Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.[O-:21][C:22]#[N:23].[K+]>CO.Cl.O>[CH3:20][C:12]1[N:11]=[C:10]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:22]([NH2:23])=[O:21])=[CH:3][CH:4]=2)[CH3:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc(N(C)c2ccc(NC(N)=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of (4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine (48 mg, 0.18 mmol) in 250 uL of methanol and 750 uL of 1N HCl was added potassium cyanate (50 mg, 0.62 mmol) in 500 uL of water, and the mixture was stirred overnight at room temperature. The precipitated product was collected by filtration under vacuum, washed with 1 mL of cold water and dried to give the title compound (12.3 mg, 0.04 mmol, 22%). 1H NMR (DMSO): 8.75 (s, 1H), 7.60 (m, 2H), 7.45 (m, 2H), 6.99-7.13 (m, 4H), 5.92 (s, 2H), 3.45 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
[I] A solution prepared by dissolving 0.75 g of 4-amino-4'-bromobiphenyl in 10 ml of pyridine, was cooled with ice, and 1.0 g of acetyl chloride was dropwise added thereto. The mixture was stirred over a period of 30 minutes. After the completion of the reaction, the reaction solution was extracted with ethyl acetate and water. The organic layer was washed with dilute hydrochloric acid and further with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.8 g of N-(4'-bromo-4-biphenylyl)acetamide as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:27]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:27])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: COCCOCCOC(=O)CCCCCCCBr
Product: COCCOCCOC(=O)CCCCCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 25 %

Procedure:
4,5-Diphenylimidazole (2.85 g) was treated with 2-(2-methoxy-ethoxy)ethyl 8-bromooctanoate (8.63 g) as described in Example 20 to give 2-(2-methoxyethoxy)ethyl 8-(4,5-diphenylimidazole-1-yl)octanoate as a colourless oil (1.5 g, 25%). Found: C, 72.28; H, 7.91; N, 6.35% C28H36N2O4 requires: C, 72.38; H, 7.81; N, 6.03%
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-bromosalicylaldehyde (5.00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) was added heptyl bromide (4.10 ml), and the mixture was stirred at room temperature for 1.5 hr, and further at 50° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (7.61 g) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(Cc3ccccc3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCNCC1)N1CCN(Cc2ccccc2)CC1
Temperature: 24 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of 1-benzyl-4-[(1-t-butoxycarbonyl-4-piperidyl)carbonyl]piperazine (115.7 g) in dry dichloromethane (222 ml) was added dropwise over 45 minutes to trifluoroacetic acid (575 ml), maintaining the temperature below 25° C. under an atmosphere of argon. The solution was stirred at 23-25° C. for 1 hour. The solution was evaporated using a bath temperature of 30° C. The residual oil was poured, in portions, into saturated aqueous sodium carbonate solution (770 ml) while maintaining the temperature below 30° C. The aqueous mixture was extracted with dichloromethane (3×575 ml). The dichloromethane extracts were combined, dried (Na2SO4) and evaporated to give 1-benzyl-4-[(4-piperidyl)carbonyl]piperazine (56.2 g, 65% yield) as a white solid;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1F
Product: Fc1ccccc1-c1ccc(Br)cn1
Yield: 50 %

