Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H]1P(CCP2[C@H](C)CC[C@H]2C)[C@H](C)CC1.[OH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:23][O:24][C:20]=2[CH:19]=1.[H][H]>CO>[OH:17][C:18]1[CH:31]=[CH:30][C:21]2[CH:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][O:24][C:20]=2[CH:19]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Agent: C[C@@H]1CC[C@@H](C)P1CCP1[C@H](C)CC[C@H]1C
Solvent: CO
Product: COC(=O)CC1COc2cc(O)ccc21
Temperature: 25 °C
Yield: 41.5 %

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (12 mg) and (R,R)-Me-BPE (6.5 mg) was added methanol (2.5 mL) sufficiently substituted with argon gas, and the mixture was stirred at room temperature for min. This was added to methyl (6-hydroxy-1-benzofuran-3-yl)acetate (51 mg), and the mixture was stirred at 70° C. for 3 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 47.9%, and the yield was 41.5%.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]12([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:24](Cl)=[O:25])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>N1C=CC=CC=1>[C:11]12([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:24]([S:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)=[O:25])[CH2:12][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:19]3)[CH2:18]1)[CH2:20]2
Reactant: O=C(O)c1ccc(S)cc1
Reactant: COCCOCOc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Product: COCCOCOc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.54 g (10 mmol) of 4-mercaptobenzoic acid and 40 ml of pyridine were introduced into a round-bottomed flask. A solution of 3.75 g (10 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoyl chloride prepared in Example 10(c) was added dropwise and the mixture was stirred at room temperature for six hours. The mixture was evaporated to dryness, the residue was taken up in water and ethyl ether. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The solid obtained was recrystallized from a diisopropyl ether/methanol mixture, filtered off and dried. 2.94 g (59%) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxybenzoylthio]benzoic acid, having a melting point of 187°-8° C., were recovered.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[N:8]([CH3:20])[C:7]1=O)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>C1(C)C=CC=CC=1.O1CCCC1.C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:11]2[CH2:10][CH2:9][N:8]([CH3:20])[CH2:7][C@H:6]2[CH2:4][OH:3])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1C(=O)N(C)C(=O)C[C@H]1c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Reaction time: 3 h

Procedure:
Compound E4 (34 g) in toluene (150 ml) was added slowly to a slurry of lithium aluminium hydride (10 g) in a tetrahydrofuran (50 ml)/toluene (150 ml) mixture, maintaining the temperature at 0°-5° C. under nitrogen. (Commercially available solutions of lithium aluminium hydride in tetrahydrofuran/toluene have also been used successfully). The mixture was stirred for a further 1-5 hours and then allowed to warm up to 15°-25° C. overnight. The excess lithium aluminium hydride was destroyed by the carefully controlled addition of water (10 ml), dilute 15% sodium hydroxide (10 mls) and water (30 ml). The solids were then removed by filtration and reslurried in toluene (100 ml). The combined rich toluene layers were concentrated to a low volume (75 ml) and poured into petroleum ether [100°-120°] (25 ml). After stirring for 8-24 hours the product was isolated by filtration, washed with petroleum ether (10 ml) and dried.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:28]1[C:32]2[CH:33]=[CH:34][C:35](B(O)O)=[CH:36][C:31]=2[O:30][CH2:29]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([N:8]3[C:9](=[O:26])[C:10]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:14][CH:13]=4)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]3[CH3:27])=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2ccc3c(c2)OCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 1,3-benzodioxol-5-ylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.99 g, 74%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:5]=[C:4]([N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][O:15]3)[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])(=O)C.[K+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C@H:16]12[CH2:18][C@H:13]([N:12]([C:4]3[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=[C:2]([C:27]4[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=4)[CH:3]=3)[CH2:17]1)[CH2:14][O:15]2
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H]3C[C@H]2CO3)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1nc(-c2cnc(N)nc2)cc(N2C[C@@H]3C[C@H]2CO3)n1
Yield: 99.2 %

