 mmol) was suspended in
tetrahydrofuran (20 ml). Sodium borohydride (851 mg, 22.5 mmol) was
added thereto under ice-cooling. After stirring for 10 minutes,
(5-bromofuran-2-yl)-(4-fluorophenyl)metanone (2.02 g, 7.5 mmol) was
added thereto and the mixture was refluxed under heating for 30
minutes. After cooling, water (20 ml) was added dropwise to the
solution and the mixture was extracted with diethyl ether. The
extract was washed and dried. The solvent was evaporated under
reduced pressure to give 2-bromo-5-(4-fluorobenzyl)furan (1.74 g,
yield: 91%). This residue (715 mg, 2.80 mmol) was dissolved in
tetrahydrofuran (9 ml). n-butyllithium (1.79 ml, 2.80 mmol) was
added dropwise thereto at -78.degree. C. After stirring for 5
minutes, a solution of the above-mentioned compound M-4 (449 mg,
1.87 mmol) in tetrahydrofuran (1 ml) was added thereto and the
mixture was stirred for 30 minutes. The ammonium chloride aqueous
solution and water were added to the solution at -78.degree. C. and
the mixture was extracted with ethyl acetate. The extract was
washed and dried. The solvent was evaporated under reduced pressure
and the residue was purified with silica gel column chromatography
(n-hexane-ethyl acetate=1:1) to give
(4,5-dimethoxy-6-methylpyridine-3-yl)-[5-(4-fluorobe-
nzyl)furan-2-yl]-metanone (348 mg, yield: 52%).
[3074] NMR(CDCl.sub.3).delta.: 2.54(3H, s), 3.84(3H, s), 3.91(3H,
s), 4.05(2H, s), 6.15(1H, d, J=3.7 Hz), 6.99-7.06(3H, m),
7.21-7.26(2H, m), 8.26(1H, s).
[3075] (M-6) To a solution of the above-mentioned compound M-5 (289
mg, 0.81 mmol) in methylene chloride (6 ml), boron
tribromidemethylene chloride solution (4.05 ml) was added under
ice-cooling. The mixture was stirred at 0.degree. C. for 30
minutes, warmed to room temperature and then stirred for 2 hours.
2n-hydrochloric acid (6 ml) was added to the solution and the
mixture was stirred for 10 minutes and neutralized with sodium
hydrogen carbonate. The mixture was extracted with ethyl acetate
and the extract was washed and dried. The solvent was evaporated
and the obtained precipitated crystal was washed with chloroform,
recrystallized with ethanol and dried under reduced pressure to
give
5-[5-(4-fluorobenzyl)furan-2-carbonyl]-3-hydroxy-2-methyl-1H-pyridine-4-o-
ne (123 mg, yield: 46%).
[3076] Melting point: 190-192.degree. C.
[3077] Elementary analysis as C.sub.18H.sub.14FNO.sub.4
[3078] Calcd. (%): C, 66.05; H, 4.31; N, 4.28; F, 5.80. Found (%):
C, 65.17; H, 4.18; N, 4.27; F, 5.56.
[3079] NMR(DMSO-d6).delta.: 2.20(3H, s), 4.08(2H, s), 6.34(1H, d,
J=3.7 Hz), 7.14-7.20(2H, m), 7.25(1H, d, J=3.7 Hz), 7.30-7.35(2H,
m), 7.72(1H, s).
[3080] The compounds of the present invention include the following
compounds which can be synthesized with a manner similar to that of
the above examples. 293
[3081] The substituents of R.sup.1, R.sup.2, X, R.sup.4 and R.sup.5
of above compound include the following substitution group.
[3082] R.sup.1=H (1A), Me(1B), OMe(1C), Cl(1D), Ph(1E)
[3083] R.sup.2=H (2A), Me(2B), OMe(2C), Cl(2D), Ph(2E)
[3084] X=O(3A), NH(3B) 294
[3085] R.sup.5=H (5A), Me(5B), OMe(5C), Cl(5D), Ph(5E)
[3086] The preferable combinations (R.sup.1,R.sup.2,X,
R.sup.4,R.sup.5) of the substituents of above compound include the
followings.
[3087]
(1A,2A,3A,4A,5A),(1A,2A,3A,4A,5B),(1A,2A,3A,4A,5C),(1A,2A,3A,4A,5D)-
,(1A,2A,3A,4A,
5E),(1A,2A,3A,4B,5A),(1A,2A,3A,4B,5B),(1A,2A,3A,4B,5C),(1A,-
2A,3A,4B,5D),(1A,2A,3A,4B,5E),(1A,2A,3A,4C,5A),(1A,2A,3A,4C,5B),(1A,2A,3A,-
4C,5C),(1A,2A,3A,4C,5D),(1A,
2A,3A,4C,5E),(1A,2A,3A,4D,5A),(1A,2A,3A,4D,5B-
),(1A,2A,3A,4D,5C),(1A,2A,3A,4D,5D),
(1A,2A,3A,4D,5E),(1A,2A,3A,4E,5A),(1A-
,2A,3A,4E,5B),(1A,2A,3A,4E,5C),(1A,2A,3A,4E,
5D),(1A,2A,3A,4E,5E),(1A,2A,3-
B,4A,5A),(1A,2A,3B,4A,5B),(1A,2A,3B,4A,5C),(1A,2A,3B,4A,5D),(1A,2A,3B,4A,5-
E),(1A,2A,3B,4B,5A),(1A,2A,3B,4B,5B),(1A,2A,3B,4B,5C),(1A,
2A,3B,4B,5D),(1A,2A,3B,4B,5E),(1A,2A,3B,4C,5A),(1A,2A,3B,4C,5B),(1A,2A,3B-
,4C,5C),
(1A,2A,3B,4C,5D),(1A,2A,3B,4C,5E),(1A,2A,3B,4D,5A),(1A,2A,3B,4D,5-
B),(1A,2A,3B,4D,
5C),(1A,2A,3B,4D,5D),(1A,2A,3B,4D,5E),(1A,2A,3B,4E,5A),(1-
A,2A,3B,4E,5B),(1A,2A,3B,4E,5C),(1A,2A,3B,4E,5D),(1A,2A,3B,4E,5E),(1A,2B,3-
A,4A,5A),(1A,2B,3A,4A,5B),(1A,
2B,3A,4A,5C),(1A,2B,3A,4A,5D),(1A,2B,3A,4A,-
5E),(1A,2B,3A,4B,5A),(1A,2B,3A,4B,5B),
(1A,2B,3A,4B,5C),(4A,2B,3A,4B,5D), (1A,2B,3A,4B,5E),
(1A,2B,3A,4C,5A), (1A,2B,3A,4C, 5B),(1A,2B,3A,4C,5C),(1-
A,2B,3A,4C,5D),(1A,2B,3A,4C,5E),(1A,2B,3A,4D,5A),(1A,2B,3A,4D,5B),(1A,2B,3-
A,4D,5C),(1A,2B,3A,4D,5D),(1A,2B,3A,4D,5E),(1A,2B,3A,4E,5A),(1A,
2B,3A,4E,5B),(1A,2B,3A,4E,5C),(1A,2B,3A,4E,5D),(1A,2B,3A,4E,5E),(1A,2B,3B-
,4A,5A),
(1A,2B,3B,4A,5B),(1A,2B,3B,4A,5C),(1A,2B,3B,4A,5D),(1A,2B,3B,4A,5-
E),(1A,2B,3B,4B,
5A),(1A,2B,3B,4B,5B),(1A,2B,3B,4B,5C),(1A,2B,3B,4B,5D),(1-
A,2B,3B,4B,5E),(1A,2B,3B,4C,5A),(1A,2B,3B,4C,5B),(1A,2B,3B,4C,5C),(1A,2B,3-
B,4C,5D),(1A,2B,3B,4C,5E),(1A,
2B,3B,4D,5A),(1A,2B,3B,4D,5B),(1A,2B,3B,4D,-
5C),(1A,2B,3B,4D,5D),(1A,2B,3B,4D,5E),
(1A,2B,3B,4E,5A),(1A,2B,3B,4E,5B),(-
1A,2B,3B,4E,5C),(1A,2B,3B,4E,5D),(1A,2B,3B,4E,
5E),(1A,2C,3A,4A,5A),(1A,2C-
,3A,4A,5B),(1A,2C,3A,4A,5C),(1A,2C,3A,4A,5D),(1A,2C,3A,4A,5E),(1A,2C,3A,4B-
,5A),(1A,2C,3A,4B,5B),(1A,2C,3A,4B,5C),(1A,2C,3A,4B,5D),(1A,
2C,3A,4B,5E),(1A,2C,3A,4C,5A),(1A,2C,3A,4C,5B),(1A,2C,3A,4C,5C),(1A,2C,3A-
,4C,5D),
(1A,2C,3A,4C,5E),(1A,2C,3A,4D,5A),(1A,2C,3A,4D,5B),(1A,2C,3A,4D,5-
C),(1A,2C,3A,4D,
5D),(1A,2C,3A,4D,5E),(5A,2C,3A,4E,5A),(1A,2C,3A,4E,5B),(1-
A,2C,3A,4E,5C),(1A,2C,3A,4E,5D),(1A,2C,3A,4E,5E),(1A,2C,3B,4A,5A),(1A,2C,3-
B,4A,5B),(1A,2C,3B,4A35C),(1A,2C,3B,4A,5D),(1A,2C,3B,4A,5E),(1A,2C,3B,4B,5-
A),(1A,2C,3B,4B,5B),(1A,2C,3B,4B,5C),
(1A,2C,3B,4B,5D),(1A,2C,3B,4B,5E),(1-
A,2C,3B,4C,5A),(1A,2C,3B,4C,5B),(1A,2C,3B,4C,
5C),(1A,2C,3B,4C,5D),(1A,2C,-
3B,4C,5E),(1A,2C,3B,4D,5A),(1A,2C,3B,4D,5B),(1A,2C,3B,4D,5C),(1A,2C,3B,4D,-
5D),(1A,2C,3B,4D,5E),(1A,2C,3B,4E,5A),(1A,2C,3B,4E,5B),(1A,
2C,3B,4E,5C),(1A,2C,3B,4E,5D),(1A,2C,3B,4E,5E),(1A,2D,3A,4A,5A),(1A,2D,3A-
,4A,5B),
(1A,2D,3A,4A,5C),(1A,2D,3A,4A,5D),(1A,2D,3A,4A,5E),(1A,2D,3A,4B,5-
A),(1A,2D,3A,4B,
5B),(1A,2D,3A,4B,5C),(1A,2D,3A,4B,5D),(1A,2D,3A,4B,5E),(1-
A,2D,3A,4C,5A),(1A,2D,3A,4C,5B),(1A,2D,3A,4C,5C),(1A,2D,3A,4C,5D),(1A,2D,3-
A,4C,5E),(1A,2D,3A,4D,5A),(1A,
2D,3A,4D,5B),(1A,2D,3A,4D,5C),(1A,2D,3A,4D,-
5D),(1A,2D,3A,4D,5E),(1A,2D,3A,4E,5A),
(1A,2D,3A,4E,5B),(1A,2D,3A,4E,5C),(-
1A,2D,3A,4E,5D),(1A,2D,3A,4E,5E),(1A,2D,3B,4A,
5A),(1A,2D,3B,4A,5B),(1A,2D-
,3B,4A,5C),(1A,2D,3B,4A,5D),(1A,2D,3B,4A,5E),(1A,2D,3B,4B,5A),(1A,2D,3B,4B-
,5B),(1A,2D,3B,4B,5C),(1A,2D,3B,4B,5D),(1A,2D,3B,4B,5E),(1A,
2D,3B,4C,5A),(1A,2D,3B,4C,5B),(1A,2D,3B,4C,5C),(1A,2D,3B,4C,5D),(1A,2D,3B-
,4C,5E),
(1A,2D,3B,4D,5A),(1A,2D,3B,4D,5B),(1A,2D,3B,4D,5C),(1A,2D,3B,4D,5-
D),(1A,2D,3B,4D,
5E),(1A,2D,3B,4E,5A),(1A,2D,3B,4E,5B),(1A,2D,3B,4E,5C),(0-
A,2D,3B,4E,5D),(1A,2D,3B,4E,5E),(1A,2E,3A,4A,5A),(1A,2E,3A,4A,5B),(1A,2E,3-
A,4A,5C),(1A,2E,3A,4A,5D),(1A,
2E,3A,4A,5E),(1A,2E,3A,4B,5A),(1A,2E,3A,4B,-
5B),(1A,2E,3A,4B,5C),(1A,2E,3A,4B,5D),
(1A,2E,3A,4B,5E),(1A,2E,3A,4C,5A),(-
1A,2E,3A,4C,5B),(1A,2E,3A,4C,5C),(1A,2E,3A,4C,
5D),(1A,2E,3A,4C,5E),(1A,2E-
,3A,4D,5A),(1A,2E,3A,4D,5B),(1A,2E,3A,4D,5C),(1A,2E,3A,4D,5D),(1A,2E,3A,4D-
,5E),(1A,2E,3A,4E,5A),(1A,2E,3A,4E,5B),(1A,2E,3A,4E,5C),(1A,
2E,3A,4E,5D),(1A,2E,3A,4E,5E),(1A,2E,3B,4A,5A),(1A,2E,3B,4A,5B),(1A,2E,3B-
,4A,5C),
(1A,2E,3B,4A,5D),(1A,2E,3B,4A,5E),(1A,2E,3B,4B,5A),(1A,2E,3B,4B,5-
B),(1A,2E,3B,4B,
5C),(1A,2E,3B,4B,5D),(1A,2E,3B,4B,5E),(1A,2E,3B,4C,5A),(1-
A,2E,3B,4C,5B),(1A,2E,3B,4C,5C),(1A,2E,3B,4C,5D),(1A,2E,3B,4C,5E),(1A,2E,3-
B,4D,5A),(1A,2E,3B,4D,5B),(1A,
2E,3B,4D,5C),(1A,2E,3B,4D,5D),(1A,2E,3B,4D,-
5E),(1A,2E,3B,4E,5A),(1A,2E,3B,4E,5B),
(1A,2E,3B,4E,5C),(1A,2E,3B,4E,5D),(-
1A,2E,3B,4E,5E),(1B,2A,3A,4A,5A),(1B,2A,3A,4A,
5B),(1B,2A,3A,4A,5C),(1B,2A-
,3A,4A,5D),(1B,2A,3A,4A,5E),(1B,2A,3A,4B,5A),(1B,2A,3A,4B,5B),(1B,2A,3A,4B-
,5C),(1B,2A,3A,4B,5D),(1B,2A,3A,4B,5E),(1B,2A,3A,4C,5A),(1B,
2A,3A,4C,5B),(1B,2A,3A,4C,5C),(1B,2A,3A,4C,5D),(1B,2A,3A,4C,5E),(1B,2A,3A-
,4D,5A),
(1B,2A,3A,4D,5B),(1B,2A,3A,4D,5C),(1B,2A,3A,4D,5D),(1B,2A,3A,4D,5-
E),(1B,2A,3A,4E,
5A),(1B,2A,3A,4E,5B),(1B,2A,3A,4E,5C),(1B,2A,3A,4E,5D),(1-
B,2A,3A,4E,5E),(1B,2A,3B,4A,5A),(1B,2A,3B,4A,5B),(1B,2A,3B,4A,5C),(1B,2A,3-
B,4A,5D),(1B,2A,3B,4A,5E),(1B,
2A,3B,4B,5A),(1B,2A,3B,4B,5B),(1B,2A,3B,4B,-
5C),(1B,2A,3B,4B,5D),(1B,2A,3B,4B,5E),
(1B,2A,3B,4C,5A),(1B,2A,3B,4C,5B),(-
1B,2A,3B,4C,5C),(1B,2A,3B,4C,5D),(1B,2A,3B,4C,
5E),(1B,2A,3B,4D,5A),(1B,2A-
,3B,4D,5B),(1B,2A,3B,4D,5C),(1B,2A,3B,4D,5D),(1B,2A3B,4D,5E),(1B,2A,3B,4E,-
5A),(1B,2A,3B,4E,5B),(1B,2A,3B,4E,5C),(1B,2A,3B,4E,5D),(1B,
2A,3B,4E,5E),(1B,2B,3A,4A,5A),(1B,2B,3A,4A,5B),(1B,2B,3A,4A,5C),(1B,2B,3A-
,4A,5D),
(1B,2B,3A,4A,5E),(1B,2B,3A,4B,5A),(1B,2B,3A,4B,5B),(1B,2B,3A,4B,5-
C),(1B,2B,3A,4B,
5D),(1B,2B,3A,4B,5E),(1B,2B,3A,4C,5A),(1B,2B,3A,4C,5B),(1-
B,2B,3A,4C,5C),(1B,2B,3A,4C,5D),(1B,2B,3A,4C,5E),(1B,2B,3A,4D,5A),(1B,2B,3-
A,4D,5B),(1B,2B,3A,4D,5C),(1B,
2B,3A,4D,5D),(1B,2B,3A,4D,5E),(1B,2B,3A,4E,-
5A),(1B,2B,3A,4E,5B),(1B,2B,3A,4E,5C),
(1B,2B,3A,4E,5D),(1B,2B,3A,4E,5E),(-
1B,2B,3B,4A,5A),(1B,2B,3B,4A,5B),(1B,2B,3B,4A,
5C),(1B,2B,3B,4A,5D),(1B,2B-
,3B,4A,5E),(1B,2B,3B,4B,5A),(1B,2B,3B,4B,5B),(1B,2B,3B,4B,5C),(1B,2B,3B,4B-
,5D),(1B,2B,3B,4B,5E),(1B,2B,3B,4C,5A),(1B,2B,3B,4C,5B),(1B,
2B,3B,4C,5C),(1B,2B,3B,4C,5D),(1B,2B,3B,4C,5E),(1B,2B,3B,4D,5A),(1B,2B,3B-
,4D,5B), (1B,2B,3B,4D,5C), (1B,2B,3B,4D,5D), (1B,2B,3B,4D,5E),
(1B,2B,3B,4E,5A), (1B,2B,3B,4E, 5B), (1B,2B,3B,4E,5C),
(1B,2B,3B,4E,5D), (1B,2B,3B,4E,5E), (1B,2C,3A,4A,5A),
(1B,2C,3A,4A,5B), (1B,2C,3A,4A,5C), (1B,2C,3A,4A,5D),
(1B,2C,3A,4A,5E), (1B,2C,3A,4B,5A), (1B, 2C,3A,4B,5B),
(1B,2C,3A,4B,5C), (1B,2C,3A,4B,5D), (1B,2C,3A,4B,5E),
(1B,2C,3A,4C,5A), (1B,2C,3A,4C,5B), (1B,2C,3A,4C,5C),
(1B,2C,3A,4C,5D),(1B,2C,3A,4C,5E),(1B- ,2C,3A,4D, 5A),
(1B,2C,3A,4D,5B), (1B,2C,3A,4D,5C), (1B,2C,3A,4D,5D),
(1B,2C,3A,4D,5E), (1B,2C,3A,4E,5A), (1B,2C,3A,4E,5B),
(1B,2C,3A,4E,5C), (1B,2C,3A,4E,5D), (1B,2C,3A,4E,5E), (1B,
2C,3B,4A,5A), (1B,2C,3B,4A,5B), (1B,2C,3B,4A,5C), (1B,2C,3B,4A,5D),
(1B,2C,3B,4A, 5E), (1B,2C,3B,4B,5A), (1B,2C,3B,4B,5B),
(1B,2C,3B,4B,5C), (1B,2C,3B,4B,5D), (1B,2C,3B,4B, 5E),
(1B,2C,3B,4C,5A), (1B,2C,3B,4C,5B), (1B,2C,3B,4C, 5C),
(1B,2C,3B,4C,5D), (1B,2C,3B,4C,5E), (1B,2C,3B,4D,5A),
(1B,2C,3B,4D,5B), (1B,2C,3B,4D,5C), (1B,2C,3B,4D,5D), (1B,
2C,3B,4D,5E), (1B,2C,3B,4E,5A), (1B,2C,3B,4E,5B), (1B,2C,3B,4E,5C),
(1B,2C,3B,4E,5D), (1B,2C,3B,4E,5E),
(1B,2D,3A,4A,5A),(1B,2D,3A,4A,5B), (1B,2D,3A,4A,5C), (1B,2D,3A,4A,
5D),(1B,2D,3A,4A,5E),(1B,2D,3A,4B,5A),(1B,2D,3A,4B,5B),(1B,2D,3A,4B,5C),(-
1B,2D,3A,4B,5D),(1B,2D,3A,4B,5E),(1B,2D,3A,4C,5A),(1B,2D,3A,4C,5B),(1B,2D,-
3A,4C,5C),(1B, 2D,3A,4C,5D),(1B,2D,3A,4C,5E),
(1B,2D,3A,4D,5A),(1B,2D,3A,4- D,5B),(1B,2D,3A,4D, 5C),
(1B,2D,3A,4D,5D), (1B,2D,3A,4D,5E), (1B,2D,3A,4E,5A),
(1B,2D,3A,4E,5B), (1B,2D,3A,4E, 5C), (1B,2D,3A,4E,5D),
(1B,2D,3A,4E,5E), (1B,2D,3B,4A,5A), (1B,2D,3B,4A,5B),
(1B,2D,3B,4A,5C), (1B,2D,3B,4A,5D), (1B,2D,3B,4A,5E),
(1B,2D,3B,4B,5A), (1B,2D,3B,4B,5B), (1B, 2D,3B,4B,5C),
(1B,2D,3B,4B,5D),(1B,2D,3B,4B,5E), (1B,2D,3B,4C,5A),(1B,2D,3B,4C,
5B), (1B,2D,3B,4C,5C), (1B,2D,3B,4C,5D), (1B,2D,3B,4C,5E),
(1B,2D,3B,4D,5A), (1B,2D,3B,4D, 5B), (1B,2D,3B,4D, 5C),
(1B,2D,3B,4D,5D), (1B,2D,3B,4D,5E), (1B,2D,3B,4E,5A),
(1B,2D,3B,4E,5B), (1B,2D,3B,4E,5C), (1B,2D,3B,4E,5D),
(1B,2D,3B,4E,5E), (1B,2E,3A,4A,5A), (1B, 2E,3A,4A,5B),
(1B,2E,3A,4A,5C), (1B,2E,3A,4A,5D), (1B,2E,3A,4A,5E),
(1B,2E,3A,4B,5A), (1B,2E,3A,4B,5B), (1B,2E,3A,4B,5C),
(1B,2E,3A,4B,5D), (1B,2E,3A,4B,5E), (1B,2E,3A,4C, 5A),
(1B,2E,3A,4C,5B), (1B,2E,3A,4C,5C), (1B,2E,3A,4C,5D),
(1B,2E,3A,4C,5E), (1B,2E,3A,4D,5A), (1B,2E,3A,4D,5B),
(1B,2E,3A,4D,5C), (1B,2E,3A,4D,5D), (1B,2E,3A,4D,5E), (1B,
2E,3A,4E,5A),(1B,2E,3A,4E,5B), (1B,2E,3A,4E,5C), (1B,2E,3A,4E,5D),
(1B,2E,3A,4E,5E), (1B,2E,3B,4A,5A), (1B,2E,3B,4A,5B),
(1B,2E,3B,4A,5C),(1B,2E,3B,4A,5D), (1B,2E,3B,4A,
5E),(1B,2E,3B,4B,5A),(1B-
,2E,3B,4B,5B),(1B,2E,3B,4B,5C),(1B,2E,3B,4B,5D),(1B,2E,3B,4B,5E),(1B,2E,3B-
,4C,5A),(1B,2E,3B,4C,5B),(1B,2E,3B,4C,5C),(1B,2E,3B,4C,5D),(1B,
2E,3B,4C,5E),(1B,2E,3B,4D,5A),(1B,2E,3B,4D,5B),(1B,2E,3B,4D,5C),(1B,2E,3B-
,4D,5D),
(1B,2E,3B,4D,5E),(1B,2E,3B,4E,5A),(1B,2E,3B,4E,5B),(1B,2E,3B,4E,5-
C),(1B,2E,3B,4E,
5D),(1B,2E,3B,4E,5E),(1C,2A,3A,4A,5A),(1C,2A,3A,4A,5B),(1-
C,2A,3A,4A,5C),(1C,2A,3A,4A,5D),(1C,2A,3A,4A,5E),(1C,2A,3A,4B,5A),(1C,2A,3-
A,4B,5B),(1C,2A,3A,4B,5C),(1C,
2A,3A,4B,5D),(1C,2A,3A,4B,5E),(1C,2A,3A,4C,-
5A),(1C,2A,3A,4C,5B),(1C,2A,3A,4C,5C),
(1C,2A,3A,4C,5D),(1C,2A,3A,4C,5E),(-
1C,2A,3A,4D,5A),(1C,2A,3A,4D,5B),(1C,2A,3A,4D,
5C),(1C,2A,3A,4D,5D),(1C,2A-
,3A,4D,5E),(1C,2A,3A,4E,5A),(1C,2A,3A,4E,5B),(1C,2A,3A,4E,5C),(1C,2A,3A,4E-
,5D),(1C,2A,3A,4E,5E),(1C,2A,3B,4A,5A),(1C,2A,3B,4A,5B),(1C,
2A,3B,4A,5C),(1C,2A,3B,4A,5D),(1C,2A,3B,4A,5E),(1C,2A,3B,4B,5A),(1C,2A,3B-
,4B,5B),
(1C,2A,3B,4B,5C),(1C,2A,3B,4B,5D),(1C,2A,3B,4B,5E),(1C,2A,3B,4C,5-
A),(1C,2A,3B,4C,
5B),(1C,2A,3B,4C,5C),(1C,2A,3B,4C,5D),(1C,2A,3B,4C,5E),(1-
C,2A,3B,4D,5A),(1C,2A,3B,4D,5B),(1C,2A,3B,4D,5C),(1C,2A,3B,4D,5D),(1C,2A,3-
B,4D,5E),(1C,2A,3B,4E,5A),(1C,
2A,3B,4E,5B),(1C,2A,3B,4E,5C),(1C,2A,3B,4E,-
5D),(1C,2A,3B,4E,5E),(1C,2B,3A,4A,5A),
(1C,2B,3A,4A,5B),(1C,2B,3A,4A,5C),(-
1C,2B,3A,4A,5D),(1C,2B,3A,4A,5E),(1C,2B,3A,4B,
5A),(1C,2B,3A,4B,5B),(1C,2B-
,3A,4B,5C),(1C,2B,3A,4B,5D),(1C,2B,3A,4B,5E),(1C,2B,3A,4C,5A),(1C,2B,3A,4C-
,5B),(1C,2B,3A,4C,5C),(1C,2B,3A,4C,5D),(1C,2B,3A,4C,5E),(1C,
2B,3A,4D,5A),(1C,2B,3A,4D,5B),(1C,2B,3A,4D,5C),(1C,2B,3A,4D,5D),
(1C,2B,3A,4D,5E),
(1C,2B,3A,4E,5A),(1C,2B,3A,4E,5B),(1C,2B,3A,4E,5C),(1C,-
2B,3A,4E,5D),(1C,2B,3A,4E,
5E),(1C,2B,3B,4A,5A),(1C,2B,3B,4A,5B),(1C,2B,3B-
,4A,5C),(1C,2B,3B,4A,5D),(1C,2B,3B,4A,5E),(1C,2B,3B,4B,5A),(1C,2B,3B,4B,5B-
),(1C,2B,3B,4B,5C),(1C,2B,3B,4B,5D),(1C,
2B,3B,4B,5E),(1C,2B,3B,4C,5A),(1C-
,2B,3B,4C,5B),(1C,2B,3B,4C,5C),(1C,2B,3B,4C,5D),
(1C,2B,3B,4C,5E),(1C,2B,3-
B,4D,5A),(1C,2B,3B,4D,5B),(1C,2B,3B,4D,5C),(1C,2B,3B,4D,
5D),(5C,2B,3B,4D,5E),(1C,2B,3B,4E,5A),(1C,2B,3B,4E,5B),(1C,2B,3B,4E,5C),(-
1C,2B,3B,4E,5D),(1C,2B,3B,4E,5E),(1C,2C,3A,4A,5A),(1C,2C,3A,4A,5B),(1C,2C,-
3A,4A,5C),(BC,
2C,3A,4A,5D),(1C,2C,3A,4A,5E),(1C,2C,3A,4B,5A),(1C,2C,3A,4B-
,5B),(1C,2C,3A,4B,5C),
(1C,2C,3A,4B,5D),(1C,2C,3A,4B,5E),(1C,2C,3A,4C,5A),-
(1C,2C,3A,4C,5B),(1C,2C,3A,4C,
5C),(1C,2C,3A,4C,5D),(1C,2C,3A,4C,5E),(1C,2-
C,3A,4D,5A),(1C,2C,3A,4D,5B),(1C,2C,3A,4D,5C),(1C,2C,3A,4D,5D),(1C,2C,3A,4-
D,5E),(1C,2C,3A,4E,5A),(1C,2C,3A,4E,5B),(1C,
2C,3A,4E,5C),(1C,2C,3A,4E,5D)-
,(1C,2C,3A,4E,5E),(1C,2C,3B,4A,5A),(1C,2C,3B,4A,5B),
(1C,2C,3B,4A,5C),(1C,2C,3B,4A,5D),(1C,2C,3B,4A,5E),(1C,2C,3B,4B,5A),(1C,2-
C,3B,4B,
5B),(1C,2C,3B,4B,5C),(1C,2C,3B,4B,5D),(1C,2C,3B,4B,5E),(1C,2C,3B,-
4C,5A),(1C,2C,3B,4C,5B),(1C,2C,3B,4C,5C),(1C,2C,3B,4C,5D),(1C,2C,3B,4C,5E)-
,(1C,2C,3B,4D,5A),(1C,
2C,3B,4D,5B),(1C,2C,3B,4D,5C),(1C,2C,3B,4D,5D),(1C,-
2C,3B,4D,5E),(1C,2C,3B,4E,5A),
(1C,2C,3B,4E,5B),(1C,2C,3B,4E,5C),(1C,2C,3B-
,4E,5D),(1C,2C,3B,4E,5E),(1C,2D,3A,4A,
5A),(1C,2D,3A,4A,5B),(1C,2D,3A,4A,5-
C),(1C,2D,3A,4A,5D),(1C,2D,3A,4A,5E),(1C,2D,3A,4B,5A),(1C,2D,3A,4B,5B),(1C-
,2D,3A,4B,5C),(1C,2D,3A,4B,5D),(1C,2D,3A,4B,5E),(1C,
2D,3A,4C,5A),(1C,2D,3A,4C,5B),(1C,2D,3A,4C,5C),(1C,2D,3A,4C,5D),(1C,2D,3A-
,4C,5E),
(1C,2D,3A,4D,5A),(1C,2D,3A,4D,5B),(1C,2D,3A,4D,5C),(1C,2D,3A,4D,5-
D),(1C,2D,3A,4D,
5E),(1C,2D,3A,4E,5A),(1C,2D,3A,4E,5B),(1C,2D,3A,4E,5C),(1-
C,2D,3A,4E,5D),(1C,2D,3A,4E,5E),(1C,2D,3B,4A,5A),(1C,2D,3B,4A,5B),(1C,2D,3-
B,4A,5C),(1C,2D,3B,4A,5D),(1C,
2D,3B,4A,5E),(1C,2D,3B,4B,5A),(1C,2D,3B,4B,-
5B),(1C,2D,3B,4B,5C),(1C,2D,3B,4B,5D),
(1C,2D,3B,4B,5E),(1C,2D,3B,4C,5A),(-
1C,2D,3B,4C,5B),(1C,2D,3B,4C,5C),(1C,2D,3B,4C,
5D),(1C,2D,3B,4C,5E),(1C,2D-
,3B,4D,5A),(1C,2D,3B,4D,5B),(1C,2D,3B,4D,5C),(1C,2D,3B,4D,5D),(1C,2D,3B,4D-
,5E),(1C,2D,3B,4E,5A),(1C,2D,3B,4E,5B),(1C,2D,3B,4E,5C),(1C,
2D,3B,4E,5D),(1C,2D,3B,4E,5E),(1C,2E,3A,4A,5A),(1C,2E,3A,4A,5B),(1C,2E,3A-
,4A,5C),
(1C,2E,3A,4A,5D),(1C,2E,3A,4A,5E),(1C,2E,3A,4B,5A),(1C,2E,3A,4B,5-
B),(1C,2E,3A,4B,
5C),(1C,2E,3A,4B,5D),(1C,2E,3A,4B,5E),(1C,2E,3A,4C,5A),(1-
C,2E,3A,4C,5B),(1C,2E,3A,4C,5C),(1C,2E,3A,4C,5D),(1C,2E,3A,4C,5E),(1C,2E,3-
A,4D,5A),(1C,2E,3A,4D,5B),(1C,
2E,3A,4D,5C),(1C,2E,3A,4D,5D),(1C,2E,3A,4D,-
5E),(1C,2E,3A,4E,5A),(1C,2E,3A,4E,5B),
(1C,2E,3A,4E,5C),(1C,2E,3A,4E,5D),(-
1C,2E,3A,4E,5E),(1C,2E,3B,4A,5A),(1C,2E,3B,4A,
5B),(1C,2E,3B,4A,5C),(1C,2E-
,3B,4A,5D),(1C,2E,3B,4A,5E),(1C,2E,3B,4B,5A),(1C,2E,3B,4B,5B),(1C,2E,3B,4B-
,5C),(1C,2E,3B,4B,5D),(1C,2E,3B,4B,5E),(1C,2E,3B,4C,5A),(1C,
2E,3B,4C,5B),(1C,2E,3B,4C,5C),(1C,2E,3B,4C,5D),(1C,2E,3B,4C,5E),(1C,2E,3B-
,4D,5A),
(1C,2E,3B,4D,5B),(1C,2E,3B,4D,5C),(1C,2E,3B,4D,5D),(1C,2E,3B,4D,5-
E),(1C,2E,3B,4E,
5A),(1C,2E,3B,4E,5B),(1C,2E,3B,4E,5C),(1C,2E,3B,4E,5D),(1-
C,2E,3B,4E,5E),(1D,2A,3A,4A,5A),(1D,2A,3A,4A,5B),(1D,2A,3A,4A,5C),(1D,2A,3-
A,4A,5D),(1D,2A,3A,4A,5E),(1D,
2A,3A,4B,5A),(1D,2A,3A,4B,5B),(1D,2A,3A,4B,-
5C),(1D,2A,3A,4B,5D),(1D,2A,3A,4B,5E),
(1D,2A,3A,4C,5A),(1D,2A,3A,4C,5B),(-
1D,2A,3A,4C,5C),(1D,2A,3A,4C,5D),(1D,2A,3A,4C,
5E),(1D,2A,3A,4D,5A),(1D,2A-
,3A,4D,5B),(1D,2A,3A,4D,5C),(1D,2A,3A,4D,5D),(1D,2A,3A,4D,5E),(1D,2A,3A,4E-
,5A),(1D,2A,3A,4E,5B),(1D,2A,3A,4E,5C),(1D,2A,3A,4E,5D),(1D,
2A,3A,4E,5E),(1D,2A,3B,4A,5A),(1D,2A,3B,4A,5B),(1D,2A,3B,4A,5C),(1D,2A,3B-
,4A,5D),
(1D,2A,3B,4A,5E),(1D,2A,3B,4B,5A),(1D,2A,3B,4B,5B),(1D,2A,3B,4B,5-
C),(1D,2A,3B,4B,
5D),(1D,2A,3B,4B,5E),(1D,2A,3B,4C,5A),(1D,2A,3B,4C,5B),(1-
D,2A,3B,4C,5C),(1D,2A,3B,4C,5D),(1D,2A,3B,4C,5E),(1D,2A,3B,4D,5A),(1D,2A,3-
B,4D,5B),(1D,2A,3B,4D,5C),(1D,
2A,3B,4D,5D),(1D,2A,3B,4D,5E),(1D,2A,3B,4E,-
5A),(1D,2A,3B,4E,5B),(1D,2A,3B,4E,5C),
(1D,2A,3B,4E,5D),(1D,2A,3B,4E,5E),(-
1D,2B,3A,4A,5A),(1D,2B,3A,4A,5B),(1D,2B,3A,4A,
5C),(1D,2B,3A,4A,5D),(1D,2B-
,3A,4A,5E),(1D,2B,3A,4B,5A),(1D,2B,3A,4B,5B),(1D,2B,3A,4B,5C),(1D,2B,3A,4B-
,5D),(1D,2B,3A,4B,5E),(1D,2B,3A,4C,5A),(1D,2B,3A,4C,5B),(1D,
2B,3A,4C,5C),(1D,2B,3A,4C,5D),(1D,2B,3A,4C,5E),(1D,2B,3A,4D,5A),(1D,2B,3A-
,4D,5B),
(1D,2B,3A,4D,5C),(1D,2B,3A,4D,5D),(1D,2B,3A,4D,5E),(1D,2B,3A,4E,5-
A),(1D,2B,3A,4E,
5B),(1D,2B,3A,4E,5C),(1D,2B,3A,4E,5D),(1D,2B,3A,4E,5E),(1-
D,2B,3B,4A,5A),(1D,2B,3B,4A,5B),(1D,2B,3B,4A,5C),(1D,2B,3B,4A,5D),(1D,2B,3-
B,4A,5E),(1D,2B,3B,4B,5A),(1D,
2B,3B,4B,5B),(1D,2B,3B,4B,5C),(1D,2B,3B,4B,-
5D),(1D,2B,3B,4B,5E),(1D,2B,3B,4C,5A),
(1D,2B,3B,4C,5B),(1D,2B,3B,4C,5C),(-
1D,2B,3B,4C,5D),(1D,2B,3B,4C,5E),(1D,2B,3B,4D,
5A),(1D,2B,3B,4D,5B),(1D,2B-
,3B,4D,5C),(1D,2B,3B,4D,5D),(1D,2B,3B,4D,5E),(1D,2B,3B,4E,5A),(1D,2B,3B,4E-
,5B),(1D,2B,3B,4E,5C),(1D,2B,3B,4E,5D),(1D,2B,3B,4E,5E),(1D,
2C,3A,4A,5A),(1D,2C,3A,4A,5B),(1D,2C,3A,4A,5C),(1D,2C,3A,4A,5D),(1D,2C,3A-
,4A,5E),
(1D,2C,3A,4B,5A),(1D,2C,3A,4B,5B),(1D,2C,3A,4B,5C),(1D,2C,3A,4B,5-
D),(1D,2C,3A,4B,
5E),(1D,2C,3A,4C,5A),(1D,2C,3A,4C,5B),(1D,2C,3A,4C,5C),(1-
D,2C,3A,4C,5D),(1D,2C,3A,4C,5E),(1D,2C,3A,4D,5A),(1D,2C,3A,4D,5B),(1D,2C,3-
A,4D,5C),(1D,2C,3A,4D,5D),(1D,
2C,3A,4D,5E),(1D,2C,3A,4E,5A),(1D,2C,3A,4E,-
5B),(1D,2C,3A,4E,5C),(1D,2C,3A,4E,5D),
(1D,2C,3A,4E,5E),(1D,2C,3B,4A,5A),(-
1D,2C,3B,4A,5B),(1D,2C,3B,4A,5C),(1D,2C,3B,4A,
5D),(1D,2C,3B,4A,5E),(1D,2C-
,3B,4B,5A),(1D,2C,3B,4B,5B),(1D,2C,3B,4B,5C),(1D,2C,3B,4B,5D),(1D,2C,3B,4B-
,5E),(1D,2C,3B,4C,5A),(1D,2C,3B,4C,5B),(1D,2C,3B,4C,5C),(1D,
2C,3B,4C,5D),(1D,2C,3B,4C,5E),(1D,2C,3B,4D,5A),(1D,2C,3B,4D,5B),(1D,2C,3B-
,4D,5C),
(1D,2C,3B,4D,5D),(1D,2C,3B,4D,5E),(1D,2C,3B,4E,5A),(1D,2C,3B,4E,5-
B),(1D,2C,3B,4E,
5C),(1D,2C,3B,4E,5D),(1D,2C,3B,4E,5E),(1D,2D,3A,4A,5A),(1-
D,2D,3A,4A,5B),(1D,2D,3A,4A,5C),(1D,2D,3A,4A,5D),(1D,2D,3A,4A,5E),(1D,2D,3-
A,4B,5A),(1D,2D,3A,4B,5B),(1D,
2D,3A,4B,5C),(1D,2D,3A,4B,5D),(1D,2D,3A,4B,-
5E),(1D,2D,3A,4C,5A),(1D,2D,3A,4C,5B), (1D,2D,3A,4C,5C),
(1D,2D,3A,4C,5D), (1D,2D,3A,4C,5E), (1D,2D,3A,4D,5A), (1D,2D,3A,4D,
5B), (1D,2D,3A,4D,5C), (1D,2D,3A,4D,5D), (1D,2D,3A,4D,5E),
(1D,2D,3A,4E,5A), (1D,2D,3A,4E,5B), (1D,2D,3A,4E,5C),
(1D,2D,3A,4E,5D), (1D,2D,3A,4E,5E), (1D,2D,3B,4A,5A), (1D,
2D,3B,4A,5B), (1D,2D,3B,4A,5C), (1D,2D,3B,4A,5D), (1D,2D,3B,4A,5E),
(1D,2D,3B,4B,5A), (1D,2D,3B,4B,5B), (1D,2D,3B,4B,5C),
(1D,2D,3B,4B,5D), (1D,2D,3B,4B,5E), (1D,2D,3B,4C,
5A),(1D,2D,3B,4C,5B),(1D,2D,3B,4C,5C),(1D-
,2D,3B,4C,5D),(1D,2D,3B,4C,5E),(1D,2D,3B,4D,5A), (1D,2D,3B,4D,5B),
(1D,2D,3B,4D,5C), (1D,2D,3B,4D,5D), (1D,2D,3B,4D,5E), (1D,
2D,3B,4E,5A), (1D,2D,3B,4E,5B), (1D,2D,3B,4E, 5C),
(1D,2D,3B,4E,5D), (1D,2D,3B,4E,5E), (1D,2E,3A,4A,5A), (1D,2E,3A,4A,
5B), (1D,2E,3A, 4A, 5C), (1D,2E,3A, 4A, 5D), (1D,2E,3A,4A,
5E),(1D,2E,3A,4B,5A),(1D,2E,3A,4B,5B),(1D,2E,3A,4B,5C)-
,(1D,2E,3A,4B,5D),(1D,2E,3A,4B,5E),(1D,2E,3A,4C,5A),(1D,2E,3A,4C,5B),(1D,2-
E,3A,4C,5C),(1D,2E,3A,4C,5D),(1D, 2E,3A,4C,5E), (1D,2E,3A,4D,5A),
(1D,2E,3A, 4D, 5B), (1D, 2E,3A, 4D, 5C), (1D,2E,3A,4D,5D),
(1D,2E,3A,4D,5E), (1D,2E,3A,4E,5A), (1D,2E,3A,4E,5B),
(1D,2E,3A,4E,5C), (1D,2E,3A,4E,
5D),(1D,2E,3A,4E,5E),(1D,2E,3B,4A,5A),(1D,2E,3B,4A,5B),(1D,-
2E,3B,4A,5C),(1D,2E,3B,4A,5D),(1D,2E,3B,4A,5E),(1D,2E,3B,4B,5A),(1D,2E,3B,-
4B,5B),(1D,2E,3B,4B,5C),(1D, 2E,3B,4B,5D), (1D,2E,3B,4B,5E),
(1D,2E,3B,4C,5A), (1D,2E,3B,4C,5B), (1D,2E,3B,4C,5C),
(1D,2E,3B,4C,5D), (1D,2E,3B,4C,5E), (1D,2E,3B,4D,5A),
(1D,2E,3B,4D,5B), (1D,2E,3B,4D, 5C), (1D,2E,3B,4D,5D),
(1D,2E,3B,4D,5E), (1D,2E,3B,4E,5A), (1D,2E,3B,4E,5B),
(1D,2E,3B,4E,5C),(1D,2E,3B,4E,5D),(1D,2E,3B,4E,5E),(1E,2A,3A,4A,5A),(1E,2-
A,3A,4A,5B),(1E,
2A,3A,4A,5C),(1E,2A,3A,4A,5D),(1E,2A,3A,4A,5E),(1E,2A,3A,-
4B,5A),(1E,2A,3A,4B,5B), (1E,2A,3A,4B,5C), (1E,2A,3A,4B,5D),
(1E,2A,3A,4B,5E), (1E,2A,3A,4C,5A), (1E,2A,3A,4C, 5B),
(1E,2A,3A,4C,5C), (1E,2A,3A,4C,5D), (1E,2A,3A,4C,5E),
(1E,2A,3A,4D,5A),
(1E,2A,3A,4D,5B),(1E,2A,3A,4D,5C),(1E,2A,3A,4D,5D),(1E,2A,3A,4D,5E),(1E,2-
A,3A,4E,5A),(1E,
2A,3A,4E,5B),(1E,2A,3A,4E,5C),(1E,2A,3A,4E,5D),(1E,2A,3A,-
4E,5E),(1E,2A,3B,4A,5A),
(1E,2A,3B,4A,5B),(1E,2A,3B,4A,5C),(1E,2A,3B,4A,5D-
),(1E,2A,3B,4A,5E),(1E,2A,3B,4B, 5A), (1E,2A,3B,4B,5B),
(1E,2A,3B,4B,5C), (1E,2A, 3B,4B, 5D), (1E,2A,3B,4B,5E),
(1E,2A,3B,4C,5A),(1E,2A,3B,4C,5B),(-
1E,2A,3B,4C,5C),(1E,2A,3B,4C,5D),(1E,2A,3B,4C,5E),(1E,
2A,3B,4D,5A),(1E,2A,3B,4D,5B),(1E,2A,3B,4D,5C),(1E,2A,3B,4D,5D),(1E,2A,3B-
,4D,5E),
(1E,2A,3B,4E,5A),(1E,2A,3B,4E,5B),(1E,2A,3B,4E,5C),(1E,2A,3B,4E,5-
D),(1E,2A,3B,4E, 5E), (1E,2B,3A,4A,5A), (1E,2B,3A, 4A, 5B),
(1E,2B,3A,4A, 5C), (1E,2B,3A,4A, 5D), (1E,2B,3A,4A,5E),
(1E,2B,3A,4B,5A), (1E,2B,3A,4B,5B), (1E,2B,3A,4B,5C),
(1E,2B,3A,4B,5D), (1E, 2B,3A,4B,5E),(1E,2B,3A,4C,5A),
(1E,2B,3A,4C,5B),(1E,2B,3A,4C,5C),(1E,2B,3- A,4C,5D),
(1E,2B,3A,4C,5E), (1E,2B,3A,4D,5A), (1E,2B,3A,4D,5B),
(1E,2B,3A,4D,5C), (1E,2B,3A,4D, 5D),
(E,2B,3A,4D,5E),(1E,2B,3A,4E,5A),(1E-
,2B,3A,4E,5B),(1E,2B,3A,4E,5C),
(1E,2B,3A,4E,5D),(1E,2B,3A,4E,5E),(1E,2B,3-
B,4A,5A),(1E,2B,3B,4A,5B),(1E,2B,3B,4A,5C),(1E,
2B,3B,4A,5D),(1E,2B,3B,4A,- 5E),(1E,2B,3B,4B,5A), (1E,2B,3B,4B,5B),
(1E,2B,3B,4B,5C), (1E,2B,3B,4B,5D), (1E,2B,3B,4B,5E),
(1E,2B,3B,4C,5A), (1E,2B,3B,4C,5B), (1E,2B,3B,4C, 5C),
(1E,2B,3B,4C,5D), (1E,2B,3B,4C,5E), (1E,2B,3B,4D,5A),
(1E,2B,3B,4D,5B), (1E,2B,3B,4D,5C), (1E,2B,3B,4D,5D),
(1E,2B,3B,4D,5E), (1E,2B,3B,4E,5A), (1E,2B,3B,4E,5B), (1E,
2B,3B,4E, 5C), (1E,2B,3B,4E,5D), (1E,2B,3B,4E, 5E),
(1E,2C,3A,4A,5A), (1E,2C,3A,4A, 5B), (1E,2C,3A,4A,5C),
(1E,2C,3A,4A,5D), (1E,2C,3A,4A,5E), (1E,2C,3A,4B,5A), (1E,2C,3A,4B,
5B),(1E,2C,3A,4B,5C),(1E,2C,3A,4B,5D),(1E,2C,3A,4B,5E),(1E,2C,3A,4C,5A),(-
1E,2C,3A,4C,5B), (1E,2C,3A,4C,5C), (1E,2C,3A,4C,5D),
(1E,2C,3A,4C,5E), (1E,2C,3A,4D,5A), (1E, 2C,3A,4D,5B),
(1E,2C,3A,4D,5C), (1E,2C,3A,4D,5D), (1E,2C,3A,4D,5E),
(1E,2C,3A,4E,5A), (1E,2C,3A,4E,5B),(1E,2C,3A,4E,5C),(1E-
,2C,3A,4E,5D),(1E,2C,3A,4E,5E),(1E,2C,3B,4A, 5A), (1E,2C,3B,4A,5B),
(1E,2C,3B,4A,5C), (1E,2C,3B,4A,5D), (1E,2C,3B,4A,5E),
(1E,2C,3B,4B,5A), (1E,2C,3B,4B,5B), (1E,2C,3B,4B,5C),
(1E,2C,3B,4B,5D), (1E,2C,3B,4B,5E), (1E,
2C,3B,4C,5A),(1E,2C,3B,4C,5B),(1E,2C,3B,4C,5C),(1E,2C,3B,4C,5D),(1E,-
2C,3B,4C,5E),
(1E,2C,3B,4D,5A),(1E,2C,3B,4D,5B),(1E,2C,3B,4D,5C),(1E,2C,3B-
,4D,5D),(1E,2C,3B,4D,
5E),(1E,2C,3B,4E,5A),(1E,2C,3B,4E,5B),(1E,2C,3B,4E,5-
C),(1E,2C,3B,4E,5D),(1E,2C,3B,4E,5E), (1E,2D,3A,4A,5A),
(1E,2D,3A,4A,5B), (1E,2D,3A,4A,5C), (1E,2D,3A,4A,5D), (1E,
2D,3A,4A,5E),(1E,2D,3A,4B,5A),(1- E,2D,3A,4B,5B),(1E,2D,3A,4B,5C),
(1E,2D,3A,4B,5D), (1E,2D,3A,4B,5E),(1E,2D-
,3A,4C,5A),(1E,2D,3A,4C,5B),(1E,2D,3A,4C,5C),(1E,2D,3A,4C,
5D),(5E,2D,3A,4C,5E),(1E,2D,3A,4D,5A),(1E,2D,3A,4D,5B),(1E,2D,3A,4D,5C),(-
1E,2D,3A,4D,5D),(1E,2D,3A,4D,5E),(1E,2D,3A,4E,5A),(1E,2D,3A,4E,5B),(1E,2D,-
3A,4E,5C)3(1E,
2D,3A,4E,5D),(1E,2D,3A,4E,5E),(1E,2D,3B,4A,5A),(1E,2D,3B,4A-
,5B),(1E,2D,3B,4A,5C),
(1E,2D,3B,4A,5D),(1E,2D,3B,4A,5E),(1E,2D,3B,4B,5A),-
(1E,2D,3B,4B,5B),(1E,2D,3B,4B,
5C),(1E,2D,3B,4B,5D),(1E,2D,3B,4B,5E),(1E,2-
D,3B,4C,5A),(1E,2D,3B,4C,5B),(1E,2D,3B,4C,5C), (1E,2D,3B,4C,5D),
(1E,2D,3B,4C,5E), (1E,2D,3B,4D,5A), (1E,2D,3B,4D,5B), (1E,
2D,3B,4D,5C),(1E,2D,3B,4D,5D),(1E,2D,3B,4D,5E),(1E,2D,3B,4E,5A),(1E,2D,3B-
,4E,5B),
(1E,2D,3B,4E,5C),(1E,2D,3B,4E,5D),(1E,2D,3B,4E,5E),(1E,2E,3A,4A,5-
A),(1E,2E,3A,4A,
5B),(1E,2E,3A,4A,5C),(1E,2E,3A,4A,5D),(1E,2E,3A,4A,5E),(1-
E,2E,3A,4B,5A),(1E,2E,3A,4B,5B),(1E,2E,3A,4B,5C),(1E,2E,3A,4B,5D),(1E,2E,3-
A,4B,5E),(1E,2E,3A,4C,5A),(1E,
2E,3A,4C,5B),(1E,2E,3A,4C,5C),(1E,2E,3A,4C,-
5D),(1E,2E,3A,4C,5E),(1E,2E,3A,4D,5A),
(1E,2E,3A,4D,5B),(1E,2E,3A,4D,5C),(-
1E,2E,3A,4D,5D),(1E,2E,3A,4D,5E),(1E,2E,3A,4E,
5A),(1E,2E,3A,4E,5B),(1E,2E-
,3A,4E,5C),(1E,2E,3A,4E,5D),(1E,2E,3A,4E,5E),(1E,2E,3B,4A,5A),(1E,2E,3B,4A-
,5B),(1E,2E,3B,4A,5C),(1E,2E,3B,4A,5D),(1E,2E,3B,4A,5E),(1E,
2E,3B,4B,5A),(1E,2E,3B,4B,5B),(1E,2E,3B,4B,5C),(1E,2E,3B,4B,5D),(1E,2E,3B-
,4B,5E),
(1E,2E,3B,4C,5A),(1E,2E,3B,4C,5B),(1E,2E,3B,4C,5C),(1E,2E,3B,4C,5-
D),(1E,2E,3B,4C,
5E),(1E,2E,3B,4D,5A),(1E,2E,3B,4D,5B),(1E,2E,3B,4D,5C),(1-
E,2E,3B,4D,5D),(1E,2E,3B,4D,5E),(1E,2E,3B,4E,5A),(1E,2E,3B,4E,5B),(1E,2E,3-
B,4E,5C),(1E,2E,3B,4E,5D),(1E, 2E,3B,4E,5E)
[3088] And (R.sup.1,R.sup.2,X, R.sup.4,R.sup.5)=(1A,2A,3A,4A,5A) is
the compound which R.sup.1 is 1A, R.sup.2 is 2A, X is 3A, R.sup.4
is 4A and R.sup.5 is 5A. The other combinations are the same.
[3089] The compounds of the present invention include the following
compounds. The following compounds are synthesized with a same
manner similar to the above examples. 295
[3090] The substituents of R.sup.1, R.sup.2, R.sup.3, R.sup.4, X,
R.sup.1 and R.sup.7 of above compound include the following
substitution group.
[3091] R.sup.1=H (1A), Me(1B), OMe(1C), Cl(1D), Ph(1E)
[3092] R.sup.2=H (2A), Me(2B), OMe(2C), Cl(2D), Ph(2E)
[3093] R.sup.3=H (3A), Me(3B), OMe(3C), Cl(3D), Ph(3E)
[3094] R.sup.4=H (4A), Me(4B), OMe(4C), Cl(4D), Ph(4E)
[3095] X=O(3A), NH(3B) 296
[3096] The preferable combinations
(R.sup.1,R.sup.2,R.sup.3,R.sup.4,X, R.sup.6,R.sup.7) of the
substituents of above compound include the followings.
[3097]
(1A,2A,3A,4A,5A,6A,7A),(1A,2A,3A,4A,5A,6A,7B),(1A,2A,3A,4A,5A,6A,7C-
),(1A,2A,3A,4A,5A,6B,7A),(1A,2A,3A,4A,5A,6B,7B),(1A,2A,3A,4A,5A,6B,7C),(1A-
,2A,3A,4A,5A,6C,7A),
(1A,2A,3A,4A,5A,6C,7B),(1A,2A,3A,4A,5A,6C,7C),(1A,2A,-
3A,4A,5A,6D,7A),(1A,2A,3A,4A,5A,6D,7B),(1A,2A,3A,4A,5A,6D,7C),(1A,2A,3A,4A-
,5B,6A,7A),(1A,2A,3A,4A,5B,6A,7B),
(1A,2A,3A,4A,5B,6A,7C),(1A,2A,3A,4A,5B,-
6B,7A),(1A,2A,3A,4A,5B,6B,7B),(1A,2A,3A,4A,5B,6B,7C),(1A,2A,3A,4A,5B,6C,7A-
),(1A,2A,3A,4A,5B,6C,7B),(1A,2A,3A,4A,5B,6C,7C),
(1A,2A,3A,4A,5B,6D,7A),(1-
A,2A,3A,4A,5B,6D,7B),(1A,2A,3A,4A,5B,6D,7C),(1A,2A,3A,4B,5A,6A,7A),(1A,2A,-
3A,4B,5A,6A,7B),(1A,2A,3A,4B,5A,6A,7C),(1A,2A,3A,4B,5A,6B,7A),
(1A,2A,3A,4B,5A,6B,7B),(1A,2A,3A,4B,5A,6B,7C),(1A,2A,3A,4B,5A,6C,7A),(1A,-
2A,3A,4B,5A,6C,7B),(1A,2A,3A,4B,5A,6C,7C),(1A,2A,3A,4B,5A,6D,7A),(1A,2A,3A-
,4B,5A,6D,7B),
(1A,2A,3A,4B,5A,6D,7C),(1A,2A,3A,4B,5B,6A,7A),(1A,2A,3A,4B,-
5B,6A,7B),(1A,2A,3A,4B,5B,6A,7C),(1A,2A,3A,4B,5B,6B,7A),(1A,2A,3A,4B,5B,6B-
,7B),(1A,2A,3A,4B,5B,6B,7C),
(1A,2A,3A,4B,5B,6C,7A),(1A,2A,3A,4B,5B,6C,7B)-
,(1A,2A,3A,4B,5B,6C,7C),(1A,2A,3A,4B,5B,6D,7A),(1A,2A,3A,4B,5B,6D,7B),(1A,-
2A,3A,4B,5B,6D,7C),(1A,2A,3A,4C,5A,6A,7A),
(1A,2A,3A,4C,5A,6A,7B),(1A,2A,3-
A,4C,5A,6A,7C),(1A,2A,3A,4C,5A,6B,7A),(1A,2A,3A,4C,5A,6B,7B),(1A,2A,3A,4C,-
5A,6B,7C),(1A,2A,3A,4C,5A,6C,7A),(1A,2A,3A,4C,5A,6C,7B),
(1A,2A,3A,4C,5A,6C,7C),(1A,2A,3A,4C,5A,6D,7A),(1A,2A,3A,4C,5A,6D,7B),(1A,-
2A,3A,4C,5A,6D,7C),(1A,2A,3A,4C,5B,6A,7A),(1A,2A,3A,4C,5B,6A,7B),(1A,2A,3A-
,4C,5B,6A,7C),
(1A,2A,3A,4C,5B,6B,7A),(1A,2A,3A,4C,5B,6B,7B),(1A,2A,3A,4C,-
5B,6B,7C),(1A,2A,3A,4C,5B,6C,7A),(1A,2A,3A,4C,5B,6C,7B),(1A,2A,3A,4C,5B,6C-
,7C),(1A,2A,3A,4C,5B,6D,7A),
(1A,2A,3A,4C,5B,6D,7B),(1A,2A,3A,4C,5B,6D,7C)-
,(1A,2A,3A,4D,5A,6A,7A),(1A,2A,3A,4D,5A,6A,7B),(1A,2A,3A,4D,5A,6A,7C),(1A,-
2A,3A,4D,5A,6B,7A),(1A,2A,3A,4D,5A,6B,7B),
(1A,2A,3A,4D,5A,6B,7C),(1A,2A,3-
A,4D,5A,6C,7A),(1A,2A,3A,4D,5A,6C,7B),(1A,2A,3A,4D,5A,6C,7C),(1A,2A,3A,4D,-
5A,6D,7A),(1A,2A,3A,4D,5A,6D,7B),(1A,2A,3A,4D,5A,6D,7C),
(1A,2A,3A,4D,5B,6A,7A),(1A,2A,3A,4D,5B,6A,7B),(1A,2A,3A,4D,5B,6A,7C),(1A,-
2A,3A,4D,5B,6B,7A),(1A,2A,3A,4D,5B,6B,7B),(1A,2A,3A,4D,5B,6B,7C),(1A,2A,3A-
,4D,5B,6C,7A),
(1A,2A,3A,4D,5B,6C,7B),(1A,2A,3A,4D,5B,6C,7C),(1A,2A,3A,4D,-
5B,6D,7A),(1A,2A,3A,4D,5B,6D,7B),(1A,2A,3A,4D,5B,6D,7C),(1A,2A,3A,4E,5A,6A-
,7A),(1A,2A,3A,4E,5A,6A,7B),
(1A,2A,3A,4E,5A,6A,7C),(1A,2A,3A,4E,5A,6B,7A)-
,(1A,2A,3A,4E,5A,6B,7B),(1A,2A,3A,4E,5A,6B,7C),(1A,2A,3A,4E,5A,6C,7A),(1A,-
2A,3A,4E,5A,6C,7B),(1A,2A,3A,4E,5A,6C,7C),
(1A,2A,3A,4E,5A,6D,7A),(1A,2A,3-
A,4E,5A,6D,7B),(1A,2A,3A,4E,5A,6D,7C),(1A,2A,3A,4E,5B,6A,7A),(1A,2A,3A,4E,-
5B,6A,7B),(1A,2A,3A,4E,5B,6A,7C),(1A,2A,3A,4E,5B,6B,7A),
(1A,2A,3A,4E,5B,6B,7B),(1A,2A,3A,4E,5B,6B,7C),(1A,2A,3A,4E,5B,6C,7A),(1A,-
2A,3A,4E,5B,6C,7B),(1A,2A,3A,4E,5B,6C,7C),(1A,2A,3A,4E,5B,6D,7A),(1A,2A,3A-
,4E,5B,6D,7B),
(1A,2A,3A,4E,5B,6D,7C),(1A,2A,3B,4A,5A,6A,7A),(1A,2A,3B,4A,-
5A,6A,7B),(1A,2A,3B,4A,5A,6A,7C),(1A,2A,3B,4A,5A,6B,7A),(1A,2A,3B,4A,5A,6B-
,7B),(1A,2A,3B,4A,5A,6B,7C),
(1A,2A,3B,4A,5A,6C,7A),(1A,2A,3B,4A,5A,6C,7B)-
,(1A,2A,3B,4A,5A,6C,7C),(1A,2A,3B,4A,5A,6D,7A),(1A,2A,3B,4A,5A,6D,7B),(1A,-
2A,3B,4A,5A,6D,7C),(1A,2A,3B,4A,5B,6A,7A),
(1A,2A,3B,4A,5B,6A,7B),(1A,2A,3-
B,4A,5B,6A,7C),(1A,2A,3B,4A,5B,6B,7A),(1A,2A,3B,4A,5B,6B,7B),(1A,2A,3B,4A,-
5B,6B,7C),(1A,2A,3B,4A,5B,6C,7A),(1A,2A,3B,4A,5B,6C,7B),
(1A,2A,3B,4A,5B,6C,7C),(1A,2A,3B,4A,5B,6D,7A),(1A,2A,3B,4A,5B,6D,7B),(1A,-
2A,3B,4A,5B,6D,7C),(1A,2A,3B,4B,5A,6A,7A),(1A,2A,3B,4B,5A,6A,7B),(1A,2A,3B-
,4B,5A,6A,7C),
(1A,2A,3B,4B,5A,6B,7A),(1A,2A,3B,4B,5A,6B,7B),(1A,2A,3B,4B,-
5A,6B,7C),(1A,2A,3B,4B,5A,6C,7A),(1A,2A,3B,4B,5A,6C,7B),(1A,2A,3B,4B,5A,6C-
,7C),(1A,2A,3B,4B,5A,6D,7A),
(1A,2A,3B,4B,5A,6D,7B),(1A,2A,3B,4B,5A,6D,7C)-
,(1A,2A,3B,4B,5B,6A,7A),(1A,2A,3B,4B,5B,6A,7B),(1A,2A,3B,4B,5B,6A,7C),(1A,-
2A,3B,4B,5B,6B,7A),(1A,2A,3B,4B,5B,6B,7B),
(1A,2A,3B,4B,5B,6B,7C),(1A,2A,3-
B,4B,5B,6C,7A),(1A,2A,3B,4B,5B,6C,7B),(1A,2A,3B,4B,5B,6C,7C),(1A,2A,3B,4B,-
5B,6D,7A),(1A,2A,3B,4B,5B,6D,7B),(1A,2A,3B,4B,5B,6D,7C),
(1A,2A,3B,4C,5A,6A,7A),(1A,2A,3B,4C,5A,6A,7B),(1A,2A,3B,4C,5A,6A,7C),(1A,-
2A,3B,4C,5A,6B,7A),(1A,2A,3B,4C,5A,6B,7B),(1A,2A,3B,4C,5A,6B,7C),(1A,2A,3B-
,4C,5A,6C,7A),
(1A,2A,3B,4C,5A,6C,7B),(1A,2A,3B,4C,5A,6C,7C),(1A,2A,3B,4C,-
5A,6D,7A),(1A,2A,3B,4C,5A,6D,7B),(1A,2A,3B,4C,5A,6D,7C),(1A,2A,3B,4C,5B,6A-
,7A),(1A,2A,3B,4C,5B,6A,7B),
(1A,2A,3B,4C,5B,6A,7C),(1A,2A,3B,4C,5B,6B,7A)-
,(1A,2A,3B,4C,5B,6B,7B),(1A,2A,3B,4C,5B,6B,7C),(1A,2A?3B,4C,5B,6C,7A),(1A,-
2A,3B,4C,5B,6C,7B),(1A,2A,3B,4C,5B,6C,7C),
(1A,2A,3B,4C,5B,6D,7A),(1A,2A,3-
B,4C,5B,6D,7B),(1A,2A,3B,4C,5B,6D,7C),(1A,2A,3B,4D,5A,6A,7A),(1A,2A,3B,4D,-
5A,6A,7B),(1A,2A,3B,4D,5A,6A,7C),(1A,2A,3B,4D,5A,6B,7A),
(1A,2A,3B,4D,5A,6B,7B),(1A,2A,3B,4D,5A,6B,7C),(1A,2A,3B,4D,5A,6C,7A),(1A,-
2A,3B,4D,5A,6C,7B),(1A,2A,3B,4D,5A,6C,7C),(1A,2A,3B,4D,5A,6D,7A),(1A,2A,3B-
,4D,5A,6D,7B),
(1A,2A,3B,4D,5A,6D,7C),(1A,2A,3B,4D,5B,6A,7A),(1A,2A,3B,4D,-
5B,6A,7B),(1A,2A,3B,4D,5B,6A,7C),(1A,2A,3B,4D,5B,6B,7A),(1A,2A,3B,4D,5B,6B-
,7B),(1A,2A,3B,4D,5B,6B,7C),
(1A,2A,3B,4D,5B,6C,7A),(1A,2A,3B,4D,5B,6C,7B)-
,(1A,2A,3B,4D,5B,6C,7C),(1A,2A,3B,4D,5B,6D,7A),(1A,2A,3B,4D,5B,6D,7B),(1A,-
2A,3B,4D,5B,6D,7C),(1A,2A,3B,4E,5A,6A,7A),
(1A,2A,3B,4E,5A,6A,7B),(1A,2A,3-
B,4E,5A,6A,7C),(1A,2A,3B,4E,5A,6B,7A),(1A,2A,3B,4E,5A,6B,7B),(1A,2A,3B,4E,-
5A,6B,7C),(1A,2A,3B,4E,5A,6C,7A),(1A,2A,3B,4E,5A,6C,7B),
(1A,2A,3B,4E,5A,6C,7C),(1A,2A,3B,4E,5A,6D,7A),(1A,2A,3B,4E,5A,6D,7B),(1A,-
2A,3B,4E,5A,6D,7C),(1A,2A,3B,4E,5B,6A,7A),(1A,2A,3B,4E,5B,6A,7B),(1A,2A,3B-
,4E,5B,6A,7C),
(1A,2A,3B,4E,5B,6B,7A),(1A,2A,3B,4E,5B,6B,7B),(1A,2A,3B,4E,-
5B,6B,7C),(1A,2A,3B,4E,5B,6C,7A),(1A,2A,3B,4E,5B,6C,7B),(1A,2A,3B,4E,5B,6C-
,7C),(1A,2A,3B,4E,5B,6D,7A),
(1A,2A,3B,4E,5B,6D,7B),(1A,2A,3B,4E,5B,6D,7C)-
,(1A,2A,3C,4A,5A,6A,7A),(1A,2A,3C,4A,5A,6A,7B),(1A,2A,3C,4A,5A,6A,7C),(1A,-
2A,3C,4A,5A,6B,7A),(1A,2A,3C,4A,5A,6B,7B),
(1A,2A,3C,4A,5A,6B,7C),(1A,2A,3-
C,4A,5A,6C,7A),(1A,2A,3C,4A,5A,6C,7B),(1A,2A,3C,4A,5A,6C,7C),(1A,2A,3C,4A,-
5A,6D,7A),(1A,2A,3C,4A,5A,6D,7B),(1A,2A,3C,4A,5A,6D,7C),
(1A,2A,3C,4A,5B,6A,7A),(1A,2A,3C,4A,5B,6A,7B),(1A,2A,3C,4A,5B,6A,7C),(1A,-
2A,3C,4A,5B,6B,7A),(1A,2A,3C,4A,5B,6B,7B),(1A,2A,3C,4A,5B,6B,7C),(1A,2A,3C-
,4A,5B,6C,7A),
(1A,2A,3C,4A,5B,6C,7B),(1A,2A,3C,4A,5B,6C,7C),(1A,2A,3C,4A,-
5B,6D,7A),(1A,2A,3C,4A,5B,6D,7B),(1A,2A,3C,4A,5B,6D,7C),(1A,2A,3C,4B,5A,6A-
,7A),(1A,2A,3C,4B,5A,6A,7B),
(1A,2A,3C,4B,5A,6A,7C),(1A,2A,3C,4B,5A,6B,7A)-
,(1A,2A,3C,4B,5A,6B,7B),(1A,2A,3C,4B,5A,6B,7C),(1A,2A,3C,4B,5A,6C,7A),(1A,-
2A,3C,4B,5A,6C,7B),(1A,2A,3C,4B,5A,6C,7C),
(1A,2A,3C,4B,5A,6D,7A),(1A,2A,3-
C,4B,5A,6D,7B),(1A,2A,3C,4B,5A,6D,7C),(1A,2A,3C,4B,5B,6A,7A),
(1A,2A,3C,4B,5B,6A,7B),(1A,2A,3C,4B,5B,6A,7C),(1A,2A,3C,4B,5B,6B,7A),
(1A,2A,3C,4B,5B,6B,7B), (1A,2A,3C,4B,5B,6B,7C),
(1A,2A,3C,4B,5B,6C,7A), (A,2A,3C,4B,5B,6C,7B), (1A,2A,3C,4B,5B,6C,
7C), (1A,2A,3C,4B, 5B,6D,7A), (1A,2A,3C,4B,5B,6D, 7B),
(1A,2A,3C,4B,5B,6D,7C), (1A,2A,3C,4C,5A,6A,7A),
(1A,2A,3C,4C,5A,6A,7B), (1A,2A,3C,4C,5A,6A,7C),
(1A,2A,3C,4C,5A,6B,7A),(1-
A,2A,3C,4C,5A,6B,7B),(1A,2A,3C,4C,5A,6B,7C),
(1A,2A,3C,4C,5A,6C,7A),(1A,2A-
,3C,4C,5A,6C,7B),(1A,2A,3C,4C,5A,6C,7C),(1A,2A,3C,4C,5A,6D,7A),
(1A,2A,3C,4C,5A,6D,7B),(1A,2A,3C,4C,5A,6D,7C),(1A,2A,3C,4C,5B,6A,7A),
(1A,2A,3C,4C,5B,6A,7B),(1A,2A,3C,4C,5B,6A,7C),(1A,2A,3C,4C,5B,6B,7A),(1A,-
2A,3C,4C,5B,6B,7B),
(1A,2A,3C,4C,5B,6B,7C),(1A,2A,3C,4C,5B,6C,7A),(1A,2A,3-
C,4C,5B,6C,7B),
(1A,2A,3C,4C,5B,6C,7C),(1A,2A,3C,4C,5B,6D,7A),(1A,2A,3C,4C-
,5B,6D,7B),(1A,2A,3C,4C,5B,6D,7C), (1A,2A,3C,4D,5A,6A,7A),
(1A,2A,3C,4D,5A,6A,7B),(1A,2A,3C,4D,5A,6A,7C),
(1A,2A,3C,4D,5A,6B,7A),(1A-
,2A,3C,4D,5A,6B,7B),(1A,2A,3C,4D,5A,6B,7C),(1A,2A,3C,4D,5A,6C,7A),
(1A,2A,3C,4D,5A,6C,7B),(1A,2A,3C,4D,5A,6C,7C),(1A,2A,3C,4D,5A,6D,7A),
(1A,2A,3C,4D,5A,6D,7B),(1A,2A,3C,4D,5A,6D,7C),(1A,2A,3C,4D,5B,6A,7A),(1A,-
2A,3C,4D,5B,6A,7B),
(1A,2A,3C,4D,5B,6A,7C),(1A,2A,3C,4D,5B,6B,7A),(1A,2A,3-
C,4D,5B,6B,7B),
(1A,2A,3C,4D,5B,6B,7C),(1A,2A,3C,4D,5B,6C,7A),(1A,2A,3C,4D-
,5B,6C,7B),(1A,2A,3C,4D,5B,6C,7C), (1A,2A,3C,4D,5B,6D,7A),
(1A,2A,3C,4D,5B,6D,7B), (1A,2A,3C,4D, 5B,6D, 7C),
(1A,2A,3C,4E,5A,6A,7A),-
(1A,2A,3C,4E,5A,6A,7B),(1A,2A,3C,4E,5A,6A,7C),(1A,2A,3C,4E,5A,6B,7A),(1A,2-
A,3C,4E,5A,6B,7B),(1A,2A,3C,4E,5A,6B,7C),(1A,2A,3C,4E,5A,6C,7A),
(1A,2A,3C,4E,5A,6C,7B),(1A,2A,3C,4E,5A,6C,7C),(1A,2A,3C,4E,5A,6D,7A),(1A,-
2A,3C,4E,5A,6D,7B),
(1A,2A,3C,4E,5A,6D,7C),(1A,2A,3C,4E,5B,6A,7A),(1A,2A,3-
C,4E,5B,6A,7B), (1A,2A,3C,4E,5B,6A,7C), (1A,2A,3C,4E,5B,6B,7A),
(1A,2A,3C,4E,5B,6B,7B), (1A, 2A,
3C,4E,5B,6B,7C),(1A,2A,3C,4E,5B,6C,7A),(-
1A,2A,3C,4E,5B,6C,7B),(1A,2A,3C,4E,5B,6C,7C),
(1A,2A,3C,4E,5B,6D,7A), (1A,2A,3C,4E, 5B,6D,7B), (1A, 2A,
3C,4E,5B,6D,7C), (1A,2A,3D,4A,5A,6A,7A), (1A,2A,3D,4A,5A,6A,7B),
(1A,2A,3D,4A,5A,6A,7C), (1A,2A,3D,4A,5A,6B,7A),
(1A,2A,3D,4A,5A,6B,7B), (1A,2A,3D,4A,5A,6B,7C),
(1A,2A,3D,4A,5A,6C,7A), (1A,2A,3D,4A,5A,6C,7B),
(1A,2A,3D,4A,5A,6C,7C),(1-
A,2A,3D,4A,5A,6D,7A),(1A,2A,3D,4A,5A,6D,7B), (1A,2A,3D,4A,
5A,6D,7C), (1A,2A,3D,4A,5B,6A,7A), (1A,2A,3D,4A,5B,6A, 7B),
(1A,2A,3D,4A,5B,6A,7C),
(1A,2A,3D,4A,5B,6B,7A),(1A,2A,3D,4A,5B,6B,7B),(1A,2A,3D,4A,5B,6B,7C),
(1A,2A,3D,4A,5B,6C,7A), (1A,2A,3D,4A,5B,6C,7B),
(1A,2A,3D,4A,5B,6C,7C), (1A,2A,3D,4A,5B,6D, 7A),
(1A,2A,3D,4A,5B,6D, 7B), (1A,2A,3D,4A,5B, 6D, 7C), (1A,2A,3D,4B,
5A,6A, 7A), (1A,2A,3D,4B,5A,6A,7B), (1A,2A,3D,4B,5A,6A,7C),
(1A,2A,3D,4B,5A,6B, 7A), (1A,2A,3D,4B,5A,6B,7B),
(1A,2A,3D,4B,5A,6B,7C),(1A,2A,3D,4B,5A,6C,7A),(1A,2A,3D,4B,5A,6C,7B),
(1A,2A,3D,4B,5A,6C,7C), (1A,2A,3D,4B,5A,6D,7A),
(1A,2A,3D,4B,5A,6D,7B),(1- A,2A,3D,4B,5A,6D,7C),
(1A,2A,3D,4B,5B,6A,7A),(1A,2A,3D,4B,5B,6A,7B),(1A,2A-
,3D,4B,5B,6A,7C), (1A,2A,3D,4B,5B,6B,7A), (1A,2A,3D,4B,5B,6B,7B),
(1A,2A,3D,4B,5B,6B,7C),
(1A,2A,3D,4B,5B,6C,7A),(1A,2A,3D,4B,5B,6C,7B),(1A-
,2A,3D,4B,5B,6C,7C),(1A,2A,3D,4B,5B,6D,7A),
(1A,2A,3D,4B,5B,6D,7B),(1A,2A,-
3D,4B,5B,6D,7C),(1A,2A,3D,4C,5A,6A,7A),(1A,2A,3D,4C,5A,6A,7B),(1A,2A,3D,4C-
,5A,6A,7C),(1A,2A,3D,4C,5A,6B,7A),(1A,2A,3D,4C,5A,6B,7B),
(1A,2A,3D,4C,5A,6B,7C),(1A,2A,3D,4C,5A,6C,7A),(1A,2A,3D,4C,5A,6C,7B),(1A,-
2A,3D,4C,5A,6C,7C),(1A,2A,3D,4C,5A,6D,7A),(1A,2A,3D,4C,5A,6D,7B),(1A,2A,3D-
,4C,5A,6D,7C),
(1A,2A,3D,4C,5B,6A,7A),(1A,2A,3D,4C,5B,6A,7B),(1A,2A,3D,4C,-
5B,6A,7C),(1A,2A,3D,4C,5B,6B,7A),(1A,2A,3D,4C,5B,6B,7B),(1A,2A,3D,4C,5B,6B-
,7C),(1A,2A,3D,4C,5B,6C,7A),
(1A,2A,3D,4C,5B,6C,7B),(1A,2A,3D,4C,5B,6C,7C)-
,(1A,2A,3D,4C,5B,6D,7A),(1A,2A,3D,4C,5B,6D,7B),(1A,2A,3D,4C,5B,6D,7C),(1A,-
2A,3D,4D,5A,6A,7A),(1A,2A,3D,4D,5A,6A,7B),
(1A,2A,3D,4D,5A,6A,7C),(1A,2A,3-
D,4D,5A,6B,7A),(1A,2A,3D,4D,5A,6B,7B),(1A,2A,3D,4D,5A,6B,7C),(1A,2A,3D,4D,-
5A,6C,7A),(1A,2A,3D,4D,5A,6C,7B),(1A,2A,3D,4D,5A,6C,7C),
(1A,2A,3D,4D,5A,6D,7A),(1A,2A,3D,4D,5A,6D,7B),(1A,2A,3D,4D,5A,6D,7C),(1A,-
2A,3D,4D,5B,6A,7A),(1A,2A,3D,4D,5B,6A,7B),(1A,2A,3D,4D,5B,6A,7C),(1A,2A,3D-
,4D,5B,6B,7A),
(1A,2A,3D,4D,5B,6B,7B),(1A,2A,3D,4D,5B,6B,7C),(1A,2A,3D,4D,-
5B,6C,7A),(1A,2A,3D,4D,5B,6C,7B),(1A,2A,3D,4D,5B,6C,7C),(1A,2A,3D,4D,5B,6D-
,7A),(1A,2A,3D,4D,5B,6D,7B),
(1A,2A,3D,4D,5B,6D,7C),(1A,2A,3D,4E,5A,6A,7A)-
,(1A,2A,3D,4E,5A,6A,7B),(1A,2A,3D,4E,5A,6A,7C),(1A,2A,3D,4E,5A,6B,7A),(1A,-
2A,3D,4E,5A,6B,7B),(1A,2A,3D,4E,5A,6B,7C),
(1A,2A,3D,4E,5A,6C,7A),(1A,2A,3-
D,4E,5A,6C,7B),(1A,2A,3D,4E,5A,6C,7C),(1A,2A,3D,4E,5A,6D,7A),(1A,2A,3D,4E,-
5A,6D,7B),(1A,2A,3D,4E,5A,6D,7C),(1A,2A,3D,4E,5B,6A,7A),
(1A,2A,3D,4E,5B,6A,7B),(1A,2A,3D,4E,5B,6A,7C),(1A,2A,3D,4E,5B,6B,7A),(1A,-
2A,3D,4E,5B,6B,7B),(1A,2A,3D,4E,5B,6B,7C),(1A,2A,3D,4E,5B,6C,7A),(1A,2A,3D-
,4E,5B,6C,7B),
(1A,2A,3D,4E,5B,6C,7C),(1A,2A,3D,4E,5B,6D,7A),(1A,2A,3D,4E,-
5B,6D,7B),(1A,2A,3D,4E,5B,6D,7C),(1A,2A,3E,4A,5A,6A,7A),(1A,2A,3E,4A,5A,6A-
,7B),(1A,2A,3E,4A,5A,6A,7C),
(1A,2A,3E,4A,5A,6B,7A),(1A,2A,3E,4A,5A,6B,7B)-
,(1A,2A,3E,4A,5A,6B,7C),(1A,2A,3E,4A,5A,6C,7A),(1A,2A,3E,4A,5A,6C,7B),(1A,-
2A,3E,4A,5A,6C,7C),(1A,2A,3E,4A,5A,6D,7A),
(1A,2A,3E,4A,5A,6D,7B),(1A,2A,3-
E,4A,5A,6D,7C),(1A,2A,3E,4A,5B,6A,7A),(1A,2A,3E,4A,5B,6A,7B),(1A,2A,3E,4A,-
5B,6A,7C),(1A,2A,3E,4A,5B,6B,7A),(1A,2A,3E,4A,5B,6B,7B),
(1A,2A,3E,4A,5B,6B,7C),(1A,2A,3E,4A,5B,6C,7A),(1A,2A,3E,4A,5B,6C,7B),(1A,-
2A,3E,4A,5B,6C,7C),(1A,2A,3E,4A,5B,6D,7A),(1A,2A,3E,4A,5B,6D,7B),(1A,2A,3E-
,4A,5B,6D,7C),
(1A,2A,3E,4B,5A,6A,7A),(1A,2A,3E,4B,5A,6A,7B),(1A,2A,3E,4B,-
5A,6A,7C),(1A,2A,3E,4B,5A,6B,7A),(1A,2A,3E,4B,5A,6B,7B),(1A,2A,3E,4B,5A,6B-
,7C),(1A,2A,3E,4B,5A,6C,7A),
(1A,2A,3E,4B,5A,6C,7B),(1A,2A,3E,4B,5A,6C,7C)-
,(1A,2A,3E,4B,5A,6D,7A),(1A,2A,3E,4B,5A,6D,7B),(1A,2A,3E,4B,5A,6D,7C),(1A,-
2A,3E,4B,5B,6A,7A),(1A,2A,3E,4B,5B,6A,7B),
(1A,2A,3E,4B,5B,6A,7C),(1A,2A,3-
E,4B,5B,6B,7A),(1A,2A,3E,4B,5B,6B,7B),
(1A,2A,3E,4B,5B,6B,7C),(1A,2A,3E,4B-
,5B,6C,7A),(1A,2A,3E,4B,5B,6C,7B),(1A,2A,3E,4B,5B,6C,7C),
(1A,2A,3E,4B,5B,6D,7A),(1A,2A,3E,4B,5B,6D,7B),(1A,2A,3E,4B,5B,6D,7C),(1A,-
2A,3E,4C,5A,6A,7A),(1A,2A,3E,4C,5A,6A,7B),(1A,2A,3E,4C,5A,6A,7C),(1A,2A,3E-
,4C,5A,6B,7A),
(1A,2A,3E,4C,5A,6B,7B),(1A,2A,3E,4C,5A,6B,7C),(1A,2A,3E,4C,-
5A,6C,7A),(1A,2A,3E,4C,5A,6C,7B),(1A,2A,3E,4C,5A,6C,7C),(1A,2A,3E,4C,5A,6D-
,7A),(1A,2A,3E,4C,5A,6D,7B),
(1A,2A,3E,4C,5A,6D,7C),(1A,2A,3E,4C,5B,6A,7A)-
,(1A,2A,3E,4C,5B,6A,7B),(1A,2A,3E,4C,5B,6A,7C),(1A,2A,3E,4C,5B,6B,7A),(1A,-
2A,3E,4C,5B,6B,7B),(1A,2A,3E,4C,5B,6B,7C),
(1A,2A,3E,4C,5B,6C,7A),(1A,2A,3-
E,4C,5B,6C,7B),(1A,2A,3E,4C,5B,6C,7C),(1A,2A,3E,4C,5B,6D,7A),(1A,2A,3E,4C,-
5B,6D,7B),(1A,2A,3E,4C,5B,6D,7C),(1A,2A,3E,4D,5A,6A,7A),
(1A,2A,3E,4D,5A,6A,7B),(1A,2A,3E,4D,5A,6A,7C),(1A,2A,3E,4D,5A,6B,7A),(1A,-
2A,3E,4D,5A,6B,7B),(1A,2A,3E,4D,5A,6B,7C),(1A,2A,3E,4D,5A,6C,7A),(1A,2A,3E-
,4D,5A,6C,7B),
(1A,2A,3E,4D,5A,6C,7C),(1A,2A,3E,4D,5A,6D,7A),(1A,2A,3E,4D,-
5A,6D,7B),(1A,2A,3E,4D,5A,6D,7C),(1A,2A,3E,4D,5B,6A,7A),(1A,2A,3E,4D,5B,6A-
,7B),(1A,2A,3E,4D,5B,6A,7C),
(1A,2A,3E,4D,5B,6B,7A),(1A,2A,3E,4D,5B,6B,7B)-
,(1A,2A,3E,4D,5B,6B,7C),(1A,2A,3E,4D,5B,6C,7A),(1A,2A,3E,4D,5B,6C,7B),(1A,-
2A,3E,4D,5B,6C,7C),(1A,2A,3E,4D,5B,6D,7A),
(1A,2A,3E,4D,5B,6D,7B),(1A,2A,3-
E,4D,5B,6D,7C),(1A,2A,3E,4E,5A,6A,7A),(1A,2A,3E,4E,5A,6A,7B),(1A,2A,3E,4E,-
5A,6A,7C),(1A,2A,3E,4E,5A,6B,7A),(1A,2A,3E,4E,5A,6B,7B),
(1A,2A,3E,4E,5A,6B,7C),(1A,2A,3E,4E,5A,6C,7A),(1A,2A,3E,4E,5A,6C,7B),(1A,-
2A,3E,4E,5A,6C,7C),(1A,2A,3E,4E,5A,6D,7A),(1A,2A,3E,4E,5A,6D,7B),(1A,2A,3E-
,4E,5A,6D,7C),
(1A,2A,3E,4E,5B,6A,7A),(1A,2A,3E,4E,5B,6A,7B),(1A,2A,3E,4E,-
5B,6A,7C),(1A,2A,3E,4E,5B,6B,7A), (1A,2A,3E,4E,5B,6B,7B),
(1A,2A,3E,4E,5B,6B,7C), (1A,2A,3E,4E,5B,6C,7A),
(1A,2A,3E,4E,5B,6C,7B), (1A,2A,3E,4E,5B,6C,7C),
(1A,2A,3E,4E,5B,6D,7A), (1A,2A,3E,4E,5B,6D,7B),
(1A,2A,3E,4E,5B,6D,7C),(1A,2B,3A,4A,5A,6A,7A),(1A,2B,3A,4A,5A,6A,7B),
(1A,2B,3A,4A,5A,6A,7C), (1A,2B,3A,4A,5A,6B,7A),
(1A,2B,3A,4A,5A,6B,7B), (1A,2B,3A,4A,5A,6B,7C),
(1A,2B,3A,4A,5A,6C,7A),(1A,2B,3A,4A,5A,6C,7B),(1A-
,2B,3A,4A,5A,6C,7C), (1A,2B,3A,4A,5A,6D,7A),
(1A,2B,3A,4A,5A,6D,7B), (1A,2B,3A,4A,5A,6D,7C),
(1A,2B,3A,4A,5B,6A,7A), (1A,2B,3A,4A,5B,6A,7B),
(1A,2B,3A,4A,5B,6A,7C), (1A,2B,3A,4A,5B,6B,7A),
(1A,2B,3A,4A,5B,6B,7B), (1A,2B,3A,4A,5B,6B,7C),
(1A,2B,3A,4A,5B,6C,7A), (1A,2B,3A,4A,5B,6C,7B),
(1A,2B,3A,4A,5B,6C,7C), (1A,2B,3A,4A,5B,6D,7A),
(1A,2B,3A,4A,5B,6D,7B), (1A,2B,3A,4A,5B,6D,7C),
(1A,2B,3A,4B,5A,6A,7A), (1A,2B,3A,4B,5A,6A,7B),
(1A,2B,3A,4B,5A,6A,7C), (1A,2B,3A,4B,5A,6B,7A),(1A,2B,3A,4B,5A,6B,
7B),(1A,2B,3A,4B,5A,6B,7C), (1A,2B,3A,4B,5A,6C,7A),
(1A,2B,3A,4B,5A,6C,7B), (1A,2B,3A,4B,5A,6C,7C),
(1A,2B,3A,4B,5A,6D,7A), (1A,2B,3A,4B,5A,6D,7B),
(1A,2B,3A,4B,5A,6D,7C), (1A,2B,3A,4B,5B,6A,7A),
(1A,2B,3A,4B,5B,6A,7B), (1A,2B,3A,4B,5B,6A,7C),
(1A,2B,3A,4B,5B,6B,7A), (1A,2B,3A,4B,5B,6B,7B),
(1A,2B,3A,4B,5B,6B,7C),(1A,2B,3A,4B,5B,6C,7A),(1A-
,2B,3A,4B,5B,6C,7B), (1A,2B,3A,4B,5B,6C,7C),(1A,2B,3A,4B,5B,6D,7A),
(1A,2B,3A,4B,5B,6D,7B),(1A,2B,3A,4B,5B,6D,7C),(1A,2B,3A,4C,5A,6A,7A),(1A,-
2B,3A,4C,5A,6A,7B),(1A,2B,3A,4C,5A,6A,7C),
(1A,2B,3A,4C,5A,6B,7A),(1A,2B,3-
A,4C,5A,6B,7B),(1A,2B,3A,4C,5A,6B,7C),(1A,2B,3A,4C,5A,6C,7A),(1A,2B,3A,4C,-
5A,6C,7B),(1A,2B,3A,4C,5A,6C,7C),(1A,2B,3A,4C,5A,6D,7A),
(1A,2B,3A,4C,5A,6D,7B),(1A,2B,3A,4C,5A,6D,7C),(1A,2B,3A,4C,5B,6A,7A),(1A,-
2B,3A,4C,5B,6A,7B),(1A,2B,3A,4C,5B,6A,7C),(1A,2B,3A,4C,5B,6B,7A),(1A,2B,3A-
,4C,5B,6B,7B),
(1A,2B,3A,4C,5B,6B,7C),(1A,2B,3A,4C,5B,6C,7A),(1A,2B,3A,4C,-
5B,6C,7B),(1A,2B,3A,4C,5B,6C,7C),(1A,2B,3A,4C,5B,6D,7A),(1A,2B,3A,4C,5B,6D-
,7B),(1A,2B,3A,4C,5B,6D,7C),
(1A,2B,3A,4D,5A,6A,7A),(1A,2B,3A,4D,5A,6A,7B)-
,(1A,2B,3A,4D,5A,6A,7C),(1A,2B,3A,4D,5A,6B,7A),(1A,2B,3A,4D,5A,6B,7B),(1A,-
2B,3A,4D,5A,6B,7C),(1A,2B,3A,4D,5A,6C,7A),
(1A,2B,3A,4D,5A,6C,7B),(1A,2B,3-
A,4D,5A,6C,7C),(1A,2B,3A,4D,5A,6D,7A),(1A,2B,3A,4D,5A,6D,7B),(1A,2B,3A,4D,-
5A,6D,7C),(1A,2B,3A,4D,5B,6A,7A),(1A,2B,3A,4D,5B,6A,7B),
(1A,2B,3A,4D,5B,6A,7C),(1A,2B,3A,4D,5B,6B,7A),(1A,2B,3A,4D,5B,6B,7B),(1A,-
2B,3A,4D,5B,6B,7C),(1A,2B,3A,4D,5B,6C,7A),(1A,2B,3A,4D,5B,6C,7B),(1A,2B,3A-
,4D,5B,6C,7C),
(1A,2B,3A,4D,5B,6D,7A),(1A,2B,3A,4D,5B,6D,7B),(1A,2B,3A,4D,-
5B,6D,7C),(1A,2B,3A,4E,5A,6A,7A),
(1A,2B,3A,4E,5A,6A,7B),(1A,2B,3A,4E,5A,6-
A,7C),(1A,2B,3A,4E,5A,6B,7A), (1A,2B,3A,4E,5A,6B,7B),
(1A,2B,3A,4E,5A,6B,7C), (1A,2B,3A,4E,5A,6C,7A),
(1A,2B,3A,4E,5A,6C,7B), (1A,2B,3A,4E,5A,6C,7C),
(1A,2B,3A,4E,5A,6D,7A), (1A,2B,3A,4E,5A,6D,7B),
(1A,2B,3A,4E,5A,6D,7C), (1A,2B,3A,4E,5B,6A,7A),
(1A,2B,3A,4E,5B,6A,7B),(1- A,2B,3A,4E,5B,6A,7C),
(1A,2B,3A,4E,5B,6B,7A),(1A,2B,3A,4E,5B,6B,
7B),(1A,2B,3A,4E,5B,6B,7C), (1A,2B,3A,4E,5B,6C,7A),
(1A,2B,3A,4E,5B,6C,7B), (1A,2B,3A,4E,5B,6C,7C),
(1A,2B,3A,4E,5B,6D,7A),
(1A,2B,3A,4E,5B,6D,7B),(1A,2B,3A,4E,5B,6D,7C),(1A,2B,3B,4A,5A,6A,7A),
(1A,2B,3B,4A,5A,6A,7B),(1A,2B,3B,4A,5A,6A,7C),(1A,2B,3B,4A,5A,6B,7A),(1A,-
2B,3B,4A,5A,6B,7B),(1A,2B,3B,4A,5A,6B,7C),(1A,2B,3B,4A,5A,6C,7A),(1A,2B,3B-
,4A,5A,6C,7B),
(1A,2B,3B,4A,5A,6C,7C),(1A,2B,3B,4A,5A,6D,7A),(1A,2B,3B,4A,-
5A,6D,7B),(1A,2B,3B,4A,5A,6D,7C),(1A,2B,3B,4A,5B,6A,7A),(1A,2B,3B,4A,5B,6A-
,7B),(1A,2B,3B,4A,5B,6A,7C),
(1A,2B,3B,4A,5B,6B,7A),(1A,2B,3B,4A,5B,6B,7B)-
,(1A,2B,3B,4A,5B,6B,7C),(1A,2B,3B,4A,5B,6C,7A),(1A,2B,3B,4A,5B,6C,7B),(1A,-
2B,3B,4A,5B,6C,7C),(1A,2B,3B,4A,5B,6D,7A),
(1A,2B,3B,4A,5B,6D,7B),(1A,2B,3-
B,4A,5B,6D,7C),(1A,2B,3B,4B,5A,6A,7A),(1A,2B,3B,4B,5A,6A,7B),(1A,2B,3B,4B,-
5A,6A,7C),(1A,2B,3B,4B,5A,6B,7A),(1A,2B,3B,4B,5A,6B,7B),
(1A,2B,3B,4B,5A,6B,7C),(1A,2B,3B,4B,5A,6C,7A),(1A,2B,3B,4B,5A,6C,7B),(1A,-
2B,3B,4B,5A,6C,7C),(1A,2B,3B,4B,5A,6D,7A),(1A,2B,3B,4B,5A,6D,7B),(1A,2B,3B-
,4B,5A,6D,7C),
(1A,2B,3B,4B,5B,6A,7A),(1A,2B,3B,4B,5B,6A,7B),(1A,2B,3B,4B,-
5B,6A,7C),(1A,2B,3B,4B,5B,6B,7A),(1A,2B,3B,4B,5B,6B,7B),(1A,2B,3B,4B,5B,6B-
,7C),(1A,2B,3B,4B,5B,6C,7A),
(1A,2B,3B,4B,5B,6C,7B),(1A,2B,3B,4B,5B,6C,7C)-
,(1A,2B,3B,4B,5B,6D,7A),(1A,2B,3B,4B,5B,6D,7B),(1A,2B,3B,4B,5B,6D,7C),(1A,-
2B,3B,4C,5A,6A,7A),(1A,2B,3B,4C,5A,6A,7B),
(1A,2B,3B,4C,5A,6A,7C),(1A,2B,3-
B,4C,5A,6B,7A),(1A,2B,3B,4C,5A,6B,7B),(1A,2B,3B,4C,5A,6B,7C),(1A,2B,3B,4C,-
5A,6C,7A),(1A,2B,3B,4C,5A,6C,7B),(1A,2B,3B,4C,5A,6C,7C),
(1A,2B,3B,4C,5A,6D,7A),(1A,2B,3B,4C,5A,6D,7B),(1A,2B,3B,4C,5A,6D,7C),(1A,-
2B,3B,4C,5B,6A,7A),(1A,2B,3B,4C,5B,6A,7B),(1A,2B,3B,4C,5B,6A,7C),(1A,2B,3B-
,4C,5B,6B,7A),
(1A,2B,3B,4C,5B,6B,7B),(1A,2B,3B,4C,5B,6B,7C),(1A,2B,3B,4C,-
5B,6C,7A),(1A,2B,3B,4C,5B,6C,7B),(1A,2B,3B,4C,5B,6C,7C),(1A,2B,3B,4C,5B,6D-
,7A),(1A,2B,3B,4C,5B,6D,7B),
(1A,2B,3B,4C,5B,6D,7C),(1A,2B,3B,4D,5A,6A,7A)-
,(1A,2B,3B,4D,5A,6A,7B),(1A,2B,3B,4D,5A,6A,7C),(1A,2B,3B,4D,5A,6B,7A),(1A,-
2B,3B,4D,5A,6B,7B),(1A,2B,3B,4D,5A,6B,7C),
(1A,2B,3B,4D,5A,6C,7A),(1A,2B,3-
B,4D,5A,6C,7B),(1A,2B,3B,4D,5A,6C,7C),(1A,2B,3B,4D,5A,6D,7A),
(1A,2B,3B,4D,5A,6D,7B),(1A,2B,3B,4D,5A,6D,7C),
(1A,2B,3B,4D,5B,6A,7A), (1A,2B,3B,4D,5B,6A,7B), (1A,2B,3B,4D,
5B,6A,7C), (1A,2B,3B,4D,5B,6B, 7A),
(1A,2B,3B,4D,5B,6B,7B),(1A,2B,3B,4D,5B,6B,7C),(1A,2B,3B,4D,5B,6C,7A),
(A,2B,3B,4D,5B,6C, 7B), (1A,2B,3B,4D,5B,6C,7C),
(1A,2B,3B,4D,5B,6D,7A),(1- A,2B,3B,4D,5B,6D, 7B),
(1A,2B,3B,4D,5B,6D,7C), (1A,2B,3B,4E,5A,6A,7A),(1A,-
2B,3B,4E,5A,6A,7B),(1A,2B,3B,4E,5A,6A,7C), (1A,2B,3B,4E,5A,6B,7A),
(1A,2B,3B,4E,5A,6B,7B),(1A,2B,3B,4E,5A,6B,7C),(1A,2B,3B,4E,5A,6C,7A),
(1A,2B,3B,4E,5A,6C,7B), (1A,2B,3B,4E,5A,6C,7C),
(1A,2B,3B,4E,5A,6D,7A),
(1A,2B,3B,4E,5A,6D,7B),(1A,2B,3B,4E,5A,6D,7C),(1A,2B,3B,4E,5B,6A,7A),(1A,-
2B,3B,4E,5B,6A,7B),(1A,2B,3B,4E,5B,6A,7C),(1A,2B,3B,4E,5B,6B,7A),(1A,2B,3B-
,4E,5B,6B,7B),
(1A,2B,3B,4E,5B,6B,7C),(1A,2B,3B,4E,5B,6C,7A),(1A,2B,3B,4E,-
5B,6C,7B),(1A,2B,3B,4E,5B,6C,7C),(1A,2B,3B,4E,5B,6D,7A),(1A,2B,3B,4E,5B,6D-
,7B),(1A,2B,3B,4E,5B,6D,7C),
(1A,2B,3C,4A,5A,6A,7A),(1A,2B,3C,4A,5A,6A,7B)-
,(1A,2B,3C,4A,5A,6A,7C),(1A,2B,3C,4A,5A,6B,7A),(1A,2B,3C,4A,5A,6B,7B),(1A,-
2B,3C,4A,5A,6B,7C),(1A,2B,3C,4A,5A,6C,7A),
(1A,2B,3C,4A,5A,6C,7B),(1A,2B,3-
C,4A,5A,6C,7C),(1A,2B,3C,4A,5A,6D,7A),(1A,2B,3C,4A,5A,6D,7B),(1A,2B,3C,4A,-
5A,6D,7C),(1A,2B,3C,4A,5B,6A,7A),(1A,2B,3C,4A,5B,6A,7B),
(1A,2B,3C,4A,5B,6A,7C),(1A,2B,3C,4A,5B,6B,7A),(1A,2B,3C,4A,5B,6B,7B),(1A,-
2B,3C,4A,5B,6B,7C),(1A,2B,3C,4A,5B,6C,7A),(1A,2B,3C,4A,5B,6C,7B),(1A,2B,3C-
,4A,5B,6C,7C),
(1A,2B,3C,4A,5B,6D,7A),(1A,2B,3C,4A,5B,6D,7B),(1A,2B,3C,4A,-
5B,6D,7C),(1A,2B,3C,4B,5A,6A,7A),(1A,2B,3C,4B,5A,6A,7B),(1A,2B,3C,4B,5A,6A-
,7C),(1A,2B,3C,4B,5A,6B,7A),
(1A,2B,3C,4B,5A,6B,7B),(1A,2B,3C,4B,5A,6B,7C)-
,(1A,2B,3C,4B,5A,6C,7A),(1A,2B,3C,4B,5A,6C,7B),(1A,2B,3C,4B,5A,6C,7C),(1A,-
2B,3C,4B,5A,6D,7A),(1A,2B,3C,4B,5A,6D,7B),
(1A,2B,3C,4B,5A,6D,7C),(1A,2B,3-
C,4B,5B,6A,7A),(1A,2B,3C,4B,5B,6A,7B),(1A,2B,3C,4B,5B,6A,7C),(1A,2B,3C,4B,-
5B,6B,7A),(1A,2B,3C,4B,5B,6B,7B),(1A,2B,3C,4B,5B,6B,7C),
(1A,2B,3C,4B,5B,6C,7A),(1A,2B,3C,4B,5B,6C,7B),(1A,2B,3C,4B,5B,6C,7C),(1A,-
2B,3C,4B,5B,6D,7A),(1A,2B,3C,4B,5B,6D,7B),(1A,2B,3C,4B,5B,6D,7C),(1A,2B,3C-
,4C,5A,6A,7A),
(1A,2B,3C,4C,5A,6A,7B),(1A,2B,3C,4C,5A,6A,7C),(1A,2B,3C,4C,-
5A,6B,7A),(1A,2B,3C,4C,5A,6B,7B),(1A,2B,3C,4C,5A,6B,7C),(1A,2B,3C,4C,5A,6C-
,7A),(1A,2B,3C,4C,5A,6C,7B),
(1A,2B,3C,4C,5A,6C,7C),(1A,2B,3C,4C,5A,6D,7A)-
,(1A,2B,3C,4C,5A,6D,7B),(1A,2B,3C,4C,5A,6D,7C),(1A,2B,3C,4C,5B,6A,7A),(1A,-
2B,3C,4C,5B,6A,7B),(1A,2B,3C,4C,5B,6A,7C),
(1A,2B,3C,4C,5B,6B,7A),(1A,2B,3-
C,4C,5B,6B,7B),(1A,2B,3C,4C,5B,6B,7C),(1A,2B,3C,4C,5B,6C,7A),(1A,2B,3C,4C,-
5B,6C,7B),(1A,2B,3C,4C,5B,6C,7C),(1A,2B,3C,4C,5B,6D,7A),
(1A,2B,3C,4C,5B,6D,7B),(1A,2B,3C,4C,5B,6D,7C),(1A,2B,3C,4D,5A,6A,7A),(1A,-
2B,3C,4D,5A,6A,7B),(1A,2B,3C,4D,5A,6A,7C),(1A,2B,3C,4D,5A,6B,7A),(1A,2B,3C-
,4D,5A,6B,7B),
(1A,2B,3C,4D,5A,6B,7C),(1A,2B,3C,4D,5A,6C,7A),(1A,2B,3C,4D,-
5A,6C,7B),(1A,2B,3C,4D,5A,6C,7C),(1A,2B,3C,4D,5A,6D,7A),(1A,2B,3C,4D,5A,6D-
,7B),(1A,2B,3C,4D,5A,6D,7C),
(1A,2B,3C,4D,5B,6A,7A),(1A,2B,3C,4D,5B,6A,7B)-
,(1A,2B,3C,4D,5B,6A,7C),(1A,2B,3C,4D,5B,6B,7A),(1A,2B,3C,4D,5B,6B,7B),(1A,-
2B,3C,4D,5B,6B,7C),(1A,2B,3C,4D,5B,6C,7A),
(1A,2B,3C,4D,5B,6C,7B),(1A,2B,3-
C,4D,5B,6C,7C),(1A,2B,3C,4D,5B,6D,7A),(1A,2B,3C,4D,5B,6D,7B),(1A,2B,3C,4D,-
5B,6D,7C),(1A,2B,3C,4E,5A,6A,7A),(1A,2B,3C,4E,5A,6A,7B),
(1A,2B,3C,4E,5A,6A,7C),(1A,2B,3C,4E,5A,6B,7A),(1A,2B,3C,4E,5A,6B,7B),(1A,-
2B,3C,4E,5A,6B,7C),(1A,2B,3C,4E,5A,6C,7A),(1A,2B,3C,4E,5A,6C,7B),(1A,2B,3C-
,4E,5A,6C,7C),
(1A,2B,3C,4E,5A,6D,7A),(1A,2B,3C,4E,5A,6D,7B),(1A,2B,3C,4E,-
5A,6D,7C),(1A,2B,3C,4E,5B,6A,7A),(1A,2B,3C,4E,5B,6A,7B),(1A,2B,3C,4E,5B,6A-
,7C),(1A,2B,3C,4E,5B,6B,7A),
(1A,2B,3C,4E,5B,6B,7B),(1A,2B,3C,4E,5B,6B,7C)-
,(1A,2B,3C,4E,5B,6C,7A),(1A,2B,3C,4E,5B,6C,7B),(1A,2B,3C,4E,5B,6C,7C),(1A,-
2B,3C,4E,5B,6D,7A),(1A,2B,3C,4E,5B,6D,7B),
(1A,2B,3C,4E,5B,6D,7C),(1A,2B,3-
D,4A,5A,6A,7A),(1A,2B,3D,4A,5A,6A,7B),(1A,2B,3D,4A,5A,6A,7C),(1A,2B,3D,4A,-
5A,6B,7A),(1A,2B,3D,4A,5A,6B,7B),(1A,2B,3D,4A,5A,6B,7C),
(1A,2B,3D,4A,5A,6C,7A),(1A,2B,3D,4A,5A,6C,7B),(1A,2B,3D,4A,5A,6C,7C),(1A,-
2B,3D,4A,5A,6D,7A),(1A,2B,3D,4A,5A,6D,7B),(1A,2B,3D,4A,5A,6D,7C),(1A,2B,3D-
,4A,5B,6A,7A),
(1A,2B,3D,4A,5B,6A,7B),(1A,2B,3D,4A,5B,6A,7C),(1A,2B,3D,4A,-
5B,6B,7A),(1A,2B,3D,4A,5B,6B,7B),(1A,2B,3D,4A,5B,6B,7C),(1A,2B,3D,4A,5B,6C-
,7A),(1A,2B,3D,4A,5B,6C,7B),
(1A,2B,3D,4A,5B,6C,7C),(1A,2B,3D,4A,5B,6D,7A)-
,(1A,2B,3D,4A,5B,6D,7B),(1A,2B,3D,4A,5B,6D,7C),(1A,2B,3D,4B,5A,6A,7A),(1A,-
2B,3D,4B,5A,6A,7B),(1A,2B,3D,4B,5A,6A,7C),
(1A,2B,3D,4B,5A,6B,7A),(1A,2B,3-
D,4B,5A,6B,7B),(1A,2B,3D,4B,5A,6B,7C),(1A,2B,3D,4B,5A,6C,7A),(1A,2B,3D,4B,-
5A,6C,7B),(1A,2B,3D,4B,5A,6C,7C),(1A,2B,3D,4B,5A,6D,7A),
(1A,2B,3D,4B,5A,6D,7B),(1A,2B,3D,4B,5A,6D,7C),(1A,2B,3D,4B,5B,6A,7A),(1A,-
2B,3D,4B,5B,6A,7B),(1A,2B,3D,4B,5B,6A,7C),(1A,2B,3D,4B,5B,6B,7A),(1A,2B,3D-
,4B,5B,6B,7B),
(1A,2B,3D,4B,5B,6B,7C),(1A,2B,3D,4B,5B,6C,7A),(1A,2B,3D,4B,-
5B,6C,7B),(1A,2B,3D,4B,5B,6C,7C),(1A,2B,3D,4B,5B,6D,7A),(1A,2B,3D,4B,5B,6D-
,7B),(1A,2B,3D,4B,5B,6D,7C),
(1A,2B,3D,4C,5A,6A,7A),(1A,2B,3D,4C,5A,6A,7B)-
,(1A,2B,3D,4C,5A,6A,7C),(1A,2B,3D,4C,5A,6B,7A),
(1A,2B,3D,4C,5A,6B,7B),(1A-
,2B,3D,4C,5A,6B,7C),(1A,2B,3D,4C,5A,6C,7A), (1A,2B,3D,4C,5A,6C,7B),
(1A,2B,3D,4C,5A,6C,7C), (1A,2B,3D,4C,5A,6D,7A), (1A,2B,3D,4C,5A,6D,
7B), (1A,2B,3D,4C,5A,6D,7C), (1A,2B,3D,4C,5B,6A, 7A), (1A,2B,3D,4C,
5B,6A,7B), (1A,2B,3D,4C,5B,6A,7C), (1A,2B,3D,4C, 5B,6B,7A),
(1A,2B,3D,4C,5B,6B, 7B), (1A,2B,3D,4C,5B,6B,7C),
(1A,2B,3D,4C,5B,6C,7A), (1A,2B,3D,4C,5B,6C,7B),(1-
A,2B,3D,4C,5B,6C,7C), (1A,2B,3D,4C,5B,6D,7A), (1A,2B,3D,4C,
5B,6D,7B), (1A,2B,3D,4C,5B,6D, 7C), (1A,2B,3D,4D,5A,6A,7A),
(1A,2B,3D,4D,5A,6A,7B),(-
1A,2B,3D,4D,5A,6A,7C),(1A,2B,3D,4D,5A,6B,7A),
(1A,2B,3D,4D,5A,6B,7B), (1A,2B,3D,4D,5A,6B,7C),
(1A,2B,3D,4D,5A,6C,7A), (1A,2B,3D,4D,5A,6C,7B),
(1A,2B,3D,4D,5A,6C,7C),(1A,2B,3D,4D,5A,6D,7A),(1A,2B,3D,4D,5A,6D,7B),
(1A,2B,3D,4D,5A,6D,7C),(1A,2B,3D,4D,5B,6A,7A),(1A,2B,3D,4D,5B,6A,7B),(1A,-
2B,3D,4D,5B,6A,7C),(1A,2B,3D,4D,5B,6B,7A),(1A,2B,3D,4D,5B,6B,7B),(1A,2B,3D-
,4D,5B,6B,7C),
(1A,2B,3D,4D,5B,6C,7A),(1A,2B,3D,4D,5B,6C,7B),(1A,2B,3D,4D,-
