Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[N:13]([C:16]1[CH:17]=[C:18]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:19]=[CH:20][CH:21]=1)=[C:14]=[O:15]>C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:14]([NH:13][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:17]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC1(C)OB(c2cccc(N=C=O)c2)OC1(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 93.1 %

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (0.79 ml, 4.5 mmol) was added slowly to a stirred solution of 2-(3-isocyanato-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 g, 4.1 mmol) in dry THF (8 ml) at RT under N2 After 16 hours the volatiles were removed in vacuo and the residue was partitioned between EtOAc/H2O. The organic layer was washed with brine (×1), then dried (Na2SO4), filtered and evaporated to give the title compound (1.6 g) as a colourless solid. 1H NMR (400 MHz, DMSO-d6): 8.52 (1H, s), 7.77 (1H, s), 7.47 (1H, dt), 7.25-7.17 (2H, m), 6.80 (1H, t), 6.08 (1H, t), 3.13-3.02 (2H, m), 3.02-2.89 (2H, m), 1.57-1.48 (2H, m), 1.39 (9H, s), 1.29 (12H, s).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:29][CH2:30][NH2:31]
Reactant: CC(C)(C)OC(=O)NCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (0.490 g, 0.94 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1 h. Sodium hydroxide (2 M, 30 mL) was added and the mixture was extracted with chloroform (3×20 mL). The extracts were dried over Na2SO4 and concentrated. Purification of the crude material by column chromatography on silica gel (90:5:5 CH2Cl2—CH3OH—NH4OH) provided 294 mg (97%) of N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine as a colorless oil. 1H NMR (CDCl3) δ 1.60-1.75 (m, 1H), 1.87-1.98 (m, 1H), 2.01 (m, 1H), 2.22 (m, 1H), 2.56-2.85 (m, 6H), 4.03 (m, 1H), 4.04 (d, J=16.8 Hz, 1H), 4.17 (d, J=16.8 Hz, 1H), 7.11-7.21 (m, 3H), 7.40 (d, J=7.8 Hz, 1H), 7.56 (brs, 2H), 8.55 (d, J=4.2 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([OH:17])[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][C:30]=3[CH3:35])[N:27]=[CH:28][C:21]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([O:17][C:20]2[C:21]3[CH:28]=[N:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][C:30]=4[CH3:35])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1
Reactant: Cc1cnccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ccncc1C)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H3) (199 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) added portionwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford (2S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-[1-(3-methylpyridin-4-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamide (370 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.23 (3H, t), 2.34 (3H, s), 3.61-3.69 (2H, m), 4.06-4.14 (2H, m), 6.05 (1H, t), 7.49 (1H, d), 7.68 (1H, dd), 8.22 (1H, dd), 8.23-8.25 (1H, m), 8.44 (1H, s), 8.61 (1H, s), 8.63 (1H, dd), 8.69 (1H, s), 8.76 (1H, s); m/z (ESI+) (M+H)+=454; HPLC tR=1.93 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C[O:13][C:14]([C:16]#[C:17][C:18](OC)=[O:19])=[O:15]>>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[C:18](=[O:19])[CH:17]=[C:16]([C:14]([OH:15])=[O:13])[NH:1]2
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(O)c1cc(=O)c2c(C(F)(F)F)cccc2[nH]1
Yield: 0.1 %

Procedure:
Using the method described in Example 15 with 3-aminobenzotrifluoride (40 g) and dimethylacetylene dicarboxylate (35 g) gave 5-trifluoromethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.04 g) m.p. 265°-267° C. (dec), δ (360 MHz, DMSO-d6) 6.65 and (1H, s, 3-H), 7.78 (2H, m, 7-H, 8-H), 8.26 (1H, d, 6-H) and 12.08 (1H, N-H).
Reaction SMILES: [CH2:1]([NH:5][CH:6]([CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[C:22](OC(=O)C)(=O)[CH3:23]>>[CH2:1]([N:5]([CH2:22][CH3:23])[CH:6]([CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(CO)CCOc1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Product: CCCCN(CC)C(CO)CCOc1cccc2ccccc12

Procedure:
2-(butylamino)-4-(1-naphthyloxy)-1-butanol, described in Example 6, with acetic anhydride, followed by reduction, gives 2-(butylethylamino)-4-(1-naphthyloxy)-1-butanol.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[C:8]([CH:9]=[N:10][C@H:11]([CH3:30])[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[OH:13])[C:7]([OH:32])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1>CCCCCCC>[N+:1]([C:4]1[CH:31]=[C:8]([CH:9]=[N:10][CH:11]([CH3:30])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[OH:13])[C:7]([OH:32])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](C)N=Cc1cc([N+](=O)[O-])ccc1O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1C(O)(c1ccccc1OC)C(C)N=Cc1cc([N+](=O)[O-])ccc1O
Temperature: 10 °C
Yield: 99 %