Procedure:
To a solution of (1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (500 mg, 1.73 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (382 mg, 1.73 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (63.8 mg, 0.0863 mmol) in acetonitrile (6.90 mL) was added potassium acetate in water (3.45 mL) in a microwave vial equipped with a stirbar. The mixture was microwaved at 110° C. for 5 min. The solid was and washed with ethyl acetate (5 mL) filtered under vacuum, providing 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine (598 mg, crude). 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=5.6, 2.8 Hz, 2H), 7.40-6.97 (m, 1H), 7.28 (s, 2H), 5.14 (d, J=16.0 Hz, 1H), 4.76 (d, J=27.9 Hz, 1H), 3.82 (d, J=7.7, 1.5 Hz, 1H), 3.76-3.66 (m, 1H), 3.60-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.35 (d, J=6.1 Hz, 3H), 1.95 (d, J=22.0 Hz, 2H).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH2:24][OH:25])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:25][CH2:24][CH2:23][O:22][CH2:21][C@@H:12]1[CH2:13][C@@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:15][NH:11]1
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCO)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)O[C@H]1CN[C@H](COCCO)C1
Yield: 90 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (53.0 g) in methanol (530 ml) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 4 hours in the presence of 10% palladium on carbon (5.3 g, 50% wet). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (200 g) and eluted with a mixture of methanol and dichloromethane (5:95 V/V) to give (2S,4R)-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (30.55 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH:18]2[CH2:19][CH2:20][CH:9]1[CH2:10][C:11]1[CH:12]=[C:13]([CH2:21][CH2:22][CH:23]=O)[CH:14]=[CH:15][C:16]=1[CH2:17]2)([CH3:4])([CH3:3])[CH3:2].Cl.[F:27][C:28]([F:36])([F:35])[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH:18]2[CH2:19][CH2:20][CH:9]1[CH2:10][C:11]1[CH:12]=[C:13]([CH2:21][CH2:22][CH2:23][N:32]3[CH2:33][CH2:34][CH:29]([C:28]([F:36])([F:35])[F:27])[CH2:30][CH2:31]3)[CH:14]=[CH:15][C:16]=1[CH2:17]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1C2CCC1Cc1cc(CCC=O)ccc1C2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1C2CCC1Cc1cc(CCCN3CCC(C(F)(F)F)CC3)ccc1C2
Yield: 44.4 %

Procedure:
The product from Step 2 (140 mg, 0.408 mmol), 4-trifluoromethylpiperidine hydrochloride (78 mg, 0.408 mmol) and sodium cyanoborohydride (77 mg, 1.22 mmol) in methanol (15 ml) were stirred at room temperature for 18 hours. The mixture was quenched with water and then with sodium bicarbonate solution (sat). The product was extracted with DCM and the organic phase was dried and concentrated. The crude product was purified by column chromatography on silica gel eluting with 40:1 DCM-2M NH3 in MeOH to give a colourless oil. The product was re-purified by column chromatography on silica gel eluting with 7:1 isohexane-ethyl acetate to give a colourless oil 87 mg (44%). 1H NMR (CDCl3, 400 MHz) δ 6.99 (1H, d, J=8.0 Hz), 6.89 (2H, m), 4.98 (1H, m), 4.02 (1H, m), 2.95–3.02 (4H, m), 2.45–2.62 (6H, m), 2.35 (2H, m), 1.58–2.04 (11H, m), 1.47 (9H, m), 1.19 (2H, m). m/z 481 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To 0.06 g of methyl 4-[2-(4-chlorobenzenesulfonamido)-2-(3-pyridyl)ethyl]phenylacetate in 10 ml of methanol-1,4 dioxane (1:1) solution was added 2 ml of aqueous 2N sodium hydroxide solution, and stirred overnight at room temperature. After completion of reaction, the solution was neutralized with 2 ml of 2N hydrogen chloride. The crystalline deposited was filtered to produce 49 mg of 4-[2-(4-chlorobenzenesulfonamido)-2-(3-pyridyl)ethyl]phenylacetic acid. The spectrometric data thereof supports the structure of [29] as follows.
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[N:8]1[CH2:17][CH2:16][N+:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:2][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:14][CH2:13][CH2:12][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)[CH2:16][CH2:17]1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cnc4ccccc43)CC2)nc1

