Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([N:9]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[S:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[N:19]=3)[CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(OCC)C>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[S:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])[N:19]=3)[CH2:10]2)=[O:8])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1)NO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 155.5 %

Procedure:
10% Metallic hydrogen chloride (1.4 mL) was added to the solution of (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.6 g) in MeOH (12 ml) and the mixture was stirred at ambient temperature for 3.5 hours. To the reaction mixture was added ethyl ether and isolated precipitate was collected by filtration to give (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-hydroxyacrylamide hydrochloride (0.42 g)
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[O:30][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1
Reactant: CCc1cc(CC)n(-c2cccc3nc(Cl)n(C)c23)n1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(CC)n(-c2cccc3nc(Oc4c(C)cc(Cl)cc4Cl)n(C)c23)n1
Yield: 78.3 %

Procedure:
A suspension of 2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole (92 mg, 0.318 mmol), 2,4-dichloro-6-methylphenol (114 mg, 0.643 mmol), potassium carbonate (89 mg, 0.643 mmol) in N,N-dimethylformamide (1.5 ml) was stirred at 90° C. for 5.5 days (2,4-dichloro-6-methylphenol and potassium carbonate were added in three equal portions each over 5.5 days). After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture to give 107 mg (0.249 mmol, 78.3%) of the title compound as an oil. The oil was crystallized from hexane to give 70 mg (51%) as a pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:2]1([CH3:1])[CH2:7][CH2:6][CH:5]([NH:17][NH:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][CH2:3]1)[CH3:14]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)CC1(C)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC1(C)CCC(NNC(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 72.3 %

Procedure:
Ethyl 2-(1-methyl-4-oxocyclohexyl)acetate (1.5 g, 7.57 mmol) and tert-butyl carbazate (1.100 g, 8.32 mmol) were dissolved in chloroform (30 mL), and AcOH (1.0 mL) and NaBH(OAc)3 (5.65 g) were added under ice-cooling. The mixture was allowed to gradually return to room temperature, and the mixture was stirred for 4 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:EtOAc, 100%-35%) to give tert-butyl 2-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)hydrazinecarboxylate (1.72 g, 5.47 mmol, 72.3% yield) as a mixture of isomers (colorless oil). LCMS=315.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([N:22]=[C:23]=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:23]([NH:22][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: O=C=NCCc1ccccc1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NCCc2ccccc2)c1O
Yield: 54.6 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (120 mg, 0.54 mmol) and phenethyl isocyanate (82 μL, 0.59 mmol) in 1.0 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), gave the desired product (109 mg, 55%). LC-MS (m/z) 369.8 (M+).
Reaction SMILES: N1(O[C:11]([N:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C@H:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=[C:14]2[C:32]2[CH:37]=[C:36]([S:38](=[O:42])(=[O:41])[NH:39][CH3:40])[C:35]([Cl:43])=[CH:34][C:33]=2[O:44][CH2:45][CH3:46])=[O:12])C2C=CC=CC=2N=N1.[N:47]1([C:53](=[O:61])[CH2:54][N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:16]2[C@@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:13]([C:11]([N:58]3[CH2:59][CH2:60][N:55]([CH2:54][C:53]([N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[O:61])[CH2:56][CH2:57]3)=[O:12])[C:14]([C:32]3[C:33]([O:44][CH2:45][CH3:46])=[CH:34][C:35]([Cl:43])=[C:36]([S:38]([NH:39][CH3:40])(=[O:41])=[O:42])[CH:37]=3)=[N:15]2)=[CH:30][CH:29]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)On1nnc2ccccc21
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 40 °C
Yield: 100.4 %

