Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)[CH:11]([CH3:13])[CH3:12].ClC1C=C(C=CC=1)C(OO)=[O:38]>ClCCl.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][S:5]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)[CH:11]([CH3:13])[CH3:12])=[O:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CSCCCCN(c1cnc(-c2ccccc2)c(-c2ccccc2)n1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CS(=O)CCCCN(c1cnc(-c2ccccc2)c(-c2ccccc2)n1)C(C)C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 600 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}acetic acid methyl ester obtained in Example 36 in 10 ml of dichloromethane was ice-cooled and 329 mg of 70% m-chloroperoxybenzoic acid was added. After stirring under ice cooling for 2 hours, the reaction solution was diluted with an aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 385 mg of the desired compound as a yellowish crystal having a melting point of 128 to 130° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCCl)c23)ccc1OCc1ccccn1
Reactant: OC1CCNCC1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1ccccn1
Yield: 39 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 39% yield; NMR Spectrum: 1.36 (d, 2H), 1.69 (d, 2H), 2.18 (t, 2H), 2.26 (s, 3H), 2.78 (m, 4H), 4.39 (t, 2H), 4.54 (d, 1H), 5.20 (s, 2H), 6.98 (d, 1H), 7.35 (t, 1H), 7.44 (m, 2H), 7.55 (d, 1H), 7.86 (t, 1H), 8.21 (s, 1H), 8.23 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C1([Li])C=CC=CC=1.[CH3:22][N:23]=[C:24]=[S:25].Cl>C1C=CC=CC=1.CCOCC.O.C1C=CC=CC=1>[CH3:22][NH:23][C:24](=[S:25])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CN=C=S
Reactant: c1ccc(CCN2CCOCC2)nc1
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CNC(=S)C(CN1CCOCC1)c1ccccn1
Reaction time: 0.5 h

Procedure:
N-[2-(2-pyridyl)ethyl]morpholine (12.7 g., 0.07 mole) in 60 ml. of dry benzene is added dropwise to 35 ml. of 2M phenyl lithium (0.07 mole) in benzene/ether with cooling. The mixture is stirred for 30 minutes, then methyl isothiocyanate (5.2 g., 0.07 mole), dissolved in 60 ml. of dry benzene, is added dropwise with cooling. The resulting solution is stirred overnight. An equal volume of water is added and the solution is cooled and made acidic with 10% hydrochloric acid. The phases are separated, the organic phase is washed with water, and the combined aqueous phases are made basic to about pH 9, then extracted with chloroform. The chloroform extracts are washed with water and dried over magnesium sulfate. Filtration and removal of solvent gives a residue which is recrystallized from ethyl acetate to give N-methyl-3-morpholino-2-(2-pyridyl)thiopropanamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15](O)[CH3:16])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:19]>C(Cl)(Cl)Cl>[Br:19][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1)[CH3:16]
Reactant: BrP(Br)Br
Reactant: COc1ccc(-c2ccc(C(C)O)nc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc(C(C)Br)nc2)cc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a stirred solution of 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanol (0.2 g, 0.8 mmol) in chloroform (4 mL) was added PBr3 (0.3 mL, 1.3 mmol) at 0° C. and the reaction was stirred at 0° C. to rt for about 1 h. The reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to provide 2-(1-bromoethyl)-5-(4-methoxyphenyl)pyridine (0.15 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (d, 1H), 7.84 (dd, 1H), 7.51 (dd, 3H), 7.01 (d, 2H), 5.32-5.26 (m, 1H), 3.86 (s, 3H), 2.11 (d, 3H), LC-MS m/z calcd for [M+H]+ 292.0. found 292.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Br)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 87.1 %

Procedure:
Using 5-bromo-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH2:1]([C:15]1[NH:19][C:18]([C:20]([O:22]CC)=[O:21])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+]>C(O)C>[CH2:1]([C:15]1[NH:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccc(C(=O)OCC)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCc1ccc(C(=O)O)[nH]1
Yield: 73.7 %

