Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>O>[CH2:27]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:26]=[CH2:25]
Reactant: CC(=NO)c1ccc(NC(=O)NCC(=O)OC(C)C)cc1
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=C(C)c1ccc(NC(=O)NCC(=O)OC(C)C)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-isopropoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-allyloxyiminoethyl)phenyl]-N'-isopropoxycarbonylmethylurea.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[CH:14](O)=O.C=O>O>[CH3:14][N:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:9]1
Reactant: c1cncc(N2CCCNCC2)c1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CN1CCCN(c2cccnc2)CC1

Procedure:
A solution of 1-(3-pyridyl)-homopiperazine (0.42 g, 2.4 mmol), formic acid (3.3 g, 71.7 mmol), formaldehyde (2.1 g, 37%) and water (10 ml) was stirred at reflux for 15 h. The mixture was evaporated and sodium hydroxide (15 ml, 4 M) was added and the product was extracted two times with ethyl acetate (15 ml). The product was obtained as an oil. Yield 0.46 g, 100%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](N)=[C:9]2[O:13][CH:12]=[CH:11][C:10]=12)=[O:4].[N:15]1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:22]([CH3:21])(=[O:24])=[O:23])=[C:9]2[O:13][C:12]([NH2:15])=[CH:11][C:10]=12)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: COC(=O)c1ccc(N)c2occc12
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c2oc(N)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.4 %

Procedure:
To a solution of 7-amino-benzofuran-4-carboxylic acid methyl ester (6.14 g, 32.1 mmol) and pyridine (13.69 g, 173 mmole) in dichloromethane (100 mL) was added methanesulfonyl chloride (2.8 mL, 36.2 mmol). The reaction mixture was stirred at room temperature under nitrogen for 72 hours. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane and 1 N hydrochloric acid. The organic extract was dried (anhydrous sodium sulfate) and concentrated. The residue was purified by flash column chromatography over silica gel eluting with 20 to 30% ethyl acetate in hexane to give 7-methanesulfonyl-amino-benzofuran-4-carboxylic acid methyl ester (7.73 g, 89%) as a solid. 1H NMR (CDCl3) δ: 3.15 (s, 3H), 3.98 (s, 3H), 7.43 (d, 1H, J=2.2 Hz), 7.50 (d, 1H, J=8.4 Hz), 7.74 (d, 1H, J=2.1 Hz), 8.00 (d, 1H, J=8.3 Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH3:28])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[NH:13][C:14]1[S:15][C:16]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26]O)=[CH:19][C:17]=2[N:18]=1.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:26][C:20]1[CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:16]2[S:15][C:14]([NH:13][C:6]3[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=3[CH3:28])=[N:18][C:17]=2[CH:19]=1
Reactant: Cc1cc(C)c(Nc2nc3cc(CO)cc([N+](=O)[O-])c3s2)c(C)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(Nc2nc3cc(CCl)cc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
Thionyl chloride (0.191 ml, 2.62 mmol) was added to a solution of (2-mesitylamino-7-nitro-1,3-benzothiazol-5-yl)methanol (180 mg, 0.524 mmol) in chloroform. The mixture was stirred at room temperature for 18 h and at 60° C. for 24h. The mixture was poured into water and neutralized with saturated NaHCO3 solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 122 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[O:18][CH3:19].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([N:5]([CH2:4][C:3]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[C:10]([O:18][CH3:19])[CH:11]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCO)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,4-difluorobenzyl)-N-heptyl-2-[4-(2-hydroxyethyl)-2-methoxyphenoxy]acetamide (A)(132 mg, 0.294 mmol) was dissolved in DCM (10 ml). It was cooled in an ice-bath. Triethylamine (0.05 ml, 0.352 mmol) was added and then methanesulfonyl chloride (37 mg, 0.323 mmol) was dropped in. The cooling-bath was removed after 30 minutes. The mixture was stirred at room temperature overnight. LS-MS showed that ca 50% of A was not reacted. The mixture was cooled in an ice-bath and 0.05 ml of triethylamine was added, followed by 0.025 ml of methanesulfonyl chloride. After addition, the cooling-bath was removed and the mixture was stirred for 5 hours more. It was then washed with water (×2) and brine, dried (magnesium sulphate) and evaporated. Oil product 138 mg was left and used for next step without further purification.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH2:14]1[O:16][CH2:15]1>CO.C(#N)C>[S:1]([C:5]1[S:13][C:8]2[CH2:9][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Reactant: C1CO1
Solvent: CO
Solvent: CC#N
Product: NS(=O)(=O)c1cc2c(s1)CN(CCO)CC2
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a solution of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1.74 g, 8.0 mmol) in methanol (25 ml) and acetonitrile (50 ml) was bubbled ethylene oxide gas for 10 minutes. The reaction vessel was stoppered and the mixture was stirred for 18 hours. The precipitated product was collected by filtration. The filtrates were concentrated to provide additional product (total weight, 2.02 g). This material was crystallized from acetonitrile to give 1.67 g (80% yield) of pure product; m.p. 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:47])[NH:24][C@H:25]([C@H:33]([N:36](C)[C:37](OCC[Si](C)(C)C)=O)[CH2:34][CH3:35])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[OH:57][C:51]([C:53]([F:56])([F:55])[F:54])=[O:52].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:47])[NH:24][C@H:25]([C@H:33]([NH:36][CH3:37])[CH2:34][CH3:35])[CH2:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H]([C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1)N(C)C(=O)OCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](NC)[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Reaction time: 0.5 h

