Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[CH:27]1([S:33][CH2:34][CH2:35]Cl)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.CO>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:35][CH2:34][S:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reaction time: 20 h
Yield: 53 %

Procedure:
A stirred mixture of 0.54 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate, 0.295 g of 2-chloroethyl cyclohexyl sulfide, 0.23 g of potassium carbonate, and 0.27 g of potassium iodide in 9 cm3 of acetonitrile and 1 cm3 of methanol was brought to a temperature in the region of the boiling point under an inert atmosphere for 20 hours. The reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under an argon pressure of 80 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 35 cm), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and 35-cm3 fractions were collected. Fractions 23 to 40 were combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.4 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylate was obtained in the form of a lacquer with a brown color.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:6][CH2:5][C:4]([CH2:15]O)=[CH:3]1.C(O)(=O)CC.[C:23]([O-])([O-:28])([O:25][CH2:26][CH3:27])[CH3:24]>>[CH2:26]([O:25][C:23](=[O:28])[CH2:24][CH:3]1[C:4](=[CH2:15])[CH2:5][CH2:6][C@H:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[C:2]1([CH3:17])[CH3:1])[CH3:27]
Reactant: CC1(C)C=C(CO)CC[C@@H]1OC1CCCCO1
Reactant: CCOC(C)([O-])[O-]
Solvent: CCC(=O)O
Product: C=C1CC[C@H](OC2CCCCO2)C(C)(C)C1CC(=O)OCC
Temperature: 140 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Compound (9) (9.45 g, 39.3 mmoles) and propionic acid were dissolved in newly distilled ethyl ortho-acetate (51.0 g, 314 mmoles). The solution was stirred at 140° C. for 6 hours while distilling off ethanol. Ethyl ortho-acetate was removed from the resulting reaction mixture, and the residue was concentrated. After cooling, the residue was diluted with ether. The ether solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (200 g of silica gel; n-hexane/ethyl acetate) to give a compound (10) as a mixture of the (1S,3S)-isomer and (1R,3S)-isomer (11.7 g, 37.7 mmoles, yield 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])=[C:10]2[C:6]=1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2c(C)ccc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.7 %

Procedure:
To a mixed solution of ethyl 7-amino-4-methyl-1H-indole-2-carboxylate (0.71 g) and pyridine (20 mL) was added 2-thiophenesulfonyl chloride (0.78 g) under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-20:80), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (957 mg, yield 81%) as colorless needle crystals. melting point 180-181° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>O>[OH:26][CH:22]1[CH2:23][CH2:24][CH2:25][N:20]([S:17]([C:4]2[S:3][CH:2]=[C:6]([C:7]3[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=3[CH3:16])[CH:5]=2)(=[O:19])=[O:18])[CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCCC(O)C3)sc2Br)s1
Agent: [Li]CCCC
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCCC(O)C3)c2)s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
N-(5-{2-bromo-5-[(3-hydroxypiperidin-1-yl)sulfonyl]-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide obtained in Step I as described above (54 mg; 0.112 mmol; 1 eq), is dissolved in dry TBF (5 ml) at −70° C. under an inert atmosphere. n-Butyllithium (0.15 ml; 1.6 M; 0.24 mmol; 2.20 eq) is added slowly and reaction stirred at −70° C. for 1 hour before being hydrolyzed with water (0.3 ml). Reaction is warmed up to room temperature before being concentrated to dryness. Residue is taken up with water (2 ml) and EtOAc (10 ml). The organic phases are decanted, dried over MgSO4, filtrated and evaporated. Title compound is purified by reverse preparative HPLC, affording expected Compound (48) as a white solid (20 mg; 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[S:5].C(Cl)(=O)C([Cl:15])=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[S:5]
Reactant: Cc1ccc(Cl)c(C(O)=S)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(C(=S)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-5-methylthiobenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 2-chloro-5-methylthiobenzoyl chloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: Oc1ccccc1
Reactant: CC(C)CCC(=O)Cl
Solvent: O
Product: CC(C)CCC(=O)Oc1ccccc1
Reaction time: 3 h
Yield: 88 %

Procedure:
4-Methylpentanoyl chloride (3.0 g, 22.3 mmol) was added dropwise to phenol (2.1 g, 22.3 mmol). After 3 hours, H2O was added and the reaction mixture was extracted with Et2O. The organic phase was washed with NaHCO3, then brine to neutrality, then dried (Na2SO4), concentrated and bulb-to-bulb distilled to afford the title compound in 88% yield.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1sccc1C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccsc1C
Temperature: 25 °C
Reaction time: 20.25 h

