Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][CH2:10]1.O>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[C:27]5[Br:1])=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Nc1ccc2[nH]ccc2c1)C1(c2ccc3c(c2)OCO3)CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]cc(Br)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
Freshly recrystallized N-bromosuccinimide (0.278 g, 1.56 mmol) was added portionwise to a solution of 1-(benzo[d][1,3]-dioxol-5-yl)-N-(1H-indol-5-yl)cyclopropanecarboxamide (0.500 g, 1.56 mmol) in N,N-dimethylformamide (2 mL) over 2 minutes. The reaction mixture was protected from light and was stirred bar for 5 minutes. The resulting green solution was poured into 40 mL of water. The grey precipitate which formed was filtered and washed with water to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide (0.564 g, 91%). ESI-MS m/z calc. 398.0, found 399.3 (M+1)+. Retention time of 3.38 minutes. 1H NMR (400 MHz, DMSO-d6) 11.37 (s, 1H), 8.71 (s, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.50 (d, J 2.6 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.22 (dd, J=2.0, 8.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.03 (s, 2H), 1.43-1.40 (m, 2H), 1.09-1.04 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7]([O:9]C(C)(C)C)=O.[CH3:24][CH:25]([CH3:31])[CH2:26][CH2:27]C(O)=O.[CH3:32][S:33]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](O)=[O:43])[N:41]=1)(=[O:35])=[O:34]>>[CH2:17]([C@H:2]([NH:1][C:42]([C:40]1[N:41]=[C:37]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])[S:38][CH:39]=1)=[O:43])[C@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7](=[O:9])[CH2:27][CH2:26][CH:25]([CH3:24])[CH3:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)CCC(=O)O
Reactant: CS(=O)(=O)Nc1nc(C(=O)O)cs1
Reactant: CCN(C[C@@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Product: CCN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1csc(NS(C)(=O)=O)n1)NC(=O)CCC(C)C

Procedure:
Synthesized as described above from tert-butyl 2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate, 4-methylpentanoic acid and 2-methanesulfonylamino-thiazole-4-carboxylic acid. MS (ESI+) for C23H35N5O5S2 m/z 526.7 (M+H)+.
Reaction SMILES: CC(C)(OC(N1CCCC(O)C1)=O)C.[NH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1.C([O:37][C@@H:38]1[C@H:42]([O:43]C(=O)C2C=CC=CC=2)[C@@H:41]([CH2:52][O:53]C(=O)C2C=CC=CC=2)[O:40][C@H:39]1[N:62]1[CH:70]=[N:69][C:68]2[C:63]1=[N:64][C:65]([Cl:72])=[N:66][C:67]=2Cl)(=O)C1C=CC=CC=1.N>>[C:23]1([S:22][CH:18]2[CH2:19][CH2:20][CH2:21][NH:16][CH2:17]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl:72][C:65]1[N:66]=[C:67]([NH:15][N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17]2)[C:68]2[N:69]=[CH:70][N:62]([C:63]=2[N:64]=1)[C@@H:39]1[O:40][C@H:41]([CH2:52][OH:53])[C@@H:42]([OH:43])[C@H:38]1[OH:37]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCCC(Sc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCC(Sc5ccccc5)C4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: c1ccc(SC2CCCNC2)cc1
Yield: 90.3 %

Procedure:
3-Phenylthiopiperidine was prepared from 1-(1,1-dimethylethoxycarbonyl)-3-hydroxypiperidine by the method described by Kotsuki et al., Tetrahedron Letters, 1991, 32, 4155-4158; otherwise the synthesis proceeded as described in Example 16. 1-Amino-3-phenylthiopiperidine (0.98 g, 4.0 mmol) was reacted with 9-(2',3',5'tri-O-benzoyl-β-D-ribofuranosyl)2,6-dichloro-9H-purine (2.11 g, 3.3 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(3-phenylthio-1-piperidinyl)adenosine (0.89 g, 55%) as a foam, 1H NMR (DMSO-d6) δ 3.52-3.59 (1H, m, H-5'a), 3.63-3.71 (1H, m, H-5'b) 3.95 (1H, q, H-4'), 4.13 (1H, q, H-3'), 4.46-4.54 (1H, q, H-2'), 5.07 (1H, t, 5'-0H), 5.22, 5.49 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 7.20-7.50 (5H, 2m, Ar--H), 8.43 (1H, s, H-8), 9.50 (1H, s, N--H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7]CC)(=[O:4])[CH:2]=[CH2:3].COC(=O)C(C)=C.[CH2:17]([S:21]C(O)C)[CH2:18][CH2:19][CH3:20].C(OC(=O)C=C)C.S1C=CC=C1CC(O)=O>C(O)(=O)C>[CH2:17]([S:21][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCSC(C)O
Reactant: C=CC(=O)OCCCC
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)OCC
Agent: O=C(O)Cc1cccs1
Solvent: CC(=O)O
Product: C=CC(=O)OCCSCCCC

