Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:22]=1[C:16]1([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[N:15]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:14]2=[S:32].C([O-])([O-])=O.[K+].[K+].[CH:39]12[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH:40]1[N:49]=[C:50]=[O:51])[CH2:46]2.NC(N)=O>CC#N>[Cl:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:22]=1[C:16]1([CH2:21][CH2:20][N:19]([C:50]([NH:49][CH:40]3[CH:39]4[CH2:48][CH:43]5[CH2:44][CH:45]([CH2:47][CH:41]3[CH2:42]5)[CH2:46]4)=[O:51])[CH2:18][CH2:17]1)[N:15]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:14]2=[S:32]
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: COc1ccc(CN2C(=S)c3cccc(Cl)c3C23CCNCC3)cc1
Agent: NC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=S)c3cccc(Cl)c3C23CCN(C(=O)NC2C4CC5CC(C4)CC2C5)CC3)cc1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of crude 7-chloro-2-(4-methoxybenzyl)spiro[isoindoline-1,4′-piperidine]-3-thione TFA salt (prepared from TFA deprotection of tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate (52 mg, 0.11 mmol)) in 1:1 MeCN:10% aq K2CO3 (10 mL), was added 2-adamantylisocyanate (50 mg, 0.30 mmol, 2.6 equiv) and the mixture stirred was for 2 h. After this time LC-MS analysis showed formation of the desired urea. The mixture was concentrated to ˜50% of its original volume and diluted with EtOAc. The mixture was washed with 1.0 M aq HCl and brine, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography on silica gel (4 g), eluting with 20-80% EtOAc in hexanes, affording 7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide (51 mg, 0.093 mmol, 85% yield) of the desired thiolactam-urea as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)(=[O:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:42][C:43]([CH3:45])=[O:44].CO>C1COCC1>[CH3:42][C:43]([OH:44])([CH3:45])[CH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 5-(2-methanesulfonyl-phenyl)-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.030 g, 0.0671 mmol) in THF (3 mL) was added lithium bis(trimethylsilyl)amide (0.20 mL, 0.201 mmol, 1.0 M solution in THF) at −78° C. After stirring for 30 min, acetone (0.2 mL) was added. The mixture was further stirred another 30 min. followed by an addition of MeOH to quench the reaction. Solvent evaporation provided a residue, which was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a white solid (0.030 g, 88%). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.19 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.75-7.70 (m, 2H), 7.66-7.62 (m, 4H), 7.46 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.35 (d, 1H, J=7.6 Hz), 7.25 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 2.92 (s, 2H), 1.08 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H24F3N2O4S: 505.5 (M+H), Found 505.3.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][OH:15]>O1CCCC1>[CH3:18][O:17][C:13]([CH2:14][O:15][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1)=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
1.26 g of sodium hydride was added to a mixture of 5.0 g of 2-chloro-5-nitropyridine, 3.13 g of methyl glycolate and 50 ml of tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for 15 minutes, then at room temperature for 1 hour. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5.18 g of 2-(methoxycarbonyl)methoxy-5-nitropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[CH3:14][NH:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH2:12])[N:15]([CH3:14])[N:16]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: N#CCC(=O)Cc1ccc(Cl)cc1
Solvent: CCO
Product: Cn1nc(Cc2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.8 %

Procedure:
A solution of 4-(4-chloro-phenyl)-3-oxo-butyronitrile (200 mg, 1 mmol, 1.0 equiv) and N-methylhydrazine (153 mg, 3.32 mmol, 3.2 equiv) in 4 mL of ethanol was heated at 100° C. in a sealed tube. After 4 d, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a yellow solid (188 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](Cl)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH:13][C:38]([C:34]3[C:33](=[O:41])[N:32]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH:37]=[CH:36][CH:35]=3)=[O:39])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A solution of Example A1 (0.147 g, 0.572 mmol) in THF (1 mL) was treated with Et3N (0.120 mL, 0.858 mmol) and a suspension of Example A3 (0.216 g, 0.858 mmol) in THF (2 mL). The mixture was layered with argon and stirred at RT overnight. The mixture was cooled to RT, the solid removed via filtration, rinsed with THF and the filtrate concentrated to dryness. The residue was triturated with MeCN, sonicated and the resulting solid collected via filtration and dried to afford N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (104 mg, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.51 (s, 1H), 8.71-8.61 (m, 2H), 8.38 (d, J=5.8 Hz, 1H), 8.23 (dd, J=6.6, 2.2 Hz, 1H), 7.69 (m, 3H), 7.49 (m, 2H), 7.25 (d, J=2.3 Hz, 1H), 7.13 (dd, J=5.8, 2.3 Hz, 1H), 6.82 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.N1CCCCC1.[Cl:24][CH2:25][CH:26]1[O:28][CH2:27]1>>[Cl:24][CH2:25][CH:26]([OH:28])[CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc(=O)c2ccc(OCC(O)CCl)cc2o1
Reaction time: 1 h

