Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH:11]1([C:16](=O)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([C:16]2[CH:17]=[C:18]([NH2:19])[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH3:2])[N:10]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1ccccc1NN
Reactant: N#CCC(=O)C1CCCC1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1nc(C2CCCC2)cc1N
Yield: 62 %

Procedure:
A solution of (2-methylphenyl)hydrazine hydrochloride (2.00 g, 14.6 mmol) and crude 3-cyclopentyl-3-oxopropanenitrile from the previous step (2.32 g, ˜14.6 mmol) in toluene (6 mL) was heated to reflux for 16 h. Removal of the solvent under reduced pressure provided a residue which was purified by silica gel chromatography using hexane/EtOAc (3:1, v/v) as the eluent. Concentration under reduced pressure provided 3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine as a light orange solid (2.19 g, 62%). ES-MS m/z 241.9 (MH+); HPLC RT (min) 1.69. 1H NMR (400 MHz, CDCl3) δ 1.58-1.82 (m, 6H), 2.00-2.16 (m, 2H), 2.17-2.21 (s, 3H), 2.93-3.11 (m, 1H), 3.42-3.58 (s, 2H), 5.41-5.46 (s, 1H), 7.20-7.28 (m, 2H) 7.29-7.37 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(CCCn3ccnc3)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69.1 %

Procedure:
A mixture of 3-(4-benzyloxyphenyl)propyl methanesulfonate (55.0 g), imidazole (17.6 g), potassium carbonate (35.7 g) and N,N-dimethylformamide (500 ml) was stirred for 6 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give 1-[3-(4-benzyloxyphenyl)propyl]imidazole (34.7 g, 69%). Recrystallization from ethyl acetate-hexane gave colorless needles, mp 80-81° C.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.[C:9]([O:12][C@@H:13]1[N:16]([S:17]([OH:20])(=[O:19])=[O:18])[C:15](=[O:21])[C@H:14]1[NH2:22])(=[O:11])[CH3:10].[Na+:23].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C1COCC1.O>[C:9]([O:12][C@@H:13]1[N:16]([S:17]([O-:20])(=[O:19])=[O:18])[C:15](=[O:21])[C@H:14]1[NH:22][C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:11])[CH3:10].[Na+:23]
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Reaction time: 1.5 h

Procedure:
To a solution of 0.61 g of acetate of sodium (3S,4S)-4-acetoxy-3-amino-2-oxoazetidine-1-sulfonate obtained in Example 21B in 20 ml of a mixture of water and THF (1:1) is added under ice-cooling 0.61 g of phenylacetyl chloride while keeping the pH of the reaction mixture at pH 7.0-7.5 by use of sodium hydrogen carbonate. The stirring is continued for 1.5 hours at the same temperature. THF is removed by evaporation under reduced pressure. The residue is purified on an XAD-II (Rohm and Haas Co.) column chromatography to give 0.42 g of sodium (3S,4S)-4-acetoxy-3-phenylacetamido-2-oxoazetidine-1-sulfonate. The IR spectrum and NMR data of this compound are in agreement with those of the compound obtained in Example 19B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.ClC1C=CC([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[N:15]([C:37]4[CH:36]=[CH:35][CH:40]=[CH:39][N:38]=4)[N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: Fc1ccc(N2CCN(CCCc3c4c(nn3-c3ccccn3)CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 10 and 1-(4-fluorophenyl)piperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazole is obtained.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][NH2:12])[CH:9]=2)[CH:4]=[N:3]1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>CCO>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:11]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[N:3][NH:2]3)=[CH:6][CH:7]=2)[N:12]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: NNc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3cn[nH]c3c2)n1
Yield: 58 %

