Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([CH3:27])[CH:9]=1>>[CH3:27][C:10]1[CH:9]=[C:8]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: OC1CCOC1
Reactant: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Product: Cc1cc(C)c(-c2cccc3c(OC4CCOC4)cc(C)nc23)c(C)c1

Procedure:
The title compound was prepared as a light yellow solid starting from 3-hydroxytetrahydrofuran and 4-chloro-2-methyl-8-(2,4,6-trimethyl-phenyl)-quinoline using procedure analogous to that described in Example 5. 1H NMR (CDCl3) δ 8.17(d,1H), 7.39-7.46(m,2H), 6.96(s,2H), 6.49(s,1H), 5.13(m,1H), 4.14(d,2H), 3.8-4.1(m,4H), 2.51(s,3H), 2.36(s,3H), 2.15-2.20(m,2H), 1.89(s,6H)ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[S:12]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[CH:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:5]=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)N1CCCCC1
Reactant: CC(C)c1ccc(N)cc1
Product: COc1ccc(C(=O)Nc2ccc(C(C)C)cc2)cc1S(=O)(=O)N1CCCCC1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 4-methoxy-3-(piperidin-1-ylsulfonyl)benzoic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.[CH:28]12[N:34]([S:35]([CH2:38][C:39]3[C:44]([C:45]([O:47][CH3:48])=[O:46])=[C:43]([O:49][CH3:50])[C:42](Br)=[CH:41][CH:40]=3)(=[O:37])=[O:36])[CH:31]([CH2:32][CH2:33]1)[CH2:30][CH2:29]2>>[CH:28]12[N:34]([S:35]([CH2:38][C:39]3[C:44]([C:45]([O:47][CH3:48])=[O:46])=[C:43]([O:49][CH3:50])[C:42]([C:23]4[CH:27]=[CH:26][O:25][CH:24]=4)=[CH:41][CH:40]=3)(=[O:37])=[O:36])[CH:31]([CH2:32][CH2:33]1)[CH2:30][CH2:29]2
Reactant: COC(=O)c1c(CS(=O)(=O)N2C3CCC2CC3)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)N2C3CCC2CC3)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(7-azabicyclo[2.2.1]heptane-7-ylsulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 177) as a white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH2:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N+](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-]>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:20][CH:25]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)C1CC1c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 135 °C
Yield: 50 %

Procedure:
A mixture of 2-vinylphenyl 4-(trifluoromethyl)benzenesulfonate (1.8 g, 5.5 mmol) and ethyl diazoacetate (0.70 mL, 6.7 mmol) under argon is heated at 135° C. for 90 min. The product is purified on silica gel in methylene chloride and ethyl acetate-methylene chloride mixtures. The product, ethyl 2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]cyclopropanecarboxylate, is obtained as a mixture of isomers. A yield of 50% is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C.CN(C)C=O>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1cccc(N2CCOCC2)c1
Yield: 75.3 %

Procedure:
A flask containing 5% palladium on carbon (1.95 g) was evacuated and refilled with hydrogen. 4-(3-Nitrophenyl)morpholine (intermediate 2) (19.5 g, 93.75 mmol) was introduced into the flask as a solution in ethanol and dimethylformamide (1000 ml, 4:1 v/v). The reaction was stirred at room temperature until further uptake of hydrogen ceased (after approximately 7 L). The reaction was then filtered through celite and solvent removed in vacuo to yield the desired product (12.6 g, 70.6 mmol) as a beige solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][NH2:24])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.C(NC(C1C(C2C=CC=CC=2C(S(C2C=CC=C(F)C=2)(=O)=O)N)=CC=CC=1)=O)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][NH:24][S:32]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=2)(=[O:34])=[O:33])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: NC(c1ccccc1-c1ccccc1C(=O)NCc1ccccc1)S(=O)(=O)c1cccc(F)c1
Product: O=C(NCc1ccccc1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc(F)c1

Procedure:
From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid benzylamide (precursor 5b) and 3-fluorophenylsulfonyl chloride, according to the general working procedure 112 mg of 2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid benzylamide were obtained;
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2CNC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccc(OCCCN)cc2CNC1=O
Yield: 100 %

Procedure:
A solution of methyl (±)-8-[3-(tert-butoxycarbonylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.70 g) in CH2Cl2 (7 mL) and TFA (2 mL) was stirred under argon at 0° C. for 1 hr, then was concentrated to give the title compound (0.75 g, 100%) as a colorless glass: MS (ES) m/e 321.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]2[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=CC2CCC(C#N)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CCC2CCC(C#N)CC2)cc1
Yield: 81.8 %

