Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]([F:23])([F:24])[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C

Procedure:
The mixture of 6-bromo-1H-indole (1.22 g, 6.22 mmol), 4-trifluoromethoxyphenyl boronic acid (1.41 g, 6.84 mmol), tetrakis(triphenylphosphine)palladium (0.213 g, 0.184 mmol) and sodium carbonate (2.64 g, 24.9 mmoles) in water (12.5 mL), ethanol (4 mL), and toluene (25 mL) was heated at reflux for 1.5 hours then cooled to room temperature. The mixture was then evaporated to dryness and the residue was partitioned in methylene chloride and water. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using 10-30% chloroform in hexane as an eluant. The title compound was obtained as a white solid (0.874 g, 51%), mp: 165-166° C. 1HNMR (300 MHz, DMSO-d6): δ 11.25 (s, 1H), 7.8 (d, 2H, J=7.0 Hz), 7.65 (d, 2H, J=7.0 Hz), 7.4-7.5 (m, 3H), 7.3 (d, 1H, J=8.8 Hz), and 6.45 ppm (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][CH2:43]O>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:43][CH2:42][CH:38]3[CH2:39][CH2:40][CH2:41][N:37]3[CH3:36])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CN1CCCC1CCO
Reactant: CCOC(=O)c1ccc2cc(O)ccc2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(OCCC3CCCN3C)ccc2n1
Temperature: 35 °C

Procedure:
A mixture of 0.400 g (0.002 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 0.966 g (0.004 mmol) of triphenylphospine (Fluka), 0.396 g (0.003 mmol) of 1-methyl-2-pyrrolidineethanol and 0.68 ml (0.004 mmol) di-tert.-butyl azadicarboxylate 40% in toluene in 40 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH/NH4OH from 97/3/0.5 to 90/10/0.5. The ]
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]1[C:18]2[CH:17]([CH2:19][O:20][C:21](Cl)=[O:22])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.O>O1CCOCC1>[NH:1]([C:21]([O:20][CH2:19][CH:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:18]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:22])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Glycine (Gly) (0.5 g, 6.66 mmole) was dissolved in 10% NaCO3 (14 ml) under stirring in a 50-ml flask. To the resulting solution, which had been put into an ice bath, 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) (1.72 g, 6.66 mmol) in dioxane (12 ml) was gradually added. The reaction mixture was stirred at room temperature for 4 hours, and water (150 ml) was then added. The aqueous phase layer was separated from the reaction mixture and stripped with ether three times (75 ml×3). The stripped aqueous layer was acidified with 2N HCl aqueous solution to a pH value of 2, followed by extraction with ethyl acetate three times (75 ml×3). The organic phase layer was recovered and concentrated to obtain crude product of 1.70 g. The crude product was recrystallized in a mixed solvent of ethyl acetate hexane=1:2 (30 ml), and white solid denoted as Fmoc-Gly was obtained after filtration at a reduced pressure. Yield: 1.69 g (85%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([NH:14][C:15]([C:17]2[N:21]([CH3:22])[N:20]=[C:19]([CH3:23])[CH:18]=2)=O)[CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:22][N:21]1[C:17]([CH2:15][NH:14][C:12]2[CH:13]=[C:8]([OH:7])[CH:9]=[CH:10][C:11]=2[CH3:24])=[CH:18][C:19]([CH3:23])=[N:20]1
Reactant: Cc1cc(C(=O)Nc2cc(O)ccc2C)n(C)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(CNc2cc(O)ccc2C)n(C)n1
Yield: 51.3 %

Procedure:
To a solution of 3-amino-4-methylphenol (930 mg, 7.5 mmol) in N,N-dimethylacetamide (10 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1370 mg, 8.7 mmol) in N, N-dimethylacetamide (5 mL), and the mixture was stirred at 0° C. for 20 min. To the mixture were added ethyl acetate/tetrahydrofuran, saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted 4 times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give N-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1170 mg, 63%) as a white solid. To a suspension of lithium aluminum hydride (1130 mg, 24 mmol) in tetrahydrofuran (35 mL) was slowly added dropwise a solution of N-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1170 mg, 4.8 mmol) in tetrahydrofuran (10 mL) under ice-cooling. After dropwise addition, the reaction mixture was heated under reflux for 5 hr. A saturated aqueous sodium sulfate solution was added to the mixture under cooling, magnesium sulfate was added and the insoluble material was filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (570 mg, 52%) as a white solid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][O:8][C@H:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[OH:23])=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:9][O:8][C@H:7]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][C@H:5]1[OH:23]
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Yield: 98 %