Procedure:
A mixture of (1H-indazol-6-yl)-hydrazine hydrochloride and 4,4-dimethyl-3-oxo-pentanenitrile (17 g, 1.05 eq) in EtOH (200 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified by column chromatography to yield 3-t-butyl-1-(1H-indazol-6-yl)-1H-pyrazol-5-amine (21 g, 58% yield, for two steps). 1H NMR (300 MHz, DMSO-d6): 8.21 (s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.25 (d, J=8.1 Hz, 1H), 5.71 (s, 1H), 1.31 (s, 9H); MS (ESI) m/z: 256 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]=[C:43]=[O:44])[CH:37]=1>ClCCl>[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])[CH:37]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (70 mg, 0.19 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (64.9 uL, 0.48 mmol) (Aldrich), followed by the addition of 3-isocyanato-benzoic acid methyl ester (39.7 mg, 0.22 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester as a white solid. (Yield 70 mg, 68%).
Reaction SMILES: [C:1]([C:3]([CH:20]([CH3:22])[CH3:21])([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)[CH2:4][CH2:5][CH:6]=O)#[N:2].[N+:23]([C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][NH2:32])([O-:25])=[O:24].[BH4-].[Na+]>CO>[CH:20]([C:3]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)([CH2:4][CH2:5][CH2:6][NH:32][CH2:31][CH2:30][CH2:29][O:28][C:27]1[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=1[N+:23]([O-:25])=[O:24])[C:1]#[N:2])([CH3:21])[CH3:22]
Reactant: NCCCOc1ccccc1[N+](=O)[O-]
Reactant: COc1cc(C(C#N)(CCC=O)C(C)C)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(C#N)(CCCNCCCOc2ccccc2[N+](=O)[O-])C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A solution of 8.09 g of 4-cyano-4-isopropyl-4-(3,4,5-trimethoxyphenyl)butyraldehyde and 4.96 g of 3-(2-nitrophenoxy)-propylamine in 100 ml of methanol was refluxed for 3 hours. After cooling, to the solution was added 0.50 g of sodium borohydride and the solution was stirred overnight at room temperature. The solvent was removed and to the residue was added water. The solution was extracted with chloroform and the extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using 10% methanol-chloroform as an eluent to give 6.48 g of the desired compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]([C:17]([O:19][CH3:20])=[O:18])[N:4](C)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Cl)[CH:9]=2)=[CH:6][N:7]=1.[CH2:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[Ag]=O>[NH2:1][C:2]1[C:3]([C:17]([O:19][CH3:20])=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)C1C(N)=NC=C(c2cccc(CCl)c2)N1C
Reactant: OCc1ccccc1
Agent: O=[Ag]
Product: COC(=O)c1nc(-c2cccc(COCc3ccccc3)c2)cnc1N
Temperature: 110 °C
Yield: 28 %

Procedure:
Methyl 3-amino-6-(3-chloromethylphenyl)-N-methylpyrazine-2-carboxylate (18 mg, 0.06 mmol) and silver oxide (15 mg, 0.06 mmol) were added to benzyl alcohol (2 mL) and the mixture was heated to 110° C. over 15 hours. The benzyl alcohol was removed in vacuo and the residue purified by silica gel flash chromatography using ethyl acetate:hexanes (1:1) as eluent. The pure fractions were combined and concentrated then dried ill vacuo to give methyl 3-amino-6-(3-{[(phenylmethyl)oxy]methyl}phenyl)pyrazine-2-carboxylate (5.8 mg, 28% yield) as a yellow solid: MS (EI) for C20H20N3O3: 350 (MH+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2)(=[O:13])=[O:12].[O:24]=[C:25]1[C:30]2=[CH:31][NH:32][C:33]([CH:34]=O)=[C:29]2[CH2:28][CH2:27][O:26]1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[CH:34][C:33]1[NH:32][CH:31]=[C:30]2[C:25](=[O:24])[O:26][CH2:27][CH2:28][C:29]=12)(=[O:13])=[O:12]
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc4C3)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4ccccc4C3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.O1CCCC1.[H-].[Na+].[H][H].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C(OCC)(=O)C>[CH2:29]([O:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [H][H]
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(C(OCc2ccccc2)c2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a suitable reaction flask was charged (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol (5.85 mmoles; 2.00 g) and tetrahydrofuran (245.77 mmoles; 20.00 mL; 17.72 g) to afford a clear solution. Sodium hydride (8.78 mmoles; 351.22 mg) was then added in small portions to minimize the rate of hydrogen gas evolution. The reaction was stirred for approximately 30 minutes at room temperature, and then benzyl bromide (8.78 mmoles; 1.05 mL; 1.50 g) was added slowly. The reaction was allowed to stir at room temperature until completion (as determined by HPLC analysis). To the reaction mixture was then added 1N hydrochloric acid (10 mL) and ethyl acetate (30 mL). The layers were shaken together, allowed to settle and then were separated. The organic phase was washed with saturated aqueous sodium chloride (10 mL) and then was dried over magnesium sulfate, filtered and concentrated to provide the crude product (3.12 g). The crude oil was purified by flash chromatography on silica gel eluting with a gradient of 0 to 5% ethyl acetate in hexanes to afford 1.98 g of product as a clear oil (78% yield).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+].O.[N+:12]([CH3:15])([O-:14])=[O:13]>C(O)C>[N+:12]([CH2:15][C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:14])=[O:13]
Reactant: O=C1CCCC1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])CC1(O)CCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of cyclopentanone (40.0 mL, 452 mmol) in nitromethane (36 mL) and ethanol (14 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 8.5 mL, 23 mmol). The solution was stirred for 5 d at rt. Water (400 mL) was added and the mixture was extracted with ethyl acetate (2×350 mL). The combined organic extracts were washed with water (2×200) and brine (200 mL), dried over MgSO4, filtered, and concentrated. The starting materials and solvent were removed from the product by distillation under reduced pressure to yield 1-(nitromethyl)cyclopentanol as a yellow liquid, 8.3 g (13%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](Cl)[C:14]1O[CH:16]=[CH:17][CH:18]=1)[C:11]#[N:12].[OH2:20].[NH2:21][NH2:22]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:13]([C:14]2[O:20][CH:16]=[CH:17][CH:18]=2)=[N:22][NH:21][C:11]=1[NH2:12]
Reactant: NN
Reactant: N#CC(=C(Cl)c1ccco1)c1nc2ccccc2s1
Reactant: O
Solvent: CO
Product: Nc1[nH]nc(-c2ccco2)c1-c1nc2ccccc2s1
Yield: 27.1 %