5B,6C,7C),(1A,2B,3D,4D,5B,6D,7A),(1A,2B,3D,4D,5B,6D,7B),(1A,2B,3D,4D,5B,6D-
,7C),(1A,2B,3D,4E,5A,6A,7A),
(1A,2B,3D,4E,5A,6A,7B),(1A,2B,3D,4E,5A,6A,7C)-
,(1A,2B,3D,4E,5A,6B,7A),(1A,2B,3D,4E,5A,6B,7B),(1A,2B,3D,4E,5A,6B,7C),(1A,-
2B,3D,4E,5A,6C,7A),(1A,2B,3D,4E,5A,6C,7By),
(1A,2B,3D,4E,5A,6C,7C),(1A,2B,- 3D,4E,5A,6D,7A),(1A,2B,3D,4E,5A,6D,
7B),(1A,2B,3D,4E,5A,6D,7C),(1A,2B,3D,4-
E,5B,6A,7A),(1A,2B,3D,4E,5B,6A,7B),(1A,2B,3D,4E,5B,6A,7C),
(1A,2B,3D,4E,5B,6B,7A),(1A,2B,3D,4E,5B,6B,7B),(1A,2B,3D,4E,5B,6B,7C),(1A,-
2B,3D,4E,5B,6C,7A),(1A,2B,3D,4E,5B,6C,7B),(1A,2B,3D,4E,5B,6C,7C),(1A,2B,3D-
,4E,5B,6D,7A),
(1A,2B,3D,4E,5B,6D,7B),(1A,2B,3D,4E,5B,6D,7C),(1A,2B,3E,4A,-
5A,6A,7A),(1A,2B,3E,4A,5A,6A,7B),(1A,2B,3E,4A,5A,6A,7C),(1A,2B,3E,4A,5A,6B-
,7A),(1A,2B,3E,4A,5A,6B,7B),
(1A,2B,3E,4A,5A,6B,7C),(1A,2B,3E,4A,5A,6C,7A)-
,(1A,2B,3E,4A,5A,6C,7B),(1A,2B,3E,4A,5A,6C,7C),(1A,2B,3E,4A,5A,6D,7A),(1A,-
2B,3E,4A,5A,6D,7B),(1A,2B,3E,4A,5A,6D,7C),
(1A,2B,3E,4A,5B,6A,7A),(1A,2B,3-
E,4A,5B,6A,7B),(1A,2B,3E,4A,5B,6A,7C),(1A,2B,3E,4A,5B,6B,7A),(1A,2B,3E,4A,-
5B,6B,7B),(1A,2B,3E,4A,5B,6B,7C),(1A,2B,3E,4A,5B,6C,7A),
(1A,2B,3E,4A,5B,6C,7B),(1A,2B,3E,4A,5B,6C,7C),(1A,2B,3E,4A,5B,6D,7A),(1A,-
2B,3E,4A,5B,6D,7B),(1A,2B,3E,4A,5B,6D,7C),(1A,2B,3E,4B,5A,6A,7A),(1A,2B,3E-
,4B,5A,6A,7B),
(1A,2B,3E,4B,5A,6A,7C),(1A,2B,3E,4B,5A,6B,7A),(1A,2B,3E,4B,-
5A,6B,7B),(1A,2B,3E,4B,5A,6B,7C),(1A,2B,3E,4B,5A,6C,7A),(1A,2B,3E,4B,5A,6C-
,7B),(1A,2B,3E,4B,5A,6C,7C),
(1A,2B,3E,4B,5A,6D,7A),(1A,2B,3E,4B,5A,6D,7B)-
,(1A,2B,3E,4B,5A,6D,7C),(1A,2B,3E,4B,5B,6A,7A),
(1A,2B,3E,4B,5B,6A,7B),(1A-
,2B,3E,4B,5B,6A,7C),(1A,2B,3E,4B,5B,6B,7A),
(1A,2B,3E,4B,5B,6B,7B),(1A,2B,- 3E,4B,5B,6B,7C),
(1A,2B,3E,4B,5B,6C,7A), (1A,2B,3E,4B,5B,6C,7B),
(1A,2B,3E,4B,5B,6C,7C),(1A,2B,3E,4B,5B,6D,7A),(1A,2B,3E,4B,5B,6D,7B),
(1A,2B,3E,4B,5B,6D,7C),(1A,2B,3E,4C,5A,6A,7A),(1A,2B,3E,4C,5A,6A,7B),(1A,-
2B,3E,4C,5A,6A,7C),(1A,2B,3E,4C,5A,6B,7A),(1A,2B,3E,4C,5A,6B,7B),(1A,2B,3E-
,4C,5A,6B,7C),
(1A,2B,3E,4C,5A,6C,7A),(1A,2B,3E,4C,5A,6C,7B),(1A,2B,3E,4C,-
5A,6C,7C),(1A,2B,3E,4C,5A,6D,7A),(1A,2B,3E,4C,5A,6D,7B),(1A,2B,3E,4C,5A,6D-
,7C),(1A,2B,3E,4C,5B,6A,7A),
(1A,2B,3E,4C,5B,6A,7B),(1A,2B,3E,4C,5B,6A,7C)-
,(1A,2B,3E,4C,5B,6B,7A),(1A,2B,3E,4C,5B,6B,7B),(1A,2B,3E,4C,5B,6B,7C),(A,2-
B,3E,4C,5B,6C,7A),(1A,2B,3E,4C,5B,6C,7B),
(1A,2B,3E,4C,5B,6C,7C),(1A,2B,3E-
,4C,5B,6D,7A),(1A,2B,3E,4C,5B,6D,7B),(1A,2B,3E,4C,5B,6D,7C),(1A,2B,3E,4D,5-
A,6A,7A),(1A,2B,3E,4D,5A,6A,7B),(1A,2B,3E,4D,5A,6A,7C),
(1A,2B,3E,4D,5A,6B,7A),(1A,2B,3E,4D,5A,6B,7B),(1A,2B,3E,4D,5A,6B,7C),(1A,-
2B,3E,4D,5A,6C,7A),(1A,2B,3E,4D,5A,6C,7B),(1A,2B,3E,4D,5A,6C,7C),(1A,2B,3E-
,4D,5A,6D,7A),
(1A,2B,3E,4D,5A,6D,7B),(1A,2B,3E,4D,5A,6D,7C),(1A,2B,3E,4D,-
5B,6A,7A),(1A,2B,3E,4D,5B,6A,7B),(1A,2B,3E,4D,5B,6A,7C),(1A,2B,3E,4D,5B,6B-
,7A),(1A,2B,3E,4D,5B,6B,7B),
(1A,2B,3E,4D,5B,6B,7C),(1A,2B,3E,4D,5B,6C,7A)-
,(1A,2B,3E,4D,5B,6C,7B),(1A,2B,3E,4D,5B,6C,7C),(1A,2B,3E,4D,5B,6D,7A),(1A,-
2B,3E,4D,5B,6D,7B),(1A,2B,3E,4D,5B,6D,7C),
(1A,2B,3E,4E,5A,6A,7A),(1A,2B,3-
E,4E,5A,6A,7B),(1A,2B,3E,4E,5A,6A,7C),(1A,2B,3E,4E,5A,6B,7A),(1A,2B,3E,4E,-
5A,6B,7B),(1A,2B,3E,4E,5A,6B,7C),(1A,2B,3E,4E,5A,6C,7A),
(1A,2B,3E,4E,5A,6C,7B),(1A,2B,3E,4E,5A,6C,7C),(1A,2B,3E,4E,5A,6D,7A),(1A,-
2B,3E,4E,5A,6D,7B),(1A,2B,3E,4E,5A,6D,7C),(1A,2B,3E,4E,5B,6A,7A),(1A,2B,3E-
,4E,5B,6A,7B),
(1A,2B,3E,4E,5B,6A,7C),(1A,2B,3E,4E,5B,6B,7A),(1A,2B,3E,4E,-
5B,6B,7B),(1A,2B,3E,4E,5B,6B,7C),(1A,2B,3E,4E,5B,6C,7A),(1A,2B,3E,4E,5B,6C-
,7B),(1A,2B,3E,4E,5B,6C,7C),
(1A,2B,3E,4E,5B,6D,7A),(1A,2B,3E,4E,5B,6D,7B)-
,(1A,2B,3E,4E,5B,6D,7C),(1A,2C,3A,4A,5A,6A,7A),(1A,2C,3A,4A,5A,6A,7B),(1A,-
2C,3A,4A,5A,6A,7C),(1A,2C,3A,4A,5A,6B,7A),
(1A,2C,3A,4A,5A,6B,7B),(1A,2C,3-
A,4A,5A,6B,7C),(1A,2C,3A,4A,5A,6C,7A),(1A,2C,3A,4A,5A,6C,7B),(1A,2C,3A,4A,-
5A,6C,7C),(1A,2C,3A,4A,5A,6D,7A),(1A,2C,3A,4A,5A,6D,7B),
(1A,2C,3A,4A,5A,6D,7C),(1A,2C,3A,4A,5B,6A,7A),(1A,2C,3A,4A,5B,6A,7B),(1A,-
2C,3A,4A,5B,6A,7C),(1A,2C,3A,4A,5B,6B,7A),(1A,2C,3A,4A,5B,6B,7B),(1A,2C,3A-
,4A,5B,6B,7C),
(1A,2C,3A,4A,5B,6C,7A),(1A,2C,3A,4A,5B,6C,7B),(1A,2C,3A,4A,-
5B,6C,7C),(1A,2C,3A,4A,5B,6D,7A),(1A,2C,3A,4A,5B,6D,7B),
(1A,2C,3A,4A,5B,6D,7C),(1A,2C,3A,4B,5A,6A,7A),
(1A,2C,3A,4B,5A,6A,7B),(1A-
,2C,3A,4B,5A,6A,7C),(1A,2C,3A,4B,5A,6B,7A),(1A,2C,3A,4B,5A,6B,7B),(1A,2C,3-
A,4B,5A,6B,7C),(1A,2C,3A,4B,5A,6C,7A),(1A,2C,3A,4B,5A,6C,7B),
(1A,2C,3A,4B,5A,6C,7C),(1A,2C,3A,4B,5A,6D,7A),(1A,2C,3A,4B,5A,6D,7B),(1A,-
2C,3A,4B,5A,6D,7C),(1A,2C,3A,4B,5B,6A,7A),(1A,2C,3A,4B,5B,6A,7B),(1A,2C,3A-
,4B,5B,6A,7C),
(1A,2C,3A,4B,5B,6B,7A),(1A,2C,3A,4B,5B,6B,7B),(1A,2C,3A,4B,-
5B,6B,7C),(1A,2C,3A,4B,5B,6C,7A),(1A,2C,3A,4B,5B,6C,7B),(1A,2C,3A,4B,5B,6C-
,7C),(1A,2C,3A,4B,5B,6D,7A),
(1A,2C,3A,4B,5B,6D,7B),(1A,2C,3A,4B,5B,6D,7C)-
,(1A,2C,3A,4C,5A,6A,7A),(1A,2C,3A,4C,5A,6A,7B),(1A,2C,3A,4C,5A,6A,7C),(1A,-
2C,3A,4C,5A,6B,7A),(1A,2C,3A,4C,5A,6B,7B),
(1A,2C,3A,4C,5A,6B,7C),(1A,2C,3-
A,4C,5A,6C,7A),(1A,2C,3A,4C,5A,6C,7B),(1A,2C,3A,4C,5A,6C,7C),(1A,2C,3A,4C,-
5A,6D,7A),(1A,2C,3A,4C,5A,6D,7B),(1A,2C,3A,4C,5A,6D,7C),
(1A,2C,3A,4C,5B,6A,7A),(1A,2C,3A,4C,5B,6A,7B),(1A,2C,3A,4C,5B,6A,7C),(1A,-
2C,3A,4C,5B,6B,7A),(1A,2C,3A,4C,5B,6B,7B),(1A,2C,3A,4C,5B,6B,7C),(1A,2C,3A-
,4C,5B,6C,7A),
(1A,2C,3A,4C,5B,6C,7B),(1A,2C,3A,4C,5B,6C,7C),(1A,2C,3A,4C,-
5B,6D,7A),(1A,2C,3A,4C,5B,6D,7B),(1A,2C,3A,4C,5B,6D,7C),(1A,2C,3A,4D,5A,6A-
,7A),(1A,2C,3A,4D,5A,6A,7B),
(1A,2C,3A,4D,5A,6A,7C),(1A,2C,3A,4D,5A,6B,7A)-
,(1A,2C,3A,4D,5A,6B,7B),(1A,2C,3A,4D,5A,6B,7C),(1A,2C,3A,4D,5A,6C,7A),(1A,-
2C,3A,4D,5A,6C,7B),(1A,2C,3A,4D,5A,6C,7C),
(1A,2C,3A,4D,5A,6D,7A),(1A,2C,3-
A,4D,5A,6D,7B),(1A,2C,3A,4D,5A,6D,7C),(1A,2C,3A,4D,5B,6A,7A),(1A,2C,3A,4D,-
5B,6A,7B),(1A,2C,3A,4D,5B,6A,7C),(1A,2C,3A,4D,5B,6B,7A),
(1A,2C,3A,4D,5B,6B,7B),(1A,2C,3A,4D,5B,6B,7C),(1A,2C,3A,4D,5B,6C,7A),(1A,-
2C,3A,4D,5B,6C,7B),(1A,2C,3A,4D,5B,6C,7C),(1A,2C,3A,4D,5B,6D,7A),(1A,2C,3A-
,4D,5B,6D,7B),
(1A,2C,3A,4D,5B,6D,7C),(1A,2C,3A,4E,5A,6A,7A),(1A,2C,3A,4E,-
5A,6A,7B),(1A,2C,3A,4E,5A,6A,7C),(1A,2C,3A,4E,5A,6B,7A),(1A,2C,3A,4E,5A,6B-
,7B),(1A,2C,3A,4E,5A,6B,7C),
(1A,2C,3A,4E,5A,6C,7A),(1A,2C,3A,4E,5A,6C,7B)-
,(1A,2C,3A,4E,5A,6C,7C),(1A,2C,3A,4E,5A,6D,7A),(1A,2C,3A,4E,5A,6D,7B),(1A,-
2C,3A,4E,5A,6D,7C),(1A,2C,3A,4E,5B,6A,7A),
(1A,2C,3A,4E,5B,6A,7B),(1A,2C,3-
A,4E,5B,6A,7C),(1A,2C,3A,4E,5B,6B,7A),(1A,2C,3A,4E,5B,6B,7B),(1A,2C,3A,4E,-
5B,6B,7C),(1A,2C,3A,4E,5B,6C,7A),(1A,2C,3A,4E,5B,6C,7B),
(1A,2C,3A,4E,5B,6C,7C),(1A,2C,3A,4E,5B,6D,7A),(1A,2C,3A,4E,5B,6D,7B),(1A,-
2C,3A,4E,5B,6D,7C),(1A,2C,3B,4A,5A,6A,7A),(1A,2C,3B,4A,5A,6A,7B),(1A,2C,3B-
,4A,5A,6A,7C),
(1A,2C,3B,4A,5A,6B,7A),(1A,2C,3B,4A,5A,6B,7B),(1A,2C,3B,4A,-
5A,6B,7C),(1A,2C,3B,4A,5A,6C,7A),(1A,2C,3B,4A,5A,6C,7B),(1A,2C,3B,4A,5A,6C-
,7C),(1A,2C,3B,4A,5A,6D,7A),
(1A,2C,3B,4A,5A,6D,7B),(1A,2C,3B,4A,5A,6D,7C)-
,(1A,2C,3B,4A,5B,6A,7A),(1A,2C,3B,4A,5B,6A,7B),(1A,2C,3B,4A,5B,6A,7C),(1A,-
2C,3B,4A,5B,6B,7A),(1A,2C,3B,4A,5B,6B,7B),
(1A,2C,3B,4A,5B,6B,7C),(1A,2C,3-
B,4A,5B,6C,7A),(1A,2C,3B,4A,5B,6C,7B),(1A,2C,3B,4A,5B,6C,7C),(1A,2C,3B,4A,-
5B,6D,7A),(1A,2C,3B,4A,5B,6D,7B),(1A,2C,3B,4A,5B,6D,7C),
(1A,2C,3B,4B,5A,6A,7A),(1A,2C,3B,4B,5A,6A,7B),(1A,2C,3B,4B,5A,6A,7C),(1A,-
2C,3B,4B,5A,6B,7A),(1A,2C,3B,4B,5A,6B,7B),(1A,2C,3B,4B,5A,6B,7C),(1A,2C,3B-
,4B,5A,6C,7A),
(1A,2C,3B,4B,5A,6C,7B),(1A,2C,3B,4B,5A,6C,7C),(1A,2C,3B,4B,-
5A,6D,7A),(1A,2C,3B,4B,5A,6D,7B),(1A,2C,3B,4B,5A,6D,7C),(1A,2C,3B,4B,5B,6A-
,7A),(1A,2C,3B,4B,5B,6A,7B),
(1A,2C,3B,4B,5B,6A,7C),(1A,2C,3B,4B,5B,6B,7A)-
,(1A,2C,3B,4B,5B,6B,7B),(1A,2C,3B,4B,5B,6B,7C),(1A,2C,3B,4B,5B,6C,7A),(1A,-
2C,3B,4B,5B,6C,7B),(1A,2C,3B,4B,5B,6C,7C),
(1A,2C,3B,4B,5B,6D,7A),(1A,2C,3-
B,4B,5B,6D,7B),(1A,2C,3B,4B,5B,6D,7C),(1A,2C,3B,4C,5A,6A,7A),(1A,2C,3B,4C,-
5A,6A,7B),(1A,2C,3B,4C,5A,6A,7C),(1A,2C,3B,4C,5A,6B,7A),
(1A,2C,3B,4C,5A,6B,7B),(1A,2C,3B,4C,5A,6B,7C),(1A,2C,3B,4C,5A,6C,7A),(1A,-
2C,3B,4C,5A,6C,7B),(1A,2C,3B,4C,5A,6C,7C),(1A,2C,3B,4C,5A,6D,7A),(1A,2C,3B-
,4C,5A,6D,7B),
(1A,2C,3B,4C,5A,6D,7C),(1A,2C,3B,4C,5B,6A,7A),(1A,2C,3B,4C,-
5B,6A,7B),(1A,2C,3B,4C,5B,6A,7C),(1A,2C,3B,4C,5B,6B,7A),(1A,2C,3B,4C,5B,6B-
,7B),(1A,2C,3B,4C,5B,6B,7C),
(1A,2C,3B,4C,5B,6C,7A),(1A,2C,3B,4C,5B,6C,7B)-
,(1A,2C,3B,4C,5B,6C,7C),(1A,2C,3B,4C,5B,6D,7A),(1A,2C,3B,4C,5B,6D,7B),(1A,-
2C,3B,4C,5B,6D,7C),(1A,2C,3B,4D,5A,6A,7A),
(1A,2C,3B,4D,5A,6A,7B),(1A,2C,3-
B,4D,5A,6A,7C),(1A,2C,3B,4D,5A,6B,7A),(1A,2C,3B,4D,5A,6B,7B),(1A,2C,3B,4D,-
5A,6B,7C),(1A,2C,3B,4D,5A,6C,7A),(1A,2C,3B,4D,5A,6C,7B),
(1A,2C,3B,4D,5A,6C,7C),(1A,2C,3B,4D,5A,6D,7A),(1A,2C,3B,4D,5A,6D,7B),(1A,-
2C,3B,4D,5A,6D,7C),(1A,2C,3B,4D,5B,6A,7A),(1A,2C,3B,4D,5B,6A,7B),(1A,2C,3B-
,4D,5B,6A,7C),
(1A,2C,3B,4D,5B,6B,7A),(1A,2C,3B,4D,5B,6B,7B),(1A,2C,3B,4D,-
5B,6B,7C),(1A,2C,3B,4D,5B,6C,7A),(1A,2C,3B,4D,5B,6C,7B),(1A,2C,3B,4D,5B,6C-
,7C),(1A,2C,3B,4D,5B,6D,7A),
(1A,2C,3B,4D,5B,6D,7B),(1A,2C,3B,4D,5B,6D,7C)-
,(1A,2C,3B,4E,5A,6A,7A),(1A,2C,3B,4E,5A,6A,7B),(1A,2C,3B,4E,5A,6A,7C),(1A,-
2C,3B,4E,5A,6B,7A),(1A,2C,3B,4E,5A,6B,7B),
(1A,2C,3B,4E,5A,6B,7C),(1A,2C,3-
B,4E,5A,6C,7A),(1A,2C,3B,4E,5A,6C,7B),(1A,2C,3B,4E,5A,6C,7C),(1A,2C,3B,4E,-
5A,6D,7A),(1A,2C,3B,4E,5A,6D,7B),(1A,2C,3B,4E,5A,6D,7C),
(1A,2C,3B,4E,5B,6A,7A),(1A,2C,3B,4E,5B,6A,7B),(1A,2C,3B,4E,5B,6A,7C),(1A,-
2C,3B,4E,5B,6B,7A),(1A,2C,3B,4E,5B,6B,7B),
(1A,2C,3B,4E,5B,6B,7C),(1A,2C,3- B,4E,5B,6C,7A),
(1A,2C,3B,4E,5B,6C,7B), (1A,2C,3B,4E,5B,6C,7C),
(1A,2C,3B,4E,5B,6D,7A), (1A,2C,3B,4E,5B,6D,7B),
(1A,2C,3B,4E,5B,6D,7C), (1A,2C,3C,4A,5A,6A, 7A),
(A,2C,3C,4A,5A,6A,7B), (1A,2C,3C,4A,5A,6A,7C),(1-
A,2C,3C,4A,5A,6B,7A),(1A,2C,3C,4A,5A,6B,7B),(1A,2C,3C,4A,5A,6B,7C),(1A,2C,-
3C,4A,5A,6C,7A),(1A,2C,3C,4A,5A,6C,7B),(1A,2C,3C,4A,5A,6C,7C),
(1A,2C,3C,4A,5A,6D,7A),(1A,2C,3C,4A,5A,6D,7B),(1A,2C,3C,4A,5A,6D,7C),(1A,-
2C,3C,4A,5B,6A,7A),
(1A,2C,3C,4A,5B,6A,7B),(1A,2C,3C,4A,5B,6A,7C),(1A,2C,3-
C,4A,5B,6B,7A),
(1A,2C,3C,4A,5B,6B,7B),(1A,2C,3C,4A,5B,6B,7C),(1A,2C,3C,4A-
,5B,6C,7A),(1A,2C,3C,4A,5B,6C,7B),
(1A,2C,3C,4A,5B,6C,7C),(1A,2C,3C,4A,5B,-
6D,7A),(1A,2C,3C,4A,5B,6D,7B),
(1A,2C,3C,4A,5B,6D,7C),(1A,2C,3C,4B,5A,6A,7-
A),(1A,2C,3C,4B,5A,6A,7B),(1A,2C,3C,4B,5A,6A,7C),
(1A,2C,3C,4B,5A,6B,7A),(-
1A,2C,3C,4B,5A,6B,7B),(1A,2C,3C,4B,5A,6B,7C),
(1A,2C,3C,4B,5A,6C,7A),(1A,2-
C,3C,4B,5A,6C,7B),(1A,2C,3C,4B,5A,6C,7C),(1A,2C,3C,4B,5A,6D,7A),
(1A,2C,3C,4B,5A,6D,7B),(1A,2C,3C,4B,5A,6D,7C),(1A,2C,3C,4B,5B,6A,7A),
(1A,2C,3C,4B,5B,6A,7B),(1A,2C,3C,4B,5B,6A,7C),(1A,2C,3C,4B,5B,6B,7A),(1A,-
2C,3C,4B,5B,6B,7B), (1A,2C,3C,4B,5B,6B,7C), (1A,2C,3C,4B,5B,6C,7A),
(1A,2C,3C,4B,5B,6C,7B),
(1A,2C,3C,4B,5B,6C,7C),(1A,2C,3C,4B,5B,6D,7A),(1A-
,2C,3C,4B,5B,6D,7B),(1A,2C,3C,4B,5B,6D,7C),(1A,2C,3C,4C,5A,6A,7A),(1A,2C,3-
C,4C,5A,6A,7B),(1A,2C,3C,4C,5A,6A,7C),
(1A,2C,3C,4C,5A,6B,7A),(1A,2C,3C,4C-
,5A,6B,7B),(1A,2C,3C,4C,5A,6B,7C),(1A,2C,3C,4C,5A,6C,7A),(1A,2C,3C,4C,5A,6-
C,7B),(1A,2C,3C,4C,5A,6C,7C),(1A,2C,3C,4C,5A,6D,7A),
(1A,2C,3C,4C,5A,6D,7B),(1A,2C,3C,4C,5A,6D,7C),(1A,2C,3C,4C,5B,6A,7A),(1A,-
2C,3C,4C,5B,6A,7B), (1A,2C,3C,4C,5B,6A,7C), (1A,2C,3C,4C,5B,6B,
7A), (1A,2C,3C,4C,5B,6B, 7B),
(1A,2C,3C,4C,5B,6B,7C),(1A,2C,3C,4C,5B,6C,7A),(1-
A,2C,3C,4C,5B,6C,7B),(1A,2C,3C,4C,5B,6C,7C),
(1A,2C,3C,4C,5B,6D,7A),(1A,2C-
,3C,4C,5B,6D,7B),(1A,2C,3C,4C,5B,6D,7C),
(1A,2C,3C,4D,5A,6A,7A),(1A,2C,3C,-
4D,5A,6A,7B),(1A,2C,3C,4D,5A,6A,7C),(1A,2C,3C,4D,5A,6B,7A),
(1A,2C,3C,4D,5A,6B,7B),(1A,2C,3C,4D,5A,6B,7C),(1A,2C,3C,4D,5A,6C,7A),
(1A,2C,3C,4D,5A,6C,7B),(1A,2C,3C,4D,5A,6C,7C),(1A,2C,3C,4D,5A,6D,7A),(1A,-
2C,3C,4D,5A,6D,7B),
(1A,2C,3C,4D,5A,6D,7C),(1A,2C,3C,4D,5B,6A,7A),(1A,2C,3-
C,4D,5B,6A,7B),
(1A,2C,3C,4D,5B,6A,7C),(1A,2C,3C,4D,5B,6B,7A),(1A,2C,3C,4D-
,5B,6B,7B),(1A,2C,3C,4D,5B,6B,7C), (1A,2C,3C,4D,5B,6C,7A),
(1A,2C,3C,4D,5B,6C,7B), (1A,2C,3C,4D,5B,6C, 7C),
(1A,2C,3C,4D,5B,6D,7A), (1A,2C,3C,4D,5B,6D,7B),
(1A,2C,3C,4D,5B,6D,7C), (1A,2C,3C,4E,5A,6A,7A),(1-
A,2C,3C,4E,5A,6A,7B),
(1A,2C,3C,4E,5A,6A,7C),.(1A,2C,3C,4E,5A,6B,7A),
(1A,2C,3C,4E,5A,6B,7B),(1A,2C,3C,4E,5A,6B,7C),
(1A,2C,3C,4E,5A,6C,7A),(1A-
,2C,3C,4E,5A,6C,7B),(1A,2C,3C,4E,5A,6C,7C),
(1A,2C,3C,4E,5A,6D,7A),(1A,2C,- 3C,4E,5A,6D,7B),
(1A,2C,3C,4E,5A,6D,7C),(1A,2C,3C,4E,5B,6A,7A), (1A,2C,3C,4E,5B,6A,
7B),(1A,2C,3C,4E,5B,6A,7C), (1A,2C,3C,4E,5B,6B,7A),(1-
A,2C,3C,4E,5B,6B,7B),(1A,2C,3C,4E,5B,6B,7C),
(1A,2C,3C,4E,5B,6C,7A),(1A,2C- ,3C,4E,5B,6C,7B),
(1A,2C,3C,4E,5B,6C,7C),(1A,2C,3C,4E,5B,6D,7A),
(1A,2C,3C,4E,5B,6D,7B),(1A,2C,3C,4E,5B,6D,7C),(1A,2C,3D,4A,5A,6A,7A),
(1A,2C,3D,4A,5A,6A,7B),(1A,2C,3D,4A,5A,6A,7C),
(1A,2C,3D,4A,5A,6B,7A),(1A- ,2C,3D,4A,5A,6B,7B),
(1A,2C,3D,4A,5A,6B,7C),(1A,2C,3D,4A,5A,6C,7A),(1A,2C,-
3D,4A,5A,6C,7B), (1A,2C,3D,4A,5A,6C,7C), (1A,2C,3D,4A,5A,6D,7A),
(1A,2C,3D,4A,5A,6D, 7B),
(1A,2C,3D,4A,5A,6D,7C),(1A,2C,3D,4A,5B,6A,7A),(1-
A,2C,3D,4A,5B,6A,7B),(1A,2C,3D,4A,5B,6A,7C),
(1A,2C,3D,4A,5B,6B,7A), (1A,2C,3D,4A,5B,6B,7B),
(1A,2C,3D,4A,5B,6B,7C), (1A,2C,3D,4A,5B,6C,7A),(1-
A,2C,3D,4A,5B,6C,7B),(1A,2C,3D,4A,5B,6C,7C),(1A,2C,3D,4A,5B,6D,7A),
(1A,2C,3D,4A,5B,6D,7B),(1A,2C,3D,4A,5B,6D,7C),(1A,2C,3D,4B,5A,6A,7A),(1A,-
2C,3D,4B,5A,6A,7B),(1A,2C,3D,4B,5A,6A,7C),(1A,2C,3D,4B,5A,6B,7A),(1A,2C,3D-
,4B,5A,6B,7B),
(1A,2C,3D,4B,5A,6B,7C),(1A,2C,3D,4B,5A,6C,7A),(1A,2C,3D,4B,- 5A,6C,
7B),(1A,2C,3D,4B,5A,6C,7C),(1A,2C,3D,4B,5A,6D,7A),(1A,2C,3D,4B,5A,6-
D,7B),(1A,2C,3D,4B,5A,6D,7C),
(1A,2C,3D,4B,5B,6A,7A),(1A,2C,3D,4B,5B,6A,7B-
),(1A,2C,3D,4B,5B,6A,7C),(1A,2C,3D,4B,5B,6B,7A),(1A,2C,3D,4B,5B,6B,7B),(1A-
,2C,3D,4B,5B,6B,7C),(1A,2C,3D,4B,5B,6C,7A),
(1A,2C,3D,4B,5B,6C,7B),(1A,2C,-
3D,4B,5B,6C,7C),(1A,2C,3D,4B,5B,6D,7A),(1A,2C,3D,4B,5B,6D,7B),(1A,2C,3D,4B-
,5B,6D,7C),(1A,2C,3D,4C,5A,6A,7A),(1A,2C,3D,4C,5A,6A,7B),
(1A,2C,3D,4C,5A,6A,7C),(1A,2C,3D,4C,5A,6B,7A),(1A,2C,3D,4C,5A,6B,7B),(1A,-
2C,3D,4C,5A,6B,7C),(1A,2C,3D,4C,5A,6C,7A),(1A,2C,3D,4C,5A,6C,7B),(1A,2C,3D-
,4C,5A,6C,7C),
(1A,2C,3D,4C,5A,6D,7A),(1A,2C,3D,4C,5A,6D,7B),(1A,2C,3D,4C,-
5A,6D,7C),(1A,2C,3D,4C,5B,6A,7A),(1A,2C,3D,4C,5B,6A,7B),(1A,2C,3D,4C,5B,6A-
,7C),(1A,2C,3D,4C,5B,6B,7A),
(1A,2C,3D,4C,5B,6B,7B),(1A,2C,3D,4C,5B,6B,7C)-
,(1A,2C,3D,4C,5B,6C,7A),(1A,2C,3D,4C,5B,6C,7B),(1A,2C,3D,4C,5B,6C,7C),(1A,-
2C,3D,4C,5B,6D,7A),(1A,2C,3D,4C,5B,6D,7B),
(1A,2C,3D,4C,5B,6D,7C),(1A,2C,3-
D,4D,5A,6A,7A),(1A,2C,3D,4D,5A,6A,7B),(1A,2C,3D,4D,5A,6A,7C),(1A,2C,3D,4D,-
5A,6B,7A),(1A,2C,3D,4D,5A,6B,7B),(1A,2C,3D,4D,5A,6B,7C),
(1A,2C,3D,4D,5A,6C,7A),(1A,2C,3D,4D,5A,6C,7B),(1A,2C,3D,4D,5A,6C,7C),(1A,-
2C,3D,4D,5A,6D,7A),
(1A,2C,3D,4D,5A,6D,7B),(1A,2C,3D,4D,5A,6D,7C),(1A,2C,3-
D,4D,5B,6A,7A),
(1A,2C,3D,4D,5B,6A,7B),(1A,2C,3D,4D,5B,6A,7C),(1A,2C,3D,4D-
,5B,6B,7A),(1A,2C,3D,4D,5B,6B,7B),(1A,2C,3D,4D,5B,6B,7C),(1A,2C,3D,4D,5B,6-
C,7A),(1A,2C,3D,4D,5B,6C,7B),
(1A,2C,3D,4D,5B,6C,7C),(1A,2C,3D,4D,5B,6D,7A-
),(1A,2C,3D,4D,5B,6D,7B),(1A,2C,3D,4D,5B,6D,7C),(1A,2C,3D,4E,5A,6A,7A),(1A-
,2C,3D,4E,5A,6A,7B),(1A,2C,3D,4E,5A,6A,7C),
(1A,2C,3D,4E,5A,6B,7A),(1A,2C,-
3D,4E,5A,6B,7B),(1A,2C,3D,4E,5A,6B,7C),(1A,2C,3D,4E,5A,6C,7A),(1A,2C,3D,4E-
,5A,6C,7B),(1A,2C,3D,4E,5A,6C,7C),(1A,2C,3D,4E,5A,6D,7A),
(1A,2C,3D,4E,5A,6D,7B),(1A,2C,3D,4E,5A,6D,7C),(1A,2C,3D,4E,5B,6A,7A),(1A,-
2C,3D,4E,5B,6A,7B),(1A,2C,3D,4E,5B,6A,7C),(1A,2C,3D,4E,5B,6B,7A),(1A,2C,3D-
,4E,5B,6B,7B),
(1A,2C,3D,4E,5B,6B,7C),(1A,2C,3D,4E,5B,6C,7A),(1A,2C,3D,4E,-
5B,6C,7B),(1A,2C,3D,4E,5B,6C,7C),(1A,2C,3D,4E,5B,6D,7A),(1A,2C,3D,4E,5B,6D-
,7B),(1A,2C,3D,4E,5B,6D,7C),
(1A,2C,3E,4A,5A,6A,7A),(1A,2C,3E,4A,5A,6A,7B)-
,(1A,2C,3E,4A,5A,6A,7C),(1A,2C,3E,4A,5A,6B,7A),(1A,2C,3E,4A,5A,6B,7B),(1A,-
2C,3E,4A,5A,6B,7C),(1A,2C,3E,4A,5A,6C,7A),
(1A,2C,3E,4A,5A,6C,7B),(1A,2C,3-
E,4A,5A,6C,7C),(1A,2C,3E,4A,5A,6D,7A),(1A,2C,3E,4A,5A,6D,7B),(1A,2C,3E,4A,-
5A,6D,7C),(1A,2C,3E,4A,5B,6A,7A),(1A,2C,3E,4A,5B,6A,7B),
(1A,2C,3E,4A,5B,6A,7C),(1A,2C,3E,4A,5B,6B,7A),(1A,2C,3E,4A,5B,6B,7B),(1A,-
2C,3E,4A,5B,6B,7C),(1A,2C,3E,4A,5B,6C,7A),(1A,2C,3E,4A,5B,6C,7B),(1A,2C,3E-
,4A,5B,6C,7C),
(1A,2C,3E,4A,5B,6D,7A),(1A,2C,3E,4A,5B,6D,7B),(1A,2C,3E,4A,-
5B,6D,7C),(1A,2C,3E,4B,5A,6A,7A),(1A,2C,3E,4B,5A,6A,7B),(1A,2C,3E,4B,5A,6A-
,7C),(1A,2C,3E,4B,5A,6B,7A),
(1A,2C,3E,4B,5A,6B,7B),(1A,2C,3E,4B,5A,6B,7C)-
,(1A,2C,3E,4B,5A,6C,7A),(1A,2C,3E,4B,5A,6C,7B),(1A,2C,3E,4B,5A,6C,7C),(1A,-
2C,3E,4B,5A,6D,7A),(1A,2C,3E,4B,5A,6D,7B),
(1A,2C,3E,4B,5A,6D,7C),(1A,2C,3-
E,4B,5B,6A,7A),(1A,2C,3E,4B,5B,6A,7B),(1A,2C,3E,4B,5B,6A,7C),(1A,2C,3E,4B,-
5B,6B,7A),(1A,2C,3E,4B,5B,6B,7B),(1A,2C,3E,4B,5B,6B,7C),
(1A,2C,3E,4B,5B,6C,7A),(1A,2C,3E,4B,5B,6C,7B),(1A,2C,3E,4B,5B,6C,7C),(1A,-
2C,3E,4B,5B,6D,7A),(1A,2C,3E,4B,5B,6D,7B),(1A,2C,3E,4B,5B,6D,7C),(1A,2C,3E-
,4C,5A,6A,7A),
(1A,2C,3E,4C,5A,6A,7B),(1A,2C,3E,4C,5A,6A,7C),(1A,2C,3E,4C,-
5A,6B,7A),(1A,2C,3E,4C,5A,6B,7B),(1A,2C,3E,4C,5A,6B,7C),(1A,2C,3E,4C,5A,6C-
,7A),(1A,2C,3E,4C,5A,6C,7B),
(1A,2C,3E,4C,5A,6C,7C),(1A,2C,3E,4C,5A,6D,7A)-
,(1A,2C,3E,4C,5A,6D,7B),(1A,2C,3E,4C,5A,6D,7C),(1A,2C,3E,4C,5B,6A,7A),(1A,-
2C,3E,4C,5B,6A,7B),(1A,2C,3E,4C,5B,6A,7C),
(1A,2C,3E,4C,5B,6B,7A),(1A,2C,3-
E,4C,5B,6B,7B),(1A,2C,3E,4C,5B,6B,7C),(1A,2C,3E,4C,5B,6C,7A),
(1A,2C,3E,4C,5B,6C, 7B),
(1A,2C,3E,4C,5B,6C,7C),(1A,2C,3E,4C,5B,6D,7A),
(1A,2C,3E,4C,5B,6D,7B),(1A,2C,3E,4C,5B,6D,7C),(1A,2C,3E,4D,5A,6A,7A),
(1A,2C,3E,4D,5A,6A,7B), (1A,2C,3E,4D,5A,6A,7C),
(1A,2C,3E,4D,5A,6B,7A), (1A,2C,3E,4D,5A,6B,7B),
(1A,2C,3E,4D,5A,6B,7C), (1A,2C,3E,4D,5A,6C,7A),(1-
A,2C,3E,4D,5A,6C,7B), (1A,2C,3E,4D,5A,6C,7C),
(1A,2C,3E,4D,5A,6D,7A), (1A,2C,3E,4D,5A,6D,7B),
(1A,2C,3E,4D,5A,6D,7C), (1A,2C,3E,4D,5B,6A,7A),
(1A,2C,3E,4D,5B,6A,7B), (1A,2C,3E,4D,5B,6A,7C),
(1A,2C,3E,4D,5B,6B,7A),
(1A,2C,3E,4D,5B,6B,7B),(1A,2C,3E,4D,5B,6B,7C),(1A,2C,3E,4D,5B,6C,7A),
(1A,2C,3E,4D,5B,6C,7B), (1A,2C,3E,4D,5B,6C,7C),
(1A,2C,3E,4D,5B,6D,7A), (1A,2C,3E,4D,5B,6D,7B),
(1A,2C,3E,4D,5B,6D,7C), (1A,2C,3E,4E,5A,6A,7A),
(1A,2C,3E,4E,5A,6A,7B), (1A,2C,3E,4E,5A,6A,7C),
(1A,2C,3E,4E,5A,6B,7A), (1A,2C,3E,4E,5A,6B,7B),
(1A,2C,3E,4E,5A,6B,7C),(1A,2C,3E,4E,5A,6C,7A),(1A-
,2C,3E,4E,5A,6C,7B),(1A,2C,3E,4E,5A,6C,7C),
(1A,2C,3E,4E,5A,6D,7A),(1A,2C,-
3E,4E,5A,6D,7B),(1A,2C,3E,4E,5A,6D,7C),(1A,2C,3E,4E,5B,6A,7A),(1A,2C,3E,4E-
,5B,6A,7B),(1A,2C,3E,4E,5B,6A,7C),(1A,2C,3E,4E,5B,6B,7A),
(1A,2C,3E,4E,5B,6B,7B),(1A,2C,3E,4E,5B,6B,7C),(1A,2C,3E,4E,5B,6C,7A),(1A,-
2C,3E,4E,5B,6C,7B),(1A,2C,3E,4E,5B,6C,7C),(1A,2C,3E,4E,5B,6D,7A),(1A,2C,3E-
,4E,5B,6D,7B),
(1A,2C,3E,4E,5B,6D,7C),(1A,2D,3A,4A,5A,6A,7A),(1A,2D,3A,4A,-
5A,6A,7B),(1A,2D,3A,4A,5A,6A,7C),(1A,2D,3A,4A,5A,6B,7A),(1A,2D,3A,4A,5A,6B-
,7B),(1A,2D,3A,4A,5A,6B,7C),
(1A,2D,3A,4A,5A,6C,7A),(1A,2D,3A,4A,5A,6C,7B)-
,(1A,2D,3A,4A,5A,6C,7C),(1A,2D,3A,4A,5A,6D,7A),(1A,2D,3A,4A,5A,6D,7B),(1A,-
2D,3A,4A,5A,6D,7C),(1A,2D,3A,4A,5B,6A,7A),
(1A,2D,3A,4A,5B,6A,7B),(1A,2D,3-
A,4A,5B,6A,7C),(1A,2D,3A,4A,5B,6B,7A),(1A,2D,3A,4A,5B,6B,7B),(1A,2D,3A,4A,-
5B,6B,7C),(1A,2D,3A,4A,5B,6C,7A),(1A,2D,3A,4A,5B,6C,7B),
(1A,2D,3A,4A,5B,6C,7C),(1A,2D,3A,4A,5B,6D,7A),(1A,2D,3A,4A,5B,6D,7B),(1A,-
2D,3A,4A,5B,6D,7C),(1A,2D,3A,4B,5A,6A,7A),(1A,2D,3A,4B,5A,6A,7B),(1A,2D,3A-
,4B,5A,6A,7C),
(1A,2D,3A,4B,5A,6B,7A),(1A,2D,3A,4B,5A,6B,7B),(1A,2D,3A,4B,-
5A,6B,7C),(1A,2D,3A,4B,5A,6C,7A),(1A,2D,3A,4B,5A,6C,7B),(1A,2D,3A,4B,5A,6C-
,7C),(1A,2D,3A,4B,5A,6D,7A),
(1A,2D,3A,4B,5A,6D,7B),(1A,2D,3A,4B,5A,6D,7C)-
,(1A,2D,3A,4B,5B,6A,7A),(1A,2D,3A,4B,5B,6A,7B),(1A,2D,3A,4B,5B,6A,7C),(1A,-
2D,3A,4B,5B,6B,7A),(1A,2D,3A,4B,5B,6B,7B),
(1A,2D,3A,4B,5B,6B,7C),(1A,2D,3-
A,4B,5B,6C,7A),(1A,2D,3A,4B,5B,6C,7B),(1A,2D,3A,4B,5B,6C,7C),(1A,2D,3A,4B,-
5B,6D,7A),(1A,2D,3A,4B,5B,6D,7B),(1A,2D,3A,4B,5B,6D,7C),
(1A,2D,3A,4C,5A,6A,7A),(1A,2D,3A,4C,5A,6A,7B),(1A,2D,3A,4C,5A,6A,7C),(1A,-
2D,3A,4C,5A,6B,7A),(1A,2D,3A,4C,5A,6B,7B),(1A,2D,3A,4C,5A,6B,7C),(1A,2D,3A-
,4C,5A,6C,7A),
(1A,2D,3A,4C,5A,6C,7B),(1A,2D,3A,4C,5A,6C,7C),(1A,2D,3A,4C,-
5A,6D,7A),(1A,2D,3A,4C,5A,6D,7B),(1A,2D,3A,4C,5A,6D,7C),(1A,2D,3A,4C,5B,6A-
,7A),(1A,2D,3A,4C,5B,6A,7B),
(1A,2D,3A,4C,5B,6A,7C),(1A,2D,3A,4C,5B,6B,7A)-
,(1A,2D,3A,4C,5B,6B,7B),(1A,2D,3A,4C,5B,6B,7C),(1A,2D,3A,4C,5B,6C,7A),(1A,-
2D,3A,4C,5B,6C,7B),(1A,2D,3A,4C,5B,6C,7C),
(1A,2D,3A,4C,5B,6D,7A),(1A,2D,3-
A,4C,5B,6D,7B),(1A,2D,3A,4C,5B,6D,7C),(1A,2D,3A,4D,5A,6A,7A),(1A,2D,3A,4D,-
5A,6A,7B),(1A,2D,3A,4D,5A,6A,7C),(1A,2D,3A,4D,5A,6B,7A),
(1A,2D,3A,4D,5A,6B,7B),(1A,2D,3A,4D,5A,6B,7C),(1A,2D,3A,4D,5A,6C,7A),(1A,-
2D,3A,4D,5A,6C,7B),(1A,2D,3A,4D,5A,6C,7C),(1A,2D,3A,4D,5A,6D,7A),(1A,2D,3A-
,4D,5A,6D,7B),
(1A,2D,3A,4D,5A,6D,7C),(1A,2D,3A,4D,5B,6A,7A),(1A,2D,3A,4D,-
5B,6A,7B),(1A,2D,3A,4D,5B,6A,7C),(1A,2D,3A,4D,5B,6B,7A),(1A,2D,3A,4D,5B,6B-
,7B),(1A,2D,3A,4D,5B,6B,7C),
(1A,2D,3A,4D,5B,6C,7A),(1A,2D,3A,4D,5B,6C,7B)-
,(1A,2D,3A,4D,5B,6C,7C),(1A,2D,3A,4D,5B,6D,7A),(1A,2D,3A,4D,5B,6D,7B),(1A,-
2D,3A,4D,5B,6D,7C),(1A,2D,3A,4E,5A,6A,7A),
(1A,2D,3A,4E,5A,6A,7B),(1A,2D,3-
A,4E,5A,6A,7C),(1A,2D,3A,4E,5A,6B,7A),(1A,2D,3A,4E,5A,6B,7B),(1A,2D,3A,4E,-
5A,6B,7C),(1A,2D,3A,4E,5A,6C,7A),(1A,2D,3A,4E,5A,6C,7B),
(1A,2D,3A,4E,5A,6C,7C),(1A,2D,3A,4E,5A,6D,7A),(1A,2D,3A,4E,5A,6D,7B),(1A,-
2D,3A,4E,5A,6D,7C),(1A,2D,3A,4E,5B,6A,7A),(1A,2D,3A,4E,5B,6A,7B),(1A,2D,3A-
,4E,5B,6A,7C),
(1A,2D,3A,4E,5B,6B,7A),(1A,2D,3A,4E,5B,6B,7B),(1A,2D,3A,4E,-
5B,6B,7C),(1A,2D,3A,4E,5B,6C,7A),(1A,2D,3A,4E,5B,6C,7B),(1A,2D,3A,4E,5B,6C-
,7C),(1A,2D,3A,4E,5B,6D,7A),
(1A,2D,3A,4E,5B,6D,7B),(1A,2D,3A,4E,5B,6D,7C)-
,(1A,2D,3B,4A,5A,6A,7A),(1A,2D,3B,4A,5A,6A,7B),(1A,2D,3B,4A,5A,6A,7C),(1A,-
2D,3B,4A,5A,6B,7A),(1A,2D,3B,4A,5A,6B,7B),
(1A,2D,3B,4A,5A,6B,7C),(1A,2D,3-
B,4A,5A,6C,7A),(1A,2D,3B,4A,5A,6C,7B),(1A,2D,3B,4A,5A,6C,7C),(1A,2D,3B,4A,-
5A,6D,7A),(1A,2D,3B,4A,5A,6D,7B),(1A,2D,3B,4A,5A,6D,7C),
(1A,2D,3B,4A,5B,6A,7A),(1A,2D,3B,4A,5B,6A,7B),(1A,2D,3B,4A,5B,6A,7C),(1A,-
2D,3B,4A,5B,6B,7A),(1A,2D,3B,4A,5B,6B,7B),(1A,2D,3B,4A,5B,6B,7C),(1A,2D,3B-
,4A,5B,6C,7A),
(1A,2D,3B,4A,5B,6C,7B),(1A,2D,3B,4A,5B,6C,7C),(1A,2D,3B,4A,-
5B,6D,7A),(1A,2D,3B,4A,5B,6D,7B),(1A,2D,3B,4A,5B,6D,7C),(1A,2D,3B,4B,5A,6A-
,7A),(1A,2D,3B,4B,5A,6A,7B),
(1A,2D,3B,4B,5A,6A,7C),(1A,2D,3B,4B,5A,6B,7A)-
,(1A,2D,3B,4B,5A,6B,7B),(1A,2D,3B,4B,5A,6B,7C),(1A,2D,3B,4B,5A,6C,7A),(1A,-
2D,3B,4B,5A,6C,7B),(1A,2D,3B,4B,5A,6C,7C),
(1A,2D,3B,4B,5A,6D,7A),(1A,2D,3-
B,4B,5A,6D,7B),(1A,2D,3B,4B,5A,6D,7C),(1A,2D,3B,4B,5B,6A,7A),
(1A,2D,3B,4B,5B,6A,7B),(1A,2D,3B,4B,5B,6A,7C),(1A,2D,3B,4B,5B,6B,7A),
(1A,2D,3B,4B,5B,6B,7B), (1A,2D,3B,4B,5B,6B,7C),
(1A,2D,3B,4B,5B,6C,7A),(1- A,2D,3B,4B,5B,6C,7B),
(1A,2D,3B,4B,5B,6C,7C),(1A,2D,3B,4B,5B,6D,7A),(1A,2D-
,3B,4B,5B,6D,7B), (1A,2D,3B,4B,5B,6D,7C),(1A,2D,3B,4C,5A,6A,7A),
(1A,2D,3B,4C,5A,6A,7B),(1A,2D,3B,4C,5A,6A,7C),
(1A,2D,3B,4C,5A,6B,7A),(1A-
,2D,3B,4C,5A,6B,7B),(1A,2D,3B,4C,5A,6B,7C),
(1A,2D,3B,4C,5A,6C,7A),(1A,2D,-
3B,4C,5A,6C,7B),(1A,2D,3B,4C,5A,6C,7C),(1A,2D,3B,4C,5A,6D,7A),(1A,2D,3B,4C-
,5A,6D,7B),(1A,2D,3B,4C,5A,6D,7C),(1A,2D,3B,4C,5B,6A,7A),
(1A,2D,3B,4C,5B,6A,7B),(1A,2D,3B,4C,5B,6A,7C),(1A,2D,3B,4C,5B,6B,7A),(1A,-
2D,3B,4C,5B,6B,7B),(1A,2D,3B,4C,5B,6B,7C),(1A,2D,3B,4C,5B,6C,7A),(1A,2D,3B-
,4C,5B,6C,7B),
(1A,2D,3B,4C,5B,6C,7C),(1A,2D,3B,4C,5B,6D,7A),(1A,2D,3B,4C,-
5B,6D,7B),(1A,2D,3B,4C,5B,6D,7C),(1A,2D,3B,4D,5A,6A,7A),(1A,2D,3B,4D,5A,6A-
,7B),(1A,2D,3B,4D,5A,6A,7C),
(1A,2D,3B,4D,5A,6B,7A),(1A,2D,3B,4D,5A,6B,7B)-
,(1A,2D,3B,4D,5A,6B,7C),(1A,2D,3B,4D,5A,6C,7A),(1A,2D,3B,4D,5A,6C,7B),(1A,-
2D,3B,4D,5A,6C,7C),(1A,2D,3B,4D,5A,6D,7A),
(1A,2D,3B,4D,5A,6D,7B),(1A,2D,3-
B,4D,5A,6D,7C),(1A,2D,3B,4D,5B,6A,7A),(1A,2D,3B,4D,5B,6A,7B),(1A,2D,3B,4D,-
5B,6A,7C),(1A,2D,3B,4D,5B,6B,7A),(1A,2D,3B,4D,5B,6B,7B),
(1A,2D,3B,4D,5B,6B,7C),(1A,2D,3B,4D,5B,6C,7A),(1A,2D,3B,4D,5B,6C,7B),(1A,-
2D,3B,4D,5B,6C,7C),(1A,2D,3B,4D,5B,6D,7A),(1A,2D,3B,4D,5B,6D,7B),(1A,2D,3B-
,4D,5B,6D,7C),
(1A,2D,3B,4E,5A,6A,7A),(1A,2D,3B,4E,5A,6A,7B),(1A,2D,3B,4E,-
5A,6A,7C),(1A,2D,3B,4E,5A,6B,7A),(1A,2D,3B,4E,5A,6B,7B),(1A,2D,3B,4E,5A,6B-
,7C),(1A,2D,3B,4E,5A,6C,7A),
(1A,2D,3B,4E,5A,6C,7B),(1A,2D,3B,4E,5A,6C,7C)-
,(1A,2D,3B,4E,5A,6D,7A),(1A,2D,3B,4E,5A,6D,7B),(1A,2D,3B,4E,5A,6D,7C),(1A,-
2D,3B,4E,5B,6A,7A),(1A,2D,3B,4E,5B,6A,7B),
(1A,2D,3B,4E,5B,6A,7C),(1A,2D,3-
B,4E,5B,6B,7A),(1A,2D,3B,4E,5B,6B,7B),(1A,2D,3B,4E,5B,6B,7C),(1A,2D,3B,4E,-
5B,6C,7A),(1A,2D,3B,4E,5B,6C,7B),(1A,2D,3B,4E,5B,6C,7C),
(1A,2D,3B,4E,5B,6D,7A),(1A,2D,3B,4E,5B,6D,7B),(1A,2D,3B,4E,5B,6D,7C),(1A,-
2D,3C,4A,5A,6A,7A),(1A,2D,3C,4A,5A,6A,7B),(1A,2D,3C,4A,5A,6A,7C),(1A,2D,3C-
,4A,5A,6B,7A),
(1A,2D,3C,4A,5A,6B,7B),(1A,2D,3C,4A,5A,6B,7C),(1A,2D,3C,4A,-
5A,6C,7A),(1A,2D,3C,4A,5A,6C,7B),(1A,2D,3C,4A,5A,6C,7C),(1A,2D,3C,4A,5A,6D-
,7A),(1A,2D,3C,4A,5A,6D,7B),
(1A,2D,3C,4A,5A,6D,7C),(1A,2D,3C,4A,5B,6A,7A)-
,(1A,2D,3C,4A,5B,6A,7B),(1A,2D,3C,4A,5B,6A,7C),(1A,2D,3C,4A,5B,6B,7A),(1A,-
2D,3C,4A,5B,6B,7B),(1A,2D,3C,4A,5B,6B,7C),
(1A,2D,3C,4A,5B,6C,7A),(1A,2D,3-
C,4A,5B,6C,7B),(1A,2D,3C,4A,5B,6C,7C),(1A,2D,3C,4A,5B,6D,7A),
(1A,2D,3C,4A,5B,6D,7B),(1A,2D,3C,4A,5B,6D,7C),(1A,2D,3C,4B,5A,6A,7A),
(1A,2D,3C,4B,5A,6A,7B),(1A,2D,3C,4B,5A,6A,7C),(1A,2D,3C,4B,5A,6B,7A),(1A,-
2D,3C,4B,5A,6B,7B),(1A,2D,3C,4B,5A,6B,7C),(1A,2D,3C,4B,5A,6C,7A),(1A,2D,3C-
,4B,5A,6C,7B),
(1A,2D,3C,4B,5A,6C,7C),(1A,2D,3C,4B,5A,6D,7A),(1A,2D,3C,4B,-
5A,6D,7B),(1A,2D,3C,4B,5A,6D,7C),(1A,2D,3C,4B,5B,6A,7A),(1A,2D,3C,4B,5B,6A-
,7B),(1A,2D,3C,4B,5B,6A,7C),
(1A,2D,3C,4B,5B,6B,7A),(1A,2D,3C,4B,5B,6B,7B)-
,(1A,2D,3C,4B,5B,6B,7C),(1A,2D,3C,4B,5B,6C,7A),(1A,2D,3C,4B,5B,6C,7B),(1A,-
2D,3C,4B,5B,6C,7C),(1A,2D,3C,4B,5B,6D,7A),
(1A,2D,3C,4B,5B,6D,7B),(1A,2D,3-
C,4B,5B,6D,7C),(1A,2D,3C,4C,5A,6A,7A),(1A,2D,3C,4C,5A,6A,7B),(1A,2D,3C,4C,-
5A,6A,7C),(1A,2D,3C,4C,5A,6B,7A),(1A,2D,3C,4C,5A,6B,7B),
(1A,2D,3C,4C,5A,6B,7C),(1A,2D,3C,4C,5A,6C,7A),(1A,2D,3C,4C,5A,6C,7B),(1A,-
2D,3C,4C,5A,6C,7C),(1A,2D,3C,4C,5A,6D,7A),(1A,2D,3C,4C,5A,6D,7B),(1A,2D,3C-
,4C,5A,6D,7C),
(1A,2D,3C,4C,5B,6A,7A),(1A,2D,3C,4C,5B,6A,7B),(1A,2D,3C,4C,-
5B,6A,7C),(1A,2D,3C,4C,5B,6B,7A),(1A,2D,3C,4C,5B,6B,7B),(1A,2D,3C,4C,5B,6B-
,7C),(1A,2D,3C,4C,5B,6C,7A),
(1A,2D,3C,4C,5B,6C,7B),(1A,2D,3C,4C,5B,6C,7C)-
,(1A,2D,3C,4C,5B,6D,7A),(1A,2D,3C,4C,5B,6D,7B),(1A,2D,3C,4C,5B,6D,7C),(1A,-
2D,3C,4D,5A,6A,7A),(1A,2D,3C,4D,5A,6A,7B),
(1A,2D,3C,4D,5A,6A,7C),(1A,2D,3-
C,4D,5A,6B,7A),(1A,2D,3C,4D,5A,6B,7B),(1A,2D,3C,4D,5A,6B,7C),(1A,2D,3C,4D,-
5A,6C,7A),(1A,2D,3C,4D,5A,6C,7B),(1A,2D,3C,4D,5A,6C,7C),
(1A,2D,3C,4D,5A,6D,7A),(1A,2D,3C,4D,5A,6D,7B),(1A,2D,3C,4D,5A,6D,7C),(1A,-
2D,3C,4D,5B,6A,7A),(1A,2D,3C,4D,5B,6A,7B),(1A,2D,3C,4D,5B,6A,7C),(1A,2D,3C-
,4D,5B,6B,7A),
(1A,2D,3C,4D,5B,6B,7B),(1A,2D,3C,4D,5B,6B,7C),(1A,2D,3C,4D,-
5B,6C,7A),(1A,2D,3C,4D,5B,6C,7B),(1A,2D,3C,4D,5B,6C,7C),(1A,2D,3C,4D,5B,6D-
,7A),(1A,2D,3C,4D,5B,6D,7B),
(1A,2D,3C,4D,5B,6D,7C),(1A,2D,3C,4E,5A,6A,7A)-
,(1A,2D,3C,4E,5A,6A,7B),(1A,2D,3C,4E,5A,6A,7C),(1A,2D,3C,4E,5A,6B,7A),(1A,-
2D,3C,4E,5A,6B,7B),(1A,2D,3C,4E,5A,6B,7C),
(1A,2D,3C,4E,5A,6C,7A),(1A,2D,3-
C,4E,5A,6C,7B),(1A,2D,3C,4E,5A,6C,7C),(1A,2D,3C,4E,5A,6D,7A),(1A,2D,3C,4E,-
5A,6D,7B),(1A,2D,3C,4E,5A,6D,7C),(1A,2D,3C,4E,5B,6A,7A),
(1A,2D,3C,4E,5B,6A,7B),(1A,2D,3C,4E,5B,6A,7C),(1A,2D,3C,4E,5B,6B,7A),(1A,-
2D,3C,4E,5B,6B,7B),(1A,2D,3C,4E,5B,6B,7C),(1A,2D,3C,4E,5B,6C,7A),(1A,2D,3C-
,4E,5B,6C,7B),
(1A,2D,3C,4E,5B,6C,7C),(1A,2D,3C,4E,5B,6D,7A),(1A,2D,3C,4E,-
5B,6D,7B),(1A,2D,3C,4E,5B,6D,7C),(1A,2D,3D,4A,5A,6A,7A),(1A,2D,3D,4A,5A,6A-
,7B),(1A,2D,3D,4A,5A,6A,7C),
(1A,2D,3D,4A,5A,6B,7A),(1A,2D,3D,4A,5A,6B,7B)-
,(1A,2D,3D,4A,5A,6B,7C),(1A,2D,3D,4A,5A,6C,7A),(1A,2D,3D,4A,5A,6C,7B),(1A,-
2D,3D,4A,5A,6C,7C),(1A,2D,3D,4A,5A,6D,7A),
(1A,2D,3D,4A,5A,6D,7B),(1A,2D,3-
D,4A,5A,6D,7C),(1A,2D,3D,4A,5B,6A,7A),(1A,2D,3D,4A,5B,6A,7B),(1A,2D,3D,4A,-
5B,6A,7C),(1A,2D,3D,4A,5B,6B,7A),(1A,2D,3D,4A,5B,6B,7B),
(1A,2D,3D,4A,5B,6B,7C),
(1A,2D,3D,4A,5B,6C,7A),(1A,2D,3D,4A,5B,6C,7B),(1A-
,2D,3D,4A,5B,6C,7C),(1A,2D,3D,4A,5B,6D,7A),(1A,2D,3D,4A,5B,6D,7B),(1A,2D,3-
D,4A,5B,6D,7C),
(1A,2D,3D,4B,5A,6A,7A),(1A,2D,3D,4B,5A,6A,7B),(1A,2D,3D,4B-
,5A,6A,7C),(1A,2D,3D,4B,5A,6B,7A),(1A,2D,3D,4B,5A,6B,7B),(1A,2D,3D,4B,5A,6-
B,7C),(1A,2D,3D,4B,5A,6C,7A),
(1A,2D,3D,4B,5A,6C,7B),(1A,2D,3D,4B,5A,6C,7C-
),(1A,2D,3D,4B,5A,6D,7A),(1A,2D,3D,4B,5A,6D,7B),(1A,2D,3D,4B,5A,6D,7C),(1A-
,2D,3D,4B,5B,6A,7A),(1A,2D,3D,4B,5B,6A,7B),
(1A,2D,3D,4B,5B,6A,7C),(1A,2D,-
3D,4B,5B,6B,7A),(1A,2D,3D,4B,5B,6B,7B),(1A,2D,3D,4B,5B,6B,7C),(1A,2D,3D,4B-
,5B,6C,7A),(1A,2D,3D,4B,5B,6C,7B),(1A,2D,3D,4B,5B,6C,7C),
(1A,2D,3D,4B,5B,6D,7A),(1A,2D,3D,4B,5B,6D,7B),(1A,2D,3D,4B,5B,6D,7C),(1A,-
2D,3D,4C,5A,6A,7A),(1A,2D,3D,4C,5A,6A,7B),(1A,2D,3D,4C,5A,6A,7C),(1A,2D,3D-
,4C,5A,6B,7A),
(1A,2D,3D,4C,5A,6B,7B),(1A,2D,3D,4C,5A,6B,7C),(1A,2D,3D,4C,-
5A,6C,7A),(1A,2D,3D,4C,5A,6C,7B),(1A,2D,3D,4C,5A,6C,7C),(1A,2D,3D,4C,5A,6D-
,7A),(1A,2D,3D,4C,5A,6D,7B),
(1A,2D,3D,4C,5A,6D,7C),(1A,2D,3D,4C,5B,6A,7A)-
,(1A,2D,3D,4C,5B,6A,7B),(1A,2D,3D,4C,5B,6A,7C),(1A,2D,3D,4C,5B,6B,7A),(1A,-
2D,3D,4C,5B,6B,7B),(1A,2D,3D,4C,5B,6B,7C),
(1A,2D,3D,4C,5B,6C,7A),(1A,2D,3-
D,4C,5B,6C,7B),(1A,2D,3D,4C,5B,6C,7C),(1A,2D,3D,4C,5B,6D,7A),(1A,2D,3D,4C,-
5B,6D,7B),(1A,2D,3D,4C,5B,6D,7C),(1A,2D,3D,4D,5A,6A,7A),
(1A,2D,3D,4D,5A,6A,7B),(1A,2D,3D,4D,5A,6A,7C),(1A,2D,3D,4D,5A,6B,7A),(1A,-
2D,3D,4D,5A,6B,7B),(1A,2D,3D,4D,5A,6B,7C),(1A,2D,3D,4D,5A,6C,7A),(1A,2D,3D-
,4D,5A,6C,7B),
(1A,2D,3D,4D,5A,6C,7C),(1A,2D,3D,4D,5A,6D,7A),(1A,2D,3D,4D,-
5A,6D,7B),(1A,2D,3D,4D,5A,6D,7C),(1A,2D,3D,4D,5B,6A,7A),(1A,2D,3D,4D,5B,6A-
,7B),(1A,2D,3D,4D,5B,6A,7C),
(1A,2D,3D,4D,5B,6B,7A),(1A,2D,3D,4D,5B,6B,7B)-
,(1A,2D,3D,4D,5B,6B,7C),(1A,2D,3D,4D,5B,6C,7A),(1A,2D,3D,4D,5B,6C,7B),(1A,-
2D,3D,4D,5B,6C,7C),(1A,2D,3D,4D,5B,6D,7A),
(1A,2D,3D,4D,5B,6D,7B),(1A,2D,3-
D,4D,5B,6D,7C),(1A,2D,3D,4E,5A,6A,7A),(1A,2D,3D,4E,5A,6A,7B),(1A,2D,3D,4E,-
5A,6A,7C),(1A,2D,3D,4E,5A,6B,7A),(1A,2D,3D,4E,5A,6B,7B),
(1A,2D,3D,4E,5A,6B,7C),(1A,2D,3D,4E,5A,6C,7A),(1A,2D,3D,4E,5A,6C,7B),(1A,-
2D,3D,4E,5A,6C,7C),(1A,2D,3D,4E,5A,6D,7A),(1A,2D,3D,4E,5A,6D,7B),(1A,2D,3D-
,4E,5A,6D,7C),
(1A,2D,3D,4E,5B,6A,7A),(1A,2D,3D,4E,5B,6A,7B),(1A,2D,3D,4E,-
5B,6A,7C),(1A,2D,3D,4E,5B,6B,7A),(1A,2D,3D,4E,5B,6B,7B),
(1A,2D,3D,4E,5B,6B,7C),(1A,2D,3D,4E,5B,6C,7A),
(1A,2D,3D,4E,5B,6C,7B),
(1A,2D,3D,4E,5B,6C,7C),(1A,2D,3D,4E,5B,6D,7A),(1A,2D,3D,4E,5B,6D,7B),
(1A,2D,3D,4E,5B,6D,7C),(1A,2D,3E,4A,5A,6A,7A),(1A,2D,3E,4A,5A,6A,
7B),
(1A,2D,3E,4A,5A,6A,7C),(1A,2D,3E,4A,5A,6B,7A),(1A,2D,3E,4A,5A,6B,7B),(1A,-
2D,3E,4A,5A,6B,7C),(1A,2D,3E,4A,5A,6C,7A),(1A,2D,3E,4A,5A,6C,7B),(1A,2D,3E-
,4A,5A,6C,7C),
(1A,2D,3E,4A,5A,6D,7A),(1A,2D,3E,4A,5A,6D,7B),(1A,2D,3E,4A,-
5A,6D,7C),(1A,2D,3E,4A,5B,6A,7A),(1A,2D,3E,4A,5B,6A,7B),(1A,2D,3E,4A,5B,6A-
,7C),(1A,2D,3E,4A,5B,6B,7A),
(1A,2D,3E,4A,5B,6B,7B),(1A,2D,3E,4A,5B,6B,7C)-
,(1A,2D,3E,4A,5B,6C,7A),(1A,2D,3E,4A,5B,6C,7B),(1A,2D,3E,4A,5B,6C,7C),(1A,-
2D,3E,4A,5B,6D,7A),(1A,2D,3E,4A,5B,6D,7B),
(1A,2D,3E,4A,5B,6D,7C),(1A,2D,3-
E,4B,5A,6A,7A),(1A,2D,3E,4B,5A,6A,7B),(1A,2D,3E,4B,5A,6A,7C),(1A,2D,3E,4B,-
5A,6B,7A),(1A,2D,3E,4B,5A,6B,7B),(1A,2D,3E,4B,5A,6B,7C),
(1A,2D,3E,4B,5A,6C,7A),(1A,2D,3E,4B,5A,6C,7B),(1A,2D,3E,4B,5A,6C,7C),(1A,-
2D,3E,4B,5A,6D,7A),(1A,2D,3E,4B,5A,6D,7B),(1A,2D,3E,4B,5A,6D,7C),(1A,2D,3E-
,4B,5B,6A,7A),
(1A,2D,3E,4B,5B,6A,7B),(1A,2D,3E,4B,5B,6A,7C),(1A,2D,3E,4B,-
5B,6B,7A),(1A,2D,3E,4B,5B,6B,7B),(1A,2D,3E,4B,5B,6B,7C),(1A,2D,3E,4B,5B,6C-
,7A),(1A,2D,3E,4B,5B,6C,7B),
(1A,2D,3E,4B,5B,6C,7C),(1A,2D,3E,4B,5B,6D,7A)-
,(1A,2D,3E,4B,5B,6D,7B),(1A,2D,3E,4B,5B,6D,7C),(1A,2D,3E,4C,5A,6A,7A),(1A,-
2D,3E,4C,5A,6A,7B),(1A,2D,3E,4C,5A,6A,7C),
(1A,2D,3E,4C,5A,6B,7A),(1A,2D,3-
E,4C,5A,6B,7B),(1A,2D,3E,4C,5A,6B,7C),(1A,2D,3E,4C,5A,6C,7A),(1A,2D,3E,4C,-
5A,6C,7B),(1A,2D,3E,4C,5A,6C,7C),(1A,2D,3E,4C,5A,6D,7A),
(1A,2D,3E,4C,5A,6D,7B3),(1A,2D,3E,4C,5A,6D,7C),(1A,2D,3E,4C,5B,6A,7A),(1A-
,2D,3E,4C,5B,6A,7B),(1A,2D,3E,4C,5B,6A,7C),(1A,2D,3E,4C,5B,6B,7A),(1A,2D,3-
E,4C,5B,6B,7B),
(1A,2D,3E,4C,5B,6B,7C),(1A,2D,3E,4C,5B,6C,7A),(1A,2D,3E,4C-
,5B,6C,7B),(1A,2D,3E,4C,5B,6C,7C),(1A,2D,3E,4C,5B,6D,7A),(1A,2D,3E,4C,5B,6-
D,7B),(1A,2D,3E,4C,5B,6D,7C),
(1A,2D,3E,4D,5A,6A,7A),(1A,2D,3E,4D,5A,6A,7B-
),(1A,2D,3E,4D,5A,6A,7C),(1A,2D,3E,4D,5A,6B,7A),(1A,2D,3E,4D,5A,6B,7B),(1A-
,2D,3E,4D,5A,6B,7C),(1A,2D,3E,4D,5A,6C,7A),
(1A,2D,3E,4D,5A,6C,7B),(1A,2D,-
3E,4D,5A,6C,7C),(1A,2D,3E,4D,5A,6D,7A),(1A,2D,3E,4D,5A,6D,7B),(1A,2D,3E,4D-
,5A,6D,7C),(1A,2D,3E,4D,5B,6A,7A),(1A,2D,3E,4D,5B,6A,7B),
(1A,2D,3E,4D,5B,6A,7C),(1A,2D,3E,4D,5B,6B,7A),(1A,2D,3E,4D,5B,6B,7B),(1A,-
2D,3E,4D,5B,6B,7C),(1A,2D,3E,4D,5B,6C,7A),(1A,2D,3E,4D,5B,6C,7B),(1A,2D,3E-
,4D,5B,6C,7C),
(1A,2D,3E,4D,5B,6D,7A),(1A,2D,3E,4D,5B,6D,7B),(1A,2D,3E,4D,-
5B,6D,7C),(1A,2D,3E,4E,5A,6A,7A),
(1A,2D,3E,4E,5A,6A,7B),(1A,2D,3E,4E,5A,6-
A,7C),(1A,2D,3E,4E,5A,6B,7A), (1A,2D,3E,4E,5A,6B,7B),
(1A,2D,3E,4E,5A,6B,7C),(1A,2D,3E,4E,5A,6C,7A),(1A,2D,3E,4E,5A,6C,7B),
(1A,2D,3E,4E,5A,6C,7C),(1A,2D,3E,4E,5A,6D,7A),(1A,2D,3E,4E,5A,6D,7B),
(1A,2D,3E,4E,5A,6D,7C), (1A,2D,3E,4E,5B,6A,7A),
(1A,2D,3E,4E,5B,6A,7B), (1A,2D,3E,4E,5B,6A,7C),
(1A,2D,3E,4E,5B,6B,7A), (1A,2D,3E,4E,5B,6B,7B),
(1A,2D,3E,4E,5B,6B,7C), (1A,2D,3E,4E,5B,6C,7A),
(1A,2D,3E,4E,5B,6C,7B), (1A,2D,3E,4E,5B,6C,7C),
(1A,2D,3E,4E,5B,6D,7A), (1A,2D,3E,4E,5B,6D,7B),(1-
A,2D,3E,4E,5B,6D,7C),(1A,2E,3A,4A,5A,6A,7A),
(1A,2E,3A,4A,5A,6A,7B),(1A,2E-
,3A,4A,5A,6A,7C),(1A,2E,3A,4A,5A,6B,7A),(1A,2E,3A,4A,5A,6B,7B),(1A,2E,3A,4-
A,5A,6B,7C),(1A,2E,3A,4A,5A,6C,7A),(1A,2E,3A,4A,5A,6C,7B),
(1A,2E,3A,4A,5A,6C,7C),(1A,2E,3A,4A,5A,6D,7A),(1A,2E,3A,4A,5A,6D,7B),(1A,-
2E,3A,4A,5A,6D,7C),(1A,2E,3A,4A,5B,6A,7A),(1A,2E,3A,4A,5B,6A,7B),(1A,2E,3A-
,4A,5B,6A,7C),
(1A,2E,3A,4A,5B,6B,7A),(1A,2E,3A,4A,5B,6B,7B),(1A,2E,3A,4A,-
5B,6B,7C),(1A,2E,3A,4A,5B,6C,7A),(1A,2E,3A,4A,5B,6C,7B),(1A,2E,3A,4A,5B,6C-
,7C),(1A,2E,3A,4A,5B,6D,7A),
(1A,2E,3A,4A,5B,6D,7B),(1A,2E,3A,4A,5B,6D,7C)-
,(1A,2E,3A,4B,5A,6A,7A),(1A,2E,3A,4B,5A,6A,7B),(1A,2E,3A,4B,5A,6A,7C),(1A,-
2E,3A,4B,5A,6B,7A),(1A,2E,3A,4B,5A,6B,7B),
(1A,2E,3A,4B,5A,6B,7C),(1A,2E,3-
A,4B,5A,6C,7A),(1A,2E,3A,4B,5A,6C,7B),(1A,2E,3A,4B,5A,6C,7C),(1A,2E,3A,4B,-
5A,6D,7A),(1A,2E,3A,4B,5A,6D,7B),(1A,2E,3A,4B,5A,6D,7C),
(1A,2E,3A,4B,5B,6A,7A),(1A,2E,3A,4B,5B,6A,7B),(1A,2E,3A,4B,5B,6A,7C),(1A,-
2E,3A,4B,5B,6B,7A),(1A,2E,3A,4B,5B,6B,7B),(1A,2E,3A,4B,5B,6B,7C),(1A,2E,3A-
,4B,5B,6C,7A),
(1A,2E,3A,4B,5B,6C,7B1),(1A,2E,3A,4B,5B,6C,7C),(1A,2E,3A,4B-
,5B,6D,7A),(1A,2E,3A,4B,5B,6D,7B),(1A,2E,3A,4B,5B,6D,7C),(1A,2E,3A,4C,5A,6-
A,7A),(1A,2E,3A,4C,5A,6A,7B),
(1A,2E,3A,4C,5A,6A,7C),(1A,2E,3A,4C,5A,6B,7A-
),(1A,2E,3A,4C,5A,6B,7B),(1A,2E,3A,4C,5A,6B,7C),(1A,2E,3A,4C,5A,6C,7A),(1A-
,2E,3A,4C,5A,6C,7B),(1A,2E,3A,4C,5A,6C,7C),
(1A,2E,3A,4C,5A,6D,7A),(1A,2E,-
3A,4C,5A,6D,7B),(1A,2E,3A,4C,5A,6D,7C),(1A,2E,3A,4C,5B,6A,7A),(1A,2E,3A,4C-
,5B,6A,7B),(1A,2E,3A,4C,5B,6A,7C),(1A,2E,3A,4C,5B,6B,7A),
(1A,2E,3A,4C,5B,6B,7B),(1A,2E,3A,4C,5B,6B,7C),(1A,2E,3A,4C,5B,6C,7A),(1A,-
2E,3A,4C,5B,6C,7B),(1A,2E,3A,4C,5B,6C,7C),(1A,2E,3A,4C,5B,6D,7A),(1A,2E,3A-
,4C,5B,6D,7B),
(1A,2E,3A,4C,5B,6D,7C),(1A,2E,3A,4D,5A,6A,7A),(1A,2E,3A,4D,-
5A,6A,7B),(1A,2E,3A,4D,5A,6A,7C),(1A,2E,3A,4D,5A,6B,7A),(1A,2E,3A,4D,5A,6B-
,7B),(1A,2E,3A,4D,5A,6B,7C),
(1A,2E,3A,4D,5A,6C,7A),(1A,2E,3A,4D,5A,6C,7B)-
,(1A,2E,3A,4D,5A,6C,7C),(1A,2E,3A,4D,5A,6D,7A),(1A,2E,3A,4D,5A,6D,7B),(1A,-
2E,3A,4D,5A,6D,7C),(1A,2E,3A,4D,5B,6A,7A),
(1A,2E,3A,4D,5B,6A,7B),(1A,2E,3-
A,4D,5B,6A,7C),(1A,2E,3A,4D,5B,6B,7A),(1A,2E,3A,4D,5B,6B,7B),(1A,2E,3A,4D,-
5B,6B,7C),(1A,2E,3A,4D,5B,6C,7A),(1A,2E,3A,4D,5B,6C,7B),
(1A,2E,3A,4D,5B,6C,7C),(1A,2E,3A,4D,5B,6D,7A),(1A,2E,3A,4D,5B,6D,7B),(1A,-
2E,3A,4D,5B,6D,7C),(1A,2E,3A,4E,5A,6A,7A),(1A,2E,3A,4E,5A,6A,7B),(1A,2E,3A-
,4E,5A,6A,7C),
(1A,2E,3A,4E,5A,6B,7A),(1A,2E,3A,4E,5A,6B,7B),(1A,2E,3A,4E,-
5A,6B,7C),(1A,2E,3A,4E,5A,6C,7A),(1A,2E,3A,4E,5A,6C,7B),(1A,2E,3A,4E,5A,6C-
,7C),(1A,2E,3A,4E,5A,6D,7A),
(1A,2E,3A,4E,5A,6D,7B),(1A,2E,3A,4E,5A,6D,7C)-
,(1A,2E,3A,4E,5B,6A,7A),(1A,2E,3A,4E,5B,6A,7B),(1A,2E,3A,4E,5B,6A,7C),(1A,-
2E,3A,4E,5B,6B,7A),(1A,2E,3A,4E,5B,6B,7B),
(1A,2E,3A,4E,5B,6B,7C),(1A,2E,3-
A,4E,5B,6C,7A),(1A,2E,3A,4E,5B,6C,7B),(1A,2E,3A,4E,5B,6C,7C),(1A,2E,3A,4E,-
5B,6D,7A),(1A,2E,3A,4E,5B,6D,7B),(1A,2E,3A,4E,5B,6D,7C),
(1A,2E,3B,4A,5A,6A,7A),(1A,2E,3B,4A,5A,6A,7B),(1A,2E,3B,4A,5A,6A,7C),(1A,-
2E,3B,4A,5A,6B,7A),(1A,2E,3B,4A,5A,6B,7B),(1A,2E,3B,4A,5A,6B,7C),(1A,2E,3B-
,4A,5A,6C,7A),
(1A,2E,3B,4A,5A,6C,7B),(1A,2E,3B,4A,5A,6C,7C),(1A,2E,3B,4A,-
5A,6D,7A),(1A,2E,3B,4A,5A,6D,7B),(1A,2E,3B,4A,5A,6D,7C),(1A,2E,3B,4A,5B,6A-
,7A),(1A,2E,3B,4A,5B,6A,7B),
(1A,2E,3B,4A,5B,6A,7C),(1A,2E,3B,4A,5B,6B,7A)-
,(1A,2E,3B,4A,5B,6B,7B),(1A,2E,3B,4A,5B,6B,7C),(1A,2E,3B,4A,5B,6C,7A),(1A,-
2E,3B,4A,5B,6C,7B),(1A,2E,3B,4A,5B,6C,7C),
(1A,2E,3B,4A,5B,6D,7A),(1A,2E,3-
B,4A,5B,6D,7B),(1A,2E,3B,4A,5B,6D,7C),(1A,2E,3B,4B,5A,6A,7A),(1A,2E,3B,4B,-
5A,6A,7B),(1A,2E,3B,4B,5A,6A,7C),(1A,2E,3B,4B,5A,6B,7A),
(1A,2E,3B,4B,5A,6B,7B),(1A,2E,3B,4B,5A,6B,7C),(1A,2E,3B,4B,5A,6C,7A),(1A,-
2E,3B,4B,5A,6C,7B),(1A,2E,3B,4B,5A,6C,7C),(1A,2E,3B,4B,5A,6D,7A),(1A,2E,3B-
,4B,5A,6D,7B),
(1A,2E,3B,4B,5A,6D,7C),(1A,2E,3B,4B,5B,6A,7A),(1A,2E,3B,4B,-
5B,6A,7B),(1A,2E,3B,4B,5B,6A,7C),(1A,2E,3B,4B,5B,6B,7A),(1A,2E,3B,4B,5B,6B-
,7B),(1A,2E,3B,4B,5B,6B,7C),
(1A,2E,3B,4B,5B,6C,7A),(1A,2E,3B,4B,5B,6C,7B)-
,(1A,2E,3B,4B,5B,6C,7C),(1A,2E,3B,4B,5B,6D,7A),(1A,2E,3B,4B,5B,6D,7B),(1A,-
2E,3B,4B,5B,6D,7C),(1A,2E,3B,4C,5A,6A,7A),
(1A,2E,3B,4C,5A,6A,7B),(1A,2E,3-
B,4C,5A,6A,7C),(1A,2E,3B,4C,5A,6B,7A),(1A,2E,3B,4C,5A,6B,7B),(1A,2E,3B,4C,-
5A,6B,7C),(1A,2E,3B,4C,5A,6C,7A),(1A,2E,3B,4C,5A,6C,7B),
(1A,2E,3B,4C,5A,6C,7C),(1A,2E,3B,4C,5A,6D,7A),(1A,2E,3B,4C,5A,6D,7B),(1A,-
2E,3B,4C,5A,6D,7C),(1A,2E,3B,4C,5B,6A,7A),(1A,2E,3B,4C,5B,6A,7B),(1A,2E,3B-
,4C,5B,6A,7C),
(1A,2E,3B,4C,5B,6B,7A),(1A,2E,3B,4C,5B,6B,7B),(1A,2E,3B,4C,-
5B,6B,7C),(1A,2E,3B,4C,5B,6C,7A), (1A,2E,3B,4C,5B,6C,7B),
(1A,2E,3B,4C,5B,6C,7C), (1A,2E,3B,4C,5B,6D,7A),
(1A,2E,3B,4C,5B,6D,7B),(1-
A,2E,3B,4C,5B,6D,7C),(1A,2E,3B,4D,5A,6A,7A),
(1A,2E,3B,4D,5A,6A,7B),
(1A,2E,3B,4D,5A,6A,7C),(1A,2E,3B,4D,5A,6B,7A),(1A,2E,3B,4D,5A,6B,7B),
(1A,2E,3B,4D,5A,6B,7C),(1A,2E,3B,4D,5A,6C,7A),(1A,2E,3B,4D,5A,6C,7B),
(1A,2E,3B,4D,5A,6C,7C),
(1A,2E,3B,4D,5A,6D,7A),(1A,2E,3B,4D,5A,6D,7B),(1A-
,2E,3B,4D,5A,6D,7C), (1A,2E,3B,4D,5B,6A,7A),
(1A,2E,3B,4D,5B,6A,7B), (1A,2E,3B,4D,5B,6A,7C),
(1A,2E,3B,4D,5B,6B,7A), (1A,2E,3B,4D,5B,6B,7B),(1-
A,2E,3B,4D,5B,6B,7C),(1A,2E,3B,4D,5B,6C,7A), (1A,
2E,3B,4D,5B,6C,7B), (1A,2E,3B,4D,5B,6C,7C), (1A,2E,3B,4D,5B,6D,7A),
(1A,2E,3B,4D,5B,6D,7B), (1A,2E,3B,4D,5B,6D,7C),
(1A,2E,3B,4E,5A,6A,7A), (1A,2E,3B,4E,5A,6A,7B),
(1A,2E,3B,4E,5A,6A,7C),(1A,2E,3B,4E,5A,6B,7A),(1A,2E,3B,4E,5A,6B,7B),(1A,-
2E,3B,4E,5A,6B,7C),(1A,2E,3B,4E,5A,6C,7A),(1A,2E,3B,4E,5A,6C,7B),(1A,2E,3B-
,4E,5A,6C,7C),
(1A,2E,3B,4E,5A,6D,7A),(1A,2E,3B,4E,5A,6D,7B),(1A,2E,3B,4E,-
5A,6D,7C),(1A,2E,3B,4E,5B,6A,7A),(1A,2E,3B,4E,5B,6A,7B),(1A,2E,3B,4E,5B,6A-
,7C),(1A,2E,3B,4E,5B,6B,7A),
(1A,2E,3B,4E,5B,6B,7B),(1A,2E,3B,4E,5B,6B,7C)-
,(1A,2E,3B,4E,5B,6C,7A),(1A,2E,3B,4E,5B,6C,7B),(1A,2E,3B,4E,5B,6C,7C),(1A,-
2E,3B,4E,5B,6D,7A),(1A,2E,3B,4E,5B,6D,7B),
(1A,2E,3B,4E,5B,6D,7C),(1A,2E,3-
C,4A,5A,6A,7A),(1A,2E,3C,4A,5A,6A,7B),(1A,2E,3C,4A,5A,6A,7C),(1A,2E,3C,4A,-
5A,6B,7A),(1A,2E,3C,4A,5A,6B,7B),(1A,2E,3C,4A,5A,6B,7C),
(1A,2E,3C,4A,5A,6C,7A),(1A,2E,3C,4A,5A,6C,7B),(1A,2E,3C,4A,5A,6C,7C),(1A,-
2E,3C,4A,5A,6D,7A),(1A,2E,3C,4A,5A,6D,7B),(1A,2E,3C,4A,5A,6D,7C),(1A,2E,3C-
,4A,5B,6A,7A),
(1A,2E,3C,4A,5B,6A,7B),(1A,2E,3C,4A,5B,6A,7C),(1A,2E,3C,4A,-
5B,6B,7A),(1A,2E,3C,4A,5B,6B,7B),(1A,2E,3C,4A,5B,6B,7C),(1A,2E,3C,4A,5B,6C-
,7A),(1A,2E,3C,4A,5B,6C,7B),
(1A,2E,3C,4A,5B,6C,7C),(1A,2E,3C,4A,5B,6D,7A)-
,(1A,2E,3C,4A,5B,6D,7B),(1A,2E,3C,4A,5B,6D,7C),(1A,2E,3C,4B,5A,6A,7A),(1A,-
2E,3C,4B,5A,6A,7B),(1A,2E,3C,4B,5A,6A,7C),
(1A,2E,3C,4B,5A,6B,7A),(1A,2E,3-
C,4B,5A,6B,7B),(1A,2E,3C,4B,5A,6B,7C),(1A,2E,3C,4B,5A,6C,7A),(1A,2E,3C,4B,-
5A,6C,7B),(1A,2E,3C,4B,5A,6C,7C),(1A,2E,3C,4B,5A,6D,7A),
(1A,2E,3C,4B,5A,6D,7B),(1A,2E,3C,4B,5A,6D,7C),(1A,2E,3C,4B,5B,6A,7A),(1A,-
2E,3C,4B,5B,6A,7B),(1A,2E,3C,4B,5B,6A,7C),(1A,2E,3C,4B,5B,6B,7A),(1A,2E,3C-
,4B,5B,6B,7B),
(1A,2E,3C,4B,5B,6B,7C),(1A,2E,3C,4B,5B,6C,7A),(1A,2E,3C,4B,-
5B,6C,7B),(1A,2E,3C,4B,5B,6C,7C),(1A,2E,3C,4B,5B,6D,7A),(1A,2E,3C,4B,5B,6D-
,7B),(1A,2E,3C,4B,5B,6D,7C),
(1A,2E,3C,4C,5A,6A,7A),(1A,2E,3C,4C,5A,6A,7B)-
,(1A,2E,3C,4C,5A,6A,7C),(1A,2E,3C,4C,5A,6B,7A),(1A,2E,3C,4C,5A,6B,7B),(1A,-
2E,3C,4C,5A,6B,7C),(1A,2E,3C,4C,5A,6C,7A),
(1A,2E,3C,4C,5A,6C,7B),(1A,2E,3-
C,4C,5A,6C,7C),(1A,2E,3C,4C,5A,6D,7A),(1A,2E,3C,4C,5A,6D,7B),(1A,2E,3C,4C,-
5A,6D,7C),(1A,2E,3C,4C,5B,6A,7A),(1A,2E,3C,4C,5B,6A,7B),
(1A,2E,3C,4C,5B,6A,7C),(1A,2E,3C,4C,5B,6B,7A),(1A,2E,3C,4C,5B,6B,7B),(1A,-
2E,3C,4C,5B,6B,7C),(1A,2E,3C,4C,5B,6C,7A),(1A,2E,3C,4C,5B,6C,7B),(1A,2E,3C-
,4C,5B,6C,7C),
(1A,2E,3C,4C,5B,6D,7A),(1A,2E,3C,4C,5B,6D,7B),(1A,2E,3C,4C,-
5B,6D,7C),(1A,2E,3C,4D,5A,6A,7A),(1A,2E,3C,4D,5A,6A,7B),(1A,2E,3C,4D,5A,6A-
,7C),(1A,2E,3C,4D,5A,6B,7A),
(1A,2E,3C,4D,5A,6B,7B),(1A,2E,3C,4D,5A,6B,7C)-
,(1A,2E,3C,4D,5A,6C,7A),(1A,2E,3C,4D,5A,6C,7B),(1A,2E,3C,4D,5A,6C,7C),(1A,-
2E,3C,4D,5A,6D,7A),(1A,2E,3C,4D,5A,6D,7B),
(1A,2E,3C,4D,5A,6D,7C),(1A,2E,3-
C,4D,5B,6A,7A),(1A,2E,3C,4D,5B,6A,7B),(1A,2E,3C,4D,5B,6A,7C),(1A,2E,3C,4D,-
5B,6B,7A),(1A,2E,3C,4D,5B,6B,7B),(1A,2E,3C,4D,5B,6B,7C),
(1A,2E,3C,4D,5B,6C,7A),(1A,2E,3C,4D,5B,6C,7B),(1A,2E,3C,4D,5B,6C,7C),(1A,-
2E,3C,4D,5B,6D,7A),(1A,2E,3C,4D,5B,6D,7B),(1A,2E,3C,4D,5B,6D,7C),(1A,2E,3C-
,4E,5A,6A,7A),
(1A,2E,3C,4E,5A,6A,7B),(1A,2E,3C,4E,5A,6A,7C),(1A,2E,3C,4E,-
5A,6B,7A),(1A,2E,3C,4E,5A,6B,7B),(1A,2E,3C,4E,5A,6B,7C),(1A,2E,3C,4E,5A,6C-
,7A),(1A,2E,3C,4E,5A,6C,7B),
(1A,2E,3C,4E,5A,6C,7C),(1A,2E,3C,4E,5A,6D,7A)-
,(1A,2E,3C,4E,5A,6D,7B),(1A,2E,3C,4E,5A,6D,7C),(1A,2E,3C,4E,5B,6A,7A),(1A,-
2E,3C,4E,5B,6A,7B),(1A,2E,3C,4E,5B,6A,7C),
(1A,2E,3C,4E,5B,6B,7A),(1A,2E,3-
C,4E,5B,6B,7B),(1A,2E,3C,4E,5B,6B,7C),(1A,2E,3C,4E,5B,6C,7A),(1A,2E,3C,4E,-
5B,6C,7B),(1A,2E,3C,4E,5B,6C,7C),(1A,2E,3C,4E,5B,6D,7A),
(1A,2E,3C,4E,5B,6D,7B),(1A,2E,3C,4E,5B,6D,7C),(1A,2E,3D,4A,5A,6A,7A),(1A,-
2E,3D,4A,5A,6A,7B),(1A,2E,3D,4A,5A,6A,7C),(1A,2E,3D,4A,5A,6B,7A),(1A,2E,3D-
,4A,5A,6B,7B),
(1A,2E,3D,4A,5A,6B,7C),(1A,2E,3D,4A,5A,6C,7A),(1A,2E,3D,4A,-
5A,6C,7B),(1A,2E,3D,4A,5A,6C,7C),(1A,2E,3D,4A,5A,6D,7A),(1A,2E,3D,4A,5A,6D-
,7B),(1A,2E,3D,4A,5A,6D,7C),
(1A,2E,3D,4A,5B,6A,7A),(1A,2E,3D,4A,5B,6A,7B)-
,(1A,2E,3D,4A,5B,6A,7C),(1A,2E,3D,4A,5B,6B,7A),(1A,2E,3D,4A,5B,6B,7B),(1A,-
2E,3D,4A,5B,6B,7C),(1A,2E,3D,4A,5B,6C,7A),
(1A,2E,3D,4A,5B,6C,7B),(1A,2E,3-
D,4A,5B,6C,7C),(1A,2E,3D,4A,5B,6D,7A),(1A,2E,3D,4A,5B,6D,7B),(1A,2E,3D,4A,-
5B,6D,7C),(1A,2E,3D,4B,5A,6A,7A),(1A,2E,3D,4B,5A,6A,7B),
(1A,2E,3D,4B,5A,6A,7C),(1A,2E,3D,4B,5A,6B,7A),(1A,2E,3D,4B,5A,6B,7B),(1A,-
2E,3D,4B,5A,6B,7C),(1A,2E,3D,4B,5A,6C,7A),(1A,2E,3D,4B,5A,6C,7B),(1A,2E,3D-
,4B,5A,6C,7C),
(1A,2E,3D,4B,5A,6D,7A),(1A,2E,3D,4B,5A,6D,7B),(1A,2E,3D,4B,-
5A,6D,7C),(1A,2E,3D,4B,5B,6A,7A),
(1A,2E,3D,4B,5B,6A,7B),(1A,2E,3D,4B,5B,6-
A,7C),(1A,2E,3D,4B,5B,6B,7A), (1A,2E,3D,4B,5B,6B,7B),
(1A,2E,3D,4B,5B,6B,7C), (1A,2E,3D,4B,5B,6C,7A),
(1A,2E,3D,4B,5B,6C,7B),
(1A,2E,3D,4B,5B,6C,7C),(1A,2E,3D,4B,5B,6D,7A),(1A,2E,3D,4B,5B,6D,7B),
(1A,2E,3D,4B,5B,6D,7C),(1A,2E,3D,4C,5A,6A,7A),
(1A,2E,3D,4C,5A,6A,7B),
(1A,2E,3D,4C,5A,6A,7C),(1A,2E,3D,4C,5A,6B,7A),(1A,2E,3D,4C,5A,6B,7B),(1A,-
2E,3D,4C,5A,6B,7C),
(1A,2E,3D,4C,5A,6C,7A),(1A,2E,3D,4C,5A,6C,7B),(1A,2E,3-
D,4C,5A,6C,7C),(1A,2E,3D,4C,5A,6D,7A),(1A,2E,3D,4C,5A,6D,7B),(1A,2E,3D,4C,-
5A,6D,7C),(1A,2E,3D,4C,5B,6A,7A),
(1A,2E,3D,4C,5B,6A,7B),(1A,2E,3D,4C,5B,6-
A,7C),(1A,2E,3D,4C,5B,6B,7A),(1A,2E,3D,4C,5B,6B,7B),(1A,2E,3D,4C,5B,6B,7C)-
,(1A,2E,3D,4C,5B,6C,7A),(1A,2E,3D,4C,5B,6C,7B),
(1A,2E,3D,4C,5B,6C,7C),(1A-
,2E,3D,4C,5B,6D,7A),(1A,2E,3D,4C,5B,6D,7B),(1A,2E,3D,4C,5B,6D,7C),(1A,2E,3-
D,4D,5A,6A,7A),(1A,2E,3D,4D,5A,6A,7B),(1A,2E,3D,4D,5A,6A,7C),
(1A,2E,3D,4D,5A,6B,7A),(1A,2E,3D,4D,5A,6B,7B),(1A,2E,3D,4D,5A,6B,7C),(1A,-
2E,3D,4D,5A,6C,7A),(1A,2E,3D,4D,5A,6C,7B),(1A,2E,3D,4D,5A,6C,7C),(1A,2E,3D-
,4D,5A,6D,7A),
(1A,2E,3D,4D,5A,6D,7B),(1A,2E,3D,4D,5A,6D,7C),(1A,2E,3D,4D,-
5B,6A,7A),(1A,2E,3D,4D,5B,6A,7B),(1A,2E,3D,4D,5B,6A,7C),(1A,2E,3D,4D,5B,6B-
,7A),(1A,2E,3D,4D,5B,6B,7B),
(1A,2E,3D,4D,5B,6B,7C),(1A,2E,3D,4D,5B,6C,7A)-
,(1A,2E,3D,4D,5B,6C,7B),(1A,2E,3D,4D,5B,6C,7C),(1A,2E,3D,4D,5B,6D,7A),(1A,-
2E,3D,4D,5B,6D,7B),(1A,2E,3D,4D,5B,6D,7C),
(1A,2E,3D,4E,5A,6A,7A),(1A,2E,3-
D,4E,5A,6A,7B),(1A,2E,3D,4E,5A,6A,7C),(1A,2E,3D,4E,5A,6B,7A),(1A,2E,3D,4E,-
5A,6B,7B),(1A,2E,3D,4E,5A,6B,7C),(1A,2E,3D,4E,5A,6C,7A),
(1A,2E,3D,4E,5A,6C,7B),(1A,2E,3D,4E,5A,6C,7C),(1A,2E,3D,4E,5A,6D,7A),(1A,-
2E,3D,4E,5A,6D,7B),(1A,2E,3D,4E,5A,6D,7C),(1A,2E,3D,4E,5B,6A,7A),(1A,2E,3D-
,4E,5B,6A,7B),
(1A,2E,3D,4E,5B,6A,7C),(1A,2E,3D,4E,5B,6B,7A),(1A,2E,3D,4E,-
5B,6B,7B),(1A,2E,3D,4E,5B,6B,7C),(1A,2E,3D,4E,5B,6C,7A),(1A,2E,3D,4E,5B,6C-
,7B),(1A,2E,3D,4E,5B,6C,7C),
(1A,2E,3D,4E,5B,6D,7A),(1A,2E,3D,4E,5B,6D,7B)-
,(1A,2E,3D,4E,5B,6D,7C),(1A,2E,3E,4A,5A,6A,7A),(1A,2E,3E,4A,5A,6A,7B),(1A,-
2E,3E,4A,5A,6A,7C),(1A,2E,3E,4A,5A,6B,7A),
(1A,2E,3E,4A,5A,6B,7B),(1A,2E,3-
E,4A,5A,6B,7C),(1A,2E,3E,4A,5A,6C,7A),(1A,2E,3E,4A,5A,6C,7B),(1A,2E,3E,4A,-
5A,6C,7C),(1A,2E,3E,4A,5A,6D,7A),(1A,2E,3E,4A,5A,6D,7B),
(1A,2E,3E,4A,5A,6D,7C),(1A,2E,3E,4A,5B,6A,7A),(1A,2E,3E,4A,5B,6A,7B),(1A,-
2E,3E,4A,5B,6A,7C),(1A,2E,3E,4A,5B,6B,7A),(1A,2E,3E,4A,5B,6B,7B),(1A,2E,3E-
,4A,5B,6B,7C),
(1A,2E,3E,4A,5B,6C,7A),(1A,2E,3E,4A,5B,6C,7B),(1A,2E,3E,4A,-
5B,6C,7C),(1A,2E,3E,4A,5B,6D,7A), (1A,2E,3E,4A,5B,6D,7B),
(1A,2E,3E,4A,5B,6D,7C), (1A,2E,3E,4B,5A,6A,7A),
(1A,2E,3E,4B,5A,6A,7B), (1A,2E,3E,4B,5A,6A,7C),
(1A,2E,3E,4B,5A,6B,7A),(1A,2E,3E,4B,5A,6B,7B),
(A,2E,3E,4B,5A,6B,7C),(1A,2E,3E,4B,5A,6C,7A),(1A,2E,3E,4B,5A,6C,7B),
(1A,2E,3E,4B,5A,6C,7C), (1A,2E,3E,4B,5A,6D,7A),
(1A,2E,3E,4B,5A,6D,7B), (1A,2E, 3E,4B,5A,6D,7C),
(1A,2E,3E,4B,5B,6A,7A), (1A,2E,3E,4B,5B,6A,7B),
(1A,2E,3E,4B,5B,6A,7C), (1A,2E,3E,4B,5B,6B,7A),
(1A,2E,3E,4B,5B,6B,7B), (1A,2E,3E,4B,5B,6B,7C),
(1A,2E,3E,4B,5B,6C,7A), (1A,2E,3E,4B,5B,6C,7B),
(1A,2E,3E,4B,5B,6C,7C),(1A,2E,3E,4B,5B,6D,7A),
(1A,2E,3E,4B,5B,6D,7B), (1A,2E,3E,4B,5B,6D,7C),
(1A,2E,3E,4C,5A,6A,7A), (1A,2E,3E,4C,5A,6A,7B),(1-
A,2E,3E,4C,5A,6A,7C),(1A,2E,3E,4C,5A,6B,7A),(1A,2E,3E,4C,5A,6B,7B),
(1A,2E,3E,4C,5A,6B,7C),(1A,2E,3E,4C,5A,6C,7A),(1A,2E,3E,4C,5A,6C,7B),(1A,-
2E,3E,4C,5A,6C,7C),(1A,2E,3E,4C,5A,6D,7A),(1A,2E,3E,4C,5A,6D,7B),(1A,2E,3E-
,4C,5A,6D,7C),
(1A,2E,3E,4C,5B,6A,7A),(1A,2E,3E,4C,5B,6A,7B),(1A,2E,3E,4C,-
5B,6A,7C),(1A,2E,3E,4C,5B,6B,7A),(1A,2E,3E,4C,5B,6B,7B),(1A,2E,3E,4C,5B,6B-
,7C),(1A,2E,3E,4C,5B,6C,7A),
(1A,2E,3E,4C,5B,6C,7B),(1A,2E,3E,4C,5B,6C,7C)-
,(1A,2E,3E,4C,5B,6D,7A),(1A,2E,3E,4C,5B,6D,7B),(1A,2E,3E,4C,5B,6D,7C),(1A,-
2E,3E,4D,5A,6A,7A),(1A,2E,3E,4D,5A,6A,7B),
(1A,2E,3E,4D,5A,6A,7C),(1A,2E,3-
E,4D,5A,6B,7A),(1A,2E,3E,4D,5A,6B,7B),(1A,2E,3E,4D,5A,6B,7C),(1A,2E,3E,4D,-
5A,6C,7A),(1A,2E,3E,4D,5A,6C,7B),(1A,2E,3E,4D,5A,6C,7C),
(1A,2E,3E,4D,5A,6D,7A),(1A,2E,3E,4D,5A,6D,7B),(1A,2E,3E,4D,5A,6D,7C),(1A,-
2E,3E,4D,5B,6A,7A),(1A,2E,3E,4D,5B,6A,7B),(1A,2E,3E,4D,5B,6A,7C),(1A,2E,3E-
,4D,5B,6B,7A),
(1A,2E,3E,4D,5B,6B,7B),(1A,2E,3E,4D,5B,6B,7C),(1A,2E,3E,4D,-
5B,6C,7A), (A,2E,3E,4D,5B,6C,7B), (1A,2E,3E,4D,5B,6C,7C),
(1A,2E,3E,4D,5B,6D,7A), (1A,2E,3E,4D,5B,6D,7B),
(1A,2E,3E,4D,5B,6D,7C), (1A,2E,3E,4E,5A,6A,7A),
(1A,2E,3E,4E,5A,6A,7B), (1A,2E,3E,4E,5A,6A,7C),(1-
A,2E,3E,4E,5A,6B,7A),(1A,2E,3E,4E,5A,6B,7B),(1A,2E,3E,4E,5A,6B,7C),
(1A,2E,3E,4E,5A,6C,7A),(1A,2E,3E,4E,5A,6C,7B),(1A,2E,3E,4E,5A,6C,7C),(1A,-
2E,3E,4E,5A,6D,7A),(1A,2E,3E,4E,5A,6D,7B),(1A,2E,3E,4E,5A,6D,7C),(1A,2E,3E-
,4E,5B,6A,7A),
(1A,2E,3E,4E,5B,6A,7B),(1A,2E,3E,4E,5B,6A,7C),(1A,2E,3E,4E,-
5B,6B,7A),(1A,2E,3E,4E,5B,6B,7B),(1A,2E,3E,4E,5B,6B,7C),(1A,2E,3E,4E,5B,6C-
,7A),(1A,2E,3E,4E,5B,6C,7B),
(1A,2E,3E,4E,5B,6C,7C),(1A,2E,3E,4E,5B,6D,7A)-
,(1A,2E,3E,4E,5B,6D,7B),(1A,2E,3E,4E,5B,6D,7C),(1B,2A,3A,4A,5A,6A,7A),(1B,-
2A,3A,4A,5A,6A,7B),(1B,2A,3A,4A,5A,6A,7C),
(1B,2A,3A,4A,5A,6B,7A),(1B,2A,3-
A,4A,5A,6B,7B),(1B,2A,3A,4A,5A,6B,7C),(1B,2A,3A,4A,5A,6C,7A),(1B,2A,3A,4A,-
5A,6C,7B),(1B,2A,3A,4A,5A,6C,7C),(1B,2A,3A,4A,5A,6D,7A),
(1B,2A,3A,4A,5A,6D,7B),(1B,2A,3A,4A,5A,6D,7C),(1B,2A,3A,4A,5B,6A,7A),(1B,-
2A,3A,4A,5B,6A,7B),(1B,2A,3A,4A,5B,6A,7C),(1B,2A,3A,4A,5B,6B,7A),(1B,2A,3A-
,4A,5B,6B,7B),
(1B,2A,3A,4A,5B,6B,7C),(1B,2A,3A,4A,5B,6C,7A),(1B,2A,3A,4A,-
5B,6C,7B),(1B,2A,3A,4A,5B,6C,7C),(1B,2A,3A,4A,5B,6D)7A),(1B,2A,3A,4A,5B,6D-
,7B),(1B,2A,3A,4A,5B,6D,7C),
(1B,2A,3A,4B,5A,6A,7A),(1B,2A,3A,4B,5A,6A,7B)-
,(1B,2A,3A,4B,5A,6A,7C),(1B,2A,3A,4B,5A,6B,7A),(1B,2A,3A,4B,5A,6B,7B),(1B,-
2A,3A,4B,5A,6B,7C),(1B,2A,3A,4B,5A,6C,7A),
(1B,2A,3A,4B,5A,6C,7B),(1B,2A,3-
A,4B,5A,6C,7C),(1B,2A,3A,4B,5A,6D,7A),(1B,2A,3A,4B,5A,6D,7B),(1B,2A,3A,4B,-
5A,6D,7C),(1B,2A,3A,4B,5B,6A,7A),(1B,2A,3A,4B,5B,6A,7B),
(1B,2A,3A,4B,5B,6A,7C),(1B,2A,3A,4B,5B,6B,7A),(1B,2A,3A,4B,5B,6B,7B),(1B,-
2A,3A,4B,5B,6B,7C),(1B,2A,3A,4B,5B,6C,7A),(1B,2A,3A,4B,5B,6C,7B),(1B,2A,3A-
,4B,5B,6C,7C),
(1B,2A,3A,4B,5B,6D,7A),(1B,2A,3A,4B,5B,6D,7B),(1B,2A,3A,4B,-
5B,6D,7C),(1B,2A,3A,4C,5A,6A,7A),(1B,2A,3A,4C,5A,6A,7B),(1B,2A,3A,4C,5A,6A-
,7C),(1B,2A,3A,4C,5A,6B,7A),
(1B,2A,3A,4C,5A,6B,7B),(1B,2A,3A,4C,5A,6B,7C)-
,(1B,2A,3A,4C,5A,6C,7A),(1B,2A,3A,4C,5A,6C,7B),(1B,2A,3A,4C,5A,6C,7C),(1B,-
2A,3A,4C,5A,6D,7A),(1B,2A,3A,4C,5A,6D,7B),
(1B,2A,3A,4C,5A,6D,7C),(1B,2A,3-
A,4C,5B,6A,7A),(1B,2A,3A,4C,5B,6A,7B),(1B,2A,3A,4C,5B,6A,7C),(1B,2A,3A,4C,-
5B,6B,7A),(1B,2A,3A,4C,5B,6B,7B),(1B,2A,3A,4C,5B,6B,7C),
(1B,2A,3A,4C,5B,6C,7A),(1B,2A,3A,4C,5B,6C,7B),(1B,2A,3A,4C,5B,6C,7C),(1B,-
2A,3A,4C,5B,6D,7A),(1B,2A,3A,4C,5B,6D,7B),(1B,2A,3A,4C,5B,6D,7C),(1B,2A,3A-
,4D,5A,6A,7A),
(1B,2A,3A,4D,5A,6A,7B),(1B,2A,3A,4D,5A,6A,7C),(1B,2A,3A,4D,-
5A,6B,7A),(1B,2A,3A,4D,5A,6B,7B),(1B,2A,3A,4D,5A,6B,7C),(1B,2A,3A,4D,5A,6C-
,7A),(1B,2A,3A,4D,5A,6C,7B),
(1B,2A,3A,4D,5A,6C,7C),(1B,2A,3A,4D,5A,6D,7A)-
,(1B,2A,3A,4D,5A,6D,7B),(1B,2A,3A,4D,5A,6D,7C),(1B,2A,3A,4D,5B,6A,7A),(1B,-
2A,3A,4D,5B,6A,7B),(1B,2A,3A,4D,5B,6A,7C),
(1B,2A,3A,4D,5B,6B,7A),(1B,2A,3-
A,4D,5B,6B,7B),(1B,2A,3A,4D,5B,6B,7C),(1B,2A,3A,4D,5B,6C,7A),(1B,2A,3A,4D,-
5B,6C,7B),(1B,2A,3A,4D,5B,6C,7C),(1B,2A,3A,4D,5B,6D,7A),
(1B,2A,3A,4D,5B,6D,7B),(1B,2A,3A,4D,5B,6D,7C),(1B,2A,3A,4E,5A,6A,7A),(1B,-
2A,3A,4E,5A,6A,7B),(1B,2A,3A,4E,5A,6A,7C),(1B,2A,3A,4E,5A,6B,7A),(1B,2A,3A-
,4E,5A,6B,7B),
(1B,2A,3A,4E,5A,6B,7C),(1B,2A,3A,4E,5A,6C,7A),(1B,2A,3A,4E,-
5A,6C,7B),(1B,2A,3A,4E,5A,6C,7C),(1B,2A,3A,4E,5A,6D,7A),(1B,2A,3A,4E,5A,6D-
,7B),(1B,2A,3A,4E,5A,6D,7C),
(1B,2A,3A,4E,5B,6A,7A),(1B,2A,3A,4E,5B,6A,7B)-
,(1B,2A,3A,4E,5B,6A,7C),(1B,2A,3A,4E,5B,6B,7A),(1B,2A,3A,4E,5B,6B,7B),(1B,-
2A,3A,4E,5B,6B,7C),(1B,2A,3A,4E,5B,6C,7A),
(1B,2A,3A,4E,5B,6C,7B),(1B,2A,3-
A,4E,5B,6C,7C),(1B,2A,3A,4E,5B,6D,7A),(1B,2A,3A,4E,5B,6D,7B),(1B,2A,3A,4E,-
5B,6D,7C),(1B,2A,3B,4A,5A,6A,7A),(1B,2A,3B,4A,5A,6A,7B),
(1B,2A,3B,4A,5A,6A,7C),(1B,2A,3B,4A,5A,6B,7A),(1B,2A,3B,4A,5A,6B,7B),(1B,-
2A,3B,4A,5A,6B,7C),(1B,2A,3B,4A,5A,6C,7A),(1B,2A,3B,4A,5A,6C,7B),(1B,2A,3B-
,4A,5A,6C,7C),
(1B,2A,3B,4A,5A,6D,7A),(1B,2A,3B,4A,5A,6D,7B),(1B,2A,3B,4A,-
5A,6D,7C),(1B,2A,3B,4A,5B,6A,7A),(1B,2A,3B,4A,5B,6A,7B),(1B,2A,3B,4A,5B,6A-
,7C),(1B,2A,3B,4A,5B,6B,7A),
(1B,2A,3B,4A,5B,6B,7B),(1B,2A,3B,4A,5B,6B,7C)-
,(1B,2A,3B,4A,5B,6C,7A),(1B,2A,3B,4A,5B,6C,7B),(1B,2A,3B,4A,5B,6C,7C),(1B,-
2A,3B,4A,5B,6D,7A),(1B,2A,3B,4A,5B,6D,7B),
(1B,2A,3B,4A,5B,6D,7C),(1B,2A,3-
B,4B,5A,6A,7A),(1B,2A,3B,4B,5A,6A,7B),(1B,2A,3B,4B,5A,6A,7C),(1B,2A,3B,4B,-
5A,6B,7A),(1B,2A,3B,4B,5A,6B,7B),(1B,2A,3B,4B,5A,6B,7C),
(1B,2A,3B,4B,5A,6C,7A),(1B,2A,3B,4B,5A,6C,7B),(1B,2A,3B,4B,5A,6C,7C),(1B,-
2A,3B,4B,5A,6D,7A),(1B,2A,3B,4B,5A,6D,7B),(1B,2A,3B,4B,5A,6D,7C),(1B,2A,3B-
,4B,5B,6A,7A),
(1B,2A,3B,4B,5B,6A,7B),(1B,2A,3B,4B,5B,6A,7C),(1B,2A,3B,4B,-
5B,6B,7A),(1B,2A,3B,4B,5B,6B,7B),(1B,2A,3B,4B,5B,6B,7C),(1B,2A,3B,4B,5B,6C-
,7A),(1B,2A,3B,4B,5B,6C,7B),
(1B,2A,3B,4B,5B,6C,7C),(1B,2A,3B,4B,5B,6D,7A)-
,(1B,2A,3B,4B,5B,6D,7B),(1B,2A,3B,4B,5B,6D,7C),(1B,2A,3B,4C,5A,6A,7A),(1B,-
2A,3B,4C,5A,6A,7B),(1B,2A,3B,4C,5A,6A,7C),
(1B,2A,3B,4C,5A,6B,7A),(1B,2A,3-
B,4C,5A,6B,7B),(1B,2A,3B,4C,5A,6B,7C),(1B,2A,3B,4C,5A,6C,7A),(1B,2A,3B,4C,-
5A,6C,7B),(1B,2A,3B,4C,5A,6C,7C),(1B,2A,3B,4C,5A,6D,7A),
(1B,2A,3B,4C,5A,6D,7B),(1B,2A,3B,4C,5A,6D,7C),(1B,2A,3B,4C,5B,6A,7A),(1B,-
2A,3B,4C,5B,6A,7B),(1B,2A,3B,4C,5B,6A,7C),(1B,2A,3B,4C,5B,6B,7A),(1B,2A,3B-
,4C,5B,6B,7B),
(1B,2A,3B,4C,5B,6B,7C),(1B,2A,3B,4C,5B,6C,7A),(1B,2A,3B,4C,-
5B,6C,7B),(1B,2A,3B,4C,5B,6C,7C),(1B,2A,3B,4C,5B,6D,7A),(1B,2A,3B,4C,5B,6D-
,7B),(1B,2A,3B,4C,5B,6D,7C),
(1B,2A,3B,4D,5A,6A,7A),(1B,2A,3B,4D,5A,6A,7B)-
,(1B,2A,3B,4D,5A,6A,7C),(1B,2A,3B,4D,5A,6B,7A),(1B,2A,3B,4D,5A,6B,7B),(1B,-
2A,3B,4D,5A,6B,7C),(1B,2A,3B,4D,5A,6C,7A),
(1B,2A,3B,4D,5A,6C,7B),(1B,2A,3-
B,4D,5A,6C,7C),(1B,2A,3B,4D,5A,6D,7A),(1B,2A,3B,4D,5A,6D,7B),(1B,2A,3B,4D,-
5A,6D,7C),(1B,2A,3B,4D,5B,6A,7A),(1B,2A,3B,4D,5B,6A,7B),
(1B,2A,3B,4D,5B,6A,7C),(1B,2A,3B,4D,5B,6B,7A),(1B,2A,3B,4D,5B,6B,7B),(1B,-
2A,3B,4D,5B,6B,7C),(1B,2A,3B,4D,5B,6C,7A),(1B,2A,3B,4D,5B,6C,7B),(1B,2A,3B-
,4D,5B,6C,7C),
(1B,2A,3B,4D,5B,6D,7A),(1B,2A,3B,4D,5B,6D,7B),(1B,2A,3B,4D,-
5B,6D,7C),(1B,2A,3B,4E,5A,6A,7A),(1B,2A,3B,4E,5A,6A,7B),(1B,2A,3B,4E,5A,6A-