Procedure:
To a solution of (4S,5R)-2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester (9 mg, 0.0124 mmol) in 0.5 mL of dimethylformamide was added a solution of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (5.3 mg, 0.026 mmol) and diisopropylethylamine (4.53 uL). The resulting mixture was heated to 40° C. for 1 h. The solution was concentrated in vacuo then extracted from 1 mL of water with 1 mL of methylene chloride. The organic extract was applied to a 4 gram silica gel cartridge. The product was eluted using a gradient of methanol in methylene chloride to give 5-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide (9.69 mg, 97%). LC-MS: 777.3 [(M+H)+].
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:19][S:20]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=2)=[CH:7][CH:6]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)nc1
Product: CCOC(=O)c1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To chlorosulfonic acid (20 mL) was dropped ethyl 6-phenoxynicotinate (5.6 g) on ice bath, and the reaction mixture was stirred for 15 minutes at room temperature, and 3 hours at 60° C. To reaction mixture was added ice, and extracted with tert-butyl methyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (7.5 g) having the following physical data.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][N:17]([CH3:28])[C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1.[H-].[Na+].[CH3:31]I>CN(C)C=O>[CH3:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][N:17]([CH3:28])[C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1
Reactant: CI
Reactant: CN(C[C@H]1CC[C@H](c2nc3ccccc3[nH]2)CC1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](c2nc3ccccc3n2C)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.2 g (0.019 mol) of benzyl [[trans-4-(2-benzimidazolyl)cyclohexyl]methyl]methylcarbamate in 160 ml of dimethylformamide is treated at 15°-20° under argon with 0.023 mol of sodium hydride (1.0 g of a 55% dispersion in mineral oil) and thereupon stirred at room temperature for a further 30 minutes. A solution of 2.3 ml (0.038 mol) of methyl iodide in 10 ml of dimethylformamide is added thereto at 15°-20° within 15 minutes and the mixture is stirred at room temperature for a further 3 hours. After concentration under reduced pressure the residue is partitioned between ice-water and ethyl acetate. The organic phase, dried over sodium sulphate, is evaporated and the solid residue is recrystallized from ethyl acetate/ether. There are obtained 5.9 g (79%) of benzyl [[trans-4-(1-methyl-2-benzimidazolyl)cyclohexyl]methyl]methylcarbamate, m.p. 141°-142°, as a colourless crystalline powder.
Reaction SMILES: [Li+].[BH4-].[I:3][C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:5]=1[C:6]([NH:8][CH2:9][C:10](OCC)=[O:11])=[O:7].CO>C1COCC1>[OH:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:4]=1[I:3]
Reactant: CCOC(=O)CNC(=O)c1cc(OC)c(OC)cc1I
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(I)c(C(=O)NCCO)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
LiBH4 (63 mg, 3 mmol) was added to a stirred solution of ethyl 2-(2-iodo-4,5-dimethoxybenzamido)acetate (379 mg, 1 mmol) in THF (2 mL) at −10° C. The reaction was stirred for 5 min then methanol (0.22 mL) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 30 minutes and quenched by addition of water. The THF was removed under reduced pressure and the aqueous residue was thoroughly extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulphate and evaporated to give the crude product which was purified by re-crystallization from EtOAc and hexane to give N-(2-hydroxyethyl)-2-iodo-4,5-dimethoxybenzamide (280 mg, 80%) LC-MS (ES-API); rt 7.60 min; m/z calculated for C11H14NO4 [M+H]+ 352.0, found 352.0.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH3:26])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:27]C[O-].[Na+].CCO.O>C(O)C>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
Methyl [1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate (Example 85) (0.10 g) was dissolved in absolute ethanol (10 mL and a catalytic amount of 21% NaOEt/EtOH was added. The reaction was stirred without temperature control for 72 hours, then water (10 mL) was added. The product crystallized, the suspension was cooled to 0° C. and held for 30 minutes. The product was filtered, washed with water (5 mL) and dried to yield 0.071 g (70%) of a white solid: Mass Spectrum: MH+=406. Anal. Calc'd for C18H16N3O4ClS: C, 53.27; H, 3.97; N, 10.35; Cl, 8.74; S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl, 8.69; s, 7.97.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[CH3:14][O:13][C:3]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:12])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1nc2ccc(C)cc2nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
3-Amino-2-methoxy-6-methylquinoxaline (568 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with n-hexane:ethyl acetate (3:1) mixture and concentration gave 768 mg of the titled compound (yield, 98%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12]([O:14]C)=O)[NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.CC(C)([O-])C.[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:11]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:24][CH:23]([C:22]([O:26][CH3:27])=[O:25])[C:12]3=[O:14]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1cc2c(SC)nccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1Cn2c(cc3c(SC)nccc32)C1=O
Temperature: 80 °C

Procedure:
To a suspension of methyl 4-(methylthio)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (0.30 g, 1.35 mmol) in TBF (3 mL)-toluene (12.0 mL) were added a 1.06 M THE solution of potassium tert-butoxide (1.42 mL/1.41 mmol) and methyl acrylate (300 μL). The resulting mixture was heated at 80° C. for 18 h. The mixture was partitioned between EtOAc and NH4Cl, filtered through celite. The organic phase was separated, dried over Na2SO4 and filtered, to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([CH3:21])[NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][N:33]=[C:34]=[O:35])[CH3:29]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:20][C:34]([NH:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])=[O:35])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.1 %