Procedure:
Methyl 2-((R)-(3-chlorophenyl)((R)-1-((2S,3R)-1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)pentan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (17 mg) was dissolved in DCM/TFA (4/1 mL) and stirred for 30 min. After concentrated, the slurry was purified through preparative HPLC to afford methyl 2-((R)-(3-chlorophenyl)((R)-1-((2S,3R)-1-cyclohexyl-3-(methylamino)pentan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate TFA salt (11.9 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:7]1[O:15][CH:8]1[C:9]1C=CC=CC=1.C1(C[CH:23]=[O:24])C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:7][O:15][CH:8]([O:24][CH3:23])[CH2:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: c1ccc(C2CO2)cc1
Reactant: c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(Cc1ccccc1)OC
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a benzene (25 ml) solution of styrene oxide (1.20 g, 10 mmol), allyl(1,5-cyclooctadiene)palladium trifluoromethanesulfonate (41 mg, 0.10 mmol) was added as a catalyst, and the mixture was stirred at 50° C. for 10 minutes. The reaction solution was analyzed by an internal standard method by means of gas chromatography and the nuclear magnetic resonance spectrum, whereby it was found that the yield of phenylacetaldehyde was 75%. Then, to this reaction solution, methanol (10 ml) was added, and the mixture was stirred at 50° C. for 30 minutes. To the reaction mixture, a 2% sodium carbonate aqueous solution (20 ml) was added, and the organic layer and the aqueous layer were separated. The organic layer was analyzed by gas chromatography and the nuclear magnetic resonance spectrum, whereby it was found that phenylacetaldehyde disappeared completely and phenylacetaldehyde dimethylacetal formed substantially quantitatively relative to the aldehyde contained in the crude reaction mixture. The phenylacetaldehyde dimethylacetal fraction obtained by the gas chromatography, was subjected to the measurement of the nuclear magnetic resonance spectrum to determine the structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1C(=O)N([Cl:25])C(=O)C1>C(#N)C>[C:1]([NH:4][C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=1[Cl:25])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCO2
Yield: 85.9 %

Procedure:
A mixture of intermediate (2-c) (18.5 g) and NCS (11.4 g) in ACN (130 ml) was stirred and refluxed for one hour. The reaction mixture was cooled. The precipitate was filtered off, washed with ACN, with DIPE, then dried, yielding 18.2 g (87%) of methyl 7-(acetylamino)-6-chloro-1,3-benzodioxole-4-carboxylate (intermediate 2-d).
Reaction SMILES: C[C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[C:7]([CH3:12])[C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH:3]=1.[I:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[C:26](#N)C>>[I-:17].[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N+:9]1[C:10]2[CH:2]=[CH:3][C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6]=2[C:7]([CH3:26])([CH3:12])[C:8]=1[CH3:11])([OH:25])=[O:24]
Reactant: CC#N
Reactant: Cc1[nH]c2c(C)cc3ccccc3c2c1C
Reactant: O=C(O)CCCCCI
Product: CC1=[N+](CCCCCC(=O)O)c2ccc3ccccc3c2C1(C)C
Product: [I-]
Temperature: 100 °C
Yield: 75 %

