Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:32][CH2:33][CH:28]([C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30]1)(=[O:16])[CH3:15]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(=O)c1cccc(OCCCCCCl)c1
Product: CC(=O)c1cccc(OCCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{3-[(5-chloropentyl)oxy]phenyl}ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 451.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>ClCCl>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: CC(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](C(C)C)CC1
Temperature: 2.5 °C
Reaction time: 12 h

Procedure:
D-Phenylalanine methyl ester hydrochloride (26 g, 0.12 mol) was suspended in a solution of triethylamine (85 mL) in dichloromethane (125 mL) and the mixture was cooled to 0-5° C. A solution of trans-4-isopropylcyclohexane carbonyl chloride (25 g, 0.13 mol) in dichloromethane (75 mL) was added dropwise over a period of 10 minutes while maintaining the temperature at 0-5° C. The resulting mixture was stirred for 12 hours at ambient temperature then washed with 1.5 N HCl, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to yield 38 g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:14][C:15]1([CH3:41])[CH:19]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[N:18]2[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:17]2[S:16]1.O>C(N)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:14][C:15]2([CH3:41])[CH:19]([C:20]([O:22][CH2:23][C:24]([Cl:25])([Cl:26])[Cl:27])=[O:21])[N:18]3[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@H:17]3[S:16]2)=[N:4][N:3]=1
Reactant: Cc1nnc(S)s1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: NC=O
Solvent: O
Product: Cc1nnc(SCC2(C)S[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.8 %

Procedure:
5-Methyl-1,3,4-thiadiazole-2-thiol (0.20 g) and sodium bicarbonate (0.85 g) were dissolved in formamide (7 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.54 g), and the mixture was stirred for 5 hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.20 g) from the third fraction of fractions each of which was separated into about 30 ml.
Reaction SMILES: CO[C:3](=[O:39])[N:4]=[C:5](SC)[C:6](=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=1)[C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]2[O:15][CH2:14][O:13][CH2:12][C:11]=2[CH:16]=1.C1COCC1.[CH3:45][O:46][C:47]([C:49]1[S:50][CH:51]=[CH:52][C:53]=1[NH:54][NH2:55])=[O:48]>C(N(CC)CC)C>[CH3:45][O:46][C:47]([C:49]1[S:50][CH:51]=[CH:52][C:53]=1[N:54]1[C:3](=[O:39])[NH:4][C:5]([CH:6]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=2)[C:7]2[CH:8]=[C:9]([O:17][CH3:18])[C:10]3[O:15][CH2:14][O:13][CH2:12][C:11]=3[CH:16]=2)=[N:55]1)=[O:48]
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(CNC(=O)OC(C)(C)C)c1)c1cc2c(c(OC)c1)OCOC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sccc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc3c(c(OC)c2)OCOC3)[nH]c1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a mixture of {2-[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylimino]-2-(8-methoxy-4H-benzo[1,3]-dioxin-6-yl)-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (2c))(101 mg) and THF (2.0 mL) there were added 3-hydrazinothiophene-2-carboxylic acid methyl ester (33.1 mg) and triethylamine (27.9 μL), and the mixture was stirred at 65° C. for 15 hours under a nitrogen atmosphere. The solvent in the mixture was distilled off. DMF (2.0 mL) was added to the residue, and the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The solvent in the mixture was distilled off, and methanol (5 mL) and acetic acid (52.1 μL) were added to the residue. Sodium cyanotrihydroborate (114 mg) was then added to the mixture and the mixture was stirred overnight at room temperature. Water (25 mL) and ethyl acetate (50 mL) were added to the mixture, and after sufficiently shaking the mixture, the organic layer was separated off. The organic layer was washed twice with water (25 mL) and once with saturated aqueous sodium chloride (25 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate mixture) to obtain the target compound (103 mg) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[C:4]([F:24])[CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B(O)O)[CH:32]=2)[CH:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH:20]1([C:18]([N:16]2[CH2:17][CH:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[C:33]6[C:28]([CH:27]=[CH:26][NH:25]6)=[CH:29][CH:30]=5)=[CH:3][C:4]=4[F:24])[C:9](=[O:23])[NH:10][N:11]=3)[CH2:15]2)=[O:19])[CH2:22][CH2:21]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cc[nH]c4c3)cc2F)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromo-2-fluorophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (64 mg, 0.162 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (15 mg, 0.018 mmol), and 1H-indol-6-ylboronic acid (30 mg, 0.186 mmol) in 1,4-dioxane (1.5 mL) and 2M aq potassium carbonate (0.5 mL, 1.000 mmol) were stirred at 100° C. in an oil bath for 16 h. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), and then the layers were separated. The aqueous layer was neutralized using 1N aq HCl and then extracted with ethyl acetate (2×20 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-5% methanol/ethyl acetate) provided the title compound as an impure solid. Subsequent purification of this solid by reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) followed by dessication in a vacuum oven over the weekend provided the title compound as a white solid (16 mg, 23%). MS(ES)+ m/z 432.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Cu](C#N)[C:13]#[N:14].O>CN1C(=O)CCC1>[C:13]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)#[N:14]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1ccc(Br)cn1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C#N)cn1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
A mixture of methyl 5-bromopyridine-2-carboxylate (2.8 g) and copper cyanide (3.6 g) in NMP (30 mL) was heated with stirring at 170° C. for 1.5 hours. Water was added to the reaction solution at room temperature, and the insoluble matter was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the title compound (920 mg).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([F:27])[CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:23]1[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (3.0 g) in tetrahydrofuran (70 mL), 3,5-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 25.7 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 3.0 g of the title compound as a pale yellow oil. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)(=O)C>C(O)C>[CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH2:14][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1nc(C=O)cc(C(F)(F)F)n1
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCSc1nc(CN2CCOCC2)cc(C(F)(F)F)n1

