Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][C:18](=[O:28])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH2:1].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[N:21]=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:19][C:18](=[O:28])[CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=c1cc(CCl)nc(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O
Product: O=c1cc(CN2CCN(c3ccc(O)cc3)CC2)nc(-c2ccccc2)[nH]1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 131.4 %

Procedure:
A mixture of 4.46 g (25 mmol) of 1-(4-hydroxyphenyl)piperazine and 5.52 g (25 mmol) of 6-chloromethyl-2-phenyl-4-pyrimidone in 90 ml of absolute N,N-dimethylformamide (DMF) was warmed to 80° C., and 576 mg of powdered K2CO3 was added with stirring under a nitrogen atmosphere in each case after 10 minutes, after a further 25 minutes, and after a further 60 minutes (total addition of 1.73 g (12.5 mmol) of K2CO3), and the mixture was stirred for a further 3.5 hours at 80° C. The DMF was then substantially removed by distillation in vacuo in a rotary evaporator,170 ml of water and 17 ml of 4N HCl were added to the residue, and the resultant mixture was extracted three times with CH2Cl2. The CH2Cl2 extract was discarded. The acidic aqueous solution was treated with activated charcoal, shaken thoroughly, and filtered under suction. The filtrate was neutralized using 2N NaOH. The crystalline precipitate precipitating during this was filtered off under suction, washed with water, boiled for 5 minutes with methanol, and, after cooling to 10°-15° C., filtered off under suction and dried. 6.25 g (=69% yield) of pure 4-(4-hydroxyphenyl)-1-(2-phenyl-3,4-dihydropyrimidin-4-on-6-ylmethyl)piperazine hydrate, melting point 246°-48° C., were obtained, analysis: C21H24N4O3 (MW 380.45) calc. C 66.30, H 6.36, N 14.73; found C 65.9, H 6.1, N 14.5%.
Reaction SMILES: [O:1]([CH2:9][C:10]([F:13])([F:12])[F:11])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[N:14]12[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2>ClCCl>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[F:11][C:10]([F:13])([F:12])[CH2:9][N+:14]12[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C1CN2CCN1CC2
Solvent: ClCCl
Product: FC(F)(F)C[N+]12CCN(CC1)CC2
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 2 h
Yield: 55.9 %

Procedure:
2,2,2-Trifluoroethyl triflate (10.0 g, 43.1 mmol) was added slowly to a stirred, freshly-prepared solution of 1,4-diazabicyclo[2,2,2]octane (7.0 g, 62.5 mmol) in dichloromethane (50 cm3). The reaction mixture was stirred for 2 hours then filtered to remove a white precipitate, which was recrystallized from an ethanol-diethyl ether mixture to provide 1-(2,2,2-trifluoroethyl)-4-aza-1-azoniabicyclo [2,2,2]octane triflate (8.3 g, 24.1 mmol, 56%) (Found: C, 31.2; H, 3.8; N, 7.9%. Calc. C, 31.4; H, 4.1; N, 8.1%). m.p. 123°-125° C., δF (soln. in D2O; ext. CF3CO2H ref.) -0.2 (s; CF3SO3-) 17.8 (t, 3JHF 9 Hz; CF3CH2) p.p.m., δH (same solution) 3.30 (t; 3×ring CH2), 3.72 (t; 3×ring CH 2), 4.36 (q, 3JHF 9 Hz; CH2CF3) p.p.m.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[C:4]([CH3:9])[C:5]([NH2:6])=[CH:7][CH:8]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)ccc1N
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1N
Temperature: 80 °C
Yield: 70.8 %