Procedure:
To a 250 mL flask were added trimethylbenz[e]indole (5.21 g, 24.9 mmol), acetonitrile (80 mL) and 6-iodohexanoic acid (6.5 g, 26.9 mmol). The mixture was heated at reflux under argon for 1 h and then approx. 70 mL of the acetonitrile was removed by distillation. The mixture was heated at 100° C. for 20 h. The green mixture of solid and liquid was cooled to rt and the volatile components were removed in vacuo. The residue was triturated with ether (2×60 mL), ethyl acetate (2×60 mL) and with ether (2×60 mL) to give 12 as a powder (8.51 g, 75%).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:18])=[N:7][C:8]([Cl:17])=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:19]Br>CC(O)=O>[Br:19][CH2:18][C:6]1[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([Cl:17])[N:7]=1
Reactant: CCCCc1c(C)nc(Cl)nc1-c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCCc1c(CBr)nc(Cl)nc1-c1ccccc1

Procedure:
A solution of the 5-butyl-2-chloro-4-methyl-6-phenyl-pyrimidine (215 mg, 0.825 mmol) and Br2 (0.042 ml, 0.825 mmol) in AcOH (2 mL) is stirred at 80° C. for 2 hours. After cooling, the solution is concentrated. The residue is partitioned between Et2O and half saturated aqueous NaHCO3. The layers are separated, and the aqueous layer is reextracted once with Et2O. The combined extracts are dried over Na2SO4 and concentrated to 305 mg of crude 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine, which also contains small amounts of SM and dibromo material. This material is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[N:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:26][C:24]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][NH:26][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][N:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccncc1[N+](=O)[O-]
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To the mixture of 3-nitroisonicotinic acid (4.78 g, 28.4 mmol), methylamine hydrogen chloride (2.88 g, 1.5 eq), EDC (6.53 g, 1.2 eq), HOBt (4.59 g, 1.2 eq) in DMF (50 mL) was added DIEA (25 mL, 5.0 eq). The mixture was stirred at room temperature overnight. It was concentrated and the crude was dissolved in EtOAc. It was washed with saturated NaHCO3 solution. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product N-methyl-3-nitroisonicotinamide (878 mg, isolated yield 17%).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([OH:9])=[O:8])[CH:2]=1.[P:10]([OH:13])([OH:12])[OH:11].P(Cl)(Cl)Cl>S1(CCCC1)(=O)=O>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:10]([OH:13])([OH:12])=[O:11])([P:10]([OH:13])([OH:12])=[O:11])[OH:9])[CH:2]=1.[OH2:8]
Reactant: OP(O)O
Reactant: O=C(O)Cn1ccnc1
Solvent: ClP(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: O
Product: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A suspension of 1-imidazolylacetic acid (50 g, 0.396 mol) and phosphorous acid (48.7 g, 0.594 mol) in sulfolane (180 ml) is heated to 75° C. for 30 min. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (117 ml, 1.346 mol) while maintaining the temperature between 35-45° C. The mixture is heated to 63-67° C. for 3 hrs, whereby white solid results. It is then cooled to 0-5° C. and quenched by slow addition of water (500 ml) at 0-5° C. over a period of 1 hr. The resulting clear solution is heated at 100° C. for 3 hrs, cooled to ambient temperature and charcoalized. To the charcoalized solution is added acetone (800 ml). The mixture is then stirred for 4 hrs at 20-25° C. and the crystallized product is filtered, washed sequentially with chilled water (200 ml), acetone (100 ml) and dried in air oven at 55-60° C. until water content is between. 6.2-7.2% w/w. Yield 81.3 g, (70.7%), appearance: white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=O)[C:12](=O)[N:11]3[C@H:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:17][CH2:18][C@H:10]3[CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30].B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[C@H:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:17][CH2:18][C@@H:10]3[CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1cc(N2C[C@@H]3CC[C@@H](c4ccc(OC)c(OC)c4)N3C(=O)C2=O)ccc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCN3[C@H](CC[C@H]3c3ccc(OC)c(OC)c3)C2)ccc1Cl
Temperature: 0 °C
Yield: 30.9 %