Procedure:
2-Hexylsulfanyl-6-trifluoromethyl-pyrimidine-4-carbaldehyde (0.5 g, 1.7 mmol) and morpholine (0.16 mL, 1.9 mmol) were dissolved in ethanol (5 mL) and acetic acid (0.5 mL) and treated with borane-pyridine complex (0.19 mL, 1.9 mmol) for 4 h at 20° C. The reaction mixture was evaporated to dryness. Extraction: 2×AcOEt, 1×10% aqueous Na2CO3. One obtained a mixture of the expected product and the reduced aldehyde which was more polar. This mixture was separated by chromatography on Si-amine from Silicycle with a gradient of heptane/ethyl acetate from 10:1 up to 1:1. Gave 220 mg (35%) of a colorless oil. MS: m/z=364 (M+H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7](=[S:13])[S:8][CH2:9][C:10](Cl)=[CH2:11])=[C:4]([CH3:16])[CH:3]=1.[Br:17]C1C=CC(NC(=S)[S-])=C(C)C=1.C([NH+](CC)CC)C>>[Br:17][C:15]1[CH:2]=[CH:3][C:4]([CH3:16])=[C:5]([N:6]=[C:7]2[S:13][C:10]([CH3:11])=[CH:9][S:8]2)[CH:14]=1
Reactant: C=C(Cl)CSC(=S)Nc1ccc(Br)cc1C
Reactant: Cc1cc(Br)ccc1NC(=S)[S-]
Agent: CC[NH+](CC)CC
Product: Cc1csc(=Nc2cc(Br)ccc2C)s1

