Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([F:40])[CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:39])([F:38])[F:37]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.32 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.071 g, 13%). MS (ISP) 548.0 [(M+H)+]; mp 213.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.86 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H) naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 87 to 89/9 to 13. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.86 to 0.88%].
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:21]=[CH:20]2)(=[O:15])[CH3:14].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:10])[CH3:11])[NH:8][S:27]([C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([O:16][C:13](=[O:15])[CH3:14])[CH:18]=2)[CH:23]=1)(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Oc1ccc2cc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Yield: 67.4 %

Procedure:
D-valine tert-butyl ester (6.24 g, 35.9 mmol), 6-acetoxy naphthalene-2-sulfonyl chloride (10.2 g, 35.9 mmol) and triethylamine (12.5 mL, 89.7 mmol) are stirred in dioxane-water (1:1, 243 mL) at ambient temperature for 2 hours. The reaction mixture is acidified with a solution of aqueous citric acid (10% w/w, 800 mL). The precipitate is collected by filtration affording product as pale yellow crystals (10.2 g, 68% yield). LCMS (m/z): (439.28; M+18, 420.24; M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[N:39]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]([CH3:50])[CH3:49])=[CH:44][CH:43]=1)=[C:40]=[O:41]>>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:40]([NH:39][C:42]2[CH:47]=[CH:46][C:45]([CH:48]([CH3:50])[CH3:49])=[CH:44][CH:43]=2)=[O:41])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: CCCCCCCN(CCc1ccc(CC(OCc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Product: CCCCCCCN(CCc1ccc(CC(OCc2ccccc2)C(=O)OCC)cc1)C(=O)Nc1ccc(C(C)C)cc1

Procedure:
Synthesized from 2-benzyloxy-3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-propionic acid ethyl ester using procedures analogous to that used for Example 8 immediately followed by Example 10 and substituting 1-isocyanato-4-isopropyl-benzene in the place of 2,4-dimethoxyphenylisocyanate to give crude 2-benzyloxy-3-(4-{2-[1-heptyl-3-(4-isopropyl-phenyl)-ureido]-ethyl}-phenyl)-propionic acid ethyl ester.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[C:21]([CH:20]=[C:19]([C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:12]=1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)#[N:22]
Reactant: CN(C)C(=O)Cl
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(NC(=O)N(C)C)c2)ccc1OC
Temperature: 85 °C
Yield: 67.8 %