Procedure:
(±)-cis-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine-3,4-dione (49.7 mg, 0.115 mmol) was dissolved in dry THF (10 mL) and BH3.THF (1 mL, 1 mmol) was added dropwise to the mixture, which was then heated at reflux overnight. The solution was cooled to 0° C. and MeOH (2 mL) was added dropwise. The solvent was removed by evaporation and the crude product was dissolved in MeOH (10 mL) and 12N HCl (2 mL). The solution was refluxed for 4 hours. The reaction mixture was concentrated (˜2 mL) followed by basification with 1N NaOH. The aqueous solution was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude products were purified by preparatory TLC eluting with CH2Cl2/MeOH (97:3) to yield the (±)-cis- (20.3 mg, 43.8%) and (±)-trans-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine (14.3 mg, 30.9%) with (±)-cis-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine eluting further up the plate. (±)-trans-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine 1H NMR (CDCl3) δ 7.20 (d, J=8.7 Hz, 1H, ArH), 6.89-6.83 (m, 3H, ArH), 6.47-6.40 (m, 2H, ArH), 4.16 (m, 1H), 3.95-3.84 (m, 1H), 3.90 (s, 3H, OCH3), 3.88 (s, 6H, OCH3), 3.58-3.46 (m, 1H), 3.41-3.36 (m, 1H), 3.26-3.22 (m, 1H), 2.99-2.71 (m, 3H), 2.34-2.20 (m, 2H), 1.95-1.83 (m, 1H), 1.64-1.54 (m, 1H). LCMS m/z 403 (M++1, 100, 1.90 min).
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][SH:25])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1>C(Cl)Cl>[ClH:10].[ClH:10].[CH2:1]([NH:7][C:8](=[SH:25][CH2:24][CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:27][CH:26]=2)[CH2:17][CH2:18]1)[OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN=C=O
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CCCCCCNC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Product: Cl
Yield: 157.9 %

Procedure:
The procedure described in Example 35 was followed, using 1.4 g of n-hexyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol and 100 ml of methylene chloride, to give 2.7 g (51% of theory) of N-(n-hexyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 249°-252° C. (dec.).
Reaction SMILES: [Li]C[CH2:3][CH2:4][CH3:5].[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[CH:12]=O.[CH2:15]1COCC1>>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11](/[CH:12]=[CH:15]/[CH:4]([CH3:3])[CH3:5])[CH:14]=1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: O=Cc1cncc(Br)c1
Product: CC(C)/C=C/c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of 4.26 g (10.7 mmol) of Ph3PCH2CH(CH3)2Br in 20 mL of THF O° C. was added 12.0 mL of n-BuLi (1.6 M in hexanes). The mixture was stirred at 0° C. for 1 h, and then 521 mg (2.82 mmol) of 5-bromonicotinaldehyde in 20 mL of THF was added. After 5-10 min. the bath was removed and stirring was continued with warming to r.t. After 1 h, the reaction was quenched with water and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography 15% EtOAc/hexanes provided (E)-3-bromo-5-(3-methylbut-1-enyl)pyridine and impurity.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].C(Cl)Cl>CCCCCC>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCO
Product: N#Cc1cc(N)ccc1Sc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 904.2 %

Procedure:
To a stirred slurry of 4-nitro-2-cyanophenyl phenyl sulfide (13.3 g, 5.19 mmol) and 100 mL of absolute ethanol was added stannous chloride dihydrate (58.6 g, 26 mmol) in one portion. The mixture was heated to 60° C. where an exothermic reaction caused the solution to strongly reflux. The mixture was allowed to stir at ambient temperature for 30 min., poured onto ice-water and made strongly basic by the addition of 350 mL of 15% NaOH. The mixture was extracted with methylene chloride (4×275 mL), the extracts dried (MgSO4), filtered, and the solvent removed in vacuo to yield an oil which was chromatographedon 300 g of silica gel using a methylene chloride (20%, 40%, 60% 80% and 100%) in hexane gradient. The proper fractions were combined and the solvent removed to yield the 4-amino-2-cyanophenyl phenyl sulfide (10.62 g, 91%) as a pale yellow solid; mp 73°-75° C. 1H-NMR (300 MHz, CDCl3): 4.01 (s, 2H, NM2), 6.78 (dd 1H, J=8.5, 2.6, aromatic), 6.95 (d, 1H, J=2.6, aromatic), 7.18-7.29 (m, 5H, aromatic), 7.34 (d, 1H, J=8.5, aromatic). MS (CI, CH4):
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([F:42])[CH:41]=1>O>[F:35][C:36]1[CH:37]=[C:38]([C:13]2[C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=2)[CH:39]=[C:40]([F:42])[CH:41]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cc(F)cc(F)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 47.6 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3,5-difluorophenylboronic acid (56 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (23 mg, yield 47%).
Reaction SMILES: Br(O)(=O)=O.[Br:5][CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:8][CH2:7][CH2:6][Br:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: [O-][Br+2]([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 25 °C

Procedure:
10 g (49 mmol) of 2-bromoethylamine bromate and 15 ml of triethylamine were dissolved in dichloromethane. 7.8 ml (49 mmol) of benzyl chloroformate was added to the solution under cooling with ice, and they were stirred at room temperature. After the treatment with dichloromethane as the extractant in an ordinary manner, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound.