Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)C.[Br:30]N1C(=O)CCC1=O>C(O)(=O)C>[Br:30][C:10]1[S:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])=[N:7][C:6]=1[CH2:5][C:4]([OH:3])=[O:29]
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)c(Br)s2)c(C(=O)C2CCCC2)c1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a suspension of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.20 g, 0.52 mmol) in 10 ml of acetic acid was added N-bromosuccinimide (0.10 g, 0.57 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was concentrated under reduced pressure, dissolved in DMSO and purified by preparative HPLC to afford the title compound (0.137 g, 57%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:10])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1.CN(C)[C@@H]1CCCC[C@H]1N>[Cu]I>[NH2:10][C:7]1[N:8]([C:18]2[CH:19]=[C:20]([OH:25])[CH:21]=[C:22]([CH3:24])[CH:23]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: Cc1cc(O)cc(Br)c1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Product: Cc1cc(O)cc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 140 °C
Yield: 49.2 %

Procedure:
5-tert-Butyl-2H-pyrazol-3-ylamine (1.11 g, 8.00 mmol), potassium carbonate (2.32 g, 16.8 mmol), copper (I) iodide (0.076 g, 0.40 mmol), and 3-bromo-5-methylphenol (1.80 g, 9.60 mmol) were weighed into a large microwave vial. This was then purged with argon then trans-N,N-dimethylcyclohexane-1,2-diamine (0.25 mL, 1.60 mmol) added. To this mixture was then added degassed toluene (8 mL). The mixture was then purged with argon again, the vial sealed, and heated for 1 h at 140° C. in the microwave, then a further 4 h at 135° C. The mixture was cooled, diluted with ethyl acetate and passed through a pad of celite/silica, washing with more ethyl acetate. The dark solution was concentrated in vacuo. The residue was purified by FCC, using 0-40% DCM in EtOAc, to give the title compound (966 mg, 49%). 1H NMR (300 MHz, CDCl3): 1.32 (9H, s), 2.24 (3H, s), 3.82 (2H, br s), 5.49 (1H, s), 6.45-6.52 (1H, m), 6.65-6.71 (1H, m), 6.85-6.91 (1H, m).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([OH:19])[CH:14]([N+:16]([O-])=O)[CH3:15])[CH:10]=[CH:9][N:8]=1>[Pd].C1COCC1.CO>[NH2:16][CH:14]([CH3:15])[CH:13]([C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:6][CH3:5])[CH:12]=1)[OH:19]
Reactant: COc1cc(C(O)C(C)[N+](=O)[O-])ccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(O)C(C)N)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonium formate (1.13 g, 18 mmol) and palladium on charcoal (10%, 175 mg) is added to a solution of 1-(2-methoxypyridin-4-yl)-2-nitro-propan-1-ol (760 mg, 3.6 mmol) in 17.5 ml THF and 17.5 ml methanol. The reaction mixture is stirred overnight at room temperature, filtered through a path of cellites and concentrated. Yield 620 mg of a racemic mixture of two diastereomers, 95%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH:14]([O:16][C:17]3[C:22]([CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:36]>CO>[ClH:36].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:13][CH:14]([O:16][C:17]3[C:22]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3C3CCN(C(=O)OC(C)(C)C)CC3)C2)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3C3CCNCC3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To tert-butyl 4-(2-(3-(4-methylphenylsulfonamido)cyclobutoxy)pyridin-3-yl)piperidine-1-carboxylate (501 mg, 1 mmol) was added 4 M HCl in MeOH (100 mL). The solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give 4-methyl-N-(3-((3-(piperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzenesulfonamide hydrochloride (381 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 402 calc. for C21H27N3O3S 401.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (189 mg, 1.06 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (300 mg, 0.97 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (213 mg, 2.13 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (330 mg, 87%) as a pale yellow solid: mp 178-179° C.; EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1230.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25]O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:1])[Cl:15])[CH:11]=[C:10]([Cl:12])[C:9]=1[O:13][CH2:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution of 0.30 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.16 g of 4-phenyl-1-butanol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.21 g of diethylazodicarboxylate dissolved in 5 ml of tetrahydrofuran was added dropwise, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.32 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-phenylbutyloxy)benzene (73% yield), nD26.0 1.5716.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:34])[CH:6]([N:14]2[CH2:19][CH2:18][C@@H:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:23]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1>C(#N)C>[ClH:1].[C:29]([CH2:28][CH2:27][N:24]1[CH:25]=[CH:26][C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:4][CH2:3]3)=[O:34])[CH2:19][CH2:18][C@H:17]\2[SH:20])=[N:23]1)([OH:31])=[O:30]
Reactant: CCOC(=O)CCn1ccc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CC[C@H]2S)n1
Agent: Cl
Solvent: CC#N
Product: O=C(O)CCn1ccc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CC[C@H]2S)n1
Yield: 92.1 %