Procedure:
Ethyl 5-tetradecylpyrrole-2-carboxylate obtained in Example 1 (0.50 g, 1.5 mmol) was dissolved in 20 ml of ethanol followed by adding 3 ml (3 mmol) of aqueous 1N sodium hydroxide solution thereto. The resulting mixture was heated under reflux for 6 hours. After cooling the mixture, precipitates were filtered, washed well with ether, suspended in diluted hydrochloric acid, and extracted with ether. The extract was further washed with an aqueous saturated solution of sodium chloride and dried over anhydrous megnesium sulfate. A removal of the solvent under reduced pressure afforded 0.34 g (74% yield) of 5-tetradecylpyrrole-2-carboxylic acid, m.p. 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]=[C:10]1[C:22]2[CH:21]=[C:20]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][C:13]([S:27](Cl)(=[O:29])=[O:28])=[CH:14][CH:15]=2>N1C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][S:27]([C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[C:22](=[CH:21][C:20]([S:23]([NH:1][C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=5)(=[O:25])=[O:24])=[CH:19][CH:18]=4)[C:10](=[O:9])[C:11]=3[CH:12]=2)(=[O:29])=[O:28])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2cc(S(=O)(=O)Cl)ccc2-c2ccc(S(=O)(=O)Cl)cc21
Reactant: Nc1cccc(O)c1
Solvent: c1ccncc1
Product: O=C1c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc2-c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc21
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Aminophenol (0.91 g, 8.38 mmol) in pyridine was treated with 9-oxo-9H-fluorene-2,7-disulfonyl dichloride (1.58 g, 4.19 mmol, purchased from Maybridge) in one portion at 0° C. After two hours, the volatiles were removed at reduced pressure and the residue was partitioned between ethyl acetate and H2O. The organic layer was separated, washed with 1N HCl, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (8% CH3OH/CH2Cl2) to provide the title compound as a yellow solid (1.97 g, 90% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 2H), 9.50 (s, 2H), 7.97-8.11 (m, 4H), 7.92 (d, 2H), 7.0 (t, 2H), 6.49-6.64 (m, 4H), 6.43 (m, 2H); MS (DCI/NH3) 540 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.C(Cl)(=O)OCC.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([NH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27])=[O:10]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)Nc2cccc(C(=O)O)c2)cc1OC
Reaction time: 2 h
Yield: 50 %

Procedure:
2 Grams of 3,4-dimethoxycinnamic acid were dissolved in a mixture of 20 ml of dry dimethylformamide and 1.5 g of triethylamine. To this solution was added under ice cooling and agitation 1.1 g of ethyl chlorocarbonate and the mixture was then reacted for one hour. To this mixture were added 10 ml of dimethylformamide containing 1.5 g of 3-aminobenzoic acid and the mixture was stirred for 2 hours. After completion of the reaction, the reaction liquid was concentrated approximately to 1/2 volume and poured into an aqueous solution of hydrochloric acid. The precipitated crystals were separated by filtration, washed with water and recrystallized from an equivolume mixture of ethanol and water to obtain a yield of 50 % 3-(3', 4'-dimethoxycinnamoylamino)-benzoic acid having a melting point of 225°-226° C.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>C1COCC1>[CH:1]([O:4][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
iso-Propanol (1.41 mL, 18.48 mmol) was added drop wise into a stirred suspension of sodium hydride (60% dispersion in oil, 0.739 g, 18.48 mmol) in anhydrous THF (20 mL) at 0° C. and the resulting solution stirred for 0.5 hours. To this solution was added 2-fluoro-3-nitropyridine (2.50 g, 17.60 mmol) drop wise in anhydrous THF (10 mL). After complete addition the solution was stirred at 0° C. for 0.5 hours, before being allowed to warm to ambient temperature. The reaction was stirred at ambient temperature for 18 hours, quenched with water (50 mL) and the aqueous layer extracted with diethyl ether (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (1.975 g, 61% yield) after purification by flash-column chromatography (petroleum ether (40-60° C.)/DCM).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)=[O:17])([CH3:4])[CH3:3].[Cl:27]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:4][C:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([Cl:27])=[CH:21][NH:22]2)=[O:17])([CH3:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)NCCCOc1ccccc1C(=O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)NCCCOc1ccccc1C(=O)c1cccc2[nH]cc(Cl)c12
Yield: 79.8 %

