Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[CH:3]=1.[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>CCCCO>[Br:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:22][C:18]3[CH:17]=[C:16]([NH2:23])[CH:21]=[CH:20][CH:19]=3)[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Nc2cccc(Br)c2)ncn1
Reactant: Nc1cccc(N)c1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3cccc(Br)c3)ncn2)c1
Temperature: 150 °C
Yield: 65.1 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-(3-bromo-phenyl)-amine (300 mg, 1.1 mmol) and benzene-1,3-diamine (300 mg, 2.75 mmol) in 3 mL of n-BuOH was heated in a scaled tube to 150° C. for 16 hr. Solvent was removed by vacuum evaporation and the crude product was purified by flash chromatography on silica gel with EtOAc/DCM solvent system to afford 255 mg (65% yield) of the title compound as a yellow solid. MS (m/z): MH+=356, 358.
Reaction SMILES: [CH2:1]([Cl:3])Cl.C(Cl)(=O)C(Cl)=O.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]([C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([CH:40]([OH:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=C2>CS(C)=O>[Cl:3][C:1]1[C:18]2[C:17](=[CH:13][CH:12]=[C:11]([F:10])[CH:19]=2)[N:16]([CH3:20])[C:15]=1[C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([C:40](=[O:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22]
Reactant: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)c1c(Cl)c2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
DMSO (0.60 mL, 8.5 mmol) was added to a methylene chloride solution of oxalyl chloride (2.1 ml, 2.0 M, 4.2 mmol, in 15 mL of methylene chloride), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at −78° C. A methylene chloride solution of N-[(5-fluoro-1-methylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (820 mg, 1.7 mmol, in 8 mL of dry methylene chloride), and DMSO (0.4 mL) were added dropwise to the reaction mixture and stirred for 15 minutes at −78° C. TEA (1.4 mL, 10.2 mmol) was added to the mixture dropwise and the mixture was stirred for 10 minutes at −78° C., then was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO, solution and the aqueous layer was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine, dried over sodium sulfate, and concentrated to give the title product as a slightly yellow solid. Trituration with either afforded the title product as a white powder (705 mg, 85%). TLC (methanol/methylene chloride, 1:9): Rf=0.63. MS for C24H30ClF2N3O5: MH+=514/516; (M−H)−=512/514.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](F)=[O:16])=[C:13]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:12]=1.C(O)(=O)C>CN(C)C=O>[NH2:8][C:7]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:13]2[C:14]([C:15](=[O:16])[C:6]=1[C:5]([NH:4][CH3:3])=[O:9])=[CH:18][CH:19]=[C:11]([Cl:10])[N:12]=2
Reactant: O=C(F)c1ccc(Cl)nc1NCc1ccccn1
Reactant: CNC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CNC(=O)c1c(N)n(Cc2ccccn2)c2nc(Cl)ccc2c1=O
Reaction time: 1 h
Yield: 234.8 %

Procedure:
1.12 g (28.06 mmol) of sodium hydride at 60% in mineral oil are added, fractionwise, to a solution, cooled to 0-5° C., of 1.31 g (13.36 mmol) of N-methylcyanoacetamide (prepared according to 1.3) in 20 ml of anhydrous dimethylformamide. Stirring is continued at this temperature for ten minutes and then a solution of 3.55 g (4.93 mmol) of 6-chloro-2-[(pyridin-2-ylmethyl)amino]nicotinoyl fluoride in 20 ml of dimethylformamide is added. The medium is stirred overnight at ambient temperature and then 0.561 g (14.03 mmol) of sodium hydride at 60% is added fractionwise. Stirring is continued at this temperature for 1 hour minutes, and then the reaction mixture is poured onto ice and the subsequent mixture is acidified to pH 5-6 with an aqueous solution of acetic acid at 10%. The precipitate is isolated by filtration and, after drying in an oven, 3.98 g of the expected product are obtained in the form of a beige solid. MH+=344. Yield=87%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.[H][H]>C(O)C>[CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]([CH3:9])[O:3]1
Reactant: Cc1cc(=O)cc(C)o1
Reactant: [H][H]
Solvent: CCO
Product: CC1CC(O)CC(C)O1
Yield: 70.8 %