Procedure:
19.6 g (44.9 mmol) of (R)-N-(5-nitrosalicylidene)-2-amino-1,1-di(2-methoxyphenyl)-1-propanol, 8.96 g (44.9 mmol) of cupric acetate, and 160 g of toluene were mixed in a flask and reacted at 80° C. for 1 hr under stirring. 100 g of n-heptane were added to the reaction solution to precipitate blue-green chrystals. The precipitated reaction mixture was cooled to 10° C. and filtered to collect the crystals. Collected crystals were washed with 100 g of n-heptane, and dried at room temperature to give 22.1 g of a copper complex of (R) N-(5-nitro-salicylidene)-2amino-1,1-di(2-methoxyphenyl)-1-propanol in a yield of 99.0%.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.CN1CCCC1=O.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:19]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(I)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
Into a 300 mL three-neck flask was put 15 g (57 mmol) of 4-iodobenzoylhydrazine, 15 mL of N-methyl-2-pyrrolidone (NMP) was added thereto, and the mixture was stirred for 10 minutes at a room temperature. After the stirring, 50 mL of a mixed solution of 5 mL of N-methyl-2-pyrrolidone and 7.9 mL (69 mmol) of benzoyl chloride was dripped into the solution through a dropping funnel, and the solution was stirred at a room temperature for 18 hours. After the stirring, water was added into the solution, and a solid was precipitated. The precipitated solid was collected by suction filtration. The collected solid was added into about 500 mL of a saturated aqueous solution of sodium hydrogen carbonate, stirred, and washed. After the washing, the mixture was subjected to suction filtration to obtain a solid. The obtained solid was added into about 500 mL of water, stirred, and washed. After the washing, the mixture was subjected to suction filtration to obtain a solid. The obtained solid was washed with methanol to give 20 g of a powdery white solid in a yield of 97%.
Reaction SMILES: [F-].[Cs+].[CH:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[O:4].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>COCCOC>[F:17][C:18]([F:20])([F:19])[CH:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)[OH:4]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)CCCc1ccc(C=O)s1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)CCCc1ccc(C(O)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.4 %

Procedure:
CsF (70 mg, 0.47 mmol) was added to a solution of methyl 4-(5-formylthiophen-2-yl)butanoate (1.0 g, 4.71 mmol) in dry 1,2-dimethoxyethane (5 MI) at 0° C., followed by trifluoromethyl trimethylsilane (0.8 MI, 5.65 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 h, quenched with 3N HCl, and stirred for further 30 min. The crude product was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether) to get methyl 4-(5-(2,2,2-trifluoro-1-hydroxyethyl)thiophen-2-yl)butanoate (0.63 g, yield 47%) as yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.02-7.01 (d, J=3.5 Hz, 1H), 6.74-6.73 (m, 1H), 5.23-5.17 (m, 1H), 3.68 (s, 3H), 2.88-2.84 (t, J=7.5 Hz, 2H), 2.81-2.80 (d, J=5.3 Hz, 1H), 2.40-2.36 (t, J=7.5 Hz, 2H), 2.05-1.97 (m, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Si:5]([O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH:16]([C:18]1[CH:30]=[CH:29][C:21]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)O)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>ClCCl>[Si:5]([O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH:16]([C:18]1[CH:30]=[CH:29][C:21]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)[Cl:3])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (5.3 mL, 0.075 mol) was added to a solution of the benzhydryl alcohol from above (19.75 g, 0.048 mol) in 350 mL of dichloromethane. After stirring at room temperature overnight the solvent was evaporated, the residue was redissolved in toluene and again evaporated to drive off excess thionyl chloride and afford crude 4-(3-(tert-butyldimethylsilyloxy)-α-chlorobenzyl)-N,N-diethylbenzamide.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:14])[C:12](=[O:15])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C.Cl>O>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:11][CH2:10]3)[C:12](=[O:15])[N:13]([CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 43 %

Procedure:
A mixture of 0.406 g (0.00133 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53), 0.237 g (0.00142 mole) of 4-amino-3-methoxylbenzoic acid, 7 mL of ethanol, 28 mL of water and 1.2 mL of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.250 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methoxybenzoic acid (I-53) as a white solid.
Reaction SMILES: [OH-].[Li+].O.C([O:6][P:7]([CH2:15][C@@H:16]([OH:19])[CH2:17][NH2:18])([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:8])C.P(=O)(O)(O)O>C(O)C>[NH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][P:7]([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)(=[O:6])[OH:8]
Reactant: CCOP(=O)(C[C@@H](O)CN)C1CC=CCC1
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC[C@H](O)CP(=O)(O)C1CC=CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.2 g of lithium hydroxide and 4 ml of water are added to a solution of 1.1 g of 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid ethyl ester in 4 ml of ethanol. The mixture is heated to 60° and stirred for 20 hours. The mixture is then allowed to cool to room temperature, adjusted to pH 7 with aqueous phosphoric acid, concentrated to dryness by evaporation, taken up in methanol/water and filtered. After removal of the solvent there remains behind a foam which, after crystallisation from ethanol/methanol, yields 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid in the form of white crystals having a melting point of 221°-225°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=O)[NH:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.[OH-].[NH4+:35]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:35]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NCC(=O)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C