,7C),(1B,2A,3B,4E,5A,6B,7A),
(1B,2A,3B,4E,5A,6B,7B),(1B,2A,3B,4E,5A,6B,7C)-
,(1B,2A,3B,4E,5A,6C,7A),(1B,2A,3B,4E,5A,6C,7B),(1B,2A,3B,4E,5A,6C,7C),(1B,-
2A,3B,4E,5A,6D,7A),(1B,2A,3B,4E,5A,6D,7B),
(1B,2A,3B,4E,5A,6D,7C),(1B,2A,3-
B,4E,5B,6A,7A),(1B,2A,3B,4E,5B,6A,7B),(1B,2A,3B,4E,5B,6A,7C),(1B,2A,3B,4E,-
5B,6B,7A),(1B,2A,3B,4E,5B,6B,7B),(1B,2A,3B,4E,5B,6B,7C),
(1B,2A,3B,4E,5B,6C,7A),(1B,2A,3B,4E,5B,6C,7B),(1B,2A,3B,4E,5B,6C,7C),(1B,-
2A,3B,4E,5B,6D,7A),(1B,2A,3B,4E,5B,6D,7B),(1B,2A,3B,4E,5B,6D,7C),(1B,2A,3C-
,4A,5A,6A,7A),
(1B,2A,3C,4A,5A,6A,7B),(1B,2A,3C,4A,5A,6A,7C),(1B,2A,3C,4A,-
5A,6B,7A),(1B,2A,3C,4A,5A,6B,7B),(1B,2A,3C,4A,5A,6B,7C),(1B,2A,3C,4A,5A,6C-
,7A),(1B,2A,3C,4A,5A,6C,7B),
(1B,2A,3C,4A,5A,6C,7C),(1B,2A,3C,4A,5A,6D,7A)-
,(1B,2A,3C,4A,5A,6D,7B),(1B,2A,3C,4A,5A,6D,7C),(1B,2A,3C,4A,5B,6A,7A),(1B,-
2A,3C,4A,5B,6A,7B),(1B,2A,3C,4A,5B,6A,7C),
(1B,2A,3C,4A,5B,6B,7A),(1B,2A,3-
C,4A,5B,6B,7B),(1B,2A,3C,4A,5B,6B,7C),(1B,2A,3C,4A,5B,6C,7A),(1B,2A,3C,4A,-
5B,6C,7B),(1B,2A,3C,4A,5B,6C,7C),(1B,2A,3C,4A,5B,6D,7A),
(1B,2A,3C,4A,5B,6D,7B),(1B,2A,3C,4A,5B,6D,7C),(1B,2A,3C,4B,5A,6A,7A),(1B,-
2A,3C,4B,5A,6A,7B),(1B,2A,3C,4B,5A,6A,7C),(1B,2A,3C,4B,5A,6B,7A),(1B,2A,3C-
,4B,5A,6B,7B),
(1B,2A,3C,4B,5A,6B,7C),(1B,2A,3C,4B,5A,6C,7A),(1B,2A,3C,4B,-
5A,6C,7B),(1B,2A,3C,4B,5A,6C,7C),(1B,2A,3C,4B,5A,6D,7A),(1B,2A,3C,4B,5A,6D-
,7B),(1B,2A,3C,4B,5A,6D,7C),
(1B,2A,3C,4B,5B,6A,7A),(1B,2A,3C,4B,5B,6A,7B)-
,(1B,2A,3C,4B,5B,6A,7C),(1B,2A,3C,4B,5B,6B,7A),(1B,2A,3C,4B,5B,6B,7B),(1B,-
2A,3C,4B,5B,6B,7C),(1B,2A,3C,4B,5B,6C,7A),
(1B,2A,3C,4B,5B,6C,7B),(1B,2A,3-
C,4B,5B,6C,7C),(1B,2A,3C,4B,5B,6D,7A),(1B,2A,3C,4B,5B,6D,7B),(1B,2A,3C,4B,-
5B,6D,7C),(1B,2A,3C,4C,5A,6A,7A),(1B,2A,3C,4C,5A,6A,7B),
(1B,2A,3C,4C,5A,6A,7C),(1B,2A,3C,4C,5A,6B,7A),(1B,2A,3C,4C,5A,6B,7B),(1B,-
2A,3C,4C,5A,6B,7C),(1B,2A,3C,4C,5A,6C,7A),(1B,2A,3C,4C,5A,6C,7B),(1B,2A,3C-
,4C,5A,6C,7C),
(1B,2A,3C,4C,5A,6D,7A),(1B,2A,3C,4C,5A,6D,7B),(1B,2A,3C,4C,-
5A,6D,7C),(1B,2A,3C,4C,5B,6A,7A),(1B,2A,3C,4C,5B,6A,7B),(1B,2A,3C,4C,5B,6A-
,7C),(1B,2A,3C,4C,5B,6B,7A),
(1B,2A,3C,4C,5B,6B,7B),(1B,2A,3C,4C,5B,6B,7C)-
,(1B,2A,3C,4C,5B,6C,7A),(1B,2A,3C,4C,5B,6C,7B),(1B,2A,3C,4C,5B,6C,7C),(1B,-
2A,3C,4C,5B,6D,7A),(1B,2A,3C,4C,5B,6D,7B),
(1B,2A,3C,4C,5B,6D,7C),(1B,2A,3-
C,4D,5A,6A,7A),(1B,2A,3C,4D,5A,6A,7B),(1B,2A,3C,4D,5A,6A,7C),(1B,2A,3C,4D,-
5A,6B,7A),(1B,2A,3C,4D,5A,6B,7B),(1B,2A,3C,4D,5A,6B,7C),
(1B,2A,3C,4D,5A,6C,7A),(1B,2A,3C,4D,5A,6C,7B),(1B,2A,3C,4D,5A,6C,7C),(1B,-
2A,3C,4D,5A,6D,7A),(1B,2A,3C,4D,5A,6D,7B),
(1B,2A,3C,4D,5A,6D,7C),(1B,2A,3- C,4D,5B,6A,7A),
(1B,2A,3C,4D,5B,6A,7B), (1B,2A,3C,4D,5B,6A,7C),
(1B,2A,3C,4D,5B,6B,7A), (1B,2A,3C,4D,5B,6B,7B),
(1B,2A,3C,4D,5B,6B,7C),(1-
B,2A,3C,4D,5B,6C,7A),(1B,2A,3C,4D,5B,6C,7B),
(1B,2A,3C,4D,5B,6C,7C), (1B,2A,3C,4D,5B,6D,7A),
(1B,2A,3C,4D,5B,6D,7B), (1B,2A,3C,4D,5B,6D,7C),
(1B,2A,3C,4E,5A,6A,7A), (1B,2A,3C,4E,5A,6A,7B),
(1B,2A,3C,4E,5A,6A,7C), (1B,2A,3C,4E,5A,6B,7A),
(1B,2A,3C,4E,5A,6B,7B), (1B,2A,3C,4E,5A,6B,7C),
(1B,2A,3C,4E,5A,6C,7A), (1B,2A,3C,4E,5A,6C,7B),
(1B,2A,3C,4E,5A,6C,7C),(1- B,2A,3C,4E,5A,6D,7A),
(1B,2A,3C,4E,5A,6D,7B), (B,2A,3C,4E,5A,6D,7C), (1B,2A,3C,4E,5B,6A,
7A), (1B,2A,3C,4E,5B,6A,7B),(1B,2A,3C,4E,5B,6A,7C),
(1B,2A,3C,4E,5B,6B,7A),(1B,2A,3C,4E,5B,6B,7B),
(1B,2A,3C,4E,5B,6B,7C),(1B- ,2A,3C,4E,5B,6C,7A),
(1B,2A,3C,4E,5B,6C,7B),(1B,2A,3C,4E,5B,6C,7C),(1B,2A,-
3C,4E,5B,6D,7A),(1B,2A,3C,4E,5B,6D,7B),(1B,2A,3C,4E,5B,6D,7C),
(1B,2A,3D,4A,5A,6A,7A), (1B,2A,3D,4A,5A,6A,7B),
(1B,2A,3D,4A,5A,6A,7C),(1- B,2A,3D,4A,5A,6B,7A),
(1B,2A,3D,4A,5A,6B, 7B), (1B,2A,3D,4A,5A,6B,7C),(1B,-
2A,3D,4A,5A,6C,7A), (1B,2A,3D,4A,5A,6C,7B), (1B,2A,3D,4A,5A,6C,7C),
(1B,2A,3D,4A,5A,6D,7A), (1B,2A,3D,4A,5A,6D,7B),
(1B,2A,3D,4A,5A,6D,7C),(1-
B,2A,3D,4A,5B,6A,7A),(1B,2A,3D,4A,5B,6A,7B),
<1B,2A,3D,4A,5B,6A,7C), (1B,2A,3D,4A,5B,6B,7A),
(1B,2A,3D,4A,5B,6B, 7B),(1B,2A,3D,4A,5B,6B,7C),
(1B,2A,3D,4A,5B,6C,7A),(1B,2A,3D,4A,5B,6C,7B),(1B,2A,3D,4A,5B,6C,7C),
(1B,2A,3D,4A,5B,6D,7A),
(1B,2A,3D,4A,5B,6D,7B),(1B,2A,3D,4A,5B,6D,7C),
(1B,2A,3D,4B,5A,6A,7A),
(1B,2A,3D,4B,5A,6A,7B),(1B,2A,3D,4B,5A,6A,7C),(1B-
,2A,3D,4B,5A,6B,7A), (1B,2A,3D,4B,5A,6B,7B),
(1B,2A,3D,4B,5A,6B,7C), (1B,2A,3D,4B,5A,6C,7A), (1B,2A,3D,4B,5A,6C,
7B), (1B,2A,3D,4B,5A,6C,7C),(-
1B,2A,3D,4B,5A,6D,7A),(1B,2A,3D,4B,5A,6D,7B),
(1B,2A,3D,4B,5A,6D,7C),(1B,2-
A,3D,4B,5B,6A,7A),(1B,2A,3D,4B,5B,6A,7B), (1B,2A,3D,4B,5B,6A,7C),
(1B,2A,3D,4B,5B,6B,7A),(1B,2A,3D,4B,5B,6B,7B),(1B,2A,3D,4B,5B,6B,7C),
(1B,2A,3D,4B,5B,6C,7A), (1B,2A,3D,4B,5B,6C,7B),
(1B,2A,3D,4B,5B,6C,7C), (1B,2A,3D,4B,5B,6D,7A),
(1B,2A,3D,4B,5B,6D,7B),(1B,2A,3D,4B,5B,6D,7C),(1B-
,2A,3D,4C,5A,6A,7A),
(1B,2A,3D,4C,5A,6A,7B),(1B,2A,3D,4C,5A,6A,7C),(1B,2A,-
3D,4C,5A,6B,7A),(1B,2A,3D,4C,5A,6B,7B),(1B,2A,3D,4C,5A,6B,7C),(1B,2A,3D,4C-
,5A,6C,7A),(1B,2A,3D,4C,5A,6C,7B),
(1B,2A,3D,4C,5A,6C,7C),(1B,2A,3D,4C,5A,-
6D,7A),(1B,2A,3D,4C,5A,6D,7B),(1B,2A,3D,4C,5A,6D,7C),(1B,2A,3D,4C,5B,6A,7A-
),(1B,2A,3D,4C,5B,6A,7B),(1B,2A,3D,4C,5B,6A,7C),
(1B,2A,3D,4C,5B,6B,7A),(1-
B,2A,3D,4C,5B,6B,7B),(1B,2A,3D,4C,5B,6B,7C),(1B,2A,3D,4C,5B,6C,7A),-(1B,2A-
,3D,4C,5B,6C,7B),(1B,2A,3D,4C,5B,6C,7C), (1B,2A,3D,4C,5B,6D,7A),
(1B,2A,3D,4C,5B,6D,7B), (1B,2A,3D,4C,5B,6D,7C),
(1B,2A,3D,4D,5A,6A,7A),
(1B,2A,3D,4D,5A,6A,7B),(1B,2A,3D,4D,5A,6A,7C),(1B,2A,3D,4D,5A,6B,7A),(1B,-
2A,3D,4D,5A,6B,7B),
(1B,2A,3D,4D,5A,6B,7C),(1B,2A,3D,4D,5A,6C,7A),(1B,2A,3-
D,4D,5A,6C,7B),(1B,2A,3D,4D,5A,6C,7C),(1B,2A,3D,4D,5A,6D,7A),(1B,2A,3D,4D,-
5A,6D,7B),(1B,2A,3D,4D,5A,6D,7C),
(1B,2A,3D,4D,5B,6A,7A),(1B,2A,3D,4D,5B,6-
A,7B),(1B,2A,3D,4D,5B,6A,7C),(1B,2A,3D,4D,5B,6B,7A),(1B,2A,3D,4D,5B,6B,7B)-
,(1B,2A,3D,4D,5B,6B,7C),(1B,2A,3D,4D,5B,6C,7A),
(1B,2A,3D,4D,5B,6C,7B),(1B-
,2A,3D,4D,5B,6C,7C),(1B,2A,3D,4D,5B,6D,7A),(1B,2A,3D,4D,5B,6D,7B),(1B,2A,3-
D,4D,5B,6D,7C),(1B,2A,3D,4E,5A,6A,7A),(1B,2A,3D,4E,5A,6A,7B),
(1B,2A,3D,4E,5A,6A,7C),(1B,2A,3D,4E,5A,6B,7A),(1B,2A,3D,4E,5A,6B,7B),(1B,-
2A,3D,4E,5A,6B,7C),(1B,2A,3D,4E,5A,6C,7A),(1B,2A,3D,4E,5A,6C,7B),(1B,2A,3D-
,4E,5A,6C,7C),
(1B,2A,3D,4E,5A,6D,7A),(1B,2A,3D,4E,5A,6D,7B),(1B,2A,3D,4E,-
5A,6D,7C),(1B,2A,3D,4E,5B,6A,7A),(1B,2A,3D,4E,5B,6A,7B),(1B,2A,3D,4E,5B,6A-
,7C),(1B,2A,3D,4E,5B,6B,7A),
(1B,2A,3D,4E,5B,6B,7B),(1B,2A,3D,4E,5B,6B,7C)-
,(1B,2A,3D,4E,5B,6C,7A),(1B,2A,3D,4E,5B,6C,7B),(1B,2A,3D,4E,5B,6C,7C),
(1B,2A,3D,4E,5B,6D,7A),(1B,2A,3D,4E,5B,6D,7B),
(1B,2A,3D,4E,5B,6D,7C),(1B-
,2A,3E,4A,5A,6A,7A),(1B,2A,3E,4A,5A,6A,7B),(1B,2A,3E,4A,5A,6A,7C),(1B,2A,3-
E,4A,5A,6B,7A),(1B,2A,3E,4A,5A,6B,7B),(1B,2A,3E,4A,5A,6B,7C),
(1B,2A,3E,4A,5A,6C,7A),(1B,2A,3E,4A,5A,6C,7B),(1B,2A,3E,4A,5A,6C,7C),(1B,-
2A,3E,4A,5A,6D,7A),(1B,2A,3E,4A,5A,6D,7B),(1B,2A,3E,4A,5A,6D,7C),(1B,2A,3E-
,4A,5B,6A,7A),
(1B,2A,3E,4A,5B,6A,7B),(1B,2A,3E,4A,5B,6A,7C),(1B,2A,3E,4A,-
5B,6B,7A),(1B,2A,3E,4A,5B,6B,7B),(1B,2A,3E,4A,5B,6B,7C),(1B,2A,3E,4A,5B,6C-
,7A),(1B,2A,3E,4A,5B,6C,7B),
(1B,2A,3E,4A,5B,6C,7C),(1B,2A,3E,4A,5B,6D,7A)-
,(1B,2A,3E,4A,5B,6D,7B),(1B,2A,3E,4A,5B,6D,7C),(1B,2A,3E,4B,5A,6A,7A),(1B,-
2A,3E,4B,5A,6A,7B),(1B,2A,3E,4B,5A,6A,7C),
(1B,2A,3E,4B,5A,6B,7A),(1B,2A,3-
E,4B,5A,6B,7B),(1B,2A,3E,4B,5A,6B,7C),(1B,2A,3E,4B,5A,6C,7A),(1B,2A,3E,4B,-
5A,6C,7B),(1B,2A,3E,4B,5A,6C,7C),(1B,2A,3E,4B,5A,6D,7A),
(1B,2A,3E,4B,5A,6D,7B),(1B,2A,3E,4B,5A,6D,7C),(1B,2A,3E,4B,5B,6A,7A),(1B,-
2A,3E,4B,5B,6A,7B),(1B,2A,3E,4B,5B,6A,7C),(1B,2A,3E,4B,5B,6B,7A),(1B,2A,3E-
,4B,5B,6B,7B),
(1B,2A,3E,4B,5B,6B,7C),(1B,2A,3E,4B,5B,6C,7A),(1B,2A,3E,4B,-
5B,6C,7B),(1B,2A,3E,4B,5B,6C,7C),(1B,2A,3E,4B,5B,6D,7A),(1B,2A,3E,4B,5B,6D-
,7B),(1B,2A,3E,4B,5B,6D,7C),
(1B,2A,3E,4C,5A,6A,7A),(1B,2A,3E,4C,5A,6A,7B)-
,(1B,2A,3E,4C,5A,6A,7C),(1B,2A,3E,4C,5A,6B,7A),
(1B,2A,3E,4C,5A,6B,7B),(1B-
,2A,3E,4C,5A,6B,7C),(1B,2A,3E,4C,5A,6C,7A),
(1B,2A,3E,4C,5A,6C,7B),(1B,2A,-
3E,4C,5A,6C,7C),(1B,2A,3E,4C,5A,6D,7A),(1B,2A,3E,4C,5A,6D,7B),(1B,2A,3E,4C-
,5A,6D,7C),(1B,2A,3E,4C,5B,6A,7A),(1B,2A,3E,4C,5B,6A,7B),
(1B,2A,3E,4C,5B,6A,7C),(1B,2A,3E,4C,5B,6B,7A),(1B,2A,3E,4C,5B,6B,7B),(1B,-
2A,3E,4C,5B,6B,7C),(1B,2A,3E,4C,5B,6C,7A),(1B,2A,3E,4C,5B,6C,7B),(1B,2A,3E-
,4C,5B,6C,7C),
(1B,2A,3E,4C,5B,6D,7A),(1B,2A,3E,4C,5B,6D,7B),(1B,2A,3E,4C,-
5B,6D,7C),(1B,2A,3E,4D,5A,6A,7A),(1B,2A,3E,4D,5A,6A,7B),(1B,2A,3E,4D,5A,6A-
,7C),(1B,2A,3E,4D,5A,6B,7A),
(1B,2A,3E,4D,5A,6B,7B),(1B,2A,3E,4D,5A,6B,7C)-
,(1B,2A,3E,4D,5A,6C,7A),(1B,2A,3E,4D,5A,6C,7B),(1B,2A,3E,4D,5A,6C,7C),(1B,-
2A,3E,4D,5A,6D,7A),(1B,2A,3E,4D,5A,6D,7B),
(1B,2A,3E,4D,5A,6D,7C),(1B,2A,3-
E,4D,5B,6A,7A),(1B,2A,3E,4D,5B,6A,7B),(1B,2A,3E,4D,5B,6A,7C),(1B,2A,3E,4D,-
5B,6B,7A),(1B,2A,3E,4D,5B,6B,7B),(1B,2A,3E,4D,5B,6B,7C),
(1B,2A,3E,4D,5B,6C,7A),(1B,2A,3E,4D,5B,6C,7B),(1B,2A,3E,4D,5B,6C,7C),(1B,-
2A,3E,4D,5B,6D,7A),(1B,2A,3E,4D,5B,6D,7B),(1B,2A,3E,4D,5B,6D,7C),(1B,2A,3E-
,4E,5A,6A,7A),
(1B,2A,3E,4E,5A,6A,7B),(1B,2A,3E,4E,5A,6A,7C),(1B,2A,3E,4E,-
5A,6B,7A),(1B,2A,3E,4E,5A,6B,7B),(1B,2A,3E,4E,5A,6B,7C),(1B,2A,3E,4E,5A,6C-
,7A),(1B,2A,3E,4E,5A,6C,7B),
(1B,2A,3E,4E,5A,6C,7C),(1B,2A,3E,4E,5A,6D,7A)-
,(1B,2A,3E,4E,5A,6D,7B),(1B,2A,3E,4E,5A,6D,7C),(1B,2A,3E,4E,5B,6A,7A),(1B,-
2A,3E,4E,5B,6A,7B),(1B,2A,3E,4E,5B,6A,7C),
(1B,2A,3E,4E,5B,6B,7A),(1B,2A,3-
E,4E,5B,6B,7B),(1B,2A,3E,4E,5B,6B,7C),(1B,2A,3E,4E,5B,6C,7A),(1B,2A,3E,4E,-
5B,6C,7B),(1B,2A,3E,4E,5B,6C,7C),(1B,2A,3E,4E,5B,6D,7A),
(1B,2A,3E,4E,5B,6D,7B),(1B,2A,3E,4E,5B,6D,7C),(1B,2B,3A,4A,5A,6A,7A),(1B,-
2B,3A,4A,5A,6A,7B),(1B,2B,3A,4A,5A,6A,7C),(1B,2B,3A,4A,5A,6B,7A),(1B,2B,3A-
,4A,5A,6B,7B),
(1B,2B,3A,4A,5A,6B,7C),(1B,2B,3A,4A,5A,6C,7A),(1B,2B,3A,4A,-
5A,6C,7B),(1B,2B,3A,4A,5A,6C,7C),(1B,2B,3A,4A,5A,6D,7A),(1B,2B,3A,4A,5A,6D-
,7B),(1B,2B,3A,4A,5A,6D,7C),
(1B,2B,3A,4A,5B,6A,7A),(1B,2B,3A,4A,5B,6A,7B)-
,(1B,2B,3A,4A,5B,6A,7C),(1B,2B,3A,4A,5B,6B,7A),(1B,2B,3A,4A,5B,6B,7B),(1B,-
2B,3A,4A,5B,6B,7C),(1B,2B,3A,4A,5B,6C,7A),
(1B,2B,3A,4A,5B,6C,7B),(1B,2B,3-
A,4A,5B,6C,7C),(1B,2B,3A,4A,5B,6D,7A),(1B,2B,3A,4A,5B,6D,7B),(1B,2B,3A,4A,-
5B,6D,7C),(1B,2B,3A,4B,5A,6A,7A),(1B,2B,3A,4B,5A,6A,7B),
(1B,2B,3A,4B,5A,6A,7C),(1B,2B,3A,4B,5A,6B,7A),(1B,2B,3A,4B,5A,6B,7B),(1B,-
2B,3A,4B,5A,6B,7C),(1B,2B,3A,4B,5A,6C,7A),(1B,2B,3A,4B,5A,6C,7B),(1B,2B,3A-
,4B,5A,6C,7C),
(1B,2B,3A,4B,5A,6D,7A),(1B,2B,3A,4B,5A,6D,7B),(1B,2B,3A,4B,-
5A,6D,7C),(1B,2B,3A,4B,5B,6A,7A),(1B,2B,3A,4B,5B,6A,7B),
(1B,2B,3A,4B,5B,6A,7C),(1B,2B,3A,4B,5B,6B,7A),
(1B,2B,3A,4B,5B,6B,7B), (1B,2B,3A,4B,5B,6B,7C),
(1B,2B,3A,4B,5B,6C,7A), (1B,2B,3A,4B,5B,6C,7B),
(1B,2B,3A,4B,5B,6C,7C),(1B,2B,3A,4B,5B,6D,7A),(1B,2B,3A,4B,5B,6D,7B),
(1B,2B,3A,4B,5B,6D,7C),(1B,2B,3A,4C,5A,6A,7A),(1B,2B,3A,4C,5A,6A,7B),(1B,-
2B,3A,4C,5A,6A,7C),(1B,2B,3A,4C,5A,6B,7A),(1B,2B,3A,4C,5A,6B,7B),(1B,2B,3A-
,4C,5A,6B,7C),
(1B,2B,3A,4C,5A,6C,7A),(1B,2B,3A,4C,5A,6C,7B),(1B,2B,3A,4C,-
5A,6C,7C),(1B,2B,3A,4C,5A,6D,7A),(1B,2B,3A,4C,5A,6D,7B),(1B,2B,3A,4C,5A,6D-
,7C),(1B,2B,3A,4C,5B,6A,7A),
(1B,2B,3A,4C,5B,6A,7B),(1B,2B,3A,4C,5B,6A,7C)-
,(1B,2B,3A,4C,5B,6B,7A),(1B,2B,3A,4C,5B,6B,7B),(1B,2B,3A,4C,5B,6B,7C),(1B,-
2B,3A,4C,5B,6C,7A),(1B,2B,3A,4C,5B,6C,7B),
(1B,2B,3A,4C,5B,6C,7C),(1B,2B,3-
A,4C,5B,6D,7A),(1B,2B,3A,4C,5B,6D,7B),(1B,2B,3A,4C,5B,6D,7C),(1B,2B,3A,4D,-
5A,6A,7A),(1B,2B,3A,4D,5A,6A,7B),(1B,2B,3A,4D,5A,6A,7C),
(1B,2B,3A,4D,5A,6B,7A),(1B,2B,3A,4D,5A,6B,7B),(1B,2B,3A,4D,5A,6B,7C),(1B,-
2B,3A,4D,5A,6C,7A),(1B,2B,3A,4D,5A,6C,7B),(1B,2B,3A,4D,5A,6C,7C),(1B,2B,3A-
,4D,5A,6D,7A),
(1B,2B,3A,4D,5A,6D,7B),(1B,2B,3A,4D,5A,6D,7C),(1B,2B,3A,4D,-
5B,6A,7A),(1B,2B,3A,4D,5B,6A,7B),(1B,2B,3A,4D,5B,6A,7C),(1B,2B,3A,4D,5B,6B-
,7A),(1B,2B,3A,4D,5B,6B,7B),
(1B,2B,3A,4D,5B,6B,7C),(1B,2B,3A,4D,5B,6C,7A)-
,(1B,2B,3A,4D,5B,6C,7B),(1B,2B,3A,4D,5B,6C,7C),(1B,2B,3A,4D,5B,6D,7A),(1B,-
2B,3A,4D,5B,6D,7B),(1B,2B,3A,4D,5B,6D,7C),
(1B,2B,3A,4E,5A,6A,7A),(1B,2B,3-
A,4E,5A,6A,7B),(1B,2B,3A,4E,5A,6A,7C),(1B,2B,3A,4E,5A,6B,7A),(1B,2B,3A,4E,-
5A,6B,7B),(1B,2B,3A,4E,5A,6B,7C),(1B,2B,3A,4E,5A,6C,7A),
(1B,2B,3A,4E,5A,6C,7B),(1B,2B,3A,4E,5A,6C,7C),(1B,2B,3A,4E,5A,6D,7A),(1B,-
2B,3A,4E,5A,6D,7B),(1B,2B,3A,4E,5A,6D,7C),(1B,2B,3A,4E,5B,6A,7A),(1B,2B,3A-
,4E,5B,6A,7B),
(1B,2B,3A,4E,5B,6A,7C),(1B,2B,3A,4E,5B,6B,7A),(1B,2B,3A,4E,-
5B,6B,7B),(1B,2B,3A,4E,5B,6B,7C),(1B,2B,3A,4E,5B,6C,7A),(1B,2B,3A,4E,5B,6C-
,7B),(1B,2B,3A,4E,5B,6C,7C),
(1B,2B,3A,4E,5B,6D,7A),(1B,2B,3A,4E,5B,6D,7B)-
,(1B,2B,3A,4E,5B,6D,7C),(1B,2B,3B,4A,5A,6A,7A),(1B,2B,3B,4A,5A,6A,7B),(1B,-
2B,3B,4A,5A,6A,7C),(1B,2B,3B,4A,5A,6B,7A),
(1B,2B,3B,4A,5A,6B,7B),(1B,2B,3-
B,4A,5A,6B,7C),(1B,2B,3B,4A,5A,6C,7A),(1B,2B,3B,4A,5A,6C,7B),(1B,2B,3B,4A,-
5A,6C,7C),(1B,2B,3B,4A,5A,6D,7A),(1B,2B,3B,4A,5A,6D,7B),
(1B,2B,3B,4A,5A,6D,7C),(1B,2B,3B,4A,5B,6A,7A),(1B,2B,3B,4A,5B,6A,7B),(1B,-
2B,3B,4A,5B,6A,7C),(1B,2B,3B,4A,5B,6B,7A),(1B,2B,3B,4A,5B,6B,7B),(1B,2B,3B-
,4A,5B,6B,7C),
(1B,2B,3B,4A,5B,6C,7A),(1B,2B,3B,4A,5B,6C,7B),(1B,2B,3B,4A,-
5B,6C,7C),(1B,2B,3B,4A,5B,6D,7A), (1B,2B,3B,4A,5B,6D,7B),
(1B,2B,3B,4A,5B,6D,7C), (1B,2B,3B,4B,5A,6A,7A),
(1B,2B,3B,4B,5A,6A,7B),
(1B,2B,3B,4B,5A,6A,7C),(1B,2B,3B,4B,5A,6B,7A),
(1B,2B,3B,4B,5A,6B,7B), (1B,2B,3B,4B,5A,6B,7C),
(1B,2B,3B,4B,5A,6C,7A), (1B,2B,3B,4B,5A,6C,7B),
(1B,2B,3B,4B,5A,6C,7C), (1B,2B,3B,4B,5A,6D,7A), (1B,2B,3B,4B,5A,6D,
7B), (1B,2B,3B,4B,5A,6D,7C),
(1B,2B,3B,4B,5B,6A,7A),(1B,2B,3B,4B,5B,6A,7B),(1B-
,2B,3B,4B,5B,6A,7C), (1B,2B,3B,4B,5B,6B,7A),(1B,2B,3B,4B,5B,6B,7B),
(1B,2B,3B,4B,5B,6B,7C), (1B,2B,3B,4B,5B,6C,7A),
(1B,2B,3B,4B,5B,6C,7B),
(1B,2B,3B,4B,5B,6C,7C),(1B,2B,3B,4B,5B,6D,7A),
(1B,2B,3B,4B,5B,6D,7B), (1B,2B,3B,4B,5B,6D,7C),
(1B,2B,3B,4C,5A,6A,7A), (1B,2B,3B,4C,5A,6A,7B),
(1B,2B,3B,4C,5A,6A,7C),(1B,2B,3B,4C,5A,6B,7A),(1B,2B,3B,4C,5A,6B,7B),
(1B,2B,3B,4C,5A,6B,7C),(1B,2B,3B,4C,5A,6C,7A),(1B,2B,3B,4C,5A,6C,7B),(1B,-
2B,3B,4C,5A,6C,7C),(1B,2B,3B,4C,5A,6D,7A),(1B,2B,3B,4C,5A,6D,7B),(1B,2B,3B-
,4C,5A,6D,7C),
(1B,2B,3B,4C,5B,6A,7A),(1B,2B,3B,4C,5B,6A,7B),(1B,2B,3B,4C,-
5B,6A,7C),(1B,2B,3B,4C,5B,6B,7A),(1B,2B,3B,4C,5B,6B,7B),(1B,2B,3B,4C,5B,6B-
,7C),(1B,2B,3B,4C,5B,6C,7A),
(1B,2B,3B,4C,5B,6C,7B),(1B,2B,3B,4C,5B,6C,7C)-
,(1B,2B,3B,4C,5B,6D,7A),(1B,2B,3B,4C,5B,6D,7B),(1B,2B,3B,4C,5B,6D,7C),(1B,-
2B,3B,4D,5A,6A,7A),(1B,2B,3B,4D,5A,6A,7B),
(1B,2B,3B,4D,5A,6A,7C),(1B,2B,3-
B,4D,5A,6B,7A),(1B,2B,3B,4D,5A,6B,7B),(1B,2B,3B,4D,5A,6B,7C),(1B,2B,3B,4D,-
5A,6C,7A),(1B,2B,3B,4D,5A,6C,7B),(1B,2B,3B,4D,5A,6C,7C),
(1B,2B,3B,4D,5A,6D,7A),(1B,2B,3B,4D,5A,6D,7B),(1B,2B,3B,4D,5A,6D,7C),(1B,-
2B,3B,4D,5B,6A,7A),(1B,2B,3B,4D,5B,6A,7B),(1B,2B,3B,4D,5B,6A,7C),(1B,2B,3B-
,4D,5B,6B,7A),
(1B,2B,3B,4D,5B,6B,7B),(1B,2B,3B,4D,5B,6B,7C),(1B,2B,3B,4D,-
5B,6C,7A),(1B,2B,3B,4D,5B,6C,7B),(1B,2B,3B,4D,5B,6C,7C),(1B,2B,3B,4D,5B,6D-
,7A),(1B,2B,3B,4D,5B,6D,7B),
(1B,2B,3B,4D,5B,6D,7C),(1B,2B,3B,4E,5A,6A,7A)-
,(1B,2B,3B,4E,5A,6A,7B),(1B,2B,3B,4E,5A,6A,7C),(1B,2B,3B,4E,5A,6B,7A),(1B,-
2B,3B,4E,5A,6B,7B),(1B,2B,3B,4E,5A,6B,7C),
(1B,2B,3B,4E,5A,6C,7A),(1B,2B,3-
B,4E,5A,6C,7B),(1B,2B,3B,4E,5A,6C,7C),(1B,2B,3B,4E,5A,6D,7A),(1B,2B,3B,4E,-
5A,6D,7B),(1B,2B,3B,4E,5A,6D,7C),(1B,2B,3B,4E,5B,6A,7A),
(1B,2B,3B,4E,5B,6A,7B),(1B,2B,3B,4E,5B,6A,7C),(1B,2B,3B,4E,5B,6B,7A),(1B,-
2B,3B,4E,5B,6B,7B),(1B,2B,3B,4E,5B,6B,7C),(1B,2B,3B,4E,5B,6C,7A),(1B,2B,3B-
,4E,5B,6C,7B),
(1B,2B,3B,4E,5B,6C,7C),(1B,2B,3B,4E,5B,6D,7A),(1B,2B,3B,4E,-
5B,6D,7B),(1B,2B,3B,4E,5B,6D,7C),(1B,2B,3C,4A,5A,6A,7A),(1B,2B,3C,4A,5A,6A-
,7B),(1B,2B,3C,4A,5A,6A,7C),
(1B,2B,3C,4A,5A,6B,7A),(1B,2B,3C,4A,5A,6B,7B)-
,(1B,2B,3C,4A,5A,6B,7C),(1B,2B,3C,4A,5A,6C,7A),(1B,2B,3C,4A,5A,6C,7B),(1B,-
2B,3C,4A,5A,6C,7C),(1B,2B,3C,4A,5A,6D,7A),
(1B,2B,3C,4A,5A,6D,7B),(1B,2B,3-
C,4A,5A,6D,7C),(1B,2B,3C,4A,5B,6A,7A),(1B,2B,3C,4A,5B,6A,7B),(1B,2B,3C,4A,-
5B,6A,7C),(1B,2B,3C,4A,5B,6B,7A),(1B,2B,3C,4A,5B,6B,7B),
(1B,2B,3C,4A,5B,6B,7C),(1B,2B,3C,4A,5B,6C,7A),(1B,2B,3C,4A,5B,6C,7B),(1B,-
2B,3C,4A,5B,6C,7C),(1B,2B,3C,4A,5B,6D,7A),(1B,2B,3C,4A,5B,6D,7B),(1B,2B,3C-
,4A,5B,6D,7C),
(1B,2B,3C,4B,5A,6A,7A),(1B,2B,3C,4B,5A,6A,7B),(1B,2B,3C,4B,-
5A,6A,7C),(1B,2B,3C,4B,5A,6B,7A),(1B,2B,3C,4B,5A,6B,7B),(1B,2B,3C,4B,5A,6B-
,7C),(1B,2B,3C,4B,5A,6C,7A),
(1B,2B,3C,4B,5A,6C,7B),(1B,2B,3C,4B,5A,6C,7C)-
,(1B,2B,3C,4B,5A,6D,7A),(1B,2B,3C,4B,5A,6D,7B),(1B,2B,3C,4B,5A,6D,7C),(1B,-
2B,3C,4B,5B,6A,7A),(1B,2B,3C,4B,5B,6A,7B),
(1B,2B,3C,4B,5B,6A,7C),(1B,2B,3-
C,4B,5B,6B,7A),(1B,2B,3C,4B,5B,6B,7B),(1B,2B,3C,4B,5B,6B,7C),(1B,2B,3C,4B,-
5B,6C,7A),(1B,2B,3C,4B,5B,6C,7B),(1B,2B,3C,4B,5B,6C,7C),
(1B,2B,3C,4B,5B,6D,7A),(1B,2B,3C,4B,5B,6D,7B),(1B,2B,3C,4B,5B,6D,7C),(1B,-
2B,3C,4C,5A,6A,7A),(1B,2B,3C,4C,5A,6A,7B),(1B,2B,3C,4C,5A,6A,7C),(1B,2B,3C-
,4C,5A,6B,7A),
(1B,2B,3C,4C,5A,6B,7B),(1B,2B,3C,4C,5A,6B,7C),(1B,2B,3C,4C,-
5A,6C,7A),(1B,2B,3C,4C,5A,6C,7B),(1B,2B,3C,4C,5A,6C,7C),(1B,2B,3C,4C,5A,6D-
,7A),(1B,2B,3C,4C,5A,6D,7B),
(1B,2B,3C,4C,5A,6D,7C),(1B,2B,3C,4C,5B,6A,7A)-
,(1B,2B,3C,4C,5B,6A,7B),(1B,2B,3C,4C,5B,6A,7C),(1B,2B,3C,4C,5B,6B,7A),(1B,-
2B,3C,4C,5B,6B,7B),(1B,2B,3C,4C,5B,6B,7C),
(1B,2B,3C,4C,5B,6C,7A),(1B,2B,3-
C,4C,5B,6C,7B),(1B,2B,3C,4C,5B,6C,7C),(1B,2B,3C,4C,5B,6D,7A),(1B,2B,3C,4C,-
5B,6D,7B),(1B,2B,3C,4C,5B,6D,7C),(1B,2B,3C,4D,5A,6A,7A),
(1B,2B,3C,4D,5A,6A,7B),(1B,2B,3C,4D,5A,6A,7C),(1B,2B,3C,4D,5A,6B,7A),(1B,-
2B,3C,4D,5A,6B,7B),(1B,2B,3C,4D,5A,6B,7C),(1B,2B,3C,4D,5A,6C,7A),(1B,2B,3C-
,4D,5A,6C,7B),
(1B,2B,3C,4D,5A,6C,7C),(1B,2B,3C,4D,5A,6D,7A),(1B,2B,3C,4D,-
5A,6D,7B),(1B,2B,3C,4D,5A,6D,7C),(1B,2B,3C,4D,5B,6A,7A),(1B,2B,3C,4D,5B,6A-
,7B),(1B,2B,3C,4D,5B,6A,7C),
(1B,2B,3C,4D,5B,6B,7A),(1B,2B,3C,4D,5B,6B,7B)-
,(1B,2B,3C,4D,5B,6B,7C),(1B,2B,3C,4D,5B,6C,7A),(1B,2B,3C,4D,5B,6C,7B),(1B,-
2B,3C,4D,5B,6C,7C),(1B,2B,3C,4D,5B,6D,7A),
(1B,2B,3C,4D,5B,6D,7B),(1B,2B,3-
C,4D,5B,6D,7C),(1B,2B,3C,4E,5A,6A,7A),(1B,2B,3C,4E,5A,6A,7B),(1B,2B,3C,4E,-
5A,6A,7C),(1B,2B,3C,4E,5A,6B,7A),(1B,2B,3C,4E,5A,6B,7B),
(1B,2B,3C,4E,5A,6B,7C),(1B,2B,3C,4E,5A,6C,7A),(1B,2B,3C,4E,5A,6C,7B),(1B,-
2B,3C,4E,5A,6C,7C),(1B,2B,3C,4E,5A,6D,7A),(1B,2B,3C,4E,5A,6D,7B),(1B,2B,3C-
,4E,5A,6D,7C),
(1B,2B,3C,4E,5B,6A,7A),(1B,2B,3C,4E,5B,6A,7B),(1B,2B,3C,4E,-
5B,6A,7C),(1B,2B,3C,4E,5B,6B,7A), (1B,2B,3C,4E,5B,6B,7B),
(1B,2B,3C,4E,5B,6B,7C), (1B,2B,3C,4E,5B,6C,7A),
(1B,2B,3C,4E,5B,6C,7B),(1-
B,2B,3C,4E,5B,6C,7C),(1B,2B,3C,4E,5B,6D,7A),(1B,2B,3C,4E,5B,6D,7B),
(1B,2B,3C,4E,5B,6D,7C),(1B,2B,3D,4A,5A,6A,7A),(1B,2B,3D,4A,5A,6A,7B),
(1B,2B,3D,4A,5A,6A,7C),(1B,2B,3D,4A,5A,6B,7A),(1B,2B,3D,4A,5A,6B,7B),(1B,-
2B,3D,4A,5A,6B,7C),(1B,2B,3D,4A,5A,6C,7A),(1B,2B,3D,4A,5A,6C,7B),(1B,2B,3D-
,4A,5A,6C,7C),
(1B,2B,3D,4A,5A,6D,7A),(1B,2B,3D,4A,5A,6D,7B),(1B,2B,3D,4A,-
5A,6D,7C),(1B,2B,3D,4A,5B,6A,7A),(1B,2B,3D,4A,5B,6A,7B),(1B,2B,3D,4A,5B,6A-
,7C),(1B,2B,3D,4A,5B,6B,7A),
(1B,2B,3D,4A,5B,6B,7B),(1B,2B,3D,4A,5B,6B,7C)-
,(1B,2B,3D,4A,5B,6C,7A),(1B,2B,3D,4A,5B,6C,7B),(1B,2B,3D,4A,5B,6C,7C),(1B,-
2B,3D,4A,5B,6D,7A),(1B,2B,3D,4A,5B,6D,7B),
(1B,2B,3D,4A,5B,6D,7C),(1B,2B,3-
D,4B,5A,6A,7A),(1B,2B,3D,4B,5A,6A,7B),(1B,2B,3D,4B,5A,6A,7C),(1B,2B,3D,4B,-
5A,6B,7A),(1B,2B,3D,4B,5A,6B,7B),(1B,2B,3D,4B,5A,6B,7C),
(1B,2B,3D,4B,5A,6C,7A),(1B,2B,3D,4B,5A,6C,7B),(1B,2B,3D,4B,5A,6C,7C),(1B,-
2B,3D,4B,5A,6D,7A),(1B,2B,3D,4B,5A,6D,7B),(1B,2B,3D,4B,5A,6D,7C),(1B,2B,3D-
,4B,5B,6A,7A),
(1B,2B,3D,4B,5B,6A,7B),(1B,2B,3D,4B,5B,6A,7C),(1B,2B,3D,4B,-
5B,6B,7A),(1B,2B,3D,4B,5B,6B,7B),(1B,2B,3D,4B,5B,6B,7C),(1B,2B,3D,4B,5B,6C-
,7A),(1B,2B,3D,4B,5B,6C,7B),
(1B,2B,3D,4B,5B,6C,7C),(1B,2B,3D,4B,5B,6D,7A)-
,(1B,2B,3D,4B,5B,6D,7B),(1B,2B,3D,4B,5B,6D,7C),(1B,2B,3D,4C,5A,6A,7A),(1B,-
2B,3D,4C,5A,6A,7B),(1B,2B,3D,4C,5A,6A,7C),
(1B,2B,3D,4C,5A,6B,7A),(1B,2B,3-
D,4C,5A,6B,7B),(1B,2B,3D,4C,5A,6B,7C),(1B,2B,3D,4C,5A,6C,7A),(1B,2B,3D,4C,-
5A,6C,7B),(1B,2B,3D,4C,5A,6C,7C),(1B,2B,3D,4C,5A,6D,7A),
(1B,2B,3D,4C,5A,6D,7B),(1B,2B,3D,4C,5A,6D,7C),(1B,2B,3D,4C,5B,6A,7A),(1B,-
2B,3D,4C,5B,6A,7B),(1B,2B,3D,4C,5B,6A,7C),(1B,2B,3D,4C,5B,6B,7A),(1B,2B,3D-
,4C,5B,6B,7B),
(1B,2B,3D,4C,5B,6B,7C),(1B,2B,3D,4C,5B,6C,7A),(1B,2B,3D,4C,-
5B,6C,7B),(1B,2B,3D,4C,5B,6C,7C),(1B,2B,3D,4C,5B,6D,7A),(1B,2B,3D,4C,5B,6D-
,7B),(1B,2B,3D,4C,5B,6D,7C),
(1B,2B,3D,4D,5A,6A,7A),(1B,2B,3D,4D,5A,6A,7B)-
,(1B,2B,3D,4D,5A,6A,7C),(1B,2B,3D,4D,5A,6B,7A),(1B,2B,3D,4D,5A,6B,7B),(1B,-
2B,3D,4D,5A,6B,7C),(1B,2B,3D,4D,5A,6C,7A),
(1B,2B,3D,4D,5A,6C,7B),(1B,2B,3-
D,4D,5A,6C,7C),(1B,2B,3D,4D,5A,6D,7A),(1B,2B,3D,4D,5A,6D,7B),(1B,2B,3D,4D,-
5A,6D,7C),(1B,2B,3D,4D,5B,6A,7A),(1B,2B,3D,4D,5B,6A,7B),
(1B,2B,3D,4D,5B,6A,7C),(1B,2B,3D,4D,5B,6B,7A),(1B,2B,3D,4D,5B,6B,7B),(1B,-
2B,3D,4D,5B,6B,7C),(1B,2B,3D,4D,5B,6C,7A),(1B,2B,3D,4D,5B,6C,7B),(1B,2B,3D-
,4D,5B,6C,7C),
(1B,2B,3D,4D,5B,6D,7A),(1B,2B,3D,4D,5B,6D,7B),(1B,2B,3D,4D,-
5B,6D,7C),(1B,2B,3D,4E,5A,6A,7A),(1B,2B,3D,4E,5A,6A,7B),(1B,2B,3D,4E,5A,6A-
,7C),(1B,2B,3D,4E,5A,6B,7A),
(1B,2B,3D,4E,5A,6B,7B),(1B,2B,3D,4E,5A,6B,7C)-
,(1B,2B,3D,4E,5A,6C,7A),(1B,2B,3D,4E,5A,6C,7B),(1B,2B,3D,4E,5A,6C,7C),(1B,-
2B,3D,4E,5A,6D,7A),(1B,2B,3D,4E,5A,6D,7B),
(1B,2B,3D,4E,5A,6D,7C),(1B,2B,3-
D,4E,5B,6A,7A),(1B,2B,3D,4E,5B,6A,7B),(1B,2B,3D,4E,5B,6A,7C),(1B,2B,3D,4E,-
5B,6B,7A),(1B,2B,3D,4E,5B,6B,7B),(1B,2B,3D,4E,5B,6B,7C),
(1B,2B,3D,4E,5B,6C,7A),(1B,2B,3D,4E,5B,6C,7B),(1B,2B,3D,4E,5B,6C,7C),(1B,-
2B,3D,4E,5B,6D,7A),(1B,2B,3D,4E,5B,6D,7B),(1B,2B,3D-4E,5B,6D,7C),(1B,2B,3E-
,4A,5A,6A,7A),
(1B,2B,3E,4A,5A,6A,7B),(1B,2B,3E,4A,5A,6A,7C),(1B,2B,3E,4A,-
5A,6B,7A),(1B,2B,3E,4A,5A,6B,7B),(1B,2B,3E,4A,5A,6B,7C),(1B,2B,3E,4A,5A,6C-
,7A),(1B,2B,3E,4A,5A,6C,7B),
(1B,2B,3E,4A,5A,6C,7C),(1B,2B,3E,4A,5A,6D,7A)-
,(1B,2B,3E,4A,5A,6D,7B),(1B,2B,3E,4A,5A,6D,7C),(1B,2B,3E,4A,5B,6A,7A),(1B,-
2B,3E,4A,5B,6A,7B),(1B,2B,3E,4A,5B,6A,7C),
(1B,2B,3E,4A,5B,6B,7A),(1B,2B,3-
E,4A,5B,6B,7B),(1B,2B,3E,4A,5B,6B,7C),(1B,2B,3E,4A,5B,6C,7A),(1B,2B,3E,4A,-
5B,6C,7B),(1B,2B,3E,4A,5B,6C,7C),(1B,2B,3E,4A,5B,6D,7A),
(1B,2B,3E,4A,5B,6D,7B),(1B,2B,3E,4A,5B,6D,7C),(1B,2B,3E,4B,5A,6A,7A),(1B,-
2B,3E,4B,5A,6A,7B),(1B,2B,3E,4B,5A,6A,7C),(1B,2B,3E,4B,5A,6B,7A),(1B,2B,3E-
,4B,5A,6B,7B),
(1B,2B,3E,4B,5A,6B,7C),(1B,2B,3E,4B,5A,6C,7A),(1B,2B,3E,4B,-
5A,6C,7B),(1B,2B,3E,4B,5A,6C,7C),(1B,2B,3E,4B,5A,6D,7A),(1B,2B,3E,4B,5A,6D-
,7B),(1B,2B,3E,4B,5A,6D,7C),
(1B,2B,3E,4B,5B,6A,7A),(1B,2B,3E,4B,5B,6A,7B)-
,(1B,2B,3E,4B,5B,6A,7C),(1B,2B,3E,4B,5B,6B,7A),(1B,2B,3E,4B,5B,6B,7B),(1B,-
2B,3E,4B,5B,6B,7C),(1B,2B,3E,4B,5B,6C,7A),
(1B,2B,3E,4B,5B,6C,7B),(1B,2B,3-
E,4B,5B,6C,7C),(1B,2B,3E,4B,5B,6D,7A),(0B,2B,3E,4B,5B,6D,7B),(1B,2B,3E,4B,-
5B,6D,7C),(1B,2B,3E,4C,5A,6A,7A),(1B,2B,3E,4C,5A,6A,7B),
(1B,2B,3E,4C,5A,6A,7C),(1B,2B,3E,4C,5A,6B,7A),(1B,2B,3E,4C,5A,6B,7B),(1B,-
2B,3E,4C,5A,6B,7C),(1B,2B,3E,4C,5A,6C,7A),(1B,2B,3E,4C,5A,6C,7B),(1B,2B,3E-
,4C,5A,6C,7C),
(1B,2B,3E,4C,5A,6D,7A),(1B,2B,3E,4C,5A,6D,7B),(1B,2B,3E,4C,-
5A,6D,7C),(1B,2B,3E,4C,5B,6A,7A),(1B,2B,3E,4C,5B,6A,7B),(1B,2B,3E,4C,5B,6A-
,7C),(1B,2B,3E,4C,5B,6B,7A),
(1B,2B,3E,4C,5B,6B,7B),(1B,2B,3E,4C,5B,6B,7C)-
,(1B,2B,3E,4C,5B,6C,7A),(1B,2B,3E,4C,5B,6C,7B),(1B,2B,3E,4C,5B,6C,7C),(1B,-
2B,3E,4C,5B,6D,7A),(1B,2B,3E,4C,5B,6D,7B),
(1B,2B,3E,4C,5B,6D,7C),(1B,2B,3-
E,4D,5A,6A,7A),(1B,2B,3E,4D,5A,6A,7B),(1B,2B,3E,4D,5A,6A,7C),(1B,2B,3E,4D,-
5A,6B,7A),(1B,2B,3E,4D,5A,6B,7B),(1B,2B,3E,4D,5A,6B,7C),
(1B,2B,3E,4D,5A,6C,7A),(1B,2B,3E,4D,5A,6C,7B),(1B,2B,3E,4D,5A,6C,7C),(1B,-
2B,3E,4D,5A,6D,7A), (1B,2B,3E,4D,5A,6D,7B),(1B,2B,3E,4D,5A,6D,7C),
(1B,2B,3E,4D,5B,6A,7A), (1B,2B,3E,4D,5B,6A,7B),
(1B,2B,3E,4D,5B,6A,7C), (1B,2B,3E,4D,5B,6B, 7A),
(1B,2B,3E,4D,5B,6B,7B), (1B,2B,3E,4D,5B,6B,7C),(-
1B,2B,3E,4D,5B,6C,7A),(1B,2B,3E,4D,5B,6C,7B),
(1B,2B,3E,4D,5B,6C,7C), (1B,2B,3E,4D,5B,6D,7A),
(1B,2B,3E,4D,5B,6D,7B), (1B,2B,3E,4D,5B,6D,7C),
(1B,2B,3E,4E,5A,6A,7A),(1B,2B,3E,4E,5A,6A,7B),(1B,2B,3E,4E,5A,6A,7C),
(1B,2B,3E,4E,5A,6B,7A), (1B,2B,3E,4E,5A,6B,7B),
(1B,2B,3E,4E,5A,6B,7C), (1B,2B,3E,4E,6A,6C,7A),
(1B,2B,3E,4E,5A,6C,7B),(1B,2B,3E,4E,5A,6C,7C),(1B-
,2B,3E,4E,5A,6D,7A), (1B,2B,3E,4E,5A,6D,7B),
(1B,2B,3E,4E,5A,6D,7C), (1B,2B,3E,4E,5B,6A,7A),
(1B,2B,3E,4E,5B,6A,7B), (1B,2B,3E,4E,5B,6A,7C),(1-
B,2B,3E,4E,5B,6B,7A),(1B,2B,3E,4E,5B,6B,7B),
(1B,2B,3E,4E,5B,6B,7C),(1B,2B-
,3E,4E,5B,6C,7A),(1B,2B,3E,4E,5B,6C,7B),(1B,2B,3E,4E,5B,6C,7C),
(1B,2B,3E,4E,5B,6D,7A), (1B,2B,3E,4E,5B, 6D,7B),(1B,2B,3E,4E, 5B,
6D,7C),
(1B,2C,3A,4A,5A,6A,7A),(1B,2C,3A,4A,5A,6A,7B),(1B,2C,3A,4A,5A,6A,7C),(1B,-
2C,3A,4A,5A,6B,7A),(1B,2C,3A,4A,5A,6B,7B),(1B,2C,3A,4A,5A,6B,7C),(1B,2C,3A-
,4A,5A,6C,7A),
(1B,2C,3A,4A,5A,6C,7B),(1B,2C,3A,4A,5A,6C,7C),(1B,2C,3A,4A,-
5A,6D,7A),(1B,2C,3A,4A,5A,6D,7B),(1B,2C,3A,4A,5A,6D,7C),(1B,2C,3A,4A,5B,6A-
,7A),(1B,2C,3A,4A,5B,6A,7B),
(1B,2C,3A,4A,5B,6A,7C),(1B,2C,3A,4A,5B,6B,7A)-
,(1B,2C,3A,4A,5B,6B,7B),(1B,2C,3A,4A,5B,6B,7C),(1B,2C,3A,4A,5B,6C,7A),(1B,-
2C,3A,4A,5B,6C,7B),(1B,2C,3A,4A,5B,6C,7C),
(1B,2C,3A,4A,5B,6D,7A),(1B,2C,3-
A,4A,5B,6D,7B),(1B,2C,3A,4A,5B,6D,7C),(1B,2C,3A,4B,5A,6A,7A),(1B,2C,3A,4B,-
5A,6A,7B),(1B,2C,3A,4B,5A,6A,7C),(1B,2C,3A,4B,5A,6B,7A),
(1B,2C,3A,4B,5A,6B,7B),(1B,2C,3A,4B,5A,6B,7C),(1B,2C,3A,4B,5A,6C,7A),(1B,-
2C,3A,4B,5A,6C,7B),(1B,2C,3A,4B,5A,6C,7C),(1B,2C,3A,4B,5A,6D,7A),(1B,2C,3A-
,4B,5A,6D,7B),
(1B,2C,3A,4B,5A,6D,7C),(1B,2C,3A,4B,5B,6A,7A),(1B,2C,3A,4B,-
5B,6A,7B),(1B,2C,3A,4B,5B,6A,7C),(1B,2C,3A,4B,5B,6B,7A),(1B,2C,3A,4B,5B,6B-
,7B),(1B,2C,3A,4B,5B,6B,7C),
(1B,2C,3A,4B,5B,6C,7A),(1B,2C,3A,4B,5B,6C,7B)-
,(1B,2C,3A,4B,5B,6C,7C),(1B,2C,3A,4B,5B,6D,7A),(1B,2C,3A,4B,5B,6D,7B),(1B,-
2C,3A,4B,5B,6D,7C),(1B,2C,3A,4C,5A,6A,7A),
(1B,2C,3A,4C,5A,6A,7B),(1B,2C,3-
A,4C,5A,6A,7C),(1B,2C,3A,4C,5A,6B,7A),(1B,2C,3A,4C,5A,6B,7B),(1B,2C,3A,4C,-
5A,6B,7C),(1B,2C,3A,4C,5A,6C,7A),(1B,2C,3A,4C,5A,6C,7B),
(1B,2C,3A,4C,5A,6C,7C),(1B,2C,3A,4C,5A,6D,7A),(1B,2C,3A,4C,5A,6D,7B),(1B,-
2C,3A,4C,5A,6D,7C),(1B,2C,3A,4C,5B,6A,7A),(1B,2C,3A,4C,5B,6A,7B),(1B,2C,3A-
,4C,5B,6A,7C),
(1B,2C,3A,4C,5B,6B,7A),(1B,2C,3A,4C,5B,6B,7B),(1B,2C,3A,4C,-
5B,6B,7C),(1B,2C,3A,4C,5B,6C,7A),(1B,2C,3A,4C,5B,6C,7B),(1B,2C,3A,4C,5B,6C-
,7C),(1B,2C,3A,4C,5B,6D,7A),
(1B,2C,3A,4C,5B,6D,7B),(1B,2C,3A,4C,5B,6D,7C)-
,(1B,2C,3A,4D,5A,6A,7A),(1B,2C,3A,4D,5A,6A,7B),(1B,2C,3A,4D,5A,6A,7C),(1B,-
2C,3A,4D,5A,6B,7A),(1B,2C,3A,4D,5A,6B,7B),
(1B,2C,3A,4D,5A,6B,7C),(1B,2C,3-
A,4D,5A,6C,7A),(1B,2C,3A,4D,5A,6C,7B),(1B,2C,3A,4D,5A,6C,7C),(1B,2C,3A,4D,-
5A,6D,7A),(1B,2C,3A,4D,5A,6D,7B),(1B,2C,3A,4D,5A,6D,7C),
(1B,2C,3A,4D,5B,6A,7A),(1B,2C,3A,4D,5B,6A,7B),(1B,2C,3A,4D,5B,6A,7C),(1B,-
2C,3A,4D,5B,6B,7A),(1B,2C,3A,4D,5B,6B,7B),(1B,2C,3A,4D,5B,6B,7C),(1B,2C,3A-
,4D,5B,6C,7A),
(1B,2C,3A,4D,5B,6C,7B),(1B,2C,3A,4D,5B,6C,7C),(1B,2C,3A,4D,-
5B,6D,7A),(1B,2C,3A,4D,5B,6D,7B),(1B,2C,3A,4D,5B,6D,7C),(1B,2C,3A,4E,5A,6A-
,7A),(1B,2C,3A,4E,5A,6A,7B),
(1B,2C,3A,4E,5A,6A,7C),(1B,2C,3A,4E,5A,6B,7A)-
,(1B,2C,3A,4E,5A,6B,7B),(1B,2C,3A,4E,5A,6B,7C),(1B,2C,3A,4E,5A,6C,7A),(1B,-
2C,3A,4E,5A,6C,7B),(1B,2C,3A,4E,5A,6C,7C),
(1B,2C,3A,4E,5A,6D,7A),(1B,2C,3-
A,4E,5A,6D,7B),(1B,2C,3A,4E,5A,6D,7C),(1B,2C,3A,4E,5B,6A,7A),(1B,2C,3A,4E,-
5B,6A,7B),(1B,2C,3A,4E,5B,6A,7C),(1B,2C,3A,4E,5B,6B,7A),
(1B,2C,3A,4E,5B,6B,7B),(1B,2C,3A,4E,5B,6B,7C),(1B,2C,3A,4E,5B,6C,7A),(1B,-
2C,3A,4E,5B,6C,7B),(1B,2C,3A,4E,5B,6C,7C),(1B,2C,3A,4E,5B,6D,7A),(1B,2C,3A-
,4E,5B,6D,7B),
(1B,2C,3A,4E,5B,6D,7C),(1B,2C,3B,4A,5A,6A,7A),(1B,2C,3B,4A,-
5A,6A,7B),(1B,2C,3B,4A,5A,6A,7C),(1B,2C,3B,4A,5A,6B,7A),(1B,2C,3B,4A,5A,6B-
,7B),(1B,2C,3B,4A,5A,6B,7C),
(1B,2C,3B,4A,5A,6C,7A),(1B,2C,3B,4A,5A,6C,7B)-
,(1B,2C,3B,4A,5A,6C,7C),(1B,2C,3B,4A,5A,6D,7A),(1B,2C,3B,4A,5A,6D,7B),(1B,-
2C,3B,4A,5A,6D,7C),(1B,2C,3B,4A,5B,6A,7A),
(1B,2C,3B,4A,5B,6A,7B),(1B,2C,3-
B,4A,5B,6A,7C),(1B,2C,3B,4A,5B,6B,7A),(1B,2C,3B,4A,5B,6B,7B),(1B,2C,3B,4A,-
5B,6B,7C),(1B,2C,3B,4A,5B,6C,7A),(1B,2C,3B,4A,5B,6C,7B),
(1B,2C,3B,4A,5B,6C,7C),(1B,2C,3B,4A,5B,6D,7A),(1B,2C,3B,4A,5B,6D,7B),(1B,-
2C,3B,4A,5B,6D,7C),(1B,2C,3B,4B,5A,6A,7A),(1B,2C,3B,4B,5A,6A,7B),(1B,2C,3B-
,4B,5A,6A,7C),
(1B,2C,3B,4B,5A,6B,7A),(1B,2C,3B,4B,5A,6B,7B),(1B,2C,3B,4B,-
5A,6B,7C),(1B,2C,3B,4B,5A,6C,7A),(1B,2C,3B,4B,5A,6C,7B),(1B,2C,3B,4B,5A,6C-
,7C),(1B,2C,3B,4B,5A,6D,7A),
(1B,2C,3B,4B,5A,6D,7B),(1B,2C,3B,4B,5A,6D,7C)-
,(1B,2C,3B,4B,5B,6A,7A),(1B,2C,3B,4B,5B,6A,7B),(1B,2C,3B,4B,5B,6A,7C),(1B,-
2C,3B,4B,5B,6B,7A),(1B,2C,3B,4B,5B,6B,7B),
(1B,2C,3B,4B,5B,6B,7C),(1B,2C,3-
B,4B,5B,6C,7A),(1B,2C,3B,4B,5B,6C,7B),(1B,2C,3B,4B,5B,6C,7C),(1B,2C,3B,4B,-
5B,6D,7A),(1B,2C,3B,4B,5B,6D,7B),(1B,2C,3B,4B,5B,6D,7C),
(1B,2C,3B,4C,5A,6A,7A),(1B,2C,3B,4C,5A,6A,7B),(1B,2C,3B,4C,5A,6A,7C),(1B,-
2C,3B,4C,5A,6B,7A),
(1B,2C,3B,4C,5A,6B,7B),(1B,2C,3B,4C,5A,6B,7C),(1B,2C,3-
B,4C,5A,6C,7A), (1B,2C,3B,4C,5A,6C,7B),
(1B,2C,3B,4C,5A,6C,7C),(1B,2C,3B,4-
C,5A,6D,7A),(1B,2C,3B,4C,5A,6D,7B),
(1B,2C,3B,4C,5A,6D,7C),(1B,2C,3B,4C,5B-
,6A,7A),(1B,2C,3B,4C,5B,6A,7B), (1B,2C,3B,4C,5B,6A,7C),
(1B,2C,3B,4C,5B,6B,7A),
(1B,2C,3B,4C,5B,6B,7B),(1B,2C,3B,4C,5B,6B,7C),
(1B,2C,3B,4C,5B,6C,7A),
(1B,2C,3B,4C,5B,6C,7B),(1B,2C,3B,4C,5B,6C,7C),
(1B,2C,3B,4C,5B,6D,7A), (1B,2C,3B,4C,5B,6D,7B),
(1B,2C,3B,4C,5B,6D,7C),(1- B,2C,3B,4D,5A,6A,7A),
(1B,2C,3B,4D,5A,6A,7B),(1B,2C,3B,4D,5A,6A,7C),(1B,2C-
,3B,4D,5A,6B,7A), (1B,2C,3B,4D,5A,6B,7B), (B,2C,3B,4D,5A,6B,7C),
(1B,2C,3B,4D,5A,6C,7A),(1B,2C,3B,4D,5A,6C,7B),
(1B,2C,3B,4D,5A,6C,7C),(1B-
,2C,3B,4D,5A,6D,7A),(1B,2C,3B,4D,5A,6D,7B),
(1B,2C,3B,4D,5A,6D,7C),(1B,2C,-
3B,4D,5B,6A,7A),(1B,2C,3B,4D,5B,6A,7B),(1B,2C,3B,4D,5B,6A,7C),(1B,2C,3B,4D-
,5B,6B,7A),(1B,2C,3B,4D,5B,6B,7B),(1B,2C,3B,4D,5B,6B,7C),
(1B,2C,3B,4D,5B,6C,7A),(1B,2C,3B,4D,5B,6C,7B),(1B,2C,3B,4D,5B,6C,7C),(1B,-
2C,3B,4D,5B,6D,7A),(1B,2C,3B,4D,5B,6D,7B),(1B,2C,3B,4D,5B,6D,7C),(1B,2C,3B-
,4E,5A,6A,7A),
(1B,2C,3B,4E,5A,6A,7B),(1B,2C,3B,4E,5A,6A,7C),(1B,2C,3B,4E,-
5A,6B,7A),(1B,2C,3B,4E,5A,6B,7B),(1B,2C,3B,4E,5A,6B,7C),(1B,2C,3B,4E,5A,6C-
,7A),(1B,2C,3B,4E,5A,6C,7B),
(1B,2C,3B,4E,5A,6C,7C),(1B,2C,3B,4E,5A,6D,7A)-
,(1B,2C,3B,4E,5A,6D,7B),(1B,2C,3B,4E,5A,6D,7C),(1B,2C,3B,4E,5B,6A,7A),(1B,-
2C,3B,4E,5B,6A,7B),(1B,2C,3B,4E,5B,6A,7C),
(1B,2C,3B,4E,5B,6B,7A),(1B,2C,3-
B,4E,5B,6B,7B),(1B,2C,3B,4E,5B,6B,7C),(1B,2C,3B,4E,5B,6C,7A),(1B,2C,3B,4E,-
5B,6C,7B),(1B,2C,3B,4E,5B,6C,7C),(1B,2C,3B,4E,5B,6D,7A),
(1B,2C,3B,4E,5B,6D,7B),(1B,2C,3B,4E,5B,6D,7C),(1B,2C,3C,4A,5A,6A,7A),(1B,-
2C,3C,4A,5A,6A,7B),(1B,2C,3C,4A,5A,6A,7C),(1B,2C,3C,4A,5A,6B,7A),(1B,2C,3C-
,4A,5A,6B,7B),
(1B,2C,3C,4A,5A,6B,7C),(1B,2C,3C,4A,5A,6C,7A),(1B,2C,3C,4A,-
5A,6C,7B),(1B,2C,3C,4A,5A,6C,7C),(1B,2C,3C,4A,5A,6D,7A),(1B,2C,3C,4A,5A,6D-
,7B),(1B,2C,3C,4A,5A,6D,7C),
(1B,2C,3C,4A,5B,6A,7A),(1B,2C,3C,4A,5B,6A,7B)-
,(1B,2C,3C,4A,5B,6A,7C),(1B,2C,3C,4A,5B,6B,7A),(1B,2C,3C,4A,5B,6B,7B),(1B,-
2C,3C,4A,5B,6B,7C),(1B,2C,3C,4A,5B,6C,7A),
(1B,2C,3C,4A,5B,6C,7B),(1B,2C,3-
C,4A,5B,6C,7C),(1B,2C,3C,4A,5B,6D,7A),(1B,2C,3C,4A,5B,6D,7B),(1B,2C,3C,4A,-
5B,6D,7C),(1B,2C,3C,4B,5A,6A,7A),(1B,2C,3C,4B,5A,6A,7B),
(1B,2C,3C,4B,5A,6A,7C),(1B,2C,3C,4B,5A,6B,7A),(1B,2C,3C,4B,5A,6B,7B),(1B,-
2C,3C,4B,5A,6B,7C),(1B,2C,3C,4B,5A,6C,7A),(1B,2C,3C,4B,5A,6C,7B),(1B,2C,3C-
,4B,5A,6C,7C),
(1B,2C,3C,4B,5A,6D,7A),(1B,2C,3C,4B,5A,6D,7B),(1B,2C,3C,4B,-
5A,6D,7C),(1B,2C,3C,4B,5B,6A,7A),
(1B,2C,3C,4B,5B,6A,7B),(1B,2C,3C,4B,5B,6-
A,7C),(1B,2C,3C,4B,5B,6B,7A),
(1B,2C,3C,4B,5B,6B,7B),(1B,2C,3C,4B,5B,6B,7C-
),(1B,2C,3C,4B,5B,6C,7A),(1B,2C,3C,4B,5B,6C,7B),(1B,2C,3C,4B,5B,6C,7C),(1B-
,2C,3C,4B,5B,6D,7A),(1B,2C,3C,4B,5B,6D,7B),
(1B,2C,3C,4B,5B,6D,7C),(1B,2C,-
3C,4C,5A,6A,7A),(1B,2C,3C,4C,5A,6A,7B),(1B,2C,3C,4C,5A,6A,7C),(1B,2C,3C,4C-
,5A,6B,7A),(1B,2C,3C,4C,5A,6B,7B),(1B,2C,3C,4C,5A,6B,7C),
(1B,2C,3C,4C,5A,6C,7A),(1B,2C,3C,4C,5A,6C,7B),(1B,2C,3C,4C,5A,6C,7C),(1B,-
2C,3C,4C,5A,6D,7A),(1B,2C,3C,4C,5A,6D,7B),(1B,2C,3C,4C,5A,6D,7C),(1B,2C,3C-
,4C,5B,6A,7A),
(1B,2C,3C,4C,5B,6A,7B),(1B,2C,3C,4C,5B,6A,7C),(1B,2C,3C,4C,-
5B,6B,7A),(1B,2C,3C,4C,5B,6B,7B),(1B,2C,3C,4C,5B,6B,7C),(1B,2C,3C,4C,5B,6C-
,7A),(1B,2C,3C,4C,5B,6C,7B),
(1B,2C,3C,4C,5B,6C,7C),(1B,2C,3C,4C,5B,6D,7A)-
,(1B,2C,3C,4C,5B,6D,7B),(1B,2C,3C,4C,5B,6D,7C),(1B,2C,3C,4D,5A,6A,7A),(1B,-
2C,3C,4D,5A,6A,7B),(1B,2C,3C,4D,5A,6A,7C),
(1B,2C,3C,4D,5A,6B,7A),(1B,2C,3-
C,4D,5A,6B,7B),(1B,2C,3C,4D,5A,6B,7C),(1B,2C,3C,4D,5A,6C,7A),(1B,2C,3C,4D,-
5A,6C,7B),(1B,2C,3C,4D,5A,6C,7C),(1B,2C,3C,4D,5A,6D,7A),
(1B,2C,3C,4D,5A,6D,7B),(1B,2C,3C,4D,5A,6D,7C),(1B,2C,3C,4D,5B,6A,7A),(1B,-
2C,3C,4D,5B,6A,7B),(1B,2C,3C,4D,5B,6A,7C),(1B,2C,3C,4D,5B,6B,7A),(1B,2C,3C-
,4D,5B,6B,7B),
(1B,2C,3C,4D,5B,6B,7C),(1B,2C,3C,4D,5B,6C,7A),(1B,2C,3C,4D,-
5B,6C,7B),(1B,2C,3C,4D,5B,6C,7C),(1B,2C,3C,4D,5B,6D,7A),(1B,2C,3C,4D,5B,6D-
,7B),(1B,2C,3C,4D,5B,6D,7C),
(1B,2C,3C,4E,5A,6A,7A),(1B,2C,3C,4E,5A,6A,7B)-
,(1B,2C,3C,4E,5A,6A,7C),(1B,2C,3C,4E,5A,6B,7A),(1B,2C,3C,4E,5A,6B,7B),(1B,-
2C,3C,4E,5A,6B,7C),(1B,2C,3C,4E,5A,6C,7A),
(1B,2C,3C,4E,5A,6C,7B),(1B,2C,3-
C,4E,5A,6C,7C),(1B,2C,3C,4E,5A,6D,7A),(1B,2C,3C,4E,5A,6D,7B),(1B,2C,3C,4E,-
5A,6D,7C),(1B,2C,3C,4E,5B,6A,7A),(1B,2C,3C,4E,5B,6A,7B),
(1B,2C,3C,4E,5B,6A,7C),(1B,2C,3C,4E,5B,6B,7A),(1B,2C,3C,4E,5B,6B,7B),(1B,-
2C,3C,4E,5B,6B,7C),(1B,2C,3C,4E,5B,6C,7A),(1B,2C,3C,4E,5B,6C,7B),(1B,2C,3C-
,4E,5B,6C,7C),
(1B,2C,3C,4E,5B,6D,7A),(1B,2C,3C,4E,5B,6D,7B),(1B,2C,3C,4E,-
5B,6D,7C),(1B,2C,3D,4A,5A,6A,7A),(1B,2C,3D,4A,5A,6A,7B),(1B,2C,3D,4A,5A,6A-
,7C),(1B,2C,3D,4A,5A,6B,7A),
(1B,2C,3D,4A,5A,6B,7B),(1B,2C,3D,4A,5A,6B,7C)-
,(1B,2C,3D,4A,5A,6C,7A),(1B,2C,3D,4A,5A,6C,7B),(1B,2C,3D,4A,5A,6C,7C),(1B,-
2C,3D,4A,5A,6D,7A),(1B,2C,3D,4A,5A,6D,7B),
(1B,2C,3D,4A,5A,6D,7C),(1B,2C,3-
D,4A,5B,6A,7A),(1B,2C,3D,4A,5B,6A,7B),(1B,2C,3D,4A,5B,6A,7C),(1B,2C,3D,4A,-
5B,6B,7A),(1B,2C,3D,4A,5B,6B,7B),(1B,2C,3D,4A,5B,6B,7C),
(1B,2C,3D,4A,5B,6C,7A),(1B,2C,3D,4A,5B,6C,7B),(1B,2C,3D,4A,5B,6C,7C),(1B,-
2C,3D,4A,5B,6D,7A),
(1B,2C,3D,4A,5B,6D,7B),(1B,2C,3D,4A,5B,6D,7C),(1B,2C,3-
D,4B,5A,6A,7A), (1B,2C,3D,4B,5A,6A,7B), (1B,2C,3D,4B,5A,6A,7C),
(1B,2C,3D,4B, 5A,6B,7A), (1B,2C,3D,4B,5A,6B,7B),
(B,2C,3D,4B,5A,6B,7C),(1-
B,2C,3D,4B,5A,6C,7A),(1B,2C,3D,4B,5A,6C,7B),
(1B,2C,3D,4B,5A,6C,7C),(1B,2C-
,3D,4B,5A,6D,7A),(1B,2C,3D,4B,5A,6D,7B),(1B,2C,3D,4B,5A,6D,7C),(1B,2C,3D,4-
B,5B,6A,7A),(1B,2C,3D,4B,5B,6A,7B),(1B,2C,3D,4B,5B,6A,7C),
(1B,2C,3D,4B,5B,6B,7A),(1B,2C,3D,4B,5B,6B,7B),(1B,2C,3D,4B,5B,6B,7C),(1B,-
2C,3D,4B,5B,6C,7A),(1B,2C,3D,4B,5B,6C,7B),(1B,2C,3D,4B,5B,6C,7C),(1B,2C,3D-
,4B,5B,6D,7A),
(1B,2C,3D,4B,5B,6D,7B),(1B,2C,3D,4B,5B,6D,7C),(1B,2C,3D,4C,-
5A,6A,7A),(1B,2C,3D,4C,5A,6A,7B),(1B,2C,3D,4C,5A,6A,7C),(1B,2C,3D,4C,5A,6B-
,7A),(1B,2C,3D,4C,5A,6B,7B),
(1B,2C,3D,4C,5A,6B,7C),(1B,2C,3D,4C,5A,6C,7A)-
,(1B,2C,3D,4C,5A,6C,7B),(1B,2C,3D,4C,5A,6C,7C),(1B,2C,3D,4C,5A,6D,7A),(1B,-
2C,3D,4C,5A,6D,7B),(1B,2C,3D,4C,5A,6D,7C),
(1B,2C,3D,4C,5B,6A,7A),(1B,2C,3-
D,4C,5B,6A,7B),(1B,2C,3D,4C,5B,6A,7C),(1B,2C,3D,4C,5B,6B,7A),(1B,2C,3D,4C,-
5B,6B,7B),(1B,2C,3D,4C,5B,6B,7C),(1B,2C,3D,4C,5B,6C,7A),
(1B,2C,3D,4C,5B,6C,7B),(1B,2C,3D,4C,5B,6C,7C),(1B,2C,3D,4C,5B,6D,7A),(1B,-
2C,3D,4C,5B,6D,7B),(1B,2C,3D,4C,5B,6D,7C),(1B,2C,3D,4D,5A,6A,7A),(1B,2C,3D-
,4D,5A,6A,7B),
(1B,2C,3D,4D,5A,6A,7C),(1B,2C,3D,4D,5A,6B,7A),(1B,2C,3D,4D,-
5A,6B,7B),(1B,2C,3D,4D,5A,6B,7C),(1B,2C,3D,4D,5A,6C,7A),(1B,2C,3D,4D,5A,6C-
,7B),(1B,2C,3D,4D,5A,6C,7C),
(1B,2C,3D,4D,5A,6D,7A),(1B,2C,3D,4D,5A,6D,7B)-
,(1B,2C,3D,4D,5A,6D,7C),(1B,2C,3D,4.
D,5B,6A,7A),(1B,2C,3D,4D,5B,6A,7B),(1-
B,2C,3D,4D,5B,6A,7C),(1B,2C,3D,4D,5B,6B,7A),
(1B,2C,3D,4D,5B,6B,7B),(1B,2C-
,3D,4D,5B,6B,7C),(1B,2C,3D,4D,5B,6C,7A),(1B,2C,3D,4D,5B,6C,7B),(1B,2C,3D,4-
D,5B,6C,7C),(1B,2C,3D,4D,5B,6D,7A),(1B,2C,3D,4D,5B,6D,7B),
(1B,2C,3D,4D,5B,6D,7C),(1B,2C,3D,4E,5A,6A,7A),(1B,2C,3D,4E,5A,6A,7B),(1B,-
2C,3D,4E,5A,6A,7C),(1B,2C,3D,4E,5A,6B,7A),(1B,2C,3D,4E,5A,6B,7B),(1B,2C,3D-
,4E,5A,6B,7C),
(1B,2C,3D,4E,5A,6C,7A),(1B,2C,3D,4E,5A,6C,7B),(1B,2C,3D,4E,-
5A,6C,7C),(1B,2C,3D,4E,5A,6D,7A),(1B,2C,3D,4E,5A,6D,7B),(1B,2C,3D,4E,5A,6D-
,7C),(1B,2C,3D,4E,5B,6A,7A),
(1B,2C,3D,4E,5B,6A,7B),(1B,2C,3D,4E,5B,6A,7C)-
,(1B,2C,3D,4E,5B,6B,7A),(1B,2C,3D,4E,5B,6B,7B),(1B,2C,3D,4E,5B,6B,7C),(1B,-
2C,3D,4E,5B,6C,7A),(1B,2C,3D,4E,5B,6C,7B),
(1B,2C,3D,4E,5B,6C,7C),(1B,2C,3-
D,4E,5B,6D,7A),(1B,2C,3D,4E,5B,6D,7B),(1B,2C,3D,4E,5B,6D,7C),(1B,2C,3E,4A,-
5A,6A,7A),(1B,2C,3E,4A,5A,6A,7B),(1B,2C,3E,4A,5A,6A,7C),
(1B,2C,3E,4A,5A,6B,7A),(1B,2C,3E,4A,5A,6B,7B),(1B,2C,3E,4A,5A,6B,7C),(1B,-
2C,3E,4A,5A,6C,7A),
(1B,2C,3E,4A,5A,6C,7B),(1B,2C,3E,4A,5A,6C,7C),(1B,2C,3-
E,4A,5A,6D,7A), (1B,2C,3E,4A,5A,6D,7B), (1B,2C,3E,4A,5A,6D,7C),
(1B,2C,3E,4A,5B,6A, 7A), (1B,2C,3E,4A,5B,6A,7B),
(1B,2C,3E,4A,5B,6A,7C),(-
1B,2C,3E,4A,5B,6B,7A),(1B,2C,3E,4A,5B,6B,7B),
(1B,2C,3E,4A,5B,6B,7C), (1B,2C,3E,4A,5B,6C,7A),
(1B,2C,3E,4A,5B,6C,7B), (1B,2C,3E,4A,5B,6C,7C),
(1B,2C,3E,4A,5B,6D,7A),(1B,2C,3E,4A,5B,6D,7B),(1B,2C,3E,4A,5B,6D,7C),
(1B,2C,3E,4B,5A,6A,7A),(1B,2C,3E,4B,5A,6A,7B),(1B,2C,3E,4B,5A,6A,7C),(1B,-
2C,3E,4B,5A,6B,7A),(1B,2C,3E,4B,5A,6B,7B),(1B,2C,3E,4B,5A,6B,7C),(1B,2C,3E-
,4B,5A,6C,7A),
(1B,2C,3E,4B,5A,6C,7B),(1B,2C,3E,4B,5A,6C,7C),(1B,2C,3E,4B,-
5A,6D,7A),(1B,2C,3E,4B,5A,6D,7B),(1B,2C,3E,4B,5A,6D,7C),(1B,2C,3E,4B,5B,6A-
,7A),(1B,2C,3E,4B,5B,6A,7B),
(1B,2C,3E,4B,5B,6A,7C),(1B,2C,3E,4B,5B,6B,7A)-
,(1B,2C,3E,4B,5B,6B,7B),(1B,2C,3E,4B,5B,6B,7C),(1B,2C,3E,4B,5B,6C,7A),(1B,-
2C,3E,4B,5B,6C,7B),(1B,2C,3E,4B,5B,6C,7C),
(1B,2C,3E,4B,5B,6D,7A),(1B,2C,3-
E,4B,5B,6D,7B),(1B,2C,3E,4B,5B,6D,7C),(1B,2C,3E,4C,5A,6A,7A),(1B,2C,3E,4C,-
5A,6A,7B),(1B,2C,3E,4C,5A,6A,7C),(1B,2C,3E,4C,5A,6B,7A),
(1B,2C,3E,4C,5A,6B,7B),(1B,2C,3E,4C,5A,6B,7C),(1B,2C,3E,4C,5A,6C,7A),(1B,-
2C,3E,4C,5A,6C,7B),(1B,2C,3E,4C,5A,6C,7C),(1B,2C,3E,4C,5A,6D,7A),(1B,2C,3E-
,4C,5A,6D,7B),
(1B,2C,3E,4C,5A,6D,7C),(1B,2C,3E,4C,5B,6A,7A),(1B,2C,3E,4C,-
5B,6A,7B),(1B,2C,3E,4C,5B,6A,7C),(1B,2C,3E,4C,5B,6B,7A),(1B,2C,3E,4C,5B,6B-
,7B),(1B,2C,3E,4C,5B,6B,7C),
(1B,2C,3E,4C,5B,6C,7A),(1B,2C,3E,4C,5B,6C,7B)-
,(1B,2C,3E,4C,5B,6C,7C),(1B,2C,3E,4C,5B,6D,7A),(1B,2C,3E,4C,5B,6D,7B),(1B,-
2C,3E,4C,5B,6D,7C),(1B,2C,3E,4D,5A,6A,7A),
(1B,2C,3E,4D,5A,6A,7B),(1B,2C,3-
E,4D,5A,6A,7C),(1B,2C,3E,4D,5A,6B,7A),(1B,2C,3E,4D,5A,6B,7B),
(1B,2C,3E,4D,5A,6B,7C), (1B,2C,3E,4D,5A,6C, 7A),
(1B,2C,3E,4D,5A,6C, 7B),
(1B,2C,3E,4D,5A,6C,7C),(1B,2C,3E,4D,5A,6D,7A),(1B,2C,3E,4D,5A,6D,7B),(1B,-
2C,3E,4D,5A,6D,7C),(1B,2C,3E,4D,5B,6A,7A),(1B,2C,3E,4D,5B,6A,7B),(1B,2C,3E-
,4D,5B,6A,7C),
(1B,2C,3E,4D,5B,6B,7A),(1B,2C,3E,4D,5B,6B,7B),(1B,2C,3E,4D,-
5B,6B,7C),(1B,2C,3E,4D,5B,6C,7A),(1B,2C,3E,4D,5B,6C,7B),(1B,2C,3E,4D,5B,6C-
,7C),(1B,2C,3E,4D,5B,6D,7A),
(1B,2C,3E,4D,5B,6D,7B),(1B,2C,3E,4D,5B,6D,7C)-
,(1B,2C,3E,4E,5A,6A,7A),(1B,2C,3E,4E,5A,6A,7B),(1B,2C,3E,4E,5A,6A,7C),(1B,-
2C,3E,4E,5A,6B,7A),(1B,2C,3E,4E,5A,6B,7B),
(1B,2C,3E,4E,5A,6B,7C),(1B,2C,3-
E,4E,5A,6C,7A),(1B,2C,3E,4E,5A,6C,7B),(1B,2C,3E,4E,5A,6C,7C),(1B,2C,3E,4E,-
5A,6D,7A),(1B,2C,3E,4E,5A,6D,7B),(1B,2C,3E,4E,5A,6D,7C),
(1B,2C,3E,4E,5B,6A,7A),(1B,2C,3E,4E,5B,6A,7B),(1B,2C,3E,4E,5B,6A,7C),(1B,-
2C,3E,4E,5B,6B,7A), (1B,2C,3E,4E,5B,6B,7B),
(1B,2C,3E,4E,5B,6B,7C),(1B,2C,- 3E,4E,5B,6C,7A),
(1B,2C,3E,4E,5B,6C,7B), (1B,2C,3E,4E,5B,6C,7C), (1B,2C,3E,4E,5B,6D,
7A), (1B,2C,3E,4E,5B,6D,7B),(1B,2C,3E,4E,5B,6D,7C),(1-
B,2D,3A,4A,5A,6A,7A),(1B,2D,3A,4A,5A,6A,7B),
(1B,2D,3A,4A,5A,6A,7C),(1B,2D-
,3A,4A,5A,6B,7A),(1B,2D,3A,4A,5A,6B,7B),(1B,2D,3A,4A,5A,6B,7C),(1B,2D,3A,4-
A,5A,6C,7A),(1B,2D,3A,4A,5A,6C,7B),(1B,2D,3A,4A,5A,6C,7C),
(1B,2D,3A,4A,5A,6D,7A),(1B,2D,3A,4A,5A,6D,7B),(1B,2D,3A,4A,5A,6D,7C),(1B,-
2D,3A,4A,5B,6A,7A),(1B,2D,3A,4A,5B,6A,7B),(1B,2D,3A,4A,5B,6A,7C),(1B,2D,3A-
,4A,5B,6B,7A),
(1B,2D,3A,4A,5B,6B,7B),(1B,2D,3A,4A,5B,6B,7C),(1B,2D,3A,4A,-
5B,6C,7A),(1B,2D,3A,4A,5B,6C,7B),(1B,2D,3A,4A,5B,6C,7C),(1B,2D,3A,4A,5B,6D-
,7A),(1B,2D,3A,4A,5B,6D,7B),
(1B,2D,3A,4A,5B,6D,7C),(1B,2D,3A,4B,5A,6A,7A)-
,(1B,2D,3A,4B,5A,6A,7B),(1B,2D,3A,4B,5A,6A,7C),(1B,2D,3A,4B,5A,6B,7A),(1B,-
2D,3A,4B,5A,6B,7B),(1B,2D,3A,4B,5A,6B,7C),
(1B,2D,3A,4B,5A,6C,7A),(1B,2D,3-
A,4B,5A,6C,7B),(1B,2D,3A,4B,5A,6C,7C),(1B,2D,3A,4B,5A,6D,7A),(1B,2D,3A,4B,-
5A,6D,7B),(1B,2D,3A,4B,5A,6D,7C),(1B,2D,3A,4B,5B,6A,7A),
(1B,2D,3A,4B,5B,6A,7B),(1B,2D,3A,4B,5B,6A,7C),(1B,2D,3A,4B,5B,6B,7A),(1B,-
2D,3A,4B,5B,6B,7B),(1B,2D,3A,4B,5B,6B,7C),(1B,2D,3A,4B,5B,6C,7A),(1B,2D,3A-
,4B,5B,6C,7B),
(1B,2D,3A,4B,5B,6C,7C),(1B,2D,3A,4B,5B,6D,7A),(1B,2D,3A,4B,-
5B,6D,7B),(1B,2D,3A,4B,5B,6D,7C),(1B,2D,3A,4C,5A,6A,7A),(1B,2D,3A,4C,5A,6A-
,7B),(1B,2D,3A,4C,5A,6A,7C),
(1B,2D,3A,4C,5A,6B,7A),(1B,2D,3A,4C,5A,6B,7B)-
,(1B,2D,3A,4C,5A,6B,7C),(1B,2D,3A,4C,5A,6C,7A),(1B,2D,3A,4C,5A,6C,7B),(1B,-
2D,3A,4C,5A,6C,7C),(1B,2D,3A,4C,5A,6D,7A),
(1B,2D,3A,4C,5A,6D,7B),(1B,2D,3-
A,4C,5A,6D,7C),(1B,2D,3A,4C,5B,6A,7A),(1B,2D,3A,4C,5B,6A,7B),(1B,2D,3A,4C,-
5B,6A,7C),(1B,2D,3A,4C,5B,6B,7A),(1B,2D,3A,4C,5B,6B,7B),
(1B,2D,3A,4C,5B,6B,7C),(1B,2D,3A,4C,5B,6C,7A),(1B,2D,3A,4C,5B,6C,7B),(1B,-
2D,3A,4C,5B,6C,7C),(1B,2D,3A,4C,5B,6D,7A),(1B,2D,3A,4C,5B,6D,7B),(1B,2D,3A-
,4C,5B,6D,7C),
(1B,2D,3A,4D,5A,6A,7A),(1B,2D,3A,4D,5A,6A,7B),(1B,2D,3A,4D,-
5A,6A,7C),(1B,2D,3A,4D,5A,6B,7A),(1B,2D,3A,4D,5A,6B,7B),(1B,2D,3A,4D,5A,6B-
,7C),(1B,2D,3A,4D,5A,6C,7A),
(1B,2D,3A,4D,5A,6C,7B),(1B,2D,3A,4D,5A,6C,7C)-
,(1B,2D,3A,4D,5A,6D,7A),(1B,2D,3A,4D,5A,6D,7B),(1B,2D,3A,4D,5A,6D,7C),(1B,-
2D,3A,4D,5B,6A,7A),(1B,2D,3A,4D,5B,6A,7B),
(1B,2D,3A,4D,5B,6A,7C),(1B,2D,3-
A,4D,5B,6B,7A),(1B,2D,3A,4D,5B,6B,7B),(1B,2D,3A,4D,5B,6B,7C),(1B,2D,3A,4D,-
5B,6C,7A),(1B,2D,3A,4D,5B,6C,7B),(1B,2D,3A,4D,5B,6C,7C),
(1B,2D,3A,4D,5B,6D,7A),(1B,2D,3A,4D,5B,6D,7B),(1B,2D,3A,4D,5B,6D,7C),(1B,-
2D,3A,4E,5A,6A,7A),
(1B,2D,3A,4E,5A,6A,7B),(1B,2D,3A,4E,5A,6A,7C),(1B,2D,3-
A,4E,5A,6B,7A), (1B,2D,3A,4E,5A,6B,7B),
(1B,2D,3A,4E,5A,6B,7C),(1B,2D,3A,4-
E,5A,6C,7A),(1B,2D,3A,4E,5A,6C,7B),
(1B,2D,3A,4E,5A,6C,7C),(1B,2D,3A,4E,5A-
,6D,7A),(1B,2D,3A,4E,5A,6D,7B), (1B,2D,3A,4E,5A,6D,7C),
(1B,2D,3A,4E,5B,6A,7A),
(1B,2D,3A,4E,5B,6A,7B),(1B,2D,3A,4E,5B,6A,7C),
(1B,2D,3A,4E,5B,6B,7A),(1B,2D,3A,4E,5B,6B,7B),(1B,2D,3A,4E,5B,6B,7C),
(1B,2D,3A,4E,5B,6C,7A), (1B,2D,3A,4E,5B,6C,7B),
(1B,2D,3A,4E,5B,6C,7C), (1B,2D,3A,4E,5B,6D,7A),
(1B,2D,3A,4E,5B,6D,7B),(1B,2D,3A,4E,5B,6D,7C),(1B-
,2D,3B,4A,5A,6A,7A), (1B,2D,3B,4A,5A,6A,7B),
(1B,2D,3B,4A,5A,6A,7C), (1B,2D,3B,4A,5A,6B,7A),
(1B,2D,3B,4A,5A,6B,7B), (1B,2D,3B,4A,5A,6B,7C),(1-
B,2D,3B,4A,5A,6C,7A),(1B,2D,3B,4A,5A,6C,7B),
(1B,2D,3B,4A,5A,6C,7C), (1B,2D,3B,4A,5A,6D,7A),
(1B,2D,3B,4A,5A,6D,7B), (1B,2D,3B,4A,5A,6D,7C),
(1B,2D,3B,4A,5B,6A,7A),(1B,2D,3B,4A,5B,6A,7B),(1B,2D,3B,4A,5B,6A,7C),
(1B,2D,3B,4A,5B,6B,7A), (1B,2D,3B,4A,5B,6B,7B),
(1B,2D,3B,4A,5B,6B,7C), (1B,2D,3B,4A,5B,6C,7A),
(1B,2D,3B,4A,5B,6C,7B),(1B,2D,3B,4A,5B,6C,7C),(1B-
,2D,3B,4A,5B,6D,7A), (1B,2D,3B,4A,5B,6D,7B),
(1B,2D,3B,4A,5B,6D,7C), (1B,2D,3B,4B,5A,6A,7A),
(1B,2D,3B,4B,5A,6A,7B), (1B,2D,3B,4B,5A,6A,7C),(1-
B,2D,3B,4B,5A,6B,7A),(1B,2D,3B,4B,5A,6B,7B),
(1B,2D,3B,4B,5A,6B,7C),(1B,2D-
,3B,4B,5A,6C,7A),(1B,2D,3B,4B,5A,6C,7B),(1B,2D,3B,4B,5A,6C,7C),(1B,2D,3B,4-
B,5A,6D,7A),(1B,2D,3B,4B,5A,6D,7B),(1B,2D,3B,4B,5A,6D,7C),
(1B,2D,3B,4B,5B,6A,7A),(1B,2D,3B,4B,5B,6A,7B),(1B,2D,3B,4B,5B,6A,7C),(1B,-
2D,3B,4B,5B,6B,7A),(1B,2D,3B,4B,5B,6B,7B),(1B,2D,3B,4B,5B,6B,7C),(1B,2D,3B-
,4B,5B,6C,7A),
(1B,2D,3B,4B,5B,6C,7B),(1B,2D,3B,4B,5B,6C,7C),(1B,2D,3B,4B,-
5B,6D,7A),(1B,2D,3B,4B,5B,6D,7B),(1B,2D,3B,4B,5B,6D,7C),(1B,2D,3B,4C,5A,6A-
,7A),(1B,2D,3B,4C,5A,6A,7B),
(1B,2D,3B,4C,5A,6A,7C),(1B,2D,3B,4C,5A,6B,7A)-
,(1B,2D,3B,4C,5A,6B,7B),(1B,2D,3B,4C,5A,6B,7C),(1B,2D,3B,4C,5A,6C,7A),(1B,-
2D,3B,4C,5A,6C,7B),(1B,2D,3B,4C,5A,6C,7C),
(1B,2D,3B,4C,5A,6D,7A),(1B,2D,3-
B,4C,5A,6D,7B),(1B,2D,3B,4C,5A,6D,7C),(1B,2D,3B,4C,5B,6A,7A),(1B,2D,3B,4C,-
5B,6A,7B),(1B,2D,3B,4C,5B,6A,7C),(1B,2D,3B,4C,5B,6B,7A),
(1B,2D,3B,4C,5B,6B,7B),(1B,2D,3B,4C,5B,6B,7C),(1B,2D,3B,4C,5B,6C,7A),(1B,-
2D,3B,4C,5B,6C,7B),(1B,2D,3B,4C,5B,6C,7C),(1B,2D,3B,4C,5B,6D,7A),(1B,2D,3B-
,4C,5B,6D,7B),
(1B,2D,3B,4C,5B,6D,7C),(1B,2D,3B,4D,5A,6A,7A),(1B,2D,3B,4D,-
5A,6A,7B),(1B,2D,3B,4D,5A,6A,7C),(1B,2D,3B,4D,5A,6B,7A),(1B,2D,3B,4D,5A,6B-
,7B),(1B,2D,3B,4D,5A,6B,7C),
(1B,2D,3B,4D,5A,6C,7A),(1B,2D,3B,4D,5A,6C,7B)-
,(1B,2D,3B,4D,5A,6C,7C),(1B,2D,3B,4D,5A,6D,7A),
(1B,2D,3B,4D,5A,6D,7B),(1B-
,2D,3B,4D,5A,6D,7C),(1B,2D,3B,4D,5B,6A,7A), (1B,2D,3B,4D,5B,6A,7B),
(1B,2D,3B,4D,5B,6A,7C), (1B,2D,3B,4D,5B,6B,7A),
(1B,2D,3B,4D,5B,6B,7B),
(1B,2D,3B,4D,5B,6B,7C),(1B,2D,3B,4D,5B,6C,7A),(1B,2D,3B,4D,5B,6C,7B),
(1B,2D,3B,4D,5B,6C,7C), (1B,2D,3B,4D,5B,6D,7A),
(1B,2D,3B,4D,5B,6D,7B), (1B,2D,3B,4D,5B,6D,7C),
(1B,2D,3B,4E,5A,6A,7A),(1B,2D,3B,4E,5A,6A,7B),(1B-
,2D,3B,4E,5A,6A,7C), (1B,2D,3B,4E,5A,6B,7A),
(1B,2D,3B,4E,5A,6B,7B), (1B,2D,3B,4E,5A,6B,7C),
(1B,2D,3B,4E,5A,6C,7A), (1B,2D,3B,4E,5A,6C,7B),(1-
B,2D,3B,4E,5A,6C,7C),(1B,2D,3B,4E,5A,6D, 7A),
(1B,2D,3B,4E,5A,6D,7B),
(1B,2D,3B,4E,5A,6D,7C),(1B,2D,3B,4E,5B,6A,7A),
(1B,2D,3B,4E,5B,6A,7B),
(1B,2D,3B,4E,5B,6A,7C),(1B,2D,3B,4E,5B,6B,7A),(1B,2D,3B,4E,5B,6B,7B),
(1B,2D,3B,4E,5B,6B,7C), (1B,2D,3B,4E,5B,6C,7A),
(1B,2D,3B,4E,5B,6C,7B), (1B,2D,3B,4E,5B,6C,7C),
(1B,2D,3B,4E,5B,6D,7A), (1B,2D,3B,4E,5B,6D,7B), (1B,2D,3B,4E,5B,6D,
7C), (1B,2D,3C,4A,5A,6A,7A), (1B,2D,3C,4A,5A,6A,7B),
(1B,2D,3C,4A,5A,6A,7C), (1B,2D,3C,4A,5A,6B,7A),
(1B,2D,3C,4A,5A,6B,7B), (1B,2D,3C,4A,5A,6B,7C), (1B,2D,3C,4A,5A,6C,
7A), (1B,2D,3C,4A,5A,6C,7B), (B,2D,3C,4A,5A,6C,7C),
(1B,2D,3C,4A,5A,6D,7A),(1B,2D,3C,4A,5A,6D,7B),
(1B,2D,3C,4A,5A,6D,7C),(1B,2D,3C,4A,5B,6A,7A),(1B,2D,3C,4A,5B,6A,7B),
(1B,2D,3C,4A,5B,6A,7C), (1B,2D,3C,4A,5B,6B,7A),
(1B,2D,3C,4A,5B,6B,7B), (1B,2D,3C,4A,5B,6B,7C),
(1B,2D,3C,4A,5B,6C,7A), (1B,2D,3C,4A,5B,6C,7B),(1-
B,2D,3C,4A,5B,6C,7C), (1B,2D,3C,4A,5B,6D,7A),
(1B,2D,3C,4A,5B,6D,7B),(1B,2- D,3C,4A,5B,6D,7C),
(1B,2D,3C,4B,5A,6A,7A), (1B,2D,3C,4B,5A,6A,7B),
(1B,2D,3C,4B,5A,6A,7C),(1B,2D,3C,4B,5A,6B,7A),
(1B,2D,3C,4B,5A,6B,7B),(1B-
,2D,3C,4B,5A,6B,7C),(1B,2D,3C,4B,5A,6C,7A), (1B,2D,3C,4B,5A,6C,
7B), (1B,2D,3C,4B,5A,6C,7C),
(1B,2D,3C,4B,5A,6D,7A),(1B,2D,3C,4B,5A,6D,7B),
(1B,2D,3C,4B,5A,6D,7C), (1B,2D,3C,4B,5B,6A,7A),
(1B,2D,3C,4B,5B,6A,7B), (1B,2D,3C,4B,5B,6A,7C),
(1B,2D,3C,4B,5B,6B,7A),(1B,2D,3C,4B,5B,6B,7B),(1B-
,2D,3C,4B,5B,6B,7C), (1B,2D,3C,4B,5B,6C,7A),
(1B,2D,3C,4B,5B,6C,7B), (1B,2D,3C,4B,5B,6C,7C),
(1B,2D,3C,4B,5B,6D,7A), (1B,2D,3C,4B,5B,6D,7B),(1-
B,2D,3C,4B,5B,6D,7C),(1B,2D,3C,4C,5A,6A,7A),
(1B,2D,3C,4C,5A,6A,7B), (1B,2D,3C,4C,5A,6A,7C),
(1B,2D,3C,4C,5A,6B,7A), (1B,2D,3C,4C,5A,6B,7B),
(1B,2D,3C,4C,5A,6B,7C),(1B,2D,3C,4C,5A,6C,7A),(1B,2D,3C,4C,5A,6C,7B),
(1B,2D,3C,4C,5A,6C,7C),(1B,2D,3C,4C,5A,6D,7A),
(1B,2D,3C,4C,5A,6D,7B), (1B,2D,3C,4C,5A,6D,7C),
(1B,2D,3C,4C,5B,6A,7A),(1B,2D,3C,4C,5B,6A,7B),(1B-
,2D,3C,4C,5B,6A,7C), (1B,2D,3C,4C,5B,6B,7A),
(1B,2D,3C,4C,5B,6B,7B),(1B,2D- ,3C,4C,5B,6B,7C),
(1B,2D,3C,4C,5B,6C,7A),(1B,2D,3C,4C,5B,6C,7B),(1B,2D,3C,-
4C,5B,6C,7C),(1B,2D,3C,4C,5B,6D,7A),
(1B,2D,3C,4C,5B,6D,7B),(1B,2D,3C,4C,5-
B,6D,7C),(1B,2D,3C,4D,5A,6A,7A),(1B,2D,3C,4D,5A,6A,7B),(1B,2D,3C,4D,5A,6A,-
7C),(1B,2D,3C,4D,5A,6B,7A),(1B,2D,3C,4D,5A,6B,7B),
(1B,2D,3C,4D,5A,6B,7C),-
(1B,2D,3C,4D,5A,6C,7A),(1B,2D,3C,4D,5A,6C,7B),(1B,2D,3C,4D,5A,6C,7C),(1B,2-
D,3C,4D,5A,6D,7A),(1B,2D,3C,4D,5A,6D,7B),(1B,2D,3C,4D,5A,6D,7C),
(1B,2D,3C,4D,5B,6A,7A),(1B,2D,3C,4D,5B,6A,7B),(1B,2D,3C,4D,5B,6A,7C),(1B,-
2D,3C,4D,5B,6B,7A),(1B,2D,3C,4D,5B,6B,7B),(1B,2D,3C,4D,5B,6B,7C),(1B,2D,3C-
,4D,5B,6C,7A),
(1B,2D,3C,4D,5B,6C,7B),(1B,2D,3C,4D,5B,6C,7C),(1B,2D,3C,4D,-
5B,6D,7A),(1B,2D,3C,4D,5B,6D,7B),(1B,2D,3C,4D,5B,6D,7C),(1B,2D,3C,4E,5A,6A-
,7A),(1B,2D,3C,4E,5A,6A,7B),
(1B,2D,3C,4E,5A,6A,7C),(1B,2D,3C,4E,5A,6B,7A)-
,(1B,2D,3C,4E,5A,6B,7B),(1B,2D,3C,4E,5A,6B,7C),(1B,2D,3C,4E,5A,6C,7A),(1B,-
2D,3C,4E,5A,6C,7B),(1B,2D,3C,4E,5A,6C,7C),
(1B,2D,3C,4E,5A,6D,7A),(1B,2D,3-
C,4E,5A,6D,7B),(1B,2D,3C,4E,5A,6D,7C),(1B,2D,3C,4E,5B,6A,7A),(1B,2D,3C,4E,-
5B,6A,7B),(1B,2D,3C,4E,5B,6A,7C),(1B,2D,3C,4E,5B,6B,7A),
(1B,2D,3C,4E,5B,6B,7B),(1B,2D,3C,4E,5B,6B,7C),(1B,2D,3C,4E,5B,6C,7A),(1B,-
2D,3C,4E,5B,6C,7B),(1B,2D,3C,4E,5B,6C,7C),(1B,2D,3C,4E,5B,6D,7A),(1B,2D,3C-
,4E,5B,6D,7B),
(1B,2D,3C,4E,5B,6D,7C),(1B,2D,3D,4A,5A,6A,7A),(1B,2D,3D,4A,-
5A,6A,7B),(1B,2D,3D,4A,5A,6A,7C),(1B,2D,3D,4A,5A,6B,7A),(1B,2D,3D,4A,5A,6B-
,7B),(1B,2D,3D,4A,5A,6B,7C),
(1B,2D,3D,4A,5A,6C,7A),(1B,2D,3D,4A,5A,6C,7B)-
,(1B,2D,3D,4A,5A,6C,7C),(1B,2D,3D,4A,5A,6D,7A),(1B,2D,3D,4A,5A,6D,7B),(1B,-
2D,3D,4A,5A,6D,7C),(1B,2D,3D,4A,5B,6A,7A),
(1B,2D,3D,4A,5B,6A,7B),(1B,2D,3-
D,4A,5B,6A,7C),(1B,2D,3D,4A,5B,6B,7A),(1B,2D,3D,4A,5B,6B,7B),(1B,2D,3D,4A,-
5B,6B,7C),(1B,2D,3D,4A,5B,6C,7A),(1B,2D,3D,4A,5B,6C,7B),
(1B,2D,3D,4A,5B,6C,7C),(1B,2D,3D,4A,5B,6D,7A),(1B,2D,3D,4A,5B,6D,7B),(1B,-
2D,3D,4A,5B,6D,7C),(1B,2D,3D,4B,5A,6A,7A),(1B,2D,3D,4B,5A,6A,7B),(1B,2D,3D-
,4B,5A,6A,7C),
(1B,2D,3D,4B,5A,6B,7A),(1B,2D,3D,4B,5A,6B,7B),(1B,2D,3D,4B,-
5A,6B,7C),(1B,2D,3D,4B,5A,6C,7A),(1B,2D,3D,4B,5A,6C,7B),(1B,2D,3D,4B,5A,6C-
,7C),(1B,2D,3D,4B,5A,6D,7A),
(1B,2D,3D,4B,5A,6D,7B),(1B,2D,3D,4B,5A,6D,7C)-
,(1B,2D,3D,4B,5B,6A,7A),(1B,2D,3D,4B,5B,6A,7B),(1B,2D,3D,4B,5B,6A,7C),(1B,-
2D,3D,4B,5B,6B,7A),(1B,2D,3D,4B,5B,6B,7B),
(1B,2D,3D,4B,5B,6B,7C),(1B,2D,3-
D,4B,5B,6C,7A),(1B,2D,3D,4B,5B,6C,7B),(1B,2D,3D,4B,5B,6C,7C),(1B,2D,3D,4B,-
5B,6D,7A),(1B,2D,3D,4B,5B,6D,7B),(1B,2D,3D,4B,5B,6D,7C),
(1B,2D,3D,4C,5A,6A,7A),(1B,2D,3D,4C,5A,6A,7B),(1B,2D,3D,4C,5A,6A,7C),(1B,-
2D,3D,4C,5A,6B,7A),
(1B,2D,3D,4C,5A,6B,7B),(1B,2D,3D,4C,5A,6B,7C),(1B,2D,3-
D,4C,5A,6C,7A), (1B,2D,3D,4C,5A,6C,7B), (1B,2D,3D,4C,5A,6C,7C),
(1B,2D,3D,4C,5A,6D,7A), (1B,2D,3D,4C,5A,6D,7B),
(1B,2D,3D,4C,5A,6D,7C),(1-
B,2D,3D,4C,5B,6A,7A),(1B,2D,3D,4C,5B,6A,7B),
(1B,2D,3D,4C,5B,6A,7C), (1B,2D,3D,4C,5B,6B,7A),
(1B,2D,3D,4C,5B,6B,7B), (1B,2D,3D,4C,5B,6B,7C),
(1B,2D,3D,4C,5B,6C,7A),(1B,2D,3D,4C,5B,6C,7B),(1B,2D,3D,4C,5B,6C,7C),
(1B,2D,3D,4C,5B,6D,7A), (1B,2D,3D,4C,5B,6D,7B),
(1B,2D,3D,4C,5B,6D,7C), (1B,2D,3D,4D,5A,6A,7A),
(1B,2D,3D,4D,5A,6A,7B),(1B,2D,3D,4D,5A,6A,7C),(1B-
,2D,3D,4D,5A,6B,7A), (1B,2D,3D,4D,5A,6B,7B),(1B,2D,3D,4D,5A,6B,7C),
(B,2D,3D,4D,5A,6C,7A),(1B,2D,3D,4D,5A,6C,7B),
(1B,2D,3D,4D,5A,6C,7C),(1B,-
2D,3D,4D,5A,6D,7A),(1B,2D,3D,4D,5A,6D,7B),
(1B,2D,3D,4D,5A,6D,7C),(1B,2D,3- D,4D,5B,6A,7A),
(1B,2D,3D,4D,5B,6A,7B),(1B,2D,3D,4D,5B,6A,7C),
(1B,2D,3D,4D,5B,6B,7A),
(B,2D,3D,4D,5B,6B,7B),(1B,2D,3D,4D,5B,6B,7C),
(1B,2D,3D,4D,5B,6C,7A), (1B,2D,3D,4D,5B,6C,7B),
(1B,2D,3D,4D,5B,6C,7C),(1- B,2D,3D,4D,5B,6D,7A),
(1B,2D,3D,4D,5B,6D,7B),(1B,2D,3D,4D,5B,6D,7C),(1B,2D-
,3D,4E,5A,6A,7A), (1B,2D,3D,4E,5A,6A,7B), (1B,2D,3D,4E,5A,6A,7C),
(1B,2D,3D,4E,5A,6B,7A), (1B,2D,3D,4E,5A,6B, 7B),
(1B,2D,3D,4E,5A,6B,7C),(-
1B,2D,3D,4E,5A,6C,7A),(1B,2D,3D,4E,5A,6C,7B),
(1B,2D,3D,4E,5A,6C,7C),(1B,2-
D,3D,4E,5A,6D,7A),(1B,2D,3D,4E,5A,6D,7B),(1B,2D,3D,4E,5A,6D,7C),(1B,2D,3D,-
4E,5B,6A,7A),(1B,2D,3D,4E,5B,6A,7B),(1B,2D,3D,4E,5B,6A,7C),
(1B,2D,3D,4E,5B,6B,7A),(1B,2D,3D,4E,5B,6B,7B),(1B,2D,3D,4E,5B,6B,7C),(1B,-
2D,3D,4E,5B,6C,7A),(1B,2D,3D,4E,5B,6C,7B),(1B,2D,3D,4E,5B,6C,7C),(1B,2D,3D-
,4E,5B,6D,7A),
(1B,2D,3D,4E,5B,6D,7B),(1B,2D,3D,4E,5B,6D,7C),(1B,2D,3E,4A,-
5A,6A,7A),(1B,2D,3E,4A,5A,6A,7B),(1B,2D,3E,4A,5A,6A,7C),(1B,2D,3E,4A,5A,6B-
,7A),(1B,2D,3E,4A,5A,6B,7B),
(1B,2D,3E,4A,5A,6B,7C),(1B,2D,3E,4A,5A,6C,7A)-
,(1B,2D,3E,4A,5A,6C,7B),(1B,2D,3E,4A,5A,6C,7C),(1B,2D,3E,4A,5A,6D,7A),(1B,-
2D,3E,4A,5A,6D,7B),(1B,2D,3E,4A,5A,6D,7C),
(1B,2D,3E,4A,5B,6A,7A),(1B,2D,3-
E,4A,5B,6A,7B),(1B,2D,3E,4A,5B,6A,7C),(1B,2D,3E,4A,5B,6B,7A),(1B,2D,3E,4A,-
5B,6B,7B),(1B,2D,3E,4A,5B,6B,7C),(1B,2D,3E,4A,5B,6C,7A),
(1B,2D,3E,4A,5B,6C,7B),(1B,2D,3E,4A,5B,6C,7C),(1B,2D,3E,4A,5B,6D,7A),(1B,-
2D,3E,4A,5B,6D,7B),(1B,2D,3E,4A,5B,6D,7C),(1B,2D,3E,4B,5A,6A,7A),(1B,2D,3E-
,4B,5A,6A,7B),
(1B,2D,3E,4B,5A,6A,7C),(1B,2D,3E,4B,5A,6B,7A),(1B,2D,3E,4B,-
5A,6B,7B),(1B,2D,3E,4B,5A,6B,7C),(1B,2D,3E,4B,5A,6C,7A),(1B,2D,3E,4B,5A,6C-
,7B),(1B,2D,3E,4B,5A,6C,7C),
(1B,2D,3E,4B,5A,6D,7A),(1B,2D,3E,4B,5A,6D,7B)-
,(1B,2D,3E,4B,5A,6D,7C),(1B,2D,3E,4B,5B,6A,7A),
(1B,2D,3E,4B,5B,6A,7B),(1B-
,2D,3E,4B,5B,6A,7C),(1B,2D,3E,4B,5B,6B,7A), (1B,2D,3E,4B,5B,6B,7B),
(1B,2D,3E,4B,5B,6B,7C), (1B,2D,3E,4B,5B,6C, 7A),
(1B,2D,3E,4B,5B,6C,7B),
(1B,2D,3E,4B,5B,6C,7C),(1B,2D,3E,4B,5B,6D,7A),(1B,2D,3E,4B,5B,6D,7B),
(1B,2D,3E,4B,5B,6D,7C), (1B,2D,3E,4C,5A,6A,7A),
(1B,2D,3E,4C,5A,6A,7B), (1B,2D,3E,4C,5A,6A,7C),
(1B,2D,3E,4C,5A,6B,7A),(1B,2D,3E,4C,5A,6B,7B),(1B-
,2D,3E,4C,5A,6B,7C),
(1B,2D,3E,4C,5A,6C,7A),(1B,2D,3E,4C,5A,6C,7B),(1B,2D,-
3E,4C,5A,6C,7C),(1B,2D,3E,4C,5A,6D,7A),
(1B,2D,3E,4C,5A,6D,7B),(1B,2D,3E,4-
C,5A,6D,7C),(1B,2D,3E,4C,5B,6A,7A),
(1B,2D,3E,4C,5B,6A,7B),(1B,2D,3E,4C,5B-
,6A,7C),(1B,2D,3E,4C,5B,6B,7A),(1B,2D,3E,4C,5B,6B,7B),(1B,2D,3E,4C,5B,6B,7-
C),(1B,2D,3E,4C,5B,6C,7A),(1B,2D,3E,4C,5B,6C,7B),
(1B,2D,3E,4C,5B,6C,7C),(-
1B,2D,3E,4C,5B,6D,7A),(1B,2D,3E,4C,5B,6D,7B),(1B,2D,3E,4C,5B,6D,7C),(1B,2D-
,3E,4D,5A,6A37A),(1B,2D,3E,4D,5A,6A,7B),(1B,2D33E,4D,5A,6A,7C),
(1B,2D,3E,4D,5A,6B,7A),(1B,2D,3E,4D,5A,6B,7B),(1B,2D,3E,4D,5A,6B,7C),(1B,-
2D,3E,4D,5A,6C,7A),(1B,2D,3E,4D,5A,6C,7B),(1B,2D,3E,4D,5A,6C,7C),(1B,2D,3E-
,4D,5A,6D,7A),
(1B,2D,3E,4D,5A,6D,7B),(1B,2D,3E,4D,5A,6D,7C),(1B,2D,3E,4D,-
5B,6A,7A),(1B,2D,3E,4D,5B,6A,7B),(1B,2D,3E,4D,5B,6A,7C),(1B,2D,3E,4D,5B,6B-
,7A),(1B,2D,3E,4D,5B,6B,7B),
(1B,2D,3E,4D,5B,6B,7C),(1B,2D,3E,4D,5B,6C,7A)-
,(1B,2D,3E,4D,5B,6C,7B),(1B,2D,3E,4D,5B,6C,7C),(1B,2D,3E,4D,5B,6D,7A),(1B,-
2D,3E,4D,5B,6D,7B),(1B,2D,3E,4D,5B,6D,7C),
(1B,2D,3E,4E,5A,6A,7A),(1B,2D,3-
E,4E,5A,6A,7B),(1B,2D,3E,4E,5A,6A,7C),(1B,2D,3E,4.