Procedure:
2,6-Dimethyl-4H-pyran-4-one (5.0 g) in ethanol (40 ml) was hydrogenated under 10% Pd-C (0.5 g) at 10 bar of hydrogen for 2 days. The solution was then evaporated to an oil which was purified by silica-gel MPLC [using a 1:1 mixture of ethyl acetate and hexane as eluant] to give the title product (3.71 g, 74%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][OH:9].[C:10]([C:12]1([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:15][CH2:14][CH2:13]1)#[N:11]>CCO>[CH3:20][C:19]([CH3:22])([S:17]([NH:16][C:12]1(/[C:10](=[N:8]/[OH:9])/[NH2:11])[CH2:13][CH2:14][CH2:15]1)=[O:18])[CH3:21]
Reactant: NO
Reactant: CC(C)(C)S(=O)NC1(C#N)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)S(=O)NC1(/C(N)=N/O)CCC1
Temperature: 60 °C
Yield: 52.4 %

Procedure:
Potassium carbonate (1.38 g, 9.98 mmol) was added to a stirring solution of hydroxylamine hydrochloride (347 mg, 4.99 mmol) and N-(1-cyanocyclobutyl)-2-methylpropane-2-sulfinamide (500 mg, 2.50 mmol) in EtOH (8 ml) at rt. The reaction was then heated to 60° C. for 16 h. The mixture was then concentrated and the resulting residue was diluted with EtOAc and washed with H2O followed by sat NaCl (aq). The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product (Z)-1-(1,1-dimethylethylsulfinamido)-N′-hydroxycyclobutanecarboximidamide (305 mg, 1.31 mmol, 52% yield) as a white solid consistent by LCMS and NMR. LC-MS retention time: 0.456 min; m/z (MH+): 234. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 5.60 (s, 1H), 5.10 (s, 2H), 2.35-2.30 (m, 1H), 2.27-2.17 (m, 1H), 2.10-2.03 (m, 1H), 1.99 (s, 1H), 1.80-1.75 (m, 1H), 1.73-1.62 (m, 1H), 1.13 (s, 9H).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:17]=[CH:16][C:12]2[NH:13][CH:14]=[N:15][C:11]=2[CH:10]=1)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6].[OH-].[Li+].O>O1CCCC1>[O:1]=[C:2]([C:9]1[CH:17]=[CH:16][C:12]2[NH:13][CH:14]=[N:15][C:11]=2[CH:10]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CCC(=O)c1ccc2[nH]cnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(=O)c1ccc2[nH]cnc2c1
Yield: 78 %

Procedure:
Prepared analogously to Example 5 from methyl γ-oxo-1H-benzimidazol-5-butanoate, lithium hydroxide and water in the presence of tetrahydrofuran in a yield of 78% of theoretical. Colourless crystals, m.p. 251–255° C. (decomp.).
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1cc(C)c(Cc2nc(C)nc(O)c2C)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(Cc2nc(C)nc(Cl)c2C)c(C)c1
Yield: 97 %

Procedure:
A mixture of 4-hydroxy-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine (1.2 g, 4.68 mmol) and POCl3 (25 ml) was heated at reflux for 1 hour. The mixture was cooled and evaporated to dryness. The residue was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to dryness to give 1.24 g (97%) of golden crystals, mp 82–84° C.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]#[N:4].[OH2:18]>Cl>[OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([NH2:4])=[O:18]
Reactant: CCCCCCCCCCCCCC(O)C#N
Reactant: O
Agent: Cl
Product: CCCCCCCCCCCCCC(O)C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Hydroxypentadecanenitrile (1.0 g) was suspended in concentrated hydrochloric acid (15 ml), and this suspension was vigorously stirred at room temperature for 24 hours. Then, this mixture was diluted with water (45 ml). The insoluble powder was collected by filtration, washed with water (10 ml×3), and dried to give 2-hydroxypentadecanamide (1.06 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:7]=1.[B:14]1(B2OCC(C)(C)CO2)[O:19]CC(C)(C)C[O:15]1>>[F:13][C:5]1[CH:4]=[CH:3][C:2]([B:14]([OH:19])[OH:15])=[CH:7][C:6]=1[N:8]1[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: Fc1ccc(Br)cc1-n1cncn1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: OB(O)c1ccc(F)c(-n2cncn2)c1

