Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]>[Pd]>[NH2:19][CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH:2]([CH3:1])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:16][CH:15]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCN)cc1
Yield: 36.6 %

Procedure:
Scheme Va, step B: N-{2-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]ethyl}(phenylmethoxy)carboxamide (0.6 g, 1.44 mmol) and 10% palladium on carbon (0.5 g, 35 mole %) were combined and hydrogenation was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, {2-[4-(2-aminoethyl)phenyl]propyl}[(methylethyl)sulfonyl]amine, (0.15 g, 37%) as colorless oil. Electron spray M.S. 285 (M*+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:9]([C:13]2[CH:23]=[CH:22][C:16]([C:17](OCC)=[O:18])=[CH:15][N:14]=2)[CH:10]=[CH:11][N:12]=1.O.[OH-].[Na+]>C1COCC1>[CH3:7][C:8]1[N:9]([C:13]2[N:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:22][CH:23]=2)[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccc(-n2ccnc2C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1-c1ccc(CO)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Lithium aluminum hydride (164 mg, 4.33 mmol) was suspended in THF (5 mL). A solution of ethyl 6-(2-methyl-1H-imidazol-1-yl)nicotinate (455 mg, 1.96 mmol) obtained in Step 1 in THF (5 mL) was added at 0° C. and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture were sequentially added water (0.146 mL), a 15% aqueous sodium hydroxide solution (0.146 mL), and water (0.492 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite. The solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=97/3) to give (6-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)methanol (341 mg, 92% yield).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)=[CH:4][C:3]=1[CH3:13].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([CH3:12])([CH3:11])[C:8]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:10])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(C(C)(C)C(=O)O)sc1Br
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C(=O)N2CCCC2)sc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of the 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoic acid in dichloromethane (10 ml) with a catalytic amount of dimethylformamide was added oxalyl chloride (0.30 ml, 0.34 mmol). The mixture was allowed to stir at ambient temperature for 2 hours. The solvent was evaporated and the crude acid chloride dried under vacuum. The crude acid chloride was dissolved in dichloromethane (10 ml) and cooled in an ice-bath. Pyrrolidine (1.2 ml, 14 mmol) was added and the mixture was allowed to stir for 30 minutes while being cooled in an ice-bath. The mixture was poured into ethyl acetate (25 ml) and then extracted with 1N hydrochloric acid. The organic layer was washed with a saturated brine solution, dried over magnesium sulfate and then evaporated to leave 1-[2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoyl]pyrrolidine as a red oil which was used in the next step without purification.
Reaction SMILES: C1(C)C=CC(S([N:10]([CH2:18][CH2:19][N:20](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH2:22][N:23](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:24][CH3:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])(=O)=O)=CC=1.P([O-])([O-])(O)=O.[Na+].[Na+]>CO.[Na].[Hg]>[CH2:16]([OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH3:25]
Reactant: CCN(CCN(CCN(CCCCCCO)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=P([O-])([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: CO
Product: CCNCCNCCNCCCCCCO

Procedure:
About 8 g of 7,10,13-tri-p-toluenesulfonyl-7,10,13-triazapentadecaneol was added to 3.9 g of sodium hydrogen phosphate and 66 g of sodium amalgam in 250 ml of methanol. The mixture was stirred and refluxed for 40 hours. The mixture was cooled down and was filtered. The solvent was evaporated from the filtrate and to the residue 50 ml of CH2Cl2 and 50 ml of 2N HCl was added. After shaking, the acidic layer was separated and neutralized with 20% NaOH. From the mixture, water was evaporated under reduced pressure and to the residue was added 100 ml of methylene chloride. Next the inorganic salts were filtered off. About 2.6 g of crude product was transferred to the next step without further purification. The reaction is shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:17])=[C:6]([CH:16]=1)[CH:7]([OH:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(c1ccccc1F)c1cc(Cl)ccc1I
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 54 g (0.15 mole) of 5-chloro-2'-fluoro-2-iodobenzophenone and 28.4 g (0.75 mole) of sodium borohydride in 1000 ml of ethanol was stirred at 0° C. for 15 min. The solution was diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a deep yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:8]([C:17]([OH:19])=O)[CH2:7][CH2:6]1)=[O:4]>C(OC(=O)C)(=O)C>[CH2:10]([N:9]1[CH:5]2[CH2:6][CH2:7][CH:8]1[C:17](=[O:19])[N:2]([CH3:1])[C:3]2=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNC(=O)[C@@H]1CC[C@H](C(=O)O)N1Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)C2CCC(C1=O)N2Cc1ccccc1

