Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#[N:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:29].[Ca+2].[OH-:31]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:31])(=[O:29])[C:7]=2[CH:17]=1)#[N:2]
Reactant: [OH-]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
800 Mg. 3-cyano-10,11-dihydrodibenzo[b,f]thiepin is dissolved in 75 cc. methylene chloride and 1.73 g. m-chloroperbenzoic acid is added and the solution stirred at room temperature for three hours. An additional 10 cc. methylene chloride is added, followed by a large excess of powdered calcium hydroxide. After stirring for 5 minutes, the mixture is filtered through celite and the filtrate stripped to dryness and the residual solid triturated with ether and filtered to yield 854 mg. (94%) of the desired pure white solid.
Reaction SMILES: C=O.[C:3]([BH3-])#[N:4].[Na+].[O:7]=[C:8]1[NH:13][C:12]([C:14]2[CH:19]=[C:18](N)[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH3:23])=[N:11][CH:10]=[C:9]1[C:24]([O:26]CC)=[O:25].[C:29](O)(=O)C>O.C(#N)C.C(OCC)C>[O:7]=[C:8]1[NH:13][C:12]([C:14]2[CH:19]=[C:18]([N:4]([CH3:3])[CH3:29])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH3:23])=[N:11][CH:10]=[C:9]1[C:24]([OH:26])=[O:25]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1cnc(-c2cc(N)ccc2OCC)[nH]c1=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CCOc1ccc(N(C)C)cc1-c1ncc(C(=O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
A solution (1.9 ml.) of 37% formaldehyde (23.8 mmoles) in water followed by sodium cyanoborohydride (450 mg., 7.15 mmoles) were added to a stirred solution of ethyl 1,6-dihydro-6-oxo-2-(5-amino-2-ethoxyphenyl)pyrimidine-5-carboxylate (720 mg., 2.38 mmoles) in acetonitrile (14 ml.). Glacial acetic acid (0.24 ml.) was then added over a period of one minute. The mixture was stirred at room temperature for 2 hours. Additional glacial acetic acid (0.24 ml.) was added and stirring was continued for an extra 0.5 hour. The mixture was treated with diethyl ether (35 ml.). The organic layer was washed with 10% aqueous sodium bicarbonate (3 × 10 ml.) followed by brine (30 ml.) and dried (sodium sulfate). The solvent was removed and a solution of the residue in acetonitrile-diethyl ether was extracted with 1 N sodium hydroxide (3 × 20 ml.). The aqueous extract was acidified with glacial acetic acid to pH 6. The precipitate was collected and recrystallized from acetonitrile to give the title compound (210 mg., 29%), m.p. 187°-196°. Recrystallization from benzene-Skellysolve B gave analytical material, m.p. 195°-198°.
Reaction SMILES: ClC1SN=C(SC)N=1.ClC1C=CC=C(C(OO)=O)C=1.Cl[C:21]1[S:25][N:24]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[N:22]=1.Cl[C:31]1[S:35][N:34]=[C:33]([S:36]([CH3:38])=[O:37])[N:32]=1.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>O.C(Cl)(Cl)Cl>[CH3:29][S:26]([C:23]1[N:22]=[C:21]([N:39]2[CH2:44][CH2:43][S:42][CH2:41][CH2:40]2)[S:25][N:24]=1)(=[O:28])=[O:27].[CH3:38][S:36]([C:33]1[N:32]=[C:31]([N:39]2[CH2:44][CH2:43][S:42][CH2:41][CH2:40]2)[S:35][N:34]=1)=[O:37]
Reactant: CS(=O)c1nsc(Cl)n1
Reactant: CS(=O)(=O)c1nsc(Cl)n1
Reactant: C1CSCCN1
Agent: CSc1nsc(Cl)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1nsc(N2CCSCC2)n1
Product: CS(=O)c1nsc(N2CCSCC2)n1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
With 12 ml of chloroform was mixed 1.0 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, and 2.59 g of 3-chloroperbenzoic acid (content: 70-75 weight %) was added under ice-cooling. The mixture was stirred at room temperature for 2.25 hours and left as it was for 15 hours to obtain a crude mixture of 5-chloro-3-methylsulfonyl-1,2,4-thiadiazole and 5-chloro-3-methylsulfinyl-1,2,4-thiadiazole. Into the crude mixture of 5-chloro-3-methylsulfonyl-1,2,4-thiadiazole and 5-chloro-3-methylsulfinyl-1,2,4-thiadiazole was added 2.46 g of thiomorpholine dropwise under water-cooling. The mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with chloroform after the addition of saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.08 g of 3-methylsulfonyl-5-thiomorpholino-1,2,4-thiadiazole and 6 mg of 3-methylsulfinyl-5-thiomorpholino-1,2,4-thiadiazole.