E,5A,6B,7A),(1B,2D,3E,4-
E,5A,6B,7B),(1B,2D,3E,4E,5A,6B,7C),(1B,2D,3E,4E,5A,6C,7A),
(1B,2D,3E,4E,5A,6C,7B),(1B,2D,3E,4E,5A,6C,7C),(1B,2D,3E,4E,5A,6D,7A),(1B,-
2D,3E,4E,5A,6D,7B),(1B,2D,3E,4E,5A,6D,7C),(1B,2D,3E,4E,5B,6A,7A),(1B,2D,3E-
,4E,5B,6A,7B),
(1B,2D,3E,4E,5B,6A,7C),(1B,2D,3E,4E,5B,6B,7A),(1B,2D,3E,4E,-
5B,6B,7B),(1B,2D,3E,4E,5B,6B,7C),(1B,2D,3E,4E,5B,6C,7A),(1B,2D,3E,4E,5B,6C-
,7B),(1B,2D,3E,4E,5B,6C,7C),
(1B,2D,3E,4E,5B,6D,7A),(1B,2D,3E,4E,5B,6D,7B)-
,(1B,2D,3E,4E,5B,6D,7C),(1B,2E,3A,4A,5A,6A,7A),(1B,2E,3A,4A,5A,6A,7B),(1B,-
2E,3A,4A,5A,6A,7C),(1B,2E,3A,4A,5A,6B,7A),
(1B,2E,3A,4A,5A,6B,7B),(1B,2E,3-
A,4A,5A,6B,7C),(1B,2E,3A,4A,5A,6C,7A),(1B,2E,3A,4A,5A,6C,7B),(1B,2E,3A,4A,-
5A,6C,7C),(1B,2E,3A,4A,5A,6D,7A),(1B,2E,3A,4A,5A,6D,7B),
(1B,2E,3A,4A,5A,6D,7C),(1B,2E,3A,4A,5B,6A,7A),(1B,2E,3A,4A,5B,6A,7B),(1B,-
2E,3A,4A,5B,6A,7C),(1B,2E,3A,4A,5B,6B,7A),(1B,2E,3A,4A,5B,6B,7B),(1B,2E,3A-
,4A,5B,6B,7C),
(1B,2E,3A,4A,5B,6C,7A),(1B,2E,3A,4A,5B,6C,7B),(1B,2E,3A,4A,-
5B,6C,7C),(1B,2E,3A,4A,5B,6D,7A),
(1B,2E,3A,4A,5B,6D,7B),(1B,2E,3A,4A,5B,6-
D,7C),(1B,2E,3A,4B,5A,6A,7A),
(1B,2E,3A,4B,5A,6A,7B),(1B,2E,3A,4B,5A,6A,7C-
),(1B,2E,3A,4B,5A,6B,7A),(1B,2E,3A,4B,5A,6B,7B),
(1B,2E,3A,4B,5A,6B,7C),(1-
B,2E,3A,4B,5A,6C,7A),(1B,2E,3A,4B,5A,6C,7B),
(1B,2E,3A,4B,5A,6C,7C), (1B,2E,3A,4B,5A,6D,7A),
(1B,2E,3A,4B,5A,6D,7B), (1B,2E,3A,4B,5A,6D,7C),(1-
B,2E,3A,4B,5B,6A,7A),(1B,2E,3A,4B,5B,6A,7B),(1B,2E,3A,4B,5B,6A,7C),
(1B,2E,3A,4B,5B,6B,7A),(1B,2E,3A,4B,5B,6B,7B),(1B,2E,3A,4B,5B,6B,7C),(1B,-
2E,3A,4B,5B,6C,7A),(1B,2E,3A,4B,5B,6C,7B),(1B,2E,3A,4B,5B,6C,7C),(1B,2E,3A-
,4B,5B,6D,7A),
(1B,2E,3A,4B,5B,6D,7B),(1B,2E,3A,4B,5B,6D,7C),(1B,2E,3A,4C,-
5A,6A,7A),(1B,2E,3A,4C,5A,6A,7B), (1B,2E,3A,4C,5A,6A,7C),
(1B,2E,3A,4C,5A,6B,7A), (1B,2E,3A,4C,5A,6B,7B),
(1B,2E,3A,4C,5A,6B,7C), (1B,2E,3A,4C,5A,6C,7A),
(1B,2E,3A,4C,5A,6C,7B), (1B,2E,3A,4C,5A,6C,7C),
(1B,2E,3A,4C,5A,6D,7A),(1B,2E,3A,4C,5A,6D,7B),(1B,2E,3A,4C,5A,6D,7C),
(1B,2E,3A,4C,5B,6A,7A), (1B,2E,3A,4C,5B,6A,7B),
(1B,2E,3A,4C,5B,6A,7C),
(1B,2E,3A,4C,5B,6B,7A),(1B,2E,3A,4C,5B,6B,7B),(1B,2E,3A,4C,5B,6B,7C),(1B,-
2E,3A,4C,5B,6C,7A), (1B,2E,3A,4C,5B,6C,7B), (1B,2E,3A,4C,5B,6C,7C),
(1B,2E,3A,4C,5B,6D,7A),
(1B,2E,3A,4C,5B,6D,7B),(1B,2E,3A,4C,5B,6D,7C),(1B-
,2E,3A,4D,5A,6A,7A),(1B,2E,3A,4D,5A,6A,7B), (1B,2E,3A,4D,5A,6A,7C),
(1B,2E,3A,4D,5A,6B,7A), (1B,2E,3A,4D,5A,6B,7B),
(1B,2E,3A,4D,5A,6B,7C),
(1B,2E,3A,4D,5A,6C,7A),(1B,2E,3A,4D,5A,6C,7B),(1B,2E,3A,4D,5A,6C,7C),
(1B,2E,3A,4D,5A,6D,7A), (1B,2E,3A,4D,5A,6D,7B),
(1B,2E,3A,4D,5A,6D,7C),(1- B,2E,3A,4D,5B,6A,7A),
(1B,2E,3A,4D,5B,6A,7B), (1B,2E,3A,4D,5B,6A,7C),(1B,2-
E,3A,4D,5B,6B,7A), (1B,2E,3A,4D,5B,6B,7B), (1B,2E,3A,4D,5B,6B,7C),
(1B,2E,3A,4D,5B,6C,7A),
(1B,2E,3A,4D,5B,6C,7B),(1B,2E,3A,4D,5B,6C,7C),(1B-
,2E,3A,4D,5B,6D,7A),(1B,2E,3A,4D,5B,6D,7B), (1B,2E,3A,4D,5B,6D,7C),
(1B,2E,3A,4E,5A,6A,7A), (1B,2E,3A,4E,5A,6A,7B),
(B,2E,3A,4E,5A,6A,7C),
(1B,2E,3A,4E,5A,6B,7A),(1B,2E,3A,4E,5A,6B,7B),(1B,2E,3A,4E,5A,6B,7C),
(1B,2E,3A,4E,5A,6C,7A), (1B,2E,3A,4E,5A,6C,7B),
(1B,2E,3A,4E,5A,6C,7C),(1- B,2E,3A,4E,5A,6D,7A),
(1B,2E,3A,4E,5A,6D,7B),(1B,2E,3A,4E,5A,6D,7C),(1B,2E-
,3A,4E,5B,6A,7A), (1B,2E,3A,4E,5B,6A,7B), (1B,2E,3A,4E,5B,6A,7C),
(1B,2E,3A,4E,5B,6B,7A), (1B,2E,3A,4E,5B,6B,7B),
(1B,2E,3A,4E,5B,6B,7C), (1B,2E,3A,4E,5B,6C,7A),
(1B,2E,3A,4E,5B,6C,7B), (1B,2E,3A,4E,5B,6C,7C),
(1B,2E,3A,4E,5B,6D,7A), (1B,2E,3A,4E,5B,6D, 7B), (1B,2E,3A,4E,
5B,6D,7C), (1B,2E,3B,4A,5A,6A,7A), (1B,2E,3B,4A,5A,6A, 7B),
(1B,2E,3B,4A,5A,6A, 7C), (1B,2E,3B,4A,5A,6B,7A),
(1B,2E,3B,4A,5A,6B,7B), (1B,2E,3B,4A,5A,6B,7C),
(1B,2E,3B,4A,5A,6C,7A),(1B,2E,3B,4A,5A,6C,7B),(1B,2E,3B,4A,5A,6C,7C),(1B,-
2E,3B,4A,5A,6D,7A),
(1B,2E,3B,4A,5A,6D,7B),(1B,2E,3B,4A,5A,6D,7C),(1B,2E,3-
B,4A,5B,6A,7A),(1B,2E,3B,4A,5B,6A,7B),(1B,2E,3B,4A,5B,6A,7C),(1B,2E,3B,4A,-
5B,6B,7A),(1B,2E,3B,4A,5B,6B,7B),
(1B,2E,3B,4A,5B,6B,7C),(1B,2E,3B,4A,5B,6-
C,7A),(1B,2E,3B,4A,5B,6C,7B),(1B,2E,3B,4A,5B,6C,7C),(1B,2E,3B,4A,5B,6D,7A)-
,(1B,2E,3B,4A,5B,6D,7B),(1B,2E,3B,4A,5B,6D,7C),
(1B,2E,3B,4B,5A,6A,7A),(1B-
,2E,3B,4B,5A,6A,7B),(1B,2E,3B,4B,5A,6A,7C),(1B,2E,3B,4B,5A,6B,7A),(1B,2E,3-
B,4B,5A,6B,7B),(1B,2E,3B,4B,5A,6B,7C),(1B,2E,3B,4B,5A,6C,7A),
(1B,2E,3B,4B,5A,6C,7B),(1B,2E,3B,4B,5A,6C,7C),(1B,2E,3B,4B,5A,6D,7A),(1B,-
2E,3B,4B,5A,6D,7B),(1B,2E,3B,4B,5A,6D,7C),(1B,2E,3B,4B,5B,6A,7A),(1B,2E,3B-
,4B,5B,6A,7B),
(1B,2E,3B,4B,5B,6A,7C),(1B,2E,3B,4B,5B,6B,7A),(1B,2E,3B,4B,-
5B,6B,7B),(1B,2E,3B,4B,5B,6B,7C),(1B,2E,3B,4B,5B,6C,7A),(1B,2E,3B,4B,5B,6C-
,7B),(1B,2E,3B,4B,5B,6C,7C),
(1B,2E,3B,4B,5B,6D,7A),(1B,2E,3B,4B,5B,6D,7B)-
,(1B,2E,3B,4B,5B,6D,7C),(1B,2E,3B,4C,5A,6A,7A),(1B,2E,3B,4C,5A,6A,7B),(1B,-
2E,3B,4C,5A,6A,7C),(1B,2E,3B,4C,5A,6B,7A),
(1B,2E,3B,4C,5A,6B,7B),(1B,2E,3-
B,4C,5A,6B,7C),(1B,2E,3B,4C,5A,6C,7A),(1B,2E,3B,4C,5A,6C,7B),(1B,2E,3B,4C,-
5A,6C,7C),(1B,2E,3B,4C,5A,6D,7A),(1B,2E,3B,4C,5A,6D,7B),
(1B,2E,3B,4C,5A,6D,7C),(1B,2E,3B,4C,5B,6A,7A),(1B,2E,3B,4C,5B,6A,7B),(1B,-
2E,3B,4C,5B,6A,7C),(1B,2E,3B,4C,5B,6B,7A),(1B,2E,3B,4C,5B,6B,7B),(1B,2E,3B-
,4C,5B,6B,7C),
(1B,2E,3B,4C,5B,6C,7A),(1B,2E,3B,4C,5B,6C,7B),(1B,2E,3B,4C,-
5B,6C,7C),(1B,2E,3B,4C,5B,6D,7A),(1B,2E,3B,4C,5B,6D,7B),(1B,2E,3B,4C,5B,6D-
,7C),(1B,2E,3B,4D,5A,6A,7A),
(1B,2E,3B,4D,5A,6A,7B),(1B,2E,3B,4D,5A,6A,7C)-
,(1B,2E,3B,4D,5A,6B,7A),(1B,2E,3B,4D,5A,6B,7B),(1B,2E,3B,4D,5A,6B,7C),(1B,-
2E,3B,4D,5A,6C,7A),(1B,2E,3B,4D,5A,6C,7B),
(1B,2E,3B,4D,5A,6C,7C),(1B,2E,3-
B,4D,5A,6D,7A),(1B,2E,3B,4D,5A,6D,7B),(1B,2E,3B,4D,5A,6D,7C),(1B,2E,3B,4D,-
5B,6A,7A),(1B,2E,3B,4D,5B,6A,7B),(1B,2E,3B,4D,5B,6A,7C),
(1B,2E,3B,4D,5B,6B,7A),(1B,2E,3B,4D,5B,6B,7B),(1B,2E,3B,4D,5B,6B,7C),(1B,-
2E,3B,4D,5B,6C,7A),(1B,2E,3B,4D,5B,6C,7B),(1B,2E,3B,4D,5B,6C,7C),(1B,2E,3B-
,4D,5B,6D,7A),
(1B,2E,3B,4D,5B,6D,7B),(1B,2E,3B,4D,5B,6D,7C),(1B,2E,3B,4E,-
5A,6A,7A),(1B,2E,3B,4E,5A,6A,7B),(1B,2E,3B,4E,5A,6A,7C),(1B,2E,3B,4E,5A,6B-
,7A),(1B,2E,3B,4E,5A,6B,7B),
(1B,2E,3B,4E,5A,6B,7C),(1B,2E,3B,4E,5A,6C,7A)-
,(1B,2E,3B,4E,5A,6C,7B),(1B,2E,3B,4E,5A,6C,7C),(1B,2E,3B,4E,5A,6D,7A),(1B,-
2E,3B,4E,5A,6D,7B),(1B,2E,3B,4E,5A,6D,7C),
(1B,2E,3B,4E,5B,6A,7A),(1B,2E,3-
B,4E,5B,6A,7B),(1B,2E,3B,4E,5B,6A,7C),(1B,2E,3B,4E,5B,6B,7A),
(1B,2E,3B,4E,5B,6B,7B),(1B,2E,3B,4E,5B,6B,7C),(1B,2E,3B,4E,5B,6C,7A),
(1B,2E,3B,4E,5B,6C,7B),(1B,2E,3B,4E,5B,6C,7C),(1B,2E,3B,4E,5B,6D,7A),(1B,-
2E,3B,4E,5B,6D,7B),(1B,2E,3B,4E,5B,6D,7C),(1B,2E,3C,4A,5A,6A,7A),(1B,2E,3C-
,4A,5A,6A,7B),
(1B,2E,3C,4A,5A,6A,7C),(1B,2E,3C,4A,5A,6B,7A),(1B,2E,3C,4A,-
5A,6B,7B),(1B,2E,3C,4A,5A,6B,7C),(1B,2E,3C,4A,5A,6C,7A),(1B,2E,3C,4A,5A,6C-
,7B),(1B,2E,3C,4A,5A,6C,7C),
(1B,2E,3C,4A,5A,6D,7A),(1B,2E,3C,4A,5A,6D,7B)-
,(1B,2E,3C,4A,5A,6D,7C),(1B,2E,3C,4A,5B,6A,7A),(1B,2E,3C,4A,5B,6A,7B),(1B,-
2E,3C,4A,5B,6A,7C),(1B,2E,3C,4A,5B,6B,7A),
(1B,2E,3C,4A,5B,6B,7B),(1B,2E,3-
C,4A,5B,6B,7C),(1B,2E,3C,4A,5B,6C,7A),(1B,2E,3C,4A,5B,6C,7B),(1B,2E,3C,4A,-
5B,6C,7C),(1B,2E,3C,4A,5B,6D,7A),(1B,2E,3C,4A,5B,6D,7B),
(1B,2E,3C,4A,5B,6D,7C),(1B,2E,3C,4B,5A,6A,7A),(1B,2E,3C,4B,5A,6A,7B),(1B,-
2E,3C,4B,5A,6A,7C),(1B,2E,3C,4B,5A,6B,7A),(1B,2E,3C,4B,5A,6B,7B),(1B,2E,3C-
,4B,5A,6B,7C),
(1B,2E,3C,4B,5A,6C,7A),(1B,2E,3C,4B,5A,6C,7B),(1B,2E,3C,4B,-
5A,6C,7C),(1B,2E,3C,4B,5A,6D,7A),(1B,2E,3C,4B,5A,6D,7B),(1B,2E,3C,4B,5A,6D-
,7C),(1B,2E,3C,4B,5B,6A,7A),
(1B,2E,3C,4B,5B,6A,7B),(1B,2E,3C,4B,5B,6A,7C)-
,(1B,2E,3C,4B,5B,6B,7A),(1B,2E,3C,4B,5B,6B,7B),(1B,2E,3C,4B,5B,6B,7C),(1B,-
2E,3C,4B,5B,6C,7A),(1B,2E,3C,4B,5B,6C,7B),
(1B,2E,3C,4B,5B,6C,7C),(1B,2E,3-
C,4B,5B,6D,7A),(1B,2E,3C,4B,5B,6D,7B),(1B,2E,3C,4B,5B,6D,7C),(1B,2E,3C,4C,-
5A,6A,7A),(1B,2E,3C,4C,5A,6A,7B),(1B,2E,3C,4C,5A,6A,7C),
(1B,2E,3C,4C,5A,6B,7A),(1B,2E,3C,4C,5A,6B,7B),(1B,2E,3C,4C,5A,6B,7C),(1B,-
2E,3C,4C,5A,6C,7A),(1B,2E,3C,4C,5A,6C,7B),(1B,2E,3C,4C,5A,6C,7C),(1B,2E,3C-
,4C,5A,6D,7A),
(1B,2E,3C,4C,5A,6D,7B),(1B,2E,3C,4C,5A,6D,7C),(1B,2E,3C,4C,-
5B,6A,7A),(1B,2E,3C,4C,5B,6A,7B),(1B,2E,3C,4C,5B,6A,7C),(1B,2E,3C,4C,5B,6B-
,7A),(1B,2E,3C,4C,5B,6B,7B),
(1B,2E,3C,4C,5B,6B,7C),(1B,2E,3C,4C,5B,6C,7A)-
,(1B,2E,3C,4C,5B,6C,7B),(1B,2E,3C,4C,5B,6C,7C),(1B,2E,3C,4C,5B,6D,7A),(1B,-
2E,3C,4C,5B,6D,7B),(1B,2E,3C,4C,5B,6D,7C),
(1B,2E,3C,4D,5A,6A,7A),(1B,2E,3-
C,4D,5A,6A,7B),(1B,2E,3C,4D,5A,6A,7C),(1B,2E,3C,4D,5A,6B,7A),(1B,2E,3C,4D,-
5A,6B,7B),(1B,2E,3C,4D,5A,6B,7C),(1B,2E,3C,4D,5A,6C,7A),
(1B,2E,3C,4D,5A,6C,7B),(1B,2E,3C,4D,5A,6C,7C),(1B,2E,3C,4D,5A,6D,7A),(1B,-
2E,3C,4D,5A,6D,7B),(1B,2E,3C,4D,5A,6D,7C),(1B,2E,3C,4D,5B,6A,7A),(1B,2E,3C-
,4D,5B,6A,7B),
(1B,2E,3C,4D,5B,6A,7C),(1B,2E,3C,4D,5B,6B,7A),(1B,2E,3C,4D,-
5B,6B,7B),(1B,2E,3C,4D,5B,6B,7C),(1B,2E,3C,4D,5B,6C,7A),(1B,2E,3C,4D,5B,6C-
,7B),(1B,2E,3C,4D,5B,6C,7C),
(1B,2E,3C,4D,5B,6D,7A),(1B,2E,3C,4D,5B,6D,7B)-
,(1B,2E,3C,4D,5B,6D,7C),(1B,2E,3C,4E,5A,6A,7A),(1B,2E,3C,4E,5A,6A,7B),(1B,-
2E,3C,4E,5A,6A,7C),(1B,2E,3C,4E,5A,6B,7A),
(1B,2E,3C,4E,5A,6B,7B),(1B,2E,3-
C,4E,5A,6B,7C),(1B,2E,3C,4E,5A,6C,7A),.(1B,2E,3C,4E,5A,6C,7B),(1B,2E,3C,4E-
,5A,6C,7C),(1B,2E,3C,4E,5A,6D,7A),(1B,2E,3C,4E,5A,6D,7B),
(1B,2E,3C,4E,5A,6D,7C),(1B,2E,3C,4E,5B,6A,7A),(1B,2E,3C,4E,5B,6A,7B),(1B,-
2E,3C,4E,5B,6A,7C),(1B,2E,3C,4E,5B,6B,7A),(1B,2E,3C,4E,5B,6B,7B),(1B,2E,3C-
,4E,5B,6B,7C),
(1B,2E,3C,4E,5B,6C,7A),(1B,2E,3C,4E,5B,6C,7B),(1B,2E,3C,4E,-
5B,6C,7C),(1B,2E,3C,4E,5B,6D,7A),(1B,2E,3C,4E,5B,6D,7B),(1B,2E,3C,4E,5B,6D-
,7C),(1B,2E,3D,4A,5A,6A,7A),
(1B,2E,3D,4A,5A,6A,7B),(1B,2E,3D,4A,5A,6A,7C)-
,(1B,2E,3D,4A,5A,6B,7A),(1B,2E,3D,4A,5A,6B,7B),(1B,2E,3D,4A,5A,6B,7C),(1B,-
2E,3D,4A,5A,6C,7A),(1B,2E,3D,4A,5A,6C,7B),
(1B,2E,3D,4A,5A,6C,7C),(1B,2E,3-
D,4A,5A,6D,7A),(1B,2E,3D,4A,5A,6D,7B),(1B,2E,3D,4A,5A,6D,7C),(1B,2E,3D,4A,-
5B,6A,7A),(1B,2E,3D,4A,5B,6A,7B),(1B,2E,3D,4A,5B,6A,7C),
(1B,2E,3D,4A,5B,6B,7A),(1B,2E,3D,4A,5B,6B,7B),(1B,2E,3D,4A,5B,6B,7C),(1B,-
2E,3D,4A,5B,6C,7A),(1B,2E,3D,4A,5B,6C,7B),(1B,2E,3D,4A,5B,6C,7C),(1B,2E,3D-
,4A,5B,6D,7A),
(1B,2E,3D,4A,5B,6D,7B),(1B,2E,3D,4A,5B,6D,7C),(1B,2E,3D,4B,-
5A,6A,7A),(1B,2E,3D,4B,5A,6A,7B),(1B,2E,3D,4B,5A,6A,7C),(1B,2E,3D,4B,5A,6B-
,7A),(1B,2E,3D,4B,5A,6B,7B),
(1B,2E,3D,4B,5A,6B,7C),(1B,2E,3D,4B,5A,6C,7A)-
,(1B,2E,3D,4B,5A,6C,7B),(1B,2E,3D,4B,5A,6C,7C),(1B,2E,3D,4B,5A,6D,7A),(1B,-
2E,3D,4B,5A,6D,7B),(1B,2E,3D,4B,5A,6D,7C),
(1B,2E,3D,4B,5B,6A,7A),(1B,2E,3-
D,4B,5B,6A,7B),(1B,2E,3D,4B,5B,6A,7C),(1B,2E,3D,4B,5B,6B,7A),(1B,2E,3D,4B,-
5B,6B,7B),(1B,2E,3D,4B,5B,6B,7C),(1B,2E,3D,4B,5B,6C,7A),
(1B,2E,3D,4B,5B,6C,7B),(1B,2E,3D,4B,5B,6C,7C),(1B,2E,3D,4B,5B,6D,7A),(1B,-
2E,3D,4B,5B,6D,7B),(1B,2E,3D,4B,5B,6D,7C),(1B,2E,3D,4C,5A,6A,7A),(1B,2E,3D-
,4C,5A,6A,7B),
(1B,2E,3D,4C,5A,6A,7C),(1B,2E,3D,4C,5A,6B,7A),(1B,2E,3D,4C,-
5A,6B,7B),(1B,2E,3D,4C,5A,6B,7C),(1B,2E,3D,4C,5A,6C,7A),(1B,2E,3D,4C,5A,6C-
,7B),(1B,2E,3D,4C,5A,6C,7C),
(1B,2E,3D,4C,5A,6D,7A),(1B,2E,3D,4C,5A,6D,7B)-
,(1B,2E,3D,4C,5A,6D,7C),(1B,2E,3D,4C,5B,6A,7A),(1B,2E,3D,4C,5B,6A,7B),(1B,-
2E,3D,4C,5B,6A,7C),(1B,2E,3D,4C,5B,6B,7A),
(1B,2E,3D,4C,5B,6B,7B),(1B,2E,3-
D,4C,5B,6B,7C),(1B,2E,3D,4C,5B,6C,7A),(1B,2E,3D,4C,5B,6C,7B),(1B,2E,3D,4C,-
5B,6C,7C),(1B,2E,3D,4C,5B,6D,7A),(1B,2E,3D,4C,5B,6D,7B),
(1B,2E,3D,4C,5B,6D,7C),(1B,2E,3D,4D,5A,6A,7A),(1B,2E,3D,4D,5A,6A,7B),(1B,-
2E,3D,4D,5A,6A,7C),(1B,2E,3D,4D,5A,6B,7A),(1B,2E,3D,4D,5A,6B,7B),(1B,2E,3D-
,4D,5A,6B,7C),
(1B,2E,3D,4D,5A,6C,7A),(1B,2E,3D,4D,5A,6C,7B),(1B,2E,3D,4D,-
5A,6C,7C),(1B,2E,3D,4D,5A,6D,7A), (1B,2E,3D,4D,5A,6D,7B),
(1B,2E,3D,4D,5A,6D,7C),(1B,2E,3D,4D,5B,6A,7A),
(1B,2E,3D,4D,5B,6A,7B),(1B-
,2E,3D,4D,5B,6A,7C),(1B,2E,3D,4D,5B,6B,7A), (1B,2E,3D,4D,5B,6B,7B),
(1B,2E,3D,4D,5B,6B,7C),(1B,2E,3D,4D,5B,6C,7A),(1B,2E,3D,4D,5B,6C,7B),
(1B,2E,3D,4D,5B,6C,7C), (1B,2E,3D,4D,5B,6D,7A), (1B,2E,3D,4D,5B,6D,
7B), (1B,2E,3D,4D,5B,6D,7C), (1B,2E,3D,4E,5A,6A,7A),
(1B,2E,3D,4E,5A,6A,7B),(1- B,2E,3D,4E,5A,6A,7C),
(1B,2E,3D,4E,5A,6B,7A), (1B,2E,3D,4E,5A,6B,7B),
(1B,2E,3D,4E,5A,6B,7C), (1B,2E,3D,4E,5A,6C,7A),
(1B,2E,3D,4E,5A,6C,7B),(1-
B,2E,3D,4E,5A,6C,7C),(1B,2E,3D,4E,5A,6D,7A),
(1B,2E,3D,4E,5A,6D,7B), (1B,2E,3D,4E,5A,6D,7C),
(1B,2E,3D,4E,5B,6A,7A), (1B,2E,3D,4E,5B,6A,7B),
(1B,2E,3D,4E,5B,6A,7C),(1B,2E,3D,4E,5B,6B,7A),(1B,2E,3D,4E,5B,6B,7B),
(1B,2E,3D,4E,5B,6B,7C),(1B,2E,3D,4E,5B,6C,7A),(1B,2E,3D,4E,5B,6C,7B),(1B,-
2E,3D,4E,5B,6C,7C),(1B,2E,3D,4E,5B,6D,7A),(1B,2E,3D,4E,5B,6D,7B),(1B,2E,3D-
,4E,5B,6D,7C),
(1B,2E,3E,4A,5A,6A,7A),(1B,2E,3E,4A,5A,6A,7B),(1B,2E,3E,4A,-
5A,6A,7C),(1B,2E,3E,4A,5A,6B,7A),(1B,2E,3E,4A,5A,6B,7B),(1B,2E,3E,4A,5A,6B-
,7C),(1B,2E,3E,4A,5A,6C,7A),
(1B,2E,3E,4A,5A,6C,7B),(1B,2E,3E,4A,5A,6C,7C)-
,(1B,2E,3E,4A,5A,6D,7A),(1B,2E,3E,4A,5A,6D,7B),(1B,2E,3E,4A,5A,6D,7C),(1B,-
2E,3E,4A,5B,6A,7A),(1B,2E,3E,4A,5B,6A,7B),
(1B,2E,3E,4A,5B,6A,7C),(1B,2E,3-
E,4A,5B,6B,7A),(1B,2E,3E,4A,5B,6B,7B),(1B,2E,3E,4A,5B,6B,7C),(1B,2E,3E,4A,-
5B,6C,7A),(1B,2E,3E,4A,5B,6C,7B),(1B,2E,3E,4A,5B,6C,7C),
(1B,2E,3E,4A,5B,6D,7A),(1B,2E,3E,4A,5B,6D,7B),(1B,2E,3E,4A,5B,6D,7C),(1B,-
2E,3E,4B,5A,6A,7A),(1B,2E,3E,4B,5A,6A,7B),(1B,2E,3E,4B,5A,6A,7C),(1B,2E,3E-
,4B,5A,6B,7A),
(1B,2E,3E,4B,5A,6B,7B),(1B,2E,3E,4B,5A,6B,7C),(1B,2E,3E,4B,-
5A,6C,7A),(1B,2E,3E,4B,5A,6C,7B),(1B,2E,3E,4B,5A,6C,7C),(1B,2E,3E,4B,5A,6D-
,7A),(1B,2E,3E,4B,5A,6D,7B),
(1B,2E,3E,4B,5A,6D,7C),(1B,2E,3E,4B,5B,6A,7A)-
,(1B,2E,3E,4B,5B,6A,7B),(1B,2E,3E,4B,5B,6A,7C),(1B,2E,3E,4B,5B,6B,7A),(1B,-
2E,3E,4B,5B,6B,7B),(1B,2E,3E,4B,5B,6B,7C),
(1B,2E,3E,4B,5B,6C,7A),(1B,2E,3-
E,4B,5B,6C,7B),(1B,2E,3E,4B,5B,6C,7C),(1B,2E,3E,4B,5B,6D,7A),(1B,2E,3E,4B,-
5B,6D,7B),(1B,2E,3E,4B,5B,6D,7C),(1B,2E,3E,4C,5A,6A,7A),
(1B,2E,3E,4C,5A,6A,7B),(1B,2E,3E,4C,5A,6A,7C),(1B,2E,3E,4C,5A,6B,7A),(1B,-
2E,3E,4C,5A,6B,7B),(1B,2E,3E,4C,5A,6B,7C),(1B,2E,3E,4C,5A,6C,7A),(1B,2E,3E-
,4C,5A,6C,7B),
(1B,2E,3E,4C,5A,6C,7C),(1B,2E,3E,4C,5A,6D,7A),(1B,2E,3E,4C,-
5A,6D,7B),(1B,2E,3E,4C,5A,6D,7C),(1B,2E,3E,4C,5B,6A,7A),(1B,2E,3E,4C,5B,6A-
,7B),(1B,2E,3E,4C,5B,6A,7C),
(1B,2E,3E,4C,5B,6B,7A),(1B,2E,3E,4C,5B,6B,7B)-
,(1B,2E,3E,4C,5B,6B,7C),(1B,2E,3E,4C,5B,6C,7A),
(1B,2E,3E,4C,5B,6C,7B), (1B,2E,3E,4C,5B,6C,7C),
(1B,2E,3E,4C,5B,6D,7A), (1B,2E,3E,4C,5B,6D,7B),
(1B,2E,3E,4C,5B,6D,7C),(1B,2E,3E,4D,5A,6A,7A),(1B,2E,3E,4D,5A,6A,7B),
(1B,2E,3E,4D,5A,6A,7C),
(1B,2E,3E,4D,5A,6B,7A),(1B,2E,3E,4D,5A,6B,7B),
(1B,2E,3E,4D,5A,6B,7C),(1B,2E,3E,4D,5A,6C,7A),
(1B,2E,3E,4D,5A,6C,7B),(1B- ,2E,3E,4D,5A,6C,7C),
(1B,2E,3E,4D,5A,6D,7A),(1B,2E,3E,4D,5A,6D,
7B),(1B,2E,3E,4D,5A,6D,7C), (1B,2E,3E,4D,5B,6A,7A),
(1B,2E,3E,4D,5B,6A,7B), (1B,2E,3E,4D,5B,6A,7C),
(1B,2E,3E,4D,5B,6B,7A),
(1B,2E,3E,4D,5B,6B,7B),(1B,2E,3E,4D,5B,6B,7C),(1B,2E,3E,4D,5B,6C,7A),
(1B,2E,3E,4D,5B,6C,7B), (1B,2E,3E,4D,5B,6C,7C),
(1B,2E,3E,4D,5B,6D,7A), (1B,2E,3E,4D,5B,6D,7B),
(1B,2E,3E,4D,5B,6D,7C),(1B,2E,3E,4E,5A,6A,7A),(1B-
,2E,3E,4E,5A,6A,7B),
(1B,2E,3E,4E,5A,6A,7C),(1B,2E,3E,4E,5A,6B,7A),(1B,2E,-
3E,4E,5A,6B,7B),(1B,2E,3E,4E,5A,6B,7C), (1B,2E,3E,4E,5A,6C,7A),
(1B,2E,3E,4E,5A,6C,7B),(1B,2E,3E,4E,5A,6C,7C),
(1B,2E,3E,4E,5A,6D,7A),(1B-
,2E,3E,4E,5A,6D,7B).,(1B,2E,3E,4E,5A,6D,7C),(1B,2E,3E,4E,5B,6A,7A),(1B,2E,-
3E,4E,5B,6A,7B),(1B,2E,3E,4E,5B,6A,7C),(1B,2E,3E,4E,5B,6B,7A),
(1B,2E,3E,4E,5B,6B,7B),(1B,2E,3E,4E,5B,6B,7C),(1B,2E,3E,4E,5B,6C,7A),(1B,-
2E,3E,4E,5B,6C,7B),(1B,2E,3E,4E,5B,6C,7C),(1B,2E,3E,4E,5B,6D,7A),(1B,2E,3E-
,4E,5B,6D,7B),
(1B,2E,3E,4E,5B,6D,7C),(1C,2A,3A,4A,5A,6A,7A),(1C,2A,3A,4A,-
5A,6A,7B),(1C,2A,3A,4A,5A,6A,7C),(1C,2A,3A,4A,5A,6B,7A),(1C,2A,3A,4A,5A,6B-
,7B),(1C,2A,3A,4A,5A,6B,7C),
(1C,2A,3A,4A,5A,6C,7A),(1C,2A,3A,4A,5A,6C,7B)-
,(1C,2A,3A,4A,5A,6C,7C),(1C,2A,3A,4A,5A,6D,7A),(1C,2A,3A,4A,5A,6D,7B),(1C,-
2A,3A,4A,5A,6D,7C),(1C,2A,3A,4A,5B,6A,7A),
(1C,2A,3A,4A,5B,6A,7B),(1C,2A,3-
A,4A,5B,6A,7C),(1C,2A,3A,4A,5B,6B,7A),(1C,2A,3A,4A,5B,6B,7B),(1C,2A,3A,4A,-
5B,6B,7C),(1C,2A,3A,4A,5B,6C,7A),(1C,2A,3A,4A,5B,6C,7B),
(1C,2A,3A,4A,5B,6C,7C),(1C,2A,3A,4A,5B,6D,7A),(1C,2A,3A,4A,5B,6D,7B),(1C,-
2A,3A,4A,5B,6D,7C),(1C,2A,3A,4B,5A,6A,7A),(1C,2A,3A,4B,5A,6A,7B),(1C,2A,3A-
,4B,5A,6A,7C),
(1C,2A,3A,4B,5A,6B,7A),(1C,2A,3A,4B,5A,6B,7B),(1C,2A,3A,4B,-
5A,6B,7C),(1C,2A,3A,4B,5A,6C,7A),(1C,2A,3A,4B,5A,6C,7B),(1C,2A,3A,4B,5A,6C-
,7C),(1C,2A,3A,4B,5A,6D,7A),
(1C,2A,3A,4B,5A,6D,7B),(1C,2A,3A,4B,5A,6D,7C)-
,(1C,2A,3A,4B,5B,6A,7A),(1C,2A,3A,4B,5B,6A,7B),(1C,2A,3A,4B,5B,6A,7C),(1C,-
2A,3A,4B,5B,6B,7A),(1C,2A,3A,4B,5B,6B,7B),
(1C,2A,3A,4B,5B,6B,7C),(1C,2A,3-
A,4B,5B,6C,7A),(1C,2A,3A,4B,5B,6C,7B),(1C,2A,3A,4B,5B,6C,7C),(1C,2A,3A,4B,-
5B,6D,7A),(1C,2A,3A,4B,5B,6D,7B),(1C,2A,3A,4B,5B,6D,7C),
(1C,2A,3A,4C,5A,6A,7A),(1C,2A,3A,4C,5A,6A,7B),(1C,2A,3A,4C,5A,6A,7C),(1C,-
2A,3A,4C,5A,6B,7A), (1C,2A,3A,4C,5A,6B, 7B),
(1C,2A,3A,4C,5A,6B,7C), (1C,2A,3A,4C,5A,6C, 7A),
(1C,2A,3A,4C,5A,6C,7B),(1C,2A,3A,4C,5A,6C,7C),(1-
C,2A,3A,4C,5A,6D,7A),(1C,2A,3A,4C,5A,6D,7B),(1C,2A,3A,4C,5A,6D,7C),(1C,2A,-
3A,4C,5B,6A,7A),(1C,2A,3A,4C,5B,6A,7B),
(1C,2A,3A,4C,5B,6A,7C),(1C,2A,3A,4-
C,5B,6B,7A),(1C,2A,3A,4C,5B,6B,7B),(1C,2A,3A,4C,5B,6B,7C),(1C,2A,3A,4C,5B,-
6C,7A),(1C,2A,3A,4C,5B,6C,7B),(1C,2A,3A,4C,5B,6C,7C),
(1C,2A,3A,4C,5B,6D,7A),(1C,2A,3A,4C,5B,6D,7B),(1C,2A,3A,4C,5B,6D,7C),(1C,-
2A,3A,4D,5A,6A,7A),(1C,2A,3A,4D,5A,6A,7B),(1C,2A,3A,4D,5A,6A,7C),(1C,2A,3A-
,4D,5A,6B,7A),
(1C,2A,3A,4D,5A,6B,7B),(1C,2A,3A,4D,5A,6B,7C),(1C,2A,3A,4D,-
5A,6C,7A),(1C,2A,3A,4D,5A,6C,7B),(1C,2A,3A,4D,5A,6C,7C),(1C,2A,3A,4D,5A,6D-
,7A),(1C,2A,3A,4D,5A,6D,7B),
(1C,2A,3A,4D,5A,6D,7C),(1C,2A,3A,4D,5B,6A,7A)-
,(1C,2A,3A,4D,5B,6A,7B),(1C,2A,3A,4D,5B,6A,7C),(1C,2A,3A,4D,5B,6B,7A),(1C,-
2A,3A,4D,5B,6B,7B),(1C,2A,3A,4D,5B,6B,7C),
(1C,2A,3A,4D,5B,6C,7A),(1C,2A,3-
A,4D,5B,6C,7B),(1C,2A,3A,4D,5B,6C,7C),(1C,2A,3A,4D,5B,6D,7A),(1C,2A,3A,4D,-
5B,6D,7B),(1C,2A,3A,4D,5B,6D,7C),(1C,2A,3A,4E,5A,6A,7A),
(1C,2A,3A,4E,5A,6A,7B),(1C,2A,3A,4E,5A,6A,7C),(1C,2A,3A,4E,5A,6B,7A),(1C,-
2A,3A,4E,5A,6B,7B),(1C,2A,3A,4E,5A,6B,7C),(1C,2A,3A,4E,5A,6C,7A),(1C,2A,3A-
,4E,5A,6C,7B),
(1C,2A,3A,4E,5A,6C,7C),(1C,2A,3A,4E,5A,6D,7A),(1C,2A,3A,4E,-
5A,6D,7B),(1C,2A,3A,4E,5A,6D,7C),(1C,2A,3A,4E,5B,6A,7A),(1C,2A,3A,4E,5B,6A-
,7B),(1C,2A,3A,4E,5B,6A,7C),
(1C,2A,3A,4E,5B,6B,7A),(1C,2A,3A,4E,5B,6B,7B)-
,(1C,2A,3A,4E,5B,6B,7C),(1C,2A,3A,4E,5B,6C,7A),(1C,2A,3A,4E,5B,6C,7B),(1C,-
2A,3A,4E,5B,6C,7C),(1C,2A,3A,4E,5B,6D,7A),
(1C,2A,3A,4E,5B,6D,7B),(1C,2A,3-
A,4E,5B,6D,7C),(1C,2A,3B,4A,5A,6A,7A),(1C,2A,3B,4A,5A,6A,7B),(1C,2A,3B,4A,-
5A,6A,7C),(1C,2A,3B,4A,5A,6B,7A),(1C,2A,3B,4A,5A,6B,7B),
(1C,2A,3B,4A,5A,6B,7C),(1C,2A,3B,4A,5A,6C,7A),(1C,2A,3B,4A,5A,6C,7B),(1C,-
2A,3B,4A,5A,6C,7C),(1C,2A,3B,4A,5A,6D,7A),(1C,2A,3B,4A,5A,6D,7B),(1C,2A,3B-
,4A,5A,6D,7C),
(1C,2A,3B,4A,5B,6A,7A),(1C,2A,3B,4A,5B,6A,7B),(1C,2A,3B,4A,-
5B,6A,7C),(1C,2A,3B,4A,5B,6B,7A),(1C,2A,3B,4A,5B,6B,7B),(1C,2A,3B,4A,5B,6B-
,7C),(1C,2A,3B,4A,5B,6C,7A),
(1C,2A,3B,4A,5B,6C,7B),(1C,2A,3B,4A,5B,6C,7C)-
,(1C,2A,3B,4A,5B,6D,7A),(1C,2A,3B,4A,5B,6D,7B),(1C,2A,3B,4A,5B,6D,7C),(1C,-
2A,3B,4B,5A,6A,7A),(1C,2A,3B,4B,5A,6A,7B),
(1C,2A,3B,4B,5A,6A,7C),(1C,2A,3-
B,4B,5A,6B,7A),(1C,2A,3B,4B,5A,6B,7B),(1C,2A,3B,4B,5A,6B,7C),(1C,2A,3B,4B,-
5A,6C,7A),(1C,2A,3B,4B,5A,6C,7B),(1C,2A,3B,4B,5A,6C,7C),
(1C,2A,3B,4B,5A,6D,7A),(1C,2A,3B,4B,5A,6D,7B),(1C,2A,3B,4B,5A,6D,7C),(1C,-
2A,3B,4B, 5B, 6A, 7A), (1C,2A,3B,4B,5B,6A, 7B), (1C,2A,3B,4B,
5B,6A, 7C), (1C,2A,3B,4B, 5B, 6B, 7A), (1C,2A,3B,4B,5B,6B,7B),
(1C,2A,3B,4B, 5B,6B,7C), (1C,2A,3B,4B,5B,6C,7A),
(1C,2A,3B,4B,5B,6C,7B),
(1C,2A,3B,4B,5B,6C,7C),(1C,2A,3B,4B,5B,6D,7A),(1C,2A,3B,4B,5B,6D,7B),
(1C,2A,3B,4B,5B,6D,7C),(1C,2A,3B,4C,5A,6A,7A),(1C,2A,3B,4C,5A,6A,7B),(1C,-
2A,3B,4C,5A,6A,7C),(1C,2A,3B,4C,5A,6B,7A),(1C,2A,3B,4C,5A,6B,7B),(1C,2A,3B-
,4C,5A,6B,7C),
(1C,2A,3B,4C,5A,6C,7A),(1C,2A,3B,4C,5A,6C,7B),(1C,2A,3B,4C,-
5A,6C,7C),(1C,2A,3B,4C,5A,6D,7A),(1C,2A,3B,4C,5A,6D,7B),(1C,2A,3B,4C,5A,6D-
,7C),(1C,2A,3B,4C,5B,6A,7A),
(1C,2A,3B,4C,5B,6A,7B),(1C,2A,3B,4C,5B,6A,7C)-
,(1C,2A,3B,4C,5B,6B,7A),(1C,2A,3B,4C,5B,6B,7B),(1C,2A,3B,4C,5B,6B,7C),(1C,-
2A,3B,4C,5B,6C,7A),(1C,2A,3B,4C,5B,6C,7B),
(1C,2A,3B,4C,5B,6C,7C),(1C,2A,3-
B,4C,5B,6D,7A),(1C,2A,3B,4C,5B,6D,7B),(1C,2A,3B,4C,5B,6D,7C),(1C,2A,3B,4D,-
5A,6A,7A),(1C,2A,3B,4D,5A,6A,7B),(1C,2A,3B,4D,5A,6A,7C),
(1C,2A,3B,4D,5A,6B,7A),(1C,2A,3B,4D,5A,6B,7B),(1C,2A,3B,4D,5A,6B,7C),(1C,-
2A,3B,4D,5A,6C,7A),(1C,2A,3B,4D,5A,6C,7B),(1C,2A,3B,4D,5A,6C,7C),(1C,2A,3B-
,4D,5A,6D,7A),
(1C,2A,3B,4D,5A,6D,7B),(1C,2A,3B,4D,5A,6D,7C),(1C,2A,3B,4D,-
5B,6A,7A),(1C,2A,3B,4D,5B,6A,7B),(1C,2A,3B,4D,5B,6A,7C),(1C,2A,3B,4D,5B,6B-
,7A),(1C,2A,3B,4D,5B,6B,7B),
(1C,2A,3B,4D,5B,6B,7C),(1C,2A,3B,4D,5B,6C,7A)-
,(1C,2A,3B,4D,5B,6C,7B),(1C,2A,3B,4D,5B,6C,7C),(1C,2A,3B,4D,5B,6D,7A),(1C,-
2A,3B,4D,5B,6D,7B),(1C,2A,3B,4D,5B,6D,7C),
(1C,2A,3B,4E,5A,6A,7A),(1C,2A,3-
B,4E,5A,6A,7B),(1C,2A,3B,4E,5A,6A,7C),(1C,2A,3B,4E,5A,6B,7A),(1C,2A,3B,4E,-
5A,6B,7B),(1C,2A,3B,4E,5A,6B,7C),(1C,2A,3B,4E,5A,6C,7A),
(1C,2A,3B,4E,5A,6C,7B),(1C,2A,3B,4E,5A,6C,7C),(1C,2A,3B,4E,5A,6D,7A),(1C,-
2A,3B,4E,5A,6D,7B),(1C,2A,3B,4E,5A,6D,7C),(1C,2A,3B,4E,5B,6A,7A),(1C,2A,3B-
,4E,5B,6A,7B),
(1C,2A,3B,4E,5B,6A,7C),(1C,2A,3B,4E,5B,6B,7A),(1C,2A,3B,4E,-
5B,6B,7B),(1C,2A,3B,4E,5B,6B,7C),(1C,2A,3B,4E,5B,6C,7A),(1C,2A,3B,4E,5B,6C-
,7B),(1C,2A,3B,4E,5B,6C,7C),
(1C,2A,3B,4E,5B,6D,7A),(1C,2A,3B,4E,5B,6D,7B)-
,(1C,2A,3B,4E,5B,6D,7C),(1C,2A,3C,4A,5A,6A,7A),(1C,2A,3C,4A,5A,6A,7B),(1C,-
2A,3C,4A,5A,6A,7C),(1C,2A,3C,4A,5A,6B,7A),
(1C,2A,3C,4A,5A,6B,7B),(1C,2A,3-
C,4A,5A,6B,7C),(1C,2A,3C,4A,5A,6C,7A),(1C,2A,3C,4A,5A,6C,7B),(1C,2A,3C,4A,-
5A,6C,7C),(1C,2A,3C,4A,5A,6D,7A),(1C,2A,3C,4A,5A,6D,7B),
(1C,2A,3C,4A,5A,6D,7C),(1C,2A,3C,4A,5B,6A,7A),(1C,2A,3C,4A,5B,6A,7B),(1C,-
2A,3C,4A,5B,6A,7C),(1C,2A,3C,4A,5B,6B,7A),(1C,2A,3C,4A,5B,6B,7B),(1C,2A,3C-
,4A,5B,6B,7C),
(1C,2A,3C,4A,5B,6C,7A),(1C,2A,3C,4A,5B,6C,7B),(1C,2A,3C,4A,-
5B,6C,7C),(1C,2A,3C,4A,5B,6D,7A), (1C,2A,3C,4A,5B,6D,7B),
(1C,2A,3C,4A,5B,6D,7C),(1C,2A,3C,4B,5A,6A,7A),
(1C,2A,3C,4B,5A,6A,7B),(1C-
,2A,3C,4B,5A,6A,7C),(1C,2A,3C,4B,5A,6B,7A),(1C,2A,3C,4B,5A,6B,7B),(1C,2A,3-
C,4B,5A,6B,7C),(1C,2A,3C,4B,5A,6C,7A),(1C,2A,3C,4B,5A,6C,7B),
(1C,2A,3C,4B,5A,6C,7C),(1C,2A,3C,4B,5A,6D,7A),(1C,2A,3C,4B,5A,6D,7B),(1C,-
2A,3C,4B,5A,6D,7C),(1C,2A,3C,4B,5B,6A,7A),(1C,2A,3C,4B,5B,6A,7B),(1C,2A,3C-
,4B,5B,6A,7C),
(1C,2A,3C,4B,5B,6B,7A),(1C,2A,3C,4B,5B,6B,7B),(1C,2A,3C,4B,-
5B,6B,7C),(1C,2A,3C,4B,5B,6C,7A),(1C,2A,3C,4B,5B,6C,7B),(1C,2A,3C,4B,5B,6C-
,7C),(1C,2A,3C,4B,5B,6D,7A),
(1C,2A,3C,4B,5B,6D,7B),(1C,2A,3C,4B,5B,6D,7C)-
,(1C,2A,3C,4C,5A,6A,7A),(1C,2A,3C,4C,5A,6A,7B),(1C,2A,3C,4C,5A,6A,7C),(1C,-
2A,3C,4C,5A,6B,7A),(1C,2A,3C,4C,5A,6B,7B),
(1C,2A,3C,4C,5A,6B,7C),(1C,2A,3-
C,4C,5A,6C,7A),(1C,2A,3C,4C,5A,6C,7B),(1C,2A,3C,4C,5A,6C,7C),(1C,2A,3C,4C,-
5A,6D,7A),(1C,2A,3C,4C,5A,6D,7B),(1C,2A,3C,4C,5A,6D,7C),
(1C,2A,3C,4C,5B,6A,7A),(1C,2A,3C,4C,5B,6A,7B),(1C,2A,3C,4C,5B,6A,7C),(1C,-
2A,3C,4C,5B,6B,7A),(1C,2A,3C,4C,5B,6B,7B),(1C,2A,3C,4C,5B,6B,7C),(1C,2A,3C-
,4C,5B,6C,7A),
(1C,2A,3C,4C,5B,6C,7B),(1C,2A,3C,4C,5B,6C,7C),(1C,2A,3C,4C,-
5B,6D,7A),(1C,2A,3C,4C,5B,6D,7B),(1C,2A,3C,4C,5B,6D,7C),(1C,2A,3C,4D,5A,6A-
,7A),(1C,2A,3C,4D,5A,6A,7B),
(1C,2A,3C,4D,5A,6A,7C),(1C,2A,3C,4D,5A,6B,7A)-
,(1C,2A,3C,4D,5A,6B,7B),(1C,2A,3C,4D,5A,6B,7C),(1C,2A,3C,4D,5A,6C,7A),(1C,-
2A,3C,4D,5A,6C,7B),(1C,2A,3C,4D,5A,6C,7C),
(1C,2A,3C,4D,5A,6D,7A),(1C,2A,3-
C,4D,5A,6D,7B),(1C,2A,3C,4D,5A,6D,7C),(1C,2A,3C,4D,5B,6A,7A),(1C,2A,3C,4D,-
5B,6A,7B),(1C,2A,3C,4D,5B,6A,7C),(1C,2A,3C,4D,5B,6B,7A),
(1C,2A,3C,4D,5B,6B,7B),(1C,2A,3C,4D,5B,6B,7C),(1C,2A,3C,4D,5B,6C,7A),(1C,-
2A,3C,4D,5B,6C,7B),(1C,2A,3C,4D,5B,6C,7C),(1C,2A,3C,4D,5B,6D,7A),(1C,2A,3C-
,4D,5B,6D,7B),
(1C,2A,3C,4D,5B,6D,7C),(1C,2A,3C,4E,5A,6A,7A),(1C,2A,3C,4E,-
5A,6A,7B),(1C,2A,3C,4E,5A,6A,7C),(1C,2A,3C,4E,5A,6B,7A),(1C,2A,3C,4E,5A,6B-
,7B),(1C,2A,3C,4E,5A,6B,7C),
(1C,2A,3C,4E,5A,6C,7A),(1C,2A,3C,4E,5A,6C,7B)-
,(1C,2A,3C,4E,5A,6C,7C),(1C,2A,3C,4E,5A,6D,7A),(1C,2A,3C,4E,5A,6D,7B),(1C,-
2A,3C,4E,5A,6D,7C),(1C,2A,3C,4E,5B,6A,7A),
(1C,2A,3C,4E,5B,6A,7B),(1C,2A,3-
C,4E,5B,6A,7C),(1C,2A,3C,4E,5B,6B,7A),(1C,2A,3C,4E,5B,6B,7B),(1C,2A,3C,4E,-
5B,6B,7C),(1C,2A,3C,4E,5B,6C,7A),(1C,2A,3C,4E,5B,6C,7B),
(1C,2A,3C,4E,5B,6C,7C),(1C,2A,3C,4E,5B,6D,7A),(1C,2A,3C,4E,5B,6D,7B),(1C,-
2A,3C,4E,5B,6D,7C),(1C,2A,3D,4A,5A,6A,7A),(1C,2A,3D,4A,5A,6A,7B),(1C,2A,3D-
,4A,5A,6A,7C),
(1C,2A,3D,4A,5A,6B,7A),(1C,2A,3D,4A,5A,6B,7B),(1C,2A,3D,4A,-
5A,6B,7C),(1C,2A,3D,4A,5A,6C,7A),(1C,2A,3D,4A,5A,6C,7B),(1C,2A,3D,4A,5A,6C-
,7C),(1C,2A,3D,4A,5A,6D,7A),
(1C,2A,3D,4A,5A,6D,7B),(1C,2A,3D,4A,5A,6D,7C)-
,(1C,2A,3D,4A,5B,6A,7A),(1C,2A,3D,4A,5B,6A,7B),(1C,2A,3D,4A,5B,6A,7C),(1C,-
2A,3D,4A,5B,6B,7A),(1C,2A,3D,4A,5B,6B,7B),
(1C,2A,3D,4A,5B,6B,7C),(1C,2A,3-
D,4A,5B,6C,7A),(1C,2A,3D,4A,5B,6C,7B),(1C,2A,3D,4A,5B,6C,7C),(1C,2A,3D,4A,-
5B,6D,7A),(1C,2A,3D,4A,5B,6D,7B),(1C,2A,3D,4A,5B,6D,7C),
(1C,2A,3D,4B,5A,6A,7A),(1C,2A,3D,4B,5A,6A,7B),(1C,2A,3D,4B,5A,6A,7C),(1C,-
2A,3D,4B,5A,6B,7A),(1C,2A,3D,4B,5A,6B,7B),(1C,2A,3D,4B,5A,6B,7C),(1C,2A,3D-
,4B,5A,6C,7A),
(1C,2A,3D,4B,5A,6C,7B),(1C,2A,3D,4B,5A,6C,7C),(1C,2A,3D,4B,-
5A,6D,7A),(1C,2A,3D,4B,5A,6D,7B),(1C,2A,3D,4B,5A,6D,7C),(1C,2A,3D,4B,5B,6A-
,7A),(1C,2A,3D,4B,5B,6A,7B),
(1C,2A,3D,4B,5B,6A,7C),(1C,2A,3D,4B,5B,6B,7A)-
,(1C,2A,3D,4B,5B,6B,7B),(1C,2A,3D,4B,5B,6B,7C),(1C,2A,3D,4B,5B,6C,7A),(1C,-
2A,3D,4B,5B,6C,7B),(1C,2A,3D,4B,5B,6C,7c),
(1C,2A,3D,4B,5B,6D,7A),(1C,2A,3-
D,4B,5B,6D,7B),(1C,2A,3D,4B,5B,6D,7C),(1C,2A,3D,4C,5A,6A,7A),(1C,2A,3D,4C,-
5A,6A,7B),(1C,2A,3D,4C,5A,6A,7C),(1C,2A,3D,4C,5A,6B,7A),
(1C,2A,3D,4C,5A,6B,7B),(1C,2A,3D,4C,5A,6B,7C),(1C,2A,3D,4C,5A,6C,7A),(1C,-
2A,3D,4C,5A,6C,7B),(1C,2A,3D,4C,5A,6C,7C),(1C,2A,3D,4C,5A,6D,7A),(1C,2A,3D-
,4C,5A,6D,7B),
(1C,2A,3D,4C,5A,6D,7C),(1C,2A,3D,4C,5B,6A,7A),(1C,2A,3D,4C,-
5B,6A,7B),(1C,2A,3D,4C,5B,6A,7C),(1C,2A,3D,4C,5B,6B,7A),(1C,2A,3D,4C,5B,6B-
,7B),(1C,2A,3D,4C,5B,6B,7C),
(1C,2A,3D,4C,5B,6C,7A),(1C,2A,3D,4C,5B,6C,7B)-
,(1C,2A,3D,4C,5B,6C,7C),(1C,2A,3D,4C,5B,6D,7A),(1C,2A,3D,4C,5B,6D,7B),(1C,-
2A,3D,4C,5B,6D,7C),(1C,2A,3D,4D,5A,6A,7A),
(1C,2A,3D,4D,5A,6A,7B),(1C,2A,3-
D,4D,5A,6A,7C),(1C,2A,3D,4D,5A,6B,7A),(1C,2A,3D,4D,5A,6B,7B),(1C,2A,3D,4D,-
5A,6B,7C),(1C,2A,3D,4D,5A,6C,7A),(1C,2A,3D,4D,5A,6C,7B),
(1C,2A,3D,4D,5A,6C,7C),(1C,2A,3D,4D,5A,6D,7A),(1C,2A,3D,4D,5A,6D,7B),(1C,-
2A,3D,4D,5A,6D,7C),(1C,2A,3D,4D,5B,6A,7A),(1C,2A,3D,4D,5B,6A,7B),(1C,2A,3D-
,4D,5B,6A,7C),
(1C,2A,3D,4D,5B,6B,7A),(1C,2A,3D,4D,5B,6B,7B),(1C,2A,3D,4D,-
5B,6B,7C),(1C,2A,3D,4D,5B,6C,7A),(1C,2A,3D,4D,5B,6C,7B),(1C,2A,3D,4D,5B,6C-
,7C),(1C,2A,3D,4D,5B,6D,7A),
(1C,2A,3D,4D,5B,6D,7B),(1C,2A,3D,4D,5B,6D,7C)-
,(1C,2A,3D,4E,5A,6A,7A),(1C,2A,3D,4E,5A,6A,7B),(1C,2A,3D,4E,5A,6A,7C),(1C,-
2A,3D,4E,5A,6B,7A),(1C,2A,3D,4E,5A,6B,7B),
(1C,2A,3D,4E,5A,6B,7C),(1C,2A,3-
D,4E,5A,6C,7A),(1C,2A,3D,4E,5A,6C,7B),(1C,2A,3D,4E,5A,6C,7C),(1C,2A,3D,4E,-
5A,6D,7A),(1C,2A,3D,4E,5A,6D,7B),(1C,2A,3D,4E,5A,6D,7C),
(1C,2A,3D,4E,5B,6A,7A),(1C,2A,3D,4E,5B,6A,7B),(1C,2A,3D,4E,5B,6A,7C),(1C,-
2A,3D,4E,5B,6B,7A), (1C,2A,3D,4E,5B,6B,7B), (1C,2A,3D,4E,5B,6B,7C),
(1C,2A,3D,4E,5B,6C,7A),
(1C,2A,3D,4E,5B,6C,7B),(1C,2A,3D,4E,5B,6C,7C),(1C-
,2A,3D,4E,5B,6D,7A),(1C,2A,3D,4E,5B,6D,7B),(1C,2A,3D,4E,5B,6D,7C),(1C,2A,3-
E,4A,5A,6A,7A),(1C,2A,3E,4A,5A,6A,7B),
(1C,2A,3E,4A,5A,6A,7C),(1C,2A,3E,4A-
,5A,6B,7A),(1C,2A,3E,4A,5A,6B,7B),(1C,2A,3E,4A,5A,6B,7C),(1C,2A,3E,4A,5A,6-
C,7A),(1C,2A,3E,4A,5A,6C,7B),(1C,2A,3E,4A,5A,6C,7C),
(1C,2A,3E,4A,5A,6D,7A),(1C,2A,3E,4A,5A,6D,7B),(1C,2A,3E,4A,5A,6D,7C),(1C,-
2A,3E,4A,5B,6A,7A),(1C,2A,3E,4A,5B,6A,7B),(1C,2A,3E,4A,5B,6A,7C),(1C,2A,3E-
,4A,5B,6B,7A),
(1C,2A,3E,4A,5B,6B,7B),(1C,2A,3E,4A,5B,6B,7C),(1C,2A,3E,4A,-
5B,6C,7A),(1C,2A,3E,4A,5B,6C,7B),(1C,2A,3E,4A,5B,6C,7C),(1C,2A,3E,4A,5B,6D-
,7A),(1C,2A,3E,4A,5B,6D,7B),
(1C,2A,3E,4A,5B,6D,7C),(1C,2A,3E,4B,5A,6A,7A)-
,(1C,2A,3E,4B,5A,6A,7B),(1C,2A,3E,4B,5A,6A,7C),(1C,2A,3E,4B,5A,6B,7A),(1C,-
2A,3E,4B,5A,6B,7B),(1C,2A,3E,4B,5A,6B,7C),
(1C,2A,3E,4B,5A,6C,7A),(1C,2A,3-
E,4B,5A,6C,7B),(1C,2A,3E,4B,5A,6C,7C),(1C,2A,3E,4B,5A,6D,7A),(1C,2A,3E,4B,-
5A,6D,7B),(1C,2A,3E,4B,5A,6D,7C),(1C,2A,3E,4B,5B,6A,7A),
(1C,2A,3E,4B,5B,6A,7B),(1C,2A,3E,4B,5B,6A,7C),(1C,2A,3E,4B,5B,6B,7A),(1C,-
2A,3E,4B,5B,6B,7B),(1C,2A,3E,4B,5B,6B,7C),(1C,2A,3E,4B,5B,6C,7A),(1C,2A,3E-
,4B,5B,6C,7B),
(1C,2A,3E,4B,5B,6C,7C),(1C,2A,3E,4B,5B,6D,7A),(1C,2A,3E,4B,-
5B,6D,7B),(1C,2A,3E,4B,5B,6D,7C),(1C,2A,3E,4C,5A,6A,7A),(1C,2A,3E,4C,5A,6A-
,7B),(1C,2A,3E,4C,5A,6A,7C),
(1C,2A,3E,4C,5A,6B,7A),(1C,2A,3E,4C,5A,6B,7B)-
,(1C,2A,3E,4C,5A,6B,7C),(1C,2A,3E,4C,5A,6C,7A),(1C,2A,3E,4C,5A,6C,7B),(1C,-
2A,3E,4C,5A,6C,7C),(1C,2A,3E,4C,5A,6D,7A).,
(1C,2A,3E,4C,5A,6D,7B),(1C,2A,-
3E,4C,5A,6D,7C),(1C,2A,3E,4C,5B,6A,7A),(1C,2A,3E,4C,5B,6A,7B),(1C,2A,3E,4C-
,5B,6A,7C),(1C,2A,3E,4C,5B,6B,7A),(1C,2A,3E,4C,5B,6B,7B),
(1C,2A,3E,4C,5B,6B,7C),(1C,2A,3E,4C,5B,6C,7A),(1C,2A,3E,4C,5B,6C,7B),(1C,-
2A,3E,4C,5B,6C,7C),(1C,2A,3E,4C,5B,6D,7A),(1C,2A,3E,4C,5B,6D,7B),(1C,2A,3E-
,4C,5B,6D,7C),
(1C,2A,3E,4D,5A,6A,7A),(1C,2A,3E,4D,5A,6A,7B),(1C,2A,3E,4D,-
5A,6A,7C),(1C,2A,3E,4D,5A,6B,7A),(1C,2A,3E,4D,5A,6B,7B),(1C,2A,3E,4D,5A,6B-
,7C),(1C,2A,3E,4D,5A,6C,7A),
(1C,2A,3E,4D,5A,6C,7B),(1C,2A,3E,4D,5A,6C,7C)-
,(1C,2A,3E,4D,5A,6D,7A),(1C,2A,3E,4D,5A,6D,7B),(1C,2A,3E,4D,5A,6D,7C),(1C,-
2A,3E,4D,5B,6A,7A),(1C,2A,3E,4D,5B,6A,7B),
(1C,2A,3E,4D,5B,6A,7C),(1C,2A,3-
E,4D,5B,6B,7A),(1C,2A,3E,4D,5B,6B,7B),(1C,2A,3E,4D,5B,6B,7C),(1C,2A,3E,4D,-
5B,6C,7A),(1C,2A,3E,4D,5B,6C,7B),(1C,2A,3E,4D,5B,6C,7C),
(1C,2A,3E,4D,5B,6D,7A),(1C,2A,3E,4D,5B,6D,7B),(1C,2A,3E,4D,5B,6D,7C),(1C,-
2A,3E,4E,5A,6A,7A), (1C,2A,3E,4E,5A,6A,7B),
(1C,2A,3E,4E,5A,6A,7C),(1C,2A,- 3E,4E,5A,6B,7A),
(1C,2A,3E,4E,5A,6B,7B),(1C,2A,3E,4E,5A,6B,7C),(1C,2A,3E,4-
E,5A,6C,7A),(1C,2A,3E,4E,5A,6C,7B),(1C,2A,3E,4E,5A,6C,7C),(1C,2A,3E,4E,5A,-
6D,7A),(1C,2A,3E,4E,5A,6D,7B),
(1C,2A,3E,4E,5A,6D,7C),(1C,2A,3E,4E,5B,6A,7-
A),(1C,2A,3E,4E,5B,6A,7B),(1C,2A,3E,4E,5B,6A,7C),(1C,2A,3E,4E,5B,6B,7A),(1-
C,2A,3E,4E,5B,6B,7B),(1C,2A,3E,4E,5B,6B,7C),
(1C,2A,3E,4E,5B,6C,7A),(1C,2A-
,3E,4E,5B,6C,7B),(1C,2A,3E,4E,5B,6C,7C),(1C,2A,3E,4E,5B,6D,7A),(1C,2A,3E,4-
E,5B,6D,7B),(1C,2A,3E,4E,5B,6D,7C),(1C,2B,3A,4A,5A,6A,7A),
(1C,2B,3A,4A,5A,6A,7B),(1C,2B,3A,4A,5A,6A,7C),(1C,2B,3A,4A,5A,6B,7A),(1C,-
2B,3A,4A,5A,6B,7B),(1C,2B,3A,4A,5A,6B,7C),(1C,2B,3A,4A,5A,6C,7A),(1C,2B,3A-
,4A,5A,6C,7B),
(1C,2B,3A,4A,5A,6C,7C),(1C,2B,3A,4A,5A,6D,7A),(1C,2B,3A,4A,-
5A,6D,7B),(1C,2B,3A,4A,5A,6D,7C),(1C,2B,3A,4A,5B,6A,7A),(1C,2B,3A,4A,5B,6A-
,7B),(1C,2B,3A,4A,5B,6A,7C),
(1C,2B,3A,4A,5B,6B,7A),(1C,2B,3A,4A,5B,6B,7B)-
,(1C,2B,3A,4A,5B,6B,7C),(1C,2B,3A,4A,5B,6C,7A),(1C,2B,3A,4A,5B,6C,7B),(1C,-
2B,3A,4A,5B,6C,7C),(1C,2B,3A,4A,5B,6D,7A),
(1C,2B,3A,4A,5B,6D,7B),(1C,2B,3-
A,4A,5B,6D,7C),(1C,2B,3A,4B,5A,6A,7A),(1C,2B,3A,4B,5A,6A,7B),(1C,2B,3A,4B,-
5A,6A,7C),(1C,2B,3A,4B,5A,6B,7A),(1C,2B,3A,4B,5A,6B,7B),
(1C,2B,3A,4B,5A,6B,7C),(1C,2B,3A,4B,5A,6C,7A),(1C,2B,3A,4B,5A,6C,7B),(1C,-
2B,3A,4B,5A,6C,7C),(1C,2B,3A,4B,5A,6D,7A),(1C,2B,3A,4B,5A,6D,7B),(1C,2B,3A-
,4B,5A,6D,7C),
(1C,2B,3A,4B,5B,6A,7A),(1C,2B,3A,4B,5B,6A,7B),(1C,2B,3A,4B,-
5B,6A,7C),(1C,2B,3A,4B,5B,6B,7A),(1C,2B,3A,4B,5B,6B,7B),(1C,2B,3A,4B,5B,6B-
,7C),(1C,2B,3A,4B,5B,6C,7A),
(1C,2B,3A,4B,5B,6C,7B),(1C,2B,3A,4B,5B,6C,7C)-
,(1C,2B,3A,4B,5B,6D,7A),(1C,2B,3A,4B,5B,6D,7B),(1C,2B,3A,4B,5B,6D,7C),(1C,-
2B,3A,4C,5A,6A,7A),(1C,2B,3A,4C,5A,6A,7B),
(1C,2B,3A,4C,5A,6A,7C),(1C,2B,3-
A,4C,5A,6B,7A),(1C,2B,3A,4C,5A,6B,7B),(1C,2B,3A,4C,5A,6B,7C),(1C,2B,3A,4C,-
5A,6C,7A),(1C,2B,3A,4C,5A,6C,7B),(1C,2B,3A,4C,5A,6C,7C),
(1C,2B,3A,4C,5A,6D,7A),(1C,2B,3A,4C,5A,6D,7B),(1C,2B,3A,4C,5A,6D,7C),(1C,-
2B,3A,4C,5B,6A,7A),(1C,2B,3A,4C,5B,6A,7B),(1C,2B,3A,4C,5B,6A,7C),(1C,2B,3A-
,4C,5B,6B,7A),
(1C,2B,3A,4C,5B,6B,7B),(1C,2B,3A,4C,5B,6B,7C),(1C,2B,3A,4C,-
5B,6C,7A),(1C,2B,3A,4C,5B,6C,7B),(1C,2B,3A,4C,5B,6C,7C),(1C,2B,3A,4C,5B,6D-
,7A),(1C,2B,3A,4C,5B,6D,7B),
(1C,2B,3A,4C,5B,6D,7C),(1C,2B,3A,4D,5A,6A,7A)-
,(1C,2B,3A,4D,5A,6A,7B),(1C,2B,3A,4D,5A,6A,7C),(1C,2B,3A,4D,5A,6B,7A),(1C,-
2B,3A,4D,5A,6B,7B),(1C,2B,3A,4D,5A,6B,7C),
(1C,2B,3A,4D,5A,6C,7A),(1C,2B,3-
A,4D,5A,6C,7B),(1C,2B,3A,4D,5A,6C,7C),(1C,2B,3A,4D,5A,6D,7A),
(1C,2B,3A,4D,5A,6D,7B),(1C,2B,3A,4D,5A,6D,7C),
(1C,2B,3A,4D,5B,6A,7A), (1C,2B,3A,4D,5B,6A,7B),
(1C,2B,3A,4D,5B,6A,7C), (1C,2B,3A,4D,5B,6B, 7A),
(1C,2B,3A,4D,5B,6B,7B),
(1C,2B,3A,4D,5B,6B,7C),(1C,2B,3A,4D,5B,6C,7A),
(1C,2B,3A,4D,5B,6C,7B),
(1C,2B,3A,4D,5B,6C,7C),(1C,2B,3A,4D,5B,6D,7A), (1C,2B,3A,4D,5B,6D,
7B), (1C,2B,3A,4D,5B,6D,7C), (1C,2B,3A,4E,5A,6A,7A),(-
1C,2B,3A,4E,5A,6A,7B), (1C,2B,3A,4E,5A,6A,7C),
(1C,2B,3A,4E,5A,6B,7A), (C,2B,3A,4E,5A,6B,7B), (1C,2B,3A,4E,5A,6B,
7C), (1C,2B,3A,4E,5A,6C,7A),(1-
C,2B,3A,4E,5A,6C,7B),(1C,2B,3A,4E,5A,6C,7C),(1C,2B,3A,4E,5A,6D,7A),
(1C,2B,3A,4E,5A,6D,7B),(1C,2B,3A,4E,5A,6D,7C),(1C,2B,3A,4E,5B,6A,7A),(1C,-
2B,3A,4E,5B,6A,7B),(1C,2B,3A,4E,5B,6A,7C),(1C,2B,3A,4E,5B,6B,7A),(1C,2B,3A-
,4E,5B,6B,7B),
(1C,2B,3A,4E,5B,6B,7C),(1C,2B,3A,4E,5B,6C,7A),(1C,2B,3A,4E,-
5B,6C,7B),(1C,2B,3A,4E,5B,6C,7C),(1C,2B,3A,4E,5B,6D,7A),(1C,2B,3A,4E,5B,6D-
,7B),(1C,2B,3A,4E,5B,6D,7C),
(1C,2B,3B,4A,5A,6A,7A),(1C,2B,3B,4A,5A,6A,7B)-
,(1C,2B,3B,4A,5A,6A,7C),(1C,2B,3B,4A,5A,6B,7A),(1C,2B,3B,4A,5A,6B,7B),(1C,-
2B,3B,4A,5A,6B,7C),(1C,2B,3B,4A,5A,6C,7A),
(1C,2B,3B,4A,5A,6C,7B),(1C,2B,3-
B,4A,5A,6C,7C),(1C,2B,3B,4A,5A,6D,7A),(1C,2B,3B,4A,5A,6D,7B),(1C,2B,3B,4A,-
5A,6D,7C),(1C,2B,3B,4A,5B,6A,7A),(1C,2B,3B,4A,5B,6A,7B),
(1C,2B,3B,4A,5B,6A,7C),(1C,2B,3B,4A,5B,6B,7A),(1C,2B,3B,4A,5B,6B,7B),(1C,-
2B,3B,4A,5B,6B,7C),(1C,2B,3B,4A,5B,6C,7A),(1C,2B,3B,4A,5B,6C,7B),(1C,2B,3B-
,4A,5B,6C,7C),
(1C,2B,3B,4A,5B,6D,7A),(1C,2B,3B,4A,5B,6D,7B),(1C,2B,3B,4A,-
5B,6D,7C),(1C,2B,3B,4B,5A,6A,7A),(1C,2B,3B,4B,5A,6A,7B),(1C,2B,3B,4B,5A,6A-
,7C),(1C,2B,3B,4B,5A,6B,7A),
(1C,2B,3B,4B,5A,6B,7B),(1C,2B,3B,4B,5A,6B,7C)-
,(1C,2B,3B,4B,5A,6C,7A),(1C,2B,3B,4B,5A,6C,7B),(1C,2B,3B,4B,5A,6C,7C),(1C,-
2B,3B,4B,5A,6D,7A),(1C,2B,3B,4B,5A,6D,7B),
(1C,2B,3B,4B,5A,6D,7C),(1C,2B,3-
B,4B,5B,6A,7A),(1C,2B,3B,4B,5B,6A,7B),(1C,2B,3B,4B,5B,6A,7C),(1C,2B,3B,4B,-
5B,6B,7A),(1C,2B,3B,4B,5B,6B,7B),(1C,2B,3B,4B,5B,6B,7C),
(1C,2B,3B,4B,5B,6C,7A),(1C,2B,3B,4B,5B,6C,7B),(1C,2B,3B,4B,5B,6C,7C),(1C,-
2B,3B,4B,5B,6D,7A),(1C,2B,3B,4B,5B,6D,7B),(1C,2B,3B,4B,5B,6D,7C),(1C,2B,3B-
,4C,5A,6A,7A),
(1C,2B,3B,4C,5A,6A,7B),(1C,2B,3B,4C,5A,6A,7C),(1C,2B,3B,4C,-
5A,6B,7A),(1C,2B,3B,4C,5A,6B,7B),(1C,2B,3B,4C,5A,6B,7C),(1C,2B,3B,4C,5A,6C-
,7A),(1C,2B,3B,4C,5A,6C,7B),
(1C,2B,3B,4C,5A,6C,7C),(1C,2B,3B,4C,5A,6D,7A)-
,(1C,2B,3B,4C,5A,6D,7B),(1C,2B,3B,4C,5A,6D,7C),(1C,2B,3B,4C,5B,6A,7A),(1C,-
2B,3B,4C,5B,6A,7B),(1C,2B,3B,4C,5B,6A,7C),
(1C,2B,3B,4C,5B,6B,7A),(1C,2B,3-
B,4C,5B,6B,7B),(1C,2B,3B,4C,5B,6B,7C),(1C,2B,3B,4C,5B,6C,7A),
(1C,2B,3B,4C,5B,6C,7B),(1C,2B,3B,4C,5B,6C,7C),(1C,2B,3B,4C,5B,6D,7A),
(1C,2B,3B,4C,5B,6D,7B),(1C,2B,3B,4C,5B,6D,7C),
(1C,2B,3B,4D,5A,6A,7A),(1C- ,2B,3B,4D,5A,6A, 7B),
(1C,2B,3B,4D,5A,6A, 7C), (1C,2B,3B,4D,5A,6B,7A),
(1C,2B,3B,4D,5A,6B, 7B), (1C,2B,3B,4D,5A,6B,7C),
(1C,2B,3B,4D,5A,6C,7A), (1C,2B,3B,4D,5A,6C, 7B),
(1C,2B,3B,4D,5A,6C,7C), (1C,2B,3B,4D,5A,6D,7A),
(1C,2B,3B,4D,5A,6D,7B), (1C,2B,3B,4D,5A,6D,7C),
(1C,2B,3B,4D,5B,6A,7A),(1-
C,2B,3B,4D,5B,6A,7B),(1C,2B,3B,4D,5B,6A,7C), (1C,2B,3B,4D,5B,6B,
7A), (1C,2B,3B,4D,5B,6B, 7B), (1C,2B,3B,4D,5B,6B, 7C),
(1C,2B,3B,4D,5B,6C, 7A), (1C,2B,3B,4D,5B,6C,7B),
(1C,2B,3B,4D,5B,6C,7C), (1C,2B,3B,4D,5B,6D,7A),
(1C,2B,3B,4D,5B,6D,7B), (1C,2B,3B,4D,5B,6D,7C),(1-
C,2B,3B,4E,5A,6A,7A),(1C,2B,3B,4E,5A,6A,7B),
(1C,2B,3B,4E,5A,6A,7C), (1C,2B,3B,4E,5A,6B,7A),
(1C,2B,3B,4E,5A,6B,7B), (1C,2B,3B,4E,5A,6B,7C),(1-
C,2B,3B,4E,5A,6C,7A),(1C,2B,3B,4E,5A,6C,7B),(1C,2B,3B,4E,5A,6C,7C),
(1C,2B,3B,4E,5A,6D,7A),(1C,2B,3B,4E,5A,6D,7B),(1C,2B,3B,4E,5A,6D,7C),(1C,-
2B,3B,4E,5B,6A,7A),(1C,2B,3B,4E,5B,6A,7B),(1C,2B,3B,4E,5B,6A,7C),(1C,2B,3B-
,4E,5B,6B,7A),
(1C,2B,3B,4E,5B,6B,7B),(1C,2B,3B,4E,5B,6B,7C),(1C,2B,3B,4E,-
5B,6C,7A),(1C,2B,3B,4E,5B,6C,7B),(1C,2B,3B,4E,5B,6C,7C),(1C,2B,3B,4E,5B,6D-
,7A),(1C,2B,3B,4E,5B,6D,7B),
(1C,2B,3B,4E,5B,6D,7C),(1C,2B,3C,4A,5A,6A,7A)-
,(1C,2B,3C,4A,5A,6A,7B),(1C,2B,3C,4A,5A,6A,7C),(1C,2B,3C,4A,5A,6B,7A),(1C,-
2B,3C,4A,5A,6B,7B),(1C,2B,3C,4A,5A,6B,7C),
(1C,2B,3C,4A,5A,6C,7A),(1C,2B,3-
C,4A,5A,6C,7B),(1C,2B,3C,4A,5A,6C,7C),(1C,2B,3C,4A,5A,6D,7A),(1C,2B,3C,4A,-
5A,6D,7B),(1C,2B,3C,4A,5A,6D,7C),(1C,2B,3C,4A,5B,6A,7A),
(1C,2B,3C,4A,5B,6A,7B),(1C,2B,3C,4A,5B,6A,7C),(1C,2B,3C,4A,5B,6B,7A),(1C,-
2B,3C,4A,5B,6B,7B),(1C,2B,3C,4A,5B,6B,7C),(1C,2B,3C,4A,5B,6C,7A),(1C,2B,3C-
,4A,5B,6C,7B),
(1C,2B,3C,4A,5B,6C,7C),(1C,2B,3C,4A,5B,6D,7A),(1C,2B,3C,4A,-
5B,6D,7B),(1C,2B,3C,4A,5B,6D,7C),(1C,2B,3C,4B,5A,6A,7A),(1C,2B,3C,4B,5A,6A-
,7B),(1C,2B,3C,4B,5A,6A,7C),
(1C,2B,3C,4B,5A,6B,7A),(1C,2B,3C,4B,5A,6B,7B)-
,(1C,2B,3C,4B,5A,6B,7C),(1C,2B,3C,4B,5A,6C,7A),(1C,2B,3C,4B,5A,6C,7B),(1C,-
2B,3C,4B,5A,6C,7C),(1C,2B,3C,4B,5A,6D,7A),
(1C,2B,3C,4B,5A,6D,7B),(1C,2B,3-
C,4B,5A,6D,7C),(1C,2B,3C,4B,5B,6A,7A),(1C,2B,3C,4B,5B,6A,7B),(1C,2B,3C,4B,-
5B,6A,7C),(1C,2B,3C,4B,5B,6B,7A),(1C,2B,3C,4B,5B,6B,7B),
(1C,2B,3C,4B,5B,6B,7C),(1C,2B,3C,4B,5B,6C,7A),(1C,2B,3C,4B,5B,6C,7B),(1C,-
2B,3C,4B,5B,6C,7C),(1C,2B,3C,4B,5B,6D,7A),(1C,2B,3C,4B,5B,6D,7B),(1C,2B,3C-
,4B,5B,6D,7C),
(1C,2B,3C,4C,5A,6A,7A),(1C,2B,3C,4C,5A,6A,7B),(1C,2B,3C,4C,-
5A,6A,7C),(1C,2B,3C,4C,5A,6B,7A),
(1C,2B,3C,4C,5A,6B,7B),(1C,2B,3C,4C,5A,6-
B,7C),(1C,2B,3C,4C,5A,6C,7A),
(1C,2B,3C,4C,5A,6C,7B),(1C,2B,3C,4C,5A,6C,7C- ),
(1C,2B,3C,4C,5A,6D,7A), (1C,2B,3C,4C,5A,6D,7B),
(1C,2B,3C,4C,5A,6D,7C),-
(1C,2B,3C,4C,5B,6A,7A),(1C,2B,3C,4C,5B,6A,7B),
(1C,2B,3C,4C,5B,6A,7C), (1C,2B,3C,4C,5B,6B,7A), (1C,2B,3C,4C,5B,6B,
7B), (1C,2B,3C,4C,5B,6B,7C),(-
1C,2B,3C,4C,5B,6C,7A),(1C,2B,3C,4C,5B,6C,7B),(1C,2B,3C,4C,5B,6C,7C),
(1C,2B,3C,4C;5B,6D,7A),(1C,2B,3C,4C,5B,6D,7B),(1C,2B,3C,4C,5B,6D,7C),(1C,-
2B,3C,4D,5A,6A,7A),(1C,2B,3C,4D,5A,6A,7B),(1C,2B,3C,4D,5A,6A,7C),(1C,2B,3C-
,4D,5A,6B,7A),
(1C,2B,3C,4D,5A,6B,7B),(1C,2B,3C,4D,5A,6B,7C),(1C,2B,3C,4D,-
5A,6C,7A),(1C,2B,3C,4D,5A,6C,7B),(1C,2B,3C,4D,5A,6C,7C),(1C,2B,3C,4D,5A,6D-
,7A),(1C,2B,3C,4D,5A,6D,7B),
(1C,2B,3C,4D,5A,6D,7C),(1C,2B,3C,4D,5B,6A,7A)-
,(1C,2B,3C,4D,5B,6A,7B),(1C,2B,3C,4D,5B,6A,7C),(1C,2B,3C,4D,5B,6B,7A),(1C,-
2B,3C,4D,5B,6B,7B),(1C,2B,3C,4D,5B,6B,7C),
(1C,2B,3C,4D,5B,6C,7A),(1C,2B,3-
C,4D,5B,6C,7B),(1C,2B,3C,4D,5B,6C,7C),(1C,2B,3C,4D,5B,6D,7A),(1C,2B,3C,4D,-
5B,6D,7B),(1C,2B,3C,4D,5B,6D,7C),(1C,2B,3C,4E,5A,6A,7A),
(1C,2B,3C,4E,5A,6A,7B),(1C,2B,3C,4E,5A,6A,7C),(1C,2B,3C,4E,5A,6B,7A),(1C,-
2B,3C,4E,5A,6B,7B),(1C,2B,3C,4E,5A,6B,7C),(1C,2B,3C,4E,5A,6C,7A),(1C,2B,3C-
,4E,5A,6C,7B),
(1C,2B,3C,4E,5A,6C,7C),(1C,2B,3C,4E,5A,6D,7A),(1C,2B,3C,4E,-
5A,6D,7B),(1C,2B,3C,4E,5A,6D,7C),(1C,2B,3C,4E,5B,6A,7A),(1C,2B,3C,4E,5B,6A-
,7B),(1C,2B,3C,4E,5B,6A,7C),
(1C,2B,3C,4E,5B,6B,7A),(1C,2B,3C,4E,5B,6B,7B)-
,(1C,2B,3C,4E,5B,6B,7C),(1C,?B,3C,4E,5B,6C,7A),(1C,2B,3C,4E,5B,6C,7B),(1C,-
2B,3C,4E,5B,6C,7C),(1C,2B,3C,4E,5B,6D,7A),
(1C,2B,3C,4E,5B,6D,7B),(1C,2B,3-
C,4E,5B,6D,7C),(1C,2B,3D,4A,5A,6A,7A),(1C,2B,3D,4A,5A,6A,7B),(1C,2B,3D,4A,-
5A,6A,7C),(1C,2B,3D,4A,5A,6B,7A),(1C,2B,3D,4A,5A,6B,7B),
(1C,2B,3D,4A,5A,6B,7C),(1C,2B,3D,4A,5A,6C,7A),(1C,2B,3D,4A,5A,6C,7B),(1C,-
2B,3D,4A,5A,6C,7C),(1C,2B,3D,4A,5A,6D,7A),(1C,2B,3D,4A,5A,6D,7B),(1C,2B,3D-
,4A,5A,6D,7C),
(1C,2B,3D,4A,5B,6A,7A),(1C,2B,3D,4A,5B,6A,7B),(1C,2B,3D,4A,-
5B,6A,7C),(1C,2B,3D,4A,5B,6B,7A),(1C,2B,3D,4A,5B,6B,7B),(1C,2B,3D,4A,5B,6B-
,7C),(1C,2B,3D,4A,5B,6C,7A),
(1C,2B,3D,4A,5B,6C,7B),(1C,2B,3D,4A,5B,6C,7C)-
,(1C,2B,3D,4A,5B,6D,7A),(1C,2B,3D,4A,5B,6D,7B),(1C,2B,3D,4A,5B,6D,7C),(1C,-
2B,3D,4B,5A,6A,7A),(1C,2B,3D,4B,5A,6A,7B),
(1C,2B,3D,4B,5A,6A,7C),(1C,2B,3-
D,4B,5A,6B,7A),(1C,2B,3D,4B,5A,6B,7B),(1C,2B,3D,4B,5A,6B,7C),(1C,2B,3D,4B,-
5A,6C,7A),(1C,2B,3D,4B,5A,6C,7B),(1C,2B,3D,4B,5A,6C,7C),
(1C,2B,3D,4B,5A,6D,7A),(1C,2B,3D,4B,5A,6D,7B),(1C,2B,3D,4B,5A,6D,7C),(1C,-
2B,3D,4B,5B,6A,7A), (1C,2B,3D,4B,5B,6A,7B), (1C,2B,3D,4B,
5B,6A,7C), (1C,2B,3D,4B,5B,6B, 7A), (1C,2B,3D,4B,5B,6B,7B),
(1C,2B,3D,4B,5B,6B,7C), (1C,2B,3D,4B,5B,6C,7A),
(1C,2B,3D,4B,5B,6C,7B), (1C,2B,3D,4B,5B,6C,7C),(1-
C,2B,3D,4B,5B,6D,7A),(1C,2B,3D,4B,5B,6D,7B),
(1C,2B,3D,4B,5B,6D,7C), (1C,2B,3D,4C,5A,6A,7A),
(1C,2B,3D,4C,5A,6A,7B), (1C,2B,3D,4C,5A,6A,7C),
(1C,2B,3D,4C,5A,6B,7A),(1C,2B,3D,4C,5A,6B,7B),(1C,2B,3D,4C,5A,6B,7C),
(1C,2B,3D,4C,5A,6C,7A), (1C,2B,3D,4C,5A,6C,7B),
(1C,2B,3D,4C,5A,6C,7C), (1C,2B,3D,4C,5A,6D,7A),
(1C,2B,3D,4C,5A,6D,7B),(1C,2B,3D,4C,5A,6D,7C),(1C-
,2B,3D,4C,5B,6A,7A), (1C,2B,3D,4C,5B,6A,7B),
(1C,2B,3D,4C,5B,6A,7C), (1C,2B,3D,4C,5B,6B,7A),
(1C,2B,3D,4C,5B,6B,7B), (1C,2B,3D,4C,5B,6B,7C),(1-
C,2B,3D,4C,5B,6C,7A),(1C,2B,3D,4C,5B,6C,7B),
(1C,2B,3D,4C,5B,6C,7C), (1C,2B,3D,4C,5B,6D,7A),
(1C,2B,3D,4C,5B,6D,7B), (1C,2B,3D,4C,5B,6D,7C),
(1C,2B,3D,4D,5A,6A,7A),(1C,2B,3D,4D,5A,6A,7B),(1C,2B,3D,4D,5A,6A,7C),
(1C,2B,3D,4D,5A,6B,7A), (1C,2B,3D,4D,5A,6B,7B),
(1C,2B,3D,4D,5A,6B,7C), (1C,2B,3D,4D,5A,6C,7A),
(1C,2B,3D,4D,5A,6C,7B), (1C,2B,3D,4D,5A,6C,7C),(1-
C,2B,3D,4D,5A,6D,7A), (1C,2B,3D,4D,5A,6D,7B),
(1C,2B,3D,4D,5A,6D,7C), (1C,2B,3D,4D,5B,6A,7A),
(1C,2B,3D,4D,5B,6A,7B),(1C,2B,3D,4D,5B,6A,7C),
(C,2B,3D,4D,5B,6B,7A),(1C,2B,3D,4D,5B,6B,7B),
(1C,2B,3D,4D,5B,6B,7C),(1C,-
2B,3D,4D,5B,6C,7A),(1C,2B,3D,4D,5B,6C,7B), (1C,2B,3D,4D,5B,6C,7C),
(1C,2B,3D,4D,5B,6D,7A),
(1C,2B,3D,4D,5B,6D,7B),(1C,2B,3D,4D,5B,6D,7C),
(1C,2B,3D,4E,5A,6A,7A),(1C,2B,3D,4E,5A,6A,7B),(1C,2B,3D,4E,5A,6A,7C),(1C,-
2B,3D,4E,5A,6B,7A),(1C,2B,3D,4E,5A,6B,7B),(1C,2B,3D,4E,5A,6B,7C),(1C,2B,3D-
,4E,5A,6C,7A),
(1C,2B,3D,4E,5A,6C,7B),(1C,2B,3D,4E,5A,6C,7C),(1C,2B,3D,4E,-
5A,6D,7A),(1C,2B,3D,4E,5A,6D,7B),(1C,2B,3D,4E,5A,6D,7C),(1C,2B,3D,4E,5B,6A-
,7A),(1C,2B,3D,4E,5B,6A,7B),
(1C,2B,3D,4E,5B,6A,7C),(1C,2B,3D,4E,5B,6B,7A)-
,(1C,2B,3D,4E,5B,6B,7B),(1C,2B,3D,4E,5B,6B,7C),(1C,2B,3D,4E,5B,6C,7A),(1C,-
2B,3D,4E,5B,6C,7B),(1C,2B,3D,4E,5B,6C,7C),
(1C,2B,3D,4E,5B,6D,7A),(1C,2B,3-
D,4E,5B,6D,7B),(1C,2B,3D,4E,5B,6D,7C),(1C,2B,3E,4A,5A,6A,7A),(1C,2B,3E,4A,-
5A,6A,7B),(1C,2B,3E,4A,5A,6A,7C),(1C,2B,3E,4A,5A,6B,7A),
(1C,2B,3E,4A,5A,6B,7B),(1C,2B,3E,4A,5A,6B,7C),(1C,2B,3E,4A,5A,6C,7A),(1C,-
2B,3E,4A,5A,6C,7B),(1C,2B,3E,4A,5A,6C,7C),(1C,2B,3E,4A,5A,6D,7A),(1C,2B,3E-
,4A,5A,6D,7B),
(1C,2B,3E,4A,5A,6D,7C),(1C,2B,3E,4A,5B,6A,7A),(1C,2B,3E,4A,-
5B,6A,7B),(1C,2B,3E,4A,5B,6A,7C),(1C,2B,3E,4A,5B,6B,7A),(1C,2B,3E,4A,5B,6B-
,7B),(1C,2B,3E,4A,5B,6B,7C),
(1C,2B,3E,4A,5B,6C,7A),(1C,2B,3E,4A,5B,6C,7B)-
,(1C,2B,3E,4A,5B,6C,7C),(1C,2B,3E,4A,5B,6D,7A),(1C,2B,3E,4A,5B,6D,7B),(1C,-
2B,3E,4A,5B,6D,7C),(1C,2B,3E,4B,5A,6A,7A),
(1C,2B,3E,4B,5A,6A,7B),(1C,2B,3- E,4B,5A,6A,7C),
(1C,2B,3E,4B,5A,6B,7A),(1C,2B,3E,4B,5A,6B,7B),(1C,2B,3E,4B-
,5A,6B,7C),(1C,2B,3E,4B,5A,6C,7A),(1C,2B,3E,4B,5A,6C,7B),
(1C,2B,3E,4B,5A,6C,7C),(1C,2B,3E,4B,5A,6D,7A),(1C,2B,3E,4B,5A,6D,7B),(1C,-
2B,3E,4B,5A,6D,7C),(1C,2B,3E,4B,5B,6A,7A),(1C,2B,3E,4B,5B,6A,7B),(1C,2B,3E-
,4B,5B,6A,7C),
(1C,2B,3E,4B,5B,6B,7A),(1C,2B,3E,4B,5B,6B,7B),(1C,2B,3E,4B,-
5B,6B,7C),(1C,2B,3E,4B,5B,6C,7A),(1C,2B,3E,4B,5B,6C,7B),(1C,2B,3E,4B,5B,6C-
,7C),(1C,2B,3E,4B,5B,6D,7A),
(1C,2B,3E,4B,5B,6D,7B),(1C,2B,3E,4B,5B,6D,7C)-
,(1C,2B,3E,4C,5A,6A,7A),(1C,2B,3E,4C,5A,6A,7B),(1C,2B,3E,4C,5A,6A,7C),(1C,-
2B,3E,4C,5A,6B,7A),(1C,2B,3E,4C,5A,6B,7B),
(1C,2B,3E,4C,5A,6B,7C),(1C,2B,3-
E,4C,5A,6C,7A),(1C,2B,3E,4C,5A,6C,7B),(1C,2B,3E,4C,5A,6C,7C),(1C,2B,3E,4C,-
5A,6D,7A),(1C,2B,3E,4C,5A,6D,7B),(1C,2B,3E,4C,5A,6D,7C),
(1C,2B,3E,4C,5B,6A,7A),(1C,2B,3E,4C,5B,6A,7B),(1C,2B,3E,4C,5B,6A,7C),(1C,-
2B,3E,4C,5B,6B,7A),(1C,2B,3E,4C,5B,6B,7B),(1C,2B,3E,4C,5B,6B,7C),(1C,2B,3E-
,4C,5B,6C,7A),
(1C,2B,3E,4C,5B,6C,7B),(1C,2B,3E,4C,5B,6C,7C),(1C,2B,3E,4C,-
5B,6D,7A),(1C,2B,3E,4C,5B,6D,7B),(1C,2B,3E,4C,5B,6D,7C),(1C,2B,3E,4D,5A,6A-
,7A),(1C,2B,3E,4D,5A,6A,7B),
(1C,2B,3E,4D,5A,6A,7C),(1C,2B,3E,4D,5A,6B,7A)-
,(1C,2B,3E,4D,5A,6B,7B),(1C,2B,3E,4D,5A,6B,7C),(1C,2B,3E,4D,5A,6C,7A),(1C,-
2B,3E,4D,5A,6C,7B),(1C,2B,3E,4D,5A,6C,7C),
(1C,2B,3E,4D,5A,6D,7A),(1C,2B,3-
E,4D,5A,6D,7B),(1C,2B,3E,4D,5A,6D,7C),(1C,2B,3E,4D,5B,6A,7A),(1C,2B,3E,4D,-
5B,6A,7B),(1C,2B,3E,4D,5B,6A,7C),(1C,2B,3E,4D,5B,6B,7A),
(1C,2B,3E,4D,5B,6B,7B),(1C,2B,3E,4D,5B,6B,7C),(1C,2B,3E,4D,5B,6C,7A),(1C,-
2B,3E,4D,5B,6C,7B),(1C,2B,3E,4D,5B,6C,7C),(1C,2B,3E,4D,5B,6D,7A),(1C,2B,3E-
,4D,5B,6D,7B),
(1C,2B,3E,4D,5B,6D,7C),(1C,2B,3E,4E,5A,6A,7A),(1C,2B,3E,4E,-
5A,6A,7B),(1C,2B,3E,4E,5A,6A,7C),(1C,2B,3E,4E,5A,6B,7A),(1C,2B,3E,4E,5A,6B-
,7B),(1C,2B,3E,4E,5A,6B,7C),
(1C,2B,3E,4E,5A,6C,7A),(1C,2B,3E,4E,5A,6C,7B)-
,(1C,2B,3E,4E,5A,6C,7C),(1C,2B,3E,4E,5A,6D,7A),(1C,2B,3E,4E,5A,6D,7B),(1C,-
2B,3E,4E,5A,6D,7C),(1C,2B,3E,4E,5B,6A,7A),
(1C,2B,3E,4E,5B,6A,7B),(1C,2B,3-
E,4E,5B,6A,7C),(1C,2B,3E,4E,5B,6B,7A),(1C,2B,3E,4E,5B,6B,7B),(1C,2B,3E,4E,-
5B,6B,7C),(1C,2B,3E,4E,5B,6C,7A),(1C,2B,3E,4E,5B,6C,7B),
(1C,2B,3E,4E,5B,6C,7C),(1C,2B,3E,4E,5B,6D,7A),(1C,2B,3E,4E,5B,6D,7B),(1C,-
2B,3E,4E,5B,6D,7C),(1C,2C,3A,4A,5A,6A,7A),(1C,2C,3A,4A,5A,6A,7B),(1C,2C,3A-
,4A,5A,6A,7C),
(1C,2C,3A,4A,5A,6B,7A),(1C,2C,3A,4A,5A,6B,7B),(1C,2C,3A,4A,-
5A,6B,7C),(1C,2C,3A,4A,5A,6C,7A),(1C,2C,3A,4A,5A,6C,7B),(1C,2C,3A,4A,5A,6C-
,7C),(1C,2C,3A,4A,5A,6D,7A),
(1C,2C,3A,4A,5A,6D,7B),(1C,2C,3A,4A,5A,6D,7C)-
,(1C,2C,3A,4A,5B,6A,7A),(1C,2C,3A,4A,5B,6A,7B),(1C,2C,3A,4A,5B,6A,7C),(1C,-
2C,3A,4A,5B,6B,7A),(1C,2C,3A,4A,5B,6B,7B),
(1C,2C,3A,4A,5B,6B,7C),(1C,2C,3-
A,4A,5B,6C,7A),(1C,2C,3A,4A,5B,6C,7B),(1C,2C,3A,4A,5B,6C,7C),(1C,2C,3A,4A,-
5B,6D,7A),(1C,2C,3A,4A,5B,6D,7B),(1C,2C,3A,4A,5B,6D,7C),
(1C,2C,3A,4B,5A,6A,7A),(1C,2C,3A,4B,5A,6A,7B),(1C,2C,3A,4B,5A,6A,7C),(1C,-
2C,3A,4B,5A,6B,7A),(1C,2C,3A,4B,5A,6B,7B),(1C,2C,3A,4B,5A,6B,7C),(1C,2C,3A-
,4B,5A,6C,7A),
(1C,2C,3A,4B,5A,6C,7B),(1C,2C,3A,4B,5A,6C,7C),(1C,2C,3A,4B,-
5A,6D,7A),(1C,2C,3A,4B,5A,6D,7B),(1C,2C,3A,4B,5A,6D,7C),(1C,2C,3A,4B,5B,6A-
,7A),(1C,2C,3A,4B,5B,6A,7B),
(1C,2C,3A,4B,5B,6A,7C),(1C,2C,3A,4B,5B,6B,7A)-
,(1C,2C,3A,4B,5B,6B,7B),(1C,2C,3A,4B,5B,6B,7C),(1C,2C,3A,4B,5B,6C,7A),(1C,-
2C,3A,4B,5B,6C,7B),(1C,2C,3A,4B,5B,6C,7C),
(1C,2C,3A,4B,5B,6D,7A),(1C,2C,3-
A,4B,5B,6D,7B),(1C,2C,3A,4B,5B,6D,7C),(1C,2C,3A,4C,5A,6A,7A),(1C,2C,3A,4C,-
5A,6A,7B),(1C,2C,3A,4C,5A,6A,7C),(1C,2C,3A,4C,5A,6B,7A),
(1C,2C,3A,4C,5A,6B,7B),(1C,2C,3A,4C,5A,6B,7C),(1C,2C,3A,4C,5A,6C,7A),(1C,-
2C,3A,4C,5A,6C,7B),(1C,2C,3A,4C,5A,6C,7C),(1C,2C,3A,4C,5A,6D,7A),(1C,2C,3A-
,4C,5A,6D,7B),
(1C,2C,3A,4C,5A,6D,7C),(1C,2C,3A,4C,5B,6A,7A),(1C,2C,3A,4C,-
5B,6A,7B),(1C,2C,3A,4C,5B,6A,7C),(1C,2C,3A,4C,5B,6B,7A),(1C,2C,3A,4C,5B,6B-
,7B),(1C,2C,3A,4C,5B,6B,7C),
(1C,2C,3A,4C,5B,6C,7A),(1C,2C,3A,4C,5B,6C,7B)-
,(1C,2C,3A,4C,5B,6C,7C),(1C,2C,3A,4C,5B,6D,7A),(1C,2C,3A,4C,5B,6D,7B),(1C,-
2C,3A,4C,5B,6D,7C),(1C,2C,3A,4D,5A,6A,7A),
(1C,2C,3A,4D,5A,6A,7B),(1C,2C,3-
A,4D,5A,6A,7C),(1C,2C,3A,4D,5A,6B,7A),(1C,2C,3A,4D,5A,6B,7B),(1C,2C,3A,4D,-
5A,6B,7C),(1C,2C,3A,4D,5A,6C,7A),(1C,2C,3A,4D,5A,6C,7B),
(1C,2C,3A,4D,5A,6C,7C),(1C,2C,3A,4D,5A,6D,7A),(1C,2C,3A,4D,5A,6D,7B),(1C,-
2C,3A,4D,5A,6D,7C),(1C,2C,3A,4D,5B,6A,7A),(1C,2C,3A,4D,5B,6A,7B),(1C,2C,3A-
,4D,5B,6A,7C),
(1C,2C,3A,4D,5B,6B,7A),(1C,2C,3A,4D,5B,6B,7B),(1C,2C,3A,4D,-
5B,6B,7C),(1C,2C,3A,4D,5B,6C,7A),(1C,2C,3A,4D,5B,6C,7B),(1C,2C,3A,4D,5B,6C-
,7C),(1C,2C,3A,4D,5B,6D,7A),
(1C,2C,3A,4D,5B,6D,7B),(1C,2C,3A,4D,5B,6D,7C)-
,(1C,2C,3A,4E,5A,6A,7A),(1C,2C,3A,4E,5A,6A,7B),(1C,2C,3A,4E,5A,6A,7C),(1C,-
2C,3A,4E,5A,6B,7A),(1C,2C,3A,4E,5A,6B,7B),
(1C,2C,3A,4E,5A,6B,7C),(1C,2C,3-
A,4E,5A,6C,7A),(1C,2C,3A,4E,5A,6C,7B),(1C,2C,3A,4E,5A,6C,7C),(1C,2C,3A,4E,-
5A,6D,7A),(1C,2C,3A,4E,5A,6D,7B),(1C,2C,3A,4E,5A,6D,7C),
(1C,2C,3A,4E,5B,6A,7A),(1C,2C,3A,4E,5B,6A,7B),(1C,2C,3A,4E,5B,6A,7C),(1C,-
2C,3A,4E,5B,6B,7A),
(1C,2C,3A,4E,5B,6B,7B),(1C,2C,3A,4E,5B,6B,7C),(1C,2C,3-
A,4E,5B,6C,7A),
(1C,2C,3A,4E,5B,6C,7B),(1C,2C,3A,4E,5B,6C,7C),(1C,2C,3A,4E-
,5B,6D,7A),(1C,2C,3A,4E,5B,6D,7B),(1C,2C,3A,4E,5B,6D,7C),(1C,2C,3B,4A,5A,6-
A,7A),(1C,2C,3B,4A,5A,6A,7B),
(1C,2C,3B,4A,5A,6A,7C),(1C,2C,3B,4A,5A,6B,7A-
),(1C,2C,3B,4A,5A,6B,7B),(1C,2C,3B,4A,5A,6B,7C),(1C,2C,3B,4A,5A,6C,7A),(1C-
,2C,3B,4A,5A,6C,7B),(1C,2C,3B,4A,5A,6C,7C),
(1C,2C,3B,4A,5A,6D,7A),(1C,2C,-
3B,4A,5A,6D,7B),(1C,2C,3B,4A,5A,6D,7C),(1C,2C,3B,4A,5B,6A,7A),(1C,2C,3B,4A-
,5B,6A,7B),(1C,2C,3B,4A,5B,6A,7C),(1C,2C,3B,4A,5B,6B,7A),
(1C,2C,3B,4A,5B,6B,7B),(1C,2C,3B,4A,5B,6B,7C),(1C,2C,3B,4A,5B,6C,7A),(1C,-
2C,3B,4A,5B,6C,7B),(1C,2C,3B,4A,5B,6C,7C),(1C,2C,3B,4A,5B,6D,7A),(1C,2C,3B-
,4A,5B,6D,7B),
(1C,2C,3B,4A,5B,6D,7C),(1C,2C,3B,4B,5A,6A,7A),(1C,2C,3B,4B,-
5A,6A,7B),(1C,2C,3B,4B,5A,6A,7C),(1C,2C,3B,4B,5A,6B,7A),(1C,2C,3B,4B,5A,6B-
,7B),(1C,2C,3B,4B,5A,6B,7C),
(1C,2C,3B,4B,5A,6C,7A),(1C,2C,3B,4B,5A,6C,7B)-
,(1C,2C,3B,4B,5A,6C,7C),(1C,2C,3B,4B,5A,6D,7A),(1C,2C,3B,4B,5A,6D,7B),(1C,-
2C,3B,4B,5A,6D,7C),(1C,2C,3B,4B,5B,6A,7A),
(1C,2C,3B,4B,5B,6A,7B),(1C,2C,3-
B,4B,5B,6A,7C),(1C,2C,3B,4B,5B,6B,7A),(1C,2C,3B,4B,5B,6B,7B),(1C,2C,3B,4B,-
5B,6B,7C),(1C,2C,3B,4B,5B,6C,7A),(1C,2C,3B,4B,5B,6C,7B),
(1C,2C,3B,4B,5B,6C,7C),(1C,2C,3B,4B,5B,6D,7A),(1C,2C,3B,4B,5B,6D,7B),(1C,-
2C,3B,4B,5B,6D,7C),(1C,2C,3B,4C,5A,6A,7A),(1C,2C,3B,4C,5A,6A,7B),(1C,2C,3B-
,4C,5A,6A,7C),
(1C,2C,3B,4C,5A,6B,7A),(1C,2C,3B,4C,5A,6B,7B),(1C,2C,3B,4C,-
5A,6B,7C),(1C,2C,3B,4C,5A,6C,7A),(1C,2C,3B,4C,5A,6C,7B),(1C,2C,3B,4C,5A,6C-
,7C),(1C,2C,3B,4C,5A,6D,7A),
(1C,2C,3B,4C,5A,6D,7B),(1C,2C,3B,4C,5A,6D,7C)-
,(1C,2C,3B,4C,5B,6A,7A),(1C,2C,3B,4C,5B,6A,7B),(1C,2C,3B,4C,5B,6A,7C),(1C,-
2C,3B,4C,5B,6B,7A),(1C,2C,3B,4C,5B,6B,7B),
(1C,2C,3B,4C,5B,6B,7C),(1C,2C,3-
B,4C,5B,6C,7A),(1C,2C,3B,4C,5B,6C,7B),(1C,2C,3B,4C,5B,6C,7C),(1C,2C,3B,4C,-
5B,6D,7A),(1C,2C,3B,4C,5B,6D,7B),(1C,2C,3B,4C,5B,6D,7C),
(1C,2C,3B,4D,5A,6A,7A),(1C,2C,3B,4D,5A,6A,7B),(1C,2C,3B,4D,5A,6A,7C),(1C,-
2C,3B,4D,5A,6B,7A),(1C,2C,3B,4D,5A,6B,7B),(1C,2C,3B,4D,5A,6B,7C),(1C,2C,3B-
,4D,5A,6C,7A),
(1C,2C,3B,4D,5A,6C,7B),(1C,2C,3B,4D,5A,6C,7C),(1C,2C,3B,4D,-
5A,6D,7A),(1C,2C,3B,4D,5A,6D,7B),(1C,2C,3B,4D,5A,6D,7C),(1C,2C,3B,4D,5B,6A-
,7A),(1C,2C,3B,4D,5B,6A,7B),
(1C,2C,3B,4D,5B,6A,7C),(1C,2C,3B,4D,5B,6B,7A)-
,(1C,2C,3B,4D,5B,6B,7B),(1C,2C,3B,4D,5B,6B,7C),(1C,2C,3B,4D,5B,6C,7A),(1C,-
2C,3B,4D,5B,6C,7B),(1C,2C,3B,4D,5B,6C,7C),
(1C,2C,3B,4D,5B,6D,7A),(1C,2C,3-
B,4D,5B,6D,7B),(1C,2C,3B,4D,5B,6D,7C),(1C,2C,3B,4E,5A,6A,7A),(1C,2C,3B,4E,-
5A,6A,7B),(1C,2C,3B,4E,5A,6A,7C),(1C,2C,3B,4E,5A,6B,7A),
(1C,2C,3B,4E,5A,6B,7B),(1C,2C,3B,4E,5A,6B,7C),(1C,2C,3B,4E,5A,6C,7A),(1C,-
2C,3B,4E,5A,6C,7B),(1C,2C,3B,4E,5A,6C,7C),(1C,2C,3B,4E,5A,6D,7A),(1C,2C,3B-
,4E,5A,6D,7B),
(1C,2C,3B,4E,5A,6D,7C),(1C,2C,3B,4E,5B,6A,7A),(1C,2C,3B,4E,-
5B,6A,7B),(1C,2C,3B,4E,5B,6A,7C),(1C,2C,3B,4E,5B,6B,7A),(1C,2C,3B,4E,5B,6B-
,7B),(1C,2C,3B,4E,5B,6B,7C),
(1C,2C,3B,4E,5B,6C,7A),(1C,2C,3B,4E,5B,6C,7B)-
,(1C,2C,3B,4E,5B,6C,7C),(1C,2C,3B,4E,5B,6D,7A),(1C,2C,3B,4E,5B,6D,7B),(1C,-
2C,3B,4E,5B,6D,7C),(1C,2C,3C,4A,5A,6A,7A),
(1C,2C,3C,4A,5A,6A,7B),(1C,2C,3-
C,4A,5A,6A,7C),(1C,2C,3C,4A,5A,6B,7A),(1C,2C,3C,4A,5A,6B,7B),(1C,2C,3C,4A,-
5A,6B,7C),(1C,2C,3C,4A,5A,6C,7A),(1C,2C,3C,4A,5A,6C,7B),
(1C,2C,3C,4A,5A,6C,7C),(1C,2C,3C,4A,5A,6D,7A),(1C,2C,3C,4A,5A,6D,7B),(1C,-
2C,3C,4A,5A,6D,7C),(1C,2C,3C,4A,5B,6A,7A),(1C,2C,3C,4A,5B,6A,7B),(1C,2C,3C-
,4A,5B,6A,7C),
(1C,2C,3C,4A,5B,6B,7A),(1C,2C,3C,4A,5B,6B,7B),(1C,2C,3C,4A,-
5B,6B,7C),(1C,2C,3C,4A,5B,6C,7A),(1C,2C,3C,4A,5B,6C,7B),(1C,2C,3C,4A,5B,6C-
,7C),(1C,2C,3C,4A,5B,6D,7A),
(1C,2C,3C,4A,5B,6D,7B),(1C,2C,3C,4A,5B,6D,7C)-
,(1C,2C,3C,4B,5A,6A,7A),(1C,2C,3C,4B,5A,6A,7B),(1C,2C,3C,4B,5A,6A,7C),(1C,-
2C,3C,4B,5A,6B,7A),(1C,2C,3C,4B,5A,6B,7B),
(1C,2C,3C,4B,5A,6B,7C),(1C,2C,3-
C,4B,5A,6C,7A),(1C,2C,3C,4B,5A,6C,7B),(1C,2C,3C,4B,5A,6C,7C),(1C,2C,3C,4B,-
5A,6D,7A),(1C,2C,3C,4B,5A,6D,7B),(1C,2C,3C,4B,5A,6D,7C),
(1C,2C,3C,4B,5B,6A,7A),(1C,2C,3C,4B,5B,6A,7B),(1C,2C,3C,4B,5B,6A,7C),(1C,-
2C,3C,4B,5B,6B,7A),(1C,2C,3C,4B,5B,6B,7B),(1C,2C,3C,4B,5B,6B,7C),(1C,2C,3C-
,4B,5B,6C,7A),
(1C,2C,3C,4B,5B,6C,7B),(1C,2C,3C,4B,5B,6C,7C),(1C,2C,3C,4B,-
5B,6D,7A),(1C,2C,3C,4B,5B,6D,7B),(1C,2C,3C,4B,5B,6D,7C),(1C,2C,3C,4C,5A,6A-
,7A),(1C,2C,3C,4C,5A,6A,7B),
(1C,2C,3C,4C,5A,6A,7C),(1C,2C,3C,4C,5A,6B,7A)-
,(1C,2C,3C,4C,5A,6B,7B),(1C,2C,3C,4C,5A,6B,7C),(1C,2C,3C,4C,5A,6C,7A),(1C,-
2C,3C,4C,5A,6C,7B),(1C,2C,3C,4C,5A,6C,7C),
(1C,2C,3C,4C,5A,6D,7A),(1C,2C,3-
C,4C,5A,6D,7B),(1C,2C,3C,4C,5A,6D,7C),(1C,2C,3C,4C,5B,6A,7A),(1C,2C,3C,4C,-
5B,6A,7B),(1C,2C,3C,4C,5B,6A,7C),(1C,2C,3C,4C,5B,6B,7A),
(1C,2C,3C,4C,5B,6B,7B),(1C,2C,3C,4C,5B,6B,7C),(1C,2C,3C,4C,5B,6C,7A),(1C,-
2C,3C,4C,5B,6C,7B),(1C,2C,3C,4C,5B,6C,7C),(1C,2C,3C,4C,5B,6D,7A),(1C,2C,3C-
,4C,5B,6D,7B),
(1C,2C,3C,4C,5B,6D,7C),(1C,2C,3C,4D,5A,6A,7A),(1C,2C,3C,4D,-
5A,6A,7B),(1C,2C,3C,4D,5A,6A,7C),(1C,2C,3C,4D,5A,6B,7A),(1C,2C,3C,4D,5A,6B-
,7B),(1C,2C,3C,4D,5A,6B,7C),
(1C,2C,3C,4D,5A,6C,7A),(1C,2C,3C,4D,5A,6C,7B)-
,(1C,2C,3C,4D,5A,6C,7C),(1C,2C,3C,4D,5A,6D,7A),(1C,2C,3C,4D,5A,6D,7B),(1C,-
2C,3C,4D,5A,6D,7C),(1C,2C,3C,4D,5B,6A,7A),
(1C,2C,3C,4D,5B,6A,7B),(1C,2C,3-
C,4D,5B,6A,7C),(1C,2C,3C,4D,5B,6B,7A),(1C,2C,3C,4D,5B,6B,7B),(1C,2C,3C,4D,-
5B,6B,7C),(1C,2C,3C,4D,5B,6C,7A),(1C,2C,3C,4D,5B,6C,7B),
(1C,2C,3C,4D,5B,6C,7C),(1C,2C,3C,4D,5B,6D,7A),(1C,2C,3C,4D,5B,6D,7B),(1C,-
2C,3C,4D,5B,6D,7C),(1C,2C,3C,4E,5A,6A,7A),(1C,2C,3C,4E,5A,6A,7B),(1C,2C,3C-
,4E,5A,6A,7C),
(1C,2C,3C,4E,5A,6B,7A),(1C,2C,3C,4E,5A,6B,7B),(1C,2C,3C,4E,-
5A,6B,7C),(1C,2C,3C,4E,5A,6C,7A),(1C,2C,3C,4E,5A,6C,7B),(1C,2C,3C,4E,5A,6C-
,7C),(1C,2C,3C,4E,5A,6D,7A),
(1C,2C,3C,4E,5A,6D,7B),(1C,2C,3C,4E,5A,6D,7C)-
,(1C,2C,3C,4E,5B,6A,7A),(1C,2C,3C,4E,5B,6A,7B),(1C,2C,3C,4E,5B,6A,7C),(1C,-
2C,3C,4E,5B,6B,7A),(1C,2C,3C,4E,5B,6B,7B),
(1C,2C,3C,4E,5B,6B,7C),(1C,2C,3-
C,4E,5B,6C,7A),(1C,2C,3C,4E,5B,6C,7B),(1C,2C,3C,4E,5B,6C,7C),(1C,2C,3C,4E,-
5B,6D,7A),(1C,2C,3C,4E,5B,6D,7B),(1C,2C,3C,4E,5B,6D,7C),
(1C,2C,3D,4A,5A,6A,7A),(1C,2C,3D,4A,5A,6A,7B),(1C,2C,3D,4A,5A,6A,7C),(1C,-
2C,3D,4A,5A,6B,7A),(1C,2C,3D,4A,5A,6B,7B),(1C,2C,3D,4A,5A,6B,7C),(1C,2C,3D-
,4A,5A,6C,7A),
(1C,2C,3D,4A,5A,6C,7B),(1C,2C,3D,4A,5A,6C,7C),(1C,2C,3D,4A,-
5A,6D,7A),(1C,2C,3D,4A,5A,6D,7B),(1C,2C,3D,4A,5A,6D,7C),(1C,2C,3D,4A,5B,6A-
,7A),(1C,2C,3D,4A,5B,6A,7B),
(1C,2C,3D,4A,5B,6A,7C),(1C,2C,3D,4A,5B,6B,7A)-
,(1C,2C,3D,4A,5B,6B,7B),(1C,2C,3D,4A,5B,6B,7C),(1C,2C,3D,4A,5B,6C,7A),(1C,-
2C,3D,4A,5B,6C,7B),(1C,2C,3D,4A,5B,6C,7C),
(1C,2C,3D,4A,5B,6D,7A),(1C,2C,3-
D,4A,5B,6D,7B),(1C,2C,3D,4A,5B,6D,7C),(1C,2C,3D,4B,5A,6A,7A),(1C,2C,3D,4B,-
5A,6A,7B),(1C,2C,3D,4B,5A,6A,7C),(1C,2C,3D,4B,5A,6B,7A),
(1C,2C,3D,4B,5A,6B,7B),(1C,2C,3D,4B,5A,6B,7C),(1C,2C,3D,4B,5A,6C,7A),(1C,-
2C,3D,4B,5A,6C,7B),(1C,2C,3D,4B,5A,6C,7C),(1C,2C,3D,4B,5A,6D,7A),(1C,2C,3D-
,4B,5A,6D,7B),
(1C,2C,3D,4B,5A,6D,7C),(1C,2C,3D,4B,5B,6A,7A),(1C,2C,3D,4B,-
5B,6A,7B),(1C,2C,3D,4B,5B,6A,7C),(1C,2C,3D,4B,5B,6B,7A),(1C,2C,3D,4B,5B,6B-