Procedure:
(4R)-(E)-1-[(1RS)-2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-4-sulfanylpiperidine hydrochloride (424.2 mg) was subjected to the reaction similar to that described in Example 134 and the crude product thus obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 30/70, v/v) to afford the title compound (369 mg, yield: 92%) as a colourless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2sccc2c1
Reactant: O=C1CCC(=O)N1Br
Product: BrCc1ccc2sccc2c1

Procedure:
5-Bromomethylbenzo[b]thiophene was prepared from 5-methylbenzo[b]thiophene and N-bromosuccinimide as in Example 1 except that the reaction was refluxed 15 hours.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].[NH2:9][C:10]([NH2:12])=[O:11].C1C=CC=CC=1>C(OCC)(=O)C>[C:10]([N:12]1[CH2:7][CH2:6][CH:2]([Br:1])[C:3]1=[O:4])(=[O:11])[NH2:9]
Reactant: NC(N)=O
Reactant: O=C(Cl)C(Br)CCBr
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: NC(=O)N1CCC(Br)C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A solution of 30 g of 2,4-dibromobutyryl chloride (J. Med. Chem., p1995, 30. 1987) and 13.63 g of urea dissolved into 150 ml of benzene was heated at 90° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature, then a very excessive amount of ethyl acetate was added thereto. The layer of ethyl acetate was washed with an aqueous solution of sodium bicarbonate and saturated brine, then the resulting solution was dried over magnesium sulfate and evaporated. The obtained residue (28 g) was dissolved into 30 ml of tetrahydrofuran (THF) and cooled. To this mixture was added 4.7 g of NaH (55% in mineral oil) bit by bit, then the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to make the amount of the solution about 50 ml, then which was poured into ethyl acetate. The layer of ethyl acetate was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was washed well with n-hexane, whereby 15.7 g of the objective compound was obtained in 66% yield.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:28][C:27]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[N:26][C:25]=3[CH2:36][C:37](OC)=[O:38])=[O:23])=[CH:17][C:16]=2[O:41][CH3:42])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CC(C)=O.C(OCC)(=O)C>C1COCC1.O>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:28][C:27]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)=[N:26][C:25]=3[CH2:36][CH2:37][OH:38])=[O:23])=[CH:17][C:16]=2[O:41][CH3:42])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)Nc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 88 %

Procedure:
Charge to a flask under an inert atmosphere a 2 M THF solution of lithium borohydride (1140 mL, 2280 mmol) and apply ice bath cooling. Meanwhile in a separate vessel dissolve 3-(4-{[2-(4-chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (2058 g, 3500 mmol) in THF (12.35 L). Agitate until complete dissolution is obtained. Transfer this solution to an addition funnel and begin the slow stream addition to the reducing agent. Once the addition is complete, remove the ice bath and stir for 30-90 min. Quench the reaction by adding acetone (407 g, 7008 mmol). Stir at ambient temperature for 30 min and add ethyl acetate (8230 mL) with water (8230 mL). Separate the layers and wash the upper organic layer a second time with water (8230 mL) followed by 5% brine (8230 mL). Distill off the solvent until <5% solvent composition is THF, by adding EtOAc as needed. Reduce the volume of the slurry to 6200 mL and add heptane (2050 mL). Allow the slurry to slowly cool back to room temperature, filter the precipitate, wash with 1:1 heptane/ethyl acetate and dry to constant weight in a vacuum oven at 40° C. to obtain the title compound (88%). ES/MS m/z (35Cl) 560 [M+1]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].O.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:14]([O:13][CH:10]1[CH2:11][CH2:12][C:7]([C:36]2[C:31]([F:30])=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:8][CH2:9]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2cccnc2F)CC1
Temperature: 80 °C