Procedure:
The 2-benzothiazol-2-yl-3-chloro-3-furan-2-ylacrylonitrile (480 mg, 1.7 mmol) prepared above and hydrazine hydrate (100 mg, 2 mmol) were refluxed in methanol (15 mL) for 3 hrs. The solvent was then evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2:MeOH=9:1 to afford 130 mg of material. This was further purified by preparative TLC eluting with CH2Cl2:MeOH=9:1 to yield 23 mg (5%) of the title compound. MS (m/z, ES+): 283.0 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:7]([O:20][CH3:21])[CH:6]=2.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[C:3]([C:22]#[N:23])[C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])=[CH:11]2)=[CH:6][C:7]=1[O:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(OC)N(C)C
Reactant: COc1cc2cc(C#N)c(N)cc2cc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2cc(C#N)c(N=CN(C)C)cc2cc1OCc1ccccc1

Procedure:
A mixture of 0.12 g (1.7 mmol) of 3-amino-6-benzyloxy-7-methoxynaphthalene-2-carbonitrile and 0.5 mL of N,N-dimethylformamide dimethyl acetal in 2.0 mL of toluene is heated under reflux for 4 hours. The solvent is evaporated and the residue is dried on high vacuum to yield N′-(7-benzyloxy-3-cyano-6-methoxynaphthalen-2-yl)-N,N-dimethylformamidine as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH:25]([F:27])[F:26])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C1COCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH:25]([F:27])[F:26])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F

Procedure:
The crude (3-Chloro-4-fluoro-phenyl )-[7-(2,2-difluoro-ethoxy)-6-nitro-quinazolin-4-yl]-amine was dissolved in THF and reduced using Raney nickel catalyst to yield N4-(3-Chloro-4-fluoro-phenyl)-7-(2,2-difluoro-ethoxy)-quinazoline-4,6-diamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.Cl.[CH3:18][C:19]1[CH:24]=[C:23]([CH:25]=[CH:26][C:27]#[N:28])[CH:22]=[C:21]([CH3:29])[C:20]=1[NH2:30].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:18][C:19]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[C:21]([CH3:29])[C:20]=1[NH:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1cc(C=CC#N)cc(C)c1N
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Nc2ccc(C#N)cc2)n1
Temperature: 87.5 °C
Yield: 69.2 %