Procedure:
Obtained (0.534 g, yield 50%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (4.22 mmol, 1.0 g), 2-fluorophenylboronic acid (4.22 mmol, 2.42 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1)[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([C:54](=[O:59])NCOC)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([C:54]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)=[O:59])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncn(C)c2n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (500 mg, 1.38 mmol) and TMEDA (312 μL, 2.07 mmol) in THF (10 mL) at −78° C. was added n-BuLi (660 μL, 1.65 mmol, 2.5M solution in hexanes) and the resulting mixture stirred for 30 min before the addition of a solution of 4-(methoxymethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (564 mg, 2.07 mmol) in THF (5 mL) The resulting mixture was stirred for 2 h then quenched with H2O and extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc:cyclohexane and the mother liquors concentrated in vacuo affording the title compound as an oil (760 mg, 96%). LCMS (method A): RT 3.67 min [M+H]+ 557.3
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C[Si]([N:11]=[C:12]=[O:13])(C)C>C(O)(C)C>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:12]([NH2:11])=[O:13])[CH2:3]1
Reactant: C[Si](C)(C)N=C=O
Reactant: OC1CCNC1
Solvent: CC(C)O
Product: NC(=O)N1CCC(O)C1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a stirred solution of 3-hydroxypyrrolidine (1.0 g, 11.48 mmol) in isopropanol (27 mL) at rt was added trimethylsilylisocyanate (2.14 mL, 16.07 mmol) and the resulting solution stirred overnight. The resulting suspension was filtered and the residue washed with isopropanol and dried to give 3-hydroxy-pyrrolidine-1-carboxylic acid amide (0.89 g, 60%); 1H-NMR (300 MHz, d6-DMSO) 5.64 (2H, s), 4.85 (1H, d), 4.21-4.22 (1H, m), 3.22-3.28 (3H, m), 3.06-3.10 (1H, m), 1.79-1.90 (1H, m), 1.67-1.76 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCOc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid methyl ester 9.9 g (50 mmol) in dimethylformamide 100 mL were added K2CO3 7.6 g (55 mmol) and chloromethoxyethoxymethane 6.3 mL (55 mmol), followed by stirring at room temperature for 2 hrs. The resulting reaction mixture was concentrated in a vacuum, diluted with ethylacetate and washed with distilled water and a saturated NaCl solution. The residue was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound 14.0 g (yield 98%).
Reaction SMILES: COC1C=CC(C[N:8]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:19][CH2:18][O:17][C:16]=3[CH:33]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1[CH:28]=[C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:33]=[C:12]([S:9]([NH:8][C:34]4[S:35][CH:36]=[CH:37][N:38]=4)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]2=3)[CH:32]=[N:31][CH:30]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2-c2cncnc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccccc1-c1cncnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of N-(4-methoxybenzyl)-4-(2-(pyrimidin-5-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (250 mg, 0.437 mmol) in DCM (5 mL) was added TFA (2 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (8 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material (69.61% by LCMS) that was purified by prep purification to obtain 4-(2-(pyrimidin-5-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (60 mg, 30.4%) as white solid. 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 9.06 (s, 1H), 8.83 (s, 2H), 7.61 (td, J=6.9, 2.0 Hz, 2H), 7.58-7.48 (m, 2H), 7.21 (d, J=4.7 Hz, 1H), 7.01 (td, J=4.8, 4.2, 1.8 Hz, 2H), 6.77 (d, J=4.7 Hz, 1H), 6.21 (d, J=9.0 Hz, 1H), 4.30 (dt, J=11.1, 3.2 Hz, 1H), 4.03 (ddd, J=10.9, 8.6, 2.7 Hz, 1H), 3.76 (ddd, J=11.3, 8.3, 3.0 Hz, 1H), 3.44 (dt, J=12.3, 3.1 Hz, 1H); MS (ESI, positive ion) m/z: 452.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CS(O[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[C:8]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COCCCCOS(C)(=O)=O
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc2c(n1CCCCOC)C(=O)CCC2
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A solution of ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (207 mg), 4-methoxybutyl methanesulfonate (273 mg) and cesium carbonate (652 mg) in N,N-dimethylacetamide (10 ml) was stirred at 60° C. for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml×2). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (250 mg).
Reaction SMILES: [CH2:1]([Si:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:32][C@@H:13]3[C@H:14](O)[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:67]>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([Si:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:32][C@@H:13]3[C@@H:14]([Cl:67])[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@@H](O)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
24 g of 3β-tribenzylsilyloxy-5,6β-epoxy-7β-hydroxy-15β,16β-methylene-5β-androstan-17-one is dissolved in a mixture of 250 ml of methylene chloride, 250 ml of carbon tetrachloride, and 125 ml of pyridine and stirred with 24 g of triphenylphosphine for 3 hours. The mixture is then washed with water, dried over sodium sulfate, and concentrated under vacuum. After chromatography on silica gel with hexane-acetone, 19.8 g of 3β-tribenzylsilyloxy-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstan-17-one is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[CH2:10](Br)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:11][CH2:10][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH3:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCc1ccncc1C
Reactant: BrCCc1ccccc1
Product: Cc1cnccc1C(C)CCc1ccccc1
Yield: 64.6 %

