Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cncc(Cl)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cncc(Cl)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 174.7 %

Procedure:
To a solution of tert-butyl ({1-[(5-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (391 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 298 mg, 95%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1>CO.ClCCl.[Pd]>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=c1c2cc(Cc3cccnc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reaction time: 8 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.12 mmol) in 1 mL of methanol and 1 mL of dichloromethane was added palladium on carbon (10 mg, 0.094 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 8 h and was then filtered through a pad of Celite, which was washed with MeOH. The filtrate was concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 388.1657 for [M+H]+ [Calc'd for C23H22N3O3, [M+H]+=388.1656]: 1H NMR (400 MHz, d6-DMSO) δ 9.96 (d, J=7.5 Hz, 1H), 8.79 (s, 1H), 8.68 (s, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.15-8.02 (m, 2H), 8.02 (s, 1H), 7.77-7.70 (m, 3H), 4.68 (s, 2H), 4.68 (br s, 1H), 4.13-4.00 (m, 1H), 3.98-3.89 (m, 2H), 3.44-3.38 (m, 1H), 3.13-3.07 (m, 2H), 2.22-2.19 (m, 1H), 1.86-1.83 (m, 1H).
Reaction SMILES: C1(O)C=CC=CC=1.C1(S)C=CC=CC=1.C[O:16][C:17]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:18]=1[C:28]1[N:29]=[N:30][C:31]([O:34][CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[CH:32][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[N:23]1([C:21]2[CH:20]=[CH:19][C:18]([C:28]3[N:29]=[N:30][C:31]([O:34][CH:35]4[CH2:39][CH2:38][NH:37][CH2:36]4)=[CH:32][CH:33]=3)=[C:17]([OH:16])[CH:22]=2)[CH:27]=[CH:26][CH:25]=[N:24]1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNC2)nn1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN1CCCC1=O
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNC2)nn1
Yield: 107 %

Procedure:
Following GENERAL METHOD 3-1 for phenol deprotection using thiophenol, 3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(pyrrolidin-3-yloxy)pyridazine (91 mg, 0.24 mmol) was treated with thiophenol (30 mg, 0.27 mmol) and K2CO3 (30 mg, 0.22 mmol) in NMP (1.6 mL) for 15 min at 190° C. After HPLC purification (0.1% trifluoroacetic acid as modifier), the product-containing fractions were free based by catch and release using SiliaBond Propylsulfonic Acid® (2 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). Solvent was concentrated under reduced pressure and a pale brown solid (83 mg, 68%) was afforded. LCMS Rt=0.48 min (LCMS method Q); [M+H]: 324.1457; 1H NMR (400 MHz, CHLOROFORM-d) δ 13.62 (bs, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.5 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.39-7.43 (m, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 6.44-6.51 (m, 1H), 5.74 (ddt, J=7.0, 5.0, 2.5 Hz, 1H), 3.24-3.31 (m, 2H), 3.17-3.24 (m, 1H), 3.02 (ddd, J=11.0, 8.5, 5.5 Hz, 1H), 2.20-2.33 (m, 1H), 2.02-2.11 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([C:27]([F:30])([F:28])[F:29])[CH:16]=2)=[N:22]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Triethylamine (0.17 g, 1.7 mmol) and ethyl isocyanate (0.12 g, 1.7 mmol) were added to a solution of 3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole (0.42 g, 1.5 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-ethyl-3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.42 g, yield: 80.1%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.2 Hz, 3H), 2.59 (d, J=0.8 Hz, 3H), 3.38 (dq, J=5.9 and 7.2 Hz, 2H), 5.73 (q, J=0.8 Hz, 1H), 6.91 (br s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.49 (dd, J=2.4 and 8.8 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H).
Reaction SMILES: [C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([OH:15])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:20](#N)[CH3:21].C(N(CC)CC)C.C(OC(OCC)=O)(=O)OCC>C(OCC)(=O)C>[C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1C
Reactant: CC#N
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCC(=O)c1cc2nc(C(=O)OCC)n(C)c2cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylic acid are introduced, in the course of 15 minutes, into a mixture of 150 ml of acetonitrile, 15 ml of triethylamine and 18.5 g of diethyl pyrocarbonate, while stirring at room temperature. The mixture is left to stand overnight, the acetonitrile is stripped off under reduced pressure, the residue is taken up in ethyl acetate and the resulting solution is washed with water, dried over sodium sulphate and evaporated to dryness. Ethyl 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate, which is initially obtained as an oil but soon crystallises, is filtered off. When recrystallised from ethyl acetate/cyclohexane, it melts at 106°-108°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:12]C(=O)[NH:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)[OH:12]
Reactant: O=C1NC(Cc2ccc(F)cc2)C(c2ccc(C(F)(F)F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Yield: 84.8 %