Procedure:
A mixture of 450 g (1.50 moles) of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide, 177 g (1.50 moles) of benzimidazole and 307 g (2.25 moles) of potassium carbonate in 2 l of dimethylformamide is heated to 140°-145° C. for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the solution is washed with water, dried over sodium sulfate and evaporated under vacuum, and 457 g (91%) of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-benzimidazole, with a melting point of 85°-88° C., are obtained.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:7]=2[N:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:5]1=[O:27])=[N+]=[N-]>[C].[Pd].C(O)C>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:7]=2[N:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:5]1=[O:27]
Reactant: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccc(-c3ccccc3)cc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(N)CCc2ccc(-c3ccccc3)cc21
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A mixture comprising 0.785 g (2.15 mmol) of 3-azido-1-ethoxycarbonylmethyl-8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one obtained in the Synthesis Example A-7, 0.05 g of 10% palladium-carbon and 20 ml of ethanol was catalytically hydrogenated at room temperature under 4 atm for 1 hour. After filtering off the catalyst, the filtrate was concentrated. Thus, 0.73 g of the title compound was obtained as a pale yellow oily product. Yield 100%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][C@H:10]([O:12]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:9][N:8]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Yield: 82.5 %

Procedure:
A solution of (4S)-1-(tert-butyloxycarbonyl)-4-(p-nitrobenzoyloxy)-L-proline tert-butyl ester (575 mg, 1.32 mmol) in ethanol (13 mL) was treated with 0.4N sodium hydroxide (4.3 mL, 1.72 mmol) for 18 hours at room temperature. The solution was neutralized with several drops of glacial acetic acid, diluted with ethyl acetate (100 mL), washed with water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The residue was subjected to flash silica gel chromatography eluting with 5% acetone/dichloromethane. The title compound (313 mg) was obtained contaminated with some p-nitrobenzoic acid and used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[N:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:10])[CH:5]=[N:4][CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(O)c1cncc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cncc(Cl)n1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.18 g (1.1 mmol) 6-chloro-pyrazine-2-carboxylic acid, 0.15 g (1.1 mmol) 5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEA in 3.0 mL DMF were mixed with 0.39 g (1.2 mmol) TBTU and stirred for 1 h at RT. The reaction mixture was mixed with water and stirred for 5 min. The precipitated solid was filtered, washed with water and dried.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH2:27][C:28]([C:31](O)=[O:32])=[N:29][N:30]=2)[CH:21]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:31]([C:28]3[CH:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[NH:30][N:29]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Reactant: Cc1c(-c2ccn(C[C@@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccn(C[C@@H](C)NC(=O)c3cc(-c4cccnc4)[nH]n3)n2)ccc(C#N)c1Cl
Yield: 43.9 %

Procedure:
The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.3 g, 1.092 mmol), 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.227 g, 1.201 mmol), DIPEA (0.285 ml, 1.638 mmol), HOBt (0.221 g, 1.638 mmol) and EDCI (0.314 g, 1.638 mmol) using the method of Example 34(d) affording 0.214 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.15-1.21 (m, 3H), 2.54 (s, 3H), 4.28-4.41 (m, 2H), 4.45-4.54 (m, 2H), 6.61 (d, 1H), 7.22 (d, 1H), 7.45-7.52 (m, 1H), 7.62-7.70 (m, 1H), 7.76-1.86 (m, 2H), 8.09-8.18 (m, 1H), 8.25-8.47 (m, 1H), 8.53-8.57 (m, 1H), 8.99 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18].C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O>[CH3:18][C:17]1[O:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([CH:2]=[O:1])[C:4]=2[CH:5]=[CH:6]1
Reactant: Cc1oc(-c2ccccc2)nc1Cn1ccc2c(CO)cccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)nc1Cn1ccc2c(C=O)cccc21
Reaction time: 0.5 h