Procedure:
N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was added to a mixture of (E/Z) 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.70 g, 2.2 mmol) and dimethylcarbamyl chloride (1.6 mL, 17.3 mmol). The reaction mixture was heated at 85° C. for 3 h. CH2Cl2 (100 ml) was added and the mixture was extracted with water (2×50 mL), 4 N HCl (2×50 mL), water (2×50 mL), saturated NaHCO3 (2×50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-1,1-dimethyl-urea as a solid (0.59 g, 69% yield): mp, 143-145° C.; 1H NMR (CDCl3) δ 1.40-1.47 (m, 6H, 2CH3), 3.02-3.05 (2s, 12H, 4CH3), 3.88-3.94 (3s, 12H, 4OCH3), 3.99-4.12 (m, 4H, 2CH2), 5.55-5.61 (2s, 2H, 2CH), 6.79-7.18 (m, 12H, Ar), 8.18-8.36 (m, 2H, 2NH); 13C NMR (CDCl3) δ 14.71, 36.33, 55.93, 56.00, 64.46, 92.06, 92.33, 109.21, 109.30, 110.93, 110.99, 112.74, 114.22, 118.56, 118.69, 118.79, 120.27, 122.25, 123.06, 123.41, 123.74, 128.97, 129.24, 129.73, 130.11, 131.68, 132.25, 147.83, 148.14, 148.81, 149.27, 150.68, 151.37, 155.22, 155.31, 162.66, 163.11; Anal. Calcd for C22H25N3O4: C, 66.82; H, 6.37; N, 10.63. Found: C, 66.84; H, 6.48; N, 10.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]([C:12]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=O.C([BH3-])#N.[Na+].C(OCC)(=O)C>CO.CN1CCCC1=O>[OH:21][C:15]1[CH:14]=[CH:13][C:12]([CH2:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: COc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(NCc2ccc(O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
p-Anisidine (1.3 g, 10.6 mmol) was dissolved in methanol (20 mL) and 5-formylsalicylic acid (1.75 g, 10.6 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The solid formed was isolated by filtration, re-dissolved in N-methyl pyrrolidone (20 mL) and methanol (2 mL). To the mixture was added sodium cyanoborohydride (1.2 g) and the mixture was heated to 70° C. for 3 hours. To the cooled mixture was added ethyl acetate (100 mL) and the mixture was extracted with water (100 mL) and saturated aqueous ammonium chloride (100 mL). The combined aqueous phases were concentrated in vacuo and a 2 g aliquot was purified by SepPac chromatography eluting with mixtures of aetonitrile and water containing 0.1% trifluoroacetic acid to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([N:11]4[CH:15]=[N:14][CH:13]=[N:12]4)=[N:9][CH:10]=3)[N:16]=2)[CH:19]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(-n2cncn2)nc1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4cncn4)nc3)cn2c1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
657 mg (corresponding to 2.46 mmol) of 5-(2-bromoacetyl)-2-(1H-1,2,4-triazole-1-yl)pyridine and 541 mg (corresponding to 2.46 mmol) of 2-amino-5-iodopyridine were dissolved in 5.0 mL of acetonitrile. The resulting solution was heated under reflux for 1.5 hours in an oil bath at 100° C. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 2 mL of water and 2 mL of methanol. Then, about 1 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 675 mg (corresponding to 1.74 mmol) of 6-iodo-2-[2-(1H-1,2,4-triazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine (FIG. 4, step 3).
Reaction SMILES: [OH-:1].[Li+].C([N:6]1[C:14]2[C:9](=[C:10]([CH3:20])[C:11](CC([O-])=O)=[CH:12][C:13]=2[CH3:15])[CH:8]=[N:7]1)(=O)C.[Cl-].[NH4+]>CO.O1CCCC1>[CH3:20][C:10]1[C:11]([OH:1])=[CH:12][C:13]([CH3:15])=[C:14]2[C:9]=1[CH:8]=[N:7][NH:6]2
Reactant: [OH-]
Reactant: CC(=O)n1ncc2c(C)c(CC(=O)[O-])cc(C)c21
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(O)cc(C)c2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A 2N-aqueous lithium hydroxide solution (85 ml, 170 mmol) was added to a solution of (1-acetyl-4,7-dimethyl-1H-indazol-5-yl)acetate (20.3 g, 82.4 mmol) in methanol-tetrahydrofuran (1:1, 170 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction solution, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was washed with acetonitrile by repulping to obtain 4,7-dimethyl-1H-indazol-5-ol (13.0 g, 97%).
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:33])[N:6]([C:30](=[O:32])[CH3:31])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:27][C:26]4[C:22](=[N:23][N:24]([CH3:28])[CH:25]=4)[CH2:21]3)=[C:16]([F:29])[CH:15]=2)[CH2:9]1)[CH3:3].[I-].[Na+].[C:36]([O:40][P:41]([O-:48])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[C:36]([O:40][P:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:48][CH:2]([O:4][C:5](=[O:33])[N:6]([C:30](=[O:32])[CH3:31])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:27][C:26]4[C:22](=[N:23][N:24]([CH3:28])[CH:25]=4)[CH2:21]3)=[C:16]([F:29])[CH:15]=2)[CH2:9]1)[CH3:3])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OC(C)OP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 65 °C
Yield: 76.5 %