Procedure:
6.3 g of [2-[3-[(1,1-dimethylethyl)-amino]-propoxy]-phenyl]-(1H-indol-4-yl) methanone of Step F of Example 3 in 50 ml of acetic acid in the presence of 2.64 g of N-chloro succinimide was stirred for 2 hours at ambient temperature and was then poured into 300 ml of saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic phase was washed with salt water, dried and concentrated to dryness. After chromatography of the residue on silica (eluant:ethyl acetate triethylamine 95-5), 5.52 g of the expected product were obtained and was used as is for the following step.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1.C(N(CC)CC)C>CN(C)C=O>[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)=[O:33]
Reactant: OC[C@@H]1CCCN1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCC[C@H]1CO
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (8.76 g) in dimethylformamide (80 ml) were added (2S)-2-(hydroxymethyl)pyrrolidine (8.72 g) and triethylamine (3.86 ml) and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.75 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[S:6]Cl)[CH2:2][CH2:3][CH3:4].[CH3:12][NH:13][C:14](=[O:27])[O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.O>CCCCCC.C(N(CC)CC)C.S(=O)=O>[CH2:1]([N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[S:6][CH2:12][NH:13][C:14](=[O:27])[O:15][C:16]1[C:24]2[O:23][C:22]([CH3:25])([CH3:26])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CCCCN(CCCC)SCl
Agent: O=S=O
Solvent: CCCCCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)SCNC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 11 °C
Yield: 90 %

Procedure:
A flask was charged with 30.2 g of a 50% solution of dibutylaminosulfenyl chloride (0.077 mole) in hexane and 15.8 g of 98% 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (0.07 mole) was added. Triethylamine (7.8 g, 0.077 mole) was added to the mixture with agitation over a period of seven minutes. A temperature rise from 24.5° to 26° C. was observed. A portion (1.9 g, 0.0115 mole) of the triethylamine/sulfur dioxide catalyst prepared in Example 3 was added dropwise. The temperature gradually rose to 30° C., and was raised further by external heating to 35° C. for a total reaction time of 100 minutes from the beginning of triethylamine addition. Twenty minutes later the mixture was cooled to 11° C. and 31 ml of water was added and mixed. The mixture was filtered to remove a small amount of solid, separated, and the organic layer was concentrated to yield 26.64 g of 90% (hplc) 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (dibutylaminothio)methylcarbamate (a 90% chemical yield based on the starting carbamate).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (79 mg, 71%), MS (ISP) m/z=447.3 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-methanesulfonyl-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(I)cc2)c1Br
Yield: 65 %

Procedure:
4-Iodo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-iodobenzenesulfonyl chloride according to the procedures described in Example 40b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 166°-173° C., yield 65%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][Si](C(C)(C)C)(C)C)=[C:6](Br)[C:5]([CH3:17])=[CH:4][C:3]=1O.[CH:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])[CH:25]=O)([CH3:21])[CH3:20].C(O)(C(F)(F)F)=O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][O:32][CH3:33])=[C:22]([CH:19]([CH3:21])[CH3:20])[CH:23]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[OH:8]
Reactant: Cc1cc(O)c(C)c(O[Si](C)(C)C(C)(C)C)c1Br
Reactant: COCOc1ccc(C=O)cc1C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCOc1ccc(Cc2cc(C)c(O)cc2C)cc1C(C)C