Procedure:
1-(5-Bromo-2-fluorophenyl)-1H-[1,2,4]triazole (1.1 g, 4.5 mmol) was reacted with bis(neopentyl glycolato)diboron (1.13 g, 5.0 mmol) using the method in Example 51 to give 4-fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid as a white solid: m/z (ES+) 208 (M++H).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][C@@H:3]2[CH2:7][NH:8][CH2:9][C@H:2]12.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[C:29]([Cl:34])[N:28]=1>CCO.O>[NH2:26][C:27]1[N:32]=[C:31]([N:8]2[CH2:7][C@@H:3]3[C@@H:2]([N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4]3)[CH2:9]2)[CH:30]=[C:29]([Cl:34])[N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2CNC[C@@H]21
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2CN(c3cc(Cl)nc(N)n3)C[C@@H]21
Yield: 77.7 %

Procedure:
To a solution of racemic tert-butyl (4aR*,7aR*)-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (460 mg, 2.03 mmol) in EtOH (1 mL) containing DIPEA (590 μL, 3.39 mmol) was added a solution of 2-amino-4,6-dichloropyrimidine (277 mg, 169 mmol) in EtOH (9 mL) with stirring and the solution was heated to reflux for 24 hours. The solution was cooled and diluted with water (10 mL) and the resulting solid was collected by filtration, washed with water (20 mL) and dried in vacuo at 60° C. to yield the title compound as a white solid (558 mg, 93%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].Cl[C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1.O>O1CCCC1>[CH2:1]([O:4][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[C:2]#[CH:3]
Reactant: C#CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of propargyl alcohol (420 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 530 mg (98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: OCc1ccc(Cl)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-(hydroxymethyl)phenol (for a preparation see intermediate 5; 1.51 g, 9.54 mmol) in ethanol (20 ml), was added sodium hydroxide (5.25 ml, 10.5 mmol). To the mixture was added a solution of benzyl bromide (Aldrich; 1.14 ml, 9.54 mmol) in ethanol (30 ml) dropwise. The reaction was stirred under nitrogen overnight at ambient temperature. The solvent was removed in vacuo to leave an aqueous suspension. The suspension was diluted with water (50 ml) and dichloromethane (40 ml). The phases were separated and the aqueous phase extracted with dichloromethane (30 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (20 ml) and the solvent removed in vacuo to leave a white solid (1.52 g). The residue was loaded in dichloromethane and purified on silica (100 g) using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.32 g) as a white solid; LCMS (System 2): (M-H)−=247, tRET=1.17 min.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH:6]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1)[N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[CH2:25][CH2:24][CH2:23][NH:22][C:21]=4[N:20]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)C.[OH-].[Li+].[Cl-].[NH4+]>C1COCC1.CO.O>[CH2:36]([O:35][C:31]1[CH:30]=[C:29]([CH:6]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[CH2:25][CH2:24][CH2:23][NH:22][C:21]=5[N:20]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:5][C:4]([OH:43])=[O:3])[CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)CC(c1cccc(OCc2ccccc2)c1)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC(c1cccc(OCc2ccccc2)c1)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Yield: 25 %

Procedure:
A solution of 3-(3-benzyloxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic acid ethyl ester (0.08 g, 0.14 mmol), lithium hydroxide (0.01 g, 0.22 mmol) and THF/methanol/water [2.0/1.0/0.2 mL] (3.2 mL) was microwave at 100° C. for 15 minutes. Saturated ammonium chloride was added (10 mL) and the product was extracted with ethyl acetate (3×10 mL). The crude product was purified via column chromatography eluting with dichloromethane:ethyl acetate (10:1) to give the title compound (25% yield) as white solid. 1H NMR (CDCl3) δ 10.5 (bs, 1H), 7.49 (d, 1H, J=3.0 Hz), 7.39–7.22 (m, 6H), 7.16 (m, 1H), 7.08 (m, 1H), 6.80 (m, 4H), 6.60 (dd, 1H, J=2.2, 6.8 Hz), 6.46 (m, 1H), 6.26 (d, 1H, J=7.3 Hz), 6.09 (m, 1H), 5.29 (s, 2H), 3.59 (s, 1H), 3.38 (m, 3H), 3.29–3.14 (m, 2H), 2.60–2.43 (m, 5H), 1.87 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C34H34N3O4 548.3 (M+H); found 548.4.
Reaction SMILES: [O:1]=[C:2]([CH2:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:4][C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Li+].C(Cl)(Cl)Cl.CO.O>S(=O)(=O)(O)O.CN(C)C=O.C(O)(=O)C.CO.C(Cl)Cl>[O:1]=[C:2]([CH2:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:4][C:5]1[NH:13][N:12]=[N:11][N:6]=1
Reactant: CC(=O)CC(=O)CCC#N
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)CC(=O)CCc1nnn[nH]1