Procedure:
Cis-5-(N-methylcarbamyl)-1-benzylpyrrolidine-2-carboxylic acid (32.3 g, 0.123 mole) and acetic anhydride (160 ml) were heated together at 100° C for 45 minutes after all of the solid had dissolved. Removal of solvent in vacuo left a red-brown oil that was dissolved in a minimum amount of benzene. After removal of 2.0 g of unreacted cis-5-(N-methylcarbamyl)-1-benzylpyrrolidine-2-carboxylic acid by filtration, the solution of desired product was chromatographed on 900 g alumina with benzene elution to give 13.2 g (44%) of pure, oily 8-benzyl-3-methyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione. Treatment of a sample with excess ethanolic hydrogen chloride in diethyl ether solution produced a hydrochloride salt, melting point 140°-170° C. A sample of the free base, melting point 73°-75° C, was subsequently obtained by slow crystallization from benzene.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:13]=CC2C=CC=CC=2)[O:11][CH:12]=1)=[O:7])[CH3:4].[OH2:21]>CC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:13]=[O:21])[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: O
Reactant: CCOC(=O)c1coc(C=Cc2ccccc2)n1
Agent: N#N
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NaIO4 (3.21 g, 15.00 mmol) in water (26.0) mL was slowly added to a vigorously stirred suspension of silica gel (15.0 g) in acetone (60.0 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (40.0 mL) was added and the reaction mixture was treated at rt with 2-styryl-oxazole-4-carboxylic acid ethyl ester (1.22 g, 5.00 mmol) and RuCl3 hydrate (82 mg, 0.15 mmol). The reaction mixture was stirred at rt in the dark for 30 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:9 to 1:2 EA-Hept) gave the title compound as a yellow solid. TLC: rf (3:2 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.51 min; [M+H2O+H]+=188.50.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[C:9]([NH-:13])([CH3:12])([CH3:11])[CH3:10].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:9]([NH:13][C:1](=[O:8])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])([CH3:12])([CH3:11])[CH3:10]
Reactant: C/C=C/C=C/C(=O)O
Reactant: CC(C)(C)[NH-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C/C=C/C(=O)NC(C)(C)C

Procedure:
Sorbic acid (5.01 g, 44.7 mmol) and t-butylamide (3.59 g, 49 mmol) were dissolved in dimethylformamide (150 ml) and the solution was stirred under ice-cooling. To the solution was added diphenylphosphoryl azide (14.8 g, 53.8 mmol) and triethylamine (9.95 g, 98.3 mmol) was added thereto. The mixture was stirred for 18 hours while allowing to rise the temperature to room temperature. The reaction mixture was diluted with ethyl acetate and the dilution was washed with an aqueous saturated sodium chloride solution. The ethyl acetate layer was washed with an aqueous saturated sodium carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1-5:1) to obtain sorbic acid N-t-butylamide as (2.82 g, 37.6%) pale yellow solid. This compound has the following NMR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8](=[O:25])[CH:9]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1)[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:31].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8](=[O:25])[CH:9]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1)[S:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:31]
Reactant: COc1cccc(CN(C)C(=O)C(Sc2ccccc2)c2cc(Cl)cc(Cl)c2)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(CN(C)C(=O)C(c2cc(Cl)cc(Cl)c2)S(=O)c2ccccc2)c1

Procedure:
A mixture of the acetamide derivative from step 5 above (1.5 g), sodium metaperiodate (1.15 g), methanol (30 ml) and water (20 ml) was heated under reflux for 2 hours. The reaction mixture was filtered and the filtrate concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate as eluent, giving N-(3-methoxybenzyl)-N-methyl-2-(3,5-dichlorophenyl)-2-(phenylsulfinyl)acetamide (1.2 g) as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[CH:29]1[CH2:31][CH2:30]1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([CH:29]3[CH2:31][CH2:30]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCOCC3)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(C3CC3)c(N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-morpholin-4-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A44(a)) and tributylcyclopropylstannane. Yellow solid. MS (m/e): 345.4 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][C:2]1([C:8](O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B#B>O1CCCC1>[CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CCCCC1
Agent: B#B
Solvent: C1CCOC1
Product: CC1(CO)CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
To a solution of 1-methyl-1-hydroxycarbonylcyclohexane (10 g, 70 mmol) in tetrahydrofuran(300 mL) at 0° C. was added 1M diborane in tetrahydrofuran (200 mL, 200 mmol) over 90 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for two days. The remaining borane was quenched by the slow addition of saturated sodium bisulfate (10 mL) over 90 min with cooling. Additional saturated sodium bisulfate (200 mL) was added and after 20 min of stirring the aqueous layer was removed. The organic layer was washed with water and saturated sodium chloride, dried, filtered and concentrated. The residue was purified by flash chromatography using 20% diethylether in hexanes to give 1-methyl-1-hydroxymethylcyclohexane (6.17 g, 48 mmol, 69%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:14]=2)[O:9][C:8]([CH3:26])([CH3:25])[CH2:7]1>NCCO>[OH:2][CH2:3][CH2:4][NH:5][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:26])([CH3:25])[CH2:7][CH:6]2[N:5]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)C(N(CCOC)S(C)(=O)=O)CC(C)(C)O2
Solvent: NCCO
Product: COCCN(C1CC(C)(C)Oc2ccc(OCCCC(=O)NCCO)cc21)S(C)(=O)=O