Procedure:
(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (80 mg, 0.22 mmol), as described in Example 1, is dissolved in 1.42 mL dichloromethane and ethylisocyanatoacetate (28.6 mg, 0.22 mmol) is dropwise added. After stirring for 45 min at r.t. the solvent is removed and the residue purified by chromatography (silicagel, eluents: hexane/ethylacetate). 85.4 mg (78.6%) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:26]=[CH:25][C:11]3/[C:12](=[CH:21]/[C:22](O)=[O:23])/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[C:30]([CH3:31])[C:4]=2[N:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:26]=[CH:25][C:11]3/[C:12](=[CH:21]/[C:22]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:23])/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:29]=[C:30]([CH3:31])[C:4]=2[N:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (50 mg, 0.10 mmol) obtained in Example 55 was dissolved in DMF (2 mL), and the mixture was cooled to 0° C. N,N′-carbonyldiimidazole (36 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 2 hr. To this mixture were added methanesulfonamide (21 mg, 0.22 mmol) and DBU (21 mg, 0.22 mmol), and the mixture was stirred at 60° C. for 5 hr. 5% Aqueous citric acid solution was added to the mixture, and the precipitate was collected by filtration, and washed with water to give the title compound (compound 57) (31 mg, 55%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:26]#[N:27])[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[K+]>C(O)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:26]([NH2:27])=[O:30])[C:15]=2[O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C#N)cnc12
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C(N)=O)cnc12
Yield: 66.7 %

Procedure:
1-Benzyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (500 mg, 1.30 mmol) prepared in Example 276 was diluted with a mixture of ethanol (8 ml) and water (2 ml). Potassium hydroxide (650 mg, 13.0 mmol) was added to the reaction mixture, which was then refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1, (v/v)) to give 350 mg of the titled compound as a white solid.
Reaction SMILES: C[N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]1[CH2:28]CC(=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].N>>[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]1[CH2:24][CH2:25][C:3]2[N:2]=[C:7]([CH3:8])[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[CH2:28]1)([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])c(=O)n1C
Agent: N
Product: Cc1nc2c(cc1[N+](=O)[O-])CC(NC(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Reaction time: 5 h
Yield: 28.3 %

Procedure:
To a sealed tube was added 1,6-dimethyl-3,5-dinitropyridin-2(1H)-one (0.16 g, 0.76 mmol), tert-butyl(4-oxocyclohexyl)carbamate (0.19 g, 0.91 mmol), and ammonia (1M in methanol, 9 mL). The resulting mixture was allowed to stir for 5 h at 60° C. and then allowed to cool to rt and concentrated. The residue was purified by column chromatography to give tert-butyl(2-methyl-3-nitro-5,6,7,8-tetrahydroquinolin-6-yl)carbamate (0.066 g, 28%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:16][C:17]([C:18]([NH:20][C@@H:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:24])=[O:23])=[O:19])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:58][C:59](=[NH:61])[CH3:60]>C(Cl)Cl>[NH2:61]/[C:59](=[N:58]\[O:23][C:22](=[O:24])[C@@H:21]([NH:20][C:18]([C:17]1[N:16]=[C:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=12)=[O:19])[C:25]([CH3:27])([CH3:28])[CH3:26])/[CH3:60]
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)N1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 2 mL dichloromethane solution of Compound 515 (320 mg, 0.68 mmol) was added to a dichloromethane solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (209 mg, 1.09 mmol) and 1-hydroxybenzotriazole hydrate (167 mg, 1.09 mmol). The solution was stirred for 15 minutes at ambient temperature. N-hydroxyacetamidine (76 mg, 1.02 mmol) was added in one portion as a solid, and the mixture was stirred overnight. After diluting with additional DCM, the reaction mixture was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated to a pale yellow foaming solid (Intermediate 49A). LCMS (+ESI) m/z 527.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)=O>>[CH3:24][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3cccc(C)c3)cs2)c(C)s1
Yield: 63 %

Procedure:
Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate, 106 mg (0.428 mmol) (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-3′methylacetophenone (0.428 mmol, 91 mg) in a manner similar to Example 22, step (a) to afford 98 mg (63% yield) of methyl 4-[4-(3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:37]2[N:38]=[C:39]([NH:42][CH:43]=[O:44])[S:40][CH:41]=2)[C:7]([NH:9][C@@H:10]2[C:35](=[O:36])[N:12]3[C:13]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:14]([CH2:17][Cl:18])[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:53])C=1>C(Cl)Cl>[CH:1]1([O:4][N:5]=[C:6]([C:37]2[N:38]=[C:39]([NH:42][CH:43]=[O:44])[S:40][CH:41]=2)[C:7]([NH:9][C@@H:10]2[C:35](=[O:36])[N:12]3[C:13]([C:19]([O:21][CH:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:14]([CH2:17][Cl:18])[CH2:15][S:16](=[O:53])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Solvent: ClCCl
Product: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Reaction time: 1.5 h

Procedure:
To a solution of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (3 g) in methylene chloride (300 ml) was dropwise added a solution of m-chloroperbenzoic acid (0.79 g, 80% purity) in methylene chloride (10 ml) below 5° C. The mixture was stirred for 1.5 hours below 5° C. to give precipitates. The precipitates were collected, washed with methylene chloride, and dried over phosphorus pentoxide to give benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4carboxylate 1-oxide (syn isomer) as a solid.