Reaction SMILES: [CH2:1]([C:3]1[S:7][CH:6]=[C:5]([C:8](Cl)=[O:9])[CH:4]=1)[CH3:2].[N+](=[CH:13][Si](C)(C)C)=[N-].[BrH:18].C(=O)(O)[O-].[Na+]>CC#N>[Br:18][CH2:13][C:8]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[S:7][CH:6]=1)=[O:9]
Reactant: Br
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCc1cc(C(=O)Cl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(C(=O)CBr)cs1
Temperature: 0 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
5-Ethylthiophene-3-carbonyl chloride (224 mg, 1.28 mmol) was dissolved in dry CH3CN (10 ml) and cooled at 0° C., under nitrogen atmosphere. (Diazomethyl)-trimethylsilane (1.92 ml, 3.85 mmol, 2M in hexane) was slowly added, and the resulting reaction was stirred at room temperature for 18 hours. Then the reaction was cooled at 0° C. and 48% HBr was added dropwise. The reaction was stirred at 0° C. for 2 hours. Smashed ice was added to the mixture, and then sodium bicarbonate was added until pH is about 7. The solution was extracted with EtOAc, and the organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography (Petroleum ether/EtOAc=9/1) to obtain 2-bromo-1-(5-ethylthiophen-3-yl)ethanone (97 mg, 32.4% yield).
Reaction SMILES: CN(N=O)C(N[C@H:6]1[CH:11]([OH:12])[O:10][C@H:9]([CH2:13][OH:14])[C@@H:8]([OH:15])[C@@H:7]1[OH:16])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:22]>>[O:14]=[CH:13][C@@H:9]([C@H:8]([C@@H:7]([C@@H:6]([CH2:11][OH:12])[OH:22])[OH:16])[OH:15])[OH:10]
Reactant: CN(N=O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
SD/IGS rats at 7 weeks of age (male, Charles River Laboratories Japan Inc.) were fasted for about 16 hours and then injected with 50 mg/kg streptozotocin (STZ) via the tail vein under ether anesthesia to prepare diabetic model rats. Similarly, another group of SD/IGS rats at 7 weeks of age was injected with 1.25 mmol/L citric acid in physiological saline (1 mL/kg) via the tail vein under ether anesthesia to prepare normal control rats. At one week after injection of STZ or 1.25 mmol/L citric acid in physiological saline, the rats were provided for an oral glucose tolerance test.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.Cl[C:12]1[C:17]2[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][O:20][C:16]=2[CH:15]=[N:14][N:13]=1>CN(C)C=O>[C:21]1([C:18]2[C:17]3[C:12]([O:10][CH2:9][CH:6]4[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]4)=[N:13][N:14]=[CH:15][C:16]=3[O:20][N:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCC1CCNCC1
Reactant: Clc1nncc2onc(-c3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2noc3cnnc(OCC4CCNCC4)c23)cc1
Reaction time: 0.5 h

Procedure:
To sodium hydride (95% dispersion in mineral oil, 0.043 g) in N,N-dimethylformamide (6 mL) at 0° C. was added piperidin-4-ylmethanol (0.206 g). After stirring for 30 minutes, the compound prepared in Example 82 was added. The ice bath was removed and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was then diluted with saturated a sodium bicarbonate solution and extracted with dichloromethane. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methanol:concentrated aqueous ammonia:dichloromethane=6:1:94) to obtain the title compound (0.20 g) having the following physical data.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7]Cl)[CH3:4].[H-].[Na+].[CH2:11]([C:13]1[C:18]([OH:19])=[N:17][C:16]([CH3:20])=[C:15]2[S:21][CH:22]=[CH:23][C:14]=12)[CH3:12].O>CN(C=O)C>[CH2:11]([C:13]1[C:18]([O:19][CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2])=[N:17][C:16]([CH3:20])=[C:15]2[S:21][CH:22]=[CH:23][C:14]=12)[CH3:12]
Reactant: CN(C)CCCCl
Reactant: CCc1c(O)nc(C)c2sccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OCCCN(C)C)nc(C)c2sccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