Procedure:
0.55 g of ethyl 4-[4-((2-methoxyethyl)methanesulfonylamino)-2,2-dimethylchroman-6-yloxy]butyrate (Example 19a) was reacted at 90° C. for 2 h in 4 ml of 2-aminoethanol, 0.6 g of oily product.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1(C)C(C)=CC=CC=1>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][CH2:33][CH2:34][NH:35][CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=1)[CH:21]1[CH2:23][CH2:22]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)NCCCNC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)C1CC1
Yield: 69.3 %

Procedure:
A solution of 3-benzyl-7-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (0.32 g, 0.92 mmol) and N-BOC-1,3-diaminopropane (Fluka, 1.0 g, 5.7 mmol) in xylene (12 mL) was heated at 110° C. under nitrogen for 4 days. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (SiO2, EtOAc/hexane 1:3 to 3:2) gave the title compound as a light yellow oil (0.31 g, 62%): 1H NMR (CDCl3) δ 7.25 (m, 3H), 7.20 (m, 1H), 7.07 (d, 2H, J=7.15 Hz), 7.00 (d, 1H, J=4.95 Hz), 6.44 (d, 1H, J=4.95 Hz), 5.41 (m, 1H), 4.82 (m, 1H), 3.33 (m 1H), 3.03 (m, 2H), 2.40 (m, 2H), 1.52 (m, 2H), 1.35 (s, 9H), 1.30 (m, 2H), 1.19 (m, 2H), 0.52 (m, 1H), 0.35 (m, 1H), 0.13 (m, 1H); MS (ESI+) 486.17, 488.17 (M++H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].O>CN(C)C=O>[N:1]1([CH:7]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(c1ccccc1)C(Br)OCc1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)C(OCc1ccc(Cl)cc1Cl)n1ccnc1
Reaction time: 2.5 h

Procedure:
1H-Imidazole (10.21 g, 150 mmole) was dissolved in dimethylformamide (20 ml) and ω-bromo-2-(2,4-dichlorobenzyloxy)acetophenone (11.2 g, 29.9 mmole) was added slowly. After stirring for 2.5 hours with ice-cooling, water (120 ml) was added and the mixture was extracted with ethyl acetate (120 ml×2). The extract was washed with water (120 ml×2) and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to chromatography on a silica gel columne and eluted with methanol/chloroform to obtain the title compound (8.37 g, 77.2%), m.p. 109°-111° C. (recrystallized from n-hexane/benzene).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=3[CH:16]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[CH:36][C:35]=1[C:48]([F:51])([F:50])[F:49])([O-:33])=[O:32]>C(#N)C>[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([CH2:11][C:12]4[O:13][C:14]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=5[CH:16]=4)[CH2:7][CH2:6]3)=[O:4])=[CH:45][CH:46]=2)=[CH:36][C:35]=1[C:48]([F:49])([F:50])[F:51])([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(Nc2ccc(O)cc2)cc1C(F)(F)F
Reactant: O=C(CCl)N1CCN(Cc2cc3cc(C(F)(F)F)ccc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1ccc(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)cc1)N1CCN(Cc2cc3cc(C(F)(F)F)ccc3o2)CC1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
To a solution of 2-chloro-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one (100 mg, 0.28 mmol) in acetonitrile (10 ml) was added potassium carbonate (57.5 mg, 0.42 mmol) and 4-[4-nitro-3-(trifluoromethyl)phenyl]aminophenol (83 mg, 0.28 mmol). The mixture was stirred and heated at 80° C. (oil bath) for 3 hours. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by Prep-TLC with 60% ethyl acetate in petroleum ether to afford 2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one as a yellow solid (125.8 mg, 73%); (ES, m/z): [M+H]+ 623.20; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.60 (m, 2H), 7.14 (overlapping s & d, 3H), 7.00 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.8 Hz, 1H), 6.72 (s, 1H), 6.29 (s, 1H), 4.74 (s, 2H), 3.91-3.53 (m, 6H), 2.60 (br s, 4H).
Reaction SMILES: C([S:8][CH2:9][C@@H:10]([C:26]([OH:28])=[O:27])[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15]CC1C=CC=CC=1)C1C=CC=CC=1.[Na].[Cl-].[NH4+]>N>[CH3:23][C:13]([CH3:24])([CH2:14][SH:15])[C:12]([NH:11][C@H:10]([C:26]([OH:28])=[O:27])[CH2:9][SH:8])=[O:25]
Reactant: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(CS)C(=O)N[C@@H](CS)C(=O)O
Yield: 69.4 %

