Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CCC(=O)O)c3)no2)cc1Cl
Reaction time: 3 h
Yield: 73.2 %

Procedure:
Ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoate (D5) (1.95 g, 4.29 mmol) was dissolved in ethanol. 2M NaOH (2.143 ml, 4.29 mmol) was added and the solution was stood at R.T. for 3 hours. Ethanol was evaporated and the mixture was dissolved in EtOAc and water and acidified with acetic acid. Organic layer was dried (MgSO4) and evaporated to give (1.34 g) of white solid. δH (d6-DMSO, 400 MHz): 1.37 (6H, d), 2.89 (2H, t), 4.65 (2H, t), 4.89 (1H, m), 7.45 (1H, d), 7.89 (1H, d), 8.06 (1H, d), 8.12 (1H, d), 8.20 (1H, s), 8.27 (1H, s), 8.55 (1H, s). MS (ES): C21H1935ClN4O4 requires 426; found 427 (MH+).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH2:18]([OH:21])[C:19]#[CH:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:21][CH2:18][C:19]#[C:20][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: CN1Cc2c(I)ncn2-c2ccccc2C1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CCO)ncn2-c2ccccc2C1=O

Procedure:
3.90 g (11.5 mmol) of 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 5 hours with 0.67 g (12 mmol) of propargyl alcohol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The solvent was then evaporated, the residue was taken up in methylene chloride, the solid was filtered off and rinsed with ethyl acetate. After drying there was obtained 4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 240°-241°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][CH3:30])[CH2:24]2)[CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:31])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][CH3:30])[CH2:24]2)[CH:3]=1
Reactant: CO[C@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Reactant: N
Product: CO[C@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 0.15 g racemic racemic 4-[4-Fluoro-2-((trans)-3-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (7 M in methanol).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.[Cl-].[NH4+]>CN(C)C=O>[CH:19]1([CH2:22][N:15]2[C:14](=[O:16])[O:13][N:12]=[C:11]2[C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=2)[CH2:21][CH2:20]1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1onc(-c2cc(C(F)(F)F)ccn2)n1CC1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.14 g of cyclopropylmethyl bromide was added, and the mixture was stirred at 80° C. for 6 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.13 g of 4-(cyclopropylmethyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (23)).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:5]([OH:26])[CH:4]=1)#[N:2].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:26][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:25]=[CH:24][C:6]=1[CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[F:19])[CH3:33]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1ccc(OC)cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C#N)ccc1CNC(=O)C(OCC)c1ccc(OC)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (example 110.3) was alkylated with ethyl bromoacetate/cesium carbonate in DMF to give (RS)-(5-cyano-2-{[2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetylamino]-methyl}-phenoxy)-acetic acid ethyl ester as a colorless solid. MS 443.4 ([M−H])
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:33]4[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=4)[O:25][C:26]4([CH2:31][CH2:30][O:29][CH2:28][CH:27]4I)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2]>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:33]4[CH:34]=[N:35][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:37][CH:38]=4)[O:25][C:26]4([CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)nc1)OC31CCOCC1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)nc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (3R,9S)-9-(tert-butyldimethylsilyloxy)-3′-iodo-4-isopropyl-7,7-dimethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]. 10% palladiumhydroxide on charcoal is used instead of 10% palladium on charcoal.
Reaction SMILES: [H-].[Na+].[N+]([C:6]1[CH:11]=C[C:9]([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:17][CH2:16]2)=[O:14])=[CH:8][CH:7]=1)([O-])=O.C1(O)CCCC1.O>O1CCCC1>[CH:9]1([O:12][C:13]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:19][CH2:20]2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:11]1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 6 mg, 0.15 mmol) was added to a solution of 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 4-nitro-phenyl ester (Example 123; 37 mg, 0.078 mmol) in anhydrous tetrahydrofuran (750 μL) under argon. Cyclopentanol (70 μL, 0.77 mmol) was added and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (sodium sulfate), filtered, evaporated, and purified on an Isco 4 g column, eluting with 0-4% methanol/dichloromethane to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (6 mg, 18%). Mass spectrum (ES) MH+=423.
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:24]1([CH2:29][O:30][C:31]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([F:43])[CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.N1(S(N)(=O)=O)CCC1.[CH:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1>C(OCC)C>[CH:24]1([CH2:29][O:30][C:31]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:34]([C:35]([NH:58][S:55]([CH:52]3[CH2:54][CH2:53]3)(=[O:57])=[O:56])=[O:37])=[C:33]([F:43])[CH:32]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCCC2)cc1F