Procedure:
1.13 g (9.35 mmol) of 3-methyl-4-ethylpyridine and 1.73 g (9.35 mmol) of phenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.36 g of the desired compound (yield: 64.5%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12](S)=[N:11][C:10]=2[CH3:15])=[CH:5][CH:4]=1)#[N:2]>[Ni].C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][CH:12]=[N:11][C:10]=2[CH3:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1nc(S)sc1-c1ccc(C#N)cc1
Agent: [Ni]
Solvent: CCO
Product: Cc1ncsc1-c1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
Raney Nickel (1 g) was added to a solution of the product of (a) (1.2 g, 5 mmol) in absolute ethanol (120 ml) and the reactants heated at 80° C. in an autoclave for 18 hours. After cooling to ambient temperature, further Raney Nickel (1 g) was added to the reaction mixture and the reactants heated at 80° C. in an autoclave for an additional 6 hours. The reaction mixture was then filtered through Arbocel and the filtrate evaporated to dryness. The residue was flash chromatographed (Merck 60 Kieselgel--ethyl acetate:hexane:diethylamine, 25:75:2) to give the title product as a gum which solidified on standing (0.36 g, 35%), and was used directly in Preparation 19.
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:19])[CH2:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH2:23]1[O:25][CH2:24]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O>[OH:25][CH2:24][CH2:23][N:11]1[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:20])[CH2:9][C:10]1=[O:19]
Reactant: C1CO1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 28.6 gm (0.1 mol) of 5-phenyl-7-chloro-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione, 500 ml of methanol, 25 ml of water, 10-15 ml of ethyleneoxide and 1 ml of Triton B (methanolic 35% solution of benzyl trimethylammonium hydroxide) was stirred at room temperature for about eight hours. Thereafter, the clear solution formed thereby was evaporated, the residue was taken up in methylene chloride, and the resulting solution was extracted with water, dried and evaporated. The residue was recrystallized from ethanol, yielding 25.6 gm (78% of theory) of the colorless crystalline compound of the formula ##SPC6##
Reaction SMILES: [OH:1][PH:2]([CH:4]([CH:21]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:3].[CH2:42](I)[CH:43]([CH3:45])[CH3:44]>CS(C)=O>[OH:3][PH:2]([CH:4]([C:21]([CH2:42][CH:43]([CH3:45])[CH3:44])([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:1]
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)C(CCCCCN1C(=O)c2ccccc2C1=O)[PH](=O)O
Reactant: CC(C)CI
Solvent: CS(C)=O
Product: CC(C)CC(C(=O)OCc1ccccc1)(C(=O)OCc1ccccc1)C(CCCCCN1C(=O)c2ccccc2C1=O)[PH](=O)O

Procedure:
3.6 g of dibenzyl 2-(6-phthalimidohexylidene)malonate were added to a solution of 0.88 g of crystalline hypophosphorus acid in 10 ml of dry dichloromethane, the solution was cooled to 0° and then 2.8 g of triethylamine and 2.8 g of trimethylsilyl chloride were added. After stirring at room temperature for 3 hours, the mixture was poured into 60 ml of 1M hydrochloric acid and the resulting solution was extracted four times with dichloromethane. The combined extracts were dried and evaporated to give 3.9 g of a colorless gum containing crude dibenzyl 2-[1(RS)-(hydroxyphosphinyl)-6-phthalimidohexyl]malonate which was dissolved in 40 ml of dry dimethyl sulphoxide and reacted with isobutyl iodide in a manner analogous to that described in Example 10(ii). After purification of the crude product by chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution, there was obtained 2.0 g of dibenzyl 2-[1(RS)-(hydroxyphosphinyl)-6phthalimidohexyl]-2-isobutylmalonate as a colorless gum.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C=O>O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][N:6]=1
Reactant: ClCc1ccccc1
Reactant: Nc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nnc(SCc2ccccc2)s1