Procedure:
To a sealable vessel was added 4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl trifluoromethanesulfonate (1.90 g, 5.27 mmol), sodium carbonate as a 2N solution in water (7.91 mL, 15.81 mmol), and 2-fluoropyridin-3-ylboronic acid (0.891 g, 6.33 mmol) before adding tetrakis(triphenylphosphine)palladium(0) (0.305 g, 0.264 mmol) under argon. The reaction mixture was sealed and set stirring at 80° C. After complete consumption of starting material, the black mixture was diluted with water before extracting with dichloromethane, drying over sodium sulfate, filtering, and concentrating under reduced pressure to an orange oil, which was used without purification. MS (ESI, pos. ion) m/z: 308.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=O)[CH:6]=[CH:5]2.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH:6]=[CH:5]2
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=Cc1ccc2cc(O)ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A mixture of 4 Å molecular sieves, 6-hydroxy-2-naphthaldehyde (1.0 g, 5.81 mmol), ethyl piperidine-4-carboxylate (0.91 g, 5.81 mmol), NaBH(OAc)3 (3.76 g, 17.43 mmol) and TsOH (0.1 g, 0.581 mmol) was stirred at rt for 2 h and then quenched with water (5 mL). The mixture was extracted with DCM (20 mL*2). The combined organics were washed with saturated brine (20 mL*3) and then concentrated. The white precipitates were filtered and dissolved in water (10 mL) and EtOAc (10 mL), NaHCO3 was added to adjust pH=8-9. The mixture was extracted with EtOAc (20 mL*2). The combined organics were washed with saturated brine (20 ml*2), dried over Na2SO4, concentrated and recystallized with EtOAc to give ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate as a white solid (0.83 g, yield: 41%), ESI-MS: 314.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.61-7.63 (m, 2H), 7.32-7.35 (m, 1H), 7.03-7.08 (m, 2H), 4.02-4.03 (q, J=7.2 Hz, 2H), 3.52 (s, 2H), 2.72-2.75 (m, 2H), 2.25-2.32 (m, 2H), 1.98-2.03 (m, 1H), 1.77-1.79 (m, 2H), 1.51-1.61 (m, 2H), 1.17 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O:38][C:39](=[O:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47](O)[CH3:48])=[CH:43][CH:42]=1)C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C@@H:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][C:39]([OH:50])=[O:38])=[CH:42][CH:43]=1)[CH3:48])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(C(C)O)cc1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: Oc1ccccc1
Product: C[C@@H](Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccc(CC(=O)O)cc1