Procedure:
By the procedure of Example 1, 2-chloroallyl 4-bromo-2-methyldithiocarbanilate is prepared substituting triethylammonium 4-bromo-2-methyldithiocarbanilate for the 4-chloro derivative of the same and cyclized as in Example 1 to yield 2-(4-bromo-o-tolyl)imino-4-methyl-1,3-dithiole in good yield and purity.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[C:21](=[O:27])[CH2:20][CH2:19][CH2:18]2.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[CH:35]=O.Cl>C1COCC1>[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1/[CH:35]=[C:20]1/[C:21](=[O:27])[C:22]2[C:17]([CH2:18][CH2:19]/1)=[CH:16][C:15]([O:14][CH3:13])=[C:24]([O:25][CH3:26])[CH:23]=2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: O=Cc1ccncc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Br)CC2
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of (i-Pr)2NH (0.3 mL, 2.2 mmol) at 0° C. in dry THF (15 mL) was added n-BuLi (1.22 M solution in hexane, 2.7 mL, 2.2 mmol), the mixture was stirred for 15 min at this temperature, after which the 6,7-dimethoxy-1-tetralone (0.412 g, 2 mmol) in dry THF (7 mL) was slowly added at −78° C. After 30 min at this temperature, 3-bromo-4-pyridinecarboxaldehyde (0.446 g, 2.4 mmol) in dry THF (7 mL) was slowly added and the solution was stirred for 30 min at −78° C. before allowed to reach room temperature and being stirred for a night. Then, the mixture was hydrolyzed by HCl 1N and extracted by AcOEt to eliminate the possible excess of tetralone. The aqueous layer was neutralized by NaHCO3 and the compound was extracted by CH2Cl2 three times. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography on SiO2 (gradient of EtOAc in petroleum ether) to afford the expected product 84 (Yield 598.7 mg, 80%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]=[CH2:19])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][SiH:22]([O:25][CH3:26])[O:23][CH3:24]>[Pt].C1(C)C=CC=CC=1>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][Si:22]([O:25][CH3:26])([O:23][CH3:24])[O:21][CH3:20])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[SiH](OC)OC
Reactant: C=CCOc1cccc(OC(=O)c2ccccc2)c1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CO[Si](CCCOc1cccc(OC(=O)c2ccccc2)c1)(OC)OC
Temperature: 20 °C

Procedure:
A mixture of 25.4 g. (0.1 mole) of 3-allyloxyphenyl benzoate, 50 mol. of dry toluene, 20 g. (0.15 mole) of trimethoxysilane and 2 drops of platinum hydrosilation catalyst is heated at 90° C. for 17 hours under nitrogen. After the reaction mixture is cooled to about 20° C., it is concentrated under reduced pressure to produce the uv precursor product. For purification, the product is passed through a short silica column using dichloromethane as an eluent.
Reaction SMILES: [C:1]([Cl:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28]>CN(C=O)C.CC(C)=O>[ClH:20].[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCOCCO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOCCN
Reaction time: 16 h
Yield: 40 %

Procedure:
Stearoyl chloride (6.4 g; 21 mmol) (commercial product) was added dropwise in 5 min to a solution of 2-(2-aminoethoxy)ethanol hydrochloride (2.9 g; 20 mmol) in DMF (50 mL) at room temperature to afford a suspension. After 16 h, the suspension was diluted with acetone and the precipitated solid filtered and washed with acetone. The crude was crystallized from EtOAc; the solid was filtered, washed with EtOAc and dried under reduced pressure to give the desired compound (3.3 g; 8 mmol). Yield 40%. Acidic titer (0.1 N NaCH): 93%. K.F.: 1.06%. The 1H-NMR, 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[SH:57][C:58]1[CH:67]=[CH:66][C:61]([C:62]([O:64][CH3:65])=[O:63])=[CH:60][CH:59]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:65][O:64][C:62](=[O:63])[C:61]1[CH:66]=[CH:67][C:58]([S:57][CH:8]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:59][CH:60]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: OC(CC1CCCCC1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (300 mg, 0.88 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 325.0 mg, 1.29 mmol) at 0° C., followed by the addition of tributylphosphine (0.32 mL, 1.29 mmol) and methyl 4-mercaptobenzoate (173.3 mg, 1.03 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid (190 mg).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([CH:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:26](=[O:33])[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[CH2:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>CO>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:26](=[O:33])[CH2:27][N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)CC(C(=O)NN(CC(C)C)C(=O)CN1CCCC1)[C@H](CC=Cc1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CN1CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.363 g of (E)-2(R)-([1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1-pyrrolidinyl)acetyl]valerohydrazide in 5 ml of methanol was treated with 0.133 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 4 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.317 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1-pyrrolidinyl)acetyl]valerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: O[C:2]([C:7]1[CH:20]=[C:19]2[C:10]([C:11]3[C:12]([CH3:36])=[CH:13][C:14]([OH:35])=[CH:15][C:16]=3[CH:17]=[C:18]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[CH:9][CH:8]=1)([CH3:6])[CH:3]([CH3:5])[CH3:4].[C:37]([O-])(O)=O.[Na+]>C(O)(=O)C.OS(O)(=O)=O>[CH3:6][C:2]([C:7]1[CH:20]=[C:19]2[C:10]([C:11]3[C:12]([CH3:36])=[CH:13][C:14]([OH:35])=[CH:15][C:16]=3[CH:17]=[C:18]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:37][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:26]=2)=[CH:9][CH:8]=1)=[C:3]([CH3:4])[CH3:5]
Reactant: O=C([O-])O
Reactant: Cc1cc(O)cc2cc(-c3ccc(OCCN4CCCC4)cc3)c3cc(C(C)(O)C(C)C)ccc3c12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)=C(C)c1ccc2c(c1)c(-c1ccc(OCCN3CCCCC3)cc1)cc1cc(O)cc(C)c12
Temperature: 75 °C
Yield: 70.7 %

Procedure:
The compound from Step A (0.587 g, 1.2 mmol) was dissolved in glacial acetic acid (7.0 ml) and concentrated H2SO4 (1 drop) was added. The mixture was heated for 20 min at 75° C. with stirring. The reaction was neutralized with NaHCO3 (10.5 g in 25 ml of water) and extracted with methyl t-butyl ether (3×25 ml), evaporated and dried under high vacuum. The residue was chromatographed on silica gel with acetone/hexane (1:2) to give 0.407 g (85%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 0.77 (3H, d, CH3), 0.83 (3H, d, CH3), 1.47 (3H, s, CH3), 1.55 (2H, m, NCH2CH2CH2), 1.76 (4H, m, NCH2CH2CH2), 2.72 (4H, br, NCH2CH2CH2), 2.95 (2H, t, OCH2CH2N), 3.11 (3H, s, CH3), 4.24 (2H, t, OCH2CH2N), 6.87-8.78 (10H, ArH).
Reaction SMILES: C12(CO)CC3CC(CC(C3)C1)C2.[C:13]12([CH2:23][CH2:24][OH:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.[Cl:26][C:27]1[C:28](F)=[CH:29][C:30](F)=[C:31]([CH:39]=1)[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33].ClC1C=C(C=CC=1F)C(NS(C)(=O)=O)=O>>[C:13]12([CH2:23][CH2:24][O:25][C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])=[CH:39][C:27]=3[Cl:26])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1ccc(F)c(Cl)c1
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CS(=O)(=O)NC(=O)c1ccc(OCCC23CC4CC(CC(C4)C2)C3)c(Cl)c1

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace adamantan-1-ylmethanol with 2-(adamantan-1-yl)ethanol and 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 3-chloro-4-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.43 g, 71%): 1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.93 (dd, J=8.7 Hz, 2.2 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 4.20 (t, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.93 (br s, 3H), 1.70-1.55 (m, 14H); MS (ES+) m/z 411.8, 413.8 (M+1).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:8][O:7][C:6]1[C:4]([O:5][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(C=O)c1OCc1ccccc1
Yield: 93 %

Procedure:
A mixture of 196.0 g (1.30 mole) of o-vanillin (Aldrich), 200 g of benzyl bromide (Aldrich), 500 g of anhydrous potassium carbonate and 1,500 mL of absolute ethanol is heated, with stirring, at reflux for 6 hours. After cooling, the supernatant is decanted and the remainder is filtered. The combined filtrate and supernatant is concentrated at reduced pressure to remove solvent. The remaining oil is extracted into 1 L of ether. The ether solution is washed with 500 mL of water, 600 mL of 1% potassium hydroxide solution, and 500 mL of water and then dried (potassium carbonate) and concentrated to give 263.4 g (84% yield) of product; mp 41°-43° C. Reported mp, 43° C. (Chem. Abstr. 62:16110a).