3-(N,N-Dimethylamino)propylchloride hydrochloride (5.51 g, 34.9 mmol) and sodium hydride (60% in oil, 1.55 g, 38.8 mmol, prewashed with pentane) in DMF (30 ml) were stirred at room temperature for one hour. This solution was then added to a mixture of 4-ethyl-7-methylthieno[2,3-c]pyridin-5-ol (2.9 g, 15.0 mmol) and sodium hydride (60% in oil, 0.60 g, 15.0 mmol, prewashed in pentane) in DMF (30 ml) which had been allowed to react for two hours. The combination was stirred at room temperature for three days, poured into H2O (500 ml), extracted with CH2Cl2 (3×200 ml) and dried over MgSO4. The solvent was removed in vacuo and the product was purified by flash chromatography on silica gel 60 (120 g) using 8% MeOH in CH2Cl2 as the eluant to give the product (2.3 g, 55% yield) as a yellow oil; IR (neat) 1440, 1580 and 2980 cm-1 ; mass spectrum m/z 279 (MH+); 1H NMR (CDCl3) δ 1.20 (t, J=7 Hz, 3H, CH2CH3), 1.68 to 2.90 (m, 6H, CH2CH2N, CH2CH3), 2.27 (s, 6H, N(CH3)2), 2.63 (s, 3H, 7-CH3), 4.43 (t, J=6 Hz, 1H, OCH2CH2), 7.27 and 7.53 each (d, J=6 Hz, 1H, thiophene-H).
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:2][CH2:1][CH:3]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH2:4][CH3:5]
Reactant: CCC(N)CC
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CCC(CC)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1-ethylpropylamine (10.0 g, 115 mmol) in tetrahydrofuran (80 mL) was added a solution of 1,3-propane sultone (13.7 g, 110 mmol) in 20 mL of THF. The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×50 mL), and dried in vacuo., to afford compound DD (18.1, 80%): 1H NMR (D2O, 500 MHz) 8 ppm 3.08 (t, 2H, J=7.3 Hz), 3.01 (m, 1H), 2.87 (t, 2H, J=7.3 Hz) 2.00 (m, 2H), 1.59 (m, 4H), 0.82 (t, 6H, J=7.3 Hz). 13C NMR (D2O, 125 MHz) 8 ppm 60.87, 48.14, 43.68, 21.81. 21.60, 8.25. ES-MS 208 (M−1).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[C:14]([CH2:15][O:16][C:17]4[C:26]5[C:25](=O)[O:24]C(C)(C)[O:22][C:21]=5[CH:20]=[CH:19][CH:18]=4)=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:5](CC1)[CH2:4][O:3][CH2:2]2.[CH3:30][CH:31](C[AlH]CC(C)C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH:4]12[O:3][CH:2]([CH2:30][CH2:31]1)[CH2:1][N:8]([C:9]1[C:14]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:26]=3[CH:25]=[O:24])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:5]2
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CC1(C)OC(=O)c2c(OCc3cccnc3N3C4CCC3COC4)cccc2O1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=Cc1c(O)cccc1OCc1cccnc1N1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a cooled (−78° C.) solution of 5-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)methoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (0.11 g, 0.28 mmol) in CH2Cl2 was added DIBAL-H (0.85 mL, 1M in CH2Cl2) and reaction mixture was allowed to warm to ambient temperature over 3 hours. The reaction mixture was then cooled (−78° C.) and MeOH was added followed by saturated potassium sodium tartrate solution (300 μL). This mixture was stirred for 2 hours at ambient temperature and filtered over Celite. The resulting solution was partitioned between EtOAc and saturated aqueous NaHCO3 and washed two times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by preparatory HPLC resulted in 2-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde (0.025 g, 25% yield). 1H NMR (400 MHz, Chloroform-d) δ 11.95 (s, 1H), 10.39 (d, J=0.6 Hz, 1H), 8.32 (dd, J=4.8, 1.9 Hz, 1H), 7.74 (dd, J=8.0, 2.1 Hz, 1H), 7.40 (t, J=8.4 Hz, 1H), 7.00 (dd, J=7.5, 4.8 Hz, 1H), 6.56 (d, J=8.5 Hz, 1H), 6.39 (d, J=8.3 Hz, 1H), 5.15 (s, 2H), 4.47-4.40 (m, 2H), 3.33 (dd, J=12.5, 2.0 Hz, 2H), 3.03 (dd, J=12.3, 1.4 Hz, 2H), 2.13-1.94 (m, 4H). MS (ES) for C19H20N2O4: 341 (MH+).