Procedure:
A mixture of 4.7 g of ethyl 7-hydroxychromone-2-carboxylate and 20 ml of 1-chloro-2,3-epoxypropane is heated at an external temperature of 100° C. for 8 hours in the presence of 0.2 ml of piperidine. The mixture is evaporated under reduced pressure and the residue is taken up with 15 ml of ethyl acetate. After filtration, the solution is evaporated under reduced pressure, the residue is taken up with 30 ml of chloroform and 10 ml of N hydrochloric acid, concentrated and stirred for one hour. The organic layer is washed with water, dried on anhydrous sodium sulfate and evaporated. The residue, crystallized from ethanol, gives 4 g of ethyl 7-(3-chloro-2-hydroxypropoxy)chromone-2-carboxylate. An amount of 1.65 g of the product thus obtained is dissolved in 40 mg of methylene chloride and to the solution thus obtained there is added 0.2 g of hexadecyltributylphosphonium bromide. To the organic solution there is added a solution of CH3SNa in 20 ml of water. The mixture is stirred for two hours at the room temperature, the aqueous layer is separated and acidified with N hydrochloric acid. The precipitate which forms, consisting of 7-(2-hydroxy-3-methylthiopropoxy)chromone2-carboxylic acid, is filtered and dried; m.p. 200°-202° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:36])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCNc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.15 g) is reacted with aniline following the procedure outlined in example 10 and reduced with lithium aluminium hydride (0.15 g) in THF at room temperature. Aqueous work-up and crystallization from methanol gives 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-24-phenylamino-5α-chola-8,14-dien (106 mg). 1H-NMR (CDCl3, 300 MHz)): δ=7.17 (2H, t); 6.69 (1H, t); 6.6 (2H, d); 5.35 (1H, s); 3.6 (1H, s); 3.2 (1H, m); 3.09 (2H, m); 0.9 (9H, s); 0.04 (6H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:21]([Si:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)Cl)([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([O:14][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reaction time: 24 h

Procedure:
To a solution of tert-butyl(cis-4-hydroxycyclohexyl)carbamate (2.0 g) in dimethylformamide (40 mL), imidazole (756 mg) and t-butyldiphenylchlorosilane (2.86 mL) were added under ice cooling, and the mixture was stirred for 24 hours. Imidazole (226 mg) and t-butyldiphenylchlorosilane (858 μL) were further added thereto, and the mixture was stirred for 6 days. To the reaction solution, ethyl acetate was added, and the organic layer was washed three times with 10% sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=98/2-9/1) to obtain the title compound (5.09 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Si]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])(C(C)(C)C)(C)C.[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:31]([S:33][C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@H:29]1[CH2:53]I)=[O:27])[CH:23]=[CH2:24].C(OCC)(=O)C>O1CCCC1>[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:31]([S:33][C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@H:29]1[CH2:53][CH:18]1[CH2:19][CH2:20][NH:16][C:17]1=[O:21])=[O:27])[CH:23]=[CH2:24]
Reactant: CC(C)(C)[Si](C)(C)N1CCCC1=O
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1CCNC1=O
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
Lithium diisopropylamide (2.1M tetrahydrofuran solution, 6.45 ml, 13.5 mmol) was dropwise added to a solution of N-tert-butyldimethylsilyl-2-oxopyrrolidine (1.80 g, 9.03 mmol) in tetrahydrofuran (150 ml) at -78° C. and the mixture was stirred at the same temperature for 15 minutes. Then, a solution of (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (2.57 g, 4.5 mmol) in tetrahydrofuran (18 ml) was dropwise added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into a mixture of ethyl acetate (150 ml) and a 10% ammonium chloride aqueous solution (50 ml) for liquid separation. The organic layer was washed sequentially with a 10% sodium dihydrogen phosphate aqueous solution (100 ml) and a saturated sodium chloride aqueous solution (100 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (12 ml) and methanol (3 ml), and 6N hydrochloric acid (3 ml) was added thereto under cooling with ice. The mixture was stirred for 1 hour. Ethyl acetate (50 ml) was added to the reaction solution, and the organic layer was washed sequentially with a saturated sodium hydrogen carbonate aqueous solution (30 ml) and a saturated sodium chloride aqueous solution (30 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel flash column chromatography (Wakogel™ C-300, 40 ml, ethyl acetate-n-hexane 3:1) to obtain (2R,4S)-N-allyloxycarbonyl-2-(2-oxopyrrolidin-3-ylmethyl)-4-tritylthiopyrrolidine (880 mg, yield: 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cccc(CCC(=O)O)c1
Reactant: CO
Product: COC(=O)CCc1cccc(N)c1