Procedure:
To a solution of (4RS,5SR)-4-((4-fluorophenyl)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3-oxazolidin-2-one (18 g, 53.1 mmol) in ethanol (300 ml) was added 8N aqueous sodium hydroxide solution (19.9 ml, 159 mmol), and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (300 ml), and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (14.1 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:18]3[C:19]4[C:11](=[N:12][NH:13][C:14]=4[N:15]=[C:16]([S:20][CH3:21])[N:17]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1.[Na+].[I-]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:36]([N:13]1[C:14]2=[C:19]3[C:18](=[N:17][C:16]([S:20][CH3:21])=[N:15]2)[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=2)[CH2:9][CH2:10][C:11]3=[N:12]1)[C:33]1[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(CN2CCc3n[nH]c4nc(SC)nc2c34)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCc3nn(Cc4ccccc4)c4nc(SC)nc2c34)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-methoxybenzyl)-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene (4.32 g, 13.22 mmol) in DMF (160 mL) was added Cs2CO3 (21.48 g, 66.11 mmol), BnBr (1.88 mL, 15.86 mmol) and NaI (0.5 g). The mixture was stirred at room temperature for 16 h. Ethyl acetate (250 mL) and water (150 mL) was added. The EtOAc layer was separated, washed with aqueous NaCl (3×150 mL), dried over Na2SO4, filtered and concentrated. The obtained residue was purified by flash silica gel chromatography (eluent: 50% then 60% EtOAc in hexane). Compound 129, 1-benzyl-5-(4-methoxybenzyl)-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene was obtained as a pale yellow solid (2.15 g, 39%). M.p. 168-170° C.; 1H NMR (CDCl3, 400 MHz) δ 7.31 (m, 5H), 7.25 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 5.42 (s, 2H), 4.76 (s, 2H), 3.79 (s, 3H), 3.52 (t, J=6.4 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 2.62 (s, 3H). LC-Mass (m/e): 418.57 (M+1) and compound 129a, 1-benzyl-6-(4-methoxybenzyl)-4-(methylthio)-1,6,7,8-tetrahydro-1,2,3,5,6-pentaazaacenaphthylene was obtained as a pale yellow solid (2.35 g, 42%). M.p.>50° C.; 1H NMR (CDCl3, 400 MHz) δ 7.29 (m, 5H), 7.22 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 4.71 (s, 2H), 3.78 (s, 3H), 3.47 (t, J=6.0 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.61 (s, 3H). LC-Mass (m/e): 418.57 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[Cl:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:29])[CH2:27]Br)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:29])[CH2:27][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[C:5]([Cl:11])[CH:6]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Yield: 100 %