,7B),(1C,2C,3D,4B,5B,6B,7C),
(1C,2C,3D,4B,5B,6C,7A),(1C,2C,3D,4B,5B,6C,7B)-
,(1C,2C,3D,4B,5B,6C,7C),(1C,2C,3D,4B,5B,6D,7A),(1C,2C,3D,4B,5B,6D,7B),(1C,-
2C,3D,4B,5B,6D,7C),(1C,2C,3D,4C,5A,6A,7A),
(1C,2C,3D,4C,5A,6A,7B),(1C,2C,3-
D,4C,5A,6A,7C),(1C,2C,3D,4C,5A,6B,7A),(1C,2C,3D,4C,5A,6B,7B),(1C,2C,3D,4C,-
5A,6B,7C),(1C,2C,3D,4C,5A,6C,7A),(1C,2C,3D,4C,5A,6C,7B),
(1C,2C,3D,4C,5A,6C,7C),(1C,2C,3D,4C,5A,6D,7A),(1C,2C,3D,4C,5A,6D,7B),(1C,-
2C,3D,4C,5A,6D,7C),(1C,2C,3D,4C,5B,6A,7A),(1C,2C,3D,4C,5B,6A,7B),(1C,2C,3D-
,4C,5B,6A,7C),
(1C,2C,3D,4C,5B,6B,7A),(1C,2C,3D,4C,5B,6B,7B),(1C,2C,3D,4C,-
5B,6B,7C),(1C,2C,3D,4C,5B,6C,7A), (1C,2C,3D,4C,5B,6C,7B),
(1C,2C,3D,4C,5B,6C,7C),(1C,2C,3D,4C,5B,6D,7A),
(1C,2C,3D,4C,5B,6D,7B), (1C,2C,3D,4C,5B,6D,7C),
(1C,2C,3D,4D,5A,6A,7A), (1C,2C,3D,4D,5A,6A,7B),
(1C,2C,3D,4D,5A,6A,7C), (1C,2C,3D,4D,5A,6B,7A),
(1C,2C,3D,4D,5A,6B,7B), (1C,2C,3D,4D,5A,6B,7C),
(1C,2C,3D,4D,5A,6C,7A), (1C,2C,3D,4D,5A,6C,7B),
(1C,2C,3D,4D,5A,6C,7C),(1C,2C,3D,4D,5A,6D,7A),(1C,2C,3D,4D,5A,6D,7B),(1C,-
2C,3D,4D,5A,6D,7C),
(1C,2C,3D,4D,5B,6A,7A),(1C,2C,3D,4D,5B,6A,7B),(1C,2C,3-
D,4D,5B,6A,7C),(1C,2C,3D,4D,5B,6B,7A),(1C,2C,3D,4D,5B,6B,7B),(1C,2C,3D,4D,-
5B,6B,7C),(1C,2C,3D,4D,5B,6C,7A),
(1C,2C,3D,4D,5B,6C,7B),(1C,2C,3D,4D,5B,6-
C,7C),(1C,2C,3D,4D,5B,6D,7A),(1C,2C,3D,4D,5B,6D,7B),(1C,2C,3D,4D,5B,6D,7C)-
,(1C,2C,3D,4E,5A,6A,7A),(1C,2C,3D,4E,5A,6A,7B),
(1C,2C,3D,4E,5A,6A,7C),(1C-
,2C,3D,4E,5A,6B,7A),(1C,2C,3D,4E,5A,6B,7B),(1C,2C,3D,4E,5A,6B,7C),(1C,2C,3-
D,4E,5A,6C,7A),(1C,2C,3D,4E,5A,6C,7B),(1C,2C,3D,4E,5A,6C,7C),
(1C,2C,3D,4E,5A,6D,7A),(1C,2C,3D,4E,5A,6D,7B),(1C,2C,3D,4E,5A,6D,7C),(1C,-
2C,3D,4E,5B,6A,7A),(1C,2C,3D,4E,5B,6A,7B),(1C,2C,3D,4E,5B,6A,7C),(1C,2C,3D-
,4E,5B,6B,7A),
(1C,2C,3D,4E,5B,6B,7B),(1C,2C,3D,4E,5B,6B,7C),(1C,2C,3D,4E,-
5B,6C,7A),(1C,2C,3D,4E,5B,6C,7B),(1C,2C,3D,4E,5B,6C,7C),(1C,2C,3D,4E,5B,6D-
,7A),(1C,2C,3D,4E,5B,6D,7B),
(1C,2C,3D,4E,5B,6D,7C),(1C,2C,3E,4A,5A,6A,7A)-
,(1C,2C,3E,4A,5A,6A,7B),(1C,2C,3E,4A,5A,6A,7C),(1C,2C,3E,4A,5A,6B,7A),(1C,-
2C,3E,4A,5A,6B,7B),(1C,2C,3E,4A,5A,6B,7C),
(1C,2C,3E,4A,5A,6C,7A),(1C,2C,3-
E,4A,5A,6C,7B),(1C,2C,3E,4A,5A,6C,7C),(1C,2C,3E,4A,5A,6D,7A),(1C,2C,3E,4A,-
5A,6D,7B),(1C,2C,3E,4A,5A,6D,7C),(1C,2C,3E,4A,5B,6A,7A),
(1C,2C,3E,4A,5B,6A,7B),(1C,2C,3E,4A,5B,6A,7C),(1C,2C,3E,4A,5B,6B,7A),(1C,-
2C,3E,4A,5B,6B,7B),(1C,2C,3E,4A,5B,6B,7C),(1C,2C,3E,4A,5B,6C,7A),(1C,2C,3E-
,4A,5B,6C,7B),
(1C,2C,3E,4A,5B,6C,7C),(1C,2C,3E,4A,5B,6D,7A),(1C,2C,3E,4A,-
5B,6D,7B),(1C,2C,3E,4A,5B,6D,7C),(1C,2C,3E,4B,5A,6A,7A),(1C,2C,3E,4B,5A,6A-
,7B),(1C,2C,3E,4B,5A,6A,7C),
(1C,2C,3E,4B,5A,6B,7A),(1C,2C,3E,4B,5A,6B,7B)-
,(1C,2C,3E,4B,5A,6B,7C),(1C,2C,3E,4B,5A,6C,7A),(1C,2C,3E,4B,5A,6C,7B),(1C,-
2C,3E,4B,5A,6C,7C),(1C,2C,3E,4B,5A,6D,7A),
(1C,2C,3E,4B,5A,6D,7B),(1C,2C,3-
E,4B,5A,6D,7C),(1C,2C,3E,4B,5B,6A,7A),(1C,2C,3E,4B,5B,6A,7B),(1C,2C,3E,4B,-
5B,6A,7C),(1C,2C,3E,4B,5B,6B,7A),(1C,2C,3E,4B,5B,6B,7B),
(1C,2C,3E,4B,5B,6B,7C),(1C,2C,3E,4B,5B,6C,7A),(1C,2C,3E,4B,5B,6C,7B),(1C,-
2C,3E,4B,5B,6C,7C),(1C,2C,3E,4B,5B,6D,7A),(1C,2C,3E,4B,5B,6D,7B),(1C,2C,3E-
,4B,5B,6D,7C),
(1C,2C,3E,4C,5A,6A,7A),(1C,2C,3E,4C,5A,6A,7B),(1C,2C,3E,4C,-
5A,6A,7C),(1C,2C,3E,4C,5A,6B,7A), (1C,2C,3E,4C,5A,6B,
7B),(1C,2C,3E,4C,5A,6B,7C),(1C,2C,3E,4C,5A,6C,7A),
(1C,2C,3E,4C,5A,6C,7B),(1C,2C,3E,4C,5A,6C,7C),(1C,2C,3E,4C,5A,6D,7A),(1C,-
2C,3E,4C,5A,6D,7B),(1C,2C,3E,4C,5A,6D,7C),(1C,2C,3E,4C,5B,6A,7A),(1C,2C,3E-
,4C,5B,6A,7B),
(1C,2C,3E,4C,5B,6A,7C),(1C,2C,3E,4C,5B,6B,7A),(1C,2C,3E,4C,-
5B,6B,7B),(1C,2C,3E,4C,5B,6B,7C),(1C,2C,3E,4C,5B,6C,7A),(1C,2C,3E,4C,5B,6C-
,7B),(1C,2C,3E,4C,5B,6C,7C),
(1C,2C,3E,4C,5B,6D,7A),(1C,2C,3E,4C,5B,6D,7B)-
,(1C,2C,3E,4C,5B,6D,7C),(1C,2C,3E,4D,5A,6A,7A),(1C,2C,3E,4D,5A,6A,7B),(1C,-
2C,3E,4D,5A,6A,7C),(1C,2C,3E,4D,5A,6B,7A),
(1C,2C,3E,4D,5A,6B,7B),(1C,2C,3-
E,4D,5A,6B,7C),(1C,2C,3E,4D,5A,6C,7A),(1C,2C,3E,4D,5A,6C,7B),(1C,2C,3E,4D,-
5A,6C,7C),(1C,2C,3E,4D,5A,6D,7A),(1C,2C,3E,4D,5A,6D,7B),
(1C,2C,3E,4D,5A,6D,7C),(1C,2C,3E,4D,5B,6A,7A),(1C,2C,3E,4D,5B,6A,7B),(1C,-
2C,3E,4D,5B,6A,7C),(1C,2C,3E,4D,5B,6B,7A),(1C,2C,3E,4D,5B,6B,7B),(1C,2C,3E-
,4D,5B,6B,7C),
(1C,2C,3E,4D,5B,6C,7A),(1C,2C,3E,4D,5B,6C,7B),(1C,2C,3E,4D,-
5B,6C,7C),(1C,2C,3E,4D,5B,6D,7A),(1C,2C,3E,4D,5B,6D,7B),(1C,2C,3E,4D,5B,6D-
,7C),(1C,2C,3E,4E,5A,6A,7A),
(1C,2C,3E,4E,5A,6A,7B),(1C,2C,3E,4E,5A,6A,7C)-
,(1C,2C,3E,4E,5A,6B,7A),(1C,2C,3E,4E,5A,6B,7B),(1C,2C,3E,4E,5A,6B,7C),(1C,-
2C,3E,4E,5A,6C,7A),(1C,2C,3E,4E,5A,6C,7B),
(1C,2C,3E,4E,5A,6C,7C),(1C,2C,3-
E,4E,5A,6D,7A),(1C,2C,3E,4E,5A,6D,7B),(1C,2C,3E,4E,5A,6D,7C),(1C,2C,3E,4E,-
5B,6A,7A),(1C,2C,3E,4E,5B,6A,7B),(1C,2C,3E,4E,5B,6A,7C),
(1C,2C,3E,4E,5B,6B,7A),(1C,2C,3E,4E,5B,6B,7B),(1C,2C,3E,4E,5B,6B,7C),(1C,-
2C,3E,4E,5B,6C,7A),(1C,2C,3E,4E,5B,6C,7B),(1C,2C,3E,4E,5B,6C,7C),(1C,2C,3E-
,4E,5B,6D,7A),
(1C,2C,3E,4E,5B,6D,7B),(1C,2C,3E,4E,5B,6D,7C),(1C,2D,3A,4A,-
5A,6A,7A),(1C,2D,3A,4A,5A,6A,7B),(1C,2D,3A,4A,5A,6A,7C),(1C,2D,3A,4A,5A,6B-
,7A),(1C,2D,3A,4A,5A,6B,7B),
(1C,2D,3A,4A,5A,6B,7C),(1C,2D,3A,4A,5A,6C,7A)-
,(1C,2D,3A,4A,5A,6C,7B),(1C,2D,3A,4A,5A,6C,7C),(1C,2D,3A,4A,5A,6D,7A),(1C,-
2D,3A,4A,5A,6D,7B),(1C,2D,3A,4A,5A,6D,7C),
(1C,2D,3A,4A,5B,6A,7A),(1C,2D,3-
A,4A,5B,6A,7B),(1C,2D,3A,4A,5B,6A,7C),(1C,2D,3A,4A,5B,6B,7A),
(C,2D,3A,4A,5B,6B,7B),(1C,2D,3A,4A,5B,6B,7C),(1C,2D,3A,4A,5B,6C,7A),
(1C,2D,3A,4A,5B,6C,7B),(1C,2D,3A,4A,5B,6C,7C),(1C,2D,3A,4A,5B,6D,7A),(1C,-
2D,3A,4A,5B,6D,7B),(1C,2D,3A,4A,5B,6D,7C.),(1C,2D,3A,4B,5A,6A,7A),(1C,2D,3-
A,4B,5A,6A,7B),
(1C,2D,3A,4B,5A,6A,7C),(1C,2D,3A,4B,5A,6B,7A),(1C,2D,3A,4B-
,5A,6B,7B),(1C,2D,3A,4B,5A,6B,7C),(1C,2D,3A,4B,5A,6C,7A),(1C,2D,3A,4B,5A,6-
C,7B),(1C,2D,3A,4B,5A,6C,7C),
(1C,2D,3A,4B,5A,6D,7A),(1C,2D,3A,4B,5A,6D,7B-
),(1C,2D,3A,4B,5A,6D,7C),(1C,2D,3A,4B,5B,6A,7A),
(1C,2D,3A,4B,5B,6A,7B), (1C,2D,3A,4B,5B,6A,7C),
(1C,2D,3A,4B,5B,6B,7A), (1C,2D,3A,4B,5B,6B,7B),(1-
C,2D,3A,4B,5B,6B,7C),(1C,2D,3A,4B,5B,6C,7A),(1C,2D,3A,4B,5B,6C,7B),(1C,2D,-
3A,4B,5B,6C,7C),(1C,2D,3A,4B,5B,6D,7A),(1C,2D,3A,4B,5B,6D,7B),
(1C,2D,3A,4B,5B,6D,7C),(1C,2D,3A,4C,5A,6A,7A),(1C,2D,3A,4C,5A,6A,7B),(1C,-
2D,3A,4C,5A,6A,7C),(1C,2D,3A,4C,5A,6B,7A),(1C,2D,3A,4C,5A,6B,7B),(1C,2D,3A-
,4C,5A,6B,7C),
(1C,2D,3A,4C,5A,6C,7A),(1C,2D,3A,4C,5A,6C,7B),(1C,2D,3A,4C,-
5A,6C,7C),(1C,2D,3A,4C,5A,6D,7A),(1C,2D,3A,4C,5A,6D,7B),(1C,2D,3A,4C,5A,6D-
,7C),(1C,2D,3A,4C,5B,6A,7A),
(1C,2D,3A,4C,5B,6A,7B),(1C,2D,3A,4C,5B,6A,7C)-
,(1C,2D,3A,4C,5B,6B,7A),(1C,2D,3A,4C,5B,6B,7B),(1C,2D,3A,4C,5B,6B,7C),(1C,-
2D,3A,4C,5B,6C,7A),(1C,2D,3A,4C,5B,6C,7B),
(1C,2D,3A,4C,5B,6C,7C),(1C,2D,3-
A,4C,5B,6D,7A),(1C,2D,3A,4C,5B,6D,7B),(1C,2D,3A,4C,5B,6D,7C),(1C,2D,3A,4D,-
5A,6A,7A),(1C,2D,3A,4D,5A,6A,7B),(1C,2D,3A,4D,5A,6A,7C),
(1C,2D,3A,4D,5A,6B,7A),(1C,2D,3A,4D,5A,6B,7B),(1C,2D,3A,4D,5A,6B,7C),(1C,-
2D,3A,4D,5A,6C,7A),(1C,2D,3A,4D,5A,6C,7B),(1C,2D,3A,4D,5A,6C,7C),(1C,2D,3A-
,4D,5A,6D,7A),
(1C,2D,3A,4D,5A,6D,7B),(1C,2D,3A,4D,5A,6D,7C),(1C,2D,3A,4D,-
5B,6A,7A),(1C,2D,3A,4D,5B,6A,7B),(1C,2D,3A,4D,5B,6A,7C),(1C,2D,3A,4D,5B,6B-
,7A),(1C,2D,3A,4D,5B,6B,7B),
(1C,2D,3A,4D,5B,6B,7C),(1C,2D,3A,4D,5B,6C,7A)-
,(1C,2D,3A,4D,5B,6C,7B),(1C,2D,3A,4D,5B,6C,7C),(1C,2D,3A,4D,5B,6D,7A),(1C,-
2D,3A,4D,5B,6D,7B),(1C,2D,3A,4D,5B,6D,7C),
(1C,2D,3A,4E,5A,6A,7A),(1C,2D,3-
A,4E,5A,6A,7B),(1C,2D,3A,4E,5A,6A,7C),(1C,2D,3A,4E,5A,6B,7A),(1C,2D,3A,4E,-
5A,6B,7B),(1C,2D,3A,4E,5A,6B,7C),(1C,2D,3A,4E,5A,6C,7A),
(1C,2D,3A,4E,5A,6C,7B),(1C,2D,3A,4E,5A,6C,7C),(1C,2D,3A,4E,5A,6D,7A),(1C,-
2D,3A,4E,5A,6D,7B),(1C,2D,3A,4E,5A,6D,7C),(1C,2D,3A,4E,5B,6A,7A),(1C,2D,3A-
,4E,5B,6A,7B),
(1C,2D,3A,4E,5B,6A,7C),(1C,2D,3A,4E,5B,6B,7A),(1C,2D,3A,4E,-
5B,6B,7B),(1C,2D,3A,4E,5B,6B,7C),(1C,2D,3A,4E,5B,6C,7A),(1C,2D,3A,4E,5B,6C-
,7B),(1C,2D,3A,4E,5B,6C,7C),
(1C,2D,3A,4E,5B,6D,7A),(1C,2D,3A,4E,5B,6D,7B)-
,(1C,2D,3A,4E,5B,6D,7C),(1C,2D,3B,4A,5A,6A,7A),(1C,2D,3B,4A,5A,6A,7B),(1C,-
2D,3B,4A,5A,6A,7C),(1C,2D,3B,4A,5A,6B,7A),
(1C,2D,3B,4A,5A,6B,7B),(1C,2D,3-
B,4A,5A,6B,7C),(1C,2D,3B,4A,5A,6C,7A),(1C,2D,3B,4A,5A,6C,7B),(1C,2D,3B,4A,-
5A,6C,7C),(1C,2D,3B,4A,5A,6D,7A),(1C,2D,3B,4A,5A,6D,7B),
(1C,2D,3B,4A,5A,6D,7C),(1C,2D,3B,4A,5B,6A,7A),(1C,2D,3B,4A,5B,6A,7B),(1C,-
2D,3B,4A,5B,6A,7C),(1C,2D,3B,4A,5B,6B,7A),(1C,2D,3B,4A,5B,6B,7B),(1C,2D,3B-
,4A,5B,6B,7C),
(1C,2D,3B,4A,5B,6C,7A),(1C,2D,3B,4A,5B,6C,7B),(1C,2D,3B,4A,-
5B,6C,7C),(1C,2D,3B,4A,5B,6D,7A),(1C,2D,3B,4A,5B,6D,7B),(1C,2D,3B,4A,5B,6D-
,7C),(1C,2D,3B,4B,5A,6A,7A),
(1C,2D,3B,4B,5A,6A,7B),(1C,2D,3B,4B,5A,6A,7C)-
,(1C,2D,3B,4B,5A,6B,7A),(1C,2D,3B,4B,5A,6B,7B),(1C,2D,3B,4B,5A,6B,7C),(1C,-
2D,3B,4B,5A,6C,7A),(1C,2D,3B,4B,5A,6C,7B),
(1C,2D,3B,4B,5A,6C,7C),(1C,2D,3-
B,4B,5A,6D,7A),(1C,2D,3B,4B,5A,6D,7B),(1C,2D,3B,4B,5A,6D,7C),(1C,2D,3B,4B,-
5B,6A,7A),(1C,2D,3B,4B,5B,6A,7B),(1C,2D,3B,4B,5B,6A,7C),
(1C,2D,3B,4B,5B,6B,7A),(1C,2D,3B,4B,5B,6B,7B),(1C,2D,3B,4B,5B,6B,7C),(1C,-
2D,3B,4B,5B,6C,7A),(1C,2D,3B,4B,5B,6C,7B),(1C,2D,3B,4B,5B,6C,7C),(1C,2D,3B-
,4B,5B,6D,7A),
(1C,2D,3B,4B,5B,6D,7B),(1C,2D,3B,4B,5B,6D,7C),(1C,2D,3B,4C,-
5A,6A,7A),(1C,2D,3B,4C,5A,6A,7B),(1C,2D,3B,4C,5A,6A,7C),(1C,2D,3B,4C,5A,6B-
,7A),(1C,2D,3B,4C,5A,6B,7B),
(1C,2D,3B,4C,5A,6B,7C),(1C,2D,3B,4C,5A,6C,7A)-
,(1C,2D,3B,4C,5A,6C,7B),(1C,2D,3B,4C,5A,6C,7C),(1C,2D,3B,4C,5A,6D,7A),(1C,-
2D,3B,4C,5A,6D,7B),(1C,2D,3B,4C,5A,6D,7C),
(1C,2D,3B,4C,5B,6A,7A),(1C,2D,3-
B,4C,5B,6A,7B),(1C,2D,3B,4C,5B,6A,7C),(1C,2D,3B,4C,5B,6B,7A),(1C,2D,3B,4C,-
5B,6B,7B),(1C,2D,3B,4C,5B,6B,7C),(1C,2D,3B,4C,5B,6C,7A),
(1C,2D,3B,4C,5B,6C,7B),(1C,2D,3B,4C,5B,6C,7C),(1C,2D,3B,4C,5B,6D,7A),(1C,-
2D,3B,4C,5B,6D,7B),(1C,2D,3B,4C,5B,6D,7C),(1C,2D,3B,4D,5A,6A,7A),(1C,2D,3B-
,4D,5A,6A,7B),
(1C,2D,3B,4D,5A,6A,7C),(1C,2D,3B,4D,5A,6B,7A),(1C,2D,3B,4D,-
5A,6B,7B),(1C,2D,3B,4D,5A,6B,7C),(1C,2D,3B,4D,5A,6C,7A),(1C,2D,3B,4D,5A,6C-
,7B),(1C,2D,3B,4D,5A,6C,7C),
(1C,2D,3B,4D,5A,6D,7A),(1C,2D,3B,4D,5A,6D,7B)-
,(1C,2D,3B,4D,5A,6D,7C),(1C,2D,3B,4D,5B,6A,7A),(1C,2D,3B,4D,5B,6A,7B),(1C,-
2D,3B,4D,5B,6A,7C),(1C,2D,3B,4D,5B,6B,7A),
(1C,2D,3B,4D,5B,6B,7B),(1C,2D,3-
B,4D,5B,6B,7C),(1C,2D,3B,4D,5B,6C,7A),(1C,2D,3B,4D,5B,6C,7B),(1C,2D,3B,4D,-
5B,6C,7C),(1C,2D,3B,4D,5B,6D,7A),(1C,2D,3B,4D,5B,6D,7B)3
(1C,2D,3B,4D,5B,6D,7C),(1C,2D,3B,4E,5A,6A,7A),(1C,2D,3B,4E,5A,6A,7B),(1C,-
2D,3B,4E,5A,6A,7C),(1C,2D,3B,4E,5A,6B,7A),(1C,2D,3B,4E,5A,6B,7B),(1C,2D,3B-
,4E,5A,6B,7C),
(1C,2D,3B,4E,5A,6C,7A),(1C,2D,3B,4E,5A,6C,7B),(1C,2D,3B,4E,-
5A,6C,7C),(1C,2D,3B,4E,5A,6D,7A),(1C,2D,3B,4E,5A,6D,7B),(1C,2D,3B,4E,5A,6D-
,7C),(1C,2D,3B,4E,5B,6A,7A),
(1C,2D,3B,4E,5B,6A,7B),(1C,2D,3B,4E,5B,6A,7C)-
,(1C,2D,3B,4E,5B,6B,7A),(1C,2D,3B,4E,5B,6B,7B),(1C,2D,3B,4E,5B,6B,7C),(1C,-
2D,3B,4E,5B,6C,7A),(1C,2D,3B,4E,5B,6C,7B),
(1C,2D,3B,4E,5B,6C,7C),(1C,2D,3-
B,4E,5B,6D,7A),(1C,2D,3B,4E,5B,6D,7B),(1C,2D,3B,4E,5B,6D,7C),(1C,2D,3C,4A,-
5A,6A,7A),(1C,2D,3C,4A,5A,6A,7B),(1C,2D,3C,4A,5A,6A,7C),
(1C,2D,3C,4A,5A,6B,7A),(1C,2D,3C,4A,5A,6B,7B),(1C,2D,3C,4A,5A,6B,7C),(1C,-
2D,3C,4A,5A,6C,7A),(1C,2D,3C,4A,5A,6C,7B),(1C,2D,3C,4A,5A,6C,7C),(1C,2D,3C-
,4A,5A,6D,7A),
(1C,2D,3C,4A,5A,6D,7B),(1C,2D,3C,4A,5A,6D,7C),(1C,2D,3C,4A,-
5B,6A,7A),(1C,2D,3C,4A,5B,6A,7B),(1C,2D,3C,4A,5B,6A,7C),(1C,2D,3C,4A,5B,6B-
,7A),(1C,2D,3C,4A,5B,6B,7B),
(1C,2D,3C,4A,5B,6B,7C),(1C,2D,3C,4A,5B,6C,7A)-
,(1C,2D,3C,4A,5B,6C,7B),(1C,2D,3C,4A,5B,6C,7C),(1C,2D,3C,4A,5B,6D,7A),(1C,-
2D,3C,4A,5B,6D,7B),(1C,2D,3C,4A,5B,6D,7C),
(1C,2D,3C,4B,5A,6A,7A),(1C,2D,3-
C,4B,5A,6A,7B),(1C,2D,3C,4B,5A,6A,7C),(1C,2D,3C,4B,5A,6B,7A),(1C,2D,3C,4B,-
5A,6B,7B),(1C,2D,3C,4B,5A,6B,7C),(1C,2D,3C,4B,5A,6C,7A),
(1C,2D,3C,4B,5A,6C,7B),(1C,2D,3C,4B,5A,6C,7C),(1C,2D,3C,4B,5A,6D,7A),(1C,-
2D,3C,4B,5A,6D,7B),(1C,2D,3C,4B,5A,6D,7C),(1C,2D,3C,4B,5B,6A,7A),(1C,2D,3C-
,4B,5B,6A,7B),
(1C,2D,3C,4B,5B,6A,7C),(1C,2D,3C,4B,5B,6B,7A),(1C,2D,3C,4B,-
5B,6B,7B),(1C,2D,3C,4B,5B,6B,7C),(1C,2D,3C,4B,5B,6C,7A),(1C,2D,3C,4B,5B,6C-
,7B),(1C,2D,3C,4B,5B,6C,7C),
(1C,2D,3C,4B,5B,6D,7A),(1C,2D,3C,4B,5B,6D,7B)-
,(1C,2D,3C,4B,5B,6D,7C),(1C,2D,3C,4C,5A,6A,7A),(1C,2D,3C,4C,5A,6A,7B),(1C,-
2D,3C,4C,5A,6A,7C),(1C,2D,3C,4C,5A,6B,7A),
(1C,2D,3C,4C,5A,6B,7B),(1C,2D,3-
C,4C,5A,6B,7C),(1C,2D,3C,4C,5A,6C,7A),(1C,2D,3C,4C,5A,6C,7B),(1C,2D,3C,4C,-
5A,6C,7C),(1C,2D,3C,4C,5A,6D,7A),(1C,2D,3C,4C,5A,6D,7B),
(1C,2D,3C,4C,5A,6D,7C),(1C,2D,3C,4C,5B,6A,7A),(1C,2D,3C,4C,5B,6A,7B),(1C,-
2D,3C,4C,5B,6A,7C),(1C,2D,3C,4C,5B,6B,7A),(1C,2D,3C,4C,5B,6B,7B),(1C,2D,3C-
,4C,5B,6B,7C),
(1C,2D,3C,4C,5B,6C,7A),(1C,2D,3C,4C,5B,6C,7B),(1C,2D,3C,4C,-
5B,6C,7C),(1C,2D,3C,4C,5B,6D,7A),(1C,2D,3C,4C,5B,6D,7B),(1C,2D,3C,4C,5B,6D-
,7C),(1C,2D,3C,4D,5A,6A,7A),
(1C,2D,3C,4D,5A,6A,7B),(1C,2D,3C,4D,5A,6A,7C)-
,(1C,2D,3C,4D,5A,6B,7A),(1C,2D,3C,4D,5A,6B,7B),(1C,2D,3C,4D,5A,6B,7C),(1C,-
2D,3C,4D,5A,6C,7A),(1C,2D,3C,4D,5A,6C,7B),
(1C,2D,3C,4D,5A,6C,7C),(1C,2D,3-
C,4D,5A,6D,7A),(1C,2D,3C,4D,5A,6D,7B),(1C,2D,3C,4D,5A,6D,7C),(1C,2D,3C,4D,-
5B,6A,7A),(1C,2D,3C,4D,5B,6A,7B),(1C,2D,3C,4D,5B,6A,7C),
(1C,2D,3C,4D,5B,6B,7A),(1C,2D,3C,4D,5B,6B,7B),(1C,2D,3C,4D,5B,6B,7C),(1C,-
2D,3C,4D,5B,6C,7A),(1C,2D,3C,4D,5B,6C,7B),(1C,2D,3C,4D,5B,6C,7C),(1C,2D,3C-
,4D,5B,6D,7A),
(1C,2D,3C,4D,5B,6D,7B),(1C,2D,3C,4D,5B,6D,7C),(1C,2D,3C,4E,-
5A,6A,7A),(1C,2D,3C,4E,5A,6A,7B),(1C,2D,3C,4E,5A,6A,7C),(1C,2D,3C,4E,5A,6B-
,7A),(1C,2D,3C,4E,5A,6B,7B),
(1C,2D,3C,4E,5A,6B,7C),(1C,2D,3C,4E,5A,6C,7A)-
,(1C,2D,3C,4E,5A,6C,7B),(1C,2D,3C,4E,5A,6C,7C),(1C,2D,3C,4E,5A,6D,7A),(1C,-
2D,3C,4E,5A,6D,7B),(1C,2D,3C,4E,5A,6D,7C),
(1C,2D,3C,4E,5B,6A,7A),(1C,2D,3-
C,4E,5B,6A,7B),(1C,2D,3C,4E,5B,6A,7C),(1C,2D,3C,4E,5B,6B,7A),
(1C,2D,3C,4E,5B,6B,7B),(1C,2D,3C,4E,5B,6B,7C),(1C,2D,3C,4E,5B,6C,7A),
(1C,2D,3C,4E,5B,6C,7B), (1C,2D,3C,4E,5B,6C,7C),
(1C,2D,3C,4E,5B,6D,7A), (1C,2D,3C,4E,5B,6D,7B),
(1C,2D,3C,4E,5B,6D,7C),(1C,2D,3D,4A,5A,6A,7A),(1C-
,2D,3D,4A,5A,6A,7B), (1C,2D,3D,4A,5A,6A,7C),
(1C,2D,3D,4A,5A,6B,7A), (1C,2D,3D,4A,5A,6B, 7B),
(C,2D,3D,4A,5A,6B,7C),(1C,2D,3D,4A,5A,6C,7A),(1C-
,2D,3D,4A,5A,6C,7B),(1C,2D,3D,4A,5A,6C,7C),
(1C,2D,3D,4A,5A,6D,7A),(1C,2D,-
3D,4A,5A,6D,7B),(1C,2D,3D,4A,5A,6D,7C),(1C,2D,3D,4A,5B,6A,7A),(1C,2D,3D,4A-
,5B,6A,7B),(1C,2D,3D,4A,5B,6A,7C),(1C,2D,3D,4A,5B,6B,7A),
(1C,2D,3D,4A,5B,6B,7B),(1C,2D,3D,4A,5B,6B,7C),(1C,2D,3D,4A,5B,6C,7A),(1C,-
2D,3D,4A,5B,6C,7B),(1C,2D,3D,4A,5B,6C,7C),(1C,2D,3D,4A,5B,6D,7A),(1C,2D,3D-
,4A,5B,6D,7B),
(1C,2D,3D,4A,5B,6D,7C),(1C,2D,3D,4B,5A,6A,7A),(1C,2D,3D,4B,-
5A,6A,7B),(1C,2D,3D,4B,5A,6A,7C),(1C,2D,3D,4B,5A,6B,7A),(1C,2D,3D,4B,5A,6B-
,7B),(1C,2D,3D,4B,5A,6B,7C),
(1C,2D,3D,4B,5A,6C,7A),(1C,2D,3D,4B,5A,6C,7B)-
,(1C,2D,3D,4B,5A,6C,7C),(1C,2D,3D,4B,5A,6D,7A),(1C,2D,3D,4B,5A,6D,7B),(1C,-
2D,3D,4B,5A,6D,7C),(1C,2D,3D,4B,5B,6A,7A),
(1C,2D,3D,4B,5B,6A,7B),(1C,2D,3-
D,4B,5B,6A,7C),(1C,2D,3D,4B,5B,6B,7A),(1C,2D,3D,4B,5B,6B,7B),(1C,2D,3D,4B,-
5B,6B,7C),(1C,2D,3D,4B,5B,6C,7A),(1C,2D,3D,4B,5B,6C,7B),
(1C,2D,3D,4B,5B,6C,7C),(1C,2D,3D,4B,5B,6D,7A),(1C,2D,3D,4B,5B,6D,7B),(1C,-
2D,3D,4B,5B,6D,7C),(1C,2D,3D,4C,5A,6A,7A),(1C,2D,3D,4C,5A,6A,7B),(1C,2D,3D-
,4C,5A,6A,7C),
(1C,2D,3D,4C,5A,6B,7A),(1C,2D,3D,4C,5A,6B,7B),(1C,2D,3D,4C,-
5A,6B,7C),(1C,2D,3D,4C,5A,6C,7A),(1C,2D,3D,4C,5A,6C,7B),(1C,2D,3D,4C,5A,6C-
,7C),(1C,2D,3D,4C,5A,6D,7A),
(1C,2D,3D,4C,5A,6D,7B),(1C,2D,3D,4C,5A,6D,7C)-
,(1C,2D,3D,4C,5B,6A,7A),(1C,2D,3D,4C,5B,6A,7B),(1C,2D,3D,4C,5B,6A,7C),(1C,-
2D,3D,4C,5B,6B,7A),(1C,2D,3D,4C,5B,6B,7B),
(1C,2D,3D,4C,5B,6B,7C),(1C,2D,3-
D,4C,5B,6C,7A),(1C,2D,3D,4C,5B,6C,7B),(1C,2D,3D,4C,5B,6C,7C),(1C,2D,3D,4C,-
5B,6D,7A),(1C,2D,3D,4C,5B,6D,7B),(1C,2D,3D,4C,5B,6D,7C),
(1C,2D,3D,4D,5A,6A,7A),(1C,2D,3D,4D,5A,6A,7B),(1C,2D,3D,4D,5A,6A,7C),(1C,-
2D,3D,4D,5A,6B,7A),(1C,2D,3D,4D,5A,6B,7B),(1C,2D,3D,4D,5A,6B,7C),(1C,2D,3D-
,4D,5A,6C,7A), (1C,2D,3D,4D,5A,6C,7B),
(1C,2D,3D,4D,5A,6C,7C),(1C,2D,3D,4D-
,5A,6D,7A),(1C,2D,3D,4D,5A,6D,7B),(1C,2D,3D,4D,5A,6D,7C),(1C,2D,3D,4D,5B,6-
A,7A),(1C,2D,3D,4D,5B,6A,7B),
(1C,2D,3D,4D,5B,6A,7C),(1C,2D,3D,4D,5B,6B,7A-
),(1C,2D,3D,4D,5B,6B,7B),(1C,2D,3D,4D,5B,6B,7C),(1C,2D,3D,4D,5B,6C,7A),(1C-
,2D,3D,4D,5B,6C,7B),(1C,2D,3D,4D,5B,6C,7C),
(1C,2D,3D,4D,5B,6D,7A),(1C,2D,-
3D,4D,5B,6D,7B),(1C,2D,3D,4D,5B,6D,7C),(1C,2D,3D,4E,5A,6A,7A),
(1C,2D,3D,4E,5A,6A,7B),
(1C,2D,3D,4E,5A,6A,7C),(1C,2D,3D,4E,5A,6B,7A),
(1C,2D,3D,4E,5A,6B,7B), (1C,2D,3D,4E,5A,6B,7C),
(1C,2D,3D,4E,5A,6C,7A), (1C,2D,3D,4E,5A,6C,7B),
(1C,2D,3D,4E,5A,6C,7C), (1C,2D,3D,4E,5A,6D,7A),(1-
C,2D,3D,4E,5A,6D,7B), (1C,2D,3D,4E,5A,6D,7C),
(1C,2D,3D,4E,5B,6A,7A), (1C,2D,3D,4E,5B,6A,7B),
(1C,2D,3D,4E,5B,6A,7C), (1C,2D,3D,4E,5B,6B,7A),(1-
C,2D,3D,4E,5B,6B,7B), (1C,2D,3D,4E,5B,6B,7C),
(1C,2D,3D,4E,5B,6C,7A), (1C,2D,3D,4E,5B,6C,7B),
(1C,2D,3D,4E,5B,6C,7C), (C,2D,3D,4E,5B,6D,7A),
(1C,2D,3D,4E,5B,6D,7B),(1C,2D,3D,4E,5B,6D,7C),(1C,2D,3E,4A,5A,6A,7A),
(1C,2D,3E,4A,5A,6A,7B), (1C,2D,3E,4A,5A,6A,7C),
(1C,2D,3E,4A,5A,6B,7A), (1C,2D,3E,4A,5A,6B,7B),
(1C,2D,3E,4A,5A,6B,7C), (1C,2D,3E,4A,5A,6C,7A),(1-
C,2D,3E,4A,5A,6C,7B), (1C,2D,3E,4A,5A,6C,7C),
(1C,2D,3E,4A,5A,6D,7A), (1C,2D,3E,4A,5A,6D,7B),
(1C,2D,3E,4A,5A,6D,7C), (1C,2D,3E,4A,5B,6A,7A),(1-
C,2D,3E,4A,5B,6A, 7B), (1C,2D,3E,4A,5B,6A,7C),
(1C,2D,3E,4A,5B,6B,7A), (1C,2D,3E,4A,5B,6B,7B),
(1C,2D,3E,4A,5B,6B,7C), (1C,2D,3E,4A,5B,6C,7A),
(1C,2D,3E,4A,5B,6C,7B), (1C,2D,3E,4A,5B,6C,7C),
(1C,2D,3E,4A,5B,6D,7A),
(1C,2D,3E,4A,5B,6D,7B),(1C,2D,3E,4A,5B,6D,7C),
(1C,2D,3E,4B,5A,6A,7A),
(1C,2D,3E,4B,5A,6A,7B),(1C,2D,3E,4B,5A,6A,7C),
(1C,2D,3E,4B,5A,6B,7A),(1C- ,2D,3E,4B,5A,6B,7B),
(1C,2D,3E,4B,5A,6B,7C), (1C,2D,3E,4B,5A,6C,7A), (1C,2D,3E,4B,5A,6C,
7B), (1C,2D,3E,4B,5A,6C,7C), (1C,2D,3E,4B,5A,6D,7A),(-
1C,2D,3E,4B,5A,6D,7B),(1C,2D,3E,4B,5A,6D,7C),
(1C,2D,3E,4B,5B,6A,7A), (1C,2D,3E,4B,5B,6A,7B),
(C,2D,3E,4B,5B,6A,7C), (1C,2D,3E,4B,5B,6B,7A),
(1C,2D,3E,4B,5B,6B,7B),(1C,2D,3E,4B,5B,6B,7C),(1C,2D,3E,4B,5B,6C,7A),
(1C,2D,3E,4B,5B,6C,7B), (1C,2D,3E,4B,5B,6C,7C),
(1C,2D,3E,4B,5B,6D,7A), (1C,2D,3E,4B,5B,6D,7B),
(1C,2D,3E,4B,5B,6D,7C),(1C,2D,3E,4C,5A,6A,7A),
(1C,2D,3E,4C,5A,6A,7B), (1C,2D,3E,4C,5A,6A,7C),
(1C,2D,3E,4C,5A,6B,7A), (1C,2D,3E,4C,5A,6B,7B),
(1C,2D,3E,4C,5A,6B,7C), (1C,2D,3E,4C,5A,6C,7A),(1-
C,2D,3E,4C,5A,6C,7B), (1C,2D,3E,4C,5A,6C,7C),
(1C,2D,3E,4C,5A,6D,7A), (1C,2D,3E,4C,5A,6D,7B),
(1C,2D,3E,4C,5A,6D,7C), (1C,2D,3E,4C,5B,6A,7A),
(1C,2D,3E,4C,5B,6A,7B),(1C,2D,3E,4C,5B,6A,7C),
(1C,2D,3E,4C,5B,6B,7A), (1C,2D,3E,4C,5B,6B,7B),
(1C,2D,3E,4C,5B,6B,7C), (1C,2D,3E,4C,5B,6C,7A),
(1C,2D,3E,4C,5B,6C,7B),
(1C,2D,3E,4C,5B,6C,7C),(1C,2D,3E,4C,5B,6D,7A),(1C-
,2D,3E,4C,5B,6D,7B), (1C,2D,3E,4C,5B,6D,7C),
(1C,2D,3E,4D,5A,6A,7A), (1C,2D,3E,4D,5A,6A,7B),
(1C,2D,3E,4D,5A,6A,7C), (1C,2D,3E,4D,5A,6B,7A),(1-
C,2D,3E,4D,5A,6B,7B),(1C,2D,3E,4D,5A,6B,7C),
(1C,2D,3E,4D,5A,6C,7A), (1C,2D,3E,4D,5A,6C,7B),
(1C,2D,3E,4D,5A,6C,7C), (1C,2D,3E,4D,5A,6D,7A),
(1C,2D,3E,4D,5A,6D,7B),
(1C,2D,3E,4D,5A,6D,7C),(1C,2D,3E,4D,5B,6A,7A),
(1C,2D,3E,4D,5B,6A,7B), (1C,2D,3E,4D,5B,6A,7C),
(1C,2D,3E,4D,5B,6B,7A), (C,2D,3E,4D,5B,6B,7B),
(1C,2D,3E,4D,5B,6B,7C), (1C,2D,3E,4D,5B,6C,7A),
(1C,2D,3E,4D,5B,6C,7B), (1C,2D,3E,4D,5B,6C,7C),
(1C,2D,3E,4D,5B,6D,7A), (1C,2D,3E,4D,5B,6D,7B),
(1C,2D,3E,4D,5B,6D,7C), (1C,2D,3E,4E,5A,6A,7A),(1-
C,2D,3E,4E,5A,6A,7B),(1C,2D,3E,4E,5A,6A,7C),
(1C,2D,3E,4E,5A,6B,7A),(1C,2D- ,3E,4E,5A,6B,7B),
(1C,2D,3E,4E,5A,6B,7C),(1C,2D,3E,4E,5A,6C,7A),(1C,2D,3E,-
4E,5A,6C,7B),(1C,2D,3E,4E,5A,6C,7C),(1C,2D,3E,4E,5A,6D,7A),
(1C,2D,3E,4E,5A,6D,7B),(1C,2D,3E,4E,5A,6D,7C),(1C,2D,3E,4E,5B,6A,7A),(1C,-
2D,3E,4E,5B,6A,7B),(1C,2D,3E,4E,5B,6A,7C),(1C,2D,3E,4E,5B,6B,7A),(1C,2D,3E-
,4E,5B,6B,7B), (1C,2D,3E,4E,5B,6B,7C), (1C,2D,3E,4E,5B,6C,7A),
(1C,2D,3E,4E,5B,6C,7B),
(1C,2D,3E,4E,5B,6C,7C),(1C,2D,3E,4E,5B,6D,7A),(1C-
,2D,3E,4E,5B,6D,7B),(1C,2D,3E,4E,5B,6D,7C),
(1C,2E,3A,4A,5A,6A,7A),(1C,2E,-
3A,4A,5A,6A,7B),(1C,2E,3A,4A,5A,6A,7C),(1C,2E,3A,4A,5A,6B,7A),(1C,2E,3A,4A-
,5A,6B,7B),(1C,2E,3A,4A,5A,6B,7C),(1C,2E,3A,4A,5A,6C,7A),
(1C,2E,3A,4A,5A,6C,7B),(1C,2E,3A,4A,5A,6C,7C),(1C,2E,3A,4A,5A,6D,7A),(1C,-
2E,3A,4A,5A,6D,7B),(1C,2E,3A,4A,5A,6D,7C),(1C,2E,3A,4A,5B,6A,7A),(1C,2E,3A-
,4A,5B,6A,7B),
(1C,2E,3A,4A,5B,6A,7C),(1C,2E,3A,4A,5B,6B,7A),(1C,2E,3A,4A,-
5B,6B,7B),(1C,2E,3A,4A,5B,6B,7C),(1C,2E,3A,4A,5B,6C,7A),(1C,2E,3A,4A,5B,6C-
,7B),(1C,2E,3A,4A,5B,6C,7C),
(1C,2E,3A,4A,5B,6D,7A),(1C,2E,3A,4A,5B,6D,7B)-
,(1C,2E,3A,4A,5B,6D,7C),(1C,2E,3A,4B,5A,6A,7A),(1C,2E,3A,4B,5A,6A,7B),(1C,-
2E,3A,4B,5A,6A,7C),(1C,2E,3A,4B,5A,6B,7A),
(1C,2E,3A,4B,5A,6B,7B),(1C,2E,3-
A,4B,5A,6B,7C),(1C,2E,3A,4B,5A,6C,7A),(1C,2E,3A,4B,5A,6C,7B),(1C,2E,3A,4B,-
5A,6C,7C),(1C,2E,3A,4B,5A,6D,7A),(1C,2E,3A,4B,5A,6D,7B),
(1C,2E,3A,4B,5A,6D,7C),(1C,2E,3A,4B,5B,6A,7A),(1C,2E,3A,4B,5B,6A,7B),(1C,-
2E,3A,4B,5B,6A,7C),(1C,2E,3A,4B,5B,6B,7A),(1C,2E,3A,4B,5B,6B,7B),(1C,2E,3A-
,4B,5B,6B,7C),
(1C,2E,3A,4B,5B,6C,7A),(1C,2E,3A,4B,5B,6C,7B),(1C,2E,3A,4B,-
5B,6C,7C),(1C,2E,3A,4B,5B,6D,7A),(1C,2E,3A,4B,5B,6D,7B),(1C,2E,3A,4B,5B,6D-
,7C),(1C,2E,3A,4C,5A,6A,7A),
(1C,2E,3A,4C,5A,6A,7B),(1C,2E,3A,4C,5A,6A,7C)-
,(1C,2E,3A,4C,5A,6B,7A),(1C,2E,3A,4C,5A,6B,7B),(1C,2E,3A,4C,5A,6B,7C),(1C,-
2E,3A,4C,5A,6C,7A),(1C,2E,3A,4C,5A,6C,7B),
(1C,2E,3A,4C,5A,6C,7C),(1C,2E,3-
A,4C,5A,6D,7A),(1C,2E,3A,4C,5A,6D,7B),(1C,2E,3A,4C,5A,6D,7C),(1C,2E,3A,4C,-
5B,6A,7A),(1C,2E,3A,4C,5B,6A,7B),(1C,2E,3A,4C,5B,6A,7C),
(1C,2E,3A,4C,5B,6B,7A),(1C,2E,3A,4C,5B,6B,7B),(1C,2E,3A,4C,5B,6B,7C),(1C,-
2E,3A,4C,5B,6C,7A),(1C,2E,3A,4C,5B,6C,7B),(1C,2E,3A,4C,5B,6C,7C),(1C,2E,3A-
,4C,5B,6D,7A),
(1C,2E,3A,4C,5B,6D,7B),(1C,2E,3A,4C,5B,6D,7C),(1C,2E,3A,4D,-
5A,6A,7A),(1C,2E,3A,4D,5A,6A,7B),(1C,2E,3A,4D,5A,6A,7C),(1C,2E,3A,4D,5A,6B-
,7A),(1C,2E,3A,4D,5A,6B,7B),
(1C,2E,3A,4D,5A,6B,7C),(1C,2E,3A,4D,5A,6C,7A)-
,(1C,2E,3A,4D,5A,6C,7B),(1C,2E,3A,4D,5A,6C,7C),(1C,2E,3A,4D,5A,6D,7A),(1C,-
2E,3A,4D,5A,6D,7B),(1C,2E,3A,4D,5A,6D,7C),
(1C,2E,3A,4D,5B,6A,7A),(1C,2E,3-
A,4D,5B,6A,7B),(1C,2E,3A,4D,5B,6A,7C),(1C,2E,3A,4D,5B,6B,7A),(1C,2E,3A,4D,-
5B,6B,7B),(1C,2E,3A,4D,5B,6B,7C),(1C,2E,3A,4D,5B,6C,7A),
(1C,2E,3A,4D,5B,6C,7B),(1C,2E,3A,4D,5B,6C,7C),(1C,2E,3A,4D,5B,6D,7A),(1C,-
2E,3A,4D,5B,6D,7B),(1C,2E,3A,4D,5B,6D,7C),(1C,2E,3A,4E,5A,6A,7A),(1C,2E,3A-
,4E,5A,6A,7B),
(1C,2E,3A,4E,5A,6A,7C),(1C,2E,3A,4E,5A,6B,7A),(1C,2E,3A,4E,-
5A,6B,7B),(1C,2E,3A,4E,5A,6B,7C),(1C,2E,3A,4E,5A,6C,7A),(1C,2E,3A,4E,5A,6C-
,7B),(1C,2E,3A,4E,5A,6C,7C),
(1C,2E,3A,4E,5A,6D,7A),(1C,2E,3A,4E,5A,6D,7B)-
,(1C,2E,3A,4E,5A,6D,7C),(1C,2E,3A,4E,5B,6A,7A),(1C,2E,3A,4E,5B,6A,7B),(1C,-
2E,3A,4E,5B,6A,7C),(1C,2E,3A,4E,5B,6B,7A),
(1C,2E,3A,4E,5B,6B,7B),(1C,2E,3-
A,4E,5B,6B,7C),(1C,2E,3A,4E,5B,6C,7A),(1C,2E,3A,4E,5B,6C,7B),(1C,2E,3A,4E,-
5B,6C,7C),(1C,2E,3A,4E,5B,6D,7A),(1C,2E,3A,4E,5B,6D,7B),
(1C,2E,3A,4E,5B,6D,7C),(1C,2E,3B,4A,5A,6A,7A),(1C,2E,3B,4A,5A,6A,7B),(1C,-
2E,3B,4A,5A,6A,7C),(1C,2E,3B,4A,5A,6B,7A),(1C,2E,3B,4A,5A,6B,7B),(1C,2E,3B-
,4A,5A,6B,7C),
(1C,2E,3B,4A,5A,6C,7A),(1C,2E,3B,4A,5A,6C,7B),(1C,2E,3B,4A,-
5A,6C,7C),(1C,2E,3B,4A,5A,6D,7A),(1C,2E,3B,4A,5A,6D,7B),(1C,2E,3B,4A,5A,6D-
,7C),(1C,2E,3B,4A,5B,6A,7A),
(1C,2E,3B,4A,5B,6A,7B),(1C,2E,3B,4A,5B,6A,7C)-
,(1C,2E,3B,4A,5B,6B,7A),(1C,2E,3B,4A,5B,6B,7B),(1C,2E,3B,4A,5B,6B,7C),(1C,-
2E,3B,4A,5B,6C,7A),(1C,2E,3B,4A,5B,6C,7B),
(1C,2E,3B,4A,5B,6C,7C),(1C,2E,3-
B,4A,5B,6D,7A),(1C,2E,3B,4A,5B,6D,7B),(1C,2E,3B,4A,5B,6D,7C),(1C,2E,3B,4B,-
5A,6A,7A),(1C,2E,3B,4B,5A,6A,7B),(1C,2E,3B,4B,5A,6A,7C),
(1C,2E,3B,4B,5A,6B,7A),(1C,2E,3B,4B,5A,6B,7B),(1C,2E,3B,4B,5A,6B,7C),(1C,-
2E,3B,4B,5A,6C,7A),(1C,2E,3B,4B,5A,6C,7B),(1C,2E,3B,4B,5A,6C,7C),(1C,2E,3B-
,4B,5A,6D,7A),
(1C,2E,3B,4B,5A,6D,7B),(1C,2E,3B,4B,5A,6D,7C),(1C,2E,3B,4B,-
5B,6A,7A),(1C,2E,3B,4B,5B,6A,7B),(1C,2E,3B,4B,5B,6A,7C),(1C,2E,3B,4B,5B,6B-
,7A),(1C,2E,3B,4B,5B,6B,7B),
(1C,2E,3B,4B,5B,6B,7C),(1C,2E,3B,4B,5B,6C,7A)-
,(1C,2E,3B,4B,5B,6C,7B),(1C,2E,3B,4B,5B,6C,7C),(1C,2E,3B,4B,5B,6D,7A),(1C,-
2E,3B,4B,5B,6D,7B),(1C,2E,3B,4B,5B,6D,7C),
(1C,2E,3B,4C,5A,6A,7A),(1C,2E,3-
B,4C,5A,6A,7B),(1C,2E,3B,4C,5A,6A,7C),(1C,2E,3B,4C,5A,6B,7A),(1C,2E,3B,4C,-
5A,6B,7B),(1C,2E,3B,4C,5A,6B,7C),(1C,2E,3B,4C,5A,6C,7A),
(1C,2E,3B,4C,5A,6C,7B),(1C,2E,3B,4C,5A,6C,7C),(1C,2E,3B,4C,5A,6D,7A),(1C,-
2E,3B,4C,5A,6D,7B),(1C,2E,3B,4C,5A,6D,7C),(1C,2E,3B,4C,5B,6A,7A),(1C,2E,3B-
,4C,5B,6A,7B),
(1C,2E,3B,4C,5B,6A,7C),(1C,2E,3B,4C,5B,6B,7A),(1C,2E,3B,4C,-
5B,6B,7B),(1C,2E,3B,4C,5B,6B,7C),(1C,2E,3B,4C,5B,6C,7A),(1C,2E,3B,4C,5B,6C-
,7B),(1C,2E,3B,4C,5B,6C,7C),
(1C,2E,3B,4C,5B,6D,7A),(1C,2E,3B,4C,5B,6D,7B)-
,(1C,2E,3B,4C,5B,6D,7C),(1C,2E,3B,4D,5A,6A,7A),(1C,2E,3B,4D,5A,6A,7B),(1C,-
2E,3B,4D,5A,6A,7C),(1C,2E,3B,4D,5A,6B,7A),
(1C,2E,3B,4D,5A,6B,7B),(1C,2E,3-
B,4D,5A,6B,7C),(1C,2E,3B,4D,5A,6C,7A),(1C,2E,3B,4D,5A,6C,7B),(1C,2E,3B,4D,-
5A,6C,7C),(1C,2E,3B,4D,5A,6D,7A),(1C,2E,3B,4D,5A,6D,7B),
(1C,2E,3B,4D,5A,6D,7C),(1C,2E,3B,4D,5B,6A,7A),(1C,2E,3B,4D,5B,6A,7B),(1C,-
2E,3B,4D,5B,6A,7C),(1C,2E,3B,4D,5B,6B,7A),(1C,2E,3B,4D,5B,6B,7B),(1C,2E,3B-
,4D,5B,6B,7C),
(1C,2E,3B,4D,5B,6C,7A),(1C,2E,3B,4D,5B,6C,7B),(1C,2E,3B,4D,-
5B,6C,7C),(1C,2E,3B,4D,5B,6D,7A),(1C,2E,3B,4D,5B,6D,7B),(1C,2E,3B,4D,5B,6D-
,7C),(1C,2E,3B,4E,5A,6A,7A),
(1C,2E,3B,4E,5A,6A,7B),(1C,2E,3B,4E,5A,6A,7C)-
,(1C,2E,3B,4E,5A,6B,7A),(1C,2E,3B,4E,5A,6B,7B),(1C,2E,3B,4E,5A,6B,7C),(1C,-
2E,3B,4E,5A,6C,7A),(1C,2E,3B,4E,5A,6C,7B),
(1C,2E,3B,4E,5A,6C,7C),(1C,2E,3-
B,4E,5A,6D,7A),(1C,2E,3B,4E,5A,6D,7B),(1C,2E,3B,4E,5A,6D,7C),(1C,2E,3B,4E,-
5B,6A,7A),(1C,2E,3B,4E,5B,6A,7B),(1C,2E,3B,4E,5B,6A,7C),
(1C,2E,3B,4E,5B,6B,7A),(1C,2E,3B,4E,5B,6B,7B).,(1C,2E,3B,4E,5B,6B,7C),(1C-
,2E,3B,4E,5B,6C,7A),(1C,2E,3B,4E,5B,6C,7B),(1C,2E,3B,4E,5B,6C,7C),(1C,2E,3-
B,4E,5B,6D,7A),
(1C,2E,3B,4E,5B,6D,7B),(1C,2E,3B,4E,5B,6D,7C),(1C,2E,3C,4A-
,5A,6A,7A),(1C,2E,3C,4A,5A,6A,7B),(1C,2E,3C,4A,5A,6A,7C),(1C,2E,3C,4A,5A,6-
B,7A),(1C,2E,3C,4A,5A,6B,7B),
(1C,2E,3C,4A,5A,6B,7C),(1C,2E,3C,4A,5A,6C,7A-
),(1C,2E,3C,4A,5A,6C,7B),(1C,2E,3C,4A,5A,6C,7C),(1C,2E,3C,4A,5A,6D,7A),(1C-
,2E,3C,4A,5A,6D,7B),(1C,2E,3C,4A,5A,6D,7C),
(1C,2E,3C,4A,5B,6A,7A),(1C,2E,-
3C,4A,5B,6A,7B),(1C,2E,3C,4A,5B,6A,7C),(1C,2E,3C,4A,5B,6B,7A),(1C,2E,3C,4A-
,5B,6B,7B),(1C,2E,3C,4A,5B,6B,7C),(1C,2E,3C,4A,5B,6C,7A),
(1C,2E,3C,4A,5B,6C,7B),(1C,2E,3C,4A,5B,6C,7C),(1C,2E,3C,4A,5B,6D,7A),(1C,-
2E,3C,4A,5B,6D,7B),(1C,2E,3C,4A,5B,6D,7C),(1C,2E,3C,4B,5A,6A,7A),(1C,2E,3C-
,4B,5A,6A,7B),
(1C,2E,3C,4B,5A,6A,7C),(1C,2E,3C,4B,5A,6B,7A),(1C,2E,3C,4B,-
5A,6B,7B),(1C,2E,3C,4B,5A,6B,7C),(1C,2E,3C,4B,5A,6C,7A),(1C,2E,3C,4B,5A,6C-
,7B),(1C,2E,3C,4B,5A,6C,7C),
(1C,2E,3C,4B,5A,6D,7A),(1C,2E,3C,4B,5A,6D,7B)-
,(1C,2E,3C,4B,5A,6D,7C),(1C,2E,3C,4B,5B,6A,7A),
(1C,2E,3C,4B,5B,6A,7B),(1C-
,2E,3C,4B,5B,6A,7C),(1C,2E,3C,4B,5B,6B,7A), (1C,2E,3C,4B,5B,6B,7B),
(1C,2E,3C,4B,5B,6B,7C), (1C,2E,3C,4B,5B,6C,7A),
(1C,2E,3C,4B,5B,6C,7B), (1C,2E,3C,4B,5B,6C,7C),
(1C,2E,3C,4B,5B,6D,7A),(1C,2E,3C,4B,5B,6D,7B),
(1C,2E,3C,4B,5B,6D,7C),(1C,2E,3C,4C,5A,6A,7A),(1C,2E,3C,4C,5A,6A,7B),(1C,-
2E,3C,4C,5A,6A,7C),
(1C,2E,3C,4C,5A,6B,7A),(1C,2E,3C,4C,5A,6B,7B),(1C,2E,3-
C,4C,5A,6B,7C),
(1C,2E,3C,4C,5A,6C,7A),(1C,2E,3C,4C,5A,6C,7B),(1C,2E,3C,4C-
,5A,6C,7C),(1C,2E,3C,4C,5A,6D,7A),(1C,2E,3C,4C,5A,6D,7B),(1C,2E,3C,4C,5A,6-
D,7C),(1C,2E,3C,4C,5B,6A,7A),
(1C,2E,3C,4C,5B,6A,7B),(1C,2E,3C,4C,5B,6A,7C-
),(1C,2E,3C,4C,5B,6B,7A),(1C,2E,3C,4C,5B,6B,7B),(1C,2E,3C,4C,5B,6B,7C),(1C-
,2E,3C,4C,5B,6C,7A),(1C,2E,3C,4C,5B,6C,7B),
(1C,2E,3C,4C,5B,6C,7C),(1C,2E,-
3C,4C,5B,6D,7A),(1C,2E,3C,4C,5B,6D,7B),(1C,2E,3C,4C,5B,6D,7C),(1C,2E,3C,4D-
,5A,6A,7A),(1C,2E,3C,4D,5A,6A,7B),(1C,2E,3C,4D,5A,6A,7C),
(1C,2E,3C,4D,5A,6B,7A),(1C,2E,3C,4D,5A,6B,7B),(1C,2E,3C,4D,5A,6B,7C),(1C,-
2E,3C,4D,5A,6C,7A),(1C,2E,3C,4D,5A,6C,7B),(1C,2E,3C,4D,5A,6C,7C),(1C,2E,3C-
,4D,5A,6D,7A),
(1C,2E,3C,4D,5A,6D,7B),(1C,2E,3C,4D,5A,6D,7C),(1C,2E,3C,4D,-
5B,6A,7A),(1C,2E,3C,4D,5B,6A,7B),(1C,2E,3C,4D,5B,6A,7C),(1C,2E,3C,4D,5B,6B-
,7A),(1C,2E,3C,4D,5B,6B,7B),
(1C,2E,3C,4D,5B,6B,7C),(1C,2E,3C,4D,5B,6C,7A)-
,(1C,2E,3C,4D,5B,6C,7B),(1C,2E,3C,4D,5B,6C,7C),(1C,2E,3C,4D,5B,6D,7A),(1C,-
2E,3C,4D,5B,6D,7B),(1C,2E,3C,4D,5B,6D,7C),
(1C,2E,3C,4E,5A,6A,7A),(1C,2E,3-
C,4E,5A,6A,7B),(1C,2E,3C,4E,5A,6A,7C),(1C,2E,3C,4E,5A,6B,7A),(1C,2E,3C,4E,-
5A,6B,7B),(1C,2E,3C,4E,5A,6B,7C),(1C,2E,3C,4E,5A,6C,7A),
(1C,2E,3C,4E,5A,6C,7B),(1C,2E,3C,4E,5A,6C,7C),(1C,2E,3C,4E,5A,6D,7A),(1C,-
2E,3C,4E,5A,6D,7B),(1C,2E,3C,4E,5A,6D,7C),(1C,2E,3C,4E,5B,6A,7A),(1C,2E,3C-
,4E,5B,6A,7B),
(1C,2E,3C,4E,5B,6A,7C),(1C,2E,3C,4E,5B,6B,7A),(1C,2E,3C,4E,-
5B,6B,7B),(1C,2E,3C,4E,5B,6B,7C),(1C,2E,3C,4E,5B,6C,7A),(1C,2E,3C,4E,5B,6C-
,7B),(1C,2E,3C,4E,5B,6C,7C),
(1C,2E,3C,4E,5B,6D,7A),(1C,2E,3C,4E,5B,6D,7B)-
,(1C,2E,3C,4E,5B,6D,7C),(1C,2E,3D,4A,5A,6A,7A),(1C,2E,3D,4A,5A,6A,7B),(1C,-
2E,3D,4A,5A,6A,7C),(1C,2E,3D,4A,5A,6B,7A),
(1C,2E,3D,4A,5A,6B,7B),(1C,2E,3-
D,4A,5A,6B,7C),(1C,2E,3D,4A,5A,6C,7A),(1C,2E,3D,4A,5A,6C,7B),(1C,2E,3D,4A,-
5A,6C,7C),(1C,2E,3D,4A,5A,6D,7A),(1C,2E,3D,4A,5A,6D,7B),
(1C,2E,3D,4A,5A,6D,7C),(1C,2E,3D,4A,5B,6A,7A),(1C,2E,3D,4A,5B,6A,7B),(1C,-
2E,3D,4A,5B,6A,7C),(1C,2E,3D,4A,5B,6B,7A),(1C,2E,3D,4A,5B,6B,7B),(1C,2E,3D-
,4A,5B,6B,7C),
(1C,2E,3D,4A,5B,6C,7A),(1C,2E,3D,4A,5B,6C,7B),(1C,2E,3D,4A,-
5B,6C,7C),(1C,2E,3D,4A,5B,6D,7A),
(1C,2E,3D,4A,5B,6D,7B),(1C,2E,3D,4A,5B,6-
D,7C),(1C,2E,3D,4B,5A,6A,7A), (1C,2E,3D,4B,5A,6A,7B),
(1C,2E,3D,4B,5A,6A,7C), (1C,2E,3D,4B,5A,6B,7A),
(1C,2E,3D,4B,5A,6B,7B),
(1C,2E,3D,4B,5A,6B,7C),(1C,2E,3D,4B,5A,6C,7A),(1C,2E,3D,4B,5A,6C,7B),
(1C,2E,3D,4B,5A,6C,7C),(1C,2E,3D,4B,5A,6D,7A),(1C,2E,3D,4B,5A,6D,7B),(1C,-
2E,3D,4B,5A,6D,7C),
(1C,2E,3D,4B,5B,6A,7A),(1C,2E,3D,4B,5B,6A,7B),(1C,2E,3-
D,4B,5B,6A,7C),
(1C,2E,3D,4B,5B,6B,7A),(1C,2E,3D,4B,5B,6B,7B),(1C,2E,3D,4B-
,5B,6B,7C),(1C,2E,3D,4B,5B,6C,7A),(1C,2E,3D,4B,5B,6C,7B),(1C,2E,3D,4B,5B,6-
C,7C),(1C,2E,3D,4B,5B,6D,7A),
(1C,2E,3D,4B,5B,6D,7B),(1C,2E,3D,4B,5B,6D,7C-
),(1C,2E,3D,4C,5A,6A,7A),(1C,2E,3D,4C,5A,6A,7B),(1C,2E,3D,4C,5A,6A,7C),(1C-
,2E,3D,4C,5A,6B,7A),(1C,2E,3D,4C,5A,6B,7B),
(1C,2E,3D,4C,5A,6B,7C),(1C,2E,-
3D,4C,5A,6C,7A),(1C,2E,3D,4C,5A,6C,7B),(1C,2E,3D,4C,5A,6C,7C),(1C,2E,3D,4C-
,5A,6D,7A),(1C,2E,3D,4C,5A,6D,7B),(1C,2E,3D,4C,5A,6D,7C),
(1C,2E,3D,4C,5B,6A,7A),(1C,2E,3D,4C,5B,6A,7B),(1C,2E,3D,4C,5B,6A,7C),(1C,-
2E,3D,4C,5B,6B,7A),(1C,2E,3D,4C,5B,6B,7B),(1C,2E,3D,4C,5B,6B,7C),(1C,2E,3D-
,4C,5B,6C,7A),
(1C,2E,3D,4C,5B,6C,7B),(1C,2E,3D,4C,5B,6C,7C),(1C,2E,3D,4C,-
5B,6D,7A),(1C,2E,3D,4C,5B,6D,7B),(1C,2E,3D,4C,5B,6D,7C),(1C,2E,3D,4D,5A,6A-
,7A),(1C,2E,3D,4D,5A,6A,7B),
(1C,2E,3D,4D,5A,6A,7C),(1C,2E,3D,4D,5A,6B,7A)-
,(1C,2E,3D,4D,5A,6B,7B),(1C,2E,3D,4D,5A,6B,7C),(1C,2E,3D,4D,5A,6C,7A),(1C,-
2E,3D,4D,5A,6C,7B),(1C,2E,3D,4D,5A,6C,7C),
(1C,2E,3D,4D,5A,6D,7A),(1C,2E,3-
D,4D,5A,6D,7B),(1C,2E,3D,4D,5A,6D,7C),(1C,2E,3D,4D,5B,6A,7A),(1C,2E,3D,4D,-
5B,6A,7B),(1C,2E,3D,4D,5B,6A,7C),(1C,2E,3D,4D,5B,6B,7A),
(1C,2E,3D,4D,5B,6B,7B),(1C,2E,3D,4D,5B,6B,7C),(1C,2E,3D,4D,5B,6C,7A),(1C,-
2E,3D,4D,5B,6C,7B),(1C,2E,3D,4D,5B,6C,7C),(1C,2E,3D,4D,5B,6D,7A),(1C,2E,3D-
,4D,5B,6D,7B),
(1C,2E,3D,4D,5B,6D,7C),(1C,2E,3D,4E,5A,6A,7A),(1C,2E,3D,4E,-
5A,6A,7B),(1C,2E,3D,4E,5A,6A,7C),(1C,2E,3D,4E,5A,6B,7A),(1C,2E,3D,4E,5A,6B-
,7B),(1C,2E,3D,4E,5A,6B,7C),
(1C,2E,3D,4E,5A,6C,7A),(1C,2E,3D,4E,5A,6C,7B)-
,(1C,2E,3D,4E,5A,6C,7C),(1C,2E,3D,4E,5A,6D,7A),(1C,2E,3D,4E,5A,6D,7B),(1C,-
2E,3D,4E,5A,6D,7C),(1C,2E,3D,4E,5B,6A,7A),
(1C,2E,3D,4E,5B,6A,7B),(1C,2E,3-
D,4E,5B,6A,7C),(1C,2E,3D,4E,5B,6B,7A),(1C,2E,3D,4E,5B,6B,7B),(1C,2E,3D,4E,-
5B,6B,7C),(1C,2E,3D,4E,5B,6C,7A),(1C,2E,3D,4E,5B,6C,7B),
(1C,2E,3D,4E,5B,6C,7C),(1C,2E,3D,4E,5B,6D,7A),(1C,2E,3D,4E,5B,6D,7B),(1C,-
2E,3D,4E,5B,6D,7C),(1C,2E,3E,4A,5A,6A,7A),(1C,2E,3E,4A,5A,6A,7B),(1C,2E,3E-
,4A,5A,6A,7C),
(1C,2E,3E,4A,5A,6B,7A),(1C,2E,3E,4A,5A,6B,7B),(1C,2E,3E,4A,-
5A,6B,7C),(1C,2E,3E,4A,5A,6C,7A),(1C,2E,3E,4A,5A,6C,7B),(1C,2E,3E,4A,5A,6C-
,7C),(1C,2E,3E,4A,5A,6D,7A),
(1C,2E,3E,4A,5A,6D,7B),(1C,2E,3E,4A,5A,6D,7C)-
,(1C,2E,3E,4A,5B,6A,7A),(1C,2E,3E,4A,5B,6A,7B),(1C,2E,3E,4A,5B,6A,7C),(1C,-
2E,3E,4A,5B,6B,7A),
(1C,2E,3E,4A,5B,6B,7B),(1C,2E,3E,4A,5B,6B,7C),(1C,2E,3-
E,4A,5B,6C,7A),(1C,2E,3E,4A,5B,6C,7B),(1C,2E,3E,4A,5B,6C,7C),(1C,2E,3E,4A,-
5B,6D,7A),(1C,2E,3E,4A,5B,6D,7B),
(1C,2E,3E,4A,5B,6D,7C),(1C,2E,3E,4B,5A,6-
A,7A),(1C,2E,3E,4B,5A,6A,7B),(1C,2E,3E,4B,5A,6A,7C),(1C,2E,3E,4B,5A,6B,7A)-
,(1C,2E,3E,4B,5A,6B,7B),(1C,2E,3E,4B,5A,6B,7C),
(1C,2E,3E,4B,5A,6C,7A),(1C-
,2E,3E,4B,5A,6C,7B),(1C,2E,3E,4B,5A,6C,7C),(1C,2E,3E,4B,5A,6D,7A),(1C,2E,3-
E,4B,5A,6D,7B),(1C,2E,3E,4B,5A,6D,7C),(1C,2E,3E,4B,5B,6A,7A),
(1C,2E,3E,4B,5B,6A,7B),(1C,2E,3E,4B,5B,6A,7C),(1C,2E,3E,4B,5B,6B,7A),(1C,-
2E,3E,4B,5B,6B,7B),(1C,2E,3E,4B,5B,6B,7C),(1C,2E,3E,4B,5B,6C,7A),(1C,2E,3E-
,4B,5B,6C,7B),
(1C,2E,3E,4B,5B,6C,7C),(1C,2E,3E,4B,5B,6D,7A),(1C,2E,3E,4B,-
5B,6D,7B),(1C,2E,3E,4B,5B,6D,7C),(1C,2E,3E,4C,5A,6A,7A),(1C,2E,3E,4C,5A,6A-
,7B),(1C,2E,3E,4C,5A,6A,7C),
(1C,2E,3E,4C,5A,6B,7A),(1C,2E,3E,4C,5A,6B,7B)-
,(1C,2E,3E,4C,5A,6B,7C),(1C,2E,3E,4C,5A,6C,7A),(1C,2E,3E,4C,5A,6C,7B),(1C,-
2E,3E,4C,5A,6C,7C),(1C,2E,3E,4C,5A,6D,7A),
(1C,2E,3E,4C,5A,6D,7B),(1C,2E,3-
E,4C,5A,6D,7C),(1C,2E,3E,4C,5B,6A,7A),(1C,2E,3E,4C,5B,6A,7B),(1C,2E,3E,4C,-
5B,6A,7C),(1C,2E,3E,4C,5B,6B,7A),(1C,2E,3E,4C,5B,6B,7B),
(1C,2E,3E,4C,5B,6B,7C),(1C,2E,3E,4C,5B,6C,7A),(1C,2E,3E,4C,5B,6C,7B),(1C,-
2E,3E,4C,5B,6C,7C),(1C,2E,3E,4C,5B,6D,7A),(1C,2E,3E,4C,5B,6D,7B),(1C,2E,3E-
,4C,5B,6D,7C),
(1C,2E,3E,4D,5A,6A,7A),(1C,2E,3E,4D,5A,6A,7B),(1C,2E,3E,4D,-
5A,6A,7C),(1C,2E,3E,4D,5A,6B,7A),(1C,2E,3E,4D,5A,6B,7B),(1C,2E,3E,4D,5A,6B-
,7C),(1C,2E,3E,4D,5A,6C,7A),
(1C,2E,3E,4D,5A,6C,7B),(1C,2E,3E,4D,5A,6C,7C)-
,(1C,2E,3E,4D,5A,6D,7A),(1C,2E,3E,4D,5A,6D,7B),(1C,2E,3E,4D,5A,6D,7C),(1C,-
2E,3E,4D,5B,6A,7A),(1C,2E,3E,4D,5B,6A,7B),
(1C,2E,3E,4D,5B,6A,7C),(1C,2E,3-
E,4D,5B,6B,7A),(1C,2E,3E,4D,5B,6B,7B),(1C,2E,3E,4D,5B,6B,7C),(1C,2E,3E,4D,-
5B,6C,7A),(1C,2E,3E,4D,5B,6C,7B),(1C,2E,3E,4D,5B,6C,7C),
(1C,2E,3E,4D,5B,6D,7A),(1C,2E,3E,4D,5B,6D,7B),(1C,2E,3E,4D,5B,6D,7C),(1C,-
2E,3E,4E,5A,6A,7A),(1C,2E,3E,4E,5A,6A,7B),(1C,2E,3E,4E,5A,6A,7C),(1C,2E,3E-
,4E,5A,6B,7A),
(1C,2E,3E,4E,5A,6B,7B),(1C,2E,3E,4E,5A,6B,7C),(1C,2E,3E,4E,-
5A,6C,7A),(1C,2E,3E,4E,5A,6C,7B),(1C,2E,3E,4E,5A,6C,7C),(1C,2E,3E,4E,5A,6D-
,7A),(1C,2E,3E,4E,5A,6D,7B),
(1C,2E,3E,4E,5A,6D,7C),(1C,2E,3E,4E,5B,6A,7A)-
,(1C,2E,3E,4E,5B,6A,7B),(1C,2E,3E,4E,5B,6A,7C),
(1C,2E,3E,4E,5B,6B,7A),(1C-
,2E,3E,4E,5B,6B,7B),(1C,2E,3E,4E,5B,6B,7C), (1C,2E,3E,4E,5B,6C,7A),
(1C,2E,3E,4E,5B,6C,7B), (1C,2E,3E,4E,5B,6C,7C),
(1C,2E,3E,4E,5B,6D,7A),(1-
C,2E,3E,4E,5B,6D,7B),(1C,2E,3E,4E,5B,6D,7C),(1D,2A,3A,4A,5A,6A,7A),
(1D,2A,3A,4A,5A,6A,7B),(1D,2A,3A,4A,5A,6A,7C),(1D,2A,3A,4A,5A,6B,7A),(1D,-
2A,3A,4A,5A,6B,7B),(1D,2A,3A,4A,5A,6B,7C),(1D,2A,3A,4A,5A,6C,7A),(1D,2A,3A-
,4A,5A,6C,7B),
(1D,2A,3A,4A,5A,6C,7C),(1D,2A,3A,4A,5A,6D,7A),(1D,2A,3A,4A,-
5A,6D,7B),(1D,2A,3A,4A,5A,6D,7C),(1D,2A,3A,4A,5B,6A,7A),(1D,2A,3A,4A,5B,6A-
,7B),(1D,2A,3A,4A,5B,6A,7C),
(1D,2A,3A,4A,5B,6B,7A),(1D,2A,3A,4A,5B,6B,7B)-
,(1D,2A,3A,4A,5B,6B,7C),(1D,2A,3A,4A,5B,6C,7A),(1D,2A,3A,4A,5B,6C,7B),(1D,-
2A,3A,4A,5B,6C,7C),(1D,2A,3A,4A,5B,6D,7A),
(1D,2A,3A,4A,5B,6D,7B),(1D,2A,3-
A,4A,5B,6D,7C),(1D,2A,3A,4B,5A,6A,7A),(1D,2A,3A,4B,5A,6A,7B),(1D,2A,3A,4B,-
5A,6A,7C),(1D,2A,3A,4B,5A,6B,7A),(1D,2A,3A,4B,5A,6B,7B),
(1D,2A,3A,4B,5A,6B,7C),(1D,2A,3A,4B,5A,6C,7A),(1D,2A,3A,4B,5A,6C,7B),(1D,-
2A,3A,4B,5A,6C,7C),(1D,2A,3A,4B,5A,6D,7A),(1D,2A,3A,4B,5A,6D,7B),(1D,2A,3A-
,4B,5A,6D,7C),
(1D,2A,3A,4B,5B,6A,7A),(1D,2A,3A,4B,5B,6A,7B),(1D,2A,3A,4B,-
5B,6A,7C),(1D,2A,3A,4B,5B,6B,7A),(1D,2A,3A,4B,5B,6B,7B),(1D,2A,3A,4B,5B,6B-
,7C),(1D,2A,3A,4B,5B,6C,7A),
(1D,2A,3A,4B,5B,6C,7B),(1D,2A,3A,4B,5B,6C,7C)-
,(1D,2A,3A,4B,5B,6D,7A),(1D,2A,3A,4B,5B,6D,7B),(1D,2A,3A,4B,5B,6D,7C),(1D,-
2A,3A,4C,5A,6A,7A),(1D,2A,3A,4C,5A,6A,7B),
(1D,2A,3A,4C,5A,6A,7C),(1D,2A,3-
A,4C,5A,6B,7A),(1D,2A,3A,4C,5A,6B,7B),(1D,2A,3A,4C,5A,6B,7C),(1D,2A,3A,4C,-
5A,6C,7A),(1D,2A,3A,4C,5A,6C,7B),(1D,2A,3A,4C,5A,6C,7C),
(1D,2A,3A,4C,5A,6D,7A),(1D,2A,3A,4C,5A,6D,7B),(1D,2A,3A,4C,5A,6D,7C),(1D,-
2A,3A,4C,5B,6A,7A),(1D,2A,3A,4C,5B,6A,7B),(1D,2A,3A,4C,5B,6A,7C),(1D,2A,3A-
,4C,5B,6B,7A),
(1D,2A,3A,4C,5B,6B,7B),(1D,2A,3A,4C,5B,6B,7C),(1D,2A,3A,4C,-
5B,6C,7A),(1D,2A,3A,4C,5B,6C,7B),(1D,2A,3A,4C,5B,6C,7C),(1D,2A,3A,4C,5B,6D-
,7A),(1D,2A,3A,4C,5B,6D,7B),
(1D,2A,3A,4C,5B,6D,7C),(1D,2A,3A,4D,5A,6A,7A)-
,(1D,2A,3A,4D,5A,6A,7B),(1D,2A,3A,4D,5A,6A,7C),(1D,2A,3A,4D,5A,6B,7A),(1D,-
2A,3A,4D,5A,6B,7B),(1D,2A,3A,4D,5A,6B,7C),
(1D,2A,3A,4D,5A,6C,7A),(1D,2A,3-
A,4D,5A,6C,7B),(1D,2A,3A,4D,5A,6C,7C),(1D,2A,3A,4D,5A,6D,7A),(1D,2A,3A,4D,-
5A,6D,7B),(1D,2A,3A,4D,5A,6D,7C),(1D,2A,3A,4D,5B,6A,7A),
(1D,2A,3A,4D,5B,6A,7B),(1D,2A,3A,4D,5B,6A,7C),(1D,2A,3A,4D,5B,6B,7A),(1D,-
2A,3A,4D,5B,6B,7B),(1D,2A,3A,4D,5B,6B,7C),(1D,2A,3A,4D,5B,6C,7A),(1D,2A,3A-
,4D,5B,6C,7B),
(1D,2A,3A,4D,5B,6C,7C),(1D,2A,3A,4D,5B,6D,7A),(1D,2A,3A,4D,-
5B,6D,7B),(1D,2A,3A,4D,5B,6D,7C),(1D,2A,3A,4E,5A,6A,7A),(1D,2A,3A,4E,5A,6A-
,7B),(1D,2A,3A,4E,5A,6A,7C),
(1D,2A,3A,4E,5A,6B,7A),(1D,2A,3A,4E,5A,6B,7B)-
,(1D,2A,3A,4E,5A,6B,7C),(1D,2A,3A,4E,5A,6C,7A),(1D,2A,3A,4E,5A,6C,7B),(1D,-
2A,3A,4E,5A,6C,7C),(1D,2A,3A,4E,5A,6D,7A),
(1D,2A,3A,4E,5A,6D,7B),(1D,2A,3-
A,4E,5A,6D,7C),(1D,2A,3A,4E,5B,6A,7A),(1D,2A,3A,4E,5B,6A,7B),(1D,2A,3A,4E,-
5B,6A,7C),(1D,2A,3A,4E,5B,6B,7A),(1D,2A,3A,4E,5B,6B,7B),
(1D,2A,3A,4E,5B,6B,7C),(1D,2A,3A,4E,5B,6C,7A),(1D,2A,3A,4E,5B,6C,7B),(1D,-
2A,3A,4E,5B,6C,7C),(1D,2A,3A,4E,5B,6D,7A),(1D,2A,3A,4E,5B,6D,7B),(1D,2A,3A-
,4E,5B,6D,7C),
(1D,2A,3B,4A,5A,6A,7A),(1D,2A,3B,4A,5A,6A,7B),(1D,2A,3B,4A,-
5A,6A,7C),(1D,2A,3B,4A,5A,6B,7A),(1D,2A,3B,4A,5A,6B,7B),(1D,2A,3B,4A,5A,6B-
,7C),(1D,2A,3B,4A,5A,6C,7A),
(1D,2A,3B,4A,5A,6C,7B),(1D,2A,3B,4A,5A,6C,7C)-
,(1D,2A,3B,4A,5A,6D,7A),(1D,2A,3B,4A,5A,6D,7B),(1D,2A,3B,4A,5A,6D,7C),(1D,-
2A,3B,4A,5B,6A,7A),(1D,2A,3B,4A,5B,6A,7B),
(1D,2A,3B,4A,5B,6A,7C),(1D,2A,3-
B,4A,5B,6B,7A),(1D,2A,3B,4A,5B,6B,7B),(1D,2A)3B,4A,5B,6B,7C),(1D,2A,3B,4A,-
5B,6C,7A),(1D,2A,3B,4A,5B,6C,7B),(1D,2A,3B,4A,5B,6C,7C),
(1D,2A,3B,4A,5B,6D,7A),(1D,2A,3B,4A,5B,6D,7B),(1D,2A,3B,4A,5B,6D,7C),(1D,-
2A,3B,4B,5A,6A,7A),(1D,2A,3B,4B,5A,6A,7B),(1D,2A,3B,4B,5A,6A,7C),(1D,2A,3B-
,4B,5A,6B,7A),
(1D,2A,3B,4B,5A,6B,7B),(1D,2A,3B,4B,5A,6B,7C),(1D,2A,3B,4B,-
5A,6C,7A),(1D,2A,3B,4B,5A,6C,7B),(1D,2A,3B,4B,5A,6C,7C),(1D,2A,3B,4B,5A,6D-
,7A),(1D,2A,3B,4B,5A,6D,7B),
(1D,2A,3B,4B,5A,-6D,7C),(1D,2A,3B,4B,5B,6A,7A-
),(1D,2A,3B,4B,5B,6A,7B),(1D,2A,3B,4B,5B,6A,7C),(1D,2A,3B,4B,5B,6B,7A),(1D-
,2A,3B,4B,5B,6B,7B),(1D,2A,3B,4B,5B,6B,7C),
(1D,2A,3B,4B,5B,6C,7A),(1D,2A,-
3B,4B,5B,6C,7B),(1D,2A,3B,4B,5B,6C,7C),(1D,2A,3B,4B,5B,6D,7A),(1D,2A,3B,4B-
,5B,6D,7B),(1D,2A,3B,4B,5B,6D,7C),(1D,2A,3B,4C,5A,6A,7A),
(1D,2A,3B,4C,5A,6A,7B),(1D,2A,3B,4C,5A,6A,7C),(1D,2A,3B,4C,5A,6B,7A),(1D,-
2A,3B,4C,5A,6B,7B),(1D,2A,3B,4C,5A,6B,7C),(1D,2A,3B,4C,5A,6C,7A),(1D,2A,3B-
,4C,5A,6C,7B),
(1D,2A,3B,4C,5A,6C,7C),(1D,2A,3B,4C,5A,6D,7A),(1D,2A,3B,4C,-
5A,6D,7B),(1D,2A,3B,4C,5A,6D,7C),(1D,2A,3B,4C,5B,6A,7A),(1D,2A,3B,4C,5B,6A-
,7B),(1D,2A,3B,4C,5B,6A,7C),
(1D,2A,3B,4C,5B,6B,7A),(1D,2A,3B,4C,5B,6B,7B)-
,(1D,2A,3B,4C,5B,6B,7C),(1D,2A,3B,4C,5B,6C,7A),(1D,2A,3B,4C,5B,6C,7B),(1D,-
2A,3B,4C,5B,6C,7C),(1D,2A,3B,4C,5B,6D,7A),
(1D,2A,3B,4C,5B,6D,7B),(1D,2A,3-
B,4C,5B,6D,7C),(1D,2A,3B,4D,5A,6A,7A),(1D,2A,3B,4D,5A,6A,7B),(1D,2A,3B,4D,-
5A,6A,7C),(1D,2A,3B,4D,5A,6B,7A),(1D,2A,3B,4D,5A,6B,7B),
(1D,2A,3B,4D,5A,6B,7C),(1D,2A,3B,4D,5A,6C,7A),(0D,2A,3B,4D,5A,6C,7B),(1D,-
2A,3B,4D,5A,6C,7C),(1D,2A,3B,4D,5A,6D,7A),(1D,2A,3B,4D,5A,6D,7B),(1D,2A,3B-
,4D,5A,6D,7C),
(1D,2A,3B,4D,5B,6A,7A),(1D,2A,3B,4D,5B,6A,7B),(1D,2A,3B,4D,-
5B,6A,7C),(1D,2A,3B,4D,5B,6B,7A),(1D,2A,3B,4D,5B,6B,7B),(1D,2A,3B,4D,5B,6B-
,7C),(1D,2A,3B,4D,5B,6C,7A),
(1D,2A,3B,4D,5B,6C,7B),(1D,2A,3B,4D,5B,6C,7C)-
,(1D,2A,3B,4D,5B,6D,7A),(1D,2A,3B,4D,5B,6D,7B),(1D,2A,3B,4D,5B,6D,7C),(1D,-
2A,3B,4E,5A,6A,7A),(1D,2A,3B,4E,5A,6A,7B),
(1D,2A,3B,4E,5A,6A,7C),(1D,2A,3-
B,4E,5A,6B,7A),(1D,2A,3B,4E,5A,6B,7B),(1D,2A,3B,4E,5A,6B,7C),(1D,2A,3B,4E,-
5A,6C,7A),(1D,2A,3B,4E,5A,6C,7B),(1D,2A,3B,4E,5A,6C,7C),
(1D,2A,3B,4E,5A,6D,7A),(1D,2A,3B,4E,5A,6D,7B),(1D,2A,3B,4E,5A,6D,7C),(1D,-
2A,3B,4E,5B,6A,7A),(1D,2A,3B,4E,5B,6A,7B),(1D,2A,3B,4E,5B,6A,7C),(1D,2A,3B-
,4E,5B,6B,7A),
(1D,2A,3B,4E,5B,6B,7B),(1D,2A,3B,4E,5B,6B,7C),(1D,2A,3B,4E,-
5B,6C,7A),(1D,2A,3B,4E,5B,6C,7B),(1D,2A,3B,4E,5B,6C,7C),(1D,2A,3B,4E,5B,6D-
,7A),(1D,2A,3B,4E,5B,6D,7B),
(1D,2A,3B,4E,5B,6D,7C),(1D,2A,3C,4A,5A,6A,7A)-
,(1D,2A,3C,4A,5A,6A,7B),(1D,2A,3C,4A,5A,6A,7C),(1D,2A,3C,4A,5A,6B,7A),(1D,-
2A,3C,4A,5A,6B,7B),(1D,2A,3C,4A,5A,6B,7C),
(1D,2A,3C,4A,5A,6C,7A),(1D,2A,3-
C,4A,5A,6C,7B),(1D,2A,3C,4A,5A,6C,7C),(1D,2A,3C,4A,5A,6D,7A),(1D,2A,3C,4A,-
5A,6D,7B),(1D,2A,3C,4A,5A,6D,7C),(1D,2A,3C,4A,5B,6A,7A),
(1D,2A,3C,4A,5B,6A,7B),(1D,2A,3C,4A,5B,6A,7C),(1D,2A,3C,4A,5B,6B,7A),(1D,-
2A,3C,4A,5B,6B,7B),(1D,2A,3C,4A,5B,6B,7C),(1D,2A,3C,4A,5B,6C,7A),(1D,2A,3C-
,4A,5B,6C,7B),
(1D,2A,3C,4A,5B,6C,7C),(1D,2A,3C,4A,5B,6D,7A),(1D,2A,3C,4A,-
5B,6D,7B),(1D,2A,3C,4A,5B,6D,7C),(1D,2A,3C,4B,5A,6A,7A),(1D,2A,3C,4B,5A,6A-
,7B),(1D,2A,3C,4B,5A,6A,7C),
(1D,2A,3C,4B,5A,6B,7A),(1D,2A,3C,4B,5A,6B,7B)-
,(1D,2A,3C,4B,5A,6B,7C),(1D,2A,3C,4B,5A,6C,7A),(1D,2A,3C,4B,5A,6C,7B),(1D,-
2A,3C,4B,5A,6C,7C),(1D,2A,3C,4B,5A,6D,7A),
(1D,2A,3C,4B,5A,6D,7B),(1D,2A,3-
C,4B,5A,6D,7C),(1D,2A,3C,4B,5B,6A,7A),(1D,2A,3C,4B,5B,6A,7B),(1D,2A,3C,4B,-
5B,6A,7C),(1D,2A,3C,4B,5B,6B,7A),(1D,2A,3C,4B,5B,6B,7B),
(1D,2A,3C,4B,5B,6B,7C),(1D,2A,3C,4B,5B,6C,7A),(1D,2A,3C,4B,5B,6C,7B),(1D,-
2A,3C,4B,5B,6C,7C),(1D,2A,3C,4B,5B,6D,7A),(1D,2A,3C,4B,5B,6D,7B),(1D,2A,3C-
,4B,5B,6D,7C),
(1D,2A,3C,4C,5A,6A,7A),(1D,2A,3C,4C,5A,6A,7B),(1D,2A,3C,4C,-
5A,6A,7C),(1D,2A,3C,4C,5A,6B,7A),(1D,2A,3C,4C,5A,6B,7B),(1D,2A,3C,4C,5A,6B-
,7C),(1D,2A,3C,4C,5A,6C,7A),
(1D,2A,3C,4C,5A,6C,7B),(1D,2A,3C,4C,5A,6C,7C)-
,(1D,2A,3C,4C,5A,6D,7A),(1D,2A,3C,4C,5A,6D,7B),(1D,2A,3C,4C,5A,6D,7C),(1D,-
2A,3C,4C,5B,6A,7A),(1D,2A,3C,4C,5B,6A,7B),
(1D,2A,3C,4C,5B,6A,7C),(1D,2A,3-
C,4C,5B,6B,7A),(1D,2A,3C,4C,5B,6B,7B),(1D,2A,3C,4C, 5B,6B,7C),
(1D,2A,3C,4C,5B,6C,7A),(1D,2A,3C,4C,5B,6C,7B),(1D,2A,3C,4C,5B,6C,7C),
(1D,2A,3C,4C,5B,6D,7A), (1D,2A,3C,4C,5B,6D,7B),
(1D,2A,3C,4C,5B,6D,7C), (1D,2A,3C,4D,5A,6A,7A),
(1D,2A,3C,4D,5A,6A,7B), (1D,2A,3C,4D,5A,6A,7C),
(1D,2A,3C,4D,5A,6B,7A), (1D,2A,3C,4D,5A,6B,7B),
(1D,2A,3C,4D,5A,6B,7C), (1D,2A,3C,4D,5A,6C,7A),
(1D,2A,3C,4D,5A,6C,7B), (1D,2A,3C,4D,5A,6C,7C),(1-
D,2A,3C,4D,5A,6D,7A),(1D,2A,3C,4D,5A,6D,7B),
(1D,2A,3C,4D,5A,6D,7C), (1D,2A,3C,4D,5B,6A,7A),
(1D,2A,3C,4D,5B,6A,7B), (1D,2A,3C,4D,5B,6A,7C),
(1D,2A,3C,4D,5B,6B,7A),(1D,2A,3C,4D,5B,6B,7B),
(1D,2A,3C,4D,5B,6B,7C),
(1D,2A,3C,4D,5B,6C,7A),(1D,2A,3C,4D,5B,6C,7B),(1D,2A,3C,4D,5B,6C,7C),(1D,-
2A,3C,4D,5B,6D,7A),(1D,2A,3C,4D,5B,6D,7B),(1D,2A,3C,4D,5B,6D,7C),(1D,2A,3C-
,4E,5A,6A,7A),
(1D,2A,3C,4E,5A,6A,7B),(1D,2A,3C,4E,5A,6A,7C),(1D,2A,3C,4E,-
5A,6B,7A),(1D,2A,3C,4E,5A,6B,7B),(1D,2A,3C,4E,5A,6B,7C),(1D,2A,3C,4E,5A,6C-
,7A),(1D,2A,3C,4E,5A,6C,7B),
(1D,2A,3C,4E,5A,6C,7C),(1D,2A,3C,4E,5A,6D,7A)-
,(1D,2A,3C,4E,5A,6D,7B),(1D,2A,3C,4E,5A,6D,7C),(1D,2A,3C,4E,5B,6A,7A),(1D,-
2A,3C,4E,5B,6A,7B),(1D,2A,3C,4E,5B,6A,7C),
(1D,2A,3C,4E,5B,6B,7A),(1D,2A,3-
C,4E,5B,6B,7B),(1D,2A,3C,4E,5B,6B,7C),(1D,2A,3C,4E,5B,6C,7A),(1D,2A,3C,4E,-
5B,6C,7B),(1D,2A,3C,4E,5B,6C,7C),(1D,2A,3C,4E,5B,6D,7A),
(1D,2A,3C,4E,5B,6D,7B),(1D,2A,3C,4E,5B,6D,7C),(1D,2A,3D,4A,5A,6A,7A),(1D,-
2A,3D,4A,5A,6A,7B),(1D,2A,3D,4A,5A,6A,7C),(1D,2A,3D,4A,5A,6B,7A),(1D,2A,3D-
,4A,5A,6B,7B),
(1D,2A,3D,4A,5A,6B,7C),(1D,2A,3D,4A,5A,6C,7A),(1D,2A,3D,4A,-
5A,6C,7B),(1D,2A,3D,4A,5A,6C,7C),(1D,2A,3D,4A,5A,6D,7A),(1D,2A,3D,4A,5A,6D-
,7B),
(1D,2A,3D,4A,5A,6D,7C),(1D,2A,3D,4A,5B,6A,7A),(1D,2A,3D,4A,5B,6A,7B)-
,(1D,2A,3D,4A,5B,6A,7C),(1D,2A,3D,4A,5B,6B,7A),(1D,2A,3D,4A,5B,6B,7B),(1D,-
2A,3D,4A,5B,6B,7C),
(1D,2A,3D,4A,5B,6C,7A),(1D,2A,3D,4A,5B,6C,7B),(1D,2A,3-
D,4A,5B,6C,7C),(1D,2A,3D,4A,5B,6D,7A),(1D,2A,3D,4A,5B,6D,7B),(1D,2A,3D,4A,-
5B,6D,7C),(1D,2A,3D,4B,5A,6A,7A),
(1D,2A,3D,4B,5A,6A,7B),(1D,2A,3D,4B,5A,6-
A,7C),(1D,2A,3D,4B,5A,6B,7A),(1D,2A,3D,4B,5A,6B,7B),(1D,2A,3D,4B,5A,6B,7C)-
,(1D,2A,3D,4B,5A,6C,7A),(1D,2A,3D,4B,5A,6C,7B),
(1D,2A,3D,4B,5A,6C,7C),(1D-
,2A,3D,4B,5A,6D,7A),(1D,2A,3D,4B,5A,6D,7B),(1D,2A,3D,4B,5A,6D,7C),(1D,2A,3-
D,4B,5B,6A,7A),(1D,2A,3D,4B,5B,6A,7B),(1D,2A,3D,4B,5B,6A,7C),
(1D,2A,3D,4B,5B,6B,7A),(1D,2A,3D,4B,5B,6B,7B),(1D,2A,3D,4B,5B,6B,7C),(1D,-
2A,3D,4B,5B,6C,7A),(1D,2A,3D,4B,5B,6C,7B),(1D,2A,3D,4B,5B,6C,7C),(1D,2A,3D-
,4B,5B,6D,7A),
(1D,2A,3D,4B,5B,6D,7B),(1D,2A,3D,4B,5B,6D,7C),(1D,2A,3D,4C,-
5A,6A,7A),(1D,2A,3D,4C,5A,6A,7B), (1D,2A,3D,4C,5A,6A,7C),
(1D,2A,3D,4C,5A,6B,7A),(1D,2A,3D,4C,5A,6B,7B),
(1D,2A,3D,4C,5A,6B,7C), (1D,2A,3D,4C,5A,6C,7A),
(1D,2A,3D,4C,5A,6C,7B),(1D,2A,3D,4C,5A,6C,7C),
(D,2A,3D,4C,5A,6D,7A),(1D,2A,3D,4C,5A,6D,7B),(1D,2A,3D,4C,5A,6D,7C),
(1D,2A,3D,4C,5B,6A,7A),(1D,2A,3D,4C,5B,6A,7B),
(1D,2A,3D,4C,5B,6A,7C),(1D- ,2A,3D,4C,5B,6B,7A),
(1D,2A,3D,4C,5B,6B,7B),(1D,2A,3D,4C,5B,6B,7C),(1D,2A,-
3D,4C,5B,6C,7A), (1D,2A,3D,4C,5B,6C,7B), (1D,2A,3D,4C,5B,6C,7C),
(1D,2A,3D,4C,5B,6D, 7A),
(1D,2A,3D,4C,5B,6D,7B),(1D,2A,3D,4C,5B,6D,7C),(1-
D,2A,3D,4D,5A,6A,7A),(1D,2A,3D,4D,5A,6A,7B),
(1D,2A,3D,4D,5A,6A,7C), (1D,2A,3D,4D,5A,6B,7A),
(1D,2A,3D,4D,5A,6B,7B), (1D,2A,3D,4D,5A,6B,7C),
(1D,2A,3D,4D,5A,6C,7A),(1D,2A,3D,4D,5A,6C,7B),(1D,2A,3D,4D,5A,6C,7C),
(1D,2A,3D,4D,5A,6D,7A), (1D,2A,3D,4D,5A,6D,7B),
(1D,2A,3D,4D,5A,6D,7C),(1- D,2A,3D,4D,5B,6A,7A),
(1D,2A,3D,4D,5B,6A,7B), (1D,2A,3D,4D,5B,6A,7C),
(1D,2A,3D,4D,5B,6B,7A), (1D,2A,3D,4D,5B,6B,7B),
(1D,2A,3D,4D,5B,6B,7C), (1D,2A,3D,4D,5B,6C,7A),
(1D,2A,3D,4D,5B,6C,7B), (1D,2A,3D,4D,5B,6C,7C),
(1D,2A,3D,4D,5B,6D,7A), (1D,2A,3D,4D,5B,6D,7B),
(1D,2A,3D,4D,5B,6D,7C),(1- D,2A,3D,4E,5A,6A,7A),(1D,2A,3D,4E,5A,6A,
7B), (1D,2A,3D,4E,5A,6A,7C),
(1D,2A,3D,4E,5A,6B,7A),(1D,2A,3D,4E,5A,6B,7B),(1D,2A,3D,4E,5A,6B,7C),
(1D,2A,3D,4E,5A,6C,7A),
(1D,2A,3D,4E,5A,6C,7B),(1D,2A,3D,4E,5A,6C,7C),
(1D,2A,3D,4E,5A,6D,7A),(1D,2A,3D,4E,5A,6D,7B),
(1D,2A,3D,4E,5A,6D,7C),(1D- ,2A,3D,4E,5B,6A,7A),
(1D,2A,3D,4E,5B,6A,7B), (1D,2A,3D,4E,5B,6A,7C),
(1D,2A,3D,4E,5B,6B,7A), (D,2A,3D,4E,5B,6B,7B),
(1D,2A,3D,4E,5B,6B,7C),(1D-
,2A,3D,4E,5B,6C,7A),(1D,2A,3D,4E,5B,6C,7B), (1D,2A,3D,4E,5B,6C,7C),
(1D,2A,3D,4E,5B,6D,7A), (1D,2A,3D,4E,5B,6D, 7B),
(1D,2A,3D,4E,5B,6D,7C), (1D,2A,3E,4A,5A,6A,7A),
(D,2A,3E,4A,5A,6A,7B),(1D,2A,3E,4A,5A,6A,7C), (1D,2A,3E,4A, 5A,6B,
7A), (1D,2A,3E,4A, 5A, 6B, 7B), (1D,2A,3E,4A, 5A, 6B, 7C),
(1D,2A,3E,4A,5A,6C,7A), (1D,2A,3E,4A,5A,6C,7B),(1D,2A,3E,4A,5A,6-
C,7C),(1D,2A,3E,4A,5A,6D,7A), (1D,2A,3E,4A,5A,6D,7B),
(1D,2A,3E,4A,5A,6D,7C), (1D,2A,3E,4A,5B,6A,7A),
(1D,2A,3E,4A,5B,6A,7B),
(1D,2A,3E,4A,5B,6A,7C),(1D,2A,3E,4A,5B,6B,7A),(1D,2A,3E,4A,5B,6B,7B),
(1D,2A,3E,4A,5B,6B,7C), (1D,2A,3E,4A,5B,6C,7A),
(1D,2A,3E,4A,5B,6C,7B), (1D,2A,3E,4A,5B,6C,7C),
(1D,2A,3E,4A,5B,6D,7A),(1D,2A,3E,4A,5B,6D,7B),(1D-
,22A,3E,4A,5B,6D,7C), (1D,2A,3E,4B,5A,6A,7A),
(1D,2A,3E,4B,5A,6A,7B), (1D,2A,3E,4B,5A,6A,7C),
(1D,2A,3E,4B,5A,6B,7A), (1D,2A,3E,4B,5A,6B,7B),
(1D,2A,3E,4B,5A,6B,7C), (1D,2A,3E,4B,5A,6C,7A),
(1D,2A,3E,4B,5A,6C,7B),(1- D,2A,3E,4B,5A,6C,7C),
(1D,2A,3E,4B,5A,6D,7A), (1D,2A,3E,4B,5A,6D,7B),
(1D,2A,3E,4B,5A,6D,7C),(1D,2A,3E,4B,5B,6A,7A),(1D,2A,3E,4B,5B,6A,7B),
(1D,2A,3E,4B,5B,6A,7C), (1D,2A,3E,4B,5B,6B,7A),
(1D,2A,3E,4B,5B,6B,7B), (1D,2A,3E,4B,5B,6B,7C),
(1D,2A,3E,4B,5B,6C,7A),(1D,2A,3E,4B,5B,6C,7B),(1D-
,2A,3E,4B,5B,6C,7C), (1D,2A,3E,4B,5B,6D,7A),
(1D,2A,3E,4B,5B,6D,7B), (1D,2A,3E,4B,5B,6D, 7C),
(1D,2A,3E,4C,5A,6A,7A), (1D,2A,3E,4C,5A,6A,7B),(-
1D,2A,3E,4C,5A,6A,7C),(1D,2A,3E,4C,5A,6B,7A),
(1D,2A,3E,4C,5A,6B,7B),(1D,2-
A,3E,4C,5A,6B,7C),(1D,2A,3E,4C,5A,6C,7A),(1D,2A,3E,4C,5A,6C,7B),(1D,2A,3E,-
4C,5A,6C,7C),(1D,2A,3E,4C,5A,6D,7A),(1D,2A,3E,4C,5A,6D,7B),
(1D,2A,3E,4C,5A,6D,7C),(1D,2A,3E,4C,5B,6A,7A),(1D,2A,3E,4C,5B,6A,7B),(1D,-
2A,3E,4C,5B,6A,7C),(1D,2A,3E,4C,5B,6B,7A),(1D,2A,3E,4C,5B,6B,7B),(1D,2A,3E-
,4C,5B,6B,7C),
(1D,2A,3E,4C,5B,6C,7A),(1D,2A,3E,4C,5B,6C,7B),(1D,2A,3E,4C,-
5B,6C,7C),(1D,2A,3E,4C,5B,6D,7A),(1D,2A,3E,4C,5B,6D,7B),(1D,2A,3E,4C,5B,6D-
,7C),(1D,2A,3E,4D,5A,6A,7A),
(1D,2A,3E,4D,5A,6A,7B),(1D,2A,3E,4D,5A,6A,7C)-
,(1D,2A,3E,4D,5A,6B,7A),(1D,2A,3E,4D,5A,6B,7B),(1D,2A,3E,4D,5A,6B,7C),(1D,-
2A,3E,4D,5A,6C,7A),(1D,2A,3E,4D,5A,6C,7B),
(1D,2A,3E,4D,5A,6C,7C),(1D,2A,3-
E,4D,5A,6D,7A),(1D,2A,3E,4D,5A,6D,7B),(1D,2A,3E,4D,5A,6D,7C),(1D,2A,3E,4D,-
5B,6A,7A),(1D,2A,3E,4D,5B,6A,7B),(1D,2A,3E,4D,5B,6A,7C),
(1D,2A,3E,4D,5B,6B,7A),(1D,2A,3E,4D,5B,6B,7B),(1D,2A,3E,4D,5B,6B,7C),(1D,-
2A,3E,4D,5B,6C,7A),(1D,2A,3E,4D,5B,6C,7B),(1D,2A,3E,4D,5B,6C,7C),(1D,2A,3E-
,4D,5B,6D,7A),
(1D,2A,3E,4D,5B,6D,7B),(1D,2A,3E,4D,5B,6D,7C),(1D,2A,3E,4E,-
5A,6A,7A),(1D,2A,3E,4E,5A,6A,7B),(1D,2A,3E,4E,5A,6A,7C),(1D,2A,3E,4E,5A,6B-
,7A),(1D,2A,3E,4E,5A,6B,7B),
(1D,2A,3E,4E,5A,6B,7C),(1D,2A,3E,4E,5A,6C,7A)-
,(1D,2A,3E,4E,5A,6C,7B),(1D,2A,3E,4E,5A,6C,7C),(1D,2A,3E,4E,5A,6D,7A),(1D,-
2A,3E,4E,5A,6D,7B),(1D,2A,3E,4E,5A,6D,7C),
(1D,2A,3E,4E,5B,6A,7A),(1D,2A,3-
E,4E,5B,6A,7B),(1D,2A,3E,4E,5B,6A,7C),(1D,2A,3E,4E,5B,6B,7A),(1D,2A,3E,4E,-
5B,6B,7B),(1D,2A,3E,4E,5B,6B,7C),(1D,2A,3E,4E,5B,6C,7A),
(1D,2A,3E,4E,5B,6C,7B),(1D,2A,3E,4E,5B,6C,7C),(1D,2A,3E,4E,5B,6D,7A),(1D,-
2A,3E,4E,5B,6D,7B),(1D,2A,3E,4E,5B,6D,7C),(1D,2B,3A,4A,5A,6A,7A),(1D,2B,3A-
,4A,5A,6A,7B),
(1D,2B,3A,4A,5A,6A,7C),(1D,2B,3A,4A,5A,6B,7A),(1D,2B,3A,4A,-
5A,6B,7B),(1D,2B,3A,4A,5A,6B,7C),(1D,2B,3A,4A,5A,6C,7A),(1D,2B,3A,4A,5A,6C-
,7B),(1D,2B,3A,4A,5A,6C,7C),
(1D,2B,3A,4A,5A,6D,7A),(1D,2B,3A,4A,5A,6D,7B)-
,(1D,2B,3A,4A,5A,6D,7C),(1D,2B,3A,4A,5B,6A,7A),(1D,2B,3A,4A,5B,6A,7B),(1D,-
2B,3A,4A,5B,6A,7C),(1D,2B,3A,4A,5B,6B,7A),
(1D,2B,3A,4A,5B,6B,7B),(1D,2B,3-
A,4A,5B,6B,7C),(1D,2B,3A,4A,5B,6C,7A),(0D,2B,3A,4A,5B,6C,7B),
(1D,2B,3A,4A,5B,6C,7C), (1D,2B,3A,4A,5B,6D,7A),
(1D,2B,3A,4A,5B,6D,7B),
(1D,2B,3A,4A,5B,6D,7C),(1D,2B,3A,4B,5A,6A,7A),(1D,2B,3A,4B,5A,6A,7B),(1D,-
2B,3A,4B,5A,6A,7C),(1D,2B,3A,4B,5A,6B,7A),(1D,2B,3A,4B,5A,6B,7B),(1D,2B,3A-
,4B,5A,6B,7C),
(1D,2B,3A,4B,5A,6C,7A),(1D,2B,3A,4B,5A,6C,7B),(1D,2B,3A,4B,-
5A,6C,7C),(1D,2B,3A,4B,5A,6D,7A),(1D,2B,3A,4B,5A,6D,7B),(1D,2B,3A,4B,5A,6D-
,7C),(1D,2B,3A,4B,5B,6A,7A),
(1D,2B,3A,4B,5B,6A,7B),(1D,2B,3A,4B,5B,6A,7C)-
,(1D,2B,3A,4B,5B,6B,7A),(1D,2B,3A,4B,5B,6B,7B),(1D,2B,3A,4B,5B,6B,7C),(1D,-
2B,3A,4B,5B,6C,7A),(1D,2B,3A,4B,5B,6C,7B),
(1D,2B,3A,4B,5B,6C,7C),(1D,2B,3-
A,4B,5B,6D,7A),(1D,2B,3A,4B,5B,6D,7B),(1D,2B,3A,4B,5B,6D,7C),(1D,2B,3A,4C,-
5A,6A,7A),(1D,2B,3A,4C,5A,6A,7B),(1D,2B,3A,4C,5A,6A,7C),
(1D,2B,3A,4C,5A,6B,7A),(1D,2B,3A,4C,5A,6B,7B),(1D,2B,3A,4C,5A,6B,7C),(1D,-
2B,3A,4C,5A,6C,7A),(1D,2B,3A,4C,5A,6C,7B),(1D,2B,3A,4C,5A,6C,7C),(1D,2B,3A-
,4C,5A,6D,7A),
(1D,2B,3A,4C,5A,6D,7B),(1D,2B,3A,4C,5A,6D,7C),(1D,2B,3A,4C,-
5B,6A,7A),(1D,2B,3A,4C,5B,6A,7B),(1D,2B,3A,4C,5B,6A,7C),(1D,2B,3A,4C,5B,6B-
,7A),(1D,2B,3A,4C,5B,6B,7B),
(1D,2B,3A,4C,5B,6B,7C),(1D,2B,3A,4C,5B,6C,7A)-
,(1D,2B,3A,4C,5B,6C,7B),(1D,2B,3A,4C,5B,6C,7C),(1D,2B,3A,4C,5B,6D,7A),(1D,-
2B,3A,4C,5B,6D,7B),(1D,2B,3A,4C,5B,6D,7C),
(1D,2B,3A,4D,5A,6A,7A),(1D,2B,3-
A,4D,5A,6A,7B),(1D,2B,3A,4D,5A,6A,7C),(1D,2B,3A,4D,5A,6B,7A),(1D,2B,3A,4D,-
5A,6B,7B),(1D,2B,3A,4D,5A,6B,7C),(1D,2B,3A,4D,5A,6C,7A),
(1D,2B,3A,4D,5A,6C,7B),(1D,2B,3A,4D,5A,6C,7C),(1D,2B,3A,4D,5A,6D,7A),(1D,-
2B,3A,4D,5A,6D,7B),(1D,2B,3A,4D,5A,6D,7C),(1D,2B,3A,4D,5B,6A,7A),(1D,2B,3A-
,4D,5B,6A,7B),
(1D,2B,3A,4D,5B,6A,7C),(1D,2B,3A,4D,5B,6B,7A),(1D,2B,3A,4D,-
5B,6B,7B),(1D,2B,3A,4D,5B,6B,7C),(1D,2B,3A,4D,5B,6C,7A),(1D,2B,3A,4D,5B,6C-
,7B),(1D,2B,3A,4D,5B,6C,7C),
(1D,2B,3A,4D,5B,6D,7A),(1D,2B,3A,4D,5B,6D,7B)-
,(1D,2B,3A,4D,5B,6D,7C),(1D,2B,3A,4E,5A,6A,7A),(1D,2B,3A,4E,5A,6A,7B),(1D,-
2B,3A,4E,5A,6A,7C),(1D,2B,3A,4E,5A,6B,7A),
(1D,2B,3A,4E,5A,6B,7B),(1D,2B,3-
A,4E,5A,6B,7C),(1D,2B,3A,4E,5A,6C,7A),(1D,2B,3A,4E,5A,6C,7B),(1D,2B,3A,4E,-
5A,6C,7C),(1D,2B,3A,4E,5A,6D,7A),(1D,2B,3A,4E,5A,6D,7B),
(1D,2B,3A,4E,5A,6D,7C),(1D,2B,3A,4E,5B,6A,7A),(1D,2B,3A,4E,5B,6A,7B),(1D,-
2B,3A,4E,5B,6A,7C),(1D,2B,3A,4E,5B,6B,7A),(1D,2B,3A,4E,5B,6B,7B),(1D,2B,3A-
,4E,5B,6B,7C),
(1D,2B,3A,4E,5B,6C,7A),(1D,2B,3A,4E,5B,6C,7B),(1D,2B,3A,4E,-
5B,6C,7C),(1D,2B,3A,4E,5B,6D,7A),(1D,2B,3A,4E,5B,6D,7B),(1D,2B,3A,4E,5B,6D-
,7C),(1D,2B,3B,4A,5A,6A,7A),
(1D,2B,3B,4A,5A,6A,7B),(1D,2B,3B,4A,5A,6A,7C)-
,(1D,2B,3B,4A,5A,6B,7A),(1D,2B,3B,4A,5A,6B,7B),(1D,2B,3B,4A,5A,6B,7C),(1D,-
2B,3B,4A,5A,6C,7A),(1D,2B,3B,4A,5A,6C,7B), (1D,2B,3B,4A,5A,6C,7C),
(1D,2B,3B,4A,5A,6D,7A),(1D,2B,3B,4A,5A,6D, 7B), (1D,2B,3B,4A,5A,6D,
7C), (1D,2B,3B,4A,5B,6A, 7A), (1D,2B,3B,4A,5B,6A, 7B),
(1D,2B,3B,4A,5B,6A,7C), (1D,2B,3B,4A,5B,6B,7A),
(1D,2B,3B,4A,5B,6B,7B), (1D,2B,3B,4A,5B,6B,7C),
(1D,2B,3B,4A,5B,6C,7A),(1D,2B,3B,4A,5B,6C,7B),(1D,2B,3B,4A,5B,6C,7C),(1D,-
2B,3B,4A,5B,6D,7A), (1D,2B, 3B,4A,5B,6D,7B), (1D,2B, 3B,4A, 5B,
6D,7C), (1D,2B,3B,4B,5A, 6A, 7A), (1D,2B,3B,4B,5A,6A,7B),
(D,2B,3B,4B,5A,6A,7C),(-
1D,2B,3B,4B,5A,6B,7A),(1D,2B,3B,4B,5A,6B,7B),
(1D,2B,3B,4B,5A,6B,7C), (1D,2B,3B,4B,5A,6C,7A),
(1D,2B,3B,4B,5A,6C,7B), (1D,2B,3B,4B,5A,6C,7C),(1-
D,2B,3B,4B,5A,6D,7A),(1D,2B,3B,4B,5A,6D,7B),
(1D,2B,3B,4B,5A,6D,7C), (1D,2B,3B,4B,5B,6A,7A),
(1D,2B,3B,4B,5B,6A,7B),(1D,2B,3B,4B,5B,6A,7C),
(1D,2B,3B,4B,5B,6B,7A),(1D,2B,3B,4B,5B,6B,7B),(1D,2B,3B,4B,5B,6B,7C),(1D,-
2B,3B,4B,5B,6C,7A), (1D,2B,3B,4B,5B,6C, 7B),
(1D,2B,3B,4B,5B,6C,7C),(1D,2B-
,3B,4B,5B,6D,7A),(1D,2B,3B,4B,5B,6D,7B),
(1D,2B,3B,4B,5B,6D,7C),(1D,2B,3B,- 4C,5A,6A,7A),
(1D,2B,3B,4C,5A,6A, 7B), (1D,2B,3B,4C,5A,6A,7C),
(1D,2B,3B,4C,5A,6B,7A), (1D,2B,3B,4C,5A,6B,7B),
(1D,2B,3B,4C,5A,6B,7C),(1-
D,2B,3B,4C,5A,6C,7A),(1D,2B,3B,4C,5A,6C,7B),(1D,2B,3B,4C,5A,6C,7C),
(1D,2B,3B,4C,5A,6D,7A),(1D,2B,3B,4C,5A,6D,7B),
(1D,2B,3B,4C,5A,6D,7C), (1D,2B,3B,4C,5B,6A,7A),
(1D,2B,3B,4C,5B,6A,7B), (1D,2B,3B,4C,5B,6A,7C),(1-
D,2B,3B,4C,5B,6B,7A), (1D,2B,3B,4C,5B,6B,7B),
(1D,2B,3B,4C,5B,6B,7C),
(1D,2B,3B,4C,5B,6C,7A),(1D,2B,3B,4C,5B,6C,7B),
(1D,2B,3B,4C,5B,6C,7C),(1D-
,2B,3B,4C,5B,6D,7A),(1D,2B,3B,4C,5B,6D,7B), (1D,2B,3B,4C,5B,6D,7C),
(1D,2B,3B,4D,5A,6A,7A), (1D,2B,3B,4D,5A,6A,7B),
(1D,2B,3B,4D,5A,6A,7C), (1D,2B,3B,4D,5A,6B,7A),
(1D,2B,3B,4D,5A,6B,7B), (1D,2B,3B,4D,5A,6B,7C),
(1D,2B,3B,4D,5A,6C,7A), (1D,2B,3B,4D,5A,6C, 7B),
(1D,2B,3B,4D,5A,6C, 7C), (1D,2B,3B,4D,5A,6D,7A),
(1D,2B,3B,4D,5A,6D,7B),(1D,2B,3B,4D,5A,6D,7C),
(1D,2B,3B,4D,5B,6A,7A),
(1D,2B,3B,4D,5B,6A,7B),(1D,2B,3B,4D,5B,6A,7C),(1D-
,2B,3B,4D,5B,6B,7A), (1D,2B,3B,4D,5B,6B,7B),
(1D,2B,3B,4D,5B,6B,7C),(1D,2B-
,3B,4D,5B,6C,7A),(1D,2B,3B,4D,5B,6C,7B), (1D,2B,3B,4D,5B,6C,7C),
(1D,2B,3B,4D,5B,6D,7A),
(1D,2B,3B,4D,5B,6D,7B),(1D,2B,3B,4D,5B,6D,7C),
(1D,2B,3B,4E,5A,6A,7A),(1D,2B,3B,4E,5A,6A,7B),(1D,2B,3B,4E,5A,6A,7C),
(1D,2B,3B,4E,5A,6B,7A), (1D,2B,3B,4E,5A,6B,7B),