Procedure:
A butylthioethylacrylate copolymer was synthesized by the solution polymerization of one mole of butyl acrylate, one mole of methylmethacrylate and one-half mole of the reaction products of butylthioethanol esterified with ethylacrylate, under standard solution polymerization conditions in 2-butoxy-ethanol-1 solvent and using one mole of thiolacetic acid as a chain transfer agent. The copolymer was hydrolyzed with acetic acid to convert the thiolacetic ester linkages into mercaptan groups. The curing agent of the previous Example then was reacted onto the copolymer.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>ClCCl>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:30]
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.06 g) in dichloromethane (80 ml) is added o-methylphenyl isocyanate (0.66 g) under ice-cooling. The mixture is stirred at room temperature for 4 hours. After completion of the reaction, the solvent is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1), and recrystallized from ethyl acetate to give 1-[4-(2-methylanilinocarbonylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.97 g) as white powder, m.p. 182°-182.5° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[Sn](CCCC)(CCCC)CCCC)[CH3:2].Br[C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1COCC
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOCn1ccnc1-c1nccs1
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole (previous experimental), 2-bromothiazole (1.05 mL, 11.6 mmol, 1.0 eq based on integration of 1H NMR of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole), and Pd(PPh3)4 (0.67 g, 0.58 mmol) in toluene (20 mL) is stirred at 80° C. for 18 h. After cooling to room temperature, the reaction mixture is poured into saturated aqueous NaHCO3 and extracted twice with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 2:1 hexanes-EtOAc (+0.5% Et3N). Fractions containing product are concentrated and resubjected to flash chromatography on silica gel. Elution with 2:1 hexanes-EtOAc (+0.5% Et3N) affords (26%) of 2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole as a bright yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=3.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H), 6.03 (s, 2H), 3.56 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.O>ClCCl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2ccc([C@H]3C[C@@H]3CCO)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Example 28F (4′-[(1S,2R)-2-(2-hydroxyethyl)cycloprop-1-yl]biphenyl-4-carbonitrile) and methanesulfonyl chloride (1.2 equivalents) in dichloromethane under N2 was added triethylamine (1.4 equivalents) at 0° C. The mixture was stirred at room temperature overnight, and then the mixture was treated with H2O. The separated organic layer was washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluted with 4:1 hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[C:12]([O:24][CH3:25])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[C:28](OC)([CH3:30])[CH3:29].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[C:4]([Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([O:24][CH3:25])[C:13]([CH2:19][CH:20]2[CH2:21][O:22][C:28]([CH3:30])([CH3:29])[O:23]2)=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])([CH3:2])[CH3:3])([CH3:5])([CH3:7])[CH3:6]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1CC(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1CC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 41 h
Yield: 82.9 %