Procedure:
3-(3-Amino-phenyl)-propionic acid (495 mg, 3 mmol) was esterified with MeOH using Method A, except that the residue was partitioned between EtOAc (10 ml) and saturated aqueous NaHCO3 (10 ml). The organic layer was dried (MgSO4), filtered and evaporated in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:20]1([CH2:23][NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][NH:24][C:25]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[C:30]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:31]=2)=[O:42])[CH2:22][CH2:21]1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NCC4CC4)ccc3C)nc2)c1

Procedure:
6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 3.07 min, MH+ 430. NMR: δH [2H6]-DMSO 9.30,(1H, t), 9.16,(1H, d), 8.62,(1H, t), 8.36,(1H, dd), 7.94,(1H, s), 7.85,(1H, d), 7.74,(1H, d), 7.43,(1H, d), 7.27,(1H, t), 6.94–6.92,(2H, m), 6.84,(1H, d), 4.51,(2H, d), 3.75,(3H, s), 3.14,(2H, t), 2.39,(3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Reaction SMILES: [OH:1][C:2]1CNC(=O)C=1C1N(C(OC(C)(C)C)=O)C2C=C(N3CCOCC3)C=C(C)C=2N=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@H:38]([OH:77])[CH2:39][NH:40][C:41]2[CH2:45][N:44]([S:46]([C:49]([F:52])([F:51])[F:50])(=[O:48])=[O:47])[C:43](=[O:53])[C:42]=2[C:54]2[N:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:57]3[CH:66]=[C:67]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)[CH:68]=[C:69]([CH3:70])[C:56]=3[N:55]=2)[CH:35]=[CH:36][CH:37]=1>C(#N)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]([OH:77])[CH2:39][NH:40][C:41]2[CH2:45][N:44]([S:46]([C:49]([F:51])([F:50])[F:52])(=[O:47])=[O:48])[C:43](=[O:53])[C:42]=2[C:54]2[N:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:57]3[CH:66]=[C:67]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)[CH:68]=[C:69]([CH3:70])[C:56]=3[N:55]=2)[CH:35]=[CH:36][C:37]=1[O:1][CH3:2]
Reactant: Cc1cc(N2CCOCC2)cc2c1nc(C1=C(O)CNC1=O)n2C(=O)OC(C)(C)C
Reactant: Cc1cc(N2CCOCC2)cc2c1nc(C1=C(NC[C@@H](O)c3cccc(Cl)c3)CN(S(=O)(=O)C(F)(F)F)C1=O)n2C(=O)OC(C)(C)C
Solvent: CC#N
Product: COc1ccc(C(O)CNC2=C(c3nc4c(C)cc(N5CCOCC5)cc4n3C(=O)OC(C)(C)C)C(=O)N(S(=O)(=O)C(F)(F)F)C2)cc1Cl
Yield: 35 %

Procedure:
4-Hydroxy-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1,5-dihydro-pyrrol-2-one (0.032 g, 0.059 mmol) was reacted as described in the procedure used to synthesize (S)-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1-trifluoromethanesulfonyl-1,5-dihydro-pyrrol-2-one and by using acetonitrile instead of N,N-dimethylformamide. This gave the title material (0.018 g, 35%). LCMS (+ESI, M+H+) m/z 730; 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.55 (9H, s), 2.57 (3H, s), 3.20 (4H, m), 3.40 (2H, d, J=5.9 Hz), 3.85 (7H, m), 4.31 (1H, d, J=17.5 Hz), 4.44 (1H, d, J=17.6 Hz), 4.72 (1H, t, J=5.7 Hz), 7.02–7.04 (2H, m), 7.18 (1H, s), 7.30 (1H, d, J=8.4 Hz), 7.44 (1H, s).
Reaction SMILES: [Cl-:1].[CH3:2][P+:3]1([CH3:8])[CH2:7][CH:6]=[CH:5][CH2:4]1.[Cl:9]Cl>C(Cl)(Cl)Cl>[Cl-:1].[Cl:1][CH:5]1[CH:6]([Cl:9])[CH2:7][P+:3]([CH3:8])([CH3:2])[CH2:4]1
Reactant: C[P+]1(C)CC=CC1
Reactant: ClCl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: C[P+]1(C)CC(Cl)C(Cl)C1

Procedure:
44.3 g (0.2 mole) of 1,1-dimethyl-3-phospholenium chloride were suspended in 250 ml of chloroform and reacted with 14.2 g (0.2 mole) of chlorine at 20° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. This gave 3,4-dichloro-1,1-dimethyl-phospholanium chloride in the form of colourless crystals of melting point 90°-100° C. (decomp.).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([N:25]([C:27]([CH3:32])([CH2:29][CH2:30]Cl)[CH3:28])[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]([C:27]([CH3:28])([CH3:32])[CH2:29][CH2:30][C:9]([C:10]#[N:11])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: CN(Cc1ccccc1)C(C)(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(Cc1ccccc1)C(C)(C)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
Sodium hydride (4.4 g of a 60% dispersion in mineral oil) was added in portions to a solution of diphenylacetonitrile (19.3 g) in anhydrous toluene (100 ml). The mixture was heated under reflux for 1.5 hours then allowed to cool to 50° whereupon a solution of 2-(N-benzyl-N-methylamino)-4-chloro-2-methylbutane (11.3 g-see Preparation 11) in anhydrous toluene (20 ml) was added and the mixture heated under reflux for 3 hours. The mixture was partitioned between toluene (200 ml) and 10% aqueous sodium hydroxide (100 ml), the layers separated and the toluene layer washed with water (100 ml). The toluene solution was dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing toluene (50% up to 100%) and then with toluene containing ethyl acetate (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a straw coloured oil, yield 14.5 g.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[CH2:23]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:20])[CH3:19])[CH3:24]
Reactant: CCI
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 12.5 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl]phenyl]acetamide (U.S. Pat. No. 4,112,095) in 500 ml of dimethylformamide under argon, was added 2.47 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 4.1 ml of ethyl iodide was added. This mixture was stirred for 2.5 days, then poured into 1.5 liters of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a Waters Prep 500 silica gel column, eluting with dichloromethane:methanol (97:3). Fractions 8-13 were combined, evaporated in vacuo and the solid recrystallized from dichloromethane-hexane, giving 6.54 g of the desired product, mp 180°-185° C.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH3:16][O:15][C:13]([O:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:14]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)=NOC(=O)OC
Temperature: 0 °C
Yield: 42.2 %

Procedure:
A mixture of sodium salt of ethyl 2-hydroxyimino-2-cyanoacetate (16.4 g), water (100 ml) and acetone (15 ml) is stirred at 0°C, and methyl chloroformate (9.4 g) is dropwise added thereto. The resulting mixture is adjusted to pH 7 to 8 with the addition of an aqueous solution of sodium hydrogencarbonate and stirred for 5 hours. The reaction mixture is extracted with ether, and the ether layer is washed with water, dried and concentrated. The residue is recrystallized from a benzene - n-hexane mixture to give ethyl 2-methoxycarbonyloxyimino-2-cyanoacetate (8.4 g) as crystals melting at 69° to 71°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl.CO>O1CCOCC1>[O:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
9.2 g (0.0323 mol, 1 eq) of 1,1-dimethylethyl [1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]carbamate, 65 mL (0.258 mol, 8 eq) of 4 M HCl in dioxane, and enough methanol to achieve dissolution were combined and stirred at ambient temperature overnight. The reaction mixture was then evaporated. Dichloromethane and 1 M NaOH were added. Sodium chloride was then added to saturate the aqueous layer. The aqueous layer was extracted with dichloromethane twice. The organic layers were combined, dried with sodium sulfate, and evaporated to yield 5.5 g (92% yield) of 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine as a low melting white solid. 1H-NMR (400 MHz, DMSO-d6): δ 3.86 (m, 2H), 3.24 (m, 2H), 2.77 (m, 2H), 2.46 (m, 1H), 2.35 (m, 1H), 2.25-1.05 (v br s, 2H, NH2), 2.07 (m, 2H), 1.64 (m, 4H), 1.39 (m, 2H), 1.16 (m, 2H); MS (ESI): 185 [M+H]+.