Procedure:
A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (39.9 g), potassium carbonate (41.4 g), α-chlorotoluene (38.0 g), and N,N-dimethylformamide (180 ml) is heated for 1.5 hours on a steam bath. The reaction mixture is drowned into water (1,000 ml) and the product collected by filtration and air dried. The crude product is recrystallized from ethanol and melts at 154°-156° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][N:14]([C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH:15]2[CH2:16][CH2:17][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2ccc(N)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(N)nc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 142 (300 mg, 0.68 mmol) is treated with acid chloride 8 (182 mg, 0.68 mmol) using Method D to give the title compound.
Reaction SMILES: Br[C:2]1[N:7]2[C:8](=[O:25])[N:9]([CH2:11][CH2:12][C:13]3[N:14]([CH3:24])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][N:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=[C:13]1[CH2:12][CH2:11][N:9]1[C:8](=[O:25])[N:7]2[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:3][CH:4]=[CH:5][C:6]2=[N:10]1
Reactant: C1COCCN1
Reactant: Cn1cc(-c2ccccc2)nc1CCn1nc2cccc(Br)n2c1=O
Product: Cn1cc(-c2ccccc2)nc1CCn1nc2cccc(N3CCOCC3)n2c1=O
Temperature: 120 °C
Yield: 31.4 %

Procedure:
In a 2 mL microwave vial were placed 11-4 (0.025 g, 0.063 mmol) and morpholine (0.459 g, 0.461 mL, 5.27 mmol). The vial was sealed and heated in an oil bath for 15 min at 120° C. The mixture was concentrated in vacuo and purified by reverse phase HPLC (5-50% MeCN/water with 0.01% TFA additive). Fractions containing pure product were treated with sat. aq. NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and filtered. The filtrate was dried under reduced pressure to give 8 mg (32%) of 12-1. LC/MS: m/z (M+H)=405.5. 1H NMR (500 MHz, CHCl3-d): δ 7.68 (d, J=7.7 Hz, 2H), 7.31 (d, J=7.6 Hz, 2H), 7.21-7.16 (m, 1H), 7.08 (s, 1H), 6.91 (dd, J=9.3, 7.0 Hz, 1H), 6.68 (d, J=9.3 Hz, 1H), 5.60 (d, J=7.3 Hz, 1H), 4.37 (t, J=7.5 Hz, 2H), 3.90-3.86 (m, 4H), 3.74-3.70 (m, 2H), 3.64 (s, 3H), 3.21 (t, J=7.5 Hz, 2H), 2.96-2.87 (m, 2H). HRMS (ES) 405.2048 found (M+H), 405.2035 required.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14][C:13]([OH:23])=[CH:12][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.ClCCl>[Cl:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14][C:13]([OH:23])=[C:12]([I:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Cl)c(-c2cccc(F)c2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1cc(-c2cccc(F)c2)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.7 %

Procedure:
N-Iodosuccinimide (261 mg, 1.16 mmol) was added to a mixture of 6-chloro-3′-fluorobiphenyl-3-ol (Preparation 100, 270 mg, 1.21 mmol) and concentrated sulphuric acid (24 μL, 0.43 mmol) in acetic acid (3 mL) and dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane (10 mL) and washed with sodium metabisulfite (0.5M, 10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with heptane:dichloromethane (70:30) to give the title compound (193 mg, 46%) as a pale yellow solid.