Procedure:
A mixture of the 3,5-dioxohexylcyanide (2.78 gm; 20 mmole), lithium azide (1.08 gm; 22 mmole) and sulfuric acid (one drop) in 10 ml dry dimethylformamide is heated to 100-120 degrees. Progress of the reaction may be checked by TLC (silica gel; chloroform:methanol 97:3). When no starting material remaines, the reaction is cooled and 20 ml of water added. The reaction is taken to dryness under reduced pressure and the residue fractionated by silica gel flash column chromatography using methylene chloride: glac. acetic acid: methanol 100:3:3 as eluant. Fractions containing the product may be pooled and concentrated.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:20])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.[H-].[Na+].[CH3:23]I.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:20][CH3:23])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2cccc(F)c2F)C1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(c2cccc(F)c2F)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Tert-butyl 3-(2,3-difluorophenyl)-3-hydroxyazetidine-1-carboxylate (0.7 g, 2.45 mmol) was dissolved in N,N-dimethylformamide (20 mL) and sodium hydride (60% dispension in mineral oil, 0.2 g, 4.90 mmoL) was added at 0° C. The mixture was stirred at 0° C. for 15 min and at ambient temperature for 20 min after which methyliodide (0.41 mL, 2.94 mmol) was added. The mixture was stirred for 1 h at ambient temperature, a mixture of aqueous lithium chloride (5%, aq, 20 mL) and ethyl acetate (20 ml) was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/isooctane 2:8 to 1:1) gave the title compound (0.7 g, 95%). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 223 (60), 198 (35), 169 (bp), 170 (bp).
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.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[F:44][C:43]([F:45])([F:46])[O:42][C:39]1[CH:38]=[CH:37][C:36]([NH:33][C:34]([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:35])=[CH:41][CH:40]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)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 (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of 1-isocyanato-4-trifluoromethoxy-benzene (52.0 mg, 0.26 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 layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-trifluoromethoxy-phenyl)-amide as a white solid. (Yield 82 mg, 66.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=O)=[CH:13][CH:12]=1)(=[O:9])=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][CH:16]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CC(=O)N3CCOCC3)cc2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(CCN3CCOCC3)cc2)c(OC)c1
Yield: 18.8 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-C-[4-(2-morpholin-4-yl-2-oxoethyl)phenyl]methanesulfonamide (313 mg) in THF (10 ml) was added, at 0° C., lithium aluminum hydride (66 mg) in portions, and the mixture was stirred at room temperature for 1 h. Then water (0.4 ml), 6 M NaOH (0.3 ml) and water again (1.2 ml) were added successively. The solids were filtered off and dichloromethane was added to the filtrate. The organic phase was removed, dried over magnesium sulfate and concentrated. The crude product was purified by means of preparative HPLC. This gave the product (57 mg) with a molecular weight of 434.6 g/mol (C22H30N2O5S).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.[BH4-].[Na+]>CO.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][CH2:42][C:41]2[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CN[C@@H]2CC[C@H](N3CC[C@H](NC(=O)OCc4ccccc4)C3=O)[C@H](NC(C)=O)C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.6 %

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (34.8 g, ca. 90 mmol) was dissolved in methanol (400 ml). The flask was purged with nitrogen and charged with triethylamine (15.61 ml, 112 mmol), followed by 4-methoxybenzaldehyde (13.62 ml, 112 mmol). The reaction was stirred at RT for 14 h, at which time LC/MS of reaction showed complete consumption of primary amine and formation of desired imine (LC/MS found [M+H]+=507.4). The reaction was cooled to 0° C. and charged with sodium borohydride (5.08 g, 134 mmol) in portions over 1 minute. The ice bath was removed after 30 min and the solution stirred for an additional 3.5 h. The reaction was concentrated in vacuo to give a white solid/gum, which was dissolved in 400 mL sat. NaHCO3 and 1200 mL EtOAc. The phases were mixed vigorously and then separated. The organic phase was washed 2×800 mL 0.5N HCl (note: a small third, oily phase was on the bottom in the first extraction; took along with the acid phase). The acid washes were combined, basified with solid NaOH to pH 13, cooled to RT, and then extracted with EtOAc (1×1000 mL; 2×600 mL). The organic extracts were combined, washed with brine (1×120 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in dichlormethane and concentrated; this procedure was repeated to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(4-methoxybenzylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (43.68 g, 86 mmol, 96% yield) as a flowing microcrystalline solid after pumping on high vacuum. LC/MS found [M+H]+=509.6.