Procedure:
To a solution of 3.30 g (23.2 mmol) of 2-methyl-3-thiophenecarboxylic acid in 100 ml of acetone was added 16.04 g (116.1 mmol) of anhydrous potassium carbonate and 16.47 g (7.2 ml, 116.1 mmol) of methyl iodide. The reaction mixture was allowed to stir at room temperature for 20.25 hours. A white precipitate formed. The white precipitate was filtered, washed with ethyl ether and discarded. The filtrate was concentrated in vacuo, partitioned between 250 ml of water and 250 ml of pentane and the layers separated. The organic phase was washed with a saturated solution of Na2 SO3, dried over Na2SO4, filtered and concentrated by rotary evaporation to give the title compound as a yellow oil which was used without further purification.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[C:11](=[O:12])([O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:13][CH2:14][CH3:15]
Reactant: OC1CCCCCCC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)OC1CCCCCCC1

Procedure:
The product was obtained similarly as in Example 1 by reacting cyclooctanol with ethyl chloroformate and a colorless liquid was obtained.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].CC([NH:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])=O.O>COCCO>[CH2:2]([S:4][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([CH:14]=1)[NH2:8])[CH3:3]
Reactant: CCS
Reactant: CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: COCCO
Product: CCSc1ccc([N+](=O)[O-])c(N)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
Sodium (2.76 g.) was added to dry 2-methoxyethanol (75 ml.) and the solution was cooled to 0°-5° C. Ethanethiol (8.72 g.) in 2-methoxyethanol (10 ml.) was added during 5 minutes and the subsequent solution was stirred at 0°-5° C. for 10 minutes and then added in portions to a solution of 5-chloro-2-nitro acetanilide (21.5 g.) in boiling 2-methoxyethanol (150 ml.) during 10 minutes. After 3 hours the mixture was cooled and poured into water (1 l.). The mixture was stirred and cooled to 10° C. The solid which formed was collected by filtration, washed with water, and recrystallized from ethanol to give 5-ethylthio-2-nitroaniline (16.4 g.), m.p. 75°-6° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH:33]C=O)[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[S:21][N:20]=[C:19]([CH3:22])[N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CO>[CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[S:21][N:20]=[C:19]([CH3:22])[N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nc(C)ns3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nc(C)ns3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.2 g.), conc. hydrochloric acid (0.8 ml.) and methanol (16 ml.) was stirred for 3 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (pH 7.5). The aqueous solution was adjusted to pH 3.5 with 10% hydrochloric acid and stirred for 1 hour. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.35 g.).
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:12]([O-])=O)=[C:5]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[NH2:6].N1C=CC=CC=1.[C:21](Cl)(=O)[CH:22]([CH3:24])[CH3:23].C(O)C>Cl.[Pd]>[OH:2][C:3]1[C:4]2[NH:12][C:21]([CH:22]([CH3:24])[CH3:23])=[N:6][C:5]=2[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: COc1cc(N)c([N+](=O)[O-])c(OC)c1
Reactant: CC(C)C(=O)Cl
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)c1nc2cc(O)cc(O)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dimethoxy-2-nitroaniline (55.0 g, 321 mmol) and pyridine (400 mL) was added isobutyryl chloride (41.0 mL, 391 mmol). After stirring for 16 hours, the reaction mixture was concentrated in vacuo. The resulting oil was partitioned between H2O (200 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with more ethyl acetate (2×200 mL). The organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated. The solid was recrystallized from hexane/ethyl acetate at 5° C. to afford yellow crystals. To a slurry of the yellow crystals, 4N HCl (200 mL) and ethanol (250 mL) was added 10% Pd/C (1.30 g). The slurry was placed under 50 psi of H2 (g) and shaken for 4 hours. The mixture was then filtered and concentration of the filtrate afforded a white solid. The white solid was dissolved in 2N HCl (200 mL) and refluxed for 4 hours. The reaction mixture was concentrated. The resulting solid was dissolved in 48% HBr (100 mL) and H2O (100 mL) and refluxed for 15 hours. The reaction was then cooled to ambient temperature and concentrated. The solids were dissolved in H2O (200 mL) and neutralized (KHCO3). The aqueous layer was then extracted with n-butanol (3×500 mL). The organic layer was washed with brine (50 mL), treated with activated charcoal and concentrated to afford 4,6-dihydroxy-2-isopropylbenzimidazole, a compound of formula (11).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][C:3]=1[O:22][CH3:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NC2CCNCC2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of 1,1-dimethylethyl 4-{[4-fluoro-3-(methyloxy)phenyl]amino}-1-piperidinecarboxylate (D9) (1.45 g, 4.48 mmol) in DCM (16 ml) was cooled in an ice bath and TFA (4 ml) was added. The reaction mixture was stirred for 1 h, then warmed to room temperature and stirred for 2 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with further saturated aqueous NaHCO3 solution. The aqueous was concentrated to ˜50% volume, further basified with 2M NaOH solution and extracted with EtOAc (×2). All organic phases were combined and washed with further 2M NaOH solution, dried and concentrated to give the title compound as an orange gum (1 g). δH (DMSO-d6, 400 MHz) 6.86 (1H, dd), 6.33 (1H, dd), 6.03 (1H, m), 5.32 (1H, d), 3.74 (3H, s), 3.33 (1H, br s), 3.18 (1H, m), 2.92 (2H, m), 2.51 (2H, m), 1.83 (2H, m), 1.17 (2H, m). MS (ES): MH+ 225.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1)(=[O:9])=[O:8].C(N(CC)CC)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][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:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:19])=[CH:13][CH:12]=1)(=[O:8])=[O:9]
Reactant: C1COCCN1
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CC(=O)O)cc2)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(CC(=O)N3CCOCC3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
To a solution of {4-[(2,4-dimethoxybenzylsulfamoyl)methyl]phenyl}acetic acid (356 mg) in DMF (15 ml) were added triethylamine (237 mg), morpholine (97 mg) and HATU (392 mg). The mixture was stirred at room temperature for 17 h, then added to water (200 ml) and extracted with ethyl acetate. After washing with water, 1 M hydrochloric acid, sodium hydrogencarbonate solution and sodium chloride solution, the organic phase was dried over magnesium sulfate and concentrated. This gave the product (313 mg) with a molecular weight of 448.5 g/mol (C22H28N2O6S).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:26](Br)[C:27]#[CH:28]>>[CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:28][C:27]#[CH:26])[CH2:4]1
Reactant: C#CCBr
Reactant: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCNC1
Product: C#CCN1CCC(OC)(c2cccc(OCc3ccc4ccccc4c3)c2)C1
Yield: 11 %