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Solvent: CCOCC
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace azetidine-1-sulfonamide with cyclopropane-sulfonamide, the title compound was obtained as a colorless solid (0.039 g, 12%) after trituration in diethyl ether followed by trituration in methanol: 1H NMR (300 MHz, DMSO-d6) δ 11.81 (br s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.1 Hz, 1H), 3.97 (d, J=6.8 Hz, 2H), 3.13-3.02 (m, 1H), 2.41-2.26 (m, 1H), 2.08-1.95 (m, 1H), 1.85-1.72 (m, 2H), 1.68-1.49 (m, 4H), 1.44-1.31 (m, 2H), 1.15-1.07 (m, 4H), 0.93-0.85 (m, 2H), 0.71-0.64 (m, 2H); MS (ES−) m/z 380.2 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)=O>C(#N)C>[O:23]1[CH2:24][CH2:25][CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][CH2:22]1
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30.0 mg, 0.154 mmol), and tetrahydro-2H-pyran-4-yl methanesulfonate (0.150 g, 0.460 mmol) in acetonitrile (1.0 mL) was stirred at 90° C. for 2 hours. The reaction was quenched with water, extracted with ethyl acetate. The combined organic layer was dried over MgSO4, then filtered and concentrated under reduced pressure to afford the desired product (35 mg, 80%), which was used directly in the next step without further purification. LCMS calculated for C14H24BN2O3 (M+H)+: m/z=279.2. Found: 279.2.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20]C(=O)OC(C)(C)C)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].OP(O)(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.O>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH2:20])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (12.35 g, 31.8 mmol, Example #3 Step E) in THF (35 mL) was added H3PO4 (20.16 mL, 350 mmol). The reaction mixture was heated to about 65° C. After about 90 min, the reaction mixture was cooled to about 0° C. and a solution of K3PO4 (29.0 mL, 350 mmol) in water (100 mL) was added. A white precipitate was removed by filtration. The organic layer was separated, dried over anhydrous MgSO4, and concd in vacuo to provide crude 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (8.58 g, 94%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.85 min; MS m/z: 289 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33](OC)=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:41].[Na+]>CO.C1COCC1>[C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:39])[CH3:40])[C@H:20]2[CH2:21][C@@H:22]([C:33]([N:6]3[CH2:7][CH2:8][O:41][CH2:1][CH2:5]3)=[O:34])[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:25]2)=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-{[(2-tert-butyl-4-hexylpyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (219 mg) was dissolved in methanol (3 ml) and THF (2 ml), 1M aqueous sodium hydroxide solution (2 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the aqueous layer of the mixture was adjusted to pH 5-6 with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue, morpholine (41 μl), 1H-benzotriazol-1-ol (30 mg) and triethylamine (140 μl) were dissolved in 1,2-dichloroethane (4 ml), WSC.HCl (115 mg) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-80:20) was concentrated under reduced pressure to give the object product (88 mg).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([CH3:39])=[CH2:38])[CH:31]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CCO.[Pd]>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH:37]([CH3:39])[CH3:38])[CH:31]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)ccc1F
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)ccc1F
Reaction time: 0.75 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 119) (18.8 mg, 0.031 mmol) in EtOH (4.5 mL) was added 10% Pd/C (15 mg). The reaction was placed under a H2 atmosphere (balloon) and stirred vigorously. After 45 minutes, the catalyst was removed by filtration. The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel with 15% EtOAc/hexanes. Further purification by PTLC with 75% CH2Cl2/hexanes afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.35 (15% EtOAc/hexanes). LCMS=608.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.71 (s, 1H), 7.70 (s, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.15 (m, 1H), 7.08-7.12 (m, 2H), 5.52 (d, J=8.0 Hz, 1H), 4.89 (d, J=15.7 Hz, 1H), 4.18 (d, J=15.8 Hz, 1H), 3.76 (m, 1H), 3.28 (m, 1H), 1.25-1.29 (m, 6H), 0.42 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:44][S:45]([CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:47])=[O:46]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:54]3[CH2:55][CH2:56][N:51]([CH2:50][CH2:49][CH2:48][S:45]([CH3:44])(=[O:46])=[O:47])[CH2:52][CH2:53]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H47N6O5S2Cl2 [(M+H)+] 804.2418, observed 804.2413.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[NH2:23]>>[F:18][C:19]([F:31])([F:32])[C:20]1[CH:21]=[C:22]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:3]=2[O:2][CH3:1])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: COc1cc(-c2ccccc2)ccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1cc(-c2ccccc2)ccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
Using 2-methoxy-4-phenylbenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)CC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Yield: 92.6 %