Procedure:
To a solution of 2b (75 mg, 0.16 mmol) in THF (1.5 mL) was added sodium iodide (66 mg, 0.44 mmol) and the tetrabutylammonium salt of di-tert-butylphosphate (200 mg, 0.04 mmol). The reaction mixture was heated at 65° C. for 48 h, concentrated in vacuo, dissolved in DMSO, filtered, and purified directly by HPLC (C-18 column, 30-100% gradient elution, MeCN:H2O). Fractions containing product were lyophilized to give 20 mg (20%) of the title compound as a 1:1 mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6): δ 7.53 (s, 1H), 7.44-7.39 (m, 1H), 7.17-7.14 (m, 1H), 6.90-6.85 (m, 1H), 6.45-6.38 (m, 1H), 4.85-4.75 (m, 1H), 4.48-4.46 (m, 4H), 4.25-4.08 (m, 2H), 3.95-3.77 (m, 2H), 3.85 (s, 3H), 2.47-2.48 (m, 3H), 1.56-1.54 (m, 3H), 1.41-1.40 (m, 18H). MS 654 (M+1)+
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl.[O-:20][C:21]#[N:22].[Na+].O1CCCC1>O>[C:21]([N:2]1[CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]3[CH:16]=[CH:17][CH:18]=[C:7]3[CH:6]2[CH2:1]1)(=[O:20])[NH2:22]
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the mixture of 100 mg of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine, 1 ml of N hydrochloric acid and 10 ml of water, the solution of 54.5 mg of sodium cyanate in 2 ml of water is added while stirring followed by 2 ml of tetrahydrofuran. After stirring overnight at room temperature, it is extracted with methylene chloride, the extract washed with saturated aqueous sodium carbonate, dried and evaporated, to yield the 2-carbamoyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine melting at 175°-177°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:6]=[CH:5][N:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[CH:5][N:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[N:6]=[CH:5][N:4]=4)[CH2:23][CH2:22]3)[CH:8]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cc(CCl)ncn2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)ncn4)CC3)ncn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-6-(3,4,5-trimethoxyphenyl)pyrimidine (126 mg) and piperazine (18 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Product: Cc1ccc(C=NNc2ccc(S(N)(=O)=O)cc2)cc1
Yield: 45 %

Procedure:
A solution of 4-methylbenzaldehyde (5 mmol) and 4-sulfamyl-phenylhydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 216–218° C., was obtained in 45% yield.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[CH:12]=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCCCCC.C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:12]=[CH:1][CH3:2])[CH:14]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC=Cc1cc(Br)ccc1F
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 16.5 g (0.044 mol) of ethyltriphenylphosphonium bromide and 387 ml of anhydrous THF is cooled to -50° C. under a nitrogen atmosphere. 27.8 ml (0.044 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise. The mixture is allowed to return to 0° and is stirred for 1 h at 0° C. The mixture is cooled to -30° C. and a solution of 8.8 g (0.0433 mol) of 5-bromo-2-fluorobenzaldehyde in 43 ml of anhydrous THF is added dropwise. The mixture is stirred overnight at room temperature and then for 2 h at 40° C. Filtration is carried out and the filtrate is evaporated under vacuum.
Reaction SMILES: [CH:1](=[O:8])C1C=CC=CC=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([OH:21])[CH:14]=[CH:15][C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18].COC(Cl)Cl.Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:21][C:13]1[CH:12]=[C:11]([O:10][CH3:9])[C:16]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:15][C:14]=1[CH:1]=[O:8]
Reactant: O=Cc1ccccc1
Reactant: COc1cc(O)ccc1C(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COC(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1C(C)(C)C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
The benzaldehyde used in Example 6 was prepared as follows: (1) To a stirred solution of 2.91 g (16.14 mmol) of 3-methoxy-4-(1,1-dimethylethyl)phenol (see C. J. R. Adderley and F. R. Hewgill, J. Chem. Soc., (C), 1438, (1968) as an example of how to obtain this material) in 65 ml of methylene chloride and cooled in an ice-water bath was added 6.12 g (3.54 ml, 32.30 mmol) of titanium (IV) chloride followed by 3.06 g (2.41 ml, 26.64 mmol) of 1,1-dichlorodimethyl ether. The reaction mixture was stirred for 10 minutes and then poured into 16 ml of lN hydrochloric acid. The organic phase was separated, dried and evaporated. The residue was chromatographed on silica gel (146 g) using 1.5:98.5 (v/v) ether,hexane as eluent. There was obtained 2.92 g (14.01 mmol, 87%) of 2-hydroxy-4-methoxy-5-(1,1-dimethylethyl)benzaldehyde as a white solid after crystallization from pentane; mp 75°-78° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C[N:5]1[C:9]2=[N:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:16].ClC1C=C(Cl)C=CC=1CN1C2C(=NC(C#N)=CC=2)N=C1C>>[CH3:16][C:6]1[NH:7][C:8]2[C:9]([N:5]=1)=[N:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2
Reactant: Cc1nc2ccc(C#N)nc2n1Cc1ccc(Cl)cc1Cl
Agent: Cc1nc2nc(C#N)ccc2n1Cc1ccc(Cl)cc1Cl
Product: Cc1nc2nc(C#N)ccc2[nH]1
Yield: 290.6 %