Procedure:
There were dissolved, in 14 ml of dimethylsulfoxide, 700 mg of 4-hydroxymethyl-1-[(5-methyl-2-phenyloxazol-4-yl)methyl]indole prepared in Example 29 and 890 mg of triethylamine, followed by addition of 700 mg of sulfur trioxide-pyridine complex to the solution and stirring for 30 minutes. The reaction solution was added to 100 ml of a 10% ammonium chloride aqueous solution, followed by extraction with ethyl acetate (50 ml×3). The resulting organic phase was washed, in turn, with water (50 ml×2) and 50 ml of a saturated common salt solution and dried over anhydrous sodium sulfate. After removal of the solvent through distillation under reduced pressure, the resulting residue was crystallized in 50 ml of ether to thus give 640 mg of 1-[(5-methyl-2-phenyloxazol-4-yl)methyl]indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 84%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[CH3:6])[CH3:2].Br[C:26]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=1[CH:28]=[O:29]>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:7]1[CH:8]=[C:9]([C:26]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=2[CH:28]=[O:29])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:10]([C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)[S:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(C#N)c3)cs2)CC1
Yield: 50.7 %

Procedure:
A solution of 3-(2-bromo-1,3-thiazol-4-yl)benzonitrile (990 mg, 4.90 mmol), tert-butyl piperazine-1-carboxylate (1.37 g, 7.34 mmol) and potassium carbonate (677 mg, 4.90 mmol) in dimethylformamide (16 ml) was stirred at 120° C. for 6 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 920 mg (50.7%) of the desired product as a solid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][NH2:14])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)[CH3:11]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCC(CC)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCC(CC)CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of cyanuric chloride (0.2 mol, 36.8 g) in acetone (300 ml) is introduced dropwise into crushed ice (100 g) in a round-bottom flask, with vigorous stirring, followed by a solution of 2-ethylhexylamine in acetone (100 ml), while maintaining the temperature between 0° and 5° C., and finally a solution of sodium carbonate (11.2 g, 0.1 mol) in 300 ml of water. The mixture is left stirring for one hour at 0°-5° C. The oil is extracted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate. After evaporation of the solvent, 2-(2-ethylhexylamino)-4,6-dichloro-s-triazine (52 g, yield=95%) having the following characteristics, is obtained:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:9]2[CH2:13][C@@H:12]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[C@@H:11]([OH:28])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:36]N(C)C=O.CI>C(#N)C.[Ag]=O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:13][C@@H:12]([NH:14][C:15](=[O:27])[C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=3)[C@@H:11]([O:28][CH3:36])[CH2:10]2)=[CH:34][CH:33]=1
Reactant: O=C(N[C@@H]1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C[C@@H]1O)c1ccc(OC(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: O=[Ag]
Solvent: CC#N
Solvent: CI
Product: CO[C@H]1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C[C@H]1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 51 %

Procedure:
To a solution of (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (75.6 mg, an optical isomer of the compound obtained in Example 2) in acetonitrile (8 mL)/dimethylformamide (2 mL) was added successively methyl iodide (233 μL) and silver oxide (216.8 mg) and the mixture was stirred at room temperature for 23 hours. The reaction mixture was filtered through Cerite, washed with acetonitrile and evaporated in vacuo. The crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=4:1→2:1) to give (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[[4-(trifluoro-methoxy)benzoyl]amino]pyrrolidine (39.5 mg; yield: 51%) as an amorphous powder.