Procedure:
The title compound was prepared using the procedure of example 69 using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol as the phenol and [4-(1-Hydroxy-ethyl)-phenyl]-acetic acid ethyl ester as the alcohol and isolated using chiral column chromatography. MS (ESI) m/z 540.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Si]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])(C(C)(C)C)(C)C.[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:31]([S:33][C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@H:29]1[CH2:53]I)=[O:27])[CH:23]=[CH2:24].C(OCC)(=O)C>O1CCCC1>[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:31]([S:33][C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@H:29]1[CH2:53][CH:18]1[CH2:19][CH2:20][NH:16][C:17]1=[O:21])=[O:27])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Reactant: CC(C)(C)[Si](C)(C)N1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1CCNC1=O
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
Lithium diisopropylamide (2.1M tetrahydrofuran solution, 6.45 ml, 13.5 mmol) was dropwise added to a solution of N-tert-butyldimethylsilyl-2-oxopyrrolidine (1.80 g, 9.03 mmol) in tetrahydrofuran (150 ml) at -78° C., and the mixture was stirred at the same temperature for 15 minutes. Then, a solution of (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (2.57 g, 4.5 mmol) in tetrahydrofuran (18 ml) was dropwise added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into a mixture of ethyl acetate (150 ml) and a 10% ammonium chloride aqueous solution (50 ml) for liquid separation. The organic layer was washed sequentially with a 10% sodium dihydrogen phosphate aqueous solution (100 ml) and a saturated sodium chloride aqueous solution (100 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (12 ml) and methanol (3 ml), and 6N hydrochloric acid (3 ml) was added thereto under cooling with ice. The mixture was stirred for 1 hour. Ethyl acetate (50 ml) was added to the reaction solution, and the organic layer was washed sequentially with a saturated sodium hydrogen carbonate aqueous solution (30 ml) and a saturated sodium chloride aqueous solution (30 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel flash column chromatography (Wakogel™ C-300, 40 ml, ethyl acetate-n-hexane 3:1) to obtain (2R,4S)-N-allyloxycarbonyl-2-(2-oxopyrrolidin-3-ylmethyl)-4-tritylthiopyrrolidine (880 mg, yield: 37%).
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][N:49]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[O:27])[CH2:48][CH2:47]2)=[CH:44][CH:45]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1CCNCC1)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.8 %

Procedure:
(1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 2; 10.0 g, 26.3 mmol), was dissolved in DMF (50 mL). DIPEA (16.0 mL, 92.0 mmol) and 4-(4-chlorophenyl)piperazine dihydrochloride (7.09 g, 26.3 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (300 mL) and washed with a 1 M aq Na2CO3 solution (6×200 mL), 10% citric acid solution (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a mixture of DCM (100 mL) and TFA (20 mL), stirred for 4 hours and then concentrated in vacuo. The residue was dissolved in 1 M aq Na2CO3 solution (220 mL), and extracted with DCM (3×200 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from EtOAc to give (1-piperidin-4-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate (4.07 g, 45.7%) as a cream solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([CH3:15])[C:9]([SH:14])=[CH:10][CH:11]=[CH:12][CH:13]=1>>[C:4]1([CH3:5])[CH:3]=[CH:2][CH:7]=[CH:6][C:15]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14]
Reactant: Cc1ccccc1S
Reactant: Ic1ccccc1
Product: Cc1ccccc1-c1ccccc1S

Procedure:
The general procedure was used to convert iodobenzene and o-toluenethiol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (383 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.20–6.98 (m, 9H; Ha, Hb, Hc, Hd, He, He′, Hf, Hf′, Hg), 2.27 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 139.90 (C8), 136.10 (C6), 133.70 (C1), 132.94 (C2), 130.54 (C5), 129.55 (C9, C13), 129.07, (C10, C12), 127.85 (C3), 126.66 (C11), 126.27 (C4), 20.54 (C7). Anal. Calcd. for C13H12S: C, 77.95; H, 6.04; S, 16.01; Found C, 78.02; H, 6.01; S, 16.01.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23]>>[CH3:28][O:27][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)cc(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine (150 mg, 0.578 mmol) and 3,5-dimethoxyaniline (95 mg, 0.621 mmol) similar to Example 160 and was isolated as off-white solid (119 mg, 0.316 mmol, 55%). 1H NMR (DMSO-d6): 10.31 (s, br, 1H), 8.80 (m, 2H), 8.17 (m, 2H), 7.17 (s, 1H), 7.04 (s, 2H), 6.32 (m, 1H), 3.80 (s, 6H), 3.53 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].Cl[CH2:35][CH2:36][O:37][CH3:38]>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:35][CH2:36][O:37][CH3:38])[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: COCCCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Product: COCCN1CC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=529.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and 2-chloroethyl-methyl-ether.