Procedure:
2-Chloro-4-hydroxy-benzoic acid methyl ester from example E41b (2.0 g, 10.9 mmol) and 4-(2-Bromo-acetyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E41a (3.68 g, 12.0 mmol) in acetonitrile (30 ml) were treated with potassium carbonate (1.6 g, 11.5 mmol), and the mixture heated at reflux 18 h. before the solvents were removed in vacuo. The residue was adsorbed onto silica gel and purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% cyclohexane to 50% EtOAc:50% cyclohexane to 70% EtOAc:30% cyclohexane) to yield the title compound (4.5 g, 100%).
Reaction SMILES: [CH:1]12[N:9]([C:10]3[C:29](Br)=[CH:28][C:13]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=4)=[O:15])=[CH:12][N:11]=3)[CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][O:3][CH2:2]2.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[CH:1]12[N:9]([C:10]3[C:29]([C:35]4[CH:36]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:28][C:13]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=4)=[O:15])=[CH:12][N:11]=3)[CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][O:3][CH2:2]2
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C3COCC2COC3)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C3COCC2COC3)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 133 using 6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 150.1) and pyrimidin-5-ylboronic acid to afford a solid. HPLC (Condition 4) tR=5.08 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=488.2 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:3]1([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4]1=[O:21])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:34][C:35]1[CH:36]=[C:37]([NH:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][CH:47]=2)=[O:44])[CH:38]=[CH:39][C:40]=1[F:41]>O1CCOCC1.O.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>[F:34][C:35]1[CH:36]=[C:37]([NH:42][C:43](=[O:44])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[C:4](=[O:21])[C@@:3]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:1][CH3:2])[CH2:12][CH2:11]4)=[CH:50][CH:51]=2)[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: CCOC(=O)C[C@]1(CC)CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1=O
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccc(F)c(F)c3)cc2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC[C@@]1(CC(=O)OC)CCc2cc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3)ccc2C1=O
Yield: 40 %

Procedure:
Pd(PPh3)4 (0.018 g, 0.015 mmol) was added to a solution of (S)-ethyl 2-(2-ethyl-1-oxo-6-(trifluoromethylsulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)acetate (129C, 0.3 g, 0.761 mmol) in 10 mL 1,4 dioxane-H2O (4:1) mixture under argon atmosphere, followed by cesium carbonate (0.74 g, 2.28 mmol) and Example 217B (0.313 g, 0.837 mmol). The reaction mixture was degassed for 30 min. The reaction mixture was refluxed for 12 h, and solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography using 20% ethyl acetate in hexane to afford title compound (0.15 g, 40%) as solid. 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 8.03 (s, 1H), 7.44-7.37 (m, 3H), 7.35-7.31 (m, 4H), 7.18 (m, 1H), 7.08-6.97 (m, 2H), 3.67 (s, 3H), 3.14 (m, 1H), 3.04 (d, J=16 Hz, 1H), 2.90 (m, 1H), 2.5 (d, J=16 Hz, 1H), 2.45 (m, 1H), 2.05 (m, 1H), 1.79-1.6 (m, 2H), 0.94 (t, J=7.6 Hz, 3H); ESI-MS m/z=493 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[N+:19]([O-])=O)[CH2:5][CH2:4]1>[Pd].CO>[NH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=1[N:6]1[CH2:5][CH2:4][CH:3]([N:2]([CH3:22])[CH3:1])[CH2:8][CH2:7]1
Reactant: CN(C)C1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1CCN(c2ccc(C(F)(F)F)cc2N)CC1
Reaction time: 96 h

Procedure:
To N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-4-amine (3.4 g, 11 mmol) was added Pd/C (10%, 0.57 g) under nitrogen. Methanol (25 mL) was added via syringe, and H2 gas was introduced and the mixture stirred vigorously under an atmosphere of H2. After 96 h, the mixture was flushed with nitrogen, filtered through celite and concentrated. The residue was resubjected to the reaction conditions. After 12 h, the reaction was flushed with nitrogen, filtered through celite and concentrated. The resulting solid was triturated with methanol ten times to give the title compound as a pink solid. MS (m/z): 288.2 (M+H)+. Calc'd for C14H20F3N3: 287.32.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:25])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1

Procedure:
According to Preparation 2: Tert-butyl 4-[2-fluoro-3-(trifluoro-methyl)phenyl]-4-hydroxypiperi-dine-1-carboxylate (3.1 g, 8.5 mmol, methylen chloride (20 ml), trifluoroacetic acid (2 ml). Yield: 0.62 g. MS m/z (rel. intensity, 70 eV) 263 (M+, 22), 245 (96), 244 (44), 191 (25), 56 (bp).
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.Br[CH2:16][C:17](=[O:24])[C:18]([CH2:22][F:23])([CH3:21])[CH2:19][F:20].[Cl-].[NH4+]>C(OCC)C>[F:20][CH2:19][C:18]([C:17]1([C:5]2[S:4][CH:3]=[N:7][CH:6]=2)[CH2:16][O:24]1)([CH3:21])[CH2:22][F:23]
Reactant: C[Si](C)(C)c1nccs1
Reactant: CC(CF)(CF)C(=O)CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(CF)(CF)C1(c2cncs2)CO1
Temperature: 25 °C