Procedure:
956 mg of the 4-[2-(p-pentylphenyl)ethenyl]cyclohexanecarbonitrile obtained were dissolved in 50 ml of toluene in a sulphonation flask, the solution was treated with 150 mg of palladium/carbon (10%) and the mixture was hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill (about 30 minutes). Filtration of the mixture (back-washing with toluene), concentration of the filtrate and low-pressure chromatography (0.4 bar) of the residue (890 mg) on silica gel with 5% ethyl acetate/petroleum ether gave 788 mg (82%) of 4-[2-(p-pentylphenyl)ethyl]cyclohexanecarbonitrile as a viscous, colourless oil. Although in the thin-layer chromatogram using different solvent systems as the eluant there appeared only a single spot, with gas-chromatographic analysis and NMR spectroscopic analysis showed this material to be a cis/trans isomer mixture (about 1:3). Two-fold crystallization of this material from pentane at -20° C. finally yielded trans-4-[2-(p-pentylphenyl)ethyl]cyclohexanecarbonitrile of sufficient purity (98.8% of trans compound and 1.2% of cis compound according to gas-chromatographic analysis); m.p. 22.4° C.; cl.p. (N-I) -14.1° C.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[N:3]=[CH:4][CH:5]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.Cl.[CH3:30][C@H:31]1[NH:36][CH2:35][C@H:34]([O:37][C:38]2[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[CH:40][N:39]=2)[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:30][C@H:31]1[N:36]([C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:2]2[N:1]=[CH:5][CH:4]=[N:3]2)=[O:10])[CH2:35][C@H:34]([O:37][C:38]2[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[CH:40][N:39]=2)[CH2:33][CH2:32]1
Reactant: C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O
Product: C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (2.46 g, 13.0 mmol) (prepared as described in WO2008/147518, WO2009/143033 and WO2010/048012), 1-hydroxy-7-azabenzotriazole (1.77 g, 13.0 mmol), and EDC (2.95 g, 15.4 mmol) in DMF (20 mL) was stirred for 5 min. A solution of 2-{[(3R,6R)-6-methylpiperidin-3-yl]oxy}pyridine-4-carbonitrile hydrochloride (3.0 g, 11.8 mmol) in DMF (20 mL) and Hunig's Base (6.20 ml, 35.5 mmol) was added quickly dropwise via addition funnel. The reaction was stirred at RT overnight, then diluted with saturated, aqueous NaHCO3 and water and extracted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-75% ethyl acetate in hexanes), providing the titled compound as a white foam. HRMS m/z (M+H) 389.1714 found, 389.1721 required.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[C:34]2[O:33][CH:32]=[CH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1.Cl>C(O)(C)C>[O:33]1[C:34]2[C:26]([NH:25][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:27][CH:28]=[CH:29][C:30]=2[CH:31]=[CH:32]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Nc1cccc2ccoc12
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc4ccoc34)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 85 °C
Yield: 70.6 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (0.1 g), 7-aminobenzofuran (0.057 g), isopropanol (4 ml) and a solution of hydrogen chloride in isopropanol (6M, 0.06 ml) was stirred and heated to 85° C. for 3 hours. The resultant mixture was cooled to ambient temperature and the precipitate was isolated by filtration, washed in turn with a 1:1 mixture of diethyl ether and isopropanol and with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.09 g) as a dihydrochloride salt; NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 2.9 (s, 3H), 3.45 (br m, 5H), 3.8 (br m, 5H), 4.05 (s, 3H), 4.35 (t, 2H), 7.1 (d, 1H), 7.45 (m, 3H), 7.75 (d, 1H), 8.05 (s, 1H), 8.25 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:35])[C:30]=1[O:31][CH2:32][CH2:33][OH:34])[CH:26]=O.S(=O)(O)[O-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][C:19]([F:21])=[CH:18][CH:17]=3)[NH:1][CH:26]2[C:25]2[CH:28]=[C:29]([CH3:35])[C:30]([O:31][CH2:32][CH2:33][OH:34])=[C:23]([CH3:22])[CH:24]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: CCC(C)c1ccc(NC(=O)c2ccc(F)cc2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(C)c1ccc(N2C(=O)c3ccc(F)cc3NC2c2cc(C)c(OCCO)c(C)c2)cc1
Temperature: 120 °C
Yield: 7.4 %

Procedure:
A mixture of 2-amino-N-(4-sec-butyl-phenyl)-4-fluoro-benzamide (0.920 g, 3.21 mmol), 3,5-dimethyl-4-(2-hydroxy-ethoxy)-benzaldehyde (0.627 g, 3.21 mmol), sodium bisulfite (0.640 g, 3.53 mmol), and p-toluenesulfonic acid (60 mg, 0.32 mmol) in N,N-dimethylacetamide (20 mL) was heated at 120° C. for 16 hours. The solvent was evaporated in vacuo and water was added to the flask. The precipitate was filtered off and washed with water. The solid was triturated with ether and filtered off to give 3-(4-sec-butyl-phenyl)-7-fluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-2,3-dihydro-1H-quinazolin-4-one (P) (0.11 g). The filtrate was evaporated under vacuum to give second crop of (1.02 g). The combined yield: 1.13 g (quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: Clc1ccc2ccccc2n1
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2ccc3ccccc3n2)CC1
Yield: 18.1 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was reacted with 2-chloroquinoline (328 mg, 2.0 mmol) to afford the title compound (39 mg), a white solid, in 18% yield.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]C2C=CC([N+]([O-])=O)=CC=2)=[CH:23][CH:22]=1>CC#N>[N:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(Nc1ccncc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 55 °C