Procedure:
(2S,4R,5R)-5-Azido-2-benzhydryl-tetrahydro-pyran-4-ol (0.05 g, 0.18 mmol) dissolved in methanol (20 ml) was hydrogenated in the presence of 10% Pd/C (0.006 g). The mixture was filtered through a short bed of cellite, and evaporation of the solvent gave (2S,4R,5R)-5-amino-2-benzhydryl-tetrahydro-pyran-4-ol 0.05 g (97%, [α]D=(−)66, c=1, MeOH), which was pure enough for the next reaction.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([N+:11]([O-])=O)=[C:9]([C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:16][C:15]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH4+].[Cl-]>C1COCC1.O.[Zn]>[CH2:30]([O:29][C:15]1[CH:16]=[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]([Cl:20])=[CH:19][C:14]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:10]=1[NH2:11])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A solution of 5-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-nitro-isoxazole-3-carboxylic acid ethylamide (1 g, 1.97 mmol) in THF (7 ml) was added to a solution of NH4Cl (2.7 g, 50 mmol) in water (15 ml). Zinc dust (4 g, 61 mmol) was then added portion wise over 15 min with stirring at 0° C. After 30 min at 0° C., the mixture was filtered and the resulting cake was rinsed with MeOH. The combined filtrate were evaporated under vacuo to give 5-[2,4-bis(benzyloxy)-5-chlorophenyl]-4-amino-N-ethylisoxazole-3-carboxamide (820 mg, 82%).
Reaction SMILES: O[C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[C:20]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:19]=[CH:18][C:17]1=[O:31].[H-].[Na+]>O1CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:9])([CH3:8])[CH:2]=[C:3]([N:16]3[CH:21]=[C:20]([CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])[CH:19]=[CH:18][C:17]3=[O:31])[C:4]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2cc(CO[Si](C)(C)C(C)(C)C)ccc2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C=C(n2cc(CO[Si](C)(C)C(C)(C)C)ccc2=O)c2cc(C#N)ccc2O1
Yield: 91.6 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, is dissolved 1.32 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-5-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 12. Then, 0.12 g of 60% oily sodium hydride is added to the solution at room temperature, and reacted under reflux for 3 hours. The reaction mixture is concentrated under reduced pressure, and the residue is mixed with ethyl acetate and water and extracted with the ethyl acetate. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/3 mixture of ethyl acetate/methylene chloride as a developing solvent to obtain 1.16 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-5-t-butyldimethylsilyloxymethyl-1-pyridinyl}-2H-benzo[b]pyran.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].CC(N(C)C)=O>O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:14][C:12](=[O:13])[C:3]2[N:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=2[N:1]=1)[CH3:16]
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 20 h
Yield: 54.1 %

Procedure:
A mixture of 1.0 g of 3-amino-5-trifluoromethylpyridine-2-carboxylic acid amide, 850 mg of 2-ethylsulfanylbenzaldehyde, 1.60 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 20 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13](=[O:16])[CH2:14][CH3:15])[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[BH4-].[Na+]>>[OH:16][CH:13]([CH2:14][CH3:15])[CH:11]([N:10]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[C:2]1[CH3:1])[CH3:12]
Reactant: CCC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Agent: [BH4-]
Agent: [Na+]
Product: CCC(O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To tert-butyl 2-methyl-1-(3-oxopentan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (100 mg, 0.32 mmol) in CH30OH (2 ml) were added NaBH4 (35.9 mg, 0.95 mmol) at 0° C. The mixture was allowed to warm 25° C. with stir for 2 h. After the reaction completed, the solution was concentrated under vacuum and the solid was partitioned between EtOAc and H2O. The organic was separated, dried over Na2SO4 and evaporated under reduced pressure to give tert-butyl 1-(3-hydroxypentan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil. (50 mg yield 50%).
Reaction SMILES: [Cl:1][C:2](OC(Cl)(Cl)Cl)=[O:3].[N:9]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:1][C:2]([N:12]1[CH2:13][CH2:14][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10][CH2:11]1)=[O:3]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trichloromethyl chloroformate (5.45 mmol, 0.657 ml) in tetrahydrofuran (20 ml) was cooled to 0° C. and a solution of benzyl 1-piperazinecarboxylate (4.54 mmol, 0.876 ml) and N,N-diisopropylethylamine (9.99 mmol, 1.651 ml) in tetrahydrofuran (20 ml) was added dropwise. After stirring for one hour at 0° C. the solids were removed by filtration over decalite and the filtrate was concentrated in vacuo to give crude benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate. The latter compound was added to 2-aminomethyl-3-chloropyrazine hydrochloride (content 69%; 3.49 mmol, 0.91 g) in dichloromethane (15 ml) and triethylamine (10.46 mmol, 1.458 ml) and the reaction mixture was stirred over night at room temperature. Then the reaction mixture was filtered over decalite (washed with dichloromethane). The filtrate was concentrated and the crude product was purified using column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give benzyl 4-((3-chloropyrazin-2-yl)methylcarbamoyl)piperazine-1-carboxylate (1.15 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][OH:19])=[CH:12][C:11]=1[O:20][CH2:21][CH:22]([CH3:24])[CH3:23].[CH:25]1([CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36](O)[CH:35]=2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:25]1([CH:28]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([O:19][CH2:18][C:13]3[C:14]([O:16][CH3:17])=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:12]=3)[CH:39]=2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:27]1
Reactant: COc1ccc(F)c(-c2nc(OC)c(CO)cc2OCC(C)C)c1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CC(c1cccc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)nc2OC)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-isobutoxy-2-methoxypyridin-3-yl)methanol (94 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (62 mg) in toluene (4.0 mL) were added 1,1′-(azodicarbonyl)dipiperidine (113 mg) and tributylphosphine (112 μL), and the mixture was stirred at room temperature for 14 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (120 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:31][NH2:32]>CO.CCO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:7]([CH2:10][C:11]([NH:32][CH3:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2