Procedure:
To 2.00 g (12.7 mmol) of 2-trimethylsilyl-1,3-thiazole dissolved in 20 ml of diethyl ether were added, at −78° C. under an argon atmosphere, 5.1 ml (2.5 M, 12.7 mmol) of n-butyllithium, and the reaction mixture was stirred at −78° C. for 20 min. Then 2.73 g (12.7 mmol) of 1-bromo-4-fluoro-3-(fluoromethyl)-3-methylbutan-2-one were added and the reaction mixture was gradually warmed to room temperature. After addition of saturated aqueous ammonium chloride solution, the phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was then purified by column chromatography (5:1 cyclohexane/ethyl acetate). This gave 2.39 g (86%) of the desired product.
Reaction SMILES: CS(O[CH2:6][C@:7]1([CH3:19])[CH2:11][C:10]2[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1)(=O)=O.[C:20]1([CH:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:19][C@@:7]1([CH2:6][N:31]2[CH2:32][CH2:33][CH:28]([NH:27][CH:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:29][CH2:30]2)[CH2:11][C:10]2[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Reactant: Cc1cc(C)c2c(c1C)O[C@](C)(COS(C)(=O)=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C)c2c(c1C)O[C@](C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 177 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A suspension of (S)-(2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl methanesulfonate (0.34 g), N-(diphenylmethyl)-4-piperidinamine (0.73 g), and potassium carbonate (0.38 g) in N,N-dimethylacetamide (2 mL) was stirred under argon gas at 177° C. for 6 hours. This reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and extracted with 1N-hydrochloric acid. The aqueous layer was made basic with 2N-sodium hydroxide/water and extracted with diisopropyl ether. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to provide the title compound (0.49 g). Yield 79%.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].[CH2:53]([C:55]1[CH:56]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:57][C:58](=[O:60])[CH:59]=1)[CH3:54].CC(O)(C)C>C1(C)C=CC=CC=1.[Cu]Cl>[CH2:53]([C@@H:55]1[CH2:59][C@H:58]([OH:60])[CH2:57][C@@H:56]1[C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH3:54]
Reactant: CCOC(=O)C1CC(=O)C=C1CC
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1C[C@@H](O)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.8 %

Procedure:
A mixture of copper (I) chloride (0.136 g, 1.37 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.854 g, 1.37 mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was stirred at ambient temperature for about 15 min then cooled to about 5° C. and polymethylhydrosiloxane (12 mL, 55 mmol) was added. The reaction mixture was stirred for about 40 min at about 5° C. then cooled to about −12° C. A solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g, 27.4 mmol) and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added in one portion and the reaction mixture was stirred for about 16 h at about −12° C. The reaction mixture was quenched by the addition of MeOH (50 mL). The solvents were removed under reduced pressure. The residue was dissolved in MeOH (35 mL) and filtered through a pad of Celite®. The filtrate was concd under reduced pressure and the residue was triturated with EtOAc (100 mL) and filtered. The filtrate was concd under reduced pressure and the residue was purified using silica gel chromatography (280 g) eluting with a gradient of 0-10% EtOAc in heptane to give (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%): 1H NMR (CDCl3) δ 4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td, J=2.1, 7.1 Hz, 1H), 2.40 (dt, J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m, 3H), 1.52-1.31 (m, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)O)cc2)S1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)Cl)cc2)S1)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(2-((S)-1-(4-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzoic acid (0.48 g, 1.29 mmol) in CH2Cl2 (6 mL) was added thionyl chloride (Aldrich, 0.19 ml, 2.58 mmol), and 2 drops of DMF. After stirring the mixture overnight at ambient temp., the crude product was concentrated in vacuo and dried on high vacuum. The product was used in next step without purification.