Procedure:
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (100 gms) and 2,6-dimethyl-4-(2-cyanoethenyl) phenylamine hydrochloride (90.65 gms) were mixed with acetonitrile (800 ml) in an inert atmosphere and heated at 85-90° C. till completion of the reaction, as monitored by HPLC. The reaction mixture was cooled to 40° C. and pH of the reaction mass was adjusted to ≈ pH 10 with 20% sodium carbonate solution. The reaction mass was filtered at 5 to 10° C. and dried to yield Rilpivirine (110 gms). Rilpivirine thus obtained was dissolved in acetone (3600 ml) and after optional charcoal treatment was concentrated to 500 ml and was filtered at 5-10° C., dried to give Rilpivirine (80 gms), which was then added to dimethyl sulfoxide (338 ml) and heated to 70-75° C. The mixture was cooled to 50 to 55° C. and mixed with hydrochloric acid (25 ml) with constant stirring. Water (1350 ml) was added to the mixture at 40 to 45° C., which was stirred and cooled further. The reaction mass was filtered at 25 to 30° C. and the wet cake was dried to give 90 gms of Rilpivirine hydrochloride (I) having Z isomer less than 0.1%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20](=[O:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21OCC[O:11]2.Cl>>[CH3:26][CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[C:20](=[O:27])[CH:19]=[CH:18][CH:17]1[CH2:16][CH2:15][C:10](=[O:11])[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CCCCC(C)C(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: Cl
Product: CCCCC(C)C(=O)C=CC1CCC(=O)C1CCCCCCCO
Temperature: 60 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]-nonane (1.0 g.) and hydrochloric acid (25 ml; 1 N) was stirred at 60° C. for 2 hours, cooled to ambient temperature and extracted with diethyl ether. The ether extract was washed with 2 N aqueous sodium carbonate solution and water respectively, then dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a crude product (0.7 g.) which was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, ethyl acetate and hexane (2:1:1 v/v) as eluant, to give 7-[2-(4-methyl-3-oxooct-1-enyl)-5-oxocyclopentyl]heptanol (0.38 g.), νmax (liquid film) 3450 cm-1, 1730 cm-1, 1690 cm-1, 1660 cm-1, 1380 cm-1, 995 cm-1 ; νmax (ethanol) 230 nm (ε=13,600); Elemental analysis: found: C, 74.9; H 11.0%; C21H36O3 requires C, 74.95; H, 10.8%, N.M.R. (approximately 10% solution in deuterochloroform): Triplets at 3.57δ (J=6 cycles/sec.) and 0.88δ, doublet of doublets at 6.81δ (J=15.5 cycles/sec. and J=7 cycles/sec.), doublets at 6.20δ (J=15.5 cycles/sec.) and 1.11δ (J=7 cycles/sec.), broad singlet 2.0δ.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C.CC(O)=O>CS(C)=O>[NH2:1][C:2]1[C:11]([Cl:12])=[C:10]([NH:32][CH2:31][CH2:30][NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(Cl)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1c(NCCNc2ccccn2)c(Cl)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 73.2 %

Procedure:
A solution of 5-amino-6-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (180 mg, 0.551 mmol), N-2-pyridyl-1,2-ethanediamine (113 mg, 0.827 mmol) and triethylamine (0.115 mL, 0.827 mmol) in DMSO (5 mL) was stirred at 100° C. for 8 h. After the reaction mixture was poured into ice-water, AcOH was added to pH<3 and the resulting precipitate was collected by filtration in vacuo, washed successibly with water and hot EtOH, dried to yield 5-amino-6-chloro-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (179 mg, 73%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.[C:9]([C:15](OC)=[O:16])#[C:10][C:11]([O:13][CH3:14])=[O:12]>CO>[OH:16][C:15]1[N:3]2[N:4]=[C:5]([CH2:7][OH:8])[N:6]=[C:2]2[N:1]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1n[nH]c(CO)n1
Solvent: CO
Product: COC(=O)c1cc(O)n2nc(CO)nc2n1
Temperature: 30 °C
Reaction time: 20 h

Procedure:
In 1.7 liters of methanol was suspended 60 g of 3-amino-5-hydroxymethyl-1,2,4-triazole and 75 ml of dimethyl acetylenedicarboxylate was added to the suspension, and the mixture was stirred at 30 ° C. for 20 hours. Precipitates were collected by filtration, washed with methanol and then dried to obtain 25.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][OH:38].CN(C)[CH:41]=[O:42]>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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([C:37]([O:42][CH3:41])=[O:38])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CN(C)C=O
Reactant: CO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 60 °C
Yield: 38 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.49 g, 0.92 mmol) in N,N-dimethylformamide (10 mL) was added triethylamine (0.4 mL, 2.8 mmol), followed by PdCl2(PPh3)2, and then methanol (5 mL). The mixture was placed under a carbon monoxide atmosphere, heated to 60° C. for 18 h, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with a step gradient of 10–20% 2 M solution of ammonia/methanol in dichloromethane. The chromatography product was recrystallized from methanol to give 0.16 g (38%) of a white solid.