Procedure:
To a solution of S-benzyl-N-(3-benzylthio-2,2-dimethylpropionyl)-L-cysteine (18.0 g) in liquid ammonia(250 ml), metallic sodium (5.0 g) cut into small pieces was added. To this solution, ammonium chloride was added and then liquid ammonia was evaporated. To the residue, water was added, and the solution was washed with ethyl acetate. The aqueous layer was acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography and recrystallized with a mixture of ethyl acetate and cyclohexane to give 7.1 g(69.6%) of the titled compound. The physical data were identical with those of the compound obtained in Example 2.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=2)O1.Br[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[CH:28]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[O:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[CH:28]=[C:24]1[C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cc2ccccc2o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 66.9 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g, 3.3 mmol), 2-bromobenzofuran (0.64 g, 3.3 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.5 g, 0.4 mmol) in a mixed solution of 1,4-dioxane (20 mL) and water (2.0 mL) was added sodium carbonate (1.0 g, 7.2 mmol). The reaction mixture was stirred at 90° C. under nitrogen for 12 hours. After the reaction, it was allowed to cool to room temperature, and concentrated in vacuo, then diluted with ethyl acetate (100 mL), washed with water (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give the pure product tert-butyl 4-(benzofuran-2-yl)benzoate as a white solid (0.65 g, 67%). 1H NMR (300 MHz, CDCl3): δ 8.06 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 7.62-7.53 (m, 2H), 7.32-7.25 (m, 2H), 7.14 (s, 1H), 1.62 (s, 9H).
Reaction SMILES: [CH:1]1([CH:7]([OH:11])[C:8](C)=[CH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[Al](OCCC)OCCC)CC>CC(C)=O>[CH:1]1([C:7](=[O:11])[CH:8]=[CH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)C(O)C1CCCCC1
Agent: CCCO[Al](OCCC)OCCC
Solvent: CC(C)=O
Product: C=CC(=O)C1CCCCC1

Procedure:
As for 1-cyclohexyl-2-propen-1-one (known compound), 1-cyclohexyl-2-methyl-2-propen-1-ol which is used as starting substance is subjected to Oppenauer oxidation with tripropoxyaluminum in acetone, to yield 1-cyclohexyl-2-propen-1-one.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16](S(C)(=O)=O)[N:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[N:17]=[C:16]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:15]=1
Reactant: OC1CCCC1
Reactant: CS(=O)(=O)c1nc(Cl)cc(C(F)(F)F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a stirred solution of cyclopentanol (0.61 mL, 6.75 mmol) in tetrahydrofuran (24 mL) at 0° C. was added potassium tert-butoxide (0.76 g, 6.75 mmol). The resulting yellow solution was added dropwise to a stirred solution of 4-chloro-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (1.76 g, 6.75 mmol) in tetrahydrofuran (24 mL) at −78° C. over 15 minutes. The reaction was then stirred at −78° C. for 2 h then allowed to warm to rt. After stirring for 15 h at room temperature, the reaction was quenched with water (20 mL) and diluted with ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (2×74 mL). The combined organic extract was washed with saturated sodium chloride (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.60 g, 33%) as a colorless oil. MW=266.65. 1H NMR (CDCl3, 500 MHz) δ 7.26 (s, 1H), 5.48 (sept, J=3.0 Hz, 1H), 2.08-1.76 (m, 6H), 1.75-1.58 (m, 2H).