Procedure:
Intermediate 2,5-dimethyl-4-(3′-iso-propyl-4′-methoxymethoxybenzyl)phenol was prepared from 2,5-dimethyl-4-bromo-t-butyldimethylsilyloxyphenol, and 3-iso-propyl-4-methoxymethoxybenzaldehyde according to the procedure described in (G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607) and transformed into the title compound by the procedure used for the synthesis of compound 7-13, step b followed by example 7, step b, (0.14 g, 90%); 1H NMR (300 MHz, CD3OD): δ 6.88 (d, J=8.7 Hz, 2H), 6.79 (s, 1 H), 6.64-6.72 (m, 2 H), 4.20 (d, J=10.2 Hz, 2 H), 3.80 (s, 2 H), 3.10-3.15 (m, 1 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 1.17 (d, J=6.9 Hz, 6 H); LC-MS m/z 365 [C20H25O6P+H]+; HPLC conditions: ODSAQ AQ-303-5 column; mobile phase=CH3OH: 0.05% TFA (7:3) flow rate=1.0 mL/min; detection=UV@254 nm retention time in min: 10.96; Anal Calcd for (C20H25O6P+0.3H2O): C, 61.84; H, 6.92. Found: C, 61.60; H, 6.72.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[NH3:12]>>[NH2:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1cnccc1Cl
Reactant: N
Product: Nc1ccncc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
15 g of 4-chloropyridine-3-sulfonamide are dissolved in 150 cm3 of concentrated aqueous ammonia. The clear solution is saturated with a stream of gaseous ammonia for exactly half an hour before being introduced into a sealed tube. The tube is placed at 150° C. for 18 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.C([Li])CCC.C([O:24][C:25]1[CH2:29][CH2:28][C:27](=O)[CH:26]=1)(C)C.Cl>O1CCCC1.O>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([C:27]3[CH2:28][CH2:29][C:25](=[O:24])[CH:26]=3)[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)OC1=CC(=O)CC1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=CC(=O)CC2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
To a solution of 4-bromo-2-cyclopentyloxy-1-methoxybenzene (preparation 4) (9.50 g, 35.0 mmol) in tetrahydrofuran (70 ml) at -78° C. under an argon atmosphere was added dropwise n-butyllithium (15 ml of 2.5M solution, 37.5 mmol). The resulting mixture was stirred at -78° C. for 1.25 hr and added dropwise to a cooled solution (0° C.) of 3-isopropoxy-2-cyclopentenone (4.95 g, 35.3 mmol) in tetrahydrofuran (20 ml). Upon completion of the addition, the reaction mixture was allowed to warm to room temperature and was stirred for 1.5 hr. Hydrochloric acid (70 ml of 0.6N solution) was added to the reaction mixture and stirring was continued for 2.5 hr. The reaction mixture was poured into water and extracted with methylene chloride (four times). The combined organic extracts were dried (magnesium sulfate), the solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 1:4:5 methylene chloride/ether/hexanes. Recrystallization from methylene chloride/ether/hexanes provided needles (5.5 g, 63%): m.p. 136°-137° C. Analysis:
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](O)(=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]>C(OCC)(=O)C.CCCCCC>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]
Reactant: C=CCCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCCCCCCCC(=O)OCCCCCCCCC=CCCCCCCCC
Yield: 96 %

Procedure:
Compound E was prepared from Oleyl alcohol and 9-decenoic acid following the general procedure previously discussed and shown in FIG. 10. Pure compound E was a colorless oil obtained by column chromatography with Ethyl acetate/Hexane=1:40.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][CH:16]([C:24]1([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]1=[O:37])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:61]1(=[O:71])[NH:65][C:64](=[O:66])[C:63]2=[CH:67][CH:68]=[CH:69][CH:70]=[C:62]12>C1COCC1>[O:66]=[C:64]1[C:63]2[C:62](=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:61](=[O:71])[N:65]1[CH2:14][CH2:15][CH:16]([C:24]1([CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]1=[O:37])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reaction time: 8 h
Yield: 52.9 %

Procedure:
Diethyl azodicarboxylate (182 uL, 1.16 mmol) is added to a mixture of tert-butyl α-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (468 mg, 1.16 mmol), triphenylphosphine (304 mg, 1.16 mmol), phthalimide (171 mg, 1.16 mmol) and THF (10 mL) at room temperature. The mixture is allowed to stir overnight and is concentrated. Purification by column chromatography (2 columns, 5% acetone/CH2Cl2 and 10% EtOAc/hexane) provided 327 mg (51%) of the title compound as a colorless oil.