Procedure:
Dissolve 5-(R)-[1-(S)-benzyloxy-2-(S)-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (187.7 mg, 0.263 mmol) in methanol (10 mL). Add 20% palladium hydroxide on carbon 100 mg) and hydrogenate at one atmosphere hydrogen gas for 18 hours. Add more 20% palladium hydroxide on carbon (100 mg) and further hydrogenate at one atmosphere hydrogen gas for 5 hours. Filter and concentrate to give the desired compound (107.8 mg, 93%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.Cl.[CH2:33]([NH2:35])[CH3:34].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:33]([NH:35][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3([C:10]4[N:6]5[CH2:7][CH2:8][S:9][C:3]([CH2:2][OH:1])([CH3:31])[CH2:4][C:5]5=[N:12][N:11]=4)[CH2:14][CH2:15]3)=[CH:21][CH:20]=2)=[N:23][CH:24]=1)[CH3:34]
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)nc1
Yield: 47.7 %

Procedure:
A solution of the compound (150 mg, 0.344 mmol) obtained in Example 66, ethylamine hydrochloride (140 mg, 1.72 mmol), N,N-dimethylaminopyridine (4 mg, 34 μmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) in N,N-dimethylformamide (3.00 mL) was stirred at room temperature for 5 h. Saturated aqueous sodium hydrogencarbonate (100 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with water and dried with anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (76 mg, 48%) as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1.[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)c1ccc(CCCCO)cn1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCCCc1ccc(C(=O)O)nc1)OCc1ccccc1
Temperature: 0 °C
Yield: 90.6 %

Procedure:
3.92 g of 5-(4-hydroxybutyl)picolinic acid was dissolved in 20 ml of pyridine, and with stirring under ice cooling, a solution of 4.6 g of carbobenzyloxy chloride in 20 ml of toluene was added dropwise. Under ice cooling, the mixture was reacted for 2 hours. Then, the reaction mixture was poured into ice water, and extracted with toluene. The extract was washed successively with water, 1 N hydrochloric acid and then with water, and the toluene was distilled off to give 5.7 g of 5-(4-carbobenzyloxybutyl)picolinic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[F:11][CH:12]([F:15])[CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([O:8][CH2:13][CH:12]([F:15])[F:11])[CH:7]=1
Reactant: OCC(F)F
Reactant: N#Cc1ncc(O)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ncc(OCC(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile [1262860-70-7] (0.200 g, 1.23 mmol) in THF (15 ml) was added at 0° C. 2,2-difluoro-ethanol (0.123 g, 1.48 mmol) and triphenylphosphine (0.484 g, 1.84 mmol). After stirring for 10 min at 0° C. DIAD (0.373 g, 1.84 mmol) was added and the reaction mixture was stirred for 2 h at 0° C. followed by 16 h at 25° C. The reaction mixture was concentrated and the title compound was obtained after CombiFlash chromatography on silica gel (hexane/EtOAc 20:1 to 1:1) as a colorless oil.