Procedure:
A slurry of ethyl {7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21, 0.39 g, 0.91 mmol) in a mixture of MeOH (5 mL) and a 33% solution of methanamine (15 mL, 0.91 mmol) in EtOH was stirred at rt over night giving clean conversion to the amide. The reaction mixture was concentrated under reduced pressure giving the title compound (0.370 g, 98%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH2:20]([N:22]([CH2:25][C:26]([NH:28][NH2:29])=O)[CH2:23][CH3:24])[CH3:21]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:26]([CH2:25][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[N:28][N:29]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CCN(CC)CC(=O)NN
Solvent: CCCCO
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Preparation 1, a solution of 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione and (diethylamino)acetic acid hydrazide in n-butyl alcohol is reacted to give 8-chloro-1-[(diethyl amino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, which is recrystallized from ethyl acetateSkellysolve B hexanes and has a melting point of 131.5°-132.5° C. Anal. calcd. for C21H22ClN5 : C, 66.39; H, 5.84; Cl, 9.33; N, 18.44. Found: C, 66.20; H, 6.06; Cl, 9.29; N, 18.55. Preparation 8 8-Nitro-1-[(diethylamino)methyl]-6-phenyl4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)=O.C[O-].[Na+]>C(#N)C>[I:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2([CH3:11])[CH2:10][O:9]2)=[CH:15][CH:16]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)c1ccc(I)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: CC1(c2ccc(I)cc2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 30 g of dimethyl sulfide in 30 ml of acetonitrile was added dropwise over a period of 30 minutes 30 g of dimethyl sulfate, while maintaining the temperature at 40° to 50° C., and the mixture was stirred for one hour at the same temperature. The reaction mixture was cooled to 25° C. and mixed with 30 g of 4-iodoacetophenone and 90 ml of acetonitrile. While stirring, 13.2 g of sodium methoxide was added to the mixture and stirring was continued for a further 30 minutes at room temperature to complete the reaction. Thereafter, the dimethyl sulfide and acetonitrile were removed by distillation, and to the residue were added 120 ml of cyclohexane and 120 ml of water, after which the mixture was thoroughly shaken. The organic layer was separated, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure to obtain 31.5 g (99% yield) of oily 2-(4-iodophenyl)-2-methyloxirane having a melting point of 44°-45° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][C:16]=2[O:32][CH3:33])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:34]([NH:36][C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([NH:45][C:46](=[O:53])[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:39][C:38]=3[O:54][CH3:55])=[O:35])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:62](Cl)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN(C)C=O>[CH2:62]([O:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][C:16]=2[O:32][CH3:33])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:34]([NH:36][C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([NH:45][C:46](=[O:53])[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:39][C:38]=3[O:54][CH3:55])=[O:35])[CH:8]=2)[CH:3]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(NC(=O)c2ccc3cc(O)c(C(=O)Nc4cc(OC)c(NC(=O)c5ccccc5)cc4OC)cc3c2)c(OC)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2ccc3cc(OCc4ccccc4)c(C(=O)Nc4cc(OC)c(NC(=O)c5ccccc5)cc4OC)cc3c2)c(OC)cc1NC(=O)c1ccccc1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
2-Hydroxy-3,6-bis(2,5-dimethoxy-4-benzoylaminophenylaminocarbonyl)naphthalene (2.5 g) obtained in Example 10 was mixed with N,N-dimethylformamide (30 g) and the mixture was dissolved by heating to 100° C. under a nitrogen atmosphere. To the solution, potassium carbonate (0.5 g) was gradually added and benzyl chloride (0.46 g) was added dropwise and the mixed solution was reacted for 5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, filtered and then washed with water and methanol to obtain 2.65 g of 2-benzyloxy-3,6-bis(2,5-dimethoxy-4-benzoylaminophenylaminocarbonyl)naphthalene as a greenish yellow crystal (DSC analysis value: 282.8° C.)
Reaction SMILES: C(=O)([O-])O.[Na+:5].[O:6]=[C:7]1[NH:12][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[N:10][CH:9]=[C:8]1[C:24]([OH:26])=[O:25].C(O)C>O>[O:6]=[C:7]1[NH:12][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)=[N:10][CH:9]=[C:8]1[C:24]([O-:26])=[O:25].[Na+:5]
Reactant: O=C(O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Sodium hydrogen carbonate (0.82 g) is dissolved in water (50 ml), and thereto is added 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylic acid (3 g), and the mixture is heated. After foaming is finished, ethanol is added to the reaction mixture, and the solution is allowed to stand overnight. The precipitate is collected by filtration and recrystallized from a mixture of methanol and water to give sodium 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (2.4 g). M.p. 256°-259° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:44]3[CH2:43][CH2:42][C:41]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:21][CH:22]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)c1ccc(C(=O)CN2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.72 mmol). Chromatograph on silica gel to give the title compound.