(1D,2B,3B,4E,5A,6B,7C),(1- D,2B,3B,4E,5A,6C,7A),
(1D,2B,3B,4E,5A,6C,7B),(1D,2B,3B,4E,5A,6C,7C),(1D,2B-
,3B,4E,5A,6D,7A), (1D,2B,3B,4E,5A,6D,7B),
(1D,2B,3B,4E,5A,6D,7C),(1D,2B,3B- ,4E,5B,6A,7A),
(1D,2B,3B,4E,5B-6A,7B), (1D,2B,3B,4E,5B,6A,7C),
(1D,2B,3B,4E,5B,6B,7A), (1D,2B,3B,4E,5B,6B,7B),
(1D,2B,3B,4E,5B,6B,7C), (1D,2B,3B,4E,5B,6C,7A),
(1D,2B,3B,4E,5B,6C,7B), (1D,2B,3B,4E,5B,6C,7C),(1-
D,2B,3B,4E,5B,6D,7A),(1D,2B,3B,4E,5B,6D,7B),(1D,2B,3B,4E,5B,6D,7C),
(1D,2B,3C,4A,5A,6A,7A),(1D,2B,3C,4A,5A,6A,7B),(1D,2B,3C,4A,5A,6A,7C),(1D,-
2B,3C,4A,5A,6B,7A),(1D,2B,3C,4A,5A,6B,7B),(1D,2B,3C,4A,5A,6B,7C),
(1D,2B,3C,4A,5A,6C,7A),(1D,2B,3C,4A,5A,6C,7B),(1D,2B,3C,4A,5A,6C,7C),(1D,-
2B,3C,4A,5A,6D,7A),(1D,2B,3C,4A,5A,6D,7B),(1D,2B,3C,4A,5A,6D,7C),(1D,2B,3C-
,4A,5B,6A,7A),
(1D,2B,3C,4A,5B,6A,7B),(1D,2B,3C,4A,5B,6A,7C),(1D,2B,3C,4A,-
5B,6B,7A),(1D,2B,3C,4A,5B,6B,7B),(1D,2B,3C,4A,5B,6B,7C),(1D,2B,3C,4A,5B,6C-
,7A),(1D,2B,3C,4A,5B,6C,7B),
(1D,2B,3C,4A,5B,6C,7C),(1D,2B,3C,4A,5B,6D,7A)-
,(1D,2B,3C,4A,5B,6D,7B),(1D,2B,3C,4A,5B,6D,7C),(1D,2B,3C,4B,5A,6A,7A),(1D,-
2B,3C,4B,5A,6A,7B),(1D,2B,3C,4B,5A,6A,7C),
(1D,2B,3C,4B,5A,6B,7A),(1D,2B,3-
C,4B,5A,6B,7B),(1D,2B,3C,4B,5A,6B,7C),(1D,2B,3C,4B,5A,6C,7A),(1D,2B,3C,4B,-
5A,6C,7B),(1D,2B,3C,4B,5A,6C,7C),(1D,2B,3C,4B,5A,6D,7A),
(1D,2B,3C,4B,5A,6D,7B),(1D,2B,3C,4B,5A,6D,7C),(1D,2B,3C,4B,5B,6A,7A),(1D,-
2B,3C,4B,5B,6A,7B),(1D,2B,3C,4B,5B,6A,7C),(1D,2B,3C,4B,5B,6B,7A),(1D,2B,3C-
,4B,5B,6B,7B),
(1D,2B,3C,4B,5B,6B,7C),(1D,2B,3C,4B,5B,6C,7A),(1D,2B,3C,4B,-
5B,6C,7B),(1D,2B,3C,4B,5B,6C,7C),(1D,2B,3C,4B,5B,6D,7A),(1D,2B,3C,4B,5B,6D-
,7B),(1D,2B,3C,4B,5B,6D,7C),
(1D,2B,3C,4C,5A,6A,7A),(1D,2B,3C,4C,5A,6A,7B)-
,(1D,2B,3C,4C,5A,6A,7C),(1D,2B,3C,4C,5A,6B,7A),(1D,2B,3C,4C,5A,6B,7B),(1D,-
2B,3C,4C,5A,6B,7C),(1D,2B,3C,4C,5A,6C,7A),
(1D,2B,3C,4C,5A,6C,7B),(1D,2B,3-
C,4C,5A,6C,7C),(1D,2B,3C,4C,5A,6D,7A),(1D,2B,3C,4C,5A,6D,7B),(1D,2B,3C,4C,-
5A,6D,7C),(1D,2B,3C,4C,5B,6A,7A),(1D,2B,3C,4C,5B,6A,7B),
(1D,2B,3C,4C,5B,6A,7C),(1D,2B,3C,4C,5B,6B,7A),(1D,2B,3C,4C,5B,6B,7B),(1D,-
2B,3C,4C,5B,6B,7C),(1D,2B,3C,4C,5B,6C,7A),(1D,2B,3C,4C,5B,6C,7B),(1D,2B,3C-
,4C,5B,6C,7C),
(1D,2B,3C,4C,5B,6D,7A),(1D,2B,3C,4C,5B,6D,7B),(1D,2B,3C,4C,-
5B,6D,7C),(1D,2B,3C,4D,5A,6A,7A),(1D,2B,3C,4D,5A,6A,7B),(1D,2B,3C,4D,5A,6A-
,7C),(1D,2B,3C,4D,5A,6B,7A),
(1D,2B,3C,4D,5A,6B,7B),(1D,2B,3C,4D,5A,6B,7C)-
,(1D,2B,3C,4D,5A,6C,7A),(1D,2B,3C,4D,5A,6C,7B),(1D,2B,3C,4D,5A,6C,7C),(1D,-
2B,3C,4D,5A,6D,7A),(1D,2B,3C,4D,5A,6D,7B),
(1D,2B,3C,4D,5A,6D,7C),(1D,2B,3-
C,4D,5B,6A,7A),(1D,2B,3C,4D,5B,6A,7B),(1D,2B,3C,4D,5B,6A,7C),(1D,2B,3C,4D,-
5B,6B,7A),(1D,2B,3C,4D,5B,6B,7B),(1D,2B,3C,4D,5B,6B,7C),
(1D,2B,3C,4D,5B,6C,7A),(1D,2B,3C,4D,5B,6C,7B),(1D,2B,3C,4D,5B,6C,7C),(1D,-
2B,3C,4D,5B,6D,7A), (1D,2B,3C,4D,5B,6D,7B),
(D,2B,3C,4D,5B,6D,7C),(1D,2B,3- C,4E,5A,6A,7A),
(1D,2B,3C,4E,5A,6A,7B), (1D,2B,3C,4E,5A,6A,7C),(1D,2B,3C,4-
E,5A,6B,7A), (1D,2B,3C,4E,5A,6B,7B),
(1D,2B,3C,4E,5A,6B,7C),(1D,2B,3C,4E,5- A,6C,7A),
(1D,2B,3C,4E,5A,6C,7B), (1D,2B,3C,4E,5A,6C,7C),
(D,2B,3C,4E,5A,6D,7A),(1D,2B,3C,4E,5A,6D,7B),(1D,2B,3C,4E,5A,6D,7C),(1D,2-
B,3C,4E,5B,6A,7A),(1D,2B,3C,4E,5B,6A 7B),(1D,2B,3C,4E,5B,6A,7C),
(1D,2B,3C,4E,5B,6B,7A),(1D,2B,3C,4E,5B,6B,7B),(1D,2B,3C,4E,5B,6B,7C),(1D,-
2B,3C,4E,5B,6C,7A),(1D,2B,3C,4E,5B,6C,7B),(1D,2B,3C,4E,5B,6C,7C),(1D,2B,3C-
,4E,5B,6D,7A),
(1D,2B,3C,4E,5B,6D,7B),(1D,2B,3C,4E,5B,6D,7C),(1D,2B,3D,4A,-
5A,6A,7A),(1D,2B,3D,4A,5A,6A,7B),(1D,2B,3D,4A,5A,6A,7C),(1D,2B,3D,4A,5A,6B-
,7A),(1D,2B,3D,4A,5A,6B,7B),
(1D,2B,3D,4A,5A,6B,7C),(1D,2B,3D,4A,5A,6C,7A)-
,(1D,2B,3D,4A,5A,6C,7B),(1D,2B,3D,4A,5A,6C,7C),(1D,2B,3D,4A,5A,6D,7A),(1D,-
2B,3D,4A,5A,6D,7B),(1D,2B,3D,4A,5A,6D,7C),
(1D,2B,3D,4A,5B,6A,7A),(1D,2B,3-
D,4A,5B,6A,7B),(1D,2B,3D,4A,5B,6A,7C),(1D,2B,3D,4A,5B,6B,7A),(1D,2B,3D,4A,-
5B,6B,7B),(1D,2B,3D,4A,5B,6B,7C),(1D,2B,3D,4A,5B,6C,7A),
(1D,2B,3D,4A,5B,6C,7B),(1D,2B,3D,4A,5B,6C,7C),(1D,2B,3D,4A,5B,6D,7A),(1D,-
2B,3D,4A,5B,6D,7B),(1D,2B,3D,4A,5B,6D,7C),(1D,2B,3D,4B,5A,6A,7A),(1D,2B,3D-
,4B,5A,6A,7B),
(1D,2B,3D,4B,5A,6A,7C),(1D,2B,3D,4B,5A,6B,7A),(1D,2B,3D,4B,-
5A,6B,7B),(1D,2B,3D,4B,5A,6B,7C),(1D,2B,3D,4B,5A,6C,7A),(1D,2B,3D,4B,5A,6C-
,7B),(1D,2B,3D,4B,5A,6C,7C),
(1D,2B,3D,4B,5A,6D,7A),(1D,2B,3D,4B,5A,6D,7B)-
,(1D,2B,3D,4B,5A,6D,7C),(1D,2B,3D,4B,5B,6A,7A),(1D,2B,3D,4B,5B,6A,7B),(1D,-
2B,3D,4B,5B,6A,7C),(1D,2B,3D,4B,5B,6B,7A),
(1D,2B,3D,4B,5B,6B,7B),(1D,2B,3-
D,4B,5B,6B,7C),(1D,2B,3D,4B,5B,6C,7A),(1D,2B,3D,4B,5B,6C,7B),(1D,2B,3D,4B,-
5B,6C,7C),(1D,2B,3D,4B,5B,6D,7A),(1D,2B,3D,4B,5B,6D,7B),
(1D,2B,3D,4B,5B,6D,7C),(1D,2B,3D,4C,5A,6A,7A),(1D,2B,3D,4C,5A,6A,7B),(1D,-
2B,3D,4C,5A,6A,7C),(1D,2B,3D,4C,5A,6B,7A),(1D,2B,3D,4C,5A,6B,7B),(1D,2B,3D-
,4C,5A,6B,7C),
(1D,2B,3D,4C,5A,6C,7A),(1D,2B,3D,4C,5A,6C,7B),(1D,2B,3D,4C,-
5A,6C,7C),(1D,2B,3D,4C,5A,6D,7A),(1D,2B,3D,4C,5A,6D,7B),(1D,2B,3D,4C,5A,6D-
,7C),(1D,2B,3D,4C,5B,6A,7A),
(1D,2B,3D,4C,5B,6A,7B),(1D,2B,3D,4C,5B,6A,7C)-
,(1D,2B,3D,4C,5B,6B,7A),(1D,2B,3D,4C,5B,6B,7B),(1D,2B,3D,4C,5B,6B,7C),(1D,-
2B,3D,4C,5B,6C,7A),(1D,2B,3D,4C,5B,6C,7B),
(1D,2B,3D,4C,5B,6C,7C),(1D,2B,3-
D,4C,5B,6D,7A),(1D,2B,3D,4C,5B,6D,7B),(1D,2B,3D,4C,5B,6D,7C),(1D,2B,3D,4D,-
5A,6A,7A),(1D,2B,3D,4D,5A,6A,7B),(1D,2B,3D,4D,5A,6A,7C),
(1D,2B,3D,4D,5A,6B,7A),(1D,2B,3D,4D,5A,6B,7B),(1D,2B,3D,4D,5A,6B,7C),(1D,-
2B,3D,4D,5A,6C,7A),(1D,2B,3D,4D,5A,6C,7B),(1D,2B,3D,4D,5A,6C,7C),(1D,2B,3D-
,4D,5A,6D,7A),
(1D,2B,3D,4D,5A,6D,7B),(1D,2B,3D,4D,5A,6D,7C),(1D,2B,3D,4D,-
5B,6A,7A),(1D,2B,3D,4D,5B,6A,7B),(1D,2B,3D,4D,5B,6A,7C),(1D,2B,3D,4D,5B,6B-
,7A),(1D,2B,3D,4D,5B,6B,7B),
(1D,2B,3D,4D,5B,6B,7C),(1D,2B,3D,4D,5B,6C,7A)-
,(1D,2B,3D,4D,5B,6C,7B),(1D,2B,3D,4D,5B,6C,7C),(1D,2B,3D,4D,5B,6D,7A),(1D,-
2B,3D,4D,5B,6D,7B),(1D,2B,3D,4D,5B,6D,7C),
(1D,2B,3D,4E,5A,6A,7A),(1D,2B,3-
D,4E,5A,6A,7B),(1D,2B,3D,4E,5A,6A,7C),(1D,2B,3D,4E,5A,6B,7A),(1D,2B,3D,4E,-
5A,6B,7B),(1D,2B,3D,4E,5A,6B,7C),(1D,2B,3D,4E,5A,6C,7A),
(1D,2B,3D,4E,5A,6C,7B),(1D,2B,3D,4E,5A,6C,7C),(1D,2B,3D,4E,5A,6D,7A),(1D,-
2B,3D,4E,5A,6D,7B),(1D,2B,3D,4E,5A,6D,7C),(1D,2B,3D,4E,5B,6A,7A),(1D,2B,3D-
,4E,5B,6A,7B),
(1D,2B,3D,4E,5B,6A,7C),(1D,2B,3D,4E,5B,6B,7A),(1D,2B,3D,4E,-
5B,6B,7B),(1D,2B,3D,4E,5B,6B,7C),(1D,2B,3D,4E,5B,6C,7A),(1D,2B,3D,4E,5B,6C-
,7B),(1D,2B,3D,4E,5B,6C,7C),
(1D,2B,3D,4E,5B,6D,7A),(1D,2B,3D,4E,5B,6D,7B)-
,(1D,2B,3D,4E,5B,6D,7C),(1D,2B,3E,4A,5A,6A,7A),(1D,2B,3E,4A,5A,6A,7B),(1D,-
2B,3E,4A,5A,6A,7C),(1D,2B,3E,4A,5A,6B,7A),
(1D,2B,3E,4A,5A,6B,7B),(1D,2B,3-
E,4A,5A,6B,7C),(1D,2B,3E,4A,5A,6C,7A),(1D,2B,3E,4A,5A,6C,7B),(1D,2B,3E,4A,-
5A,6C,7C),(1D,2B,3E,4A,5A,6D,7A),(1D,2B,3E,4A,5A,6D,7B),
(1D,2B,3E,4A,5A,6D,7C),(1D,2B,3E,4A,5B,6A,7A),(1D,2B,3E,4A,5B,6A,7B),(1D,-
2B,3E,4A,5B,6A,7C),(1D,2B,3E,4A,5B,6B,7A),(1D,2B,3E,4A,5B,6B,7B),(1D,2B,3E-
,4A,5B,6B,7C),
(1D,2B,3E,4A,5B,6C,7A),(1D,2B,3E,4A,5B,6C,7B),(1D,2B,3E,4A,-
5B,6C,7C),(1D,2B,3E,4A,5B,6D,7A),(1D,2B,3E,4A,5B,6D,7B),(1D,2B,3E,4A,5B,6D-
,7C),(1D,2B,3E,4B,5A,6A,7A),
(1D,2B,3E,4B,5A,6A,7B),(1D,2B,3E,4B,5A,6A,7C)-
,(1D,2B,3E,4B,5A,6B,7A),(1D,2B,3E,4B,5A,6B,7B),(1D,2B,3E,4B,5A,6B,7C),(1D,-
2B,3E,4B,5A,6C,7A),(1D,2B,3E,4B,5A,6C,7B),
(1D,2B,3E,4B,5A,6C,7C),(1D,2B,3-
E,4B,5A,6D,7A),(1D,2B,3E,4B,5A,6D,7B),(1D,2B,3E,4B,5A,6D,7C),(1D,2B,3E,4B,-
5B,6A,7A),(1D,2B,3E,4B,5B,6A,7B),(1D,2B,3E,4B,5B,6A 7C),
(1D,2B,3E,4B,5B,6B,7A),(1D,2B,3E,4B,5B,6B,7B),(1D,2B,3E,4B,5B,6B,7C),(1D,-
2B,3E,4B,5B,6C,7A),(1D,2B,3E,4B,5B,6C,7B),(1D,2B,3E,4B,5B,6C,7C),(1D,2B,3E-
,4B,5B,6D,7A),
(1D,2B,3E,4B,5B,6D,7B),(1D,2B,3E,4B,5B,6D,7C),(1D,2B,3E,4C,-
5A,6A,7A),(1D,2B,3E,4C,5A,6A,7B),(1D,2B,3E,4C,5A,6A,7C),(1D,2B,3E,4C,5A,6B-
,7A),(1D,2B,3E,4C,5A,6B,7B),
(1D,2B,3E,4C,5A,6B,7C),(1D,2B,3E,4C,5A,6C,7A)-
,(1D,2B,3E,4C,5A,6C,7B),(1D,2B,3E,4C,5A,6C,7C),(1D,2B,3E,4C,5A,6D,7A),(1D,-
2B,3E,4C,5A,6D,7B),(1D,2B,3E,4C,5A,6D,7C),
(1D,2B,3E,4C,5B,6A,7A),(1D,2B,3-
E,4C,5B,6A,7B),(1D,2B,3E,4C,5B,6A,7C),(1D,2B,3E,4C,5B,6B,7A),
(1D,2B,3E,4C,5B,6B,7B),(1D,2B,3E,4C,5B,6B,7C),(1D,2B,3E,4C,5B,6C,7A),
(1D,2B,3E,4C,5B,6C,7B),(1D,2B,3E,4C,5B,6C,7C),(1D,2B,3E,4C,5B,6D,7A),
(1D,2B,3E,4C,5B,6D,7B),
(1D,2B,3E,4C,5B,6D,7C),(1D,2B,3E,4D,5A,6A,7A),(1D-
,2B,3E,4D,5A,6A,7B), (1D,2B,3E,4D,5A,6A,7C),(1D,2B,3E,4D,5A,6B,7A),
(1D,2B,3E,4D,5A,6B,7B),
(1D,2B,3E,4D,5A,6B,7C),(1D,2B,3E,4D,5A,6C,7A),(1D-
,2B,3E,4D,5A,6C,7B),(1D,2B,3E,4D,5A,6C,7C),
(1D,2B,3E,4D,5A,6D,7A),(1D,2B,-
3E,4D,5A,6D,7B),(1D,2B,3E,4D,5A,6D,7C),(1D,2B,3E,4D,5B,6A,7A),(1D,2B,3E,4D-
,5B,6A,7B),(1D,2B,3E,4D,5B,6A,7C),(1D,2B,3E,4D,5B,6B,7A),
(1D,2B,3E,4D,5B,6B,7B),(1D,2B,3E,4D,5B,6B,7C),(1D,2B,3E,4D,5B,6C,7A),(1D,-
2B,3E,4D,5B,6C,7B),(1D,2B,3E,4D,5B,6C,7C),(1D,2B,3E,4D,5B,6D,7A),(1D,2B,3E-
,4D,5B,6D,7B),
(1D,2B,3E,4D,5B,6D,7C),(1D,2B,3E,4E,5A,6A,7A),(1D,2B,3E,4E,-
5A,6A,7B),(1D,2B,3E,4E,5A,6A,7C),(1D,2B,3E,4E,5A,6B,7A),(1D,2B,3E,4E,5A,6B-
,7B),(1D,2B,3E,4E,5A,6B,7C),
(1D,2B,3E,4E,5A,6C,7A),(1D,2B,3E,4E,5A,6C,7B)-
,(1D,2B,3E,4E,5A,6C,7C),(1D,2B,3E,4E,5A,6D,7A),(1D,2B,3E,4E,5A,6D,7B),(1D,-
2B,3E,4E,5A,6D,7C),(1D,2B,3E,4E,5B,6A,7A),
(1D,2B,3E,4E,5B,6A,7B),(1D,2B,3-
E,4E,5B,6A,7C),(1D,2B,3E,4E,5B,6B,7A),(1D,2B,3E,4E,5B,6B,7B),(1D,2B,3E,4E,-
5B,6B,7C),(1D,2B,3E,4E,5B,6C,7A),(1D,2B,3E,4E,5B,6C,7B),
(1D,2B,3E,4E,5B,6C,7C),(1D,2B,3E,4E,5B,6D,7A),(1D,2B,3E,4E,5B,6D,7B),(1D,-
2B,3E,4E,5B,6D,7C),(1D,2C,3A,4A,5A,6A,7A),(1D,2C,3A,4A,5A,6A,7B),(1D,2C,3A-
,4A,5A,6A,7C),
(1D,2C,3A,4A,5A,6B,7A),(1D,2C,3A,4A,5A,6B,7B),(1D,2C,3A,4A,-
5A,6B,7C),(1D,2C,3A,4A,5A,6C,7A),(1D,2C,3A,4A,5A,6C,7B),(1D,2C,3A,4A,5A,6C-
,7C),(1D,2C,3A,4A,5A,6D,7A),
(1D,2C,3A,4A,5A,6D,7B),(1D,2C,3A,4A,5A,6D,7C)-
,(1D,2C,3A,4A,5B,6A,7A),(1D,2C,3A,4A,5B,6A,7B),(1D,2C,3A,4A,5B,6A,7C),(1D,-
2C,3A,4A,5B,6B,7A),(1D,2C,3A,4A,5B,6B,7B),
(1D,2C,3A,4A,5B,6B,7C),(1D,2C,3-
A,4A,5B,6C,7A),(1D,2C,3A,4A,5B,6C,7B),(1D,2C,3A,4A,5B,6C,7C),(1D,2C,3A,4A,-
5B,6D,7A),(1D,2C,3A,4A,5B,6D,7B),(1D,2C,3A,4A,5B,6D,7C),
(1D,2C,3A,4B,5A,6A,7A),(1D,2C,3A,4B,5A,6A,7B),(1D,2C,3A,4B,5A,6A,7C),(1D,-
2C,3A,4B,5A,6B,7A),(1D,2C,3A,4B,5A,6B,7B),(1D,2C,3A,4B,5A,6B,7C),(1D,2C,3A-
,4B,5A,6C,7A),
(1D,2C,3A,4B,5A,6C,7B),(1D,2C,3A,4B,5A,6C,7C),(1D,2C,3A,4B,-
5A,6D,7A),(1D,2C,3A,4B,5A,6D,7B),(1D,2C,3A,4B,5A,6D,7C),(1D,2C,3A,4B,5B,6A-
,7A),(1D,2C,3A,4B,5B,6A,7B),
(1D,2C,3A,4B,5B,6A,7C),(1D,2C,3A,4B,5B,6B,7A)-
,(1D,2C,3A,4B,5B,6B,7B),(1D,2C,3A,4B,5B,6B,7C),(1D,2C,3A,4B,5B,6C,7A),(1D,-
2C,3A,4B,5B,6C,7B),(1D,2C,3A,4B,5B,6C,7C),
(1D,2C,3A,4B,5B,6D,7A),(1D,2C,3-
A,4B,5B,6D,7B),(1D,2C,3A,4B,5B,6D,7C),(1D,2C,3A,4C,5A,6A,7A),(1D,2C,3A,4C,-
5A,6A,7B),(1D,2C,3A,4C,5A,6A,7C),(1D,2C,3A,4C,5A,6B,7A),
(1D,2C,3A,4C,5A,6B,7B),(1D,2C,3A,4C,5A,6B,7C),(1D,2C,3A,4C,5A,6C,7A),(1D,-
2C,3A,4C,5A,6C,7B),(1D,2C,3A,4C,5A,6C,7C),(1D,2C,3A,4C,5A,6D,7A),(1D,2C,3A-
,4C,5A,6D,7B),
(1D,2C,3A,4C,5A,6D,7C),(1D,2C,3A,4C,5B,6A,7A),(1D,2C,3A,4C,-
5B,6A,7B),(1D,2C,3A,4C,5B,6A,7C),(1D,2C,3A,4C,5B,6B,7A),(1D,2C,3A,4C,5B,6B-
,7B),(1D,2C,3A,4C,5B,6B,7C),
(1D,2C,3A,4C,5B,6C,7A),(1D,2C,3A,4C,5B,6C,7B)-
,(1D,2C,3A,4C,5B,6C,7C),(1D,2C,3A,4C,5B,6D,7A),(1D,2C,3A,4C,5B,6D,7B),(1D,-
2C,3A,4C,5B,6D,7C),(1D,2C,3A,4D,5A,6A,7A),
(1D,2C,3A,4D,5A,6A,7B),(1D,2C,3-
A,4D,5A,6A,7C),(1D,2C,3A,4D,5A,6B,7A),(1D,2C,3A,4D,5A,6B,7B),(1D,2C,3A,4D,-
5A,6B,7C),(1D,2C,3A,4D,5A,6C,7A),(1D,2C,3A,4D,5A,6C,7B),
(1D,2C,3A,4D,5A,6C,7C),(1D,2C,3A,4D,5A,6D,7A),(1D,2C,3A,4D,5A,6D,7B),(1D,-
2C,3A,4D,5A,6D,7C),(1D,2C,3A,4D,5B,6A,7A),(1D,2C,3A,4D,5B,6A,7B),(1D,2C,3A-
,4D,5B,6A,7C),
(1D,2C,3A,4D,5B,6B,7A),(1D,2C,3A,4D,5B,6B,7B),(1D,2C,3A,4D,-
5B,6B,7C),(1D,2C,3A,4D,5B,6C,7A),(1D,2C,3A,4D,5B,6C,7B),(1D,2C,3A,4D,5B,6C-
,7C),(1D,2C,3A,4D,5B,6D,7A),
(1D,2C,3A,4D,5B,6D,7B),(1D,2C,3A,4D,5B,6D,7C)-
,(1D,2C,3A,4E,5A,6A,7A),(1D,2C,3A,4E,5A,6A,7B),(1D,2C,3A,4E,5A,6A,7C),(1D,-
2C,3A,4E,5A,6B,7A),(1D,2C,3A,4E,5A,6B,7B),
(1D,2C,3A,4E,5A,6B,7C),(1D,2C,3-
A,4E,5A,6C,7A),(1D,2C,3A,4E,5A,6C,7B),(1D,2C,3A,4E,5A,6C,7C),(1D,2C,3A,4E,-
5A,6D,7A),(1D,2C,3A,4E,5A,6D,7B),(1D,2C,3A,4E,5A,6D,7C),
(1D,2C,3A,4E,5B,6A,7A),(1D,2C,3A,4E,5B,6A,7B),(1D,2C,3A,4E,5B,6A,7C),(1D,-
2C,3A,4E,5B,6B,7A),(1D,2C,3A,4E,5B,6B,7B),(1D,2C,3A,4E,5B,6B,7C),(1D,2C,3A-
,4E,5B,6C,7A),
(1D,2C,3A,4E,5B,6C,7B),(1D,2C,3A,4E,5B,6C,7C),(1D,2C,3A,4E,-
5B,6D,7A),(1D,2C,3A,4E,5B,6D,7B),(1D,2C,3A,4E,5B,6D,7C),(1D,2C,3B,4A,5A,6A-
,7A),
(1D,2C,3B,4A,5A,6A,7B),(1D,2C,3B,4A,5A,6A,7C),(1D,2C,3B,4A,5A,6B,7A)-
,(1D,2C,3B,4A,5A,6B,7B),(1D,2C,3B,4A,5A,6B,7C),(1D,2C,3B,4A,5A,6C,7A),(1D,-
2C,3B,4A,5A,6C,7B),
(1D,2C,3B,4A,5A,6C,7C),(1D,2C,3B,4A,5A,6D,7A),(1D,2C,3-
B,4A,5A,6D,7B),(1D,2C,3B,4A,5A,6D,7C),(1D,2C,3B,4A,5B,6A,7A),(1D,2C,3B,4A,-
5B,6A,7B),(1D,2C,3B,4A,5B,6A,7C),
(1D,2C,3B,4A,5B,6B,7A),(1D,2C,3B,4A,5B,6-
B,7B),(1D,2C,3B,4A,5B,6B,7C),(1D,2C,3B,4A,5B,6C,7A),(1D,2C,3B,4A,5B,6C,7B)-
,(1D,2C,3B,4A,5B,6C,7C),(1D,2C,3B,4A,5B,6D,7A),
(1D,2C,3B,4A,5B,6D,7B),(1D-
,2C,3B,4A,5B,6D,7C),(1D,2C,3B,4B,5A,6A,7A),(1D,2C,3B,4B,5A,6A,7B),(1D,2C,3-
B,4B,5A,6A,7C),(1D,2C,3B,4B,5A,6B,7A),(1D,2C,3B,4B,5A,6B,7B),
(1D,2C,3B,4B,5A,6B,7C),(1D,2C,3B,4B,5A,6C,7A),(1D,2C,3B,4B,5A,6C,7B),(1D,-
2C,3B,4B,5A,6C,7C),(1D,2C,3B,4B,5A,6D,7A),(1D,2C,3B,4B,5A,6D,7B),(1D,2C,3B-
,4B,5A,6D,7C),
(1D,2C,3B,4B,5B,6A,7A),(1D,2C,3B,4B,5B,6A,7B),(1D,2C,3B,4B,-
5B,6A,7C),(1D,2C,3B,4B,5B,6B,7A),(1D,2C,3B,4B,5B,6B,7B),(1D,2C,3B,4B,5B,6B-
,7C),(1D,2C,3B,4B,5B,6C,7A),
(1D,2C,3B,4B,5B,6C,7B),(1D,2C,3B,4B,5B,6C,7C)-
,(1D,2C,3B,4B,5B,6D,7A),(1D,2C,3B,4B,5B,6D,7B),(1D,2C,3B,4B,5B,6D,7C),(1D,-
2C,3B,4C,5A,6A,7A),(1D,2C,3B,4C,5A,6A,7B),
(1D,2C,3B,4C,5A,6A,7C),(1D,2C,3-
B,4C,5A,6B,7A),(1D,2C,3B,4C,5A,6B,7B),(1D,2C,3B,4C,5A,6B,7C),(1D,2C,3B,4C,-
5A,6C,7A),(1D,2C,3B,4C,5A,6C,7B),(1D,2C,3B,4C,5A,6C,7C),
(1D,2C,3B,4C,5A,6D,7A),(1D,2C,3B,4C,5A,6D,7B),(1D,2C,3B,4C,5A,6D,7C),(1D,-
2C,3B,4C,5B,6A,7A),(1D,2C,3B,4C,5B,6A,7B),(1D,2C,3B,4C,5B,6A,7C),(1D,2C,3B-
,4C,5B,6B,7A),
(1D,2C,3B,4C,5B,6B,7B),(1D,2C,3B,4C,5B,6B,7C),(1D,2C,3B,4C,-
5B,6C,7A),(1D,2C,3B,4C,5B,6C,7B),(1D,2C,3B,4C,5B,6C,7C),(1D,2C,3B,4C,5B,6D-
,7A),(1D,2C,3B,4C,5B,6D,7B),
(1D,2C,3B,4C,5B,6D,7C),(1D,2C,3B,4D,5A,6A,7A)-
,(1D,2C,3B,4D,5A,6A,7B),(1D,2C,3B,4D,5A,6A,7C),(1D,2C,3B,4D,5A,6B,7A),(1D,-
2C,3B,4D,5A,6B,7B),(1D,2C,3B,4D,5A,6B,7C),
(1D,2C,3B,4D,5A,6C,7A),(1D,2C,3-
B,4D,5A,6C,7B),(1D,2C,3B,4D,5A,6C,7C),(1D,2C,3B,4D,5A,6D,7A),(1D,2C,3B,4D,-
5A,6D,7B),(1D,2C,3B,4D,5A,6D,7C),(1D,2C,3B,4D,5B,6A,7A),
(1D,2C,3B,4D,5B,6A,7B),(1D,2C,3B,4D,5B,6A,7C),(1D,2C,3B,4D,5B,6B,7A),(1D,-
2C,3B,4D,5B,6B,7B),(1D,2C,3B,4D,5B,6B,7C),(1D,2C,3B,4D,5B,6C,7A),(1D,2C,3B-
,4D,5B,6C,7B),
(1D,2C,3B,4D,5B,6C,7C),(1D,2C,3B,4D,5B,6D,7A),(1D,2C,3B,4D,-
5B,6D,7B),(1D,2C,3B,4D,5B,6D,7C),(1D,2C,3B,4E,5A,6A,7A),(1D,2C,3B,4E,5A,6A-
,7B),(1D,2C,3B,4E,5A,6A,7C),
(1D,2C,3B,4E,5A,6B,7A),(1D,2C,3B,4E,5A,6B,7B)-
,(1D,2C,3B,4E,5A,6B,7C),(1D,2C,3B,4E,5A,6C,7A),(1D,2C,3B,4E,5A,6C,7B),(1D,-
2C,3B,4E,5A,6C,7C),(1D,2C,3B,4E,5A,6D,7A),
(1D,2C,3B,4E,5A,6D,7B),(1D,2C,3-
B,4E,5A,6D,7C),(1D,2C,3B,4E,5B,6A,7A),(1D,2C,3B,4E,5B,6A,7B),
(1D,2C,3B,4E,5B,6A,7C),(1D,2C,3B,4E,5B,6B,7A),(1D,2C,3B,4E,5B,6B,7B),
(1D,2C,3B,4E,5B,6B,7C),(1D,2C,3B,4E,5B,6C,7A),(1D,2C,3B,4E,5B,6C,7B),(1D,-
2C,3B,4E,5B,6C,7C),(1D,2C,3B,4E,5B,6D,7A),(1D,2C,3B,4E,5B,6D,7B),(1D,2C,3B-
,4E,5B,6D,7C),
(1D,2C,3C,4A,5A,6A,7A),(1D,2C,3C,4A,5A,6A,7B),(1D,2C,3C,4A,-
5A,6A,7C),(1D,2C,3C,4A,5A,6B,7A),(1D,2C,3C,4A,5A,6B,7B),(1D,2C,3C,4A,5A,6B-
,7C),(1D,2C,3C,4A,5A,6C,7A),
(1D,2C,3C,4A,5A,6C,7B),(1D,2C,3C,4A,5A,6C,7C)-
,(1D,2C,3C,4A,5A,6D,7A),(1D,2C,3C,4A,5A,6D,7B),
(1D,2C,3C,4A,5A,6D,7C),(1D-
,2C,3C,4A,5B,6A,7A),(1D,2C,3C,4A,5B,6A,7B),
(1D,2C,3C,4A,5B,6A,7C),(1D,2C,-
3C,4A,5B,6B,7A),(1D,2C,3C,4A,5B,6B,7B),(1D,2C,3C,4A,5B,6B,7C),
(1D,2C,3C,4A,5B,6C,7A), (1D,2C,3C,4A,5B,6C,7B),
(1D,2C,3C,4A,5B,6C,7C), (1D,2C,3C,4A,5B,6D,7A),
(1D,2C,3C,4A,5B,6D,7B), (1D,2C,3C,4A,5B,6D,7C),
(1D,2C,3C,4B,5A,6A,7A),
(1D,2C,3C,4B,5A,6A,7B),(1D,2C,3C,4B,5A,6A,7C),(1D-
,2C,3C,4B,5A,6B,7A), (1D,2C,3C,4B,5A,6B,7B),
(1D,2C,3C,4B,5A,6B,7C), (1D,2C,3C,4B,5A,6C,7A),
(1D,2C,3C,4B,5A,6C,7B), (1D,2C,3C,4B,5A,6C,7C),(1-
D,2C,3C,4B,5A,6D,7A),(1D,2C,3C,4B,5A,6D,7B),
(1D,2C,3C,4B,5A,6D,7C), (1D,2C,3C,4B,5B,6A,7A),
(1D,2C,3C,4B,5B,6A,7B), (1D,2C,3C,4B,5B,6A,7C),
(1D,2C,3C,4B,5B,6B,7A),
(1D,2C,3C,4B,5B,6B,7B),(1D,2C,3C,4B,5B,6B,7C),
(1D,2C,3C,4B,5B,6C,7A),(1D,2C,3C,4B,5B,6C,7B),(1D,2C,3C,4B,5B,6C,7C),
(1D,2C,3C,4B,5B,6D,7A),(1D,2C,3C,4B,5B,6D,7B),
(D,2C,3C,4B,5B,6D,7C),(1D,- 2C,3C,4C,5A,6A,7A),
(1D,2C,3C,4C,5A,6A,7B), (1D,2C,3C,4C,5A,6A,7C),
(1D,2C,3C,4C,5A,6B,7A), (1D,2C,3C,4C,5A,6B,7B),
(1D,2C,3C,4C,5A,6B,7C), (D,2C,3C,4C,5A,6C,7A),
(1D,2C,3C,4C,5A,6C,7B), (1D,2C,3C,4C,5A,6C,7C),(1D-
,2C,3C,4C,5A,6D,7A),(1D,2C,3C,4C,5A,6D,7B),(1D,2C,3C,4C,5A,6D,7C),
(1D,2C,3C,4C,5B,6A,7A),(1D,2C,3C,4C,5B,6A,7B),(1D,2C,3C,4C,5B,6A,7C),
(1D,2C,3C,4C,5B,6B,7A), (1D,2C,3C,4C,5B,6B,7B),
(1D,2C,3C,4C,5B,6B,7C), (1D,2C,3C,4C,5B,6C,7A),
(1D,2C,3C,4C,5B,6C,7B),(1D,2C,3C,4C,5B,6C,7C),(1D-
,2C,3C,4C,5B,6D,7A), (1D, 2C, 3C,4C, 5B,6D,7B),
(1D,2C,3C,4C,5B,6D,7C), (1D,2C,3C,4D,5A,6A, 7A),
(1D,2C,3C,4D,5A,6A,7B), (1D,2C,3C,4D,5A,6A,7C),
(1D,2C,3C,4D,5A,6B,7A),(1D,2C,3C,4D,5A,6B,7B),
(1D,2C,3C,4D,5A,6B,7C),(1D-
,2C,3C,4D,5A,6C,7A),(1D,2C,3C,4D,5A,6C,7B), (1D,2C,3C,4D,5A,6C,7C),
(1D,2C,3C,4D,5A,6D,7A),(1D,2C,3C,4D,5A,6D,7B),(1D,2C,3C,4D,5A,6D,7C),
(1D,2C,3C,4D,5B,6A,7A),(1D,2C,3C,4D,5B,6A,7B),(1D,2C,3C,4D,5B,6A,7C),(1D,-
2C,3C,4D,5B,6B,7A), (1D,2C,3C,4D,5B,6B, 7B),
(1D,2C,3C,4D,5B,6B,7C), (1D,2C,3C,4D,5B,6C,7A),
(1D,2C,3C,4D,5B,6C,7B), (1D,2C,3C,4D,5B,6C,7C),(1-
D,2C,3C,4D,5B,6D,7A),(1D,2C,3C,4D,5B,6D,7B),
(1D,2C,3C,4D,5B,6D,7C),
(1D,2C,3C,4E,5A,6A,7A),(1D,2C,3C,4E,5A,6A,7B),
(1D,2C,3C,4E,5A,6A,7C), (1D,2C,3C,4E,5A,6B,7A),
(1D,2C,3C,4E,5A,6B,7B),(1D,2C,3C,4E,5A,6B,7C),(1D-
,2C,3C,4E,5A,6C,7A),(1D,2C,3C,4E,5A,6C,7B),(1D,2C,3C,4E,5A,6C,7C),
(1D,2C,3C,4E,5A,6D,7A),(1D,2C,3C,4E,5A,6D,7B),(1D,2C,3C,4E,5A,6D,7C),(1D,-
2C,3C,4E,5B,6A,7A),
(1D,2C,3C,4E,5B,6A,7B),(1D,2C,3C,4E,5B,6A,7C),(1D,2C,3-
C,4E,5B,6B,7A),
(1D,2C,3C,4E,5B,6B,7B),(1D,2C,3C,4E,5B,6B,7C),(1D,2C,3C,4E-
,5B,6C,7A),(1D,2C,3C,4E,5B,6C,7B),(1D,2C,3C,4E,5B,6C,7C),(1D,2C,3C,4E,5B,6-
D,7A),(1D,2C,3C,4E,5B,6D,7B), (1D,2C,3C,4E,5B,6D,7C),
(1D,2C,3D,4A,5A,6A,7A), (1D,2C,3D,4A,5A,6A,7B),
(1D,2C,3D,4A,5A,6A,7C),(1-
D,2C,3D,4A,5A,6B,7A),(1D,2C,3D,4A,5A,6B,7B),(1D,2C,3D,4A,5A,6B,7C),
(1D,2C,3D,4A,5A,6C,7A),(1D,2C,3D,4A,5A,6C,7B),(1D,2C,3D,4A,5A,6C,7C),(1D,-
2C,3D,4A,5A,6D,7A),(1D,2C,3D,4A,5A,6D,7B),(1D,2C,3D,4A,5A,6D,7C),(1D,2C,3D-
,4A,5B,6A,7A),
(1D,2C,3D,4A,5B,6A,7B),(1D,2C,3D,4A,5B,6A,7C),(1D,2C,3D,4A,-
5B,6B,7A),(1D,2C,3D,4A,5B,6B,7B),(1D,2C,3D,4A,5B,6B,7C),(1D,2C,3D,4A,5B,6C-
,7A),(1D,2C,3D,4A,5B,6C,7B),
(1D,2C,3D,4A,5B,6C,7C),(1D,2C,3D,4A,5B,6D,7A)-
,(1D,2C,3D,4A,5B,6D,7B),(1D,2C,3D,4A,5B,6D,7C),(1D,2C,3D,4B,5A,6A,7A),(1D,-
2C,3D,4B,5A,6A,7B),(1D,2C,3D,4B,5A,6A,7C),
(1D,2C,3D,4B,5A,6B,7A),(1D,2C,3-
D,4B,5A,6B,7B),(1D,2C,3D,4B,5A,6B,7C),(1D,2C,3D,4B,5A,6C,7A),(1D,2C,3D,4B,-
5A,6C,7B),(1D,2C,3D,4B,5A,6C,7C),(1D,2C,3D,4B,5A,6D,7A),
(1D,2C,3D,4B,5A,6D,7B),(1D,2C,3D,4B,5A,6D,7C),(1D,2C,3D,4B,5B,6A,7A),(1D,-
2C,3D,4B,5B,6A,7B),(1D,2C,3D,4B,5B,6A,7C),(1D,2C,3D,4B,5B,6B,7A),(1D,2C,3D-
,4B,5B,6B,7B),
(1D,2C,3D,4B,5B,6B,7C),(1D,2C,3D,4B,5B,6C,7A),(1D,2C,3D,4B,-
5B,6C,7B),(1D,2C,3D,4B,5B,6C,7C),(1D,2C,3D,4B,5B,6D,7A),(1D,2C,3D,4B,5B,6D-
,7B),(1D,2C,3D,4B,5B,6D,7C),
(1D,2C,3D,4C,5A,6A,7A),(1D,2C,3D,4C,5A,6A,7B)-
,(1D,2C,3D,4C,5A,6A,7C),(1D,2C,3D,4C,5A,6B,7A),(1D,2C,3D,4C,5A,6B,7B),(1D,-
2C,3D,4C,5A,6B,7C),(1D,2C,3D,4C,5A,6C,7A),
(1D,2C,3D,4C,5A,6C,7B),(1D,2C,3-
D,4C,5A,6C,7C),(1D,2C,3D,4C,5A,6D,7A),(1D,2C,3D,4C,5A,6D,7B),(1D,2C,3D,4C,-
5A,6D,7C),(1D,2C,3D,4C,5B,6A,7A),(1D,2C,3D,4C,5B,6A,7B),
(1D,2C,3D,4C,5B,6A,7C),(1D,2C,3D,4C,5B,6B,7A),(1D,2C,3D,4C,5B,6B,7B),(1D,-
2C,3D,4C,5B,6B,7C),(1D,2C,3D,4C,5B,6C,7A),(1D,2C,3D,4C,5B,6C,7B),(1D,2C,3D-
,4C,5B,6C,7C),
(1D,2C,3D,4C,5B,6D,7A),(1D,2C,3D,4C,5B,6D,7B),(1D,2C,3D,4C,-
5B,6D,7C),(1D,2C,3D,4D,5A,6A,7A),(1D,2C,3D,4D,5A,6A,7B),(1D,2C,3D,4D,5A,6A-
,7C),(1D,2C,3D,4D,5A,6B,7A),
(1D,2C,3D,4D,5A,6B,7B),(1D,2C,3D,4D,5A,6B,7C)-
,(1D,2C,3D,4D,5A,6C,7A),(1D,2C,3D,4D,5A,6C,7B),(1D,2C,3D,4D,5A,6C,7C),(1D,-
2C,3D,4D,5A,6D,7A),(1D,2C,3D,4D,5A,6D,7B),
(1D,2C,3D,4D,5A,6D,7C),(1D,2C,3-
D,4D,5B,6A,7A),(1D,2C,3D,4D,5B,6A,7B),(1D,2C,3D,4D,5B,6A,7C),(1D,2C,3D,4D,-
5B,6B,7A),(1D,2C,3D,4D,5B,6B,7B),(1D,2C,3D,4D,5B,6B,7C),
(1D,2C,3D,4D,5B,6C,7A),(1D,2C,3D,4D,5B,6C,7B),(1D,2C,3D,4D,5B,6C,7C),(1D,-
2C,3D,4D,5B,6D,7A),(1D,2C,3D,4D,5B,6D,7B),(1D,2C,3D,4D,5B,6D,7C),(1D,2C,3D-
,4E,5A,6A,7A),
(1D,2C,3D,4E,5A,6A,7B),(1D,2C,3D,4E,5A,6A,7C),(1D,2C,3D,4E,-
5A,6B,7A),(1D,2C,3D,4E,5A,6B,7B),(1D,2C,3D,4E,5A,6B,7C),(1D,2C,3D,4E,5A,6C-
,7A),(1D,2C,3D,4E,5A,6C,7B),
(1D,2C,3D,4E,5A,6C,7C),(1D,2C,3D,4E,5A,6D,7A)-
,(1D,2C,3D,4E,5A,6D,7B),(1D,2C,3D,4E,5A,6D,7C),
(1D,2C,3D,4E,5B,6A,7A),(1D- ,2C,3D,4E,5B,6A,7B),
(1D,2C,3D,4E,5B,6A,7C), (1D,2C,3D,4E,5B,6B,7A),
(1D,2C,3D,4E,5B,6B,7B), (1D,2C,3D,4E,5B,6B,7C),
(1D,2C,3D,4E,5B,6C,7A),
(1D,2C,3D,4E,5B,6C,7B),(1D,2C,3D,4E,5B,6C,7C),(1D,2C,3D,4E,5B,6D,7A),
(1D,2C,3D,4E,5B,6D,7B), (1D,2C,3D,4E,5B,6D,7C),
(1D,2C,3E,4A,5A,6A,7A),
(D,2C,3E,4A,5A,6A,7B),(1D,2C,3E,4A,5A,6A,7C),(1D,2C,3E,4A,5A,6B,7A),(1D,2-
C,3E,4A,5A,6B,7B),
(1D,2C,3E,4A,5A,6B,7C),(1D,2C,3E,4A,5A,6C,7A),.(1D,2C,3-
E,4A,5A,6C,7B),(1D,2C,3E,4A,5A,6C,7C),(1D,2C,3E,4A,5A,6D,7A),(1D,2C,3E,4A,-
5A,6D,7B),(1D,2C,3E,4A,5A,6D,7C),
(1D,2C,3E,4A,5B,6A,7A),(1D,2C,3E,4A,5B,6-
A,7B),(1D,2C,3E,4A,5B,6A,7C),(1D,2C,3E,4A,5B,6B,7A),(1D,2C,3E,4A,5B,6B,7B)-
,(1D,2C,3E,4A,5B,6B,7C),(1D,2C,3E,4A,5B,6C,7A),
(1D,2C,3E,4A,5B,6C,7B),(1D-
,2C,3E,4A,5B,6C,7C),(1D,2C,3E,4A,5B,6D,7A),(1D,2C,3E,4A,5B,6D,7B),(1D,2C,3-
E,4A,5B,6D,7C),(1D,2C,3E,4B,5A,6A,7A),(1D,2C,3E,4B,5A,6A,7B),
(1D,2C,3E,4B,5A,6A,7C),(1D,2C,3E,4B,5A,6B,7A),(1D,2C,3E,4B,5A,6B,7B),(1D,-
2C,3E,4B,5A,6B,7C),(1D,2C,3E,4B,5A,6C,7A),(1D,2C,3E,4B,5A,6C,7B),(1D,2C,3E-
,4B,5A,6C,7C),
(1D,2C,3E,4B,5A,6D,7A),(1D,2C,3E,4B,5A,6D,7B),(1D,2C,3E,4B,-
5A,6D,7C),(1D,2C,3E,4B,5B,6A,7A),(1D,2C,3E,4B,5B,6A,7B),(1D,2C,3E,4B,5B,6A-
,7C),(1D,2C,3E,4B,5B,6B,7A),
(1D,2C,3E,4B,5B,6B,7B),(1D,2C,3E,4B,5B,6B,7C)-
,(1D,2C,3E,4B,5B,6C,7A),(1D,2C,3E,4B,5B,6C,7B),(1D,2C,3E,4B,5B,6C,7C),(1D,-
2C,3E,4B,5B,6D,7A),(1D,2C,3E,4B,5B,6D,7B),
(1D,2C,3E,4B,5B,6D,7C),(1D,2C,3-
E,4C,5A,6A,7A),(1D,2C,3E,4C,5A,6A,7B),(1D,2C,3E,4C,5A,6A,7C),(1D,2C,3E,4C,-
5A,6B,7A),(1D,2C,3E,4C,5A,6B,7B),(1D,2C,3E,4C,5A,6B,7C),
(1D,2C,3E,4C,5A,6C,7A),(1D,2C,3E,4C,5A,6C,7B),(1D,2C,3E,4C,5A,6C,7C),(1D,-
2C,3E,4C,5A,6D,7A),(1D,2C,3E,4C,5A,6D,7B),(1D,2C,3E,4C,5A,6D,7C),(1D,2C,3E-
,4C,5B,6A,7A),
(1D,2C,3E,4C,5B,6A,7B),(1D,2C,3E,4C,5B,6A,7C),(1D,2C,3E,4C,-
5B,6B,7A),(1D,2C,3E,4C,5B,6B,7B),(1D,2C,3E,4C,5B,6B,7C),(1D,2C,3E,4C,5B,6C-
,7A),(1D,2C,3E,4C,5B,6C,7B),
(1D,2C,3E,4C,5B,6C,7C),(1D,2C,3E,4C,5B,6D,7A)-
,(1D,2C,3E,4C,5B,6D,7B),(1D,2C,3E,4C,5B,6D,7C),(1D,2C,3E,4D,5A,6A,7A),(1D,-
2C,3E,4D,5A,6A,7B),(1D,2C,3E,4D,5A,6A,7C),
(1D,2C,3E,4D,5A,6B,7A),(1D,2C,3-
E,4D,5A,6B,7B),(1D,2C,3E,4D,5A,6B,7C),(1D,2C,3E,4D,5A,6C,7A),(1D,2C,3E,4D,-
5A,6C,7B),(1D,2C,3E,4D,5A,6C,7C),(1D,2C,3E,4D,5A,6D,7A),
(1D,2C,3E,4D,5A,6D,7B),(1D,2C,3E,4D,5A,6D,7C),(1D,2C,3E,4D,5B,6A,7A),(1D,-
2C,3E,4D,5B,6A,7B),(1D,2C,3E,4D,5B,6A,7C),(1D,2C,3E,4D,5B,6B,7A),(1D,2C,3E-
,4D,5B,6B,7B),
(1D,2C,3E,4D,5B,6B,7C),(1D,2C,3E,4D,5B,6C,7A),(1D,2C,3E,4D,-
5B,6C,7B),(1D,2C,3E,4D,5B,6C,7C), (1D,2C,3E,4D,5B,6D,7A),
(1D,2C,3E,4D,5B,6D,7B),(1D,2C,3E,4D,5B,6D,7C),
(1D,2C,3E,4E,5A,6A,7A), (1D,2C,3E,4E,5A,6A,7B),
(1D,2C,3E,4E,5A,6A,7C), (1D,2C,3E,4E,5A,6B,7A),(1-
D,2C,3E,4E,5A,6B,7B),(1D,2C,3E,4E,5A,6B,7C),(1D,2C,3E,4E,5A,6C,7A),
(1D,2C,3E,4E,5A,6C,7B),(1D,2C,3E,4E,5A,6C,7C),(1D,2C,3E,4E,5A,6D,7A),(1D,-
2C,3E,4E,5A,6D,7B),(1D,2C,3E,4E,5A,6D,7C),(1D,2C,3E,4E,5B,6A,7A),(1D,2C,3E-
,4E,5B,6A,7B),
(1D,2C,3E,4E,5B,6A,7C),(1D,2C,3E,4E,5B,6B,7A),(1D,2C,3E,4E,-
5B,6B,7B),(1D,2C,3E,4E,5B,6B,7C),(1D,2C,3E,4E,5B,6C,7A),(1D,2C,3E,4E,5B,6C-
,7B),(1D,2C,3E,4E,5B,6C,7C),
(1D,2C,3E,4E,5B,6D,7A),(1D,2C,3E,4E,5B,6D,7B)-
,(1D,2C,3E,4E,5B,6D,7C),(1D,2D,3A,4A,5A,6A,7A),
(1D,2D,3A,4A,5A,6A,7B),(1D-
,2D,3A,4A,5A,6A,7C),(1D,2D,3A,4A,5A,6B,7A), (1D,2D,3A,4A,5A,6B,7B),
(1D,2D,3A,4A,5A,6B,7C), (1D,2D,3A,4A,5A,6C,7A),
(1D,2D,3A,4A,5A,6C,7B),(1-
D,2D,3A,4A,5A,6C,7C),(1D,2D,3A,4A,5A,6D,7A),(1D,2D,3A,4A,5A,6D,7B),
(1D,2D,3A,4A,5A,6D,7C),(1D,2D,3A,4A,5B,6A,7A),(1D,2D,3A,4A,5B,6A,7B),(1D,-
2D,3A,4A,5B,6A,7C),(1D,2D,3A,4A,5B,6B,7A),(1D,2D,3A,4A,5B,6B,7B),(1D,2D,3A-
,4A,5B,6B,7C),
(1D,2D,3A,4A,5B,6C,7A),(1D,2D,3A,4A,5B,6C,7B),(1D,2D,3A,4A,-
5B,6C,7C),(1D,2D,3A,4A,5B,6D,7A),(1D,2D,3A,4A,5B,6D,7B),(1D,2D,3A,4A,5B,6D-
,7C),(1D,2D,3A,4B,5A,6A,7A),
(1D,2D,3A,4B,5A,6A,7B),(1D,2D,3A,4B,5A,6A,7C)-
,(1D,2D,3A,4B,5A,6B,7A),(1D,2D,3A,4B,5A,6B,7B),(1D,2D,3A,4B,5A,6B,7C),(1D,-
2D,3A,4B,5A,6C,7A),(1D,2D,3A,4B,5A,6C,7B),
(1D,2D,3A,4B,5A,6C,7C),(1D,2D,3-
A,4B,5A,6D,7A),(1D,2D,3A,4B,5A,6D,7B),(1D,2D,3A,4B,5A,6D,7C),(1D,2D,3A,4B,-
5B,6A,7A),(1D,2D,3A,4B,5B,6A,7B),(1D,2D,3A,4B,5B,6A,7C),
(1D,2D,3A,4B,5B,6B,7A),(1D,2D,3A,4B,5B,6B,7B),(1D,2D,3A,4B,5B,6B,7C),(1D,-
2D,3A,4B,5B,6C,7A),(1D,2D,3A,4B,5B,6C,7B),(1D,2D,3A,4B,5B,6C,7C),(1D,2D,3A-
,4B,5B,6D,7A),
(1D,2D,3A,4B,5B,6D,7B),(1D,2D,3A,4B,5B,6D,7C),(1D,2D,3A,4C,-
5A,6A,7A),(1D,2D,3A,4C,5A,6A,7B),(1D,2D,3A,4C,5A,6A,7C),(1D,2D,3A,4C,5A,6B-
,7A),(1D,2D,3A,4C,5A,6B,7B),
(1D,2D,3A,4C,5A,6B,7C),(1D,2D,3A,4C,5A,6C,7A)-
,(1D,2D,3A,4C,5A,6C,7B),(1D,2D,3A,4C,5A,6C,7C),(1D,2D,3A,4C,5A,6D,7A),(1D,-
2D,3A,4C,5A,6D,7B),(1D,2D,3A,4C,5A,6D,7C),
(1D,2D,3A,4C,5B,6A,7A),(1D,2D,3-
A,4C,5B,6A,7B),(1D,2D,3A,4C,5B,6A,7C),(1D,2D,3A,4C,5B,6B,7A),(1D,2D,3A,4C,-
5B,6B,7B),(1D,2D,3A,4C,5B,6B,7C),(1D,2D,3A,4C,5B,6C,7A),
(1D,2D,3A,4C,5B,6C,7B),(1D,2D,3A,4C,5B,6C,7C),(1D,2D,3A,4C,5B,6D,7A),(1D,-
2D,3A,4C,5B,6D,7B),(1D,2D,3A,4C,5B,6D,7C),(1D,2D,3A,4D,5A,6A,7A),(1D,2D,3A-
,4D,5A,6A,7B),
(1D,2D,3A,4D,5A,6A,7C),(1D,2D,3A,4D,5A,6B,7A),(1D,2D,3A,4D,-
5A,6B,7B),(1D,2D,3A,4D,5A,6B,7C),(1D,2D,3A,4D,5A,6C,7A),(1D,2D,3A,4D,5A,6C-
,7B),(1D,2D,3A,4D,5A,6C,7C), (1D,2D,3A,4D,5A,6D,7A),
(1D,2D,3A,4D,5A,6D,7B), (1D,2D,3A,4D,5A,6D,7C),
(1D,2D,3A,4D,5B,6A,7A),(1-
D,2D,3A,4D,5B,6A,7B),(1D,2D,3A,4D,5B,6A,7C),(1D,2D,3A,4D,5B,6B,7A),
(1D,2D,3A,4D,5B,6B,7B),(1D,2D,3A,4D,5B,6B,7C),(1D,2D,3A,4D,5B,6C,7A),(1D,-
2D,3A,4D,5B,6C,7B),(1D,2D,3A,4D,5B,6C,7C),(1D,2D,3A,4D,5B,6D,7A),(1D,2D,3A-
,4D,5B,6D,7B),
(1D,2D,3A,4D,5B,6D,7C),(1D,2D,3A,4E,5A,6A,7A),(1D,2D,3A,4E,-
5A,6A,7B),(1D,2D,3A,4E,5A,6A,7C),(1D,2D,3A,4E,5A,6B,7A),(1D,2D,3A,4E,5A,6B-
,7B),(1D,2D,3A,4E,5A,6B,7C),
(1D,2D,3A,4E,5A,6C,7A),(1D,2D,3A,4E,5A,6C,7B)-
,(1D,2D,3A,4E,5A,6C,7C),(1D,2D,3A,4E,5A,6D,7A),(1D,2D,3A,4E,5A,6D,7B),(1D,-
2D,3A,4E,5A,6D,7C),(1D,2D,3A,4E,5B,6A,7A),
(1D,2D,3A,4E,5B,6A,7B),(1D,2D,3-
A,4E,5B,6A,7C),(1D,2D,3A,4E,5B,6B,7A),(1D,2D,3A,4E,5B,6B,7B),(1D,2D,3A,4E,-
5B,6B,7C),(1D,2D,3A,4E,5B,6C,7A),(1D,2D,3A,4E,5B,6C,7B),
(1D,2D,3A,4E,5B,6C,7C),(1D,2D,3A,4E,5B,6D,7A),(1D,2D,3A,4E,5B,6D,7B),(1D,-
2D,3A,4E,5B,6D,7C),(1D,2D,3B,4A,5A,6A,7A),(1D,2D,3B,4A,5A,6A,7B),(1D,2D,3B-
,4A,5A,6A,7C),
(1D,2D,3B,4A,5A,6B,7A),(1D,2D,3B,4A,5A,6B,7B),(1D,2D,3B,4A,-
5A,6B,7C),(1D,2D,3B,4A,5A,6C,7A),(1D,2D,3B,4A,5A,6C,7B),(1D,2D,3B,4A,5A,6C-
,7C),(1D,2D,3B,4A,5A,6D,7A),
(1D,2D,3B,4A,5A,6D,7B),(1D,2D,3B,4A,5A,6D,7C)-
,(1D,2D,3B,4A,5B,6A,7A),(1D,2D,3B,4A,5B,6A,7B),(1D,2D,3B,4A,5B,6A,7C),(1D,-
2D,3B,4A,5B,6B,7A),(1D,2D,3B,4A,5B,6B,7B),
(1D,2D,3B,4A,5B,6B,7C),(1D,2D,3-
B,4A,5B,6C,7A),(1D,2D,3B,4A,5B,6C,7B),(1D,2D,3B,4A,5B,6C,7C),(1D,2D,3B,4A,-
5B,6D,7A),(1D,2D,3B,4A,5B,6D,7B),(1D,2D,3B,4A,5B,6D,7C),
(1D,2D,3B,4B,5A,6A,7A),(1D,2D,3B,4B,5A,6A,7B),(1D,2D,3B,4B,5A,6A,7C),(1D,-
2D,3B,4B,5A,6B,7A),(1D,2D,3B,4B,5A,6B,7B),(1D,2D,3B,4B,5A,6B,7C),(1D,2D,3B-
,4B,5A,6C,7A),
(1D,2D,3B,4B,5A,6C,7B),(1D,2D,3B,4B,5A,6C,7C),(1D,2D,3B,4B,-
5A,6D,7A),(1D,2D,3B,4B,5A,6D,7B),(1D,2D,3B,4B,5A,6D,7C),(1D,2D,3B,4B,5B,6A-
,7A),(1D,2D,3B,4B,5B,6A,7B),
(1D,2D,3B,4B,5B,6A,7C),(1D,2D,3B,4B,5B,6B,7A)-
,(1D,2D,3B,4B,5B,6B,7B),(1D,2D,3B,4B,5B,6B,7C),(1D,2D,3B,4B,5B,6C,7A),(1D,-
2D,3B,4B,5B,6C,7B),(1D,2D,3B,4B,5B,6C,7C),
(1D,2D,3B,4B,5B,6D,7A),(1D,2D,3-
B,4B,5B,6D,7B),(1D,2D,3B,4B,5B,6D,7C),(1D,2D,3B,4C,5A,6A,7A),(1D,2D,3B,4C,-
5A,6A,7B),(1D,2D,3B,4C,5A,6A,7C),(1D,2D,3B,4C,5A,6B,7A),
(1D,2D,3B,4C,5A,6B,7B),(1D,2D,3B,4C,5A,6B,7C),(1D,2D,3B,4C,5A,6C,7A),(1D,-
2D,3B,4C,5A,6C,7B),(1D,2D,3B,4C,5A,6C,7C),(1D,2D,3B,4C,5A,6D,7A),(1D,2D,3B-
,4C,5A,6D,7B),
(1D,2D,3B,4C,5A,6D,7C),(1D,2D,3B,4C,5B,6A,7A),(1D,2D,3B,4C,-
5B,6A,7B), (1D,2D,3B,4C,5B,6A,7C),
(1D,2D,3B,4C,5B,6B,7A),(1D,2D,3B,4C,5B,-
6B,7B),(1D,2D,3B,4C,5B,6B,7C), (1D,2D,3B,4C,5B,6C,7A),
(1D,2D,3B,4C,5B,6C,7B), (1D,2D,3B,4C,5B,6C,7C),
(D,2D,3B,4C,5B,6D,7A),(1D-
,2D,3B,4C,5B,6D,7B),(1D,2D,3B,4C,5B,6D,7C),(1D,2D,3B,4D,5A,6A,7A),
(1D,2D,3B,4D,5A,6A,7B),(1D,2D,3B,4D,5A,6A,7C),(1D,2D,3B,4D,5A,6B,7A),(1D,-
2D,3B,4D,5A,6B,7B),(1D,2D,3B,4D,5A,6B,7C),(1D,2D,3B,4D,5A,6C,7A),(1D,2D,3B-
,4D,5A,6C,7B),
(1D,2D,3B,4D,5A,6C,7C),(1D,2D,3B,4D,5A,6D,7A),(1D,2D,3B,4D,-
5A,6D,7B),(1D,2D,3B,4D,5A,6D,7C),(1D,2D,3B,4D,5B,6A,7A),(1D,2D,3B,4D,5B,6A-
,7B),(1D,2D,3B,4D,5B,6A,7C),
(1D,2D,3B,4D,5B,6B,7A),(1D,2D,3B,4D,5B,6B,7B)-
,(1D,2D,3B,4D,5B,6B,7C),(1D,2D,3B,4D,5B,6C,7A),(1D,2D,3B,4D,5B,6C,7B),(1D,-
2D,3B,4D,5B,6C,7C),(1D,2D,3B,4D,5B,6D,7A),
(1D,2D,3B,4D,5B,6D,7B),(1D,2D,3-
B,4D,5B,6D,7C),(1D,2D,3B,4E,5A,6A,7A),(1D,2D,3B,4E,5A,6A,7B),(1D,2D,3B,4E,-
5A,6A,7C),(1D,2D,3B,4E,5A,6B,7A),(1D,2D,3B,4E,5A,6B,7B),
(1D,2D,3B,4E,5A,6B,7C),(1D,2D,3B,4E,5A,6C,7A),(1D,2D,3B,4E,5A,6C,7B),(1D,-
2D,3B,4E,5A,6C,7C),(1D,2D,3B,4E,5A,6D,7A),(1D,2D,3B,4E,5A,6D,7B),(1D,2D,3B-
,4E,5A,6D,7C),
(1D,2D,3B,4E,5B,6A,7A),(1D,2D,3B,4E,5B,6A,7B),(1D,2D,3B,4E,-
5B,6A,7C),(1D,2D,3B,4E,5B,6B,7A),(1D,2D,3B,4E,5B,6B,7B),(1D,2D,3B,4E,5B,6B-
,7C),(1D,2D,3B,4E,5B,6C,7A),
(1D,2D,3B,4E,5B,6C,7B),(1D,2D,3B,4E,5B,6C,7C)-
,(1D,2D,3B,4E,5B,6D,7A),(1D,2D,3B,4E,5B,6D,7B),(1D,2D,3B,4E,5B,6D,7C),(1D,-
2D,3C,4A,5A,6A,7A),(1D,2D,3C,4A,5A,6A,7B),
(1D,2D,3C,4A,5A,6A,7C),(1D,2D,3-
C,4A,5A,6B,7A),(1D,2D,3C,4A,5A,6B,7B),(1D,2D,3C,4A,5A,6B,7C),(1D,2D,3C,4A,-
5A,6C,7A),(1D,2D,3C,4A,5A,6C,7B),(1D,2D,3C,4A,5A,6C,7C),
(1D,2D,3C,4A,5A,6D,7A),(1D,2D,3C,4A,5A,6D,7B),(1D,2D,3C,4A,5A,6D,7C),(1D,-
2D,3C,4A,5B,6A,7A),(1D,2D,3C,4A,5B,6A,7B),(1D,2D,3C,4A,5B,6A,7C),(1D,2D,3C-
,4A,5B,6B,7A),
(1D,2D,3C,4A,5B,6B,7B),(1D,2D,3C,4A,5B,6B,7C),(1D,2D,3C,4A,-
5B,6C,7A),(1D,2D,3C,4A,5B,6C,7B),(1D,2D,3C,4A,5B,6C,7C),(1D,2D,3C,4A,5B,6D-
,7A),(1D,2D,3C,4A,5B,6D,7B),
(1D,2D,3C,4A,5B,6D,7C),(1D,2D,3C,4B,5A,6A,7A)-
,(1D,2D,3C,4B,5A,6A,7B),(1D,2D,3C,4B,5A,6A,7C),(1D,2D,3C,4B,5A,6B,7A),(1D,-
2D,3C,4B,5A,6B,7B),(1D,2D,3C,4B,5A,6B,7C),
(1D,2D,3C,4B,5A,6C,7A),(1D,2D,3-
C,4B,5A,6C,7B),(1D,2D,3C,4B,5A,6C,7C),(1D,2D,3C,4B,5A,6D,7A),(1D,2D,3C,4B,-
5A,6D,7B),(1D,2D,3C,4B,5A,6D,7C),(1D,2D,3C,4B,5B,6A,7A),
(1D,2D,3C,4B,5B,6A,7B),(1D,2D,3C,4B,5B,6A,7C),(1D,2D,3C,4B,5B,6B,7A),(1D,-
2D,3C,4B,5B,6B,7B),(1D,2D,3C,4B,5B,6B,7C),(1D,2D,3C,4B,5B,6C,7A),(1D,2D,3C-
,4B,5B,6C,7B),
(1D,2D,3C,4B,5B,6C,7C),(1D,2D,3C,4B,5B,6D,7A),(1D,2D,3C,4B,-
5B,6D,7B),(1D,2D,3C,4B,5B,6D,7C),(1D,2D,3C,4C,5A,6A,7A),(1D,2D,3C,4C,5A,6A-
,7B),(1D,2D,3C,4C,5A,6A,7C),
(1D,2D,3C,4C,5A,6B,7A),(1D,2D,3C,4C,5A,6B,7B)-
,(1D,2D,3C,4C,5A,6B,7C),(1D,2D,3C,4C,5A,6C,7A),(1D,2D,3C,4C,5A,6C,7B),(1D,-
2D,3C,4C,5A,6C,7C),(1D,2D,3C,4C,5A,6D,7A),
(1D,2D,3C,4C,5A,6D,7B),(1D,2D,3-
C,4C,5A,6D,7C),(1D,2D,3C,4C,5B,6A,7A),(1D,2D,3C,4C,5B,6A,7B),(1D,2D,3C,4C,-
5B,6A,7C),(1D,2D,3C,4C,5B,6B,7A),(1D,2D,3C,4C,5B,6B,7B),
(1D,2D,3C,4C,5B,6B,7C),(1D,2D,3C,4C,5B,6C,7A),(1D,2D,3C,4C,5B,6C,7B),(1D,-
2D,3C,4C,5B,6C,7C),(1D,2D,3C,4C,5B,6D,7A),(1D,2D,3C,4C,5B,6D,7B),(1D,2D,3C-
,4C,5B,6D,7C),
(1D,2D,3C,4D,5A,6A,7A),(1D,2D,3C,4D,5A,6A,7B),(1D,2D,3C,4D,-
5A,6A,7C),(1D,2D,3C,4D,5A,6B,7A),(1D,2D,3C,4D,5A,6B,7B),(1D,2D,3C,4D,5A,6B-
,7C),(1D,2D,3C,4D,5A,6C,7A),
(1D,2D,3C,4D,5A,6C,7B),(1D,2D,3C,4D,5A,6C,7C)-
,(1D,2D,3C,4D,5A,6D,7A),(1D,2D,3C,4D,5A,6D,7B),(1D,2D,3C,4D,5A,6D,7C),(1D,-
2D,3C,4D,5B,6A,7A),(1D,2D,3C,4D,5B,6A,7B),
(1D,2D,3C,4D,5B,6A,7C),(1D,2D,3-
C,4D,5B,6B,7A),(1D,2D,3C,4D,5B,6B,7B),(1D,2D,3C,4D,5B,6B,7C),(1D,2D,3C,4D,-
5B,6C,7A),(1D,2D,3C,4D,5B,6C,7B),(1D,2D,3C,4D,5B,6C,7C),
(1D,2D,3C,4D,5B,6D,7A),(1D,2D,3C,4D,5B,6D,7B),(1D,2D,3C,4D,5B,6D,7C),(1D,-
2D,3C,4E,5A,6A,7A),(1D,2D,3C,4E,5A,6A,7B),(1D,2D,3C,4E,5A,6A,7C),(1D,2D,3C-
,4E,5A,6B,7A),
(1D,2D,3C,4E,5A,6B,7B),(1D,2D,3C,4E,5A,6B,7C),(1D,2D,3C,4E,-
5A,6C,7A),(1D,2D,3C,4E,5A,6C,7B),(1D,2D,3C,4E,5A,6C,7C),(1D,2D,3C,4E,5A,6D-
,7A),(1D,2D,3C,4E,5A,6D,7B),
(1D,2D,3C,4E,5A,6D,7C),(1D,2D,3C,4E,5B,6A,7A)-
,(1D,2D,3C,4E,5B,6A,7B),(1D,2D,3C,4E,5B,6A,7C),(1D,2D,3C,4E,5B,6B,7A),(1D,-
2D,3C,4E,5B,6B,7B),(1D,2D,3C,4E,5B,6B,7C),
(1D,2D,3C,4E,5B,6C,7A),(1D,2D,3-
C,4E,5B,6C,7B),(1D,2D,3C,4E,5B,6C,7C),(1D,2D,3C,4E,5B,6D,7A),(1D,2D,3C,4E,-
5B,6D,7B),(1D,2D,3C,4E,5B,6D,7C),(1D,2D,3D,4A,5A,6A,7A),
(1D,2D,3D,4A,5A,6A,7B),(1D,2D,3D,4A,5A,6A,7C),(1D,2D,3D,4A,5A,6B,7A),(1D,-
2D,3D,4A,5A,6B,7B),(1D,2D,3D,4A,5A,6B,7C),(1D,2D,3D,4A,5A,6C,7A),(1D,2D,3D-
,4A,5A,6C,7B), (1D,2D,3D,4A,5A,6C,7C),
(1D,2D,3D,4A,5A,6D,7A),(1D,2D,3D,4A-
,5A,6D,7B),(1D,2D,3D,4A,5A,6D,7C),(1D,2D,3D,4A,5B,6A,7A),(1D,2D,3D,4A,5B,6-
A,7B),(1D,2D,3D,4A,5B,6A,7C),
(1D,2D,3D,4A,5B,6B,7A),(1D,2D,3D,4A,5B,6B,7B-
),(1D,2D,3D,4A,5B,6B,7C),(1D,2D,3D,4A,5B,6C,7A),(1D,2D,3D,4A,5B,6C,7B),(1D-
,2D,3D,4A,5B,6C,7C),(1D,2D,3D,4A,5B,6D,7A),
(1D,2D,3D,4A,5B,6D,7B),(1D,2D,-
3D,4A,5B,6D,7C),(1D,2D,3D,4B,5A,6A,7A),(1D,2D,3D,4B,5A,6A,7B),(1D,2D,3D,4B-
,5A,6A,7C),(1D,2D,3D,4B,5A,6B,7A),(1D,2D,3D,4B,5A,6B,7B),
(1D,2D,3D,4B,5A,6B,7C),(1D,2D,3D,4B,5A,6C,7A),(1D,2D,3D,4B,5A,6C,7B),(1D,-
2D,3D,4B,5A,6C,7C), (1D,2D,3D,4B,5A,6D,7A), (1D,2D,3D,4B,5A,6D,7B),
(1D,2D,3D,4B,5A,6D, 7C), (1D,2D,3D,4B,5B,6A,7A),
(1D,2D,3D,4B,5B,6A,7B), (1D,2D,3D,4B,5B,6A,7C),
(1D,2D,3D,4B,5B,6B,7A), (1D,2D,3D,4B,5B,6B,7B),(1-
D,2D,3D,4B,5B,6B,7C),(1D,2D,3D,4B,5B,6C,7A),
(1D,2D,3D,4B,5B,6C,7B),(1D,2D-
,3D,4B,5B,6C,7C),(1D,2D,3D,4B,5B,6D,7A), (1D,2D,3D,4B,5B,6D,7B),
(1D,2D,3D,4B,5B,6D,7C), (1D,2D,3D,4C,5A,6A,7A),
(1D,2D,3D,4C,5A,6A,7B), (1D,2D,3D,4C,5A,6A,7C),
(1D,2D,3D,4C,5A,6B,7A), (1D,2D,3D,4C,5A,6B,7B),
(1D,2D,3D,4C,5A,6B,7C),
(1D,2D,3D,4C,5A,6C,7A),(1D,2D,3D,4C,5A,6C,7B),(1D-
,2D,3D,4C,5A,6C,7C),
(1D,2D,3D,4C,5A,6D,7A),(1D,2D,3D,4C,5A,6D,7B),(1D,2D,-
3D,4C,5A,6D,7C), (1D,2D,3D,4C,5B,6A,7A),
(1D,2D,3D,4C,5B,6A,7B),(1D,2D,3D,-
4C,5B,6A,7C),(1D,2D,3D,4C,5B,6B,7A),
(1D,2D,3D,4C,5B,6B,7B),(1D,2D,3D,4C,5-
B,6B,7C),(1D,2D,3D,4C,5B,6C,7A), (1D,2D,3D,4C,5B,6C,7B),
(1D,2D,3D,4C,5B,6C,7C),(1D,2D,3D,4C,5B,6D,7A),(1D,2D,3D,4C,5B,6D,7B),
(1D,2D,3D,4C,5B,6D,7C), (1D,2D,3D,4D,5A,6A,7A),
(1D,2D,3D,4D,5A,6A,7B), (D,2D,3D,4D,5A,6A,7C),
(1D,2D,3D,4D,5A,6B,7A),(1D,2D,3D,4D,5A,6B,7B),(1D,-
2D,3D,4D,5A,6B,7C), (1D,2D,3D,4D,5A,6C,7A), (1D,2D,3D,4D,5A,6C,7B),
(1D,2D,3D,4D,5A,6C,7C), (1D,2D,3D,4D,5A,6D,7A),
(1D,2D,3D,4D,5A,6D,7B),(1-
D,2D,3D,4D,5A,6D,7C),(1D,2D,3D,4D,5B,6A,7A),
(1D,2D,3D,4D,5B,6A,7B), (1D,2D,3D,4D,5B,6A,7C),
(1D,2D,3D,4D,5B,6B,7A), (1D,2D,3D,4D,5B,6B,7B),
(1D,2D,3D,4D,5B,6B,7C),(1D,2D,3D,4D,5B,6C,7A),(1D,2D,3D,4D,5B,6C,7B),
(1D,2D,3D,4D,5B,6C,7C), (1D,2D,3D,4D,5B,6D,7A),
(1D,2D,3D,4D,5B,6D,7B), (D,2D,3D,4D,5B,6D,7C),
(1D,2D,3D,4E,5A,6A,7A),(1D,2D,3D,4E,5A,6A,7B),(1D,-
2D,3D,4E,5A,6A,7C), (1D,2D,3D,4E,5A,6B,7A), (1D,2D,3D,4E,5A,6B,7B),
(1D,2D,3D,4E,5A,6B,7C), (1D,2D,3D,4E,5A,6C,7A),
(1D,2D,3D,4E,5A,6C,7B),(1- D,2D,3D,4E,5A,6C,7C),
(1D,2D,3D,4E,5A,6D,7A), (1D,2D,3D,4E,5A,6D,7B),
(1D,2D,3D,4E,5A,6D,7C), (1D,2D,3D,4E,5B,6A,7A),
(1D,2D,3D,4E,5B,6A,7B), (1D,2D,3D,4E,5B,6A,7C),
(1D,2D,3D,4E,5B,6B,7A), (1D,2D,3D,4E,5B,6B,7B),
(1D,2D,3D,4E,5B,6B,7C), (1D,2D,3D,4E,5B,6C,7A),
(1D,2D,3D,4E,5B,6C,7B), (1D,2D,3D,4E,5B,6C,7C),
(1D,2D,3D,4E,5B,6D,7A),(1D,2D,3D,4E,5B,6D,7B),
(1D,2D,3D,4E,5B,6D,7C),
(1D,2D,3E,4A,5A,6A,7A),(1D,2D,3E,4A,5A,6A,7B),(1D-
,2D,3E,4A,5A,6A,7C),(1D,2D,3E,4A,5A,6B,7A),(1D,2D,3E,4A,5A,6B,7B),(1D,2D,3-
E,4A,5A,6B,7C),(1D,2D,3E,4A,5A,6C,7A),
(1D,2D,3E,4A,5A,6C,7B),(1D,2D,3E,4A-
,5A,6C,7C),(1D,2D,3E,4A,5A,6D,7A),(1D,2D,3E,4A,5A,6D,7B),(1D,2D,3E,4A,5A,6-
D,7C),(1D,2D,3E,4A,5B,6A,7A),(1D,2D,3E,4A,5B,6A,7B),
(1D,2D,3E,4A,5B,6A,7C),(1D,2D,3E,4A,5B,6B,7A),(1D,2D,3E,4A,5B,6B,7B),(1D,-
2D,3E,4A,5B,6B,7C),
(1D,2D,3E,4A,5B,6C,7A),(1D,2D,3E,4A,5B,6C,7B),(1D,2D,3-
E,4A,5B,6C,7C),
(1D,2D,3E,4A,5B,6D,7A),(1D,2D,3E,4A,5B,6D,7B),(1D,2D,3E,4A-
,5B,6D,7C),(1D,2D,3E,4B,5A,6A,7A),(1D,2D,3E,4B,5A,6A,7B),(1D,2D,3E,4B,5A,6-
A,7C),(1D,2D,3E,4B,5A,6B,7A),
(1D,2D,3E,4B,5A,6B,7B),(1D,2D,3E,4B,5A,6B,7C-
),(1D,2D,3E,4B,5A,6C,7A),(1D,2D,3E,4B,5A,6C,7B),(1D,2D,3E,4B,5A,6C,7C),(1D-
,2D,3E,4B,5A,6D,7A),(1D,2D,3E,4B,5A,6D,7B),
(1D,2D,3E,4B,5A,6D,7C),(1D,2D,-
3E,4B,5B,6A,7A),(1D,2D,3E,4B,5B,6A,7B),(1D,2D,3E,4B,5B,6A,7C),(1D,2D,3E,4B-
,5B,6B,7A),(1D,2D,3E,4B,5B,6B,7B),(1D,2D,3E,4B,5B,6B,7C),
(1D,2D,3E,4B,5B,6C,7A),(1D,2D,3E,4B,5B,6C,7B),(1D,2D,3E,4B,5B,6C,7C),(1D,-
2D,3E,4B,5B,6D,7A),(1D,2D,3E,4B,5B,6D,7B),(1D,2D,3E,4B,5B,6D,7C),(1D,2D,3E-
,4C,5A,6A,7A),
(1D,2D,3E,4C,5A,6A,7B),(1D,2D,3E,4C,5A,6A,7C),(1D,2D,3E,4C,-
5A,6B,7A),(1D,2D,3E,4C,5A,6B,7B),(1D,2D,3E,4C,5A,6B,7C),(1D,2D,3E,4C,5A,6C-
,7A),(1D,2D,3E,4C,5A,6C,7B),
(1D,2D,3E,4C,5A,6C,7C),(1D,2D,3E,4C,5A,6D,7A)-
,(1D,2D,3E,4C,5A,6D,7B),(1D,2D,3E,4C,5A,6D,7C),(1D,2D,3E,4C,5B,6A,7A),(1D,-
2D,3E,4C,5B,6A,7B),(1D,2D,3E,4C,5B,6A,7C),
(1D,2D,3E,4C,5B,6B,7A),(1D,2D,3-
E,4C,5B,6B,7B),(1D,2D,3E,4C,5B,6B,7C),(1D,2D,3E,4C,5B,6C,7A),(1D,2D,3E,4C,-
5B,6C,7B),(1D,2D,3E,4C,5B,6C,7C),(1D,2D,3E,4C,5B,6D,7A),
(1D,2D,3E,4C,5B,6D,7B),(1D,2D,3E,4C,5B,6D,7C),(1D,2D,3E,4D,5A,6A,7A),(1D,-
2D,3E,4D,5A,6A,7B),(1D,2D,3E,4D,5A,6A,7C),(1D,2D,3E,4D,5A,6B,7A),(1D,2D,3E-
,4D,5A,6B,7B),
(1D,2D,3E,4D,5A,6B,7C),(1D,2D,3E,4D,5A,6C,7A),(1D,2D,3E,4D,-
5A,6C,7B),(1D,2D,3E,4D,5A,6C,7C),(1D,2D,3E,4D,5A,6D,7A),(1D,2D,3E,4D,5A,6D-
,7B),(1D,2D,3E,4D,5A,6D,7C),
(1D,2D,3E,4D,5B,6A,7A),(1D,2D,3E,4D,5B,6A,7B)-
,(1D,2D,3E,4D,5B,6A,7C),(1D,2D,3E,4D,5B,6B,7A),(1D,2D,3E,4D,5B,6B,7B),(1D,-
2D,3E,4D,5B,6B,7C),(1D,2D,3E,4D,5B,6C,7A),
(1D,2D,3E,4D,5B,6C,7B),(1D,2D,3-
E,4D,5B,6C,7C),(1D,2D,3E,4D,5B,6D,7A),(1D,2D,3E,4D,5B,6D,7B),(1D,2D,3E,4D,-
5B,6D,7C),(1D,2D,3E,4E,5A,6A,7A),(1D,2D,3E,4E,5A,6A,7B),
(1D,2D,3E,4E,5A,6A,7C),(1D,2D,3E,4E,5A,6B,7A),(1D,2D,3E,4E,5A,6B,7B),(1D,-
2D,3E,4E,5A,6B,7C),(1D,2D,3E,4E,5A,6C,7A),(1D,2D,3E,4E,5A,6C,7B),(1D,2D,3E-
,4E,5A,6C,7C),
(1D,2D,3E,4E,5A,6D,7A),(1D,2D,3E,4E,5A,6D,7B),(1D,2D,3E,4E,-
5A,6D,7C),(1D,2D,3E,4E,5B,6A,7A),(1D,2D,3E,4E,5B,6A,7B),(1D,2D,3E,4E,5B,6A-
,7C),(1D,2D,3E,4E,5B,6B,7A),
(1D,2D,3E,4E,5B,6B,7B),(1D,2D,3E,4E,5B,6B,7C)-
,(1D,2D,3E,4E,5B,6C,7A),(1D,2D,3E,4E,5B,6C,7B),(1D,2D,3E,4E,5B,6C,7C),(1D,-
2D,3E,4E,5B,6D,7A),(1D,2D,3E,4E,5B,6D,7B),
(1D,2D,3E,4E,5B,6D,7C),(1D,2E,3-
A,4A,5A,6A,7A),(1D,2E,3A,4A,5A,6A,7B),(1D,2E,3A,4A,5A,6A,7C),
(1D,2E,3A,4A,5A,6B,7A), (1D,2E,3A,4A,5A,6B,7B),
(1D,2E,3A,4A,5A,6B,7C), (1D,2E,3A,4A,5A,6C,7A),
(1D,2E,3A,4A,5A,6C,7B),(1D,2E,3A,4A,5A,6C,7C),
(1D,2E,3A,4A,5A,6D,7A),(1D,2E,3A,4A,5A,6D,7B),(1D,2E,3A,4A,5A,6D,7C),(1D,-
2E,3A,4A,5B,6A,7A),
(1D,2E,3A,4A,5B,6A,7B),(1D,2E,3A,4A,5B,6A,7C),(1D,2E,3-
A,4A,5B,6B,7A),(1D,2E,3A,4A,5B,6B,7B),(1D,2E,3A,4A,5B,6B,7C),(1D,2E,3A,4A,-
5B,6C,7A),(1D,2E,3A,4A,5B,6C,7B), (1D,2E, 3A,4A, 5B, 6C, 7C),
(1D,2E, 3A,4A, 5B, 6D,7A), (1D,2E, 3A, 4A, 5B, 6D, 7B), (1D,2E,
3A,4A,5B,6D,7C),(1D,2E,3A,4B,5A,6A,7A),(1D,2E,3A,4B,5A,6A,7B),(1D,2E,3A,4-
B,5A,6A,7C),
(1D,2E,3A,4B,5A,6B,7A),(1D,2E,3A,4B,5A,6B,7B),(1D,2E,3A,4B,5A-
,6B,7C),(1D,2E,3A,4B,5A,6C,7A),(1D,2E,3A,4B,5A,6C,7B),(1D,2E,3A,4B,5A,6C,7-
C),(1D,2E,3A,4B,5A,6D,7A),
(1D,2E,3A,4B,5A,6D,7B),(1D,2E,3A,4B,5A,6D,7C),(-
1D,2E,3A,4B,5B,6A,7A),(1D,2E,3A,4B,5B,6A,7B),(1D,2E,3A,4B,5B,6A,7C),(1D,2E-
,3A,4B,5B,6B,7A),(1D,2E,3A,4B,5B,6B,7B),
(1D,2E,3A,4B,5B,6B,7C),(1D,2E,3A,-
4B,5B,6C,7A),(1D,2E,3A,4B,5B,6C,7B),(1D,2E,3A,4B,5B,6C,7C),(1D,2E,3A,4B,5B-
,6D,7A),(1D,2E,3A,4B,5B,6D,7B),(1D,2E,3A,4B,5B,6D,7C),
(1D,2E,3A,4C,5A,6A,7A),(1D,2E,3A,4C,5A,6A,7B),(1D,2E,3A,4C,5A,6A,7C),(1D,-
2E,3A,4C,5A,6B,7A),(1D,2E,3A,4C,5A,6B,7B),(1D,2E,3A,4C,5A,6B,7C),(1D,2E,3A-
,4C,5A,6C,7A),
(1D,2E,3A,4C,5A,6C,7B),(1D,2E,3A,4C,5A,6C,7C),(1D,2E,3A,4C,-
5A,6D,7A),(1D,2E,3A,4C,5A,6D,7B),(1D,2E,3A,4C,5A,6D,7C),(1D,2E,3A,4C,5B,6A-
,7A),(1D,2E,3A,4C,5B,6A,7B),
(1D,2E,3A,4C,5B,6A,7C),(1D,2E,3A,4C,5B,6B,7A)-
,(1D,2E,3A,4C,5B,6B,7B),(1D,2E,3A,4C,5B,6B,7C),(1D,2E,3A,4C,5B,6C,7A),(1D,-
2E,3A,4C,5B,6C,7B),(1D,2E,3A,4C,5B,6C,7C),
(1D,2E,3A,4C,5B,6D,7A),(1D,2E,3-
A,4C,5B,6D,7B),(1D,2E,3A,4C,5B,6D,7C),(1D,2E,3A,4D,5A,6A,7A),(1D,2E,3A,4D,-
5A,6A,7B),(1D,2E,3A,4D,5A,6A,7C),(1D,2E,3A,4D,5A,6B,7A),
(1D,2E,3A,4D,5A,6B,7B),(1D,2E,3A,4D,5A,6B,7C),(1D,2E,3A,4D,5A,6C,7A),(1D,-
2E,3A,4D,5A,6C,7B),(1D,2E,3A,4D,5A,6C,7C),(1D,2E,3A,4D,5A,6D,7A),(1D,2E,3A-
,4D,5A,6D,7B),
(1D,2E,3A,4D,5A,6D,7C),(1D,2E,3A,4D,5B,6A,7A),(1D,2E,3A,4D,-
5B,6A,7B),(1D,2E,3A,4D,5B,6A,7C),(1D,2E,3A,4D,5B,6B,7A),(1D,2E,3A,4D,5B,6B-
,7B),(1D,2E,3A,4D,5B,6B,7C),
(1D,2E,3A,4D,5B,6C,7A),(1D,2E,3A,4D,5B,6C,7B)-
,(1D,2E,3A,4D,5B,6C,7C),(1D,2E,3A,4D,5B,6D,7A),(1D,2E,3A,4D,5B,6D,7B),(1D,-
2E,3A,4D,5B,6D,7C),(1D,2E,3A,4E,5A,6A,7A),
(1D,2E,3A,4E,5A,6A,7B),(1D,2E,3-
A,4E,5A,6A,7C),(1D,2E,3A,4E,5A,6B,7A),(1D,2E,3A,4E,5A,6B,7B),(1D,2E,3A,4E,-
5A,6B,7C),(1D,2E,3A,4E,5A,6C,7A),(1D,2E,3A,4E,5A,6C,7B),
(1D,2E,3A,4E,5A,6C,7C),(1D,2E,3A,4E,5A,6D,7A),(1D,2E,3A,4E,5A,6D,7B),(1D,-
2E,3A,4E,5A,6D,7C),
(1D,2E,3A,4E,5B,6A,7A),(1D,2E,3A,4E,5B,6A,7B),(1D,2E,3-
A,4E,5B,6A,7C), (1D,2E,3A,4E,5B,6B,7A), (1D,2E,3A,4E,5B,6B,7B),
(1D,2E,3A,4E,5B,6B,7C), (1D,2E,3A,4E,5B,6C,7A),
(1D,2E,3A,4E,5B,6C,7B),
(1D,2E,3A,4E,5B,6C,7C),(1D,2E,3A,4E,5B,6D,7A),
(1D,2E,3A,4E,5B,6D,7B), (1D,2E,3A,4E,5B,6D,7C),
(1D,2E,3B,4A,5A,6A,7A), (1D,2E,3B,4A,5A,6A,7B),
(1D,2E,3B,4A,5A,6A,7C),(1D,2E,3B,4A,5A,6B,7A),(1D,2E,3B,4A,5A,6B,7B),
(1D,2E,3B,4A,5A,6B,7C),
(1D,2E,3B,4A,5A,6C,7A),(1D,2E,3B,4A,5A,6C,7B),(1D-
,2E,3B,4A,5A,6C,7C), (1D,2E,3B,4A,5A,6D,7A),(1D,2E,3B,4A,5A,6D,7B),
(1D,2E,3B,4A,5A,6D,7C), (1D,2E,3B,4A,5B,6A,7A),
(1D,2E,3B,4A,5B,6A,7B),(1-
D,2E,3B,4A,5B,6A,7C),(1D,2E,3B,4A,5B,6B,7A),
(1D,2E,3B,4A,5B,6B,7B),
(1D,2E,3B,4A,5B,6B,7C),(1D,2E,3B,4A,5B,6C,7A),
(1D,2E,3B,4A,5B,6C,7B), (1D,2E,3B,4A,5B,6C,7C),
(1D,2E,3B,4A,5B,6D,7A), (1D,2E,3B,4A,5B,6D,7B),
(1D,2E,3B,4A,5B,6D,7C),(1D,2E,3B,4B,5A,6A,7A),(1D,2E,3B,4B,5A,6A,7B),
(1D,2E,3B,4B,5A,6A,7C), (1D,2E,3B,4B,5A,6B,7A), (1D,2E,3B,4B,5A,6B,
7B),(1D,2E,3B,4B,5A,6B,7C),
(1D,2E,3B,4B,5A,6C,7A),(1D,2E,3B,4B,5A,6C,7B)-
,(1D,2E,3B,4B,5A,6C,7C), (1D,2E,3B,4B,5A,6D,7A),
(1D,2E,3B,4B,5A,6D,7B),(1-
D,2E,3B,4B,5A,6D,7C),(1D,2E,3B,4B,5B,6A,7A), (1D,2E,3B,4B,5B, 6A,
7B), (1D,2E,3B,4B,5B,6A,7C),(1D,2E,3B,4B,5B,6B,7A),
(1D,2E,3B,4B,5B,6B,7B), (1D,2E,3B,4B,5B,6B,7C),
(1D,2E,3B,4B,5B,6C,7A), (1D,2E,3B,4B,5B,6C,7B),
(1D,2E,3B,4B1,5B,6C,7C), (1D,2E,3B,4B,5B,6D,7A),(1D,2E,3B,4B,5B,6D,
7B), (1D,2E,3B,4B,5B,6D,7C), (1D,2E,3B,4C,5A,6A,7A),
(1D,2E,3B,4C,5A,6A,7B),(1- D,2E,3B,4C,5A,6A,7C),
(1D,2E,3B,4C,5A,6B,7A),(1D,2E,3B,4C,5A,6B,7B),(1D,2E-
,3B,4C,5A,6B,7C), (1D,2E,3B,4C,5A,6C,7A), (1D,2E,3B,4C,5A,6C,7B),
(1D,2E,3B,4C,5A,6C,7C),(1D,2E,3B,4C,5A,6D,7A),
(1D,2E,3B,4C,5A,6D,7B),(1D-
,2E,3B,4C,5A,6D,7C),(1D,2E,3B,4C,5B,6A,7A), (1D,2E,3B,4C,5B,6A,7B),
(1D,2E,3B,4C,5B,6A,7C), (1D,2E,3B,4C,5B,6B,7A),
(1D,2E,3B,4C,5B,6B,7B),
(1D,2E,3B,4C,5B,6B,7C),(1D,2E,3B,4C,5B,6C,7A),(1D,2E,3B,4C,5B,6C,7B),
(1D,2E,3B,4C,5B,6C,7C), (1D,2E,3B,4C,5B,6D,7A),(1D,2E,3B,4C,5B,6D,
7B),(1D,2E,3B,4C,5B,6D,7C),
(1D,2E,3B,4D,5A,6A,7A),(1D,2E,3B,4D,5A,6A,7B)-
,(1D,2E,3B,4D,5A,6A,7C), (1D,2E,3B,4D,5A,6B,7A),
(1D,2E,3B,4D,5A,6B,7B), (1D,2E,3B,4D,5A,6B,7C),
(1D,2E,3B,4D,5A,6C,7A), (1D,2E,3B,4D,5A,6C,7B),(1-
D,2E,3B,4D,5A,6C,7C),(1D,2E,3B,4D,5A,6D,7A),
(1D,2E,3B,4D,5A,6D,7B),
(1D,2E,3B,4D,5A,6D,7C),(1D,2E,3B,4D,5B,6A,7A),(1D,2E,3B,4D,5B,6A,7B),
(1D,2E,3B,4D,5B,6A,7C),(1D,2E,3B,4D,5B,6B,7A),(1D,2E,3B,4D,5B,6B,7B),
(1D,2E,3B,4D,5B,6B,7C), (1D,2E,3B,4D,5B,6C,7A),
(1D,2E,3B,4D,5B,6C,7B),
(1D,2E,3B,4D,5B,6C,7C),
(1D,2E,3B,4D,5B,6D,7A),(1D,2E,3B,4D,5B,6D,7B),(1D-
,2E,3B,4D,5B,6D,7C), (1D,2E,3B,4E,5A,6A,7A),(1D,2E,3B,4E,5A,6A,7B),
(1D,2E,3B,4E,5A,6A,7C), (1D,2E,3B,4E,5A,6B,7A),
(1D,2E,3B,4E,5A,6B,7B),(1-
D,2E,3B,4E,5A,6B,7C),(1D,2E,3B,4E,5A,6C,7A),
(1D,2E,3B,4E,5A,6C,7B), (1D,2E,3B,4E,5A,6C,7C),
(1D,2E,3B,4E,5A,6D,7A), (1D,2E,3B,4E,5A,6D,7B),
(1D,2E,3B,4E,5A,6D,7C),(1D,2E,3B,4E,5B,6A,7A),(1D,2E,3B,4E,5B,6A,7B),
(1D,2E,3B,4E,5B,6A,7C), (1D,2E,3B,4E,5B,6B,7A),
(1D,2E,3B,4E,5B,6B,7B),(1- D,2E,3B,4E,5B,6B,7C),
(1D,2E,3B,4E,5B,6C,7A),(1D,2E,3B,4E,5B,6C,7B),(1D,2E-
,3B,4E,5B,6C,7C), (1D,2E,3B,4E,5B,6D,7A), (1D,2E,3B,4E,5B,6D,7B),
(1D,2E,3B,4E,5B,6D,7C),
(1D,2E,3C,4A,5A,6A,7A),(1D,2E,3C,4A,5A,6A,7B),(1D-
,2E,3C,4A,5A,6A,7C),(1D,2E,3C,4A,5A,6B,7A),
(1D,2E,3C,4A,5A,6B,7B),(1D,2E,-
3C,4A,5A,6B,7C),(1D,2E,3C,4A,5A,6C,7A),(1D,2E,3C,4A,5A,6C,7B),(1D,2E,3C,4A-
,5A,6C,7C),(1D,2E,3C,4A,5A,6D,7A),(1D,2E,3C,4A,5A,6D,7B),
(1D,2E,3C,4A,5A,6D,7C),(1D,2E,3C,4A,5B,6A,7A),(1D,2E,3C,4A,5B,6A,7B),(1D,-
2E,3C,4A,5B,6A,7C),(1D,2E,3C,4A,5B,6B,7A),(1D,2E,3C,4A,5B,6B,7B),(1D,2E,3C-
,4A,5B,6B,7C),
(1D,2E,3C,4A,5B,6C,7A),(1D,2E,3C,4A,5B,6C,7B),(1D,2E,3C,4A,-
5B,6C,7C),(1D,2E,3C,4A,5B,6D,7A),(1D,2E,3C,4A,5B,6D,7B),(1D,2E,3C,4A,5B,6D-
,7C),(1D,2E,3C,4B,5A,6A,7A),
(1D,2E,3C,4B,5A,6A,7B),(1D,2E,3C,4B,5A,6A,7C)-
,(1D,2E,3C,4B,5A,6B,7A),(1D,2E,3C,4B,5A,6B,7B),(1D,2E,3C,4B,5A,6B,7C),(1D,-
2E,3C,4B,5A,6C,7A),(1D,2E,3C,4B,5A,6C,7B),
(1D,2E,3C,4B,5A,6C,7C),(1D,2E,3-
C,4B,5A,6D,7A),(1D,2E,3C,4B,5A,6D,7B),(1D,2E,3C,4B,5A,6D,7C),(1D,2E,3C,4B,-
5B,6A,7A),(1D,2E,3C,4B,5B,6A,7B),(1D,2E,3C,4B,5B,6A,7C),
(1D,2E,3C,4B,5B,6B,7A),(1D,2E,3C,4B,5B,6B,7B),(1D,2E,3C,4B,5B,6B,7C),(1D,-
2E,3C,4B,5B,6C,7A),(1D,2E,3C,4B,5B,6C,7B),(1D,2E,3C,4B,5B,6C,7C),(1D,2E,3C-
,4B,5B,6D,7A),
(1D,2E,3C,4B,5B,6D,7B),(1D,2E,3C,4B,5B,6D,7C),(1D,2E,3C,4C,-
5A,6A,7A),(1D,2E,3C,4C,5A,6A,7B),(1D,2E,3C,4C,5A,6A,7C),(1D,2E,3C,4C,5A,6B-
,7A),(1D,2E,3C,4C,5A,6B,7B),
(1D,2E,3C,4C,5A,6B,7C),(1D,2E,3C,4C,5A,6C,7A)-
,(1D,2E,3C,4C,5A,6C,7B),(1D,2E,3C,4C,5A,6C,7C),(1D,2E,3C,4C,5A,6D,7A),(1D,-
2E,3C,4C,5A,6D,7B),(1D,2E,3C,4C,5A,6D,7C),
(1D,2E,3C,4C,5B,6A,7A),(1D,2E,3-
C,4C,5B,6A,7B),(1D,2E,3C,4C,5B,6A,7C),(1D,2E,3C,4C,5B,6B,7A),(1D,2E,3C,4C,-
5B,6B,7B),(1D,2E,3C,4C,5B,6B,7C),(1D,2E,3C,4C,5B,6C,7A),
(1D,2E,3C,4C,5B,6C,7B),(1D,2E,3C,4C,5B,6C,7C),(1D,2E,3C,4C,5B,6D,7A),(1D,-
2E,3C,4C,5B,6D,7B),(1D,2E,3C,4C,5B,6D,7C),(1D,2E,3C,4D,5A,6A,7A),(1D,2E,3C-
,4D,5A,6A,7B),
(1D,2E,3C,4D,5A,6A,7C),(1D,2E,3C,4D,5A,6B,7A),(1D,2E,3C,4D,-
5A,6B,7B),(1D,2E,3C,4D,5A,6B,7C), (1D,2E,3C,4D,5A,
6C,7A),(1D,2E,3C,4D,5A,- 6C,7B),(1D,2E,3C,4D,5A,6C,7C),
(1D,2E,3C,4D,5A,6D,7A),(1D,2E,3C,4D,5A,6D,7-
B),(1D,2E,3C,4D,5A,6D,7C),
(1D,2E,3C,4D,5B,6A,7A),(1D,2E,3C,4D,5B,6A,7B),(-
1D,2E,3C,4D,5B,6A,7C),(1D,2E,3C,4D,5B,6B,7A),
(1D,2E,3C,4D,5B,6B,7B),(1D,2-
E,3C,4D,5B,6B,7C),(1D,2E,3C,4D,5B,6C,7A),(1D,2E,3C,4D,5B,6C,7B),(1D,2E,3C,-
4D,5B,6C,7C),(1D,2E,3C,4D,5B,6D,7A),(1D,2E,3C,4D,5B,6D,7B),
(1D,2E,3C,4D,5B,6D,7C),(1D,2E,3C,4E,5A,6A,7A),(1D,2E,3C,4E,5A,6A,7B),(1D,-
2E,3C,4E,5A,6A,7C),(1D,2E,3C,4E,5A,6B,7A),(1D,2E,3C,4E,5A,6B,7B),(1D,2E,3C-
,4E,5A,6B,7C),
(1D,2E,3C,4E,5A,6C,7A),(1D,2E,3C,4E,5A,6C,7B),(1D,2E,3C,4E,-
5A,6C,7C),(1D,2E,3C,4E,5A,6D,7A),(1D,2E,3C,4E,5A,6D,7B),(1D,2E,3C,4E,5A,6D-
,7C),(1D,2E,3C,4E,5B,6A,7A),
(1D,2E,3C,4E,5B,6A,7B),(1D,2E,3C,4E,5B,6A,7C)-
,(1D,2E,3C,4E,5B,6B,7A),(1D,2E,3C,4E,5B,6B,7B),(1D,2E,3C,4E,5B,6B,7C),(1D,-
2E,3C,4E,5B,6C,7A),(1D,2E,3C,4E,5B,6C,7B),
(1D,2E,3C,4E,5B,6C,7C),(1D,2E,3-
C,4E,5B,6D,7A),(1D,2E,3C,4E,5B,6D,7B),(1D,2E,3C,4E,5B,6D,7C),(1D,2E,3D,4A,-
5A,6A,7A),(1D,2E,3D,4A,5A,6A,7B),(1D,2E,3D,4A,5A,6A,7C),
(1D,2E,3D,4A,5A,6B,7A),(1D,2E,3D,4A,5A,6B,7B),(1D,2E,3D,4A,5A,6B,7C),(1D,-
2E,3D,4A,5A,6C,7A),(1D,2E,3D,4A,5A,6C,7B),(1D,2E,3D,4A,5A,6C,7C),(1D,2E,3D-
,4A,5A,6D,7A),
(1D,2E,3D,4A,5A,6D,7B),(1D,2E,3D,4A,5A,6D,7C),(1D,2E,3D,4A,-
5B,6A,7A),(1D,2E,3D,4A,5B,6A,7B),(1D,2E,3D,4A,5B,6A,7C),(1D,2E,3D,4A,5B,6B-
,7A),(1D,2E,3D,4A,5B,6B,7B),
(1D,2E,3D,4A,5B,6B,7C),(1D,2E,3D,4A,5B,6C,7A)-
,(1D,2E,3D,4A,5B,6C,7B),(1D,2E,3D,4A,5B,6C,7C),(1D,2E,3D,4A,5B,6D,7A),(1D,-
2E,3D,4A,5B,6D,7B),(1D,2E,3D,4A,5B,6D,7C),
(1D,2E,3D,4B,5A,6A,7A),(1D,2E,3-
D,4B,5A,6A,7B),(1D,2E,3D,4B,5A,6A,7C),(1D,2E,3D,4B,5A,6B,7A),(1D,2E,3D,4B,-
5A,6B,7B),(1D,2E,3D,4B,5A,6B,7C),(1D,2E,3D,4B,5A,6C,7A),
(1D,2E,3D,4B,5A,6C,7B),(1D,2E,3D,4B,5A,6C,7C),(1D,2E,3D,4B,5A,6D,7A),(1D,-
2E,3D,4B,5A,6D,7B),(1D,2E,3D,4B,5A,6D,7C),(1D,2E,3D,4B,5B,6A,7A),(1D,2E,3D-
,4B,5B,6A,7B),
(1D,2E,3D,4B,5B,6A,7C),(1D,2E,3D,4B,5B,6B,7A),(1D,2E,3D,4B,-
5B,6B,7B),(1D,2E,3D,4B,5B,6B,7C),(1D,2E,3D,4B,5B,6C,7A),(1D,2E,3D,4B,5B,6C-
,7B),(1D,2E,3D,4B,5B,6C,7C),
(1D,2E,3D,4B,5B,6D,7A),(1D,2E,3D,4B,5B,6D,7B)-
,(1D,2E,3D,4B,5B,6D,7C),(1D,2E,3D,4C,5A,6A,7A),(1D,2E,3D,4C,5A,6A,7B),(1D,-
2E,3D,4C,5A,6A,7C),(1D,2E,3D,4C,5A,6B,7A),
(1D,2E,3D,4C,5A,6B,7B),(1D,2E,3-
D,4C,5A,6B,7C),(1D,2E,3D,4C,5A,6C,7A),(1D,2E,3D,4C,5A,6C,7B),(1D,2E,3D,4C,-
5A,6C,7C),(1D,2E,3D,4C,5A,6D,7A),(1D,2E,3D,4C,5A,6D,7B),
(1D,2E,3D,4C,5A,6D,7C),(1D,2E,3D,4C,5B,6A,7A),(1D,2E,3D,4C,5B,6A,7B),(1D,-
2E,3D,4C,5B,6A,7C),
(1D,2E,3D,4C,5B,6B,7A),(1D,2E,3D,4C,5B,6B,7B),(1D,2E,3-
D,4C,5B,6B,7C),
(1D,2E,3D,4C,5B,6C,7A),(1D,2E,3D,4C,5B,6C,7B),(1D,2E,3D,4C-
,5B,6C,7C),(1D,2E,3D,4C,5B,6D,7A),(1D,2E,3D,4C,5B,6D,7B),(1D,2E,3D,4C,5B,6-
D,7C),(1D,2E,3D,4D,5A,6A,7A),
(1D,2E,3D,4D,5A,6A,7B),(1D,2E,3D,4D,5A,6A,7C-
),(1D,2E,3D,4D,5A,6B,7A),(1D,2E,3D,4D,5A,6B,7B),(1D,2E,3D,4D,5A,6B,7C),(1D-
,2E,3D,4D,5A,6C,7A),(1D,2E,3D,4D,5A,6C,7B),
(1D,2E,3D,4D,5A,6C,7C),(1D,2E,-
3D,4D,5A,6D,7A),(1D,2E,3D,4D,5A,6D,7B),(1D,2E,3D,4D,5A,6D,7C),(1D,2E,3D,4D-
,5B,6A,7A),(1D,2E,3D,4D,5B,6A,7B),(1D,2E,3D,4D,5B,6A,7C),
(1D,2E,3D,4D,5B,6B,7A),(1D,2E,3D,4D,5B,6B,7B),(1D,2E,3D,4D,5B,6B,7C),(1D,-
2E,3D,4D,5B,6C,7A),(1D,2E,3D,4D,5B,6C,7B),(1D,2E,3D,4D,5B,6C,7C),(1D,2E,3D-
,4D,5B,6D,7A),
(1D,2E,3D,4D,5B,6D,7B),(1D,2E,3D,4D,5B,6D,7C),(1D,2E,3D,4E,-
5A,6A,7A),(1D,2E,3D,4E,5A,6A,7B),(1D,2E,3D,4E,5A,6A,7C),(1D,2E,3D,4E,5A,6B-
,7A),(1D,2E,3D,4E,5A,6B,7B),
(1D,2E,3D,4E,5A,6B,7C),(1D,2E,3D,4E,5A,6C,7A)-
,(1D,2E,3D,4E,5A,6C,7B),(1D,2E,3D,4E,5A,6C,7C),(1D,2E,3D,4E,5A,6D,7A),(1D,-
2E,3D,4E,5A,6D,7B),(1D,2E,3D,4E,5A,6D,7C),
(1D,2E,3D,4E,5B,6A,7A),(1D,2E,3-
D,4E,5B,6A,7B),(1D,2E,3D,4E,5B,6A,7C),(1D,2E,3D,4E,5B,6B,7A),(1D,2E,3D,4E,-
5B,6B,7B),(1D,2E,3D,4E,5B,6B,7C),(1D,2E,3D,4E,5B,6C,7A),
(1D,2E,3D,4E,5B,6C,7B),(1D,2E,3D,4E,5B,6C,7C),(1D,2E,3D,4E,5B,6D,7A),(1D,-
2E,3D,4E,5B,6D,7B),(1D,2E,3D,4E,5B,6D,7C),(1D,2E,3E,4A,5A,6A,7A),(1D,2E,3E-
,4A,5A,6A,7B),
(1D,2E,3E,4A,5A,6A,7C),(1D,2E,3E,4A,5A,6B,7A),(1D,2E,3E,4A,-
5A,6B,7B),(1D,2E,3E,4A,5A,6B,7C),(1D,2E,3E,4A,5A,6C,7A),(1D,2E,3E,4A,5A,6C-
,7B),(1D,2E,3E,4A,5A,6C,7C),
(1D,2E,3E,4A,5A,6D,7A),(1D,2E,3E,4A,5A,6D,7B)-
,(1D,2E,3E,4A,5A,6D,7C),(1D,2E,3E,4A,5B,6A,7A),(1D,2E,3E,4A,5B,6A,7B),(1D,-
2E,3E,4A,5B,6A,7C),(1D,2E,3E,4A,5B,6B,7A),
(1D,2E,3E,4A,5B,6B,7B),(1D,2E,3-
E,4A,5B,6B,7C),(1D,2E,3E,4A,5B,6C,7A),(1D,2E,3E,4A,5B,6C,7B),(1D,2E,3E,4A,-
5B,6C,7C),(1D,2E,3E,4A,5B,6D,7A),(1D,2E,3E,4A,5B,6D,7B),
(1D,2E,3E,4A,5B,6D,7C),(1D,2E,3E,4B,5A,6A,7A),(1D,2E,3E,4B,5A,6A,7B),(1D,-
2E,3E,4B,5A,6A,7C),(1D,2E,3E,4B,5A,6B,7A),(1D,2E,3E,4B,5A,6B,7B),(1D,2E,3E-
,4B,5A,6B,7C),
(1D,2E,3E,4B,5A,6C,7A),(1D,2E,3E,4B,5A,6C,7B),(1D,2E,3E,4B,-
5A,6C,7C),(1D,2E,3E,4B,5A,6D,7A),(1D,2E,3E,4B,5A,6D,7B),(1D,2E,3E,4B,5A,6D-
,7C),(1D,2E,3E,4B,5B,6A,7A),
(1D,2E,3E,4B,5B,6A,7B),(1D,2E,3E,4B,5B,6A,7C)-
,(1D,2E,3E,4B,5B,6B,7A),(1D,2E,3E,4B,5B,6B,7B),(1D,2E,3E,4B,5B,6B,7C),(1D,-
2E,3E,4B,5B,6C,7A),(1D,2E,3E,4B,5B,6C,7B),
(1D,2E,3E,4B,5B,6C,7C),(1D,2E,3-
E,4B,5B,6D,7A),(1D,2E,3E,4B,5B,6D,7B),(1D,2E,3E,4B,5B,6D,7C),
(1D,2E,3E,4C,5A,6A,7A),(1D,2E,3E,4C,5A,6A,7B),(1D,2E,3E,4C,5A,6A,7C),
(1D,2E,3E,4C,5A,6B,7A), (1D,2E,3E,4C,5A,6B,7B),
(1D,2E,3E,4C,5A,6B,7C),
(1D,2E,3E,4C,5A,6C,7A),(1D,2E,3E,4C,5A,6C,7B),(1D,2E,3E,4C,5A,6C,7C),(1D,-
2E,3E,4C,5A,6D,7A),
(1D,2E,3E,4C,5A,6D,7B),(1D,2E,3E,4C,5A,6D,7C),(1D,2E,3-
E,4C,5B,6A,7A),(1D,2E,3E,4C,5B,6A,7B),(1D,2E,3E,4C,5B,6A,7C),(1D,2E,3E,4C,-
5B,6B,7A),(1D,2E,3E,4C,5B,6B,7B),
(1D,2E,3E,4C,5B,6B,7C),(1D,2E,3E,4C,5B,6-
C,7A),(1D,2E,3E,4C,5B,6C,7B),(1D,2E,3E,4C,5B,6C,7C),(1D,2E,3E,4C,5B,6D,7A)-
,(1D,2E,3E,4C,5B,6D,7B),(1D,2E,3E,4C,5B,6D,7C),
(1D,2E,3E,4D,5A,6A,7A),(1D-
,2E,3E,4D,5A,6A,7B),(1D,2E,3E,4D,5A,6A,7C),(1D,2E,3E,4D,5A,6B,7A),(1D,2E,3-
E,4D,5A,6B,7B),(1D,2E,3E,4D,5A,6B,7C),(1D,2E,3E,4D,5A,6C,7A),
(1D,2E,3E,4D,5A,6C,7B),(1D,2E,3E,4D,5A,6C,7C),(1D,2E,3E,4D,5A,6D,7A),(1D,-
2E,3E,4D,5A,6D,7B),(1D,2E,3E,4D,5A,6D,7C),(1D,2E,3E,4D,5B,6A,7A),(1D,2E,3E-
,4D,5B,6A,7B),
(1D,2E,3E,4D,5B,6A,7C),(1D,2E,3E,4D,5B,6B,7A),(1D,2E,3E,4D,-
5B,6B,7B),(1D,2E,3E,4D,5B,6B,7C),(1D,2E,3E,4D,5B,6C,7A),(1D,2E,3E,4D,5B,6C-
,7B),(1D,2E,3E,4D,5B,6C,7C),
(1D,2E,3E,4D,5B,6D,7A),(1D,2E,3E,4D,5B,6D,7B)-
,(1D,2E,3E,4D,5B,6D,7C),(1D,2E,3E,4E,5A,6A,7A),(1D,2E,3E,4E,5A,6A,7B),(1D,-
2E,3E,4E,5A,6A,7C),(1D,2E,3E,4E,5A,6B,7A),
(1D,2E,3E,4E,5A,6B,7B),(1D,2E,3-
E,4E,5A,6B,7C),(1D,2E,3E,4E,5A,6C,7A),(1D,2E,3E,4E,5A,6C,7B),(1D,2E,3E,4E,-
5A,6C,7C),(1D,2E,3E,4E,5A,6D,7A),(1D,2E,3E,4E,5A,6D,7B),
(1D,2E,3E,4E,5A,6D,7C),(1D,2E,3E,4E,5B,6A,7A),(1D,2E,3E,4E,5B,6A,7B),(1D,-
2E,3E,4E,5B,6A,7C),(1D,2E,3E,4E,5B,6B,7A),(1D,2E,3E,4E,5B,6B,7B),(1D,2E,3E-
,4E,5B,6B,7C),
(1D,2E,3E,4E,5B,6C,7A),(1D,2E,3E,4E,5B,6C,7B),(1D,2E,3E,4E,-
5B,6C,7C),(1D,2E,3E,4E,5B,6D,7A),(1D,2E,3E,4E,5B,6D,7B),(1D,2E,3E,4E,5B,6D-
,7C),(1E,2A,3A,4A,5A,6A,7A),
(1E,2A,3A,4A,5A,6A,7B),(1E,2A,3A,4A,5A,6A,7C)-
,(1E,2A,3A,4A,5A,6B,7A),(1E,2A,3A,4A,5A,6B,7B),(1E,2A,3A,4A,5A,6B,7C),(1E,-
2A,3A,4A,5A,6C,7A),(1E,2A,3A,4A,5A,6C,7B),
(1E,2A,3A,4A,5A,6C,7C),(1E,2A,3-
A,4A,5A,6D,7A),(1E,2A,3A,4A,5A,6D,7B),(1E,2A,3A,4A,5A,6D,7C),(1E,2A,3A,4A,-
5B,6A,7A),(1E,2A,3A,4A,5B,6A,7B),(1E,2A,3A,4A,5B,6A,7C),
(1E,2A,3A,4A,5B,6B,7A),(1E,2A,3A,4A,5B,6B,7B),(1E,2A,3A,4A,5B,6B,7C),(1E,-
2A,3A,4A,5B,6C,7A),(1E,2A,3A,4A,5B,6C,7B),(1E,2A,3A,4A,5B,6C,7C),(1E,2A,3A-
,4A,5B,6D,7A),
(1E,2A,3A,4A,5B,6D,7B),(1E,2A,3A,4A,5B,6D,7C),(1E,2A,3A,4B,-
5A,6A,7A),(1E,2A,3A,4B,5A,6A,7B),(1E,2A,3A,4B,5A,6A,7C),(1E,2A,3A,4B,5A,6B-
,7A),(1E,2A,3A,4B,5A,6B,7B),
(1E,2A,3A,4B,5A,6B,7C),(1E,2A,3A,4B,5A,6C,7A)-
,(1E,2A,3A,4B,5A,6C,7B),(1E,2A,3A,4B,5A,6C,7C),(1E,2A,3A,4B,5A,6D,7A),(1E,-
2A,3A,4B,5A,6D,7B),(1E,2A,3A,4B,5A,6D,7C),
(1E,2A,3A,4B,5B,6A,7A),(1E,2A,3-
A,4B,5B,6A,7B),(1E,2A,3A,4B,5B,6A,7C),(1E,2A,3A,4B,5B,6B,7A),(1E,2A,3A,4B,-
5B,6B,7B),(1E,2A,3A,4B,5B,6B,7C),(1E,2A,3A,4B,5B,6C,7A),