Procedure:
In the same manner as in the following Preparation Example 14-2, two isomers, 3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (138 mg) and 1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile (67 mg were respectively obtained as pale-brown crystals from 2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile (200 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39].C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:34]5[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=5)[CH:3]=4)[NH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3c2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (65 mg, 0.14 mmol) in CH3CN (1 mL) in a Personal Chemistry microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 μM Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and acetone (2 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue purified via preparatory HPLC to give the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 11.78 (s, 1H), 11.03 (s, 1 H), 8.51 (d, J=2.1 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.45 (s, 2H), 7.32 (m, 1H), 6.92 (s, 2H), 6.45 (m, 1 H), 3.85 (s, 6H), 3.70 (s, 3H); HPLC retention time: 2.04 minutes; MS ESI (m/z): 400.4 (M+1)+, calc. 399.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1.O>CN(C)C=O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[N:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 860 mg (2.83 mmol) benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate in 14.5 ml anhydrous N,N-dimethylformamide at ambient temperature was added 147 mg (3.68 mmol) sodium hydride. The solution was stirred for 20 minutes. 669 mg (2.83 mmol) 2-bromo-5-(methylsulfonyl)pyridine was added into the solution. It was heated to 50° C., and stirred for 3 hours. 100 ml water was added into the mixture, and it was extracted with 50 ml ethyl acetate three times. The crude product was dried and purified using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) to give the title compound as colorless oil. 1H NMR (CDCl3): δ 8.71 (d, J=2.4 Hz, 1H), δ 8.03 (dd, J=8.8 Hz, 2.5 Hz, 1H), δ 7.30-7.37 (m, 5H), δ 6.84 (d, J=8.7 Hz, 1H), δ 5.13 (s, 2H), δ 4.49 (t, J=7.1 Hz, 2H), δ 4.10-4.16 (m, 2H), δ 3.07 (s, 2H), δ 2.75-2.76 (m, 2H), δ 2.08-2.12 (m, 1H), δ 1.74-1.75 (m, 2H), δ 1.50-1.56 (m, 2H), δ 1.29-1.40 (m, 2H), δ 0.88-0.99 (m, 2H), δ 0.56-0.70 (m, 2H). LC/MS 459.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:12]2[NH:11][CH:10](OC)[CH:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19]>C(#N)C>[OH:1][C:2]1[C:12]2[N:11]=[CH:10][CH:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19]
Reactant: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Solvent: CC#N
Product: Cc1ccc2c(c1O)N=CC1CCCN1C2=O
Yield: 80 %

Procedure:
90.4 mg of 2,3,5,10,11,11a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was dissolved in 15 ml of acetonitrile at an elevated temperature. After dissolution, the solution was concentrated first at ordinary pressure and then under a reduced pressure. The concentrate was dissolved in 1.5 ml of hot benzene, and then 25 ml of n-hexane was added thereto, and the separated precipitate was collected by filtration. This procedure was repeated 2 to 3 times, and there was obtained 63.5 mg of 2,3,5,11a-tetrahydro-9-hydroxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one as a light yellow powdery product. It had a melting point of 147.5° to 150° C.