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.721 mmol) in MeCN (3 mL) was added 4-nitrophenyl pyridin-4-ylcarbamate (561 mg, 2.164 mmol). The resulting mixture was heated to 55° C. overnight. After cooling down to RT the white precipitated obtained was filtered off and washed with DCM (2×1 mL). The combined filtrates were then concentrated and the residue purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 398 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[O:8])=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound (D118) (24 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D86) (40 mg) and 4-(trifluoromethyl)benzylbromide (0.032 ml). (Na2CO3: 2.5 eq; reaction time: 4 hrs; 60° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc3cc[nH]c23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc3cc[nH]c23)CC1
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a solution of 4-(1H-indol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (100 mg) in EtOH (20 mL) was added 10% Pd/C (20 mg). The reaction was placed on a Parr shaker at 55 psi H2 for 24 h. The reaction was filtered through Celite™ and concentrated to afford 4-(1H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester (22) as a clear oil (78 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](S)[N:5]([CH2:7][C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:6]=1.O>C(O)C.[Ni]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:6]=1
Reactant: Cc1cn(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c(S)n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cc1cn(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
4-methyl-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazole-2-thiol (0.6 g, 1.44 mmol) was dissolved in ethanol (20 mL), water (5 mL) was added, and the mixture was cooled in ice. Raney nickel (4 g) was added, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was filtered though Arbocel® and concentrated in vacuo to provide a brown oil. This was purified by flash chromatography on silica gel eluting with ethyl acetate:diethylamine (95:5) to provide the title compound (0.086, 16%) as a clear oil. 1H NMR (400 MHz CDCl3) δ 1.80-1.90 (m, 6H), 2.08-2.18 (m, 7H), 2.65-2.80 (m, 6H), 3.50 (t, 2H), 3.80 (m, 2H), 3.90 (s, 2H), 4.05 (t, 2H), 6.10 (s, 1H), 6.70 (s, 1H), 6.89 (d, 2H), 7.0 (d, 2H). LRMS ESI+ m/z 384 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(#N)C.C(OCC)(=O)C>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:6][CH2:7][C:2](=[O:48])[O:1][CH2:3][CH2:4]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOC(=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
To a solution of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (262 mg) in acetonitrile (10 mL) was added m-chloroperbenzoic acid (129 mg), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=40/60→0/100 (volume ratio)] and crystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound as colorless crystals (204 mg, 75%).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[Cl:24][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1
Reactant: OCc1coc(SCCC(F)=C(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: FC(F)=C(F)CCSc1nc(CCl)co1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
6.8 g of 4-hydroxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole and 2.5 g of pyridine were dissolved in 30 ml of chloroform, to which a solution of 5.0 g of thionyl chloride in 10 ml of chloroform was added dropwise at 0° C. After the addition the mixture was refluxed for 10 hours. After cooling to room temperature, the solvent was distilled under reduced pressure. The residue was purified by column chromatography (eluent: hexane:dichloromethane=2:1) to obtain 5.7 g of 4-chloromethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 77.8%). n20D=1.4933.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=O>N1C=CC=CC=1.C(OCC)C>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]1[O:1][N:2]=[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[N:4]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3Cl)n2)CC1

Procedure:
tert-Butyl 4-(N-hydroxyamidino)-piperazine-1-carboxylate (290 mg) prepared in Example 36 was dissolved in 2 ml of pyridine, 0.20 ml of 2-chlorobenzoyl chloride was added thereto and the mixture was heated to reflux for 1 hour. The reaction solution was diluted with diethyl ether, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution and dried over anhydrous magnesium sulfate. The residue prepared by evaporation of the solvent was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=7:3) to give 64.0 mg of the title compound as a white solid.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:10]1=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:56][C:57]1[C:62]([C:63]([F:66])([F:65])[F:64])=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:67][NH2:68]>ClCCl>[Cl:56][C:57]1[C:62]([C:63]([F:65])([F:66])[F:64])=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:67][NH:68][C:14]([CH:13]1[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:10](=[O:24])[N:9]1[CH3:8])=[O:16]
Reactant: Cc1cccc(N2CC(C(=O)O)N(C)C2=O)n1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(N2CC(C(=O)NCc3cccc(C(F)(F)F)c3Cl)N(C)C2=O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
A mixture of 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (147 mg, 0.42 mmol), 1-hydroxybenzotriazole hydrate (96 mg, 0.63 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and N-ethyl morpholine (0.27 ml, 2.1 mmol) in dichloromethane (8 ml) was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (88 mg, 0.42 mmol) in dichloromethane (2 ml) was added and the reaction stirred at room temperature for 4 hours. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase was separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxamide (110 mg, 61%). LC/MS [M+H]+=427, retention time=2.66 minutes.