Procedure:
Using an analogous procedure to that described in Example 3, 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine was reacted with prop-2-ynyl bromide to give 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]-1-(prop-2-ynyl)pyrrolidine, m.p. 63°-65° C., in 11% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:38])[C@@H:15]([N:23](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:38])[C@@H:15]([NH2:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1

Procedure:
Add 2-(R)-(2-(S)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-piperidine-1-carboxylic acid tert-butyl ester (0.107 g, 0.21 mmol), 20% palladium hydroxide on carbon (60 mg) and methanol (5 mL) and stir 18 h under 1 atmosphere of hydrogen gas. Add filter agent, filter and concentrate to give the title compound as a foam.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:44][CH3:45])[C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:51])([F:50])[F:52])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:44][CH3:45])[C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(C(=O)CCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
Ethyl 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoate (140 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoic acid (137 mg). MS (m/z): 750 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([OH:33])[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CS(C)=O.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([O:33][C:11]2[C:10]([F:14])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=2)[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1cc(F)c(F)cc1F
Reactant: CC(C)COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(Oc2cnc(OCC(C)C)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2,4,5-trifluorobenzoate (135 mg, 0.661 mmol) and potassium carbonate (156 mg, 1.129 mmol) were dissolved in DMSO (3.0 mL). 5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 127.5 mg, 0.632 mmol) was added portion wise and the mixture was stirred at room temperature for 2 hours. The reaction was diluted in EtOAc (10.0 mL) and washed with brine (3×10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0 to 10% EtOAc in heptane to yield the title compound as a clear oil that solidified upon standing (155 mg, 35%):
Reaction SMILES: FC1C(C)=NC2C(N=1)=C([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)C=CC=2.NC1CCCCC1O>>[NH:20]1[C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=[CH:12]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: NC1CCCCC1O
Product: O=C1NCCc2[nH]ccc21
Temperature: 100 °C
Yield: 24 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and 2-aminocyclohexanol (37.0 mg, 0.324 mmol, TCI America, Portland, Oreg.; mixture of racemic cis- and trans-isomers) and heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2434(2-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (24% yield; mixture of racemic cis- and trans-isomers). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.50 (m, 2H) 1.54-1.86 (m, 6H) 2.56 (s, 3H) 2.88 (t, J=6.85 Hz, 2H) 3.44 (td, J=6.75, 2.15 Hz, 2H) 4.08 (br. s., 2H) 4.84 (br. s., 1H) 6.23 (d, J=7.04 Hz, 1H) 6.89 (br. s., 1H) 7.14 (d, J=2.15 Hz, 1H) 7.32 (t, J=7.82 Hz, 1H) 7.56 (d, J=6.85 Hz, 1H) 7.86 (d, J=6.26 Hz, 1H) 11.86 (br. s., 1H). MS (ESI, pos. ion) m/z: 392.3 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>C(O)(=O)C>[F:17][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[S:13]([NH2:16])(=[O:15])=[O:14])[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(F)c(S(N)(=O)=O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2c(cc1F)CCN2
Temperature: 100 °C
Yield: 99.5 %

Procedure:
A mixture of 3.6 grams of 1-Acetyl-5-fluoro-2,3-dihydro-1H-indole-6-sulfonic acid amide and 30 ml of 2N sodium hydroxide was heated at 100° C. for 3 hours. The reaction was cooled and the pH was adjusted to 7.0 with acetic acid. The resulting precipitate was filtered to give 3.0 grams of the titled compound.