Procedure:
The product prepared in Step A above (3.55 g, 9 mmol), NH4OAc (ammonium acetate) (20.8 g, 270 mmol) and AcOH (acetic acid) (30 mL) were combined at room temperature and the reaction mixture was warmed on a steam bath for about 3 hours. The reaction mixture was then cooled to room temperature and poured into an ice slurry mix (400 g). To this mixture was added concentrated ammonium hydroxide (50 mL) and ethyl ether. The layers were separated, and the aqueous phase washed with a second portion of ethyl ether. The organic phases were combined, dried over MgSO4 filtered, and concentrated under reduced pressure to yield a brown foam. This sample was purified by preparative HPLC to yield the purified title compound as a white powder. LC indicated the sample was 96% pure at 214 nm.
Reaction SMILES: [BH4-].[Na+].[NH:3]1[CH:7]=[N:6][C:5](/[CH:8]=[C:9]2\[CH2:10][N:11]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13][C:14]\2=[O:15])=[N:4]1.ClCCl>CO>[NH:3]1[CH:7]=[N:6][C:5](/[CH:8]=[C:9]2\[CH2:10][N:11]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13][CH:14]\2[OH:15])=[N:4]1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1nc[nH]n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1nc[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Sodium borohydride (131 mg) was added to a solution of (E)-3-[(1,2,4-triazol-3-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (2.92 g) in a mixed solvent of dichloromethane (60 ml) and methanol (60 ml) at 0° C. After the mixture was stirred at room temperature for 30 minutes, the reaction was quenched by addition of a saturated aqueous ammonium chloride solution. Products were extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Solvents were removed under reduced pressure to afford crude (E)-3-[(1,2,4-triazol-3-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol. The crude product was dissolved in acetonitrile (60 ml) and methyl bromoacetate (920 μl) was added. After DBU (1.25 ml) was added thereto under cooling at 0° C., the mixture was stirred at 0° C. for 15 minutes. Water and ethyl acetate were added to the mixture and the layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure gave an approximately 1:3 mixture of the two title isomers (2.98 g, yield: 87%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:22])[C:12](=[CH:18]OCC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]>>[CH2:8]([O:10][C:11](=[O:22])[C:12](=[CH:18][NH:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc(N)on1
Product: CCOC(=O)C(=CNc1cc(C)no1)C(=O)OCC
Reaction time: 0.75 h

Procedure:
112.5 g. of 3-Methyl-5-aminoisoxazole (1.14 mol.) and 248 g. of ethoxymethylenemalonic acid diethyl ester (1.14 mol.) are heated with stirring for 45 minutes at 130°. After this period, ethanol is removed under reduced pressure. The residue solidifies on cooling and is recrystallized from ethanol, m.p. 134°-136°, yield 245 g. (80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:32][CH2:31]1)[CH3:17]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:4]=1[C:5]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:33]2[CH2:34][CH2:35][CH2:36][N:30]([C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:31][CH2:32]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(S(C)=O)cc1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(S(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylsulfinylbenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography on silica gel eluting with 10% methanol/dichloromethane, the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[OH:29])=[O:18].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4ccccc4c3C(C)=O)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-acetonaphthone (250 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (100 mg, yield 60%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[O:20][C@@H:19]2[CH2:21][OH:22])[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C@@H:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)[C@H:19]([OH:20])[CH2:21][OH:22])=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: OC[C@H]1O[C@@H]1c1cccc(F)c1
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccc(F)cc21

Procedure:
In an analogous manner to EXAMPLE 117, step 5. (2S,3S)-3-(6-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol was prepared from 6-fluoro-1H-indole and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47 step 3). MS (ESI) m/z 304.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:22][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:33])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH:18]([O:20][CH3:21])[CH2:19]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC1CN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)C1
Solvent: ClCCl
Product: COC1CN(CCOc2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2-c2c(Br)cnn2C)C1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzenamine (39.2 mg, 0.103 mmol) in CH2Cl2 (4 mL) was added 4-chlorophenyl isocyanate (18.0 mg) and stirred for two hours. The resulting material was purified by HPLC. The product was dried in vacuo to afford the title compound as a white solid (50.7 mg, 92%). LCMS m/z (%)=534 (M+H 79Br, 74), 536 (M+H 81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.79 (bs, 1H), 8.70 (bs, 1H), 7.60 (s, 11H), 7.52 (dd, J=8.95, 2.71 Hz, 1H), 7.47 (d, J=8.94 Hz, 2H), 7.35 (d, J=2.70 Hz, 1H), 7.31 (d, J=8.91 Hz, 2H), 7.09 (d, J=9.03 Hz, 1H), 4.02-3.86 (m, 2H), 3.83 (quint, J=5.80 Hz, 1H), 3.66 (s, 3H), 3.35-3.29 (m, 1H), 3.27-3.18 (m, 1H), 3.08 (s, 311), 2.74-2.56 (m, 4H).