Reaction SMILES: [C:1]([P:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)C(F)(F)F.[C:24]1([B-:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>>[C:43]1([B-:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1.[C:10]([PH+:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Na+]
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C

Procedure:
Tri-tert-butylphosphine is reacted with 1,1,1,3,3,3-hexafluoro-2-propanol and with sodium tetraphenylborate to produce tri-tert-butylphosphonium tetraphenylborate (77% yield). A similar process is described in which tricyclohexylphosphine is used as starting material to produce tricyclohexylphosphonium tetraphenylborate (77% yield) (see Nonpatent Document 7).
Reaction SMILES: CO[C:3]1([O:17][CH3:18])[CH2:8][CH2:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1.C[Si]([C:23]#[N:24])(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:10]([O:9][CH:6]1[CH2:5][CH2:4][C:3]([O:17][CH3:18])([C:23]#[N:24])[CH2:8][CH2:7]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)C#N
Reactant: COC1(OC)CCC(OCc2ccccc2)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C#N)CCC(OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
1.5 g of (4,4-Dimethoxy-cyclohexyloxymethyl)-benzene (38) were dissolved in 20 mL of dry dichloromethane and cooled to 0° C. 3.05 mL of trimethylsilyl cyanide were added dropwise and after stirring for 2 minutes, 1.31 mL of trimethylsilyl trifluoromethansulfonate were added dropwise. The mixture was stirred at 0° C. for 2 h, then 20 mL of saturated aqueous sodium bicarbonate solution were added dropwise. Phases were separated and the aqueous layer was extracted several times with dichloromethane. The combined organic layer was dried and evaporated to dryness to give 1.5 g of crude product, that was purified by silica gel chromatography to give 1.3 g of the desired compound as a cis-trans-mixture. Rt=4.68 min (Method D). Detected mass: 246.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.[ClH:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: N[C@H]1CCCc2ccccc21
Solvent: Cc1ccccc1
Product: Cl
Product: c1ccc2c(c1)CCC[C@@H]2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and (S)-1,2,3,4-tetrahydro-1-naphthylamine by Procedure A (reflux in toluene for 2 days). The product was purified by preparative LCMS, added HCl and isolated as a HCl salt (white solid, mp 257-258° C.). MS(ES+) m/z 264 ([M+1]+, 100).