(1E,2A,3A,4B,5B,6C,7B),(1E,2A,3A,4B,5B,6C,7C),(1E,2A,3A,4B,5B,6D,7A),(1E,-
2A,3A,4B,5B,6D,7B),(1E,2A,3A,4B,5B,6D,7C),(1E,2A,3A,4C,5A,6A,7A),(1E,2A,3A-
,4C,5A,6A,7B),
(1E,2A,3A,4C,5A,6A,7C),(1E,2A,3A,4C,5A,6B,7A),(1E,2A,3A,4C,-
5A,6B,7B),(1E,2A,3A,4C,5A,6B,7C),(1E,2A,3A,4C,5A,6C,7A),(1E,2A,3A,4C,5A,6C-
,7B),(1E,2A,3A,4C,5A,6C,7C),
(1E,2A,3A,4C,5A,6D,7A),(1E,2A,3A,4C,5A,6D,7B)-
,(1E,2A,3A,4C,5A,6D,7C),(1E,2A,3A,4C,5B,6A,7A),(1E,2A,3A,4C,5B,6A,7B),(1E,-
2A,3A,4C,5B,6A,7C),(1E,2A,3A,4C,5B,6B,7A),
(1E,2A,3A,4C,5B,6B,7B),(1E,2A,3-
A,4C,5B,6B,7C),(1E,2A,3A,4C,5B,6C,7A),(1E,2A,3A,4C,5B,6C,7B),(1E,2A,3A,4C,-
5B,6C,7C),(1E,2A,3A,4C,5B,6D,7A),(1E,2A,3A,4C,5B,6D,7B),
(1E,2A,3A,4C,5B,6D,7C),(1E,2A,3A,4D,5A,6A,7A),(1E,2A,3A,4D,5A,6A,7B),(1E,-
2A,3A,4D,5A,6A,7C),(1E,2A,3A,4D,5A,6B,7A),(1E,2A,3A,4D,5A,6B,7B),(1E,2A,3A-
,4D,5A,6B,7C),
(1E,2A,3A,4D,5A,6C,7A),(1E,2A,3A,4D,5A,6C,7B),(1E,2A,3A,4D,-
5A,6C,7C),(1E,2A,3A,4D,5A,6D,7A),(1E,2A,3A,4D,5A,6D,7B),(1E,2A,3A,4D,5A,6D-
,7C),(1E,2A,3A,4D,5B,6A,7A),
(1E,2A,3A,4D,5B,6A,7B),(1E,2A,3A,4D,5B,6A,7C)-
,(1E,2A,3A,4D,5B,6B,7A),(1E,2A,3A,4D,5B,6B,7B),(1E,2A,3A,4D,5B,6B,7C),(1E,-
2A,3A,4D,5B,6C,7A),(1E,2A,3A,4D,5B,6C,7B),
(1E,2A,3A,4D,5B,6C,7C),(1E,2A,3-
A,4D,5B,6D,7A),(1E,2A,3A,4D,5B,6D,7B),(1E,2A,3A,4D,5B,6D,7C),(1E,2A,3A,4E,-
5A,6A,7A),(1E,2A,3A,4E,5A,6A,7B),(1E,2A,3A,4E,5A,6A,7C),
(1E,2A,3A,4E,5A,6B,7A),(1E,2A,3A,4E,5A,6B,7B),(1E,2A,3A,4E,5A,6B,7C),(1E,-
2A,3A,4E,5A,6C,7A),(1E,2A,3A,4E,5A,6C,7B),(1E,2A,3A,4E,5A,6C,7C),(1E,2A,3A-
,4E,5A,6D,7A),
(1E,2A,3A,4E,5A,6D,7B),(1E,2A,3A,4E,5A,6D,7C),(1E,2A,3A,4E,-
5B,6A,7A),(1E,2A,3A,4E,5B,6A,7B),(1E,2A,3A,4E,5B,6A,7C),(1E,2A,3A,4E,5B,6B-
,7A),(1E,2A,3A,4E,5B,6B,7B),
(1E,2A,3A,4E,5B,6B,7C),(1E,2A,3A,4E,5B,6C,7A)-
,(1E,2A,3A,4E,5B,6C,7B),(1E,2A,3A,4E,5B,6C,7C),(1E,2A,3A,4E,5B,6D,7A),(1E,-
2A,3A,4E,5B,6D,7B),(1E,2A,3A,4E,5B,6D,7C),
(1E,2A,3B,4A,5A,6A,7A),(1E,2A,3-
B,4A,5A,6A,7B),(1E,2A,3B,4A,5A,6A,7C),(1E,2A,3B,4A,5A,6B,7A),(1E,2A,3B,4A,-
5A,6B,7B),(1E,2A,3B,4A,5A,6B,7C),(1E,2A,3B,4A,5A,6C,7A),
(1E,2A,3B,4A,5A,6C,7B),(1E,2A,3B,4A,5A,6C,7C),(1E,2A,3B,4A,5A,6D,7A),(1E,-
2A,3B,4A,5A,6D,7B),(1E,2A,3B,4A,5A,6D,7C),(1E,2A,3B,4A,5B,6A,7A),(1E,2A,3B-
,4A,5B,6A,7B),
(1E,2A,3B,4A,5B,6A,7C),(1E,2A,3B,4A,5B,6B,7A),(1E,2A,3B,4A,-
5B,6B,7B),(1E,?A,3B,4A,5B,6B,7C),
(1E,2A,3B,4A,5B,6C,7A),(1E,2A,3B,4A,5B,6-
C,7B),(1E,2A,3B,4A,5B,6C,7C), (1E,2A,3B,4A,5B,6D,7A),
(1E,2A,3B,4A,5B,6D,7B),(1E,2A,3B,4A,5B,6D,7C),
(1E,2A,3B,4B,5A,6A,7A),
(1E,2A,3B,4B,5A,6A,7B),(1E,2A,3B,4B,5A,6A,7C),(1E,2A,3B,4B,5A,6B,7A),
(!E,2A,3B,4B,5A,6B,7B),(1E,2A,3B,4B,5A,6B,7C),
(1E,2A,3B,4B,5A,6C,7A), (1E,2A,3B,4B,5A,6C,7B),
(1E,2A,3B,4B,5A,6C,7C),(1E,2A,3B,4B,5A,6D,7A),(1E-
,2A,3B,4B,5A,6D,7B), (1E,2A,3B,4B,5A,6D,7C),
(1E,2A,3B,4B,5B,6A,7A), (1E,2A,3B,4B,5B,6A,7B),
(1E,2A,3B,4B,5B,6A,7C), (1E,2A,3B,4B,5B,6B,7A),(1-
E,2A,3B,4B,5B,6B,7B),(1E,2A,3B,4B,5B,6B,7C),
(1E,2A,3B,4B,5B,6C,7A),(1E,2A- ,3B,4B,5B,6C,7B),
(1E,2A,3B,4B,5B,6C,7C),(1E,2A,3B,4B,5B,6D,7A),
(1E,2A,3B,4B,5B,6D,7B), (1E,2A,3B,4B,5B,6D,7C),
(1E,2A,3B,4C,5A,6A,7A),
(1E,2A,3B,4C,5A,6A,7B),(1E,2A,3B,4C,5A,6A,7C),(1E,2A,3B,4C,5A,6B,7A),(1E,-
2A,3B,4C,5A,6B,7B),(1E,2A,3B,4C,5A,6B,7C),(1E,2A,3B,4C,5A,6C,7A),(1E,2A,3B-
,4C,5A,6C,7B),
(1E,2A,3B,4C,5A,6C,7C),(1E,2A,3B,4C,5A,6D,7A),(1E,2A,3B,4C,-
5A,6D,7B),(1E,2A,3B,4C,5A,6D,7C),(1E,2A,3B,4C,5B,6A,7A),(1E,2A,3B,4C,5B,6A-
,7B),(1E,2A,3B,4C,5B,6A,7C),
(1E,2A,3B,4C,5B,6B,7A),(1E,2A,3B,4C,5B,6B,7B)-
,(1E,2A,3B,4C,5B,6B,7C),(1E,2A,3B,4C,5B,6C,7A),(1E,2A,3B,4C,5B,6C,7B),(1E,-
2A,3B,4C,5B,6C,7C),(1E,2A,3B,4C,5B,6D,7A),
(1E,2A,3B,4C,5B,6D,7B),(1E,2A,3-
B,4C,5B,6D,7C),(1E,2A,3B,4D,5A,6A,7A),(1E,2A,3B,4D,5A,6A,7B),
(1E,2A,3B,4D,5A,6A,7C),(1E,2A,3B,4D,5A,6B,7A),
(E,2A,3B,4D,5A,6B,7B),
(1E,2A,3B,4D,5A,6B,7C),(1E,2A,3B,4D,5A,6C,7A).,(1E,2A,3B,4D,5A,6C,7B),(1E-
,2A,3B,4D,5A,6C,7C),(1E,2A,3B,4D,5A,6D,7A),(1E,2A,3B,4D,5A,6D,7B),(1E,2A,3-
B,4D,5A,6D,7C),
(1E,2A,3B,4D,5B,6A,7A),(1E,2A,3B,4D,5B,6A,7B),(1E,2A,3B,4D-
,5B,6A,7C),(1E,2A,3B,4D,5B,6B,7A),(1E,2A,3B,4D,5B,6B,7B),(1E,2A,3B,4D,5B,6-
B,7C),(1E,2A,3B,4D,5B,6C,7A),
(1E,2A,3B,4D,5B,6C,7B),(1E,2A,3B,4D,5B,6C,7C-
),(1E,2A,3B,4D,5B,6D,7A),(1E,2A,3B,4D,5B,6D,7B),(1E,2A,3B,4D,5B,6D,7C),(1E-
,2A,3B,4E,5A,6A,7A),(1E,2A,3B,4E,5A,6A,7B),
(1E,2A,3B,4E,5A,6A,7C),(1E,2A,-
3B,4E,5A,6B,7A),(1E,2A,3B,4E,5A,6B,7B),
(1E,2A,3B,4E,5A,6B,7C),(1E,2A,3B,4-
E,5A,6C,7A),(1E,2A,3B,4E,5A,6C,7B),(1E,2A,3B,4E,5A,6C,7C),(1E,2A,3B,4E,5A,-
6D,7A),(1E,2A,3B,4E,5A,6D,7B),(1E,2A,3B,4E,5A,6D,7C),
(1E,2A,3B,4E,5B,6A,7A),(1E,2A,3B,4E,5B,6A,7B),(1E,2A,3B,4E,5B,6A,7C),(1E,-
2A,3B,4E,5B,6B,7A),(1E,2A,3B,4E,5B,6B,7B),(1E,2A,3B,4E,5B,6B,7C),(1E,2A,3B-
,4E,5B,6C,7A),
(1E,2A,3B,4E,5B,6C,7B),(1E,2A,3B,4E,5B,6C,7C),(1E,2A,3B,4E,-
5B,6D,7A),(1E,2A,3B,4E,5B,6D,7B),(1E,2A,3B,4E,5B,6D,7C),(1E,2A,3C,4A,5A,6A-
,7A),(1E,2A,3C,4A,5A,6A,7B),
(1E,2A,3C,4A,5A,6A,7C),(1E,2A,3C,4A,5A,6B,7A)-
,(1E,2A,3C,4A,5A,6B,7B),(1E,2A,3C,4A,5A,6B,7C),(1E,2A,3C,4A,5A,6C,7A),(1E,-
2A,3C,4A,5A,6C,7B),(1E,2A,3C,4A,5A,6C,7C),
(1E,2A,3C,4A,5A,6D,7A),(1E,2A,3-
C,4A,5A,6D,7B),(1E,2A,3C,4A,5A,6D,7C),(1E,2A,3C,4A,5B,6A,7A),(1E,2A,3C,4A,-
5B,6A,7B),(1E,2A,3C,4A,5B,6A,7C),(1E,2A,3C,4A,5B,6B,7A),
(1E,2A,3C,4A,5B,6B,7B),(1E,2A,3C,4A,5B,6B,7C),(1E,2A,3C,4A,5B,6C,7A),(1E,-
2A,3C,4A,5B,6C,7B),(1E,2A,3C,4A,5B,6C,7C),(1E,2A,3C,4A,5B,6D,7A),(1E,2A,3C-
,4A,5B,6D,7B),
(1E,2A,3C,4A,5B,6D,7C),(1E,2A,3C,4B,5A,6A,7A),(1E,2A,3C,4B,-
5A,6A,7B),(1E,2A,3C,4B,5A,6A,7C),(1E,2A,3C,4B,5A,6B,7A),(1E,2A,3C,4B,5A,6B-
,7B),(1E,2A,3C,4B,5A,6B,7C),
(1E,2A,3C,4B,5A,6C,7A),(1E,2A,3C,4B,5A,6C,7B)-
,(1E,2A,3C,4B,5A,6C,7C),(1E,2A,3C,4B,5A,6D,7A),(1E,2A,3C,4B,5A,6D,7B),(1E,-
2A,3C,4B,5A,6D,7C),(1E,2A,3C,4B,5B,6A,7A),
(1E,2A,3C,4B,5B,6A,7B),(1E,2A,3-
C,4B,5B,6A,7C),(1E,2A,3C,4B,5B,6B,7A),(1E,2A,3C,4B,5B,6B,7B),(1E,2A,3C,4B,-
5B,6B,7C),(1E,2A,3C,4B,5B,6C,7A),(1E,2A,3C,4B,5B,6C,7B),
(1E,2A,3C,4B,5B,6C,7C),(1E,2A,3C,4B,5B,6D,7A),(1E,2A,3C,4B,5B,6D,7B),(1E,-
2A,3C,4B,5B,6D,7C),(1E,2A,3C,4C,5A,6A,7A),(1E,2A,3C,4C,5A,6A,7B),(1E,2A,3C-
,4C,5A,6A,7C),
(1E,2A,3C,4C,5A,6B,7A),(1E,2A,3C,4C,5A,6B,7B),(1E,2A,3C,4C,-
5A,6B,7C),(1E,2A,3C,4C,5A,6C,7A),(1E,2A,3C,4C,5A,6C,7B),(1E,2A,3C,4C,5A,6C-
,7C),(1E,2A,3C,4C,5A,6D,7A),
(1E,2A,3C,4C,5A,6D,7B),(1E,2A,3C,4C,5A,6D,7C)-
,(1E,2A,3C,4C,5B,6A,7A),(1E,2A,3C,4C,5B,6A,7B),(1E,2A,3C,4C,5B,6A,7C),(1E,-
2A,3C,4C,5B,6B,7A),(1E,2A,3C,4C,5B,6B,7B),
(1E,2A,3C,4C,5B,6B,7C),(1E,2A,3-
C,4C,5B,6C,7A),(1E,2A,3C,4C,5B,6C,7B),(1E,2A,3C,4C,5B,6C,7C),(1E,2A,3C,4C,-
5B,6D,7A),(1E,2A,3C,4C,5B,6D,7B),(1E,2A,3C,4C,5B,6D,7C),
(1E,2A,3C,4D,5A,6A,7A),(1E,2A,3C,4D,5A,6A,7B),(1E,2A,3C,4D,5A,6A,7C),(1E,-
2A,3C,4D,5A,6B,7A),(1E,2A,3C,4D,5A,6B,7B),(1E,2A,3C,4D,5A,6B,7C),(1E,2A,3C-
,4D,5A,6C,7A),
(1E,2A,3C,4D,5A,6C,7B),(1E,2A,3C,4D,5A,6C,7C),(1E,2A,3C,4D,-
5A,6D,7A),(1E,2A,3C,4D,5A,6D,7B),(1E,2A,3C,4D,5A,6D,7C),(1E,2A,3C,4D,5B,6A-
,7A),(1E,2A,3C,4D,5B,6A,7B),
(1E,2A,3C,4D,5B,6A,7C),(1E,2A,3C,4D,5B,6B,7A)-
,(1E,2A,3C,4D,5B,6B,7B),(1E,2A,3C,4D,5B,6B,7C),(1E,2A,3C,4D,5B,6C,7A),(1E,-
2A,3C,4D,5B,6C,7B),(1E,2A,3C,4D,5B,6C,7C),
(1E,2A,3C,4D,5B,6D,7A),(1E,2A,3-
C,4D,5B,6D,7B),(1E,2A,3C,4D,5B,6D,7C),(1E,2A,3C,4E,5A,6A,7A),(1E,2A,3C,4E,-
5A,6A,7B),(1E,2A,3C,4E,5A,6A,7C),(1E,2A,3C,4E,5A,6B,7A),
(1E,2A,3C,4E,5A,6B,7B),(1E,2A,3C,4E,5A,6B,7C),(1E,2A,3C,4E,5A,6C,7A),(1E,-
2A,3C,4E,5A,6C,7B),(1E,2A,3C,4E,5A,6C,7C),(1E,2A,3C,4E,5A,6D,7A),(1E,2A,3C-
,4E,5A,6D,7B),
(1E,2A,3C,4E,5A,6D,7C),(1E,2A,3C,4E,5B,6A,7A),(1E,2A,3C,4E,-
5B,6A,7B),(1E,2A,3C,4E,5B,6A,7C),(1E,2A,3C,4E,5B,6B,7A),(1E,2A,3C,4E,5B,6B-
,7B),(1E,2A,3C,4E,5B,6B,7C),
(1E,2A,3C,4E,5B,6C,7A),(1E,2A,3C,4E,5B,6C,7B)-
,(1E,2A,3C,4E,5B,6C,7C),(1E,2A,3C,4E,5B,6D,7A),(1E,2A,3C,4E,5B,6D,7B),(1E,-
2A,3C,4E,5B,6D,7C),(1E,2A,3D,4A,5A,6A,7A),
(1E,2A,3D,4A,5A,6A,7B),(1E,2A,3-
D,4A,5A,6A,7C),(1E,2A,3D,4A,5A,6B,7A),(1E,2A,3D,4A,5A,6B,7B),(1E,2A,3D,4A,-
5A,6B,7C),(1E,2A,3D,4A,5A,6C,7A),(1E,2A,3D,4A,5A,6C,7B),
(1E,2A,3D,4A,5A,6C,7C),(1E,2A,3D,4A,5A,6D,7A),(1E,2A,3D,4A,5A,6D,7B),(1E,-
2A,3D,4A,5A,6D,7C),(1E,2A,3D,4A,5B,6A,7A),(1E,2A,3D,4A,5B,6A,7B),(1E,2A,3D-
,4A,5B,6A,7C),
(1E,2A,3D,4A,5B,6B,7A),(1E,2A,3D,4A,5B,6B,7B),(1E,2A,3D,4A,-
5B,6B,7C),(1E,2A,3D,4A,5B,6C,7A),(1E,2A,3D,4A,5B,6C,7B),(1E,2A,3D,4A,5B,6C-
,7C),(1E,2A,3D,4A,5B,6D,7A),
(1E,2A,3D,4A,5B,6D,7B),(1E,2A,3D,4A,5B,6D,7C)-
,(1E,2A,3D,4B,5A,6A,7A),(1E,2A,3D,4B,5A,6A,7B),(1E,2A,3D,4B,5A,6A,7C),(1E,-
2A,3D,4B,5A,6B,7A),(1E,2A,3D,4B,5A,6B,7B),
(1E,2A,3D,4B,5A,6B,7C),(1E,2A,3-
D,4B,5A,6C,7A),(1E,2A,3D,4B,5A,6C,7B),(1E,2A,3D,4B,5A,6C,7C),(1E,2A,3D,4B,-
5A,6D,7A),(1E,2A,3D,4B,5A,6D,7B),(1E,2A,3D,4B,5A,6D,7C),
(1E,2A,3D,4B,5B,6A,7A),(1E,2A,3D,4B,5B,6A,7B),(1E,2A,3D,4B,5B,6A,7C),(1E,-
2A,3D,4B,5B,6B,7A),(1E,2A,3D,4B,5B,6B,7B),(1E,2A,3D,4B,5B,6B,7C),(1E,2A,3D-
,4B,5B,6C,7A),
(1E,2A,3D,4B,5B,6C,7B),(1E,2A,3D,4B,5B,6C,7C),(1E,2A,3D,4B,-
5B,6D,7A),(1E,2A,3D,4B,5B,6D,7B),(1E,2A,3D,4B,5B,6D,7C),(1E,2A,3D,4C,5A,6A-
,7A),(1E,2A,3D,4C,5A,6A,7B),
(1E,2A,3D,4C,5A,6A,7C),(1E,2A,3D,4C,5A,6B,7A)-
,(1E,2A,3D,4C,5A,6B,7B),(1E,2A,3D,4C,5A,6B,7C),(1E,2A,3D,4C,5A,6C,7A),(1E,-
2A,3D,4C,5A,6C,7B),(1E,2A,3D,4C,5A,6C,7C),
(1E,2A,3D,4C,5A,6D,7A),(1E,2A,3-
D,4C,5A,6D,7B),(1E,2A,3D,4C,5A,6D,7C),(1E,2A,3D,4C,5B,6A,7A),(1E,2A,3D,4C,-
5B,6A,7B),(1E,2A,3D,4C,5B,6A,7C),(1E,2A,3D,4C,5B,6B,7A),
(1E,2A,3D,4C,5B,6B,7B),(1E,2A,3D,4C,5B,6B,7C),(1E,2A,3D,4C,5B,6C,7A),(1E,-
2A,3D,4C,5B,6C,7B),(1E,2A,3D,4C,5B,6C,7C),(1E,2A,3D,4C,5B,6D,7A),(1E,2A,3D-
,4C,5B,6D,7B),
(1E,2A,3D,4C,5B,6D,7C),(1E,2A,3D,4D,5A,6A,7A),(1E,2A,3D,4D,-
5A,6A,7B),(1E,2A,3D,4D,5A,6A,7C),(1E,2A,3D,4D,5A,6B,7A),(1E,2A,3D,4D,5A,6B-
,7B),(1E,2A,3D,4D,5A,6B,7C),
(1E,2A,3D,4D,5A,6C,7A),(1E,2A,3D,4D,5A,6C,7B)-
,(1E,2A,3D,4D,5A,6C,7C),(1E,2A,3D,4D,5A,6D,7A),(1E,2A,3D,4D,5A,6D,7B),(1E,-
2A,3D,4D,5A,6D,7C),(1E,2A,3D,4D,5B,6A,7A),
(1E,2A,3D,4D,5B,6A,7B),(1E,2A,3-
D,4D,5B,6A,7C),(1E,2A,3D,4D,5B,6B,7A),(1E,2A,3D,4D,5B,6B,7B),(1E,2A,3D,4D,-
5B,6B,7C),(1E,2A,3D,4D,5B,6C,7A),(1E,2A,3D,4D,5B,6C,7B),
(1E,2A,3D,4D,5B,6C,7C),(1E,2A,3D,4D,5B,6D,7A),(1E,2A,3D,4D,5B,6D,7B),
(1E,2A,3D,4D,5B,6D,7C),(1E,2A,3D,4E,5A,6A,7A),(1E,2A,3D,4E,5A,6A,7B),(1E,-
2A,3D,4E,5A,6A,7C),
(1E,2A,3D,4E,5A,6B,7A),(1E,2A,3D,4E,5A,6B,7B),(1E,2A,3-
D,4E,5A,6B,7C),(1E,2A,3D,4E,5A,6C,7A),(1E,2A,3D,4E,5A,6C,7B),(1E,2A,3D,4E,-
5A,6C,7C),(1E,2A,3D,4E,5A,6D,7A),
(1E,2A,3D,4E,5A,6D,7B),(1E,2A,3D,4E,5A,6-
D,7C),(1E,2A,3D,4E,5B,6A,7A),(1E,2A,3D,4E,5B,6A,7B),(1E,2A,3D,4E,5B,6A,7C)-
,(1E,2A,3D,4E,5B,6B,7A),(1E,2A,3D,4E,5B,6B,7B),
(1E,2A,3D,4E,5B,6B,7C),(1E-
,2A,3D,4E,5B,6C,7A),(1E,2A,3D,4E,5B,6C,7B),(1E,2A,3D,4E,5B,6C,7C),(1E,2A,3-
D,4E,5B,6D,7A),(1E,2A,3D,4E,5B,6D,7B),(1E,2A,3D,4E,5B,6D,7C),
(1E,2A,3E,4A,5A,6A,7A),(1E,2A,3E,4A,5A,6A,7B),(1E,2A,3E,4A,5A,6A,7C),(1E,-
2A,3E,4A,5A,6B,7A),(1E,2A,3E,4A,5A,6B,7B),(1E,2A,3E,4A,5A,6B,7C),(1E,2A,3E-
,4A,5A,6C,7A),
(1E,2A,3E,4A,5A,6C,7B),(1E,2A,3E,4A,5A,6C,7C),(1E,2A,3E,4A,-
5A,6D,7A),(1E,2A,3E,4A,5A,6D,7B),(1E,2A,3E,4A,5A,6D,7C),(1E,2A,3E,4A,5B,6A-
,7A),(1E,2A,3E,4A,5B,6A,7B),
(1E,2A,3E,4A,5B,6A,7C),(1E,2A,3E,4A,5B,6B,7A)-
,(1E,2A,3E,4A,5B,6B,7B),(1E,2A,3E,4A,5B,6B,7C),(1E,2A,3E,4A,5B,6C,7A),(1E,-
2A,3E,4A,5B,6C,7B),(1E,2A,3E,4A,5B,6C,7C),
(1E,2A,3E,4A,5B,6D,7A),(1E,2A,3-
E,4A,5B,6D,7B),(1E,2A,3E,4A,5B,6D,7C),(1E,2A,3E,4B,5A,6A,7A),(1E,2A,3E,4B,-
5A,6A,7B),(1E,2A,3E,4B,5A,6A,7C),(1E,2A,3E,4B,5A,6B,7A),
(1E,2A,3E,4B,5A,6B,7B),(1E,2A,3E,4B,5A,6B,7C),(1E,2A,3E,4B,5A,6C,7A),(1E,-
2A,3E,4B,5A,6C,7B),(1E,2A,3E,4B,5A,6C,7C),(1E,2A,3E,4B,5A,6D,7A),(1E,2A,3E-
,4B,5A,6D,7B),
(1E,2A,3E,4B,5A,6D,7C),(1E,2A,3E,4B,5B,6A,7A),(1E,2A,3E,4B,-
5B,6A,7B),(1E,2A,3E,4B,5B,6A,7C),(1E,2A,3E,4B,5B,6B,7A),(1E,2A,3E,4B,5B,6B-
,7B),(1E,2A,3E,4B,5B,6B,7C),
(1E,2A,3E,4B,5B,6C,7A),(1E,2A,3E,4B,5B,6C,7B)-
,(1E,2A,3E,4B,5B,6C,7C),(1E,2A,3E,4B,5B,6D,7A),(1E,2A,3E,4B,5B,6D,7B),(1E,-
2A,3E,4B,5B,6D,7C),(1E,2A,3E,4C,5A,6A,7A),
(1E,2A,3E,4C,5A,6A,7B),(1E,2A,3-
E,4C,5A,6A,7C),(1E,2A,3E,4C,5A,6B,7A),(1E,2A,3E,4C,5A,6B,7B),(1E,2A,3E,4C,-
5A,6B,7C),(1E,2A,3E,4C,5A,6C,7A),(1E,2A,3E,4C,5A,6C,7B),
(1E,2A,3E,4C,5A,6C,7C),(1E,2A,3E,4C,5A,6D,7A),(1E,2A,3E,4C,5A,6D,7B),(1E,-
2A,3E,4C,5A,6D,7C),(1E,2A,3E,4C,5B,6A,7A),(1E,2A,3E,4C,5B,6A,7B),(1E,2A,3E-
,4C,5B,6A,7C),
(1E,2A,3E,4C,5B,6B,7A),(1E,2A,3E,4C,5B,6B,7B),(1E,2A,3E,4C,-
5B,6B,7C),(1E,2A,3E,4C,5B,6C,7A),(1E,2A,3E,4C,5B,6C,7B),(1E,2A,3E,4C,5B,6C-
,7C),(1E,2A,3E,4C,5B,6D,7A),
(1E,2A,3E,4C,5B,6D,7B),(1E,2A,3E,4C,5B,6D,7C)-
,(1E,2A,3E,4D,5A,6A,7A),(1E,2A,3E,4D,5A,6A,7B),(1E,2A,3E,4D,5A,6A,7C),(1E,-
2A,3E,4D,5A,6B,7A),(1E,2A,3E,4D,5A,6B,7B),
(1E,2A,3E,4D,5A,6B,7C),(1E,2A,3-
E,4D,5A,6C,7A),(1E,2A,3E,4D,5A,6C,7B),(1E,2A,3E,4D,5A,6C,7C),(1E,2A,3E,4D,-
5A,6D,7A),(1E,2A,3E,4D,5A,6D,7B),(1E,2A,3E,4D,5A,6D,7C),
(1E,2A,3E,4D,5B,6A,7A),(1E,2A,3E,4D,5B,6A,7B),(1E,2A,3E,4D,5B,6A,7C),(1E,-
2A,3E,4D,5B,6B,7A),(1E,2A,3E,4D,5B,6B,7B),(1E,2A,3E,4D,5B,6B,7C),(1E,2A,3E-
,4D,5B,6C,7A),
(1E,2A,3E,4D,5B,6C,7B),(1E,2A,3E,4D,5B,6C,7C),(1E,2A,3E,4D,-
5B,6D,7A),(1E,2A,3E,4D,5B,6D,7B),(1E,2A,3E,4D,5B,6D,7C),(1E,2A,3E,4E,5A,6A-
,7A),(1E,2A,3E,4E,5A,6A,7B),
(1E,2A,3E,4E,5A,6A,7C),(1E,2A,3E,4E,5A,6B,7A)-
,(1E,2A,3E,4E,5A,6B,7B),(1E,2A,3E,4E,5A,6B,7C),(1E,2A,3E,4E,5A,6C,7A),(1E,-
2A,3E,4E,5A,6C,7B),(1E,2A,3E,4E,5A,6C,7C),
(1E,2A,3E,4E,5A,6D,7A),(1E,2A,3-
E,4E,5A,6D,7B),(1E,2A,3E,4E,5A,6D,7C),(1E,2A,3E,4E,5B,6A,7A),(1E,2A,3E,4E,-
5B,6A,7B),(1E,2A,3E,4E,5B,6A,7C),(1E,2A,3E,4E,5B,6B,7A),
(1E,2A,3E,4E,5B,6B,7B),(1E,2A,3E,4E,5B,6B,7C),(1E,2A,3E,4E,5B,6C,7A),(1E,-
2A,3E,4E,5B,6C,7B),(1E,2A,3E,4E,5B,6C,7C),(1E,2A,3E,4E,5B,6D,7A),(1E,2A,3E-
,4E,5B,6D,7B),
(1E,2A,3E,4E,5B,6D,7C),(1E,2B,3A,4A,5A,6A,7A),(1E,2B,3A,4A,-
5A,6A,7B),(1E,2B,3A,4A,5A,6A,7C),(1E,2B,3A,4A,5A,6B,7A),(1E,2B,3A,4A,5A,6B-
,7B),(1E,2B,3A,4A,5A,6B,7C),
(1E,2B,3A,4A,5A,6C,7A),(1E,2B,3A,4A,5A,6C,7B)-
,(1E,2B,3A,4A,5A,6C,7C),(1E,2B,3A,4A,5A,6D,7A),(1E,2B,3A,4A,5A,6D,7B),(1E,-
2B,3A,4A,5A,6D,7C),(1E,2B,3A,4A,5B,6A,7A),
(1E,2B,3A,4A,5B,6A,7B),(1E,2B,3-
A,4A,5B,6A,7C),(1E,2B,3A,4A,5B,6B,7A),(1E,2B,3A,4A,5B,6B,7B),(1E,2B,3A,4A,-
5B,6B,7C),(1E,2B,3A,4A,5B,6C,7A),(1E,2B,3A,4A,5B,6C,7B),
(1E,2B,3A,4A,5B,6C,7C),(1E,2B,3A,4A,5B,6D,7A),(1E,2B,3A,4A,5B,6D,7B),(1E,-
2B,3A,4A,5B,6D,7C),(1E,2B,3A,4B,5A,6A,7A),(1E,2B,3A,4B,5A,6A,7B),(1E,2B,3A-
,4B,5A,6A,7C),
(1E,2B,3A,4B,5A,6B,7A),(1E,2B,3A,4B,5A,6B,7B),(1E,2B,3A,4B,-
5A,6B,7C),(1E,2B,3A,4B,5A,6C,7A),(1E,2B,3A,4B,5A,6C,7B),(1E,2B,3A,4B,5A,6C-
,7C),(1E,2B,3A,4B,5A,6D,7A),
(1E,2B,3A,4B,5A,6D,7B),(1E,2B,3A,4B,5A,6D,7C)-
,(1E,2B,3A,4B,5B,6A,7A),(1E,2B,3A,4B,5B,6A,7B),(1E,2B,3A,4B,5B,6A,7C),(1E,-
2B,3A,4B,5B,6B,7A),(1E,2B,3A,4B,5B,6B,7B),
(1E,2B,3A,4B,5B,6B,7C),(1E,2B,3-
A,4B,5B,6C,7A),(1E,2B,3A,4B,5B,6C,7B),(1E,2B,3A,4B,5B,6C,7C),(1E,2B,3A,4B,-
5B,6D,7A),(1E,2B,3A,4B,5B,6D,7B),(1E,2B,3A,4B,5B,6D,7C),
(1E,2B,3A,4C,5A,6A,7A),(1E,2B,3A,4C,5A,6A,7B),(1E,2B,3A,4C,5A,6A,7C),(1E,-
2B,3A,4C,5A,6B,7A),(1E,2B,3A,4C,5A,6B,7B),(1E,2B,3A,4C,5A,6B,7C),(1E,2B,3A-
,4C,5A,6C,7A),
(1E,2B,3A,4C,5A,6C,7B),(1E,2B,3A,4C,5A,6C,7C),(1E,2B,3A,4C,-
5A,6D,7A),(1E,2B,3A,4C,5A,6D,7B),(1E,2B,3A,4C,5A,6D,7C),(1E,2B,3A,4C,5B,6A-
,7A),(1E,2B,3A,4C,5B,6A,7B),
(1E,2B,3A,4C,5B,6A,7C),(1E,2B,3A,4C,5B,6B,7A)-
,(1E,2B,3A,4C,5B,6B,7B),(1E,2B,3A,4C,5B,6B,7C),(1E,2B,3A,4C,5B,6C,7A),(1E,-
2B,3A,4C,5B,6C,7B),(1E,2B,3A,4C,5B,6C,7C),
(1E,2B,3A,4C,5B,6D,7A),(1E,2B,3-
A,4C,5B,6D,7B),(1E,2B,3A,4C,5B,6D,7C),(1E,2B,3A,4D,5A,6A,7A),(1E,2B,3A,4D,-
5A,6A,7B),(1E,2B,3A,4D,5A,6A,7C),(1E,2B,3A,4D,5A,6B,7A),
(1E,2B,3A,4D,5A,6B,7B),(1E,2B,3A,4D,5A,6B,7C),(1E,2B,3A,4D,5A,6C,7A),(1E,-
2B,3A,4D,5A,6C,7B),(1E,2B,3A,4D,5A,6C,7C),(1E,2B,3A,4D,5A,6D,7A),(1E,2B,3A-
,4D,5A,6D,7B),
(1E,2B,3A,4D,5A,6D,7C),(1E,2B,3A,4D,5B,6A,7A),(1E,2B,3A,4D,-
5B,6A,7B),(1E,2B,3A,4D,5B,6A,7C),(1E,2B,3A,4D,5B,6B,7A),(1E,2B,3A,4D,5B,6B-
,7B),(1E,2B,3A,4D,5B,6B,7C),
(1E,2B,3A,4D,5B,6C,7A),(1E,2B,3A,4D,5B,6C,7B)-
,(1E,2B,3A,4D,5B,6C,7C),(1E,2B,3A,4D,5B,6D,7A),(1E,2B,3A,4D,5B,6D,7B),(1E,-
2B,3A,4D,5B,6D,7C),(1E,2B,3A,4E,5A,6A,7A),
(1E,2B,3A,4E,5A,6A,7B),(1E,2B,3-
A,4E,5A,6A,7C),(1E,2B,3A,4E,5A,6B,7A),(1E,2B,3A,4E,5A,6B,7B),(1E,2B,3A,4E,-
5A,6B,7C),(1E,2B,3A,4E,5A,6C,7A),(1E,2B,3A,4E,5A,6C,7B),
(1E,2B,3A,4E,5A,6C,7C),(1E,2B,3A,4E,5A,6D,7A),(1E,2B,3A,4E,5A,6D,7B),(1E,-
2B,3A,4E,5A,6D,7C),(1E,2B,3A,4E,5B,6A,7A),(1E,2B,3A,4E,5B,6A,7B),(1E,2B,3A-
,4E,5B,6A,7C),
(1E,2B,3A,4E,5B,6B,7A),(1E,2B,3A,4E,5B,6B,7B),(1E,2B,3A,4E,-
5B,6B,7C),(1E,2B,3A,4E,5B,6C,7A),(1E,2B,3A,4E,5B,6C,7B),(1E,2B,3A,4E,5B,6C-
,7C),(1E,2B,3A,4E,5B,6D,7A),
(1E,2B,3A,4E,5B,6D,7B),(1E,2B,3A,4E,5B,6D,7C)-
,(1E,2B,3B,4A,5A,6A,7A),(1E,2B,3B,4A,5A,6A,7B),(1E,2B,3B,4A,5A,6A,7C),(1E,-
2B,3B,4A,5A,6B,7A),(1E,2B,3B,4A,5A,6B,7B),
(1E,2B,3B,4A,5A,6B,7C),(1E,2B,3-
B,4A,5A,6C,7A),(1E,2B,3B,4A,5A,6C,7B),(1E,2B,3B,4A,5A,6C,7C),(1E,2B,3B,4A,-
5A,6D,7A),(1E,2B,3B,4A,5A,6D,7B),(1E,2B,3B,4A,5A,6D,7C),
(1E,2B,3B,4A,5B,6A,7A),(1E,2B,3B,4A,5B,6A,7B),(1E,2B,3B,4A,5B,6A,7C),(1E,-
2B,3B,4A,5B,6B,7A),(1E,2B,3B,4A,5B,6B,7B),(1E,2B,3B,4A,5B,6B,7C),(1E,2B,3B-
,4A,5B,6C,7A),
(1E,2B,3B,4A,5B,6C,7B),(1E,2B,3B,4A,5B,6C,7C),(1E,2B,3B,4A,-
5B,6D,7A),(1E,2B,3B,4A,5B,6D,7B),(1E,2B,3B,4A,5B,6D,7C),(1E,2B,3B,4B,5A,6A-
,7A),(1E,2B,3B,4B,5A,6A,7B),
(1E,2B,3B,4B,5A,6A,7C),(1E,2B,3B,4B,5A,6B,7A)-
,(1E,2B,3B,4B,5A,6B,7B),(1E,2B,3B,4B,5A,6B,7C),(1E,2B,3B,4B,5A,6C,7A),(1E,-
2B,3B,4B,5A,6C,7B),(1E,2B,3B,4B,5A,6C,7C),
(1E,2B,3B,4B,5A,6D,7A),(1E,2B,3-
B,4B,5A,6D,7B),(1E,2B,3B,4B,5A,6D,7C),(1E,2B,3B,4B,5B,6A,7A),(1E,2B,3B,4B,-
5B,6A,7B),(1E,2B,3B,4B,5B,6A,7C),(1E,2B,3B,4B,5B,6B,7A),
(1E,2B,3B,4B,5B,6B,7B),(1E,2B,3B,4B,5B,6B,7C),(1E,2B,3B,4B,5B,6C,7A),(1E,-
2B,3B,4B,5B,6C,7B),(1E,2B,3B,4B,5B,6C,7C),(1E,2B,3B,4B,5B,6D,7A),(1E,2B,3B-
,4B,5B,6D,7B), (1E,2B,3B,4B,5B,6D,7C),
(1E,2B,3B,4C,5A,6A,7A),(1E,2B,3B,4C- ,5A,6A, 7B),
(1E,2B,3B,4C,5A,6A,7C), (1E,2B,3B,4C,5A,6B,7A),(1E,2B,3B,4C,5-
A,6B,7B),(1E,2B,3B,4C,5A,6B,7C),
(1E,2B,3B,4C,5A,6C,7A),(1E,2B,3B,4C,5A,6C-
,7B),(1E,2B,3B,4C,5A,6C,7C),(1E,2B,3B,4C,5A,6D,7A),(1E,2B,3B,4C,5A,6D,7B),-
(1E,2B,3B,4C,5A,6D,7C),(1E,2B,3B,4C,5B,6A,7A),
(1E,2B,3B,4C,5B,6A,7B),(1E,-
2B,3B,4C,5B,6A,7C),(1E,2B,3B,4C,5B,6B,7A),(1E,2B,3B,4C,5B,6B,7B),(1E,2B,3B-
,4C,5B,6B,7C),(1E,2B,3B,4C,5B,6C,7A),(1E,2B,3B,4C,5B,6C,7B),
(1E,2B,3B,4C,5B,6C,7C),(1E,2B,3B,4C,5B,6D,7A),(1E,2B,3B,4C,5B,6D,7B),(1E,-
2B,3B,4C,5B,6D,7C),(1E,2B,3B,4D,5A,6A,7A),(1E,2B,3B,4D,5A,6A,7B),(1E,2B,3B-
,4D,5A,6A,7C),
(1E,2B,3B,4D,5A,6B,7A),(1E,2B,3B,4D,5A,6B,7B),(1E,2B,3B,4D,-
5A,6B,7C),(1E,2B,3B,4D,5A,6C,7A),(1E,2B,3B,4D,5A,6C,7B),(1E,2B,3B,4D,5A,6C-
,7C),(1E,2B,3B,4D,5A,6D,7A),
(1E,2B,3B,4D,5A,6D,7B),(1E,2B,3B,4D,5A,6D,7C)-
,(1E,2B,3B,4D,5B,6A,7A),(1E,2B,3B,4D,5B,6A,7B),(1E,2B,3B,4D,5B,6A,7C),(1E,-
2B,3B,4D,5B,6B,7A),(1E,2B,3B,4D,5B,6B,7B),
(1E,2B,3B,4D,5B,6B,7C),(1E,2B,3-
B,4D,5B,6C,7A),(1E,2B,3B,4D,5B,6C,7B),(1E,2B,3B,4D,5B,6C,7C),(1E,2B,3B,4D,-
5B,6D,7A),(1E,2B,3B,4D,5B,6D,7B),(1E,2B,3B,4D,5B,6D,7C),
(1E,2B,3B,4E,5A,6A,7A),(1E,2B,3B,4E,5A,6A,7B),(1E,2B,3B,4E,5A,6A,7C),(1E,-
2B,3B,4E,5A,6B,7A),(1E,2B,3B,4E,5A,6B,7B),(1E,2B,3B,4E,5A,6B,7C),(1E,2B,3B-
,4E,5A,6C,7A),
(1E,2B,3B,4E,5A,6C,7B),(1E,2B,3B,4E,5A,6C,7C),(1E,2B,3B,4E,-
5A,6D,7A),(1E,2B,3B,4E,5A,6D,7B),(1E,2B,3B,4E,5A,6D,7C),(1E,2B,3B,4E,5B,6A-
,7A),(1E,2B,3B,4E,5B,6A,7B),
(1E,2B,3B,4E,5B,6A,7C),(1E,2B,3B,4E,5B,6B,7A)-
,(1E,2B,3B,4E,5B,6B,7B),(1E,2B,3B,4E,5B,6B,7C),(1E,2B,3B,4E,5B,6C,7A),(1E,-
2B,3B,4E,5B,6C,7B),(1E,2B,3B,4E,5B,6C,7C),
(1E,2B,3B,4E,5B,6D,7A),(1E,2B,3-
B,4E,5B,6D,7B),(1E,2B,3B,4E,5B,6D,7C),(1E,2B,3C,4A,5A,6A,7A),(1E,2B,3C,4A,-
5A,6A,7B),(1E,2B,3C,4A,5A,6A,7C),(1E,2B,3C,4A,5A,6B,7A),
(1E,2B,3C,4A,5A,6B,7B),(1E,2B,3C,4A,5A,6B,7C),(1E,2B,3C,4A,5A,6C,7A),(1E,-
2B,3C,4A,5A,6C,7B),(1E,2B,3C,4A,5A,6C,7C),(1E,2B,3C,4A,5A,6D,7A),(1E,2B,3C-
,4A,5A,6D,7B),
(1E,2B,3C,4A,5A,6D,7C),(1E,2B,3C,4A,5B,6A,7A),(1E,2B,3C,4A,-
5B,6A,7B),(1E,2B,3C,4A,5B,6A,7C),(1E,2B,3C,4A,5B,6B,7A),(1E,2B,3C,4A,5B,6B-
,7B),(1E,2B,3C,4A,5B,6B,7C),
(1E,2B,3C,4A,5B,6C,7A),(1E,2B,3C,4A,5B,6C,7B)-
,(1E,2B,3C,4A,5B,6C,7C),(1E,2B,3C,4A,5B,6D,7A),(1E,2B,3C,4A,5B,6D,7B),(1E,-
2B,3C,4A,5B,6D,7C),(1E,2B,3C,4B,5A,6A,7A),
(1E,2B,3C,4B,5A,6A,7B),(1E,2B,3-
C,4B,5A,6A,7C),(1E,2B,3C,4B,5A,6B,7A),(1E,2B,3C,4B,5A,6B,7B),(1E,2B,3C,4B,-
5A,6B,7C),(1E,2B,3C,4B,5A,6C,7A),(1E,2B,3C,4B,5A,6C,7B),
(1E,2B,3C,4B,5A,6C,7C), (1E,2B,3C,4B,5A,6D,7A), (1E,2B,3C,4B,5A,6D,
7B), (1E,2B,3C,4B,5A,6D,7C),
(1E,2B,3C,4B,5B,6A,7A),(1E,2B,3C,4B,5B,6A,7B),(1E-
,2B,3C,4B,5B,6A,7C), (1E,2B,3C,4B,5B,6B,7A),
(1E,2B,3C,4B,5B,6B,7B),(1E,2B- ,3C,4B,5B,6B,7C),
(1E,2B,3C,4B,5B,6C,7A), (1E,2B,3C,4B,5B,6C,7B),(1E,2B,3C-
,4B,5B,6C,7C),(1E,2B,3C,4B,5B,6D,7A),
(1E,2B,3C,4B,5B,6D,7B),(1E,2B,3C,4B,-
5B,6D,7C),(1E,2B,3C,4C,5A,6A,7A), (1E,2B,3C,4C,5A,6A,7B),
(1E,2B,3C,4C,5A,6A,7C),(1E,2B,3C,4C,5A,6B,7A),(1E,2B,3C,4C,5A,6B,7B),
(1E,2B,3C,4C,5A,6B,7C),(1E,2B,3C,4C,5A,6C,7A),(1E,2B,3C,4C,5A,6C,7B),(1E,-
2B,3C,4C,5A,6C,7C),
(1E,2B,3C,4C,5A,6D,7A),(1E,2B,3C,4C,5A,6D,7B),(1E,2B,3-
C,4C,5A,6D,7C),
(1E,2B,3C,4C,5B,6A,7A),(1E,2B,3C,4C,5B,6A,7B),(1E,2B,3C,4C-
,5B,6A,7C),(1E,2B,3C,4C,5B,6B,7A),(1E,2B,3C,4C,5B,6B,7B),(1E,2B,3C,4C,5B,6-
B,7C),(1E,2B,3C,4C,5B,6C,7A),
(1E,2B,3C,4C,5B,6C,7B),(1E,2B,3C,4C,5B,6C,7C-
),(1E,2B,3C,4C,5B,6D,7A),(1E,2B,3C,4C,5B,6D,7B),(1E,2B,3C,4C,5B,6D,7C),(1E-
,2B,3C,4D,5A,6A,7A),(1E,2B,3C,4D,5A,6A,7B),
(1E,2B,3C,4D,5A,6A,7C),(1E,2B,-
3C,4D,5A,6B,7A),(1E,2B,3C,4D,5A,6B,7B),(1E,2B,3C,4D,5A,6B,7C),(1E,2B,3C,4D-
,5A,6C,7A),(1E,2B,3C,4D,5A,6C,7B),(1E,2B,3C,4D,5A,6C,7C),
(1E,2B,3C,4D,5A,6D,7A),(1E,2B,3C,4D,5A,6D,7B),(1E,2B,3C,4D,5A,6D,7C),(1E,-
2B,3C,4D,5B,6A,7A),(1E,2B,3C,4D,5B,6A,7B),(1E,2B,3C,4D,5B,6A,7C),(1E,2B,3C-
,4D,5B,6B,7A),
(1E,2B,3C,4D,5B,6B,7B),(1E,2B,3C,4D,5B,6B,7C),(1E,2B,3C,4D,-
5B,6C,7A),(1E,2B,3C,4D,5B,6C,7B),(1E,2B,3C,4D,5B,6C,7C),(1E,2B,3C,4D,5B,6D-
,7A),(1E,2B,3C,4D,5B,6D,7B),
(1E,2B,3C,4D,5B,6D,7C),(1E,2B,3C,4E,5A,6A,7A)-
,(1E,2B,3C,4E,5A,6A,7B),(1E,2B,3C,4E,5A,6A,7C),(1E,2B,3C,4E,5A,6B,7A),(1E,-
2B,3C,4E,5A,6B,7B),(1E,2B,3C,4E,5A,6B,7C),
(1E,2B,3C,4E,5A,6C,7A),(1E,2B,3-
C,4E,5A,6C,7B),(1E,2B,3C,4E,5A,6C,7C),(1E,2B,3C,4E,5A,6D,7A),(1E,2B,3C,4E,-
5A,6D,7B),(1E,2B,3C,4E,5A,6D,7C),(1E,2B,3C,4E,5B,6A,7A),
(1E,2B,3C,4E,5B,6A,7B),(1E,2B,3C,4E,5B,6A,7C),(1E,2B,3C,4E,5B,6B,7A),(1E,-
2B,3C,4E,5B,6B,7B),(1E,2B,3C,4E,5B,6B,7C),(1E,2B,3C,4E,5B,6C,7A),(1E,2B,3C-
,4E,5B,6C,7B),
(1E,2B,3C,4E,5B,6C,7C),(1E,2B,3C,4E,5B,6D,7A),(1E,2B,3C,4E,-
5B,6D,7B),(1E,2B,3C,4E,5B,6D,7C),(1E,2B,3D,4A,5A,6A,7A),(1E,2B,3D,4A,5A,6A-
,7B),(1E,2B,3D,4A,5A,6A,7C),
(1E,2B,3D,4A,5A,6B,7A),(1E,2B,3D,4A,5A,6B,7B)-
,(1E,2B,3D,4A,5A,6B,7C),(1E,2B,3D,4A,5A,6C,7A),(1E,2B,3D,4A,5A,6C,7B),(1E,-
2B,3D,4A,5A,6C,7C),(1E,2B,3D,4A,5A,6D,7A),
(1E,2B,3D,4A,5A,6D,7B),(1E,2B,3-
D,4A,5A,6D,7C),(1E,2B,3D,4A,5B,6A,7A),(1E,2B,3D,4A,5B,6A,7B),(1E,2B,3D,4A,-
5B,6A,7C),(1E,2B,3D,4A,5B,6B,7A),(1E,2B,3D,4A,5B,6B,7B),
(1E,2B,3D,4A,5B,6B,7C), (E,2B,3D,4A,5B,6C,7A), (1E,2B,3D,4A,5B,6C,
7B),(1E,2B,3D,4A,5B,6C,7C), (1E,2B,3D,4A,5B,6D,7A),
(1E,2B,3D,4A,5B,6D,7B),(1E,2B,3D,4A,5B,6D,7C),
(1E,2B,3D,4B,5A,6A,7A), (1E,2B,3D,4B,5A,6A,7B),
(1E,2B,3D,4B,5A,6A,7C), (1E,2B,3D,4B,5A,6B,7A),
(1E,2B,3D,4B,5A,6B,7B),(1E,2B,3D,4B,5A,6B,7C),(1E,2B,3D,4B,5A,6C,7A),
(1E,2B,3D,4B,5A,6C,7B), (E,2B,3D,4B,5A,6C,7C),
(1E,2B,3D,4B,5A,6D,7A), (1E,2B,3D,4B,5A,6D,7B),
(1E,2B,3D,4B,5A,6D,7C), (1E,2B,3D,4B,5B,6A,7A),(1-
E,2B,3D,4B,5B,6A,7B), (1E,2B,3D,4B,5B,6A,7C),
(1E,2B,3D,4B,5B,6B,7A), (1E,2B,3D,4B,5B,6B,7B),
(1E,2B,3D,4B,5B,6B,7C),(1E,2B,3D,4B,5B,6C,7A),(1E-
,2B,3D,4B,5B,6C,7B),(1E,2B,3D,4B,5B,6C,7C),
(1E,2B,3D,4B,5B,6D,7A),(1E,2B,-
3D,4B,5B,6D,7B),(1E,2B,3D,4B,5B,6D,7C),(1E,2B,3D,4C,5A,6A,7A),
(E,2B,3D,4C,5A,6A,7B),(1E,2B,3D,4C,5A,6A,7C),(1E,2B,3D,4C,5A,6B,7A),
(1E,2B,3D,4C,5A,6B,7B),(1E,2B,3D,4C,5A,6B,7C),(1E,2B,3D,4C,5A,6C,7A),(1E,-
2B,3D,4C,5A,6C,7B), (1E,2B,3D,4C,5A,6C,7C), (1E,2B,3D,4C,5A,6D,7A),
(1E,2B,3D,4C,5A,6D,7B),
(1E,2B,3D,4C,5A,6D,7C),(1E,2B,3D,4C,5B,6A,7A),(1E-
,2B,3D,4C,5B,6A,7B),(1E,2B,3D,4C,5B,6A,7C), (1E,2B,3D,4C,5B,6B,7A),
(1E,2B,3D,4C,5B,6B,7B),(1E,2B,3D,4C,5B,6B,7C),
(1E,2B,3D,4C,5B,6C,7A),(1E-
,2B,3D,4C,5B,6C,7B),(1E,2B,3D,4C,5B,6C,7C),(1E,2B,3D,4C,5B,6D,7A),(1E,2B,3-
D,4C,5B,6D,7B),(1E,2B,3D,4C,5B,6D,7C),(1E,2B,3D,4D,5A,6A,7A),
(1E,2B,3D,4D,5A,6A,7B),(1E,2B,3D,4D,5A,6A,7C),(1E,2B,3D,4D,5A,6B,7A),(1E,-
2B,3D,4D,5A,6B,7B),(1E,2B,3D,4D,5A,6B,7C),(1E,2B,3D,4D,5A,6C,7A),(1E,2B,3D-
,4D,5A,6C,7B),
(1E,2B,3D,4D,5A,6C,7C),(1E,2B,3D,4D,5A,6D,7A),(1E,2B,3D,4D,-
5A,6D,7B),(1E,2B,3D,4D,5A,6D,7C),(1E,2B,3D,4D,5B,6A,7A),(1E,2B,3D,4D,5B,6A-
,7B),(1E,2B,3D,4D,5B,6A,7C),
(1E,2B,3D,4D,5B,6B,7A),(1E,2B,3D,4D,5B,6B,7B)-
,(1E,2B,3D,4D,5B,6B,7C),(1E,2B,3D,4D,5B,6C,7A),(1E,2B,3D,4D,5B,6C,7B),(1E,-
2B,3D,4D,5B,6C,7C),(1E,2B,3D,4D,5B,6D,7A),
(1E,2B,3D,4D,5B,6D,7B),(1E,2B,3-
D,4D,5B,6D,7C),(1E,2B,3D,4E,5A,6A,7A),(1E,2B,3D,4E,5A,6A,7B),(1E,2B,3D,4E,-
5A,6A,7C),(1E,2B,3D,4E,5A,6B,7A),(1E,2B,3D,4E,5A,6B,7B),
(1E,2B,3D,4E,5A,6B,7C),(1E,2B,3D,4E,5A,6C,7A),(1E,2B,3D,4E,5A,6C,7B),(1E,-
2B,3D,4E,5A,6C,7C),
(1E,2B,3D,4E,5A,6D,7A),(1E,2B,3D,4E,5A,6D,7B),(1E,2B,3-
D,4E,5A,6D,7C),
(1E,2B,3D,4E,5B,6A,7A),(1E,2B,3D,4E,5B,6A,7B),(1E,2B,3D,4E-
,5B,6A,7C),(1E,2B,3D,4E,5B,6B,7A),
(1E,2B,3D,4E,5B,6B,7B),(1E,2B,3D,4E,5B,-
6B,7C),(1E,2B,3D,4E,5B,6C,7A),
(1E,2B,3D,4E,5B,6C,7B),(1E,2B,3D,4E,5B,6C,7-
C),(1E,2B,3D,4E,5B,6D,7A),(1E,2B,3D,4E,5B,6D,7B),
(1E,2B,3D,4E,5B,6D,7C),
(1E,2B,3E,4A,5A,6A,7A),(1E,2B,3E,4A,5A,6A,7B),
(1E,2B,3E,4A,5A,6A,7C), (1E,2B,3E,4A,5A,6B,7A),
(1E,2B,3E,4A,5A,6B,7B), (1E,2B,3E,4A,5A,6B,7C),
(1E,2B,3E,4A,5A,6C,7A),(1E,2B,3E,4A,5A,6C,7B),(1E,2B,3E,4A,5A,6C,7C),
(1E,2B,3E,4A,5A,6D,7A),(1E,2B,3E,4A,5A,6D,7B),(1E,2B,3E,4A,5A,6D,7C),(1E,-
2B,3E,4A,5B,6A,7A),(1E,2B,3E,4A,5B,6A,7B),(1E,2B,3E,4A,5B,6A,7C),(1E,2B,3E-
,4A,5B,6B,7A),
(1E,2B,3E,4A,5B,6B,7B),(1E,2B,3E,4A,5B,6B,7C),(1E,2B,3E,4A,-
5B,6C,7A),(1E,2B,3E,4A,5B,6C,7B),
(1E,2B,3E,4A,5B,6C,7C),(1E,2B,3E,4A,5B,6-
D,7A),(1E,2B,3E,4A,5B,6D,7B), (1E,2B,3E,4A,5B,6D,7C),
(1E,2B,3E,4B,5A,6A,7A), (1E,2B,3E,4B,5A,6A,7B),
(1E,2B,3E,4B,5A,6A,7C),(1-
E,2B,3E,4B,5A,6B,7A),(1E,2B,3E,4B,5A,6B,7B),(1E,2B,3E,4B,5A,6B,7C),
(1E,2B,3E,4B,5A,6C,7A),(1E,2B,3E,4B,5A,6C,7B),(1E,2B,3E,4B,5A,6C,7C),(1E,-
2B,3E,4B,5A,6D,7A),(1E,2B,3E,4B,5A,6D,7B),(1E,2B,3E,4B,5A,6D,7C),(1E,2B,3E-
,4B,5B,6A,7A),
(1E,2B,3E,4B,5B,6A,7B),(1E,2B,3E,4B,5B,6A,7C),(1E,2B,3E,4B,-
5B,6B,7A),(1E,2B,3E,4B,5B,6B,7B),(1E,2B,3E,4B,5B,6B,7C),(1E,2B,3E,4B,5B,6C-
,7A),(1E,2B,3E,4B,5B,6C,7B),
(1E,2B,3E,4B,5B,6C,7C),(1E,2B,3E,4B,5B,6D,7A)-
,(1E,2B,3E,4B,5B,6D,7B),(1E,2B,3E,4B,5B,6D,7C),(1E,2B,3E,4C,5A,6A,7A),(1E,-
2B,3E,4C,5A,6A,7B),(1E,2B,3E,4C,5A,6A,7C),
(1E,2B,3E,4C,5A,6B,7A),(1E,2B,3-
E,4C,5A,6B,7B),(1E,2B,3E,4C,5A,6B,7C),(1E,2B,3E,4C,5A,6C,7A),(1E,2B,3E,4C,-
5A,6C,7B),(1E,2B,3E,4C,5A,6C,7C),(1E,2B,3E,4C,5A,6D,7A),
(1E,2B,3E,4C,5A,6D,7B),(1E,2B,3E,4C,5A,6D,7C),(1E,2B,3E,4C,5B,6A,7A),(1E,-
2B,3E,4C,5B,6A,7B),(1E,2B,3E,4C,5B,6A,7C),(1E,2B,3E,4C,5B,6B,7A),(1E,2B,3E-
,4C,5B,6B,7B),
(1E,2B,3E,4C,5B,6B,7C),(1E,2B,3E,4C,5B,6C,7A),(1E,2B,3E,4C,-
5B,6C,7B),(1E,2B,3E,4C,5B,6C,7C),(1E,2B,3E,4C,5B,6D,7A),(1E,2B,3E,4C,5B,6D-
,7B),(1E,2B,3E,4C,5B,6D,7C),
(1E,2B,3E,4D,5A,6A,7A),(1E,2B,3E,4D,5A,6A,7B)-
,(1E,2B,3E,4D,5A,6A,7C),(1E,2B,3E,4D,5A,6B,7A),(1E,2B,3E,4D,5A,6B,7B),(1E,-
2B,3E,4D,5A,6B,7C),(1E,2B,3E,4D,5A,6C,7A),
(1E,2B,3E,4D,5A,6C,7B),(1E,2B,3-
E,4D,5A,6C,7C),(1E,2B,3E,4D,5A,6D,7A),(1E,2B,3E,4D,5A,6D,7B),(1E,2B,3E,4D,-
5A,6D,7C),(1E,2B,3E,4D,5B,6A,7A),(1E,2B,3E,4D,5B,6A,7B),
(1E,2B,3E,4D,5B,6A,7C),(1E,2B,3E,4D,5B,6B,7A),(1E,2B,3E,4D,5B,6B,7B),(1E,-
2B,3E,4D,5B,6B,7C),(1E,2B,3E,4D,5B,6C,7A),(1E,2B,3E,4D,5B,6C,7B),(1E,2B,3E-
,4D,5B,6C,7C),
(1E,2B,3E,4D,5B,6D,7A),(1E,2B,3E,4D,5B,6D,7B),(1E,2B,3E,4D,-
5B,6D,7C),(1E,2B,3E,4E,5A,6A,7A),(1E,2B,3E,4E,5A,6A,7B),(1E,2B,3E,4E,5A,6A-
,7C),(1E,2B,3E,4E,5A,6B,7A),
(1E,2B,3E,4E,5A,6B,7B),(1E,2B,3E,4E,5A,6B,7C)-
,(1E,2B,3E,4E,5A,6C,7A),(1E,2B,3E,4E,5A,6C,7B),(1E,2B,3E,4E,5A,6C,7C),(1E,-
2B,3E,4E,5A,6D,7A),(1E,2B,3E,4E,5A,6D,7B),
(1E,2B,3E,4E,5A,6D,7C),(1E,2B,3- E,4E,5B,6A,7A),
(1E,2B,3E,4E,5B,6A,7B),(1E,2B,3E,4E,5B,6A,7C),
(1E,2B,3E,4E,5B,6B,7A),
(1E,2B,3E,4E,5B,6B,7B),(1E,2B,3E,4E,5B,6B,7C), (1E,2B, 3E,4E, 5B,
6C,7A), (1E,2B, 3E,4E, 5B,6C,7B), (1E,2B,3E,4E,5B, 6C, 7C), (1E,2B,
3E,4E,5B,6D,7A), (1E,2B,3E,4E,5B,6D,7B),(1E,2B,3E,4E,5B,6D,7-
C),(1E,2C,3A,4A,5A,6A,7A),
(1E,2C,3A,4A,5A,6A,7B),(1E,2C,3A,4A,5A,6A,7C),(-
1E,2C,3A,4A,5A,6B,7A),(1E,2C,3A,4A,5A,6B,7B),(1E,2C,3A,4A,5A,6B,7C),(1E,2C-
,3A,4A,5A,6C,7A),(1E,2C,3A,4A,5A,6C,7B),
(1E,2C,3A,4A,5A,6C,7C),(1E,2C,3A,-
4A,5A,6D,7A),(1E,2C,3A,4A,5A,6D,7B),(1E,2C,3A,4A,5A,6D,7C),(1E,2C,3A,4A,5B-
,6A,7A),(1E,2C,3A,4A,5B,6A,7B),(1E,2C,3A,4A,5B,6A,7C),
(1E,2C,3A,4A,5B,6B,7A),(1E,2C,3A,4A,5B,6B,7B),(1E,2C,3A,4A,5B,6B,7C),(1E,-
2C,3A,4A,5B,6C,7A),(1E,2C,3A,4A,5B,6C,7B),(1E,2C,3A,4A,5B,6C,7C),(1E,2C,3A-
,4A,5B,6D,7A),
(1E,2C,3A,4A,5B,6D,7B),(1E,2C,3A,4A,5B,6D,7C),(1E,2C,3A,4B,-
5A,6A,7A),(1E,2C,3A,4B,5A,6A,7B),(1E,2C,3A,4B,5A,6A,7C),(1E,2C,3A,4B,5A,6B-
,7A),(1E,2C,3A,4B,5A,6B,7B),
(1E,2C,3A,4B,5A,6B,7C),(1E,2C,3A,4B,5A,6C,7A)-
,(1E,2C,3A,4B,5A,6C,7B),(1E,2C,3A,4B,5A,6C,7C),(1E,2C,3A,4B,5A,6D,7A),(1E,-
2C,3A,4B,5A,6D,7B),(1E,2C,3A,4B,5A,6D,7C),
(1E,2C,3A,4B,5B,6A,7A),(1E,2C,3-
A,4B,5B,6A,7B),(1E,2C,3A,4B,5B,6A,7C),(1E,2C,3A,4B,5B,6B,7A),(1E,2C,3A,4B,-
5B,6B,7B),(1E,2C,3A,4B,5B,6B,7C),(1E,2C,3A,4B,5B,6C,7A),
(1E,2C,3A,4B,5B,6C,7B),(1E,2C,3A,4B,5B,6C,7C),(1E,2C,3A,4B,5B,6D,7A),(1E,-
2C,3A,4B,5B,6D,7B),(1E,2C,3A,4B,5B,6D,7C),(1E,2C,3A,4C,5A,6A,7A),(1E,2C,3A-
,4C,5A,6A,7B),
(1E,2C,3A,4C,5A,6A,7C),(1E,2C,3A,4C,5A,6B,7A),(1E,2C,3A,4C,-
5A,6B,7B),(1E,2C,3A,4C,5A,6B,7C),(1E,2C,3A,4C,5A,6C,7A),(1E,2C,3A,4C,5A,6C-
,7B),(1E,2C,3A,4C,5A,6C,7C),
(1E,2C,3A,4C,5A,6D,7A),(1E,2C,3A,4C,5A,6D,7B)-
,(1E,2C,3A,4C,5A,6D,7C),(1E,2C,3A,4C,5B,6A,7A),(1E,2C,3A,4C,5B,6A,7B),(1E,-
2C,3A,4C,5B,6A,7C),(1E,2C,3A,4C,5B,6B,7A),
(1E,2C,3A,4C,5B,6B,7B),(1E,2C,3-
A,4C,5B,6B,7C),(1E,2C,3A,4C,5B,6C,7A),(1E,2C,3A,4C,5B,6C,7B),(1E,2C,3A,4C,-
5B,6C,7C),(1E,2C,3A,4C,5B,6D,7A),(1E,2C,3A,4C,5B,6D,7B),
(1E,2C,3A,4C,5B,6B,7C),(1E,2C,3A,4D,5A,6A,7A),(1E,2C,3A,4D,5A,6A,7B),(1E,-
2C,3A,4D,5A,6A,7C),(1E,2C,3A,4D,5A,6B,7A),(1E,2C,3A,4D,5A,6B,7B),(1E,2C,3A-
,4D,5A,6B,7C),
(1E,2C,3A,4D,5A,6C,7A),(1E,2C,3A,4D,5A,6C,7B),(1E,2C,3A,4D,-
5A,6C,7C),(1E,2C,3A,4D,5A,6D,7A),(1E,2C,3A,4D,5A,6D,7B),(1E,2C,3A,4D,5A,6D-
,7C),(1E,2C,3A,4D,5B,6A,7A),
(1E,2C,3A,4D,5B,6A,7B),(1E,2C,3A,4D,5B,6A,7C)-
,(1E,2C,3A,4D,5B,6B,7A),(1E,2C,3A,4D,5B,6B,7B),(1E,2C,3A,4D,5B,6B,7C),(1E,-
2C,3A,4D,5B,6C,7A),(1E,2C,3A,4D,5B,6C,7B), (1E,2C,3A,4D,5B,6C,7C),
(1E,2C,3A,4D,5B,6D,7A), (1E,2C,3A,4D,5B,6D,7B),
(1E,2C,3A,4D,5B,6D,7C),
(1E,2C,3A,4E,5A,6A,7A),(1E,2C,3A,4E,5A,6A,7B),(1E,2C,3A,4E,5A,6A,7C),
(1E,2C,3A,4E,5A,6B,7A),(1E,2C,3A,4E,5A,6B,7B),(1E,2C,3A,4E,5A,6B,7C),
(1E,2C,3A,4E,5A,6C,7A),(1E,2C,3A,4E,5A,6C,7B),(1E,2C,3A,4E,5A,6C,7C),(1E,-
2C,3A,4E,5A,6D,7A),
(1E,2C,3A,4E,5A,6D,7B),(1E,2C,3A,4E,5A,6D,7C),(1E,2C,3-
A,4E,5B,6A,7A),(1E,2C,3A,4E,5B,6A,7B),(1E,2C,3A,4E,5B,6A,7C),(1E,2C,3A,4E,-
5B,6B,7A),(1E,2C,3A,4E,5B,6B,7B),
(1E,2C,3A,4E,5B,6B,7C),(1E,2C,3A,4E,5B,6-
C,7A),(1E,2C,3A,4E,5B,6C,7B),(1E,2C,3A,4E,5B,6C,7C),(1E,2C,3A,4E,5B,6D,7A)-
,(1E,2C,3A,4E,5B,6D,7B),(1E,2C,3A,4E,5B,6D,7C),
(1E,2C,3B,4A,5A,6A,7A),(1E-
,2C,3B,4A,5A,6A,7B),(1E,2C,3B,4A,5A,6A,7C),(1E,2C,3B,4A,5A,6B,7A),(1E,2C,3-
B,4A,5A,6B,7B),(1E,2C,3B,4A,5A,6B,7C),(1E,2C,3B,4A,5A,6C,7A),
(1E,2C,3B,4A,5A,6C,7B),(1E,2C,3B,4A,5A,6C,7C),(1E,2C,3B,4A,5A,6D,7A),(1E,-
2C,3B,4A,5A,6D,7B),(1E,2C,3B,4A,5A,6D,7C),(1E,2C,3B,4A,5B,6A,7A),(1E,2C,3B-
,4A,5B,6A,7B),
(1E,2C,3B,4A,5B,6A,7C),(1E,2C,3B,4A,5B,6B,7A),(1E,2C,3B,4A,-
5B,6B,7B),(1E,2C,3B,4A,5B,6B,7C),(1E,2C,3B,4A,5B,6C,7A),(1E,2C,3B,4A,5B,6C-
,7B),(1E,2C,3B,4A,5B,6C,7C),
(1E,2C,3B,4A,5B,6D,7A),(1E,2C,3B,4A,5B,6D,7B)-
,(1E,2C,3B,4A,5B,6D,7C),(1E,2C,3B,4B,5A,6A,7A),(1E,2C,3B,4B,5A,6A,7B),(1E,-
2C,3B,4B,5A,6A,7C),(1E,2C,3B,4B,5A,6B,7A),
(1E,2C,3B,4B,5A,6B,7B),(1E,2C,3-
B,4B,5A,6B,7C),(1E,2C,3B,4B,5A,6C,7A),(1E,2C,3B,4B,5A,6C,7B),(1E,2C,3B,4B,-
5A,6C,7C),(1E,2C,3B,4B,5A,6D,7A),(1E,2C,3B,4B,5A,6D,7B),
(1E,2C,3B,4B,5A,6D,7C),(1E,2C,3B,4B,5B,6A,7A),(1E,2C,3B,4B,5B,6A,7B),(1E,-
2C,3B,4B,5B,6A,7C),(1E,2C,3B,4B,5B,6B,7A),(1E,2C,3B,4B,5B,6B,7B),(1E,2C,3B-
,4B,5B,6B,7C),
(1E,2C,3B,4B,5B,6C,7A),(1E,2C,3B,4B,5B,6C,7B),(1E,2C,3B,4B,-
5B,6C,7C),(1E,2C,3B,4B,5B,6D,7A),(1E,2C,3B,4B,5B,6D,7B),(1E,2C,3B,4B,5B,6D-
,7C),(1E,2C,3B,4C,5A,6A,7A),
(1E,2C,3B,4C,5A,6A,7B),(1E,2C,3B,4C,5A,6A,7C)-
,(1E,2C,3B,4C,5A,6B,7A),(1E,2C,3B,4C,5A,6B,7B),(1E,2C,3B,4C,5A,6B,7C),(1E,-
2C,3B,4C,5A,6C,7A),(1E,2C,3B,4C,5A,6C,7B),
(1E,2C,3B,4C,5A,6C,7C),(1E,2C,3-
B,4C,5A,6D,7A),(1E,2C,3B,4C,5A,6D,7B),(1E,2C,3B,4C,5A,6D,7C),(1E,2C,3B,4C,-
5B,6A,7A),(1E,2C,3B,4C,5B,6A,7B),(1E,2C,3B,4C,5B,6A,7C),
(1E,2C,3B,4C,5B,6B,7A),(1E,2C,3B,4C,5B,6B,7B),(1E,2C,3B,4C,5B,6B,7C),(1E,-
2C,3B,4C,5B,6C,7A),(1E,2C,3B,4C,5B,6C,7B),(1E,2C,3B,4C,5B,6C,7C),(1E,2C,3B-
,4C,5B,6D,7A),
(1E,2C,3B,4C,5B,6D,7B),(1E,2C,3B,4C,5B,6D,7C),(1E,2C,3B,4D,-
5A,6A,7A),(1E,2C,3B,4D,5A,6A,7B),(1E,2C,3B,4D,5A,6A,7C),(1E,2C,3B,4D,5A,6B-
,7A),(1E,2C,3B,4D,5A,6B,7B),
(1E,2C,3B,4D,5A,6B,7C),(1E,2C,3B,4D,5A,6C,7A)-
,(1E,2C,3B,4D,5A,6C,7B), (1E,2C,3B,4D,5A,6C,7C),
(1E,2C,3B,4D,5A,6D,7A),(1-
E,2C,3B,4D,5A,6D,7B),(1E,2C,3B,4D,5A,6D,7C), (1E,2C,
3B,4D,5B,6A,7A), (1E,2C,3B,4D,5B,6A,7B), (1E,2C,3B,4D,5B,6A, 7C),
(E,2C,3B,4D,5B,6B,7A),
(1E,2C,3B,4D,5B,6B,7B),(1E,2C,3B,4D,5B,6B,7C),(1E,2C,3B,4D,5B,6C,7A),
(1E,2C,3B,4D,5B,6C,7B),(1E,2C,3B,4D,5B,6C,7C),(1E,2C,3B,4D,5B,6D,7A),
(1E,2C,3B,4D,5B,6D,7B), (1E,2C,3B,4D,5B,6D,7C),
(1E,2C,3B,4E,5A,6A,7A),(1- E,2C,3B,4E,5A,6A,7B),
(1E,2C,3B,4E,5A,6A,7C),(1E,2C,3B,4E,5A,6B,7A),(1E,2C-
,3B,4E,5A,6B,7B),(1E,2C,3B,4E,5A,6B,7C),
(1E,2C,3B,4E,5A,6C,7A),(1E,2C,3B,-
4E,5A,6C,7B),(1E,2C,3B,4E,5A,6C,7C), (1E,2C,3B,4E,5A,6D,7A),
(1E,2C,3B,4E,5A,6D,7B), (1E,2C,3B,4E,5A,6D,7C),
(1E,2C,3B,4E,5B,6A,7A),
(1E,2C,3B,4E,5B,6A,7B),(1E,2C,3B,4E,5B,6A,7C),(1E,2C,3B,4E,5B,6B,7A),
(1E,2C,3B,4E,5B,6B, 7B), (1E,2C,3B,4E,5B,6B,7C),
(1E,2C,3B,4E,5B,6C,7A), (1E,2C,3B,4E,5B,6C,7B),
(1E,2C,3B,4E,5B,6C,7C), (1E,2C,3B,4E,5B,6D,7A),
(1E,2C,3B,4E,5B,6D,7B), (1E,2C,3B,4E,5B,6D,7C),
(1E,2C,3C,4A,5A,6A,7A), (1E,2C,3C,4A,5A,6A, 7B),
(1E,2C,3C,4A,5A,6A,7C), (1E,2C,3C,4A,5A,6B,7A),
(1E,2C,3C,4A,5A,6B,7B), (1E,2C,3C,4A,5A,6B,7C),
(1E,2C,3C,4A,5A,6C,7A),(1-
E,2C,3C,4A,5A,6C,7B),(1E,2C,3C,4A,5A,6C,7C), (E,2C,3C,4A,5A,6D,7A),
(1E,2C,3C,4A,5A,6D,7B), (1E,2C,3C,4A,5A,6D,7C),
(1E,2C,3C,4A,5B,6A,7A),
(1E,2C,3C,4A,5B,6A,7B),(1E,2C,3C,4A,5B,6A,7C),(1E,2C,3C,4A,5B,6B,7A),(1E,-
2C,3C,4A,5B,6B,7B),
(1E,2C,3C,4A,5B,6B,7C),(1E,2C,3C,4A,5B,6C,7A),(1E,2C,3-
C,4A,5B,6C,7B),
(1E,2C,3C,4A,5B,6C,7C),(1E,2C,3C,4A,5B,6D,7A),(1E,2C,3C,4A-
,5B,6D,7B),(1E,2C,3C,4A,5B,6D,7C), (1E,2C,3C,4B,5A,6A,7A),
(1E,2C,3C,4B,5A,6A,7B), (1E,2C,3C,4B,5A,6A,7C),
(1E,2C,3C,4B,5A,6B,7A),(1-
E,2C,3C,4B,5A,6B,7B),(1E,2C,3C,4B,5A,6B,7C),(1E,2C,3C,4B,5A,6C,7A),
(1E,2C,3C,4B,5A,6C,7B),(1E,2C,3C,4B,5A,6C,7C),(1E,2C,3C,4B,5A,6D,7A),
(1E,2C,3C,4B,5A,6D,7B),(1E,2C,3C,4B,5A,6D,7C),(1E,2C,3C,4B,5B,6A,7A),(1E,-
2C,3C,4B,5B,6A,7B),(1E,2C,3C,4B,5B,6A,7C),(1E,2C,3C,4B,5B,6B,7A),(1E,2C,3C-
,4B,5B,6B,7B),
(1E,2C,3C,4B,5B,6B,7C),(1E,2C,3C,4B,5B,6C,7A),(1E,2C,3C,4B,-
5B,6C,7B),(1E,2C,3C,4B,5B,6C,7C),(1E,2C,3C,4B,5B,6D,7A),(1E,2C,3C,4B,5B,6D-
,7B),(1E,2C,3C,4B,5B,6D,7C),
(1E,2C,3C,4C,5A,6A,7A),(1E,2C,3C,4C,5A,6A,7B)-
,(1E,2C,3C,4C,5A,6A,7C),(1E,2C,3C,4C,5A,6B,7A),(1E,2C,3C,4C,5A,6B,7B),(1E,-
2C,3C,4C,5A,6B,7C),(1E,2C,3C,4C,5A,6C,7A),
(1E,2C,3C,4C,5A,6C,7B),(1E,2C,3-
C,4C,5A,6C,7C),(1E,2C,3C,4C,5A,6D,7A),(1E,2C,3C,4C,5A,6D,7B),(1E,2C,3C,4C,-
5A,6D,7C),(1E,2C,3C,4C,5B,6A,7A),(1E,2C,3C,4C,5B,6A,7B),
(1E,2C,3C,4C,5B,6A,7C),(1E,2C,3C,4C,5B,6B,7A),(1E,2C,3C,4C,5B,6B,7B),(1E,-
2C,3C,4C,5B,6B,7C),(1E,2C,3C,4C,5B,6C,7A),(1E,2C,3C,4C,5B,6C,7B),(1E,2C,3C-
,4C,5B,6C,7C),
(1E,2C,3C,4C,5B,6D,7A),(1E,2C,3C,4C,5B,6D,7B),(1E,2C,3C,4C,-
5B,6D,7C),(1E,2C,3C,4D,5A,6A,7A),(1E,2C,3C,4D,5A,6A,7B),(1E,2C,3C,4D,5A,6A-
,7C),(1E,2C,3C,4D,5A,6B,7A),
(1E,2C,3C,4D,5A,6B,7B),(1E,2C,3C,4D,5A,6B,7C)-
,(1E,2C,3C,4D,5A,6C,7A),(1E,2C,3C,4D,5A,6C,7B),(1E,2C,3C,4D,5A,6C,7C),(1E,-
2C,3C,4D,5A,6D,7A),(1E,2C,3C,4D,5A,6D,7B),
(1E,2C,3C,4D,5A,6D,7C),(1E,2C,3-
C,4D,5B,6A,7A),(1E,2C,3C,4D,5B,6A,7B),(1E,2C,3C,4D,5B,6A,7C),(1E,2C,3C,4D,-
5B,6B,7A),(1E,2C,3C,4D,5B,6B,7B),(1E,2C,3C,4D,5B,6B,7C),
(1E,2C,3C,4D,5B,6C,7A),(1E,2C,3C,4D,5B,6C,7B),(1E,2C,3C,4D,5B,6C,7C),(1E,-
2C,3C,4D,5B,6D,7A),(1E,2C,3C,4D,5B,6D,7B),(1E,2C,3C,4D,5B,6D,7C),(1E,2C,3C-
,4E,5A,6A,7A),
(1E,2C,3C,4E,5A,6A,7B),(1E,2C,3C,4E,5A,6A,7C),(1E,2C,3C,4E,-
5A,6B,7A),(1E,2C,3C,4E,5A,6B,7B),(1E,2C,3C,4E,5A,6B,7C),(1E,2C,3C,4E,5A,6C-
,7A),(1E,2C,3C,4E,5A,6C,7B),
(1E,2C,3C,4E,5A,6C,7C),(1E,2C,3C,4E,5A,6D,7A)-
,(1E,2C,3C,4E,5A,6D,7B),(1E,2C,3C,4E,5A,6D,7C),(1E,2C,3C,4E,5B,6A,7A),(1E,-
2C,3C,4E,5B,6A,7B),(1E,2C,3C,4E,5B,6A,7C),
(1E,2C,3C,4E,5B,6B,7A),(1E,2C,3-
C,4E,5B,6B,7B),(1E,2C,3C,4E,5B,6B,7C),(1E,2C,3C,4E,5B,6C,7A),(1E,2C,3C,4E,-
5B,6C,7B),(1E,2C,3C,4E,5B,6C,7C),(1E,2C,3C,4E,5B,6D,7A),
(1E,2C,3C,4E,5B,6D,7B),(1E,2C,3C,4E,5B,6D,7C),(1E,2C,3D,4A,5A,6A,7A),(1E,-
2C,3D,4A,5A,6A,7B),(1E,2C,3D,4A,5A,6A,7C),(1E,2C,3D,4A,5A,6B,7A),(1E,2C,3D-
,4A,5A,6B,7B),
(1E,2C,3D,4A,5A,6B,7C),(1E,2C,3D,4A,5A,6C,7A),(1E,2C,3D,4A,-
5A,6C,7B),(1E,2C,3D,4A,5A,6C,7C),(1E,2C,3D,4A,5A,6D,7A),(1E,2C,3D,4A,5A,6D-
,7B),(1E,2C,3D,4A,5A,6D,7C),
(1E,2C,3D,4A,5B,6A,7A),(1E,2C,3D,4A,5B,6A,7B)-
,(1E,2C,3D,4A,5B,6A,7C),(1E,2C,3D,4A,5B,6B,7A),(1E,2C,3D,4A,5B,6B,7B),(1E,-
2C,3D,4A,5B,6B,7C),(1E,2C,3D,4A,5B,6C,7A),
(1E,2C,3D,4A,5B,6C,7B),(1E,2C,3-
D,4A,5B,6C,7C),(1E,2C,3D,4A,5B,6D,7A),(1E,2C,3D,4A,5B,6D,7B),(1E,2C,3D,4A,-
5B,6D,7C),(1E,2C,3D,4B,5A,6A,7A),(1E,2C,3D,4B,5A,6A,7B),
(1E,2C,3D,4B,5A,6A,7C),(1E,2C,3D,4B,5A,6B,7A),(1E,2C,3D,4B,5A,6B,7B),(1E,-
2C,3D,4B,5A,6B,7C),(1E,2C,3D,4B,5A,6C,7A),(1E,2C,3D,4B,5A,6C,7B),(1E,2C,3D-
,4B,5A,6C,7C),
(1E,2C,3D,4B,5A,6D,7A),(1E,2C,3D,4B,5A,6D,7B),(1E,2C,3D,4B,-
5A,6D,7C),(1E,2C,3D,4B,5B,6A,7A),(1E,2C,3D,4B,5B,6A,7B),(1E,2C,3D,4B,5B,6A-
,7C),(1E,2C,3D,4B,5B,6B,7A),
(1E,2C,3D,4B,5B,6B,7B),(1E,2,C,3D,4B,5B,6B,7C-
),(1E,2C,3D,4B,5B,6C,7A),(1E,2C,3D,4B,5B,6C,7B),(1E,2C,3D,4B,5B,6C,7C),(1E-
,2C,3D,4B,5B,6D,7A),(1E,2C,3D,4B,5B,6D,7B),
(1E,2C,3D,4B,5B,6D,7C),(1E,2C,-
3D,4C,5A,6A,7A),(1E,2C,3D,4C,5A,6A,7B),
(1E,2C,3D,4C,5A,6A,7C),(1E,2C,3D,4- C,5A,6B,7A),
(1E,2C,3D,4C,5A,6B,7B),(1E,2C,3D,4C,5A,6B,7C), (1E,2C,3D,4C, 5A,6C,
7A), (1E,2C,3D,4C,5A,6C,7B), (1E,2C,3D,4C,5A,6C, 7C),
(1E,2C,3D,4C,5A,6D,7A),(1E,2C,3D,4C,5A,6D,7B),(1E,2C,3D,4C,5A,6D,7C),(1E,-
2C,3D,4C,5B,6A,7A), (1E,2C,3D,4C,5B,6A,7B), (1E,2C,3D,4C,5B,6A,7C),
(1E,2C,3D,4C,5B,6B,7A), (1E,2C,3D,4C,5B,6B,7B),
(1E,2C,3D,4C,5B,6B,7C),(1-
E,2C,3D,4C,5B,6C,7A),(1E,2C,3D,4C,5B,6C,7B),
(1E,2C,3D,4C,5B,6C,7C), (E,2C,3D,4C,5B,6D,7A),(1E,2C,3D,4C,5B,6D,
7B),(1E,2C,3D,4C,5B,6D,7C),
(1E,2C,3D,4D,5A,6A,7A),(1E,2C,3D,4D,5A,6A,7B),(1E,2C,3D,4D,5A,6A,7C),
(1E,2C,3D,4D,5A,6B,7A), (1E,2C,3D,4D,5A,6B,7B),
(1E,2C,3D,4D,5A,6B,7C),
(1E,2C,3D,4D,5A,6C,7A),(1E,2C,3D,4D,5A,6C,7B),(1E,2C,3D,4D,5A,6C,7C),(1E,-
2C,3D,4D,5A,6D,7A), (1E,2C,3D,4D,5A,6D,7B), (1E,2C,3D,4D,5A,6D,7C),
(1E,2C,3D,4D,5B,6A,7A), (1E,2C,3D,4D,5B,6A,7B),
(1E,2C,3D,4D,5B,6A,7C),
(1E,2C,3D,4D,5B,6B,7A),(1E,2C,3D,4D,5B,6B,7B),
(1E,2C,3D,4D,5B,6B,7C), (1E,2C,3D,4D,5B,6C,7A),
(1E,2C,3D,4D,5B,6C,7B), (1E,2C,3D,4D,5B,6C,7C),
(1E,2C,3D,4D,5B,6D,7A),(1E,2C,3D,4D,5B,6D,7B),(1E,2C,3D,4D,5B,6D,7C),
(1E,2C,3D,4E,5A,6A,7A),(1E,2C,3D,4E,5A,6A,7B),(1E,2C,3D,4E,5A,6A,7C),(1E,-
2C,3D,4E,5A,6B,7A),(1E,2C,3D,4E,5A,6B,7B),(1E,2C,3D,4E,5A,6B,7C),(1E,2C,3D-
,4E,5A,6C,7A),
(1E,2C,3D,4E,5A,6C,7B),(1E,2C,3D,4E,5A,6C,7C),(1E,2C,3D,4E,-
5A,6D,7A),(1E,2C,3D,4E,5A,6D,7B),(1E,2C,3D,4E,5A,6D,7C),(1E,2C,3D,4E,5B,6A-
,7A),(1E,2C,3D,4E,5B,6A,7B),
(1E,2C,3D,4E,5B,6A,7C),(1E,2C,3D,4E,5B,6B,7A)-
,(1E,2C,3D,4E,5B,6B,7B),(1E,2C,3D,4E,5B,6B,7C),(1E,2C,3D,4E,5B,6C,7A),(1E,-
2C,3D,4E,5B,6C,7B),(1E,2C,3D,4E,5B,6C,7C),
(1E,2C,3D,4E,5B,6D,7A),(1E,2C,3-
D,4E,5B,6D,7B),(1E,2C,3D,4E,5B,6D,7C),(1E,2C,3E,4A,5A,6A,7A),(1E,2C,3E,4A,-
5A,6A,7B),(1E,2C,3E,4A,5A,6A,7C),(1E,2C,3E,4A,5A,6B,7A),
(1E,2C,3E,4A,5A,6B,7B),(1E,2C,3E,4A,5A,6B,7C),(1E,2C,3E,4A,5A,6C,7A),(1E,-
2C,3E,4A,5A,6C,7B),(1E,2C,3E,4A,5A,6C,7C),(1E,2C,3E,4A,5A,6D,7A),(1E,2C,3E-
,4A,5A,6D,7B),
(1E,2C,3E,4A,5A,6D,7C),(1E,2C,3E,4A,5B,6A,7A),(1E,2C,3E,4A,-
5B,6A,7B),(1E,2C,3E,4A,5B,6A,7C),(1E,2C,3E,4A,5B,6B,7A),(1E,2C,3E,4A,5B,6B-
,7B),(1E,2C,3E,4A,5B,6B,7C),
(1E,2C,3E,4A,5B,6C,7A),(1E,2C,3E,4A,5B,6C,7B)-
,(1E,2C,3E,4A,5B,6C,7C),(1E,2C,3E,4A,5B,6D,7A),(1E,2C,3E,4A,5B,6D,7B),(1E,-
2C,3E,4A,5B,6D,7C),(1E,2C,3E,4B,5A,6A,7A),
(1E,2C,3E,4B,5A,6A,7B),(1E,2C,3-
E,4B,5A,6A,7C),(1E,2C,3E,4B,5A,6B,7A),(1E,2C,3E,4B,5A,6B,7B),(1E,2C,3E,4B,-
5A,6B,7C),(1E,2C,3E,4B,5A,6C,7A),(1E,2C,3E,4B,5A,6C,7B),
(1E,2C,3E,4B,5A,6C,7C),(1E,2C,3E,4B,5A,6D,7A),(1E,2C,3E,4B,5A,6D,7B),(1E,-
2C,3E,4B,5A,6D, 7C), (1E,2C,3E,4B,5B,6A,7A),
(1E,2C,3E,4B,5B,6A,7B), (1E,2C,3E,4B,5B,6A,7C),
(1E,2C,3E,4B,5B,6B,7A),(1E,2C,3E,4B,5B,6B,7B),
(1E,2C,3E,4B,5B,6B,7C),(1E,2C,3E,4B,5B,6C,7A),
(1E,2C,3E,4B,5B,6C,7B), (1E,2C,3E,4B,5B,6C,7C),
(1E,2C,3E,4B,5B,6D,7A), (1E,2C,3E,4B,5B,6D,7B),
(1E,2C,3E,4B,5B,6D,7C), (1E,2C,3E,4C,5A,6A,7A),
(1E,2C,3E,4C,5A,6A,7B), (1E,2C,3E,4C,5A,6A,7C),
(1E,2C,3E,4C,5A,6B,7A),(1E,2C,3E,4C,5A,6B,7B),
(1E,2C,3E,4C,5A,6B,7C),(1E,2C,3E,4C,5A,6C,7A),(1E,2C,3E,4C,5A,6C,7B),(1E,-
2C,3E,4C,5A,6C,7C),(1E,2C,3E,4C,5A,6D,7A),(1E,2C,3E,4C,5A,6D,7B),(1E,2C,3E-
,4C,5A,6D,7C),
(1E,2C,3E,4C,5B,6A,7A),(1E,2C,3E,4C,5B,6A,7B),(1E,2C,3E,4C,-
5B,6A,7C),(1E,2C,3E,4C,5B,6B,7A),(1E,2C,3E,4C,5B,6B,7B),(1E,2C,3E,4C,5B,6B-
,7C),(1E,2C,3E,4C,5B,6C,7A),
(1E,2C,3E,4C,5B,6C,7B),(1E,2C,3E,4C,5B,6C,7C)-
,(1E,2C,3E,4C,5B,6D,7A),(1E,2C,3E,4C,5B,6D,7B),(1E,2C,3E,4C,5B,6D,7C),(1E,-
2C,3E,4D,5A,6A,7A),(1E,2C,3E,4D,5A,6A,7B),
(1E,2C,3E,4D,5A,6A,7C),(1E,2C,3-
E,4D,5A,6B,7A),(1E,2C,3E,4D,5A,6B,7B),(1E,2C,3E,4D,5A,6B,7C),(1E,2C,3E,4D,-
5A,6C,7A),(1E,2C,3E,4D,5A,6C,7B),(1E,2C,3E,4D,5A,6C,7C),
(1E,2C,3E,4D,5A,6D,7A),(1E,2C,3E,4D,5A,6D,7B),(1E,2C,3E,4D,5A,6D,7C),(1E,-
2C,3E,4D,5B,6A,7A),(1E,2C,3E,4D,5B,6A,7B),(1E,2C,3E,4D,5B,6A,7C),(1E,2C,3E-
,4D,5B,6B,7A),
(1E,2C,3E,4D,5B,6B,7B),(1E,2C,3E,4D,5B,6B,7C),(1E,2C,3E,4D,-
5B,6C,7A),(1E,2C,3E,4D,5B,6C,7B),(1E,2C,3E,4D,5B,6C,7C),(1E,2C,3E,4D,5B,6D-
,7A),(1E,2C,3E,4D,5B,6D,7B),
(1E,2C,3E,4D,5B,6D,7C),(1E,2C,3E,4E,5A,6A,7A)-
,(1E,2C,3E,4E,5A,6A,7B),(1E,2C,3E,4E,5A,6A,7C),(1E,2C,3E,4E,5A,6B,7A),(1E,-
2C,3E,4E,5A,6B,7B),(1E,2C,3E,4E,5A,6B,7C),
(1E,2C,3E,4E,5A,6C,7A),(1E,2C,3-
E,4E,5A,6C,7B),(1E,2C,3E,4E,5A,6C,7C),(1E,2C,3E,4E,5A,6D,7A),(1E,2C,3E,4E,-
5A,6D,7B),(1E,2C,3E,4E,5A,6D,7C),(1E,2C,3E,4E,5B,6A,7A),
(1E,2C,3E,4E,5B,6A,7B),(1E,2C,3E,4E,5B,6A,7C),(1E,2C,3E,4E,5B,6B,7A),(1E,-
2C,3E,4E,5B,6B,7B),(1E,2C,3E,4E,5B,6B,7C),(1E,2C,3E,4E,5B,6C,7A),(1E,2C,3E-
,4E,5B,6C,7B),
(1E,2C,3E,4E,5B,6C,7C),(1E,2C,3E,4E,5B,6D,7A),(1E,2C,3E,4E,-
5B,6D,7B),(1E,2C,3E,4E,5B,6D,7C),(1E,2D,3A,4A,5A,6A,7A),(1E,2D,3A,4A,5A,6A-
,7B),(1E,2D,3A,4A,5A,6A,7C),
(1E,2D,3A,4A,5A,6B,7A),(1E,2D,3A,4A,5A,6B,7B)-
,(1E,2D,3A,4A,5A,6B,7C),(1E,2D,3A,4A,5A,6C,7A),(1E,2D,3A,4A,5A,6C,7B),(1E,-
2D,3A,4A,5A,6C,7C),(1E,2D,3A,4A,5A,6D,7A),
(1E,2D,3A,4A,5A,6D,7B),(1E,2D,3-
A,4A,5A,6D,7C),(1E,2D,3A,4A,5B,6A,7A),(1E,2D,3A,4A,5B,6A,7B),(1E,2D,3A,4A,-
5B,6A,7C),(1E,2D,3A,4A,5B,6B,7A),(1E,2D,3A,4A,5B,6B,7B),
(1E,2D,3A,4A,5B,6B,7C), (1E,2D,3A,4A,5B,6C,7A), (1E,2D,3A,4A,5B,6C,
7B),
(1E,2D,3A,4A,5B,6C,7C),(1E,2D,3A,4A,5B,6D,7A),(1E,2D,3A,4A,5B,6D,7B),(1E,-
2D,3A,4A,5B,6D,7C),
(1E,2D,3A,4B,5A,6A,7A),(1E,2D,3A,4B,5A,6A,7B),(1E,2D,3-
A,4B,5A,6A,7C),(1E,2D,3A,4B,5A,6B,7A),(1E,2D,3A,4B,5A,6B,7B),(1E,2D,3A,4B,-
5A,6B,7C),(1E,2D,3A,4B,5A,6C,7A),
(1E,2D,3A,4B,5A,6C,7B),(1E,2D,3A,4B,5A,6-
C,7C),(1E,2D,3A,4B,5A,6D,7A),(1E,2D,3A,4B,5A,6D,7B),(1E,2D,3A,4B,5A,6D,7C)-
,(1E,2D,3A,4B,5B,6A,7A),(1E,2D,3A,4B,5B,6A,7B),
(1E,2D,3A,4B,5B,6A,7C),(1E-
,2D,3A,4B,5B,6B,7A),(1E,2D,3A,4B,5B,6B,7B),(1E,2D,3A,4B,5B,6B,7C),(1E,2D,3-
A,4B,5B,6C,7A),(1E,2D,3A,4B,5B,6C,7B),(1E,2D,3A,4B,5B,6C,7C),
(1E,2D,3A,4B,5B,6D,7A),(1E,2D,3A,4B,5B,6D,7B),(1E,2D,3A,4B,5B,6D,7C),(1E,-
2D,3A,4C,5A,6A,7A),(1E,2D,3A,4C,5A,6A,7B),(1E,2D,3A,4C,5A,6A,7C),(1E,2D,3A-
,4C,5A,6B,7A),
(1E,2D,3A,4C,5A,6B,7B),(1E,2D,3A,4C,5A,6B,7C),(1E,2D,3A,4C,-
5A,6C,7A),(1E,2D,3A,4C,5A,6C,7B),(1E,2D,3A,4C,5A,6C,7C),(1E,2D,3A,4C,5A,6D-
,7A),(1E,2D,3A,4C,5A,6D,7B),
(1E,2D,3A,4C,5A,6D,7C),(1E,2D,3A,4C,5B,6A,7A)-
,(1E,2D,3A,4C,5B,6A,7B),(1E,2D,3A,4C,5B,6A,7C),(1E,2D,3A,4C,5B,6B,7A),(1E,-
2D,3A,4C,5B,6B,7B),(1E,2D,3A,4C,5B,6B,7C),
(1E,2D,3A,4C,5B,6C,7A),(1E,2D,3-
A,4C,5B,6C,7B),(1E,2D,3A,4C,5B,6C,7C),(1E,2D,3A,4C,5B,6D,7A),(1E,2D,3A,4C,-
5B,6D,7B),(1E,2D,3A,4C,5B,6D,7C),(1E,2D,3A,4D,5A,6A,7A),
(1E,2D,3A,4D,5A,6A,7B),(1E,2D,3A,4D,5A,6A,7C),(1E,2D,3A,4D,5A,6B,7A),(1E,-
2D,3A,4D,5A,6B,7B),(1E,2D,3A,4D,5A,6B,7C),(1E,2D,3A,4D,5A,6C,7A),(1E,2D,3A-
,4D,5A,6C,7B),
(1E,2D,3A,4D,5A,6C,7C),(1E,2D,3A,4D,5A,6D,7A),(1E,2D,3A,4D,-
5A,6D,7B),(1E,2D,3A,4D,5A,6D,7C),(1E,2D,3A,4D,5B,6A,7A),(1E,2D,3A,4D,5B,6A-
,7B),(1E,2D,3A,4D,5B,6A,7C),
(1E,2D,3A,4D,5B,6B,7A),(1E,2D,3A,4D,5B,6B,7B)-
,(1E,2D,3A,4D,5B,6B,7C),(1E,2D,3A,4D,5B,6C,7A),(1E,2D,3A,4D,5B,6C,7B),(1E,-
2D,3A,4D,5B,6C,7C),(1E,2D,3A,4D,5B,6D,7A),
(1E,2D,3A,4D,5B,6D,7B),(1E,2D,3-
A,4D,5B,6D,7C),(1E,2D,3A,4E,5A,6A,7A),(1E,2D,3A,4E,5A,6A,7B),(1E,2D,3A,4E,-
5A,6A,7C),(1E,2D,3A,4E,5A,6B,7A),(1E,2D,3A,4E,5A,6B,7B),
(1E,2D,3A,4E,5A,6B,7C),(1E,2D,3A,4E,5A,6C,7A),(1E,2D,3A,4E,5A,6C,7B),(1E,-
2D,3A,4E,5A,6C,7C),(1E,2D,3A,4E,5A,6D,7A),(1E,2D,3A,4E,5A,6D,7B),(1E,2D,3A-
,4E,5A,6D,7C),
(1E,2D,3A,4E,5B,6A,7A),(1E,2D,3A,4E,5B,6A,7B),(1E,2D,3A,4E,-
5B,6A,7C),(1E,2D,3A,4E,5B,6B,7A),(1E,2D,3A,4E,5B,6B,7B),(1E,2D,3A,4E,5B,6B-
,7C),(1E,2D,3A,4E,5B,6C,7A),
(1E,2D,3A,4E,5B,6C,7B),(1E,2D,3A,4E,5B,6C,7C)-
,(1E,2D,3A,4E,5B,6D,7A),(1E,2D,3A,4E,5B,6D,7B),(1E,2D,3A,4E,5B,6D,7C),(1E,-
2D,3B,4A,5A,6A,7A),(1E,2D,3B,4A,5A,6A,7B),
(1E,2D,3B,4A,5A,6A,7C),(1E,2D,3- B,4A,5A,6B,7A),
(1E,2D,3B,4A,5A,6B,7B),(1E,2D,3B,4A,5A,6B,7C),
(1E,2D,3B,4A,5A,6C,7A), (1E,2D,3B,4A,5A,6C,7B),
(1E,2D,3B,4A,5A,6C,7C), (1E,2D,3B,4A,5A,6D,7A),
(1E,2D,3B,4A,5A,6D,7B), (1E,2D,3B,4A,5A,6D,7C),
(1E,2D,3B,4A,5B,6A,7A),(1E,2D,3B,4A,5B,6A,7B),(1E,2D,3B,4A,5B,6A,7C),(1E,-
2D,3B,4A,5B,6B,7A), (1E,2D,3B,4A,5B,6B,7B), (1E,2D,3B,4A,5B,6B,7C),
(1E,2D,3B,4A,5B,6C,7A), (1E,2D,3B,4A,5B,6C,7B),
(E,2D,3B,4A,5B,6C,7C),(1E-
,2D,3B,4A,5B,6D,7A),(1E,2D,3B,4A,5B,6D,7B),
(1E,2D,3B,4A,5B,6D,7C),(1E,2D,-
3B,4B,5A,6A,7A),(1E,2D,3B,4B,5A,6A,7B),(1E,2D,3B,4B,5A,6A,7C),(1E,2D,3B,4B-
,5A,6B,7A),(1E,2D,3B,4B,5A,6B,7B),(1E,2D,3B,4B,5A,6B,7C),
(1E,2D,3B,4B,5A,6C,7A),(1E,2D,3B,4B,5A,6C,7B),(1E,2D,3B,4B,5A,6C,7C),(1E,-
2D,3B,4B,5A,6D,7A),(1E,2D,3B,4B,5A,6D,7B),(1E,2D,3B,4B,5A,6D,7C),(1E,2D,3B-
,4B,5B,6A,7A),
(1E,2D,3B,4B,5B,6A,7B),(1E,2D,3B,4B,5B,6A,7C),(1E,2D,3B,4B,-
5B,6B,7A),(1E,2D,3B,4B,5B,6B,7B),(1E,2D,3B,4B,5B,6B,7C),(1E,2D,3B,4B,5B,6C-
,7A),(1E,2D,3B,4B,5B,6C,7B),
(1E,2D,3B,4B,5B,6C,7C),(1E,2D,3B,4B,5B,6D,7A)-
,(1E,2D,3B,4B,5B,6D,7B),(1E,2D,3B,4B,5B,6D,7C),(1E,2D,3B,4C,5A,6A,7A),(1E,-
2D,3B,4C,5A,6A,7B),(1E,2D,3B,4C,5A,6A,7C),
(1E,2D,3B,4C,5A,6B,7A),(1E,2D,3-
B,4C,5A,6B,7B),(1E,2D,3B,4C,5A,6B,7C),(1E,2D,3B,4C,5A,6C,7A),(1E,2D,3B,4C,-
5A,6C,7B),(1E,2D,3B,4C,5A,6C,7C),(1E,2D,3B,4C,5A,6D,7A),
(1E,2D,3B,4C,5A,6D,7B),(1E,2D,3B,4C,5A,6D,7C),(1E,2D,3B,4C,5B,6A,7A),(1E,-
2D,3B,4C,5B,6A,7B),(1E,2D,3B,4C,5B,6A,7C),(1E,2D,3B,4C,5B,6B,7A),(1E,2D,3B-
,4C,5B,6B,7B),
(1E,2D,3B,4C,5B,6B,7C),(1E,2D,3B,4C,5B,6C,7A),(1E,2D,3B,4C,-
5B,6C,7B),(1E,2D,3B,4C,5B,6C,7C),(1E,2D,3B,4C,5B,6D,7A),(1E,2D,3B,4C,5B,6D-
,7B),(1E,2D,3B,4C,5B,6D,7C),
(1E,2D,3B,4D,5A,6A,7A),(1E,2D,3B,4D,5A,6A,7B)-
,(1E,2D,3B,4D,5A,6A,7C),(1E,2D,3B,4D,5A,6B,7A),(1E,2D,3B,4D,5A,6B,7B),(1E,-
2D,3B,4D,5A,6B,7C),(1E,2D,3B,4D,5A,6C,7A),
(1E,2D,3B,4D,5A,6C,7B),(1E,2D,3-
B,4D,5A,6C,7C),(1E,2D,3B,4D,5A,6D,7A),(1E,2D,3B,4D,5A,6D,7B),(1E,2D,3B,4D,-
5A,6D,7C),(1E,2D,3B,4D,5B,6A,7A),(1E,2D,3B,4D,5B,6A,7B),
(1E,2D,3B,4D,5B,6A,7C),(1E,2D,3B,4D,5B,6B,7A),(1E,2D,3B,4D,5B,6B,7B),(1E,-
2D,3B,4D,5B,6B,7C),(1E,2D,3B,4D,5B,6C,7A),(1E,2D,3B,4D,5B,6C,7B),(1E,2D,3B-
,4D,5B,6C,7C),
(1E,2D,3B,4D,5B,6D,7A),(1E,2D,3B,4D,5B,6D,7B),(1E,2D,3B,4D,-
5B,6D,7C),(1E,2D,3B,4E,5A,6A,7A),(1E,2D,3B,4E,5A,6A,7B),(1E,2D,3B,4E,5A,6A-
,7C),(1E,2D,3B,4E,5A,6B,7A),
(1E,2D,3B,4E,5A,6B,7B),(1E,2D,3B,4E,5A,6B,7C)-
,(1E,2D,3B,4E,5A,6C,7A),(1E,2D,3B,4E,5A,6C,7B),(1E,2D,3B,4E,5A,6C,7C),(1E,-
2D,3B,4E,5A,6D,7A),(1E,2D,3B,4E,5A,6D,7B), (1E,2D,3B,4E,5A,6D,7C),
(1E,2D,3B,4E,5B,6A,7A), (1E,2D,3B,4E,5B,6A,7B),
(1E,2D,3B,4E,5B,6A,7C), (1E,2D,3B,4E,5B,6B, 7A),
(1E,2D,3B,4E,5B,6B, 7B),(1E,2D,3B,4E, 5B,6B, 7C),
(1E,2D,3B,4E,5B,6C,7A), (1E,2D,3B,4E,5B,6C,7B),
(1E,2D,3B,4E,5B,6C,7C),
(1E,2D,3B,4E,5B,6D,7A),(1E,2D,3B,4E,5B,6D,7B),(1E-
,2D,3B,4E,5B,6D,7C), (1E,2D,3C,4A,5A,6A,7A),
(1E,2D,3C,4A,5A,6A,7B), (1E,2D,3C,4A,5A,6A,7C),
(1E,2D,3C,4A,5A,6B,7A), (1E,2D,3C,4A,5A,6B,7B),
(1E,2D,3C,4A,5A,6B,7C),(1E,2D,3C,4A,5A,6C,7A),(1E,2D,3C,4A,5A,6C,
7B),
(1E,2D,3C,4A,5A,6C,7C),(1E,2D,3C,4A,5A,6D,7A),(1E,2D,3C,4A,5A,6D,
7B), (1E,2D,3C,4A,5A,6D,7C), (1E,2D,3C,4A,5B,6A,7A),
(1E,2D,3C,4A,5B,6A,7B), (1E,2D,3C,4A, 5B,6A, 7C),
(1E,2D,3C,4A,5B,6B,7A), (1E,2D,3C,4A,5B,6B,7B),-
(1E,2D,3C,4A,5B,6B,7C), (1E,2D,3C,4A,5B,6C,7A),
(1E,2D,3C,4A,5B,6C,7B),(1E-
,2D,3C,4A,5B,6C,7C),(1E,2D,3C,4A,5B,6D,7A), (1E,2D,3C,4A,5B,6D,7B),
(1E,2D,3C,4A,5B,6D,7C),
(1E,2D,3C,4B,5A,6A,7A),(1E,2D,3C,4B,5A,6A,7B), (1E,2D,3C,4B,5A,6A,
7C),(1E,2D,3C,4B,5A,6B,7A), (1E,2D,3C,4B, 5A,6B, 7B),
(1E,2D,3C,4B,5A,6B,7C), (1E,2D,3C,4B,5A,6C,7A), (1E,2D,3C,4B,5A,6C,
7B), (1E,2D,3C,4B,5A,6C,7C),
(1E,2D,3C,4B,5A,6D,7A),(1E,2D,3C,4B,5A,6D,7B),(1E-
,2D,3C,4B,5A,6D,7C), (1E,2D,3C,4B,5B,6A,7A),
(1E,2D,3C,4B,5B,6A,7B), (1E,2D,3C,4B,5B,6A,7C),
(1E,2D,3C,4B,5B,6B,7A), (1E,2D,3C,4B,5B,6B,7B),
(1E,2D,3C,4B,5B,6B,7C),(1E,2D,3C,4B,5B,6C,7A),
(1E,2D,3C,4B,5B,6C,7B), (1E,2D,3C,4B,5B,6C,7C), (1E,2D,3C,4B,5B,6D,
7A), (1E,2D,3C,4B,5B,6D, 7B),(1E,2D,3C,4B,5B,6D,7C),
(1E,2D,3C,4C,5A,6A,7A),(1E,2D,3C,4C,5A,6A,7B)- ,
(1E,2D,3C,4C,5A,6A,7C),(1E,2D,3C,4C,5A,6B,7A),(1E,2D,3C,4C,5A,6B,7B),(1E-
,2D,3C,4C,5A,6B,7C),(1E,2D,3C,4C,5A,6C,7A),(1E,2D,3C,4C,5A,6C,7B),(1E,2D,3-
C,4C,5A,6C,7C),
(1E,2D,3C,4C,5A,6D,7A),(1E,2D,3C,4C,5A,6D,7B),(1E,2D,3C,4C-
,5A,6D,7C),(1E,2D,3C,4C,5B,6A,7A),(1E,2D,3C,4C,5B,6A,7B),(1E,2D,3C,4C,5B,6-
A,7C),(1E,2D,3C,4C,5B,6B,7A),
(1E,2D,3C,4C,5B,6B,7B),(1E,2D,3C,4C,5B,6B,7C-
),(1E,2D,3C,4C,5B,6C,7A),(1E,2D,3C,4C,5B,6C,7B),(1E,2D,3C,4C,5B,6C,7C),(1E-
,2D,3C,4C,5B,6D,7A),(1E,2D,3C,4C,5B,6D,7B),
(1E,2D,3C,4C,5B,6D,7C),(1E,2D,-
3C,4D,5A,6A,7A),(1E,2D,3C,4D,5A,6A,7B),(1E,2D,3C,4D,5A,6A,7C),(1E,2D,3C,4D-
,5A,6B,7A),(1E,2D,3C,4D,5A,6B,7B),(1E,2D,3C,4D,5A,6B,7C),
(1E,2D,3C,4D,5A,6C,7A),(1E,2D,3C,4D,5A,6C,7B),(1E,2D,3C,4D,5A,6C,7C),
(1E,2D,3C,4D,5A,6D,7A),(1E,2D,3C,4D,5A,6D,7B),(1E,2D,3C,4D,5A,6D,7C),(1E,-
2D,3C,4D,5B,6A,7A),(1E,2D,3C,4D,5B,6A,7B),(1E,2D,3C,4D,5B,6A,7C),(1E,2D,3C-
,4D,5B,6B,7A),
(1E,2D,3C,4D,5B,6B,7B),(1E,2D,3C,4D,5B,6B,7C),(1E,2D,3C,4D,-
5B,6C,7A),(1E,2D,3C,4D,5B,6C,7B),
(E,2D,3C,4D,5B,6C,7C),(1E,2D,3C,4D,5B,6D-
,7A),(1E,2D,3C,4D,5B,6D,7B),
(1E,2D,3C,4D,5B,6D,7C),(1E,2D,3C,4E,5A,6A,7A)-
,(1E,2D,3C,4E,5A,6A,7B), (1E,2D,3C,4E,5A,6A,7C),
(1E,2D,3C,4E,5A,6B,7A),
(1E,2D,3C,4E,5A,6B,7B),(1E,2D,3C,4E,5A,6B,7C),
(1E,2D,3C,4E,5A,6C,7A),(1E-
,2D,3C,4E,5A,6C,7B),(1E,2D,3C,4E,5A,6C,7C),(1E,2D,3C,4E,5A,6D,7A),(1E,2D,3-
C,4E,5A,6D,7B),(1E,2D,3C,4E,5A,6D,7C),(1E,2D,3C,4E,5B,6A,7A),
(1E,2D,3C,4E,5B,6A,7B),(1E,2D,3C,4E,5B,6A,7C),(1E,2D,3C,4E,5B,6B,7A),(1E,-
2D,3C,4E,5B,6B,7B),(1E,2D,3C,4E,5B,6B,7C),(1E,2D,3C,4E,5B,6C,7A),(1E,2D,3C-
,4E,5B,6C,7B),
(1E,2D,3C,4E,5B,6C,7C),(1E,2D,3C,4E,5B,6D,7A),(1E,2D,3C,4E,-
5B,6D,7B),(1E,2D,3C,4E,5B,6D,7C),(1E,2D,3D,4A,5A,6A,7A),(1E,2D,3D,4A,5A,6A-
,7B),(1E,2D,3D,4A,5A,6A,7C),
(1E,2D,3D,4A,5A,6B,7A),(1E,2D,3D,4A,5A,6B,7B)-
,(1E,2D,3D,4A,5A,6B,7C),(1E,2D,3D,4A,5A,6C,7A),(1E,2D,3D,4A,5A,6C,7B),(1E,-
2D,3D,4A,5A,6C,7C),(1E,2D,3D,4A,5A,6D,7A),
(1E,2D,3D,4A,5A,6D,7B),(1E,2D,3-
D,4A,5A,6D,7C),(1E,2D,3D,4A,5B,6A,7A),(1E,2D,3D,4A,5B,6A,7B),(1E,2D,3D,4A,-
5B,6A,7C),(1E,2D,3D,4A,5B,6B,7A),(1E,2D,3D,4A,5B,6B,7B),
(1E,2D,3D,4A,5B,6B,7C),(1E,2D,3D,4A,5B,6C,7A),(1E,2D,3D,4A,5B,6C,7B),(1E,-
2D,3D,4A,5B,6C,7C),(1E,2D,3D,4A,5B,6D,7A),(1E,2D,3D,4A,5B,6D,7B),(1E,2D,3D-
,4A,5B,6D,7C),
(1E,2D,3D,4B,5A,6A,7A),(1E,2D,3D,4B,5A,6A,7B),(1E,2D,3D,4B,-
5A,6A,7C),(1E,2D,3D,4B,5A,6B,7A),(1E,2D,3D,4B,5A,6B,7B),(1E,2D,3D,4B,5A,6B-
,7C),(1E,2D,3D,4B,5A,6C,7A),
(1E,2D,3D,4B,5A,6C,7B),(1E,2D,3D,4B,5A,6C,7C)-
,(1E,2D,3D,4B,5A,6D,7A),(1E,2D,3D,4B,5A,6D,7B),(1E,2D,3D,4B,5A,6D,7C),(1E,-
2D,3D,4B,5B,6A,7A),(1E,2D,3D,4B,5B,6A,7B),
(1E,2D,3D,4B,5B,6A,7C),(1E,2D,3-
D,4B,5B,6B,7A),(1E,2D,3D,4B,5B,6B,7B),(1E,2D,3D,4B,5B,6B,7C),.(1E,2D,3D,4B-
,5B,6C,7A),(1E,2D,3D,4B,5B,6C,7B),(1E,2D,3D,4B,5B,6C,7C),
(1E,2D,3D,4B,5B,6D,7A),(1E,2D,3D,4B,5B,6D,7B),(1E,2D,3D,4B,5B,6D,7C),(1E,-
2D,3D,4C,5A,6A,7A),(1E,2D,3D,4C,5A,6A,7B),(1E,2D,3D,4C,5A,6A,7C),(1E,2D,3D-
,4C,5A,6B,7A),
(1E,2D,3D,4C,5A,6B,7B),(1E,2D,3D,4C,5A,6B,7C),(1E,2D,3D,4C,-
5A,6C,7A),(1E,2D,3D,4C,5A,6C,7B),(1E,2D,3D,4C,5A,6C,7C),(1E,2D,3D,4C,5A,6D-
,7A),(1E,2D,3D,4C,5A,6D,7B),
(1E,2D,3D,4C,5A,6D,7C),(1E,2D,3D,4C,5B,6A,7A)-
,(1E,2D,3D,4C,5B,6A,7B),(1E,2D,3D,4C,5B,6A,7C),(1E,2D,3D,4C,5B,6B,7A),(1E,-
2D,3D,4C,5B,6B,7B),(1E,2D,3D,4C,5B,6B,7C),
(1E,2D,3D,4C,5B,6C,7A),(1E,2D,3-
D,4C,5B,6C,7B),(1E,2D,3D,4C,5B,6C,7C),(1E,2D,3D,4C,5B,6D,7A),(1E,2D,3D,4C,-
5B,6D,7B),(1E,2D,3D,4C,5B,6D,7C),(1E,2D,3D,4D,5A,6A,7A),
(1E,2D,3D,4D,5A,6A,7B),(1E,2D,3D,4D,5A,6A,7C),(1E,2D,3D,4D,5A,6B,7A),(1E,-
2D,3D,4D,5A,6B,7B),
(1E,2D,3D,4D,5A,6B,7C),(1E,2D,3D,4D,5A,6C,7A),(1E,2D,3-
D,4D,5A,6C,7B), (1E,2D,3D,4D,5A,6C,7C), (1E,2D,3D,4D,5A,6D,7A),
(1E,2D,3D,4D,5A,6D,7B),
(1E,2D,3D,4D,5A,6D,7C),(1E,2D,3D,4D,5B,6A,7A),
(1E,2D,3D,4D,5B,6A,7B),(1E,2D,3D,4D,5B,6A,7C),
(1E,2D,3D,4D,5B,6B,7A),(1E- ,2D,3D,4D,5B,6B,7B),
(1E,2D,3D,4D,5B,6B,7C),(1E,2D,3D,4D,5B,6C,7A),
(1E,2D,3D,4D,5B,6C,7B),(1E,2D,3D,4D,5B,6C,7C),(1E,2D,3D,4D,5B,6D,7A),
(1E,2D,3D,4D,5B,6D,7B), (1E,2D,3D,4D,5B,6D,7C),
(1E,2D,3D,4E,5A,6A,7A),(1- E,2D,3D,4E,5A,6A,7B),
(1E,2D,3D,4E,5A,6A,7C),(1E,2D,3D,4E,5A,6B,7A),(1E,2D-
,3D,4E,5A,6B,7B), (1E,2D,3D,4E,5A,6B,7C), (1E,2D,3D,4E,5A,6C,7A),