Procedure:
390 mg of 3-(4-(t-butyldimethylsilyloxy-methyl)-2-methoxy-5-nitrophenyl)propane-1,2-diol was dissolved in 8 ml of acetone. Then, 0.33 g of dimethoxypropane and 26 mg of pyridinium p-toluenesulfonate were added to the reaction solution. The obtained mixture was then stirred at room temperature for 41 hours. Thereafter, the reaction solution was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 358 mg of the subject compound.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[C@H:11]([CH2:12][CH3:13])[CH2:10][N:9]1C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([C@H:8]1[C@H:11]([CH2:12][CH3:13])[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1CN(C(c2ccccc2)c2ccccc2)[C@H]1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)Cl
Product: CC[C@@H]1CN[C@H]1C(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
To a stirred solution of (+)trans-1-benzhydryl-3-ethylazetidine-2-carboxylic acid tert-butyl ester (2.85 mmol, 1 eq.) in dry MeOH (50 mL) was added 1 M acetyl chloride (3.1 mL, 3.13 mmol, 1.1 eq.) in MeOH and sonicated the mixture to obtain clear solution. To this was added palladium hydroxide on carbon (20% Pd(OH)/C, 200 mg) and the mixture was hydrogenated at 60 psi for 5 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford (+)-trans-3-ethylazetidine-2-carboxylic acid tert-butyl ester in quantitative yield. This was used without further purification.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: OC1CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C1=CCC(OCc2ccccc2)C1

Procedure:
To a solution of cyclopent-3-en-1-ol [cf. J. Org. Chem., 32, 4138 (1967)] (7.00 g) and benzyl bromide (10.5 ml) in dimethylformamide (35 ml) is added gradually 60% sodium hydride (in oil) (3.68 g) with stirring under ice-cooling, and the mixture is stirred at room temperature for 1.5 hour. The reaction mixture is diluted with ethyl acetate and washed with water six times. The ethyl acetate solution thus obtained is dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and then purified by medium pressure liquid column chromatography (eluent; n-hexane, n-hexane:ethyl acetate--50:1, v/v) to give 4-benzyloxycyclopent-1-ene (11.22 g) as an oily substance.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].O.Cl>C1COCC1>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4])=[CH2:24]
Reactant: C=COCCON
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[NH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Temperature: 22 °C
Reaction time: 0.92 h
Yield: 73.6 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (221 g, 0.53 mol) and O-(2-vinyloxyethyl)-hydroxylamine (63 g, 0.61 mol) in THF (2.85 L), under nitrogen, was added 1M lithium bis(trimethylsilylamide) solution in hexanes (1431 g), over 55 minutes, keeping the temperature between −14.7 and −12.4° C. After 2 hours at −15° C., water (165 mL, 9.2 mol) was added to the mixture, followed by 2M HCl solution (1.98 L), which was added over 20 minutes. The mixture was then allowed to warm to 22° C. and the lower aqueous phase (2.25 L) was separated and discarded. The organic phase was washed with sodium chloride solution (15% w/w, 1100 mL) and the volume was reduced to approximately 1.75 L by distillation of 2.25 L of solvent at ambient pressure. Iso-hexane (3.35 L) was added to the mixture over 2.5 hours with the temperature held at approximately 58° C. After a further 1 hour at this temperature the mixture was cooled to 20° C., held for 1 hour and then cooled to 0° C. and held at this temperature overnight. A further quantity of iso-hexane (500 mL) was added and the mixture was held for 1 hour, then more iso-hexane (500 mL) was added. After 45 minutes at 0° C. the slurry was filtered and the solid was washed with chilled iso-hexane (1.1 L) then dried in vacuum oven at 30° C. to provide 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (190 g, 0.39 mol, 74% yield). 1H NMR (D6-DMSO): δ 7.63 (dd, 1H, J 11, 2 Hz, ArH), 7.52 (s, 1H, ArH), 7.38 (d, 1H, J 8.5 Hz, ArH), 6.55-6.46 (m, 2H, ArH/OCH═CH2), 4.18 (dd, 1H, J 14, 2 Hz, OCH═CH2), 3.99 (dd, 1H, J 7, 2 Hz, OCH═CH2), 3.90-3.88 (m, 2H, OCH2), 3.81-3.79 (m, 2H, OCH2), 3.25 (s, 3H, NCH3), 2.02 (s, 3H, ArCH3).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[CH2:5][O:4][CH2:3]1.[OH-].[Na+].Cl>O>[CH3:1][C:2]1([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(OCCCCCCOCC2(C)COC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(COCCCCCCOc2ccc(C(=O)O)cc2)COC1
Yield: 82.5 %