Reaction SMILES: [CH:1]([N:4]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=O)[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:49]1[NH:54][CH2:53][CH2:52][N:51]2[CH2:55][CH2:56][CH2:57][C@H:50]12>ClCCl.CN(C)C=O.ClCCl>[CH2:49]1[N:54]([C:21]([C:20]2[CH:19]=[C:18]([N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)(=[O:7])=[O:6])[CH:26]=[CH:25][CH:24]=2)=[O:23])[CH2:53][CH2:52][N:51]2[CH2:55][CH2:56][CH2:57][C@H:50]12
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: CC(C)N(c1cccc(C(=O)O)c1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(c1cccc(C(=O)N2CCN3CCC[C@@H]3C2)c1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 3-(N-isopropyl-3-(trifluoromethyl)phenylsulfonamido)benzoic acid (155 mg, 0.4 mmol) and 1-hydroxybenzotriazole hydrate (61 mg, 0.4 mmol) in dichloromethane/N,N-dimethylformamide (4:1, 6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 62 mg, 0.4 mmol) in dichloromethane (1 mL). After 5 minutes, (R)-octahydropyrrolo[1,2-a]pyrazine (50 mg, 0.4 mmol) in dichloromethane (1 mL) was added. The mixture was stirred at room temperature overnight. Then the mixture was concentrated. The residue was diluted with ethyl acetate (100 mL), washed with water (2×20 mL), dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:12) to give the titled compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 (d, 6H, J=8 Hz), 1.35 (m, 1H), 1.65-2.10 (m, 6H), 2.80-3.05 (m, 4H), 3.45-3.55 (m, 1H), 4.40-4.50 (m, 1H), 4.60 (m, 1H), 6.98 (s, 1H), 7.15 (m, 1H), 7.50 (m, 2H), 7.88 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1(Cl)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-:17].[Na+]>C(O)C>[CH3:1][C:2]1([S:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:17]
Reactant: SCc1ccccc1
Reactant: [OH-]
Reactant: CC1(Cl)CCCCC1
Agent: [Na+]
Solvent: CCO
Product: CC1(SCc2ccccc2)CCCCC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
36.5 g of 2-methyl-2-chlorocyclohexane are dissolved in 70 ml ethanol. To this solution is added a mixture of 82 g benzylmercaptan 26.4 g of sodium hydroxide and 330 ml ethanol and the whole is heated to reflux. A pink colour appears after 15 minutes and the mixture is then allowed to cool to room temperature and the solvent is distilled off. The oily residue is taken up in 400 ml water and the resulting suspension is extracted with methylene chloride. The organic phases are united, washed with water until neutral, dried over sodium sulphate and the solvent is evaporated off. The residue is purified by fractional distillation. 120 g of 2-methyl-2-benzylthiocyclohexanone are recovered, boiling at 142°-144° (yield=78%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)=[O:28]
Reactant: Cc1csc(C(=O)CBr)n1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nc(C)cs2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (Step 1 of Example 8, Method A) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden, William B. et al., Aust. J. Chem., 1985, 38, 1257).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:14])[CH:2]=[CH2:3].C(O)(=O)C.Br>CCOCC>[CH3:3][CH:2]1[CH2:1][C:4]2[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=2[O:14]1
Reactant: C=CCc1c(C)ccc([N+](=O)[O-])c1O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc([N+](=O)[O-])c2c1CC(C)O2

Procedure:
47 g of 1B was added to a mixture of 100 ml of glacial acetic acid and 100 ml of 48% aqueous hydrobromic acid and the mixture was heated at 114°-115° C. for 2.5 hours. The resulting mixture was stripped to dryness, the residue was taken up in 500 ml of ether, and filtered. The filtrate was concentrated to 100 ml, 300 ml of hexane was added, the mixture was chilled and filtered to give 2,3-dihydro-2,4-dimethyl-7-nitrobenzofuran (1C), as a tan solid, m.p.: 69°-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][CH2:18]Br>CN(C=O)C>[Br:16][CH2:17][CH2:18][O:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1OCCBr
Temperature: 100 °C
Yield: 48.9 %

Procedure:
Into a 10 mL round bottom flask was added 2,6-dichlorophenol (326 mg, 2 mmol) and DMF (2 mL). Potassium carbonate (276 mg, 2 mmol, 10 eq) and 1,2-dibromoethane (3.76 g, 20 mmol, 10 eq) was added. The flask was fitted with a reflux condenser and nitrogen inlet and the reaction heated to 100° C. for 2 hours. The mixture was partitioned between water (20 mL) and chloroform (20 mL). The organic layer was separated and the aqueous layer was further extracted with chloroform (3×20 mL). The organic layers were combined, washed twice with 10% sodium carbonate (20 mL) and once with brine (20 mL). The combined organic phase was dried over sodium sulfate and filtered. Solvent was removed under vacuum to leave a brown oil of 2A (264 mg, 49%) which was analytically pure.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[ClH:1].[ClH:1].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][N:25]([C:20]4[N:19]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:26][CH2:27]3)[CH2:5][CH2:6]2)=[O:18])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCl)CC1
Reactant: c1cnc(N2CCNCC2)nc1
Product: Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2CCN(c3ncccn3)CC2)CC1

Procedure:
This compound was prepared from 1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine and 1-(2-pyrimidinyl) piperzine according to the process described in Example 3, Stage B.