(1E,2D,3D,4E,5A,6C,7B),(1E,2D,3D,4E,5A,6C,7C),
(1E,2D,3D,4E,5A,6D,7A),
(1E,2D,3D,4E,5A,6D,7B),(1E,2D,3D,4E,5A,6D,7C),
(1E,2D,3D,4E,5B,6A,7A),(1E-
,2D,3D,4E,5B,6A,7B),(1E,2D,3D,4E,5B,6A,7C),(1E,2D,3D,4E,5B,6B,7A),(1E,2D,3-
D,4E,5B,6B,7B),(1E,2D,3D,4E,5B,6B,7C),(1E,2D,3D,4E,5B,6C)7A),
(1E,2D,3D,4E,5B,6C,7B),(1E,2D,3D,4E,5B,6C,7C),(1E,2D,3D,4E,5B,6D,7A),(1E,-
2D,3D,4E,5B,6D,7B),(1E,2D,3D,4E,5B,6D,7C),(1E,2D,3E,4A,5A,6A,7A),(1E,2D,3E-
,4A,5A,6A,7B),
(1E,2D,3E,4A,5A,6A,7C),(1E,2D,3E,4A,5A,6B,7A),(1E,2D,3E,4A,-
5A,6B,7B),.(1E,2D,3E,4A,5A,6B,7C),(1E,2D,3E,4A,5A,6C,7A),(1E,2D,3E,4A,5A,6-
C,7B),(!E,2D,3E,4A,5A,6C,7C),
(1E,2D,3E,4A,5A,6D,7A),(1E,2D,3E,4A,5A,6D,7B-
),(1E,2D,3E,4A,5A,6D,7C),(1E,2D,3E,4A,5B,6A,7A),(1E,2D,3E,4A,5B,6A,7B),(1E-
,2D,3E,4A,5B,6A,7C),(1E,2D,3E,4A,5B,6B,7A),
(1E,2D,3E,4A,5B,6B,7B),(1E,2D,-
3E,4A,5B,6B,7C),(1E,2D,3E,4A,5B,6C,7A),(1E,2D,3E,4A,5B,6C,7B),(1E,2D,3E,4A-
,5B,6C,7C),(1E,2D,3E,4A,5B,6D,7A),(1E,2D,3E,4A,5B,6D,7B),
(1E,2D,3E,4A,5B,6D,7C),(1E,2D,3E,4B,5A,6A,7A),(1E,2D,3E,4B,5A,6A,7B),(1E,-
2D,3E,4B,5A,6A,7C),(1E,2D,3E,4B,5A,6B,7A),(1E,2D,3E,4B,5A,6B,7B),(1E,2D,3E-
,4B,5A,6B,7C),
(1E,2D,3E,4B,5A,6C,7A),(1E,2D,3E,4B,5A,6C,7B),(1E,2D,3E,4B,-
5A,6C,7C),(1E,2D,3E,4B,5A,6D,7A),(1E,2D,3E,4B,5A,6D,7B),(1E,2D,3E,4B,5A,6D-
,7C),(1E,2D,3E,4B,5B,6A,7A),
(1E,2D,3E,4B,5B,6A,7B),(1E,2D,3E,4B,5B,6A,7C)-
,(1E,2D,3E,4B,5B,6B,7A),(1E,2D,3E,4B,5B,6B,7B),(1E,2D,3E,4B,5B,6B,7C),(1E,-
2D,3E,4B,5B,6C,7A),(1E,2D,3E,4B,5B,6C,7B),
(1E,2D,3E,4B,5B,6C,7C),(1E,2D,3-
E,4B,5B,6D,7A),(1E,2D,3E,4B,5B,6D,7B),(1E,2D,3E,4B,5B,6D,7C),(1E,2D,3E,4C,-
5A,6A,7A),(1E,2D,3E,4C,5A,6A,7B),(1E,2D,3E,4C,5A,6A,7C),
(1E,2D,3E,4C,5A,6B,7A),(1E,2D,3E,4C,5A,6B,7B),(1E,2D,3E,4C,5A,6B,7C),(1E,-
2D,3E,4C,5A,6C,7A),(1E,2D,3E,4C,5A,6C,7B),(1E,2D,3E,4C,5A,6C,7C),(1E,2D,3E-
,4C,5A,6D,7A),
(1E,2D,3E,4C,5A,6D,7B),(1E,2D,3E,4C,5A,6D,7C),(1E,2D,3E,4C,-
5B,6A,7A),(1E,2D,3E,4C,5B,6A,7B),(1E,2D,3E,4C,5B,6A,7C),(1E,2D,3E,4C,5B,6B-
,7A),(1E,2D,3E,4C,5B,6B,7B), (1E,2D,3E,4C,5B,6B,7C),
(1E,2D,3E,4C,5B,6C,7A),
(E,2D,3E,4C,5B,6C,7B),(1E,2D,3E,4C,5B,6C,7C),
(E,2D,3E,4C,5B,6D,7A),(1E,2D,3E,4C,5B,6D,7B),(1E,2D,3E,4C,5B,6D,7C),
(1E,2D,3E,4D,5A,6A,7A),(1E,2D,3E,4D,5A,6A,7B),(1E,2D,3E,4D,5A,6A,7C),(1E,-
2D,3E,4D,5A,6B,7A),(1E,2D,3E,4D,5A,6B,7B),(1E,2D,3E,4D,5A,6B,7C),(1E,2D,3E-
,4D,5A,6C,7A),
(1E,2D,3E,4D,5A,6C,7B),(1E,2D,3E,4D,5A,6C,7C),(1E,2D,3E,4D,-
5A,6D,7A),(1E,2D,3E,4D,5A,6D,7B),(1E,2D,3E,4D,5A,6D,7C),(1E,2D,3E,4D,5B,6A-
,7A),(1E,2D,3E,4D,5B,6A,7B),
(1E,2D,3E,4D,5B,6A,7C),(1E,2D,3E,4D,5B,6B,7A)-
,(1E,2D,3E,4D,5B,6B,7B),(1E,2D,3E,4D,5B,6B,7C),(1E,2D,3E,4D,5B,6C,7A),(1E,-
2D,3E,4D,5B,6C,7B),(1E,2D,3E,4D,5B,6C,7C),
(1E,2D,3E,4D,5B,6D,7A),(1E,2D,3-
E,4D,5B,6D,7B),(1E,2D,3E,4D,5B,6D,7C),(1E,2D,3E,4E,5A,6A,7A),(1E,2D,3E,4E,-
5A,6A,7B),(1E,2D,3E,4E,5A,6A,7C),(1E,2D,3E,4E,5A,6B,7A),
(1E,2D,3E,4E,5A,6B,7B),(1E,2D,3E,4E,5A,6B,7C),(1E,2D,3E,4E,5A,6C,7A),(1E,-
2D,3E,4E,5A,6C,7B),(1E,2D,3E,4E,5A,6C,7C),(1E,2D,3E,4E,5A,6D,7A),(1E,2D,3E-
,4E,5A,6D,7B),
(1E,2D,3E,4E,5A,6D,7C),(1E,2D,3E,4E,5B,6A,7A),(1E,2D,3E,4E,-
5B,6A,7B),(1E,2D,3E,4E,5B,6A,7C),(1E,2D,3E,4E,5B,6B,7A),(1E,2D,3E,4E,5B,6B-
,7B),(1E,2D,3E,4E,5B,6B,7C),
(1E,2D,3E,4E,5B,6C,7A),(1E,2D,3E,4E,5B,6C,7B)-
,(1E,2D,3E,4E,5B,6C,7C),(1E,2D,3E,4E,5B,6D,7A),(1E,2D,3E,4E,5B,6D,7B),(1E,-
2D,3E,4E,5B,6D,7C),(1E,2E,3A,4A,5A,6A,7A),
(1E,2E,3A,4A,5A,6A,7B),(1E,2E,3-
A,4A,5A,6A,7C),(1E,2E,3A,4A,5A,6B,7A),(1E,2E,3A,4A,5A,6B,7B),(1E,2E,3A,4A,-
5A,6B,7C),(1E,2E,3A,4A,5A,6C,7A),(1E,2E,3A,4A,5A,6C,7B),
(1E,2E,3A,4A,5A,6C,7C),(1E,2E,3A,4A,5A,6D,7A),(1E,2E,3A,4A,5A,6D,7B),(1E,-
2E,3A,4A,5A,6D,7C),(1E,2E,3A,4A,5B,6A,7A),(1E,2E,3A,4A,5B,6A,7B),(1E,2E,3A-
,4A,5B,6A,7C),
(1E,2E,3A,4A,5B,6B,7A),(1E,2E,3A,4A,5B,6B,7B),(1E,2E,3A,4A,-
5B,6B,7C),(1E,2E,3A,4A,5B,6C,7A),(1E,2E,3A,4A,5B,6C,7B),(1E,2E,3A,4A,5B,6C-
,7C),(1E,2E,3A,4A,5B,6D,7A),
(1E,2E,3A,4A,5B,6D,7B),(1E,2E,3A,4A,5B,6D,7C)-
,(1E,2E,3A,4B,5A,6A,7A),(1E,2E,3A,4B,5A,6A,7B),(1E,2E,3A,4B,5A,6A,7C),(1E,-
2E,3A,4B,5A,6B,7A),(1E,2E,3A,4B,5A,6B,7B),
(1E,2E,3A,4B,5A,6B,7C),(1E,2E,3-
A,4B,5A,6C,7A),(1E,2E,3A,4B,5A,6C,7B),(1E,2E,3A,4B,5A,6C,7C),(1E,2E,3A,4B,-
5A,6D,7A),(1E,2E,3A,4B,5A,6D,7B),(1E,2E,3A,4B,5A,6D,7C),
(1E,2E,3A,4B,5B,6A,7A),(1E,2E,3A,4B,5B,6A,7B),(1E,2E,3A,4B,5B,6A,7C),(1E,-
2E,3A,4B,5B,6B,7A),(1E,2E,3A,4B,5B,6B,7B),(1E,2E,3A,4B,5B,6B,7C),(1E,2E,3A-
,4B,5B,6C,7A),
(1E,2E,3A,4B,5B,6C,7B),(1E,2E,3A,4B,5B,6C,7C),(1E,2E,3A,4B,-
5B,6D,7A),(1E,2E,3A,4B,5B,6D,7B),
(1E,2E,3A,4B,5B,6D,7C),(1E,2E,3A,4C,5A,6- A,7A),
(1E,2E,3A,4C,5A,6A,7B),
(1E,2E,3A,4C,5A,6A,7C),(1E,2E,3A,4C,5A,6B,7-
A),(1E,2E,3A,4C,5A,6B,7B),(1E,2E,3A,4C,5A,6B,7C),(1E,2E,3A,4C,5A,6C,7A),(1-
E,2E,3A,4C,5A,6C,7B),(1E,2E,3A,4C,5A,6C,7C),
(1E,2E,3A,4C,5A,6D,7A),(1E,2E-
,3A,4C,5A,6D,7B),(1E,2E,3A,4C,5A,6D,7C),(1E,2E,3A,4C,5B,6A,7A),(1E,2E,3A,4-
C,5B,6A,7B),(1E,2E,3A,4C,5B,6A,7C),(1E,2E,3A,4C,5B,6B,7A),
(1E,2E,3A,4C,5B,6B,7B),(1E,2E,3A,4C,5B,6B,7C),(1E,-2E,3A,4C,5B,6C,7A),(1E-
,2E,3A,4C,5B,6C,7B),(1E,2E,3A,4C,5B,6C,7C),(1E,2E,3A,4C,5B,6D,7A),(1E,2E,3-
A,4C,5B,6D,7B),
(1E,2E,3A,4C,5B,6D,7C),(1E,2E,3A,4D,5A,6A,7A),(1E,2E,3A,4D-
,5A,6A,7B),(1E,2E,3A,4D,5A,6A,7C),(1E,2E,3A,4D,5A,6B,7A),(1E,2E,3A,4D,5A,6-
B,7B),(1E,2E,3A,4D,5A,6B,7C),
(1E,2E,3A,4D,5A,6C,7A),(1E,2E,3A,4D,5A,6C,7B-
),(1E,2E,3A,4D,5A,6C,7C),(1E,2E,3A,4D,5A,6D,7A),(1E,2E,3A,4D,5A,6D,7B),(1E-
,2E,3A,4D,5A,6D,7C),(1E,2E,3A,4D,5B,6A,7A),
(1E,2E,3A,4D,5B,6A,7B),(1E,2E,-
3A,4D,5B,6A,7C),(1E,2E,3A,4D,5B,6B,7A),(1E,2E,3A,4D,5B,6B,7B),(1E,2E,3A,4D-
,5B,6B,7C),(1E,2E,3A,4D,5B,6C,7A),(1E,2E,3A,4D,5B,6C,7B),
(1E,2E,3A,4D,5B,6C,7C),(1E,2E,3A,4D,5B,6D,7A),(1E,2E,3A,4D,5B,6D,7B),(1E,-
2E,3A,4D,5B,6D,7C),(1E,2E,3A,4E,5A,6A,7A),(1E,2E,3A,4E,5A,6A,7B),(1E,2E,3A-
,4E,5A,6A,7C),
(1E,2E,3A,4E,5A,6B,7A),(1E,2E,3A,4E,5A,6B,7B),(1E,2E,3A,4E,-
5A,6B,7C),(1E,2E,3A,4E,5A,6C,7A),(1E,2E,3A,4E,5A,6C,7B),(1E,2E,3A,4E,5A,6C-
,7C),(1E,2E,3A,4E,5A,6D,7A),
(1E,2E,3A,4E,5A,6D,7B),(1E,2E,3A,4E,5A,6D,7C)-
,(1E,2E,3A,4E,5B,6A,7A),(1E,2E,3A,4E,5B,6A,7B),(1E,2E,3A,4E,5B,6A,7C),(1E,-
2E,3A,4E,5B,6B,7A),(1E,2E,3A,4E,5B,6B,7B),
(1E,2E,3A,4E,5B,6B,7C),(1E,2E,3-
A,4E,5B,6C,7A),(1E,2E,3A,4E,5B,6C,7B),(1E,2E,3A,4E,5B,6C,7C),(1E,2E,3A,4E,-
5B,6D,7A),(1E,2E,3A,4E,5B,6D,7B),(1E,2E,3A,4E,5B,6D,7C),
(1E,2E,3B,4A,5A,6A,7A),(1E,2E,3B,4A,5A,6A,7B),(1E,2E,3B,4A,5A,6A,7C),(1E,-
2E,3B,4A,5A,6B,7A),(1E,2E,3B,4A,5A,6B,7B),(1E,2E,3B,4A,5A,6B,7C),(1E,2E,3B-
,4A,5A,6C,7A),
(1E,2E,3B,4A,5A,6C,7B),(1E,2E,3B,4A,5A,6C,7C),(1E,2E,3B,4A,-
5A,6D,7A),(1E,2E,3B,4A,5A,6D,7B),(1E,2E,3B,4A,5A,6D,7C),(1E,2E,3B,4A,5B,6A-
,7A),(1E,2E,3B,4A,5B,6A,7B),
(1E,2E,3B,4A,5B,6A,7C),(1E,2E,3B,4A,5B,6B,7A)-
,(1E,2E,3B,4A,5B,6B,7B),(1E,2E,3B,4A,5B,6B,7C),(1E,2E,3B,4A,5B,6C,7A),(1E,-
2E,3B,4A,5B,6C,7B),(1E,2E,3B,4A,5B,6C,7C),
(1E,2E,3B,4A,5B,6D,7A),(1E,2E,3-
B,4A,5B,6D,7B),(1E,2E,3B,4A,5B,6D,7C),(1E,2E,3B,4B,5A,6A,7A),(1E,2E,3B,4B,-
5A,6A,7B),(1E,2E,3B,4B,5A,6A,7C),(1E,2E,3B,4B,5A,6B,7A),
(1E,2E,3B,4B,5A,6B,7B),(1E,2E,3B,4B,5A,6B,7C),(1E,2E,3B,4B,5A,6C,7A),(1E,-
2E,3B,4B,5A,6C,7B), (1E,2E,3B,4B,5A,6C,7C), (1E,2E,3B,4B,5A,6D,7A),
(1E,2E,3B,4B,5A,6D, 7B),
(1E,2E,3B,4B,5A,6D,7C),(1E,2E,3B,4B,5B,6A,7A),(1-
E,2E,3B,4B,5B,6A,7B),(1E,2E,3B,4B,5B,6A,7C),(1E,2E,3B,4B,5B,6B,7A),(1E,2E,-
3B,4B,5B,6B,7B),(1E,2E,3B,4B,5B,6B,7C),
(1E,2E,3B,4B,5B,6C,7A),(1E,2E,3B,4-
B,5B,6C,7B),(1E,2E,3B,4B,5B,6C,7C),(1E,2E,3B,4B,5B,6D,7A),(1E,2E,3B,4B,5B,-
6D,7B),(1E,2E,3B,4B,5B,6D,7C),(1E,2E,3B,4C,5A,6A,7A),
(1E,2E,3B,4C,5A,6A,7B),(1E,2E,3B,4C,5A,6A,7C),(1E,2E,3B,4C,5A,6B,7A),(1E,-
2E,3B,4C,5A,6B,7B),(1E,2E,3B,4C,5A,6B,7C),(1E,2E,3B,4C,5A,6C,7A),(1E,2E,3B-
,4C,5A,6C,7B),
(1E,2E,3B,4C,5A,6C,7C),(1E,2E,3B,4C,5A,6D,7A),(1E,2E,3B,4C,-
5A,6D,7B),(1E,2E,3B,4C,5A,6D,7C),(1E,2E,3B,4C,5B,6A,7A),(1E,2E,3B,4C,5B,6A-
,7B),(1E,2E,3B,4C,5B,6A,7C),
(1E,2E,3B,4C,5B,6B,7A),(1E,2E,3B,4C,5B,6B,7B)-
,(1E,2E,3B,4C,5B,6B,7C),(1E,2E,3B,4C,5B,6C,7A),(1E,2E,3B,4C,5B,6C,7B),(1E,-
2E,3B,4C,5B,6C,7C),(1E,2E,3B,4C,5B,6D,7A),
(1E,2E,3B,4C,5B,6D,7B),(1E,2E,3-
B,4C,5B,6D,7C),(1E,2E,3B,4D,5A,6A,7A),(1E,2E,3B,4D,5A,6A,7B),(1E,2E,3B,4D,-
5A,6A,7C),(1E,2E,3B,4D,5A,6B,7A),
(1E,2E,3B,4D,5A,6B,7B),(1E,2E,3B,4D,5A,6-
B,7C),(1E,2E,3B,4D,5A,6C,7A),(1E,2E,3B,4D,5A,6C,7B),(1E,2E,3B,4D,5A,6C,7C)-
,(1E,2E,3B,4D,5A,6D,7A),(1E,2E,3B,4D,5A,6D,7B),
(1E,2E,3B,4D,5A,6D,7C),(1E-
,2E,3B,4D,5B,6A,7A),(1E,2E,3B,4D,5B,6A,7B),(1E,2E,3B,4D,5B,6A,7C),(1E,2E,3-
B,4D,5B,6B,7A),(1E,2E,3B,4D,5B,6B,7B),(1E,2E,3B,4D,5B,6B,7C),
(1E,2E,3B,4D,5B,6C,7A),(1E,2E,3B,4D,5B,6C,7B),(1E,2E,3B,4D,5B,6C,7C),(1E,-
2E,3B,4D,5B,6D,7A),(1E,2E,3B,4D,5B,6D,7B),(1E,2E,3B,4D,5B,6D,7C),(1E,2E,3B-
,4E,5A,6A,7A),
(1E,2E,3B,4E,5A,6A,7B),(1E,2E,3B,4E,5A,6A,7C),(1E,2E,3B,4E,-
5A,6B,7A),(1E,2E,3B,4E,5A,6B,7B),(1E,2E,3B,4E,5A,6B,7C),(1E,2E,3B,4E,5A,6C-
,7A),(1E,2E,3B,4E,5A,6C,7B),
(1E,2E,3B,4E,5A,6C,7C),(1E,2E,3B,4E,5A,6D,7A)-
,(1E,2E,3B,4E,5A,6D,7B),(1E,2E,3B,4E,5A,6D,7C),(1E,2E,3B,4E,5B,6A,7A),(1E,-
2E,3B,4E,5B,6A,7B),(1E,2E,3B,4E,5B,6A,7C),
(1E,2E,3B,4E,5B,6B,7A),(1E,2E,3-
B,4E,5B,6B,7B),(1E,2E,3B,4E,5B,6B,7C),(1E,2E,3B,4E,5B,6C,7A),(1E,2E,3B,4E,-
5B,6C,7B),(1E,2E,3B,4E,5B,6C,7C),(1E,2E,3B,4E,5B,6D,7A),
(1E,2E,3B,4E,5B,6D,7B),(1E,2E,3B,4E,5B,6D,7C),(1E,2E,3C,4A,5A,6A,7A),(1E,-
2E,3C,4A,5A,6A,7B),(1E,2E,3C,4A,5A,6A,7C),(1E,2E,3C,4A,5A,6B,7A),(1E,2E,3C-
,4A,5A,6B,7B),
(1E,2E,3C,4A,5A,6B,7C),(1E,2E,3C,4A,5A,6C,7A),(1E,2E,3C,4A,-
5A,6C,7B),(1E,2E,3C,4A,5A,6C,7C),(1E,2E,3C,4A,5A,6D,7A),(1E,2E,3C,4A,5A,6D-
,7B),(1E,2E,3C,4A,5A,6D,7C),
(1E,2E,3C,4A,5B,6A,7A),(1E,2E,3C,4A,5B,6A,7B)-
,(1E,2E,3C,4A,5B,6A,7C),(1E,2E,3C,4A,5B,6B,7A),
(1E,2E,3C,4A,5B,6B,7B),(1E-
,2E,3C,4A,5B,6B,7C),(1E,2E,3C,4A,5B,6C,7A),
(1E,2E,3C,4A,5B,6C,7B),(1E,2E,-
3C,4A,5B,6C,7C),(1E,2E,3C,4A,5B,6D,7A),(1E,2E,3C,4A,5B,6D,7B),(1E,2E,3C,4A-
,5B,6D,7C),(1E,2E,3C,4B,5A,6A,7A),(1E,2E,3C,4B,5A,6A,7B),
(1E,2E,3C,4B,5A,6A,7C),(1E,2E,3C,4B,5A,6B,7A),(1E,2E,3C,4B,5A,6B,7B),(1E,-
2E,3C,4B,5A,6B,7C),(1E,2E,3C,4B,5A,6C,7A),(1E,2E,3C,4B,5A,6C,7B),(1E,2E,3C-
,4B,5A,6C,7C),
(1E,2E,3C,4B,5A,6D,7A),(1E,2E,3C,4B,5A,6D,7B),(1E,2E,3C,4B,-
5A,6D,7C),(1E,2E,3C,4B,5B,6A,7A),(1E,2E,3C,4B,5B,6A,7B),(1E,2E,3C,4B,5B,6A-
,7C),(1E,2E,3C,4B,5B,6B,7A),
(1E,2E,3C,4B,5B,6B,7B),(1E,2E,3C,4B,5B,6B,7C)-
,(1E,2E,3C,4B,5B,6C,7A),(1E,2E,3C,4B,5B,6C,7B),(1E,2E,3C,4B,5B,6C,7C),(1E,-
2E,3C,4B,5B,6D,7A),(1E,2E,3C,4B,5B,6D,7B),
(1E,2E,3C,4B,5B,6D,7C),(1E,2E,3-
C,4C,5A,6A,7A),(1E,2E,3C,4C,5A,6A,7B),(1E,2E,3C,4C,5A,6A,7C),(1E,2E,3C,4C,-
5A,6B,7A),(1E,2E,3C,4C,5A,6B,7B),(1E,2E,3C,4C,5A,6B,7C),
(1E,2E,3C,4C,5A,6C,7A),(1E,2E,3C,4C,5A,6C,7B),(1E,2E,3C,4C,5A,6C,7C),(1E,-
2E,3C,4C,5A,6D,7A),(1E,2E,3C,4C,5A,6D,7B),(1E,2E,3C,4C,5A,6D,7C),(1E,2E,3C-
,4C,5B,6A,7A),
(1E,2E,3C,4C,5B,6A,7B),(1E,2E,3C,4C,5B,6A,7C),(1E,2E,3C,4C,-
5B,6B,7A),(1E,2E,3C,4C,5B,6B,7B),(1E,2E,3C,4C,5B,6B,7C),(1E,2E,3C,4C,5B,6C-
,7A),(1E,2E,3C,4C,5B,6C,7B),
(1E,2E,3C,4C,5B,6C,7C),(1E,2E,3C,4C,5B,6D,7A)-
,(1E,2E,3C,4C,5B,6D,7B),(1E,2E,3C,4C,5B,6D,7C),(1E,2E,3C,4D,5A,6A,7A),(1E,-
2E,3C,4D,5A,6A,7B),(1E,2E,3C,4D,5A,6A,7C),
(1E,2E,3C,4D,5A,6B,7A),(1E,2E,3-
C,4D,5A,6B,7B),(1E,2E,3C,4D,5A,6B,7C),(1E,2E,3C,4D,5A,6C,7A),(1E,2E,3C,4D,-
5A,6C,7B),(1E,2E,3C,4D,5A,6C,7C),(1E,2E,3C,4D,5A,6D,7A),
(1E,2E,3C,4D,5A,6D,7B),(1E,2E,3C,4D,5A,6D,7C),(1E,2E,3C,4D,5B,6A,7A),(1E,-
2E,3C,4D,5B,6A,7B),(1E,2E,3C,4D,5B,6A,7C),(1E,2E,3C,4D,5B,6B,7A),(1E,2E,3C-
,4D,5B,6B,7B),
(1E,2E,3C,4D,5B,6B,7C),(1E,2E,3C,4D,5B,6C,7A),(1E,2E,3C,4D,-
5B,6C,7B),(1E,2E,3C,4D,5B,6C,7C),(1E,2E,3C,4D,5B,6D,7A),(1E,2E,3C,4D,5B,6D-
,7B),(1E,2E,3C,4D,5B,6D,7C),
(1E,2E,3C,4E,5A,6A,7A),(1E,2E,3C,4E,5A,6A,7B)-
,(1E,2E,3C,4E,5A,6A,7C),(1E,2E,3C,4E,5A,6B,7A),(1E,2E,3C,4E,5A,6B,7B),(1E,-
2E,3C,4E,5A,6B,7C),(1E,2E,3C,4E,5A,6C,7A),
(1E,2E,3C,4E,5A,6C,7B),(1E,2E,3-
C,4E,5A,6C,7C),(1E,2E,3C,4E,5A,6D,7A),(1E,2E,3C,4E,5A,6D,7B),(1E,2E,3C,4E,-
5A,6D,7C),(1E,2E,3C,4E,5B,6A,7A),(1E,2E,3C,4E,5B,6A,7B),
(1E,2E,3C,4E,5B,6A,7C),(1E,2E,3C,4E,5B,6B,7A),(1E,2E,3C,4E,5B,6B,7B),(1E,-
2E,3C,4E,5B,6B,7C),(1E,2E,3C,4E,5B,6C,7A),(1E,2E,3C,4E,5B,6C,7B),(1E,2E,3C-
,4E,5B,6C,7C),
(1E,2E,3C,4E,5B,6D,7A),(1E,2E,3C,4E,5B,6D,7B),(1E,2E,3C,4E,-
5B,6D,7C),(1E,2E,3D,4A,5A,6A,7A),(1E,2E,3D,4A,5A,6A,7B),(1E,2E,3D,4A,5A,6A-
,7C),(1E,2E,3D,4A,5A,6B,7A),
(1E,2E,3D,4A,5A,6B,7B),(1E,2E,3D,4A,5A,6B,7C)-
,(1E,2E,3D,4A,5A,6C,7A),(1E,2E,3D,4A,5A,6C,7B),(1E,2E,3D,4A,5A,6C,7C),(1E,-
2E,3D,4A,5A,6D,7A),(1E,2E,3D,4A,5A,6D,7B),
(1E,2E,3D,4A,5A,6D,7C),(1E,2E,3-
D,4A,5B,6A,7A),(1E,2E,3D,4A,5B,6A,7B),(1E,2E,3D,4A,5B,6A,7C),(1E,2E,3D,4A,-
5B,6B,7A),(1E,2E,3D,4A,5B,6B,7B),(1E,2E,3D,4A,5B,6B,7C),
(1E,2E,3D,4A,5B,6C,7A),(1E,2E,3D,4A,5B,6C,7B),(1E,2E,3D,4A,5B,6C,7C),(1E,-
2E,3D,4A,5B,6D,7A),(1E,2E,3D,4A,5B,6D,7B),(1E,2E,3D,4A,5B,6D,7C),(1E,2E,3D-
,4B,5A,6A,7A),
(1E,2E,3D,4B,5A,6A,7B),(1E,2E,3D,4B,5A,6A,7C),(1E,2E,3D,4B,-
5A,6B,7A),(1E,2E,3D,4B,5A,6B,7B),(1E,2E,3D,4B,5A,6B,7C),(1E,2E,3D,4B,5A,6C-
,7A),(1E,2E,3D,4B,5A,6C,7B),
(1E,2E,3D,4B,5A,6C,7C),(1E,2E,3D,4B,5A,6D,7A)-
,(1E,2E,3D,4B,5A,6D,7B),(1E,2E,3D,4B,5A,6D,7C),(1E,2E,3D,4B,5B,6A,7A),(1E,-
2E,3D,4B,5B,6A,7B),(1E,2E,3D,4B,5B,6A,7C),
(1E,2E,3D,4B,5B,6B,7A),(1E,2E,3-
D,4B,5B,6B,7B),(1E,2E,3D,4B,5B,6B,7C),(1E,2E,3D,4B,5B,6C,7A),(1E,2E,3D,4B,-
5B,6C,7B),(1E,2E,3D,4B,5B,6C,7C),(1E,2E,3D,4B,5B,6D,7A),
(1E,2E,3D,4B,5B,6D,7B),(1E,2E,3D,4B,5B,6D,7C),(1E,2E,3D,4C,5A,6A,7A),(1E,-
2E,3D,4C,5A,6A,7B),(1E,2E,3D,4C,5A,6A,7C),(1E,2E,3D,4C,5A,6B,7A),(1E,2E,3D-
,4C,5A,6B,7B),
(1E,2E,3D,4C,5A,6B,7C),(1E,2E,3D,4C,5A,6C,7A),(1E,2E,3D,4C,-
5A,6C,7B),(1E,2E,3D,4C,5A,6C,7C),(1E,2E,3D,4C,5A,6D,7A),(1E,2E,3D,4C,5A,6D-
,7B),(1E,2E,3D,4C,5A,6D,7C),
(1E,2E,3D,4C,5B,6A,7A),(1E,2E,3D,4C,5B,6A,7B)-
,(1E,2E,3D,4C,5B,6A,7C),(1E,2E,3D,4C,5B,6B,7A),(1E,2E,3D,4C,5B,6B,7B),(1E,-
2E,3D,4C,5B,6B,7C),(1E,2E,3D,4C,5B,6C,7A),
(1E,2E,3D,4C,5B,6C,7B),(1E,2E,3-
D,4C,5B,6C,7C),(1E,2E,3D,4C,5B,6D,7A),(1E,2E,3D,4C,5B,6D,7B),(1E,2E,3D,4C,-
5B,6D,7C),(1E,2E,3D,4D,5A,6A,7A),(1E,2E,3D,4D,5A,6A,7B),
(1E,2E,3D,4D,5A,6A,7C),(1E,2E,3D,4D,5A,6B,7A),(1E,2E,3D,4D,5A,6B,7B),(1E,-
2E,3D,4D,5A,6B,7C),(1E,2E,3D,4D,5A,6C,7A),(1E,2E,3D,4D,5A,6C,7B),(1E,2E,3D-
,4D,5A,6C,7C),
(1E,2E,3D,4D,5A,6D,7A),(1E,2E,3D,4D,5A,6D,7B),(1E,2E,3D,4D,-
-5A,6D,7C),(1E,2E,3D,4D,5B,6A,7A),(1E,2E,3D,4D,5B,6A,7B),(1E,2E,3D,4D,5B,6-
A,7C),(1E,2E,3D,4D,5B,6B,7A),
(1E,2E,3D,4D,5B,6B,7B),(1E,2E,3D,4D,5B,6B,7C-
),(1E,2E,3D,4D,5B,6C,7A),(1E,2E,3D,4D,5B,6C,7B),(1E,2E,3D,4D,5B,6C,7C),(1E-
,2E,3D,4D,5B,6D,7A),(1E,2E,3D,4D,5B,6D,7B),
(1E,2E,3D,4D,5B,6D,7C),(1E,2E,-
3D,4E,5A,6A,7A),(1E,2E,3D,4E,5A,6A,7B),(1E,2E,3D,4E,5A,6A,7C),(1E,2E,3D,4E-
,5A,6B,7A),(1E,2E,3D,4E,5A,6B,7B),(1E,2E,3D,4E,5A,6B,7C),
(1E,2E,3D,4E,5A,6C,7A),(1E,2E,3D,4E,5A,6C,7B),(1E,2E,3D,4E,5A,6C,7C),(1E,-
2E,3D,4E,5A,6D,7A), (1E,2E,3D,4E,5A,6D,7B), (E,2E,3D,4E,5A,6D,7C),
(1E,2E,3D,4E,5B,6A, 7A),
(1E,2E,3D,4E,5B,6A,7B),(1E,2E,3D,4E,5B,6A,7C),
(1E,2E,3D,4E,5B,6B,7A),(1E,2E,3D,4E,5B,6B,7B),
(1E,2E,3D,4E,5B,6B,7C),
(1E,2E,3D,4E,5B,6C,7A),(1E,2E,3D,4E,5B,6C,7B),
(1E,2E,3D,4E,5B,6C,7C), (1E,2E,3D,4E,5B,6D,7A),
(1E,2E,3D,4E,5B,6D,7B), (1E,2E,3D,4E,5B,6D,7C),(1-
E,2E,3E,4A,5A,6A,7A),(1E,2E,3E,4A,5A,6A,7B),(1E,2E,3E,4A,5A,6A,7C),
(1E,2E,3E,4A,5A,6B,7A),(1E,2E,3E,4A,5A,6B,7B),(1E,2E,3E,4A,5A,6B,7C),(1E,-
2E,3E,4A,5A,6C,7A),(1E,2E,3E,4A,5A,6C,7B),(1E,2E,3E,4A,5A,6C,7C),(1E,2E,3E-
,4A,5A,6D,7A),
(1E,2E,3E,4A,5A,6D,7B),(1E,2E,3E,4A,5A,6D,7C),(1E,2E,3E,4A,-
5B,6A,7A),(1E,2E,3E,4A,5B,6A,7B),(1E,2E,3E,4A,5B,6A,7C),(1E,2E,3E,4A,5B,6B-
,7A),(1E,2E,3E,4A,5B,6B,7B),
(6C,7A),(E,2E,3E,4A,5B,6C,7B),(1E,2E,3E,4A,5B-
,6C,7C),(1E,2E,3E,4A,5B,6D,7A),(1E,2E,3E,4A,5B,6D,7B),(1E,2E,3E,4A,5B,6D,7-
C),
(1E,2E,3E,4B,5A,6A,7A),(1E,2E,3E,4B,5A,6A,7B),(1E,2E,3E,4B,5A,6A,7C),(-
1E,2E,3E,4B,5A,6B,7A),(1E,2E,3E,4B,5A,6B,7B),(1E,2E,3E,4B,5A,6B,7C),(1E,2E-
,3E,4B,5A,6C,7A),
(1E,2E,3E,4B,5A,6C,7B),(1E,2E,3E,4B,5A,6C,7C),(1E,2E,3E,-
4B,5A,6D,7A),(1E,2E,3E,4B,5A,6D,7B),(1E,2E,3E,4B,5A,6D,7C),(1E,2E,3E,4B,5B-
,6A,7A),(1E,2E,3E,4B,5B,6A,7B),
(1E,2E,3E,4B,5B,6A,7C),(1E,2E,3E,4B,5B,6B,-
7A),(1E,2E,3E,4B,5B,6B,7B),(1E,2E,3E,4B,5B,6B,7C),(1E,2E,3E,4B,5B,6C,7A),(-
1E,2E,3E,4B,5B,6C,7B),(1E,2E,3E,4B,5B,6C,7C),
(1E,2E,3E,4B,5B,6D,7A),(1E,2-
E,3E,4B,5B,6D,7B),(1E,2E,3E,4B,5B,6D,7C),(1E,2E,3E,4C,5A,6A,7A),(1E,2E,3E,-
4C,5A,6A,7B),(1E,2E,3E,4C,5A,6A,7C),(1E,2E,3E,4C,5A,6B,7A),
(1E,2E,3E,4C,5A,6B,7B),(1E,2E,3E,4C,5A,6B,7C),(1E,2E,3E,4C,5A,6C,7A),(1E,-
2E,3E,4C,5A,6C,7B),(1E,2E,3E,4C,5A,6C,7C),(1E,2E,3E,4C,5A,6D,7A),(1E,2E,3E-
,4C,5A,6D,7B),
(1E,2E,3E,4C,5A,6D,7C),(1E,2E,3E,4C,5B,6A,7A),(1E,2E,3E,4C,-
5B,6A,7B),(1E,2E,3E,4C,5B,6A,7C),(1E,2E,3E,4C,5B,6B,7A),(1E,2E,3E,4C,5B,6B-
,7B),(1E,2E,3E,4C,5B,6B,7C),
(1E,2E,3E,4C,5B,6C,7A),(1E,2E,3E,4C,5B,6C,7B)-
,(1E,2E,3E,4C,5B,6C,7C),(1E,2E,3E,4C,5B,6D,7A),(1E,2E,3E,4C,5B,6D,7B),(1E,-
2E,3E,4C,5B,6D,7C),(1E,2E,3E,4D,5A,6A,7A),
(1E,2E,3E,4D,5A,6A,7B),(1E,2E,3-
E,4D,5A,6A,7C),(1E,2E,3E,4D,5A,6B,7A),(1E,2E,3E,4D,5A,6B,7B),(1E,2E,3E,4D,-
5A,6B,7C),(1E,2E,3E,4D,5A,6C,7A),(1E,2E,3E,4D,5A,6C,7B),
(1E,2E,3E,4D,5A,6C,7C),(1E,2E,3E,4D,5A,6D,7A),(1E,2E,3E,4D,5A,6D,7B),(1E,-
2E,3E,4D,5A,6D,7C),(1E,2E,3E,4D,5B,6A,7A),(1E,2E,3E,4D,5B,6A,7B),(1E,2E,3E-
,4D,5B,6A,7C),
(1E,2E,3E,4D,5B,6B,7A),(1E,2E,3E,4D,5B,6B,7B),(1E,2E,3E,4D,-
5B,6B,7C),(1E,2E,3E,4D,5B,6C,7A),
(1E,2E,3E,4D,5B,6C,7B),(1E,2E,3E,4D,5B,6-
C,7C),(1E,2E,3E,4D,5B,6D,7A),
(1E,2E,3E,4D,5B,6D,7B),(1E,2E,3E,4D,5B,6D,7C- ),
(1E,2E,3E,4E,5A,6A,7A),(1E,2E,3E,4E,5A,6A,7B),
(1E,2E,3E,4E,5A,6A,7C),(-
1E,2E,3E,4E,5A,6B,7A),(1E,2E,3E,4E,5A,6B,7B),
(1E,2E,3E,4E,5A,6B,7C), (1E,2E,3E,4E,5A,6C,7A),
(1E,2E,3E,4E,5A,6C,7B),(1E,2E,3E,4E,5A,6C,7C),
(1E,2E,3E,4E,5A,6D,7A),(1E,2E,3E,4E,5A,6D,7B),(1E,2E,3E,4E,5A,6D,7C),
(1E,2E,3E,4E, 5B,6A,7A), (1E,2E,3E,4E,5B,6A,7B),
(1E,2E,3E,4E,5B,6A,7C), (1E,2E,3E,4E,5B,6B,7A),
(1E,2E,3E,4E,5B,6B,7B),(1E,2E,3E,4E,5B,6B,7C),(1E-
,2E,3E,4E,5B,6C,7A), (1E,2E,3E,4E,5B,6C,7B),
(1E,2E,3E,4E,5B,6C,7C), (1E,2E,3E,4E,5B,6D,7A),
(1E,2E,3E,4E,5B,6D,7B), (1E,2E,3E,4E,5B,6D,7C)
[3098] And (R.sup.1,R.sup.2,R.sup.8,R.sup.4, X,
R.sup.6,R.sup.7,)=(1A,2A,3- A,4A,5A,6A,7A) is the compound which
R.sup.1 is 1A, R.sup.2 is 2A, R.sup.3 is 3A, R.sup.4 is 4A, X is
5A, R.sup.6 is 6A and R.sup.7 is 7A. The other combinations are the
same. 297
[3099] The substituents of R.sup.1, R.sup.2, X, R.sup.3 and R.sup.4
of above compound include the following substitution group.
[3100] R.sup.1=H(1A), Me(1B), CH.sub.2OH(1C), CH.sub.2OMe(1D),
COOH(1E), COOMe(1F), CONHMe(1G)
[3101] R.sup.2=H (2A), Me(2B), CH.sub.2OH(2C), CH.sub.2OMe(2D),
COOH(2E), COOMe(2F), CONHMe(2G)
[3102] X=0 (XA), NH(XB) 298
[3103] The preferable combinations (R.sup.1,R.sup.2,X,
R.sup.1,R.sup.4) of the substituents of above compound include the
followings.
[3104] (1A, 2A, XA, 3A, 4A), (1A, 2A, XA, 3A, 4B), (1A, 2A, XA, 3A,
4C), (1A, 2A, XA, 3B, 4A), (1A, 2A, XA, 3B, 4B), (1A, 2A, XA, 3B,
4C), (1A, 2A, XA, 3C, 4A), (1A, 2A, XA, 3C, 4B), (1A, 2A, XA, 3C,
4C), (1A, 2A, XA, 3D, 4A), (1A, 2A, XA, 3D, 4B), (1A, 2A, XA, 3D,
4C), (1A, 2A, XB, 3A, 4A), (1A, 2A, XB, 3A, 4B), (1A, 2A, XB, 3A,
4C), (1A, 2A, XB, 3B, 4A), (1A, 2A, XB, 3B, 4B), (1A, 2A, XB, 3B,
4C), (1A, 2A, XB, 3C, 4A), (1A, 2A, XB, 3C, 4B), (1A, 2A, XB, 3C,
4C), (1A, 2A, XB, 3D, 4A), (1A, 2A, XB, 3D, 4B), (1A, 2A, XB, 3D,
4C), (1A, 2B, XA, 3A, 4A), (1A, 2B, XA, 3A, 4B), (1A, 2B, XA, 3A,
4C), (1A, 2B, XA, 3B, 4A), (1A, 2B, XA, 3B, 4B), (1A, 2B, XA, 3B,
4C), (1A, 2B, XA, 3C, 4A), (1A, 2B, XA, 3C, 4B), (1A, 2B, XA, 3C,
4C), (1A, 2B, XA, 3D, 4A), (1A, 2B, XA, 3D, 4B), (1A, 2B, XA, 3D,
4C), (1A, 2B, XB, 3A, 4A), (1A, 2B, XB, 3A, 4B), (1A, 2B, XB, 3A,
4C), (1A, 2B, XB, 3B, 4A), (1A, 2B, XB, 3B, 4B), (1A, 2B, XB, 3B,
4C), (1A, 2B, XB, 3C, 4A), (1A, 2B, XB, 3C, 4B), (1A, 2B, XB, 3C,
4C), (1A, 2B, XB, 3D, 4A), (1A, 2B, XB, 3D, 4B), (1A, 2B, XB, 3D,
4C), (1A, 2C, XA, 3A, 4A), (1A, 2C, XA, 3A, 4B), (1A, 2C, XA, 3A,
4C), (1A, 2C, XA, 3B, 4A), (1A, 2C, XA, 3B, 4B), (1A, 2C, XA, 3B,
4C), (1A, 2C, XA, 3C, 4A), (1A, 2C, XA, 3C, 4B), (1A, 2C, XA, 3C,
4C), (1A, 2C, XA, 3D, 4A), (1A, 2C, XA, 3D, 4B), (1A, 2C, XA, 3D,
4C), (1A, 2C, XB, 3A, 4A), (1A, 2C, XB, 3A, 4B), (1A, 2C, XB, 3A,
4C), (1A, 2C, XB, 3B, 4A), (1A, 2C, XB, 3B, 4B), (1A, 2C, XB, 3B,
4C), (1A, 2C, XB, 3C, 4A), (1A, 2C, XB, 3C, 4B), (1A, 2C, XB, 3C,
4C), (1A, 2C, XB, 3D, 4A), (1A, 2C, XB, 3D, 4B), (1A, 2C, XB, 3D,
4C), (1A, 2D, XA, 3A, 4A), (1A, 2D, XA, 3A, 4B), (1A, 2D, XA, 3A,
4C), (1A, 2D, XA, 3B, 4A), (1A, 2D, XA, 3B, 4B), (1A, 2D, XA, 3B,
4C), (1A, 2D, XA, 3C, 4A), (1A, 2D, XA, 3C, 4B), (1A, 2D, XA, 3C,
4C), (1A, 2D, XA, 3D, 4A), (1A, 2D, XA, 3D, 4B), (1A, 2D, XA, 3D,
4C), (1A, 2D, XB, 3A, 4A), (1A, 2D, XB, 3A, 4B), (1A, 2D, XB, 3A,
4C), (1A, 2D, XB, 3B, 4A), (1A, 2D, XB, 3B, 4B), (1A, 2D, XB, 3B,
4C), (1A, 2D, XB, 3C, 4A), (1A, 2D, XB, 3C, 4B), (1A, 2D, XB, 3C,
4C), (1A, 2D, XB, 3D, 4A), (1A, 2D, XB, 3D, 4B), (1A, 2D, XB, 3D,
4C), (1A, 2E, XA, 3A, 4A), (1A, 2E, XA, 3A, 4B), (1A, 2E, XA, 3A,
4C), (1A, 2E, XA, 3B, 4A), (1A, 2E, XA, 3B, 4B), (1A, 2E, XA, 3B,
4C), (1A, 2E, XA, 3C, 4A), (1A, 2E, XA, 3C, 4B), (1A, 2E, XA, 3C,
4C), (1A, 2E, XA, 3D, 4A), (1A, 2E, XA, 3D, 4B), (1A, 2E, XA, 3D,
4C), (1A, 2E, XB, 3A, 4A), (1A, 2E, XB, 3A, 4B), (1A, 2E, XB, 3A,
4C), (1A, 2E, XB, 3B, 4A), (1A, 2E, XB, 3B, 4B), (1A, 2E, XB, 3B,
4C), (1A, 2E, XB, 3C, 4A), (1A, 2E, XB, 3C, 4B), (1A, 2E, XB, 3C,
4C), (1A, 2E, XB, 3D, 4A), (1A, 2E, XB, 3D, 4B), (1A, 2E, XB, 3D,
4C), (1A, 2F, XA, 3A, 4A), (1A, 2F, XA, 3A, 4B), (1A, 2F, XA, 3A,
4C), (1A, 2F, XA, 3B, 4A), (1A, 2F, XA, 3B, 4B), (1A, 2F, XA, 3B,
4C), (1A, 2F, XA, 3C, 4A), (1A, 2F, XA, 3C, 4B), (1A, 2F, XA, 3C,
4C), (1A, 2F, XA, 3D, 4A), (1A, 2F, XA, 3D, 4B), (1A, 2F, XA, 3D,
4C), (1A, 2F, XB, 3A, 4A), (1A, 2F, XB, 3A, 4B), (1A, 2F, XB, 3A,
4C), (1A, 2F, XB, 3B, 4A), (1A, 2F, XB, 3B, 4B), (1A, 2F, XB, 3B,
4C), (1A, 2F, XB, 3C, 4A), (1A, 2F, XB, 3C, 4B), (1A, 2F, XB, 3C,
4C), (1A, 2F, XB, 3D, 4A), (1A, 2F, XB, 3D, 4B), (1A, 2F, XB, 3D,
4C), (1A, 2G, XA, 3A, 4A), (1A, 2G, XA, 3A, 4B), (1A, 2G, XA, 3A,
4C), (1A, 2G, XA, 3B, 4A), (1A, 2G, XA, 3B, 4B), (1A, 2G, XA, 3B,
4C), (1A, 2G, XA, 3C, 4A), (1A, 2G, XA, 3C, 4B), (1A, 2G, XA, 3C,
4C), (1A, 2G, XA, 3D, 4A), (1A, 2G, XA, 3D, 4B), (1A, 2G, XA, 3D,
4C), (1A, 2G, XB, 3A, 4A), (1A, 2G, XB, 3A, 4B), (1A, 2G, XB, 3A,
4C), (1A, 2G, XB, 3B, 4A), (1A, 2G, XB, 3B, 4B), (1A, 2G, XB, 3B,
4C), (1A, 2G, XB, 3C, 4A), (1A, 2G, XB, 3C, 4B), (1A, 2G, XB, 3C,
4C), (1A, 2G, XB, 3D, 4A), (1A, 2G, XB, 3D, 4B), (1A, 2G, XB, 3D,
4C), (1B, 2A, XA, 3A, 4A), (1B, 2A, XA, 3A, 4B), (1B, 2A, XA, 3A,
4C), (1B, 2A, XA, 3B, 4A), (1B, 2A, XA, 3B, 4B), (1B, 2A, XA, 3B,
4C), (1B, 2A, XA, 3C, 4A), (1B, 2A, XA, 3C, 4B), (1B, 2A, XA, 3C,
4C), (1B, 2A, XA, 3D, 4A), (1B, 2A, XA, 3D, 4B), (1B, 2A, XA, 3D,
4C), (1B, 2A, XB, 3A, 4A), (1B, 2A, XB, 3A, 4B), (1B, 2A, XB, 3A,
4C), (1B, 2A, XB, 3B, 4A), (1B, 2A, XB, 3B, 4B), (1B, 2A, XB, 3B,
4C), (1B, 2A, XB, 3C, 4A), (1B, 2A, XB, 3C, 4B), (1B, 2A, XB, 3C,
4C), (1B, 2A, XB, 3D, 4A), (1B, 2A, XB, 3D, 4B); (1B, 2A, XB, 3D,
4C), (1B, 2B, XA, 3A, 4A), (1B, 2B, XA, 3A, 4B), (1B, 2B, XA, 3A,
4C), (1B, 2B, XA, 3B, 4A), (1B, 2B, XA, 3B, 4B), (1B, 2B, XA, 3B,
4C), (1B, 2B, XA, 3C, 4A), (1B, 2B, XA, 3C, 4B), (1B, 2B, XA, 3C,
4C), (1B, 2B, XA, 3D, 4A), (1B, 2B, XA, 3D, 4B), (1B, 2B, XA, 3D,
4C), (1B, 2B, XB, 3A, 4A), (1B, 2B, XB, 3A, 4B), (1B, 2B, XB, 3A,
4C), (1B, 2B, XB, 3B, 4A), (1B, 2B, XB, 3B, 4B), (1B, 2B, XB, 3B,
4C), (1B, 2B, XB, 3C, 4A), (1B, 2B, XB, 3C, 4B), (1B, 2B, XB, 3C,
4C), (1B, 2B, XB, 3D, 4A), (1B, 2B, XB, 3D, 4B), (1B, 2B, XB, 3D,
4C), (1B, 2C, XA, 3A, 4A), (1B, 2C, XA, 3A, 4B), (1B, 2C, XA, 3A,
4C), (1B, 2C, XA, 3B, 4A), (1B, 2C, XA, 3B, 4B), (1B, 2C, XA, 3B,
4C), (1B, 2C, XA, 3C, 4A), (1B, 2C, XA, 3C, 4B), (1B, 2C, XA, 3C,
4C), (1B, 2C, XA, 3D, 4A), (1B, 2C, XA, 3D, 4B), (1B, 2C, XA, 3D,
4C), (1B, 2C, XB, 3A, 4A), (1B, 2C, XB, 3A, 4B), (1B, 2C, XB, 3A,
4C), (1B, 2C, XB, 3B, 4A), (1B, 2C, XB, 3B, 4B), (1B, 2C, XB, 3B,
4C), (1B, 2C, XB, 3C, 4A), (1B, 2C, XB, 3C, 4B), (1B, 2C, XB, 3C,
4C), (1B, 2C, XB, 3D, 4A), (1B, 2C, XB, 3D, 4B), (1B, 2C, XB, 3D,
4C), (1B, 2D, XA, 3A, 4A), (1B, 2D, XA, 3A, 4B), (1B, 2D, XA, 3A,
4C), (1B, 2D, XA, 3B, 4A), (1B, 2D, XA, 3B, 4B), (1B, 2D, XA, 3B,
4C), (1B, 2D, XA, 3C, 4A), (1B, 2D, XA, 3C, 4B), (1B, 2D, XA, 3C,
4C), (1B, 2D, XA, 3D, 4A), (1B, 2D, XA, 3D, 4B), (1B, 2D, XA, 3D,
4C), (1B, 2D, XB, 3A, 4A), (1B, 2D, XB, 3A, 4B), (1B, 2D, XB, 3A,
4C), (1B, 2D, XB, 3B, 4A), (1B, 2D, XB, 3B, 4B), (1B, 2D, XB, 3B,
4C), (1B, 2D, XB, 3C, 4A), (1B, 2D, XB, 3C, 4B), (1B, 2D, XB, 3C,
4C), (1B, 2D, XB, 3D, 4A), (1B, 2D, XB, 3D, 4B), (1B, 2D, XB, 3D,
4C), (1B, 2E, XA, 3A, 4A), (1B, 2E, XA, 3A, 4B), (1B, 2E, XA, 3A,
4C), (1B, 2E, XA, 3B, 4A), (1B, 2E, XA, 3B, 4B), (1B, 2E, XA, 3B,
4C), (1B, 2E, XA, 3C, 4A), (1B, 2E, XA, 3C, 4B), (1B, 2E, XA, 3C,
4C), (1B, 2E, XA, 3D, 4A), (1B, 2E, XA, 3D, 4B), (1B, 2E, XA, 3D,
4C), (1B, 2E, XB, 3A, 4A), (1B, 2E, XB, 3A, 4B), (1B, 2E, XB, 3A,
4C), (1B, 2E, XB, 3B, 4A), (1B, 2E, XB, 3B, 4B), (1B, 2E, XB, 3B,
4C), (1B, 2E, XB, 3C, 4A), (1B, 2E, XB, 3C, 4B), (1B, 2E, XB, 3C,
4C), (1B, 2E, XB, 3D, 4A), (1B, 2E, XB, 3D, 4B), (1B, 2E, XB, 3D,
4C), (1B, 2F, XA, 3A, 4A), (1B, 2F, XA, 3A, 4B), (1B, 2F, XA, 3A,
4C), (1B, 2F, XA, 3B, 4A), (1B, 2F, XA, 3B, 4B), (1B, 2F, XA, 3B,
4C), (1B, 2F, XA, 3C, 4A), (1B, 2F, XA, 3C, 4B), (1B, 2F, XA, 3C,
4C), (1B, 2F, XA, 3D, 4A), (1B, 2F, XA, 3D, 4B), (1B, 2F, XA, 3D,
4C), (1B, 2F, XB, 3A, 4A), (1B, 2F, XB, 3A, 4B), (1B, 2F, XB, 3A,
4C), (1B, 2F, XB, 3B, 4A), (1B, 2F, XB, 3B, 4B), (1B, 2F, XB, 3B,
4C), (1B, 2F, XB, 3C, 4A), (1B, 2F, XB, 3C, 4B), (1B, 2F, XB, 3C,
4C), (1B, 2F, XB, 3D, 4A), (1B, 2F, XB, 3D, 4B), (1B, 2F, XB, 3D,
4C), (1B, 2G, XA, 3A, 4A), (1B, 2G, XA, 3A, 4B), (1B, 2G, XA, 3A,
4C), (1B, 2G, XA, 3B, 4A), (1B, 2G, XA, 3B, 4B), (1B, 2G, XA, 3B,
4C), (1B, 2G, XA, 3C, 4A), (1B, 2G, XA, 3C, 4B), (1B, 2G, XA, 3C,
4C), (1B, 2G, XA, 3D, 4A), (1B, 2G, XA, 3D, 4B), (1B, 2G, XA, 3D,
4C), (1B, 2G, XB, 3A, 4A), (1B, 2G, XB, 3A, 4B), (1B, 2G, XB, 3A,
4C), (1B, 2G, XB, 3B, 4A), (1B, 2G, XB, 3B, 4B), (1B, 2G, XB, 3B,
4C), (1B, 2G, XB, 3C, 4A), (1B, 2G, XB, 3C, 4B), (1B, 2G, XB, 3C,
4C), (1B, 2G, XB, 3D, 4A), (1B, 2G, XB, 3D, 4B), (1B, 2G, XB, 3D,
4C), (1C, 2A, XA, 3A, 4A), (1C, 2A, XA, 3A, 4B), (1C, 2A, XA, 3A,
4C), (1C, 2A, XA, 3B, 4A), (1C, 2A, XA, 3B, 4B), (1C, 2A, XA, 3B,
4C), (1C, 2A, XA, 3C, 4A), (1C, 2A, XA, 3C, 4B), (1C, 2A, XA, 3C,
4C), (1C, 2A, XA, 3D, 4A), (1C, 2A, XA, 3D, 4B), (1C, 2A, XA, 3D,
4C), (1C, 2A, XB, 3A, 4A), (1C, 2A, XB, 3A, 4B), (1C, 2A, XB, 3A,
4C), (1C, 2A, XB, 3B, 4A), (1C, 2A, XB, 3B, 4B), (1C, 2A, XB, 3B,
4C), (1C, 2A, XB, 3C, 4A), (1C, 2A, XB, 3C, 4B), (1C, 2A, XB, 3C,
4C), (1C, 2A, XB, 3D, 4A), (1C, 2A, XB, 3D, 4B), (1C, 2A, XB, 3D,
4C), (1C, 2B, XA, 3A, 4A), (1C, 2B, XA, 3A, 4B), (1C, 2B, XA, 3A,
4C), (1C, 2B, XA, 3B, 4A), (1C, 2B, XA, 3B, 4B), (1C, 2B, XA, 3B,
4C), (1C, 2B, XA, 3C, 4A), (1C, 2B, XA, 3C, 4B), (1C, 2B, XA, 3C,
4C), (1C, 2B, XA, 3D, 4A), (1C, 2B, XA, 3D, 4B), (1C, 2B, XA, 3D,
4C), (1C, 2B, XB, 3A, 4A), (1C, 2B, XB, 3A, 4B), (1C, 2B, XB, 3A,
4C), (1C, 2B, XB, 3B, 4A), (1C, 2B, XB, 3B, 4B), (0C, 2B, XB, 3B,
4C), (1C, 2B, XB, 3C, 4A), (1C, 2B, XB, 3C, 4B), (1C, 2B, XB, 3C,
4C), (1C, 2B, XB, 3D, 4A), (1C, 2B, XB, 3D, 4B), (1C, 2B, XB, 3D,
4C), (1C, 2C, XA, 3A, 4A), (1C, 2C, XA, 3A, 4B), (1C, 2C, XA, 3A,
4C), (1C, 2C, XA, 3B, 4A), (1C, 2C, XA, 3B, 4B), (1C, 2C, XA, 3B,
4C), (1C, 2C, XA, 3C, 4A), (1C, 2C, XA, 3C, 4B), (1C, 2C, XA, 3C,
4C), (1C, 2C, XA, 3D, 4A), (1C, 2C, XA, 3D, 4B), (1C, 2C, XA, 3D,
4C), (1C, 2C, XB, 3A, 4A), (1C, 2C, XB, 3A, 4B), (1C, 2C, XB, 3A,
4C), (1C, 2C, XB, 3B, 4A), (1C, 2C, XB, 3B, 4B), (1C, 2C, XB, 3B,
4C), (1C, 2C, XB, 3C, 4A), (1C, 2C, XB, 3C, 4B), (1C, 2C, XB, 3C,
4C), (1C, 2C, XB, 3D, 4A), (1C, 2C, XB, 3D, 4B), (1C, 2C, XB, 3D,
4C), (1C, 2D, XA, 3A, 4A), (1C, 2D, XA, 3A, 4B), (1C, 2D, XA, 3A,
4C), (1C, 2D, XA, 3B, 4A), (1C, 2D, XA, 3B, 4B), (1C, 2D, XA, 3B,
4C), (1C, 2D, XA, 3C, 4A), (1C, 2D, XA, 3C, 4B), (1C, 2D, XA, 3C,
4C), (1C, 2D, XA, 3D, 4A), (1C, 2D, XA, 3D, 4B), (1C, 2D, XA, 3D,
4C), (1C, 2D, XB, 3A, 4A), (1C, 2D, XB, 3A, 4B), (1C, 2D, XB, 3A,
4C), (1C, 2D, XB, 3B, 4A), (1C, 2D, XB, 3B, 4B), (1C, 2D, XB, 3B,
4C), (1C, 2D, XB, 3C, 4A), (1C, 2D, XB, 3C, 4B), (1C, 2D, XB, 3C,
4C), (1C, 2D, XB, 3D, 4A), (1C, 2D, XB, 3D, 4B), (1C, 2D, XB, 3D,
4C), (1C, 2E, XA, 3A, 4A), (1C, 2E, XA, 3A, 4B), (1C, 2E, XA, 3A,
4C), (1C, 2E, XA, 3B, 4A), (1C, 2E, XA, 3B, 4B), (1C, 2E, XA, 3B,
4C), (1C, 2E, XA, 3C, 4A), (1C, 2E, XA, 3C, 4B), (1C, 2E, XA, 3C,
4C), (1C, 2E, XA, 3D, 4A), (1C, 2E, XA, 3D, 4B), (C,2E, XA, 3D,
4C), (1C, 2E, XB, 3A, 4A), (1C, 2E, XB, 3A, 4B), (1C, 2E, XB, 3A,
4C), (1C, 2E, XB, 3B, 4A), (1C, 2E, XB, 3B, 4B), (1C, 2E, XB, 3B,
4C), (1C, 2E, XB, 3C, 4A), (1C, 2E, XB, 3C, 4B), (1C, 2E, XB, 3C,
4C), (1C, 2E, XB, 3D, 4A), (1C, 2E, XB, 3D, 4B), (1C, 2E, XB, 3D,
4C), (1C, 2F, XA, 3A, 4A), (C,2F, XA, 3A, 4B), (1C, 2F, XA, 3A,
4C), (1C, 2F, XA, 3B, 4A), (1C, 2F, XA, 3B, 4B), (1C, 2F, XA, 3B,
4C), (C,2F, XA, 3C, 4A), (1C, 2F, XA, 3C, 4B), (1C, 2F, XA, 3C,
4C), (1C, 2F, XA, 3D, 4A), (C,2F, XA, 3D, 4B), (C,2F, XA, 3D, 4C),
(1C, 2F, XB, 3A, 4A), (1C, 2F, XB, 3A, 4B), (C,2F, XB, 3A, 4C),
(1C, 2F, XB, 3B, 4A), (1C, 2F, XB, 3B, 4B), (C,2F, XB, 3B, 4C),
(C,2F, XB, 3C, 4A), (C,2F, XB, 3C, 4B), (1C, 2F, XB, 3C, 4C), (1C,
2F, XB, 3D, 4A), (1C, 2F, XB, 3D, 4B), (1C, 2F, XB, 3D, 4C), (1C,
2G, XA, 3A, 4A), (1C, 2G, XA, 3A, 4B), (1C, 2G, XA, 3A, 4C), (1C,
2G, XA, 3B, 4A), (1C, 2G, XA, 3B, 4B), (1C, 2G, XA, 3B, 4C), (1C,
2G, XA, 3C, 4A), (1C, 2G, XA, 3C, 4B), (1C, 2G, XA, 3C, 4C), (1C,
2G, XA, 3D, 4A), (1C, 2G, XA, 3D, 4B), (1C, 2G, XA, 3D, 4C), (1C,
2G, XB, 3A, 4A), (1C, 2G, XB, 3A, 4B), (1C, 2G, XB, 3A, 4C), (1C,
2G, XB, 3B, 4A), (1C, 2G, XB, 3B, 4B), (1C, 2G, XB, 3B, 4C), (1C,
2G, XB, 3C, 4A), (1C, 2G, XB, 3C, 4B), (1C, 2G, XB, 3C, 4C), (1C,
2G, XB, 3D, 4A), (1C, 2G, XB, 3D, 4B), (1C, 2G, XB, 3D, 4C), (1D,
2A, XA, 3A, 4A), (1D, 2A, XA, 3A, 4B), (1D, 2A, XA, 3A, 4C), (1D,
2A, XA, 3B, 4A), (1D, 2A, XA, 3B, 4B), (1D, 2A, XA, 3B, 4C), (1D,
2A, XA, 3C, 4A), (1D, 2A, XA, 3C, 4B), (1D, 2A, XA, 3C, 4C), (1D,
2A, XA, 3D, 4A), (1D, 2A, XA, 3D, 4B), (1D, 2A, XA, 3D, 4C), (1D,
2A, XB, 3A, 4A), (1D, 2A, XB, 3A, 4B), (1D, 2A, XB, 3A, 4C), (1D,
2A, XB, 3B, 4A), (1D, 2A, XB, 3B, 4B), (1D, 2A, XB, 3B, 4C), (1D,
2A, XB, 3C, 4A), (1D, 2A, XB, 3C, 4B), (1D, 2A, XB, 3C, 4C), (1D,
2A, XB, 3D, 4A), (1D, 2A, XB, 3D, 4B), (1D, 2A, XB, 3D, 4C), (1D,
2B, XA, 3A, 4A), (1D, 2B, XA, 3A, 4B), (1D, 2B, XA, 3A, 4C), (1D,
2B, XA, 3B, 4A), (1D, 2B, XA, 3B, 4B), (1D, 2B, XA, 3B, 4C), (1D,
2B, XA, 3C, 4A), (1D, 2B, XA, 3C, 4B), (1D, 2B, XA, 3C, 4C), (1D,
2B, XA, 3D, 4A), (1D, 2B, XA, 3D, 4B), (1D, 2B, XA, 3D, 4C), (1D,
2B, XB, 3A, 4A), (1D, 2B, XB, 3A, 4B), (1D, 2B, XB, 3A, 4C), (1D,
2B, XB, 3B, 4A), (1D, 2B, XB, 3B, 4B), (1D, 2B, XB, 3B, 4C), (1D,
2B, XB, 3C, 4A), (1D, 2B, XB, 3C, 4B), (1D, 2B, XB, 3C, 4C), (1D,
2B, XB, 3D, 4A), (1D, 2B, XB, 3D, 4B), (1D, 2B, XB, 3D, 4C), (1D,
2C, XA, 3A, 4A), (1D, 2C, XA, 3A, 4B), (1D, 2C, XA, 3A, 4C), (1D,
2C, XA, 3B, 4A), (1D, 2C, XA, 3B, 4B), (1D, 2C, XA, 3B, 4C), (1D,
2C, XA, 3C, 4A), (1D, 2C, XA, 3C, 4B), (1D, 2C, XA, 3C, 4C), (1D,
2C, XA, 3D, 4A), (1D, 2C, XA, 3D, 4B), (1D, 2C, XA, 3D, 4C), (1D,
2C, XB, 3A, 4A), (1D, 2C, XB, 3A, 4B), (1D, 2C, XB, 3A, 4C), (1D,
2Cj XB, 3B, 4A), (1D, 2C, XB, 3B, 4B), (1D, 2C, XB, 3B, 4C), (1D,
2C, XB, 3C, 4A), (1D, 2C, XB, 3C, 4B), (1D, 2C, XB, 3C, 4C), (1D,
0.2C, XB, 3D, 4A), (1D, 2C, XB, 3D, 4B), (1D, 2C, XB, 3D, 4C), (1D,
2D, XA, 3A, 4A), (1D, 2D, XA, 3A, 4B), (1D, 2D, XA, 3A, 4C), (1D,
2D, XA, 3B, 4A), (1D, 2D, XA, 3B, 4B), (1D, 2D, XA, 3B, 4C), (1D,
2D, XA, 3C, 4A), (1D, 2D, XA, 3C, 4B), (1D, 2D, XA, 3C, 4C), (1D,
2D, XA, 3D, 4A), (1D, 2D, XA, 3D, 4B), (1D, 2D, XA, 3D, 4C), (1D,
2D, XB, 3A, 4A), (1D, 2D, XB, 3A, 4B), (1D, 2D, XB, 3A, 4C), (1D,
2D, XB, 3B, 4A), (1D, 2D, XB, 3B, 4B), (1D, 2D, XB, 3B, 4C), (1D,
2D, XB, 3C, 4A), (1D, 2D, XB, 3C, 4B), (1D, 2D, XB, 3C, 4C), (1D,
2D, XB, 3D, 4A), (1D, 2D, XB, 3D, 4B), (1D, 2D, XB, 3D, 4C), (1D,
2E, XA, 3A, 4A), (1D, 2E, XA, 3A, 4B), (1D, 2E, XA, 3A, 4C), (1D,
2E, XA, 3B, 4A), (1D, 2E, XA, 3B, 4B), (1D, 2E, XA, 3B, 4C), (1D,
2E, XA, 3C, 4A), (1D, 2E, XA, 3C, 4B), (1D, 2E, XA, 3C, 4C), (1D,
2E, XA, 3D, 4A), (1D, 2E, XA, 3D, 4B), (1D, 2E, XA, 3D, 4C), (1D,
2E, XB, 3A, 4A), (1D, 2E, XB, 3A, 4B), (1D, 2E, XB, 3A, 4C), (1D,
2E, XB, 3B, 4A), (1D, 2E, XB, 3B, 4B), (1D, 2E, XB, 3B, 4C), (1D,
2E, XB, 3C, 4A), (1D, 2E, XB, 3C, 4B), (1D, 2E, XB, 3C, 4C), (1D,
2E, XB, 3D, 4A), (1D, 2E, XB, 3D, 4B), (1D, 2E, XB, 3D, 4C), (1D,
2F, XA, 3A, 4A), (1D, 2F, XA, 3A, 4B), (1D, 2F, XA, 3A, 4C), (1D,
2F, XA, 3B, 4A), (1D, 2F, XA, 3B, 4B), (1D, 2F, XA, 3B, 4C), (1D,
2F, XA, 3C, 4A), (1D, 2F, XA, 3C, 4B), (1D, 2F, XA, 3C, 4C), (1D,
2F, XA, 3D, 4A), (1D, 2F, XA, 3D, 4B), (1D, 2F, XA, 3D, 4C), (1D,
2F, XB, 3A, 4A), (1D, 2F, XB, 3A, 4B), (1D, 2F, XB, 3A, 4C), (1D,
2F, XB, 3B, 4A), (1D, 2F, XB, 3B, 4B), (1D, 2F, XB, 3B, 4C), (1D,
2F, XB, 3C, 4A), (1D, 2F, XB, 3C, 4B), (1D, 2F, XB, 3C, 4C), (1D,
2F, XB, 3D, 4A), (1D, 2F, XB, 3D, 4B), (1D, 2F, XB, 3D, 4C), (1D,
2G, XA, 3A, 4A), (1D, 2G, XA, 3A, 4B), (1D, 2G, XA, 3A, 4C), (1D,
2G, XA, 3B, 4A), (1D, 2G, XA, 3B, 4B), (1D, 2G, XA, 3B, 4C), (1D,
2G, XA, 3C, 4A), (1D, 2G, XA, 3C, 4B), (1D, 2G, XA, 3C, 4C), (1D,
2G, XA, 3D, 4A), (1D, 2G, XA, 3D, 4B), (1D, 2G, XA, 3D, 4C), (1D,
2G, XB, 3A, 4A), (1D, 2G, XB, 3A, 4B), (1D, 2G, XB, 3A, 4C), (1D,
2G, XB, 3B, 4A), (1D, 2G, XB, 3B, 4B), (1D, 2G, XB, 3B, 4C), (1D,
2G, XB, 3C, 4A), (1D, 2G, XB, 3C, 4B), (1D, 2G, XB, 3C, 4C), (1D,
2G, XB, 3D, 4A), (1D, 2G, XB, 3D, 4B), (1D, 2G, XB, 3D, 4C), (1E,
2A, XA, 3A, 4A), (1E, 2A, XA, 3A, 4B), (1E, 2A, XA, 3A, 4C), (1E,
2A, XA, 3B, 4A), (1E, 2A, XA, 3B, 4B), (1E, 2A, XA, 3B, 4C), (1E,
2A, XA, 3C, 4A), (1E, 2A, XA, 3C, 4B), (1E, 2A, XA, 3C, 4C), (1E,
2A, XA, 3D, 4A), (1E, 2A, XA, 3D, 4B), (1E, 2A, XA, 3D, 4C), (1E,
2A, XB, 3A, 4A), (1E, 2A, XB, 3A, 4B), (1E,-2A, XB, 3A, 4C), (1E,
2A, XB, 3B, 4A), (1E, 2A, XB, 3B, 4B), (1E, 2A, XB, 3B, 4C), (1E,
2A, XB, 3C, 4A), (1E, 2A, XB, 3C, 4B), (1E, 2A, XB, 3C, 4C), (1E,
2A, XB, 3D, 4A), (1E, 2A, XB, 3D, 4B), (1E, 2A, XB, 3D, 4C), (1E,
2B, XA, 3A, 4A), (1E, 2B, XA, 3A, 4B), (1E, 2B, XA, 3A, 4C), (1E,
2B, XA, 3B, 4A), (1E, 2B, XA, 3B, 4B), (1E, 2B, XA, 3B, 4C), (1E,
2B, XA, 3C, 4A), (1E, 2B, XA, 3C, 4B), (1E, 2B, XA, 3C, 4C), (1E,
2B, XA, 3D, 4A), (1E, 2B, XA, 3D, 4B), (1E, 2B, XA, 3D, 4C), (1E,
2B, XB, 3A, 4A), (1E, 2B, XB, 3A, 4B), (1E, 2B, XB, 3A, 4C), (1E,
2B, XBj 3B, 4A), (1E, 2B, XB, 3B, 4B), (1E, 2B, XB, 3B, 4C), (1E,
2B, XB, 3C, 4A), (1E, 2B, XB, 3C, 4B), (1E, 2B, XB, 3C, 4C), (1E,
2B, XB, 3D, 4A), (1E, 2B, XB, 3D, 4B), (1E, 2B, XB, 3D, 4C), (1E,
2C, XA, 3A, 4A), (1E, 2C, XA, 3A, 4B), (1E, 2C, XA, 3A, 4C), (1E,
2C, XA, 3B, 4A), (1E, 2C, XA, 3B, 4B), (1E, 2C, XA, 3B, 4C), (1E,
2C, XA, 3C, 4A), (1E, 2C, XA, 3C, 4B), (1E, 2C, XA, 3C, 4C), (1E,
2C, XA, 3D, 4A), (1E, 2C, XA, 3D, 4B), (1E, 2C, XA, 3D, 4C), (1E,
2C, XB, 3A, 4A), (1E, 2C, XB, 3A, 4B), (1E, 2C, XB, 3A, 4C), (1E,
2C, XB, 3B, 4A), (1E, 2C, XB, 3B, 4B), (1E, 2C, XB, 3B, 4C), (1E,
2C, XB, 3C, 4A), (1E, 2C, XB, 3C, 4B), (1E, 2C, XB, 3C, 4C), (1E,
2C, XB, 3D, 4A), (1E, 2C, XB, 3D, 4B), (1E, 2C, XB, 3D, 4C), (1E,
2D, XA, 3A, 4A), (1E, 2D, XA, 3A, 4B), (1E, 2D, XA, 3A, 4C), (1E,
2D, XA, 3B, 4A), (1E, 2D, XA, 3B, 4B), (1E, 2D, XA, 3B, 4C), (1E,
2D, XA, 3C; 4A), (1E, 2D, XA, 3C, 4B), (1E, 2D, XA, 3C, 4C), (1E,
2D, XA, 3D, 4A), (1E, 2D, XA, 3D, 4B), (1E, 2D, XA, 3D, 4C), (1E,
2D, XB, 3A, 4A), (1E, 2D, XB, 3A, 4B), (1E, 2D, XB, 3A, 4C), (1E,
2D, XB, 3B, 4A), (1E, 2D, XB, 3B, 4B), (1E, 2D, XB, 3B, 4C), (1E,
2D, XB, 3C, 4A), (1E, 2D, XB, 3C, 4B), (1E, 2D, XB, 3C, 4C), (1E,
2D, XB, 3D, 4A), (1E, 2D, XB, 3D, 4B), (1E, 2D, XB, 3D, 4C), (1E,
2E, XA, 3A, 4A), (1E, 2E, XA, 3A, 4B), (1E, 2E, XA, 3A, 4C), (1E,
2E, XA, 3B, 4A), (1E, 2E, XA, 3B, 4B), (1E, 2E, XA, 3B, 4C), (1E,
2E, XA, 3C, 4A), (1E, 2E, XA, 3C, 4B), (1E, 2E, XA, 3C, 4C), (1E,
2E, XA, 3D, 4A), (1E, 2E, XA, 3D, 4B), (1E, 2E, XA, 3D, 4C), (1E,
2E, XB, 3A, 4A), (1E, 2E, XB, 3A, 4B), (1E, 2E, XB, 3A, 4C), (1E,
2E, XB, 3B, 4A), (1E, 2E, XB, 3B, 4B), (1E, 2E, XB, 3B, 4C), (1E,
2E, XB, 3C, 4A), (1E, 2E, XB, 3C, 4B), (1E, 2E, XB, 3C, 4C), (1E,
2E, XB, 3D, 4A), (1E, 2E, XB, 3D, 4B), (1E, 2E, XB, 3D, 4C), (1E,
2F, XA, 3A, 4A), (1E, 2F, XA, 3A, 4B), (1E, 2F, XA, 3A, 4C), (1E,
2F, XA, 3B, 4A), (1E, 2F, XA, 3B, 4B), (1E, 2F, XA, 3B, 4C), (1E,
2F, XA, 3C, 4A), (1E, 2F, XA, 3C, 4B), (1E, 2F, XA, 3C, 4C), (1E,
2F, XA, 3D, 4A), (1E, 2F, XA, 3D, 4B), (1E, 2F, XA, 3D, 4C), (1E,
2F, XB, 3A, 4A), (1E, 2F, XB, 3A, 4B), (1E, 2F, XB, 3A, 4C), (1E,
2F, XB, 3B, 4A), (1E, 2F, XB, 3B, 4B), (1E, 2F, XB, 3B, 4C), (1E,
2F, XB, 3C, 4A), (1E, 2F, XB, 3C, 4B), (1E, 2F, XB, 3C, 4C), (1E,
2F, XB, 3D, 4A), (1E, 2F, XB, 3D, 4B), (1E, 2F, XB, 3D, 4C), (1E,
2G, XA, 3A, 4A),
(1E, 2G; XA, 3A, 4B), (1E, 2G, XA, 3A, 4C), (1E, 2G, XA, 3B, 4A),
(1E, 2G, XA, 3B, 4B), (1E, 2G, XA, 3B, 4C), (1E, 2G, XA, 3C, 4A),
(1E, 2G, XA, 3C, 4B), (1E, 2G, XA, 3C, 4C), (1E, 2G, XA, 3D, 4A),
(1E, 2G, XA, 3D, 4B), (1E, 2G, XA, 3D, 4C), (1E, 2G, XB, 3A, 4A),
(1E, 2G, XB, 3A, 4B), (1E, 2G, XB, 3A, 4C), (1E, 2G, XB, 3B, 4A),
(1E, 2G, XB, 3B, 4B), (1E, 2G, XB, 3B, 4C), (1E, 2G, XB, 3C, 4A),
(1E, 2G, XB, 3C, 4B), (1E, 2G, XB, 3C, 4C), (1E, 2G, XB, 3D, 4A),
(1E, 2G, XB, 3D, 4B), (1E, 2G, XB, 3D, 4C), (1F, 2A, XA, 3A, 4A),
(1F, 2A, XA, 3A, 4B), (1F, 2A, XA, 3A, 4C), (1F, 2A, XA, 3B, 4A),
(1F, 2A, XA, 3B, 4B), (1F, 2A, XA, 3B, 4C), (1F, 2A, XA, 3C, 4A),
(1F, 2A, XA, 3C, 4B), (1F, 2A, XA, 3C, 4C), (1F, 2A, XA, 3D, 4A),
(1F, 2A, XA, 3D, 4B), (1F, 2A, XA, 3D, 4C), (1F, 2A, XB, 3A, 4A),
(1F, 2A, XB, 3A, 4B), (1F, 2A, XB, 3A, 4C), (1F, 2A, XB, 3B, 4A),
(1F, 2A, XB, 3B, 4B), (1F, 2A, XB, 3B, 4C), (1F, 2A, XB, 3C, 4A),
(1F, 2A, XB, 3C, 4B), (1F, 2A, XB, 3C, 4C), (1F, 2A, XB, 3D, 4A),
(1F, 2A, XB, 3D, 4B), (1F, 2A, XB, 3D, 4C), (1F, 2B, XA, 3A, 4A),
(1F, 2B, XA, 3A, 4B), (1F, 2B, XA, 3A, 4C), (1F, 2B, XA, 3B, 4A),
(1F, 2B, XA, 3B, 4B), (1F, 2B, XA, 3B, 4C), (1F, 2B, XA, 3C, 4A),
(1F, 2B, XA, 3C, 4B), (1F, 2B, XA, 3C, 4C), (1F, 2B, XA, 3D, 4A),
(1F, 2B, XA, 3D, 4B), (1F, 2B, XA, 3D, 4C), (1F, 2B, XB, 3A, 4A),
(1F, 2B, XB, 3A, 4B), (1F, 2B, XB, 3A, 4C), (1F, 2B, XB, 3B, 4A),
(1F, 2B, XB, 3B, 4B), (1F, 2B, XB, 3B, 4C), (1F, 2B, XB, 3C, 4A),
(1F, 2B, XB, 3C, 4B), (1F, 2B, XB, 3C, 4C), (1F, 2B, XB, 3D, 4A),
(1F, 2B, XB, 3D, 4B), (1F, 2B, XB, 3D, 4C), (1F, 2C, XA, 3A, 4A),
(1F, 2C, XA, 3A, 4B), (1F, 2C, XA, 3A, 4C), (1F, 2C, XA, 3B, 4A),
(1F, 2C, XA, 3B, 4B), (1F, 2C, XA, 3B, 4C), (1F, 2C, XA, 3C, 4A),
(1F, 2C, XA, 3C, 4B), (1F, 2C, XA, 3C, 4C), (1F, 2C, XA, 3D, 4A),
(1F, 2C, XA, 3D, 4B), (1F, 2C, XA, 3D, 4C), (1F, 2C, XB, 3A, 4A),
(1F, 2C, XB, 3A, 4B), (1F, 2C, XB, 3A, 4C), (1F, 2C, XB, 3B, 4A),
(1F, 2C, XB, 3B, 4B), (1F, 2C, XB, 3B, 4C), (1F, 2C, XB, 3C, 4A),
(1F, 2C, XB, 3C, 4B), (1F, 2C, XB, 3C, 4C), (1F, 2C, XB, 3D, 4A),
(1F, 2C, XB, 3D, 4B), (1F, 2C, XB, 3D, 4C), (1F, 2D, XA, 3A, 4A),
(1F, 2D, XA, 3A, 4B), (1F, 2D, XA, 3A, 4C), (1F, 2D, XA, 3B, 4A),
(1F, 2D, XA, 3B, 4B), (1F, 2D, XA, 3B, 4C), (1F, 2D, XA, 3C, 4A),
(1F, 2D, XA, 3C, 4B), (1F, 2D, XA, 3C, 4C)j (1F, 2D, XA, 3D, 4A),
(1F, 2D, XA, 3D, 4B), (1F, 2D, XA, 3D, 4C), (1F, 2D, XB, 3A, 4A),
(1F, 2D, XB, 3A, 4B), (1F, 2D, XB, 3A, 4C), (1F, 2D, XB, 3B, 4A),
(1F, 2D, XB, 3B, 4B), (1F, 2D, XB, 3B, 4C), (1F, 2D, XB, 3C, 4A),
(1F, 2D, XB, 3C, 4B), (1F, 2D, XB, 3C, 4C), (1F, 2D, XB, 3D, 4A),
(1F, 2D, XB, 3D, 4B), (1F, 2D, XB, 3D, 4C), (1F, 2E, XA, 3A, 4A),
(1F, 2E, XA, 3A, 4B), (1F, 2E, XA, 3A, 4C), (1F, 2E, XA, 3B, 4A),
(1F, 2E, XA, 3B, 4B), (1F, 2E, XA, 3B, 4C), (1F, 2E, XA, 3C, 4A),
(1F, 2E, XA, 3C, 4B), (1F, 2E, XA, 3C, 4C), (1F, 2E, XA, 3D, 4A),
(1F, 2E, XA, 3D, 4B), (1F, 2E, XA, 3D, 4C), (1F, 2E, XB, 3A, 4A),
(1F, 2E, XB, 3A, 4B), (1F, 2E, XB, 3A, 4C), (1F, 2E, XB, 3B, 4A),
(1F, 2E, XB, 3B, 4B), (1F, 2E, XB, 3B, 4C), (1F, 2E, XB, 3C, 4A),
(1F, 2E, XB, 3C, 4B), (1F, 2E, XB, 3C, 4C), (1F, 2E, XB, 3D, 4A),
(1F, 2E, XB, 3D, 4B), (1F, 2E, XB, 3D, 4C), (1F, 2F, XA, 3A, 4A),
(1F, 2F, XA, 3A, 4B), (1F, 2F, XA, 3A, 4C), (1F, 2F, XA, 3B, 4A),
(1F, 2F, XA, 3B, 4B),; (1F, 2F, XA, 3B, 4C), (1F, 2F, XA, 3C, 4A),
(1F, 2F, XA, 3C, 4B), (1F, 2F, XA, 3C, 4C), (1F, 2F, XA, 3D, 4A),
(1F, 2F, XA, 3D, 4B), (1F, 2F, XA, 3D, 4C), (1F, 2F, XB, 3A, 4A),
(1F, 2F, XB, 3A, 4B), (1F, 2F, XB, 3A, 4C), (1F, 2F, XB, 3B, 4A),
(1F, 2F, XB, 3B, 4B), (1F, 2F, XB, 3B, 4C), (1F, 2F, XB, 3C, 4A),
(1F, 2F, XB, 3C, 4B), (1F, 2F, XB, 3C, 4C), (1F, 2F, XB, 3D, 4A),
(1F, 2F, XB, 3D, 4B), (1F, 2F, XB, 3D, 4C), (1F, 2G, XA, 3A, 4A),
(1F, 2G, XA, 3A, 4B), (1F, 2G, XA, 3A, 4C), (1F, 2G, XA, 3B, 4A),
(1F, 2G, XA, 3B, 4B), (1F, 2G, XA, 3B, 4C), (1F, 2G, XA, 3C, 4A),
(1F, 2G, XA, 3C, 4B), (1F, 2G, XA, 3C, 4C), (1F, 2G, XA, 3D, 4A),
(1F, 2G, XA, 3D, 4B), (1F, 2G, XA, 3D, 4C), (1F, 2G, XB, 3A, 4A),
(1F, 2G, XB, 3A, 4B), (1F, 2G, XB, 3A, 4C), (1F, 2G, XB, 3B, 4A),
(1F, 2G, XB, 3B, 4B), (1F, 2G, XB, 3B, 4C), (1F, 2G, XB, 3C, 4A),
(1F, 2G, XB, 3C, 4B), (1F, 2G, XB, 3C, 4C), (1F, 2G, XB, 3D, 4A),
(1F, 2G, XB, 3D, 4B), (1F, 2G, XB, 3D, 4C), (1G, 2A, XA, 3A, 4A),
(1G, 2A, XA, 3A, 4B), (1G, 2A, XA, 3A, 4C), (1G, 2A, XA, 3B, 4A),
(1G, 2A, XA, 3B, 4B), (1G, 2A, XA, 3B, 4C), (1G, 2A, XA, 3C, 4A),
(1G, 2A, XA, 3C, 4B), (1G, 2A, XA, 3C, 4C), (1G, 2A, XA, 3D, 4A),
(1G, 2A, XA, 3D, 4B), (1G, 2A, XA, 3D, 4C), (1G, 2A, XB, 3A, 4A),
(1G, 2A, XB, 3A, 4B), (1G, 2A, XB, 3A, 4C), (1G, 2A, XB, 3B, 4A),
(1G, 2A, XB, 3B, 4B), (1G, 2A, XB, 3B, 4C), (1G, 2A, XB, 3C, 4A),
(1G, 2A, XB, 3C, 4B), (1G, 2A, XB, 3C, 4C), (1G, 2A, XB, 3D, 4A),
(1G, 2A, XB, 3D, 4B), (1G, 2A, XBI 3D, 4C), (1G, 2B, XA, 3A, 4A),
(1G, 2B, XA, 3A, 4B), (1G, 2B, XA, 3A, 4C), (1G, 2B, XA, 3B, 4A),
(1G, 2B, XA, 3B, 4B), (1G, 2B, XA, 3B, 4C), (1G, 2B, XA, 3C, 4A),
(1G, 2B, XA, 3C, 4B), (1G, 2B, XA, 3C, 4C), (1G, 2B, XA, 3D, 4A),
(1G, 2B, XA, 3D, 4B), (1G, 2B, XA, 3D, 4C), (1G, 2B, XB, 3A, 4A),
(1G, 2B, XB, 3A, 4B), (1G, 2B, XB, 3A, 4C), (1G, 2B, XB, 3B, 4A),
(1G, 2B, XB, 3B, 4B), (1G, 2B, XB, 3B, 4C), (1G, 2B, XB, 3C, 4A),
(1G, 2B, XB, 3C, 4B), (1G, 2B, XB, 3C, 4C), (1G, 2B, XB, 3D, 4A),
(1G, 2B, XB, 3D, 4B), (1G, 2B, XB, 3D, 4C), (1G, 2C, XA, 3A, 4A),
(1G, 2C, XA, 3A, 4B), (1G, 2C, XA, 3A, 4C), (1G, 2C, XA, 3B, 4A),
(1G, 2C, XA, 3B, 4B), (1G, 2C, XA, 3B, 4C), (1G, 2C, XA, 3C, 4A),
(1G, 2C, XA, 3C, 4B), (1G, 2C, XA, 3C, 4C), (1G, 2C, XA, 3D, 4A),
(1G, 2C, XA, 3D, 4B), (1G, 2C, XA, 3D, 4C), (1G, 2C, XB, 3A, 4A),
(1G, 2C, XB, 3A, 4B), (1G, 2C, XB, 3A, 4C), (1G, 2C, XB, 3B, 4A),
(1G, 2C, XB, 3B, 4B), (1G, 2C, XB, 3B, 4C), (1G, 2C, XB, 3C, 4A),
(1G, 2C, XB, 3C, 4B), (1G, 2C, XB, 3C, 4C), (1G, 2C, XB, 3D, 4A),
(1G, 2C, XB, 3D, 4B), (1G, 2C, XB, 3D, 4C), (1G, 2D, XA, 3A, 4A),
(1G, 2D, XA, 3A, 4B), (1G, 2D, YA, 3A, 4C), (1G, 2D, XA, 3B, 4A),
(1G, 2D, XA, 3B, 4B), (1G, 2D, XA, 3B, 4C), (1G, 2D, XA, 3C, 4A),
(1G, 2D, YA, 3C, 4B), (1G, 2D, XA, 3C, 4C), (1G, 2D, XA, 3D, 4A),
(1G, 2D, XA, 3D, 4B), (1G, 2D, XA, 3D, 4C), (1G, 2D, XB, 3A, 4A),
(1G, 2D, XB, 3A, 4B), (1G, 2D, XB, 3A, 4C), (1G, 2D, XB, 3B, 4A),
(1G, 2D, XB, 3B, 4B), (1G, 2D, XB, 3B, 4C), (1G, 2D, XB, 3C, 4A),
(1G, 2D, XB, 3C, 4B), (1G, 2D, XB, 3C, 4C), (1G, 2D, XB, 3D, 4A),
(1G, 2D, XB, 3D, 4B), (1G, 2D, XB, 3D, 4C), (1G, 2E, XA, 3A, 4A),
(1G, 2E, XA, 3A, 4B), (1G, 2E, XA, 3A, 4C), (1G, 2E, XA, 3B, 4A),
(1G, 2E, XA, 3B, 4B), (1G, 2E, XA, 3B, 4C), (1G, 2E, XA, 3C, 4A),
(1G, 2E, XA, 3C, 4B), (1G, 2E, XA, 3C, 4C), (1G, 2E, XA, 3D, 4A),
(1G, 2E, XA, 3D, 4B), (1G, 2E, XA, 3D, 4C), (1G, 2E, XB, 3A, 4A),
(10, 2E, XB, 3A, 4B), (1G, 2E, XB, 3A, 4C), (1G, 2E, XB, 3B, 4A),
(1G, 2E, XB, 3B, 4B), (1G, 2E, XB, 3B, 4C), (1G, 2E, XB, 3C, 4A),
(1G, 2E, XB, 3C, 4B), (1G, 2E, XB, 3C, 4C), (1G, 2E, XB, 3D, 4A),
(1G, 2E, XB, 3D, 4B), (1G, 2E, XB, 3D, 4C), (1G, 2F, XA, 3A, 4A),
(1G, 2F, XA, 3A, 4B), (1G, 2F, XA, 3A, 4C), (1G, 2F, XA, 3B, 4A),
(1G, 2F, XA, 3B, 4B), (1G, 2F, XA, 3B, 4C), (1G, 2F, XA, 3C, 4A),
(1G, 2F, XA, 3C, 4B), (1G, 2F, XA, 3C, 4C), (1G, 2F, XA, 3D, 4A),
(1G, 2F, XA, 3D, 4B), (1G, 2F, XA, 3D, 4C), (1G, 2F, XB, 3A, 4A),
(1G, 2F, XB, 3A, 4B), (1G, 2F, XB, 3A, 4C), (1G, 2F, XB, 3B, 4A),
(1G, 2F, XB, 3B, 4B), (1G, 2F, XB, 3B, 4C), (1G, 2F, XB, 3C, 4A),
(1G, 2F, XB, 3C, 4B), (1G, 2F, XB, 3C, 4C), (1G, 2F, XB, 3D, 4A),
(1G, 2F, XB, 3D, 4B), (1G, 2F, XB, 3D, 4C), (1G, 2G, XA, 3A, 4A),
(1G, 2G, XA, 3A, 4B), (1G, 2G, XA, 3A, 4C), (1G, 2G, XA, 3B, 4A),
(1G, 2G, XA, 3B, 4B), (1G, 2G, XA, 3B, 4C), (1G, 2G, XA, 3C, 4A),
(1G, 2G, XA, 3C, 4B), (1G, 2G, XA, 3C, 4C), (1G, 2G, XA, 3D, 4A),
(1G, 2G, XA, 3D, 4B), (1G, 2G, XA, 3D, 4C), (1G, 2G, XB, 3A, 4A),
(1G, 2G, XB, 3A, 4B), (1G, 2G, XB,.3A, 4C), (1G, 2G, XB, 3B, 4A),
(1G, 2G, XB, 3B, 4B), (1G, 2G, XB, 3B, 4C), (1G, 2G, XB, 3C, 4A),
(1G, 2G, XB, 3C, 4B), (1G, 2G, XB, 3C, 4C), (1G, 2G, XB, 3D, 4A),
(1G, 2G, XB, 3D, 4B), (1G, 2G, XB, 3D, 4C)
[3105] And (R.sup.1,R.sup.2,X, R.sup.3,R.sup.4)=(1A,2A, XA,
3A,4A),is the compound which R.sup.1 is 1A, R.sup.2 is 2A, X is XA,
R.sup.3 is 3A and R.sup.4 is 4A. The other combinations are the
same.
EXPERIMENTAL EXAMPLE
[3106] The inhibitory activities against integrase of the compounds
in the present invention have been determined by the assay
described below.
[3107] (1) Preparation of DNA Solutions.
[3108] Substrate DNA and target DNA, which sequences were indicated
below, were synthesized by Amersham Pharmacia Biotech and dissolved
in KTE buffer (composition: 100 mM KCl, 1 mM EDTA, 10 mM Tris-HCl
(pH 7.6)) at concentration of 2 pmol/.mu.l and 5 pmol/.mu.l,
respectively. The DNA solutions were annealed with each complement
by slowly cooling after heating.
1 (Substrate DNA) 5'-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTC TAG
CAG T-3' 3'-GAA AAT CAG TCA CAC CTT TTA GAG ATC GTC A-5' (Target
DNA) 5'-TGA CCA AGG GCT AAT TCA CT-Dig-3' 3'-Dig-ACT GGT TCC CGA
TTA AGT GA-5'
[3109] (2) Calculations of the Percent Inhibitions (the IC.sub.50
Values of Test Compounds)
[3110] Streptavidin, obtained from Vector Laboratories, was
dissolved in 0.1M carbonate buffer (composition: 90 mM
Na.sub.2CO.sub.3, 10 mM NaHCO.sub.3) at concentration of 40
.mu.g/ml. After coating each well of microtiter plates (obtained
from NUNC) with 50 .mu.l of the above solution at 4.degree. C. over
night, each well was washed twice with PBS (composition: 13.7 mM
NaCl, 0.27 mM KCl, 0.43 mM Na.sub.2HPO.sub.4, 0.14 mM
KH.sub.2PO.sub.4) and blocked with 300 .mu.l of 1% skim milk in PBS
for 30 min. Additionally, each well was washed twice with PBS and
added 50 .mu.l of substrate DNA solution (0.04 pmol/.mu.l) diluted
to one fiftieth with NTE buffer (composition: 1M NaCl, 10 mM
Tris-HCl (pH8.0), 1 mM EDTA). The microtiter plates were kept at
room temperature for 30 min. Then, each well was washed twice with
PBS and once with H.sub.2O.
[3111] Subsequently, in the each well prepared above were added 45
.mu.A of the reaction buffer prepared from 12 .mu.l of the buffer
(composition: 150 mM MOPS (pH 7.2), 75 mM MnCl.sub.2, 50 mM
2-mercaptoethanol, 25% glycerol, 500 .mu.g/ml bovine serum
albumin-fraction V), 1 .mu.l of target DNA (5 pmol/.mu.l), and 32
.mu.l of the distilled water. Additionally, 6 .mu.l of either a
test compound in DMSO or DMSO for positive control (PC) was mixed
with the above reaction buffer, then 9 .mu.l of an integrase
solution (30 pmol) was added and mixed well. In the well of
negative control (NC) was added 9 .mu.l of the integrase dilution
buffer (composition: Hepes (pH7.6), 400 mM potassium glutamate, 1
mM EDTA, 0.1% NP-40, 20% glycerol, 1 mM DTT, 4M urea).
[3112] The microtiter plates were incubated at 30.degree. C. for 1
hour. The reaction solution was removed and each well was washed
twice with PBS. Subsequently, each well of the microtiter plates
was filled with 100 .mu.l of anti-digoxigenin antibody labeled with
alkaline phosphatase (Sheep Fab fragment: obtained from Boehringer)
and incubated at 300C for 1 hour. Then, each well was washed twice
with 0.05% Tween20 in PBS and once with PBS. Next, 150 .mu.l of the
Alkaline phosphatase reaction buffer (composition: 10 mM
p-Nitrophenylphosphate (obtained from Vector Laboratories), 5 mM
MgCl.sub.2, 100 mM NaCl, 100 mM Tris-HCl (pH 9.5)) was added in
each well. The microtiter plates were incubated at 300C for 2
hours. The optical density (OD) at 405 nm of each well was measured
and the percent inhibition was determined by the following
expression.
The percent inhibition (%)=100[1-{(C abs.-NC abs.)/(PC abs.-NC
abs.)}]
[3113] C abs.; the OD of the well of the
[3114] NC abs.: the OD of the negative control (NC)
[3115] PC abs.: the OD of the positive control (PC)
[3116] When the percent inhibition (%) is X % at the concentration
of x .mu.tg/ml and the percent inhibition (%) is Y % at the
concentration of y .mu.g/ml, one of which is more than 50% and the
other is less than 50%, IC.sub.50 can be determined by the
following expression.
IC.sub.50(.mu.g/ml)=x-{(X-50)(x-y)/(X-Y)}
[3117] The IC .sub.50 values, the concentration of the compounds at
percent inhibition 50%, are shown in the following Table 1.
Compound No. in the Table 1 is the same as compound No. of the
above example.
2 TABLE 1 compound IC.sub.50 No. (.mu.g/ml) A-7 0.76 A-12-a 0.33
A-17 0.80 A-17-c 0.94 A-50 0.16 A-141-k 0.68 A-158 0.67 B-6-a 1.6
B-6-d 2.4 B-12 0.29 B-12-b 0.21 B-29 0.12 B-68 0.22 C-22 0.48 C-26
0.36 C-39 0.23 D-5 0.45 E-8 0.14 E-16 0.12 F-4 0.57 G-7 0.48 H-7
0.68 I-4 0.50 J-4 0.26 K-4 0.57 L-4 0.49 M-6 2.9
[3118] The compounds of the present invention except the above
compounds had the same or more integrase inhibitory activities.
[3119] And the compounds of the present invention have high
stability against metabolism and they are superior inhibitory
agents against integrase.
FORMULATION EXAMPLE
[3120] It is to be noted that the following Formulation Examples 1
to 8 are mere illustration, but not intended to limit the scope of
the invention. The term "active ingredient" means the compounds of
the present invention, the tautomers, the prodrugs thereof, their
pharmaceutical acceptable salts, or their solvate.
FORMULATION EXAMPLE 1
[3121] Hard gelatin capsules are prepared using of the following
ingredients:
3 Dose (mg/capsule) Active ingredient 250 Starch, dried 200
Magnesium stearate 10 Total 460 mg
FORMULATION EXAMPLE 2
[3122] A tablet is prepared using of the following ingredients:
4 Dose (mg/tablet) Active ingredient 250 Cellulose, microcrystals
400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg
[3123] The components are blended and compressed to form tablets
each weighing 665 mg.
FORMULATION EXAMPLE 3
[3124] An aerosol solution is prepared containing the following
components:
5 Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 74.00
(chlorodifluoromethane) Total 100.00
[3125] The active ingredient is mixed with ethanol and the
admixture added to a portion of the propellant 22, cooled to
-30.degree. C. and transferred to a filling device. The required
amount is then fed to a stainless steel container and diluted with
the reminder of the propellant. The valve units are then fitted to
the container.
FORMULATION EXAMPLE 4
[3126] Tablets, each containing 60 mg of active ingredient, are
made as follows.
6 Active ingredient 60 mg Starch 45 mg Microcrystals cellulose 35
mg Polyvinylpyrrolidone 4 mg (as 10% solution in water) Sodium
carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg
Total 150 mg
[3127] The active ingredient, starch, and cellulose are passed
through a No. 45 mesh U.S. sieve, and the mixed thoroughly. The
aqueous solution containing polyvinylpyrrolidone is mixed with the
resultant powder, and the admixture then is passed through a No. 14
mesh U.S. sieve. The granules so produced are dried at 50.degree.
C. and passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate, and talc, previously
passed through No. 60 mesh U.S. sieve, are then added to the
granules which, after mixing, are compressed on a tablet machine to
yield tablets each weighing 150 mg.
FORMULATION EXAMPLE 5
[3128] Capsules, each containing 80 mg of active ingredient, are
made as follows:
7 Active ingredient 80 mg Starch 59 mg Microcrystals cellulose 59
mg Magnesium stearate 2 mg Total 200 mg
[3129] The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 45 mesh U.S. sieve, and
filled into hard gelatin capsules in 200 mg quantities.
FORMULATION EXAMPLE 6
[3130] Suppositories, each containing 225 mg of active ingredient,
are made as follows:
8 Active ingredient 225 mg Saturated fatty acid glycerides 2000 mg
Total 2225 mg
[3131] The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2 g capacity and
allowed to cool.
FORMULATION EXAMPLE 7
[3132] Suspensions, each containing 50 mg of active ingredient, are
made as follows:
9 Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v.
Purified water to total 5 ml
[3133] The active ingredient is passed through a No. 45U.S. sieve,
and mixed with the sodium carboxymethyl cellulose and syrup to form
a smooth paste. The benzoic acid solution, flavor and color are
diluted with a portion of the water and added, with stirring.
Sufficient water is then added to produce the required volume.
FORMULATION EXAMPLE 8
[3134] An intravenous formulation may be prepared as follows:
10 Active ingredient 100 mg Isotonic saline 1000 ml
[3135] The solution of the above ingredients is generally
administered intravenously to a subject at a rate of 1 ml per
minute.
INDUSTRIAL APPLICABILITY
[3136] The compounds of the present invention have inhibitory
activities against integrase and useful for treatment of AIDS as an
antiviral agent and an anti-HIV agent.
* * * * *