Procedure:
A reaction mixture comprising 83 g of ethyl 4-[6-(3-methyloxetan-3-ylmethoxy)hexyloxy]benzoate, 12 g of sodium hydroxide, 50 ml of water and 200 ml of Solmix (registered trade mark) was refluxed for 2 hours. This was made acidic with hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated away, and 63 g of 4-[6-(3-methyloxetan-3-ylmethoxy)hexyloxy]benzoic acid (OX1) was obtained. m.p.: 58.5° C.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:8]1[N:7]([CH2:17][CH2:18][O:19][CH3:20])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]=1)[CH3:15]
Reactant: CCOC(=O)Cc1nc(C(C)(C)C)n[nH]1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(C(C)(C)C)nn1CCOC
Temperature: 55 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
Ethyl (3-tert-Butyl-1H-1,2,4-triazol-5-yl)acetate (Preparation 116, 27.4 g, 0.13 mol) and 1-bromo-2-methoxyethane (13.7 mL, 0.143 mol) was dissolved in DMF (400 mL). K2CO3 (90.0 g, 0.65 mol) was added and the reaction mixture was stirred for 6 hours at 50-60° C. The reaction was cooled to room temperature, diluted with water (400 mL), and extracted with Et2O (3×100 mL). The combined organic extracts were washed with brine (3×200 mL), dried with Na2SO4, and evaporated to afford a mixture of alkylated triazole residues. The mixture was separated using HPLC (Luna 10 u 018(2), 100 A, 21.2×250 mm, H2O/acetonitrile 30-40%) to afford ethyl[3-tert-Butyl-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl]acetate (23.14 g, 66%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@@H:33]([NH:37]C(=O)C2C=CC(C)=CC=2)[CH:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@H:33]([NH:37][S:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)NS(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Triethylamine (21 ml, 0.15 mmol) and 4-fluorobenzenesulfonyl chloride (29 mg, 0.15 mmol) were added to a solution of 1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (50 mg, 0.15 mmol) [prepared as described in Example 1 above] in methylene chloride (1.5 ml). The reaction mixture was stirred for 2 h, then concentrated. Purification by flash chromatography with 20:1 methylene:methanol as the eluant gave N-{1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-fluorobenzenesulfonamide (49 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[ClH:5].[CH3:6][C:7]1[C:13](=O)[CH:12]=[C:11]([CH3:15])[C:9](=[O:10])[CH:8]=1>C(O)C>[ClH:5].[NH2:1][C:2]1[S:3][C:12]2[C:11]([CH3:15])=[C:9]([OH:10])[CH:8]=[C:7]([CH3:6])[C:13]=2[N:4]=1
Reactant: NC(N)=S
Reactant: CC1=CC(=O)C(C)=CC1=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(O)c(C)c2sc(N)nc12

Procedure:
To 2.24 g of thiourea were added 60 ml of ethanol and 2.5 ml of concentrated hydrochloric acid, followed by stirring. Then a solution of 8.0 g of p-xyloquinone in ethanol (120 ml) was slowly added dropwise thereto. The reaction mixture was stirred at room temperature for 24 hours and then concentrated to about one-half. The crystals thus precipitated were separated by filtering and washed with a small amount of ethanol. Thus 6.80 g of the title compound was obtained in the form of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:15]2[CH:16]=[CH:17][C:12]([S:9](=[O:11])(=[O:10])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][N:14]=2)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 160 °C
Yield: 31 %

Procedure:
To a solution of 6-chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (150 mg, 439 μmol) and 4-amino-1-boc piperidine (114 mg, 570 μmol) in acetonitrile (3 mL) was added DIPEA (115 μl, 658 μmol) and the reaction was heated at 160° C. in a microwave reactor for 2.5 hours. EtOAc and saturated aqueous NaHCO3 were added, extracted, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give 4-{5-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (69 mg, 31%). LCMS (m/z, Method A) ES− 506 [M−1]−.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Reactant: CN1CCNCC1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: CN1CCN(c2ccc([C@H]3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C[C@H]3c3ccccc3)cc2)CC1

Procedure:
The title compound, MS: m/e=576.1 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, N-methyl-piperazine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.