Procedure:
To a stirred, degassed solution of 4-bromo-2-methylaniline (20 g, 0.107 mol) in toluene (1200 ml) and ethanol (400 ml), under an atmosphere of nitrogen, is added 4-chlorophenylboronic acid (20.32 g, 0.13 mol) and the reaction mixture is stirred and heated to 80° C. Tetrakis(triphenylphosphine)palladium(0) (2.48 g, 0.002 mol) is added to the reaction mixture, and to this is added 2M aqueous potassium carbonate solution (160 ml). The reaction mixture is heated at reflux for 4 hours, then cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (3×500 ml) and the organic extracts are combined and concentrated under reduced pressure to give 4′-chloro-3-methylbiphen-4-ylamine (16.5 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]([NH2:14])[CH3:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([CH3:18])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:16]([NH:14][CH:12]([C:9]1[NH:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:13])([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(N)c1nc(-c2ccccc2)c[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)NC(C)c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.20 g, 1.07 mmol) and acetone (0.062 g, 1.07 mmol) were mixed in 1,2-dichloroethane (4 mL), followed by the addition of NaBH(OAc)3 (0.34 g, 1.61 mmol). The resulting mixture was stirred at rt for 3 h. The reaction was quenched with saturated NaHCO3 solution. The mixture was extracted with EtOAc and the combined extracts were dried over Na2SO4. Filtration followed by evaporation to dryness under reduced pressure gave the crude isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine (0.23 g, 100%) which was used for the next reaction without further purification. 1H NMR (300 MHz, CDCl3): δ 1.10 (3H, d), 1.18 (3H, d), 1.57 (3H, d), 2.86 (1H, m), 4.32 (1H, m), 7.24 (2H, m), 7.36 (2H, m), 7.69 (2H, m). MS (ES+): 230.2 (100%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=2)=[CH:28][CH:29]=1
Reactant: Cc1cncc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCOC=O)c(=O)n3C)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cncc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCO)c(=O)n3C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (56 mg, 0.113 mmol) in THF (3 mL) and water (3 mL) was added LiOH.H2O (9.5 mg, 0.226 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(5-methylpyridin-3-yloxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11 mg, 21% yield) as a white solid. 1H NMR (CD3OD) δ: 8.43 (s, 1H), 8.13-7.95 (m, 2H), 7.22-7.05 (m, 4H), 6.94 (s, 1H), 4.81 (s, 2H), 4.18 (t, J=7.1 Hz, 2H), 3.72 (s, 3H), 3.65 (t, J=6.3 Hz, 2H), 2.24 (s, 3H), 1.98-1.84 (m, 2H). LCMS: MH+ 467 and TR=2.631 min.
Reaction SMILES: C1COCC1.CO.[Li+].[BH4-].[CH3:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][N:12]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CC(C)=O>[CH2:21]([O:20][C:18]([N:12]1[CH2:13][CH:14]([OH:17])[CH2:15][CH2:16][CH:11]1[CH3:10])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1CCC(=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCC(O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of THF (200 mL) and MeOH (11 mL) was added LiBH4 (2 M, 89 mL, 0.18 mol). Some gas evolution and small exotherm were observed. The reaction was aged at room temperature for 30 min before being cooled to −10° C. with an acetone:ice bath. ±benzyl 2-methyl-5-oxopiperidine-1-carboxylate (22.0 g, 0.089 mol) was then added dropwise, keeping the temperature below −5° C. The reaction was then aged at −10° C. for 30 min. The reaction was quenched by adding half-saturated, aqueous NaHCO3, then extracted with EtOAc. The layers were separated and the organics dried with MgSO4. The organics were concentrated to give the titled compound as a crude, colorless oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[NH:6][N:5]=1.[CH3:22]I>CN(C)C=O>[NH2:3][C:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:6]([CH3:22])[N:5]=1.[NH2:3][C:4]1[N:5]([CH3:22])[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1N
Product: Cn1nc(N)c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %
Yield: 43 %

Procedure:
While a dimethylformamide suspension containing 0.17 g of 60% sodium hydride was being cooled with ice, 10 ml of a dimethylformamide solution containing 1.00 g of 3-amino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole was added dropwise thereto, followed by stirring at room temperature for 30 minutes. Then, 5 ml of a dimethylformamide solution containing 0.67 g of methyl iodide was added dropwise thereto, followed by stirring at room temperature for 3 hours. After the dimethylformamide was distilled off under reduced pressure, the resulting residue was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by column chromatography using 250 g of silica gel [with an elution solvent comprising chloroform-methanol (20:1)]. Thus, 0.34 g (32% yield) of 3-amino-5-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole (light-brown crystals) was obtained as a first elution product, and 0.45 g (43% yield) of 5-amino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole (light-brown crystals) as a second elution product.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:31]=1>O1CCCC1>[N:31]1[CH:30]=[CH:35][CH:34]=[CH:33][C:32]=1[C:36]1[N:37]=[C:38]([C:10]2[S:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: c1ccc(-c2cscc2-c2ccccc2)cc1
Reactant: Brc1cccc(-c2ccccn2)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(-c2csc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
After placing 3.5 g of 3,4-diphenylthiophene and 60 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 11 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 4.1 g of a zinc chloride/tetramethylethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 3.8 g of 2-bromo-6-(2-pyridyl)pyridine and 0.52 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, the organic layer was extracted, and the concentrate obtained using an evaporator was purified by recrystallization to obtain 4.5 g of 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene. After placing 3.3 g of the 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene and 80 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 6.2 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 2.4 g of a zinc chloride/tetramethyl-ethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 2.2 g of 2-bromo-6-(2-pyridyl)pyridine and 0.30 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, and the organic layer was extracted. The organic layer was concentrated with an evaporator and purified by column chromatography and recrystallization to obtain 1.1 g of BPPDPT.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][C:18]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][CH2:26][NH2:27])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)([CH3:20])([CH3:17])[CH3:19]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 5-bromo-2,4-dichloro-pyrimidine (1.4 g) in acetonitrile (10 mL) at 0° C. was added triethylamine (0.94 mL) and 3-aminopropylcarbamic acid-1,1-dimethylethyl ester (1.0 g). After removing the cooling bath the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and to the residue water (20 mL) was added. The precipitate was collected, washed with water and ether to afford the title compound (1.8 g).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[N:7][N:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[C:9]=1[NH:10][C:11](=[O:14])[CH2:12][CH3:13])#[N:4].[CH2:27](I)[CH2:28][CH3:29]>O1CCCC1>[C:3]([C:5]1[CH:6]=[N:7][N:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][C:16]=2[Cl:26])[C:9]=1[N:10]([CH2:27][CH2:28][CH3:29])[C:11](=[O:14])[CH2:12][CH3:13])#[N:4]
Reactant: CCC(=O)Nc1c(C#N)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(C(=O)CC)c1c(C#N)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Reaction time: 48 h
Yield: 66.5 %

Procedure:
0.8 g (0.033 mole) of sodium hydride is added to 10.8 g (0.03 mole) of 4-cyano-5-propionylamino-1-(2-chloro-4-trifluoromethoxyphenyl)-pyrazole in 100 ml of tetrahydrofuran and, when the evolution of gas has ended, 10.2 g (0.06 mole) of n-propyl iodide are added and the mixture is stirred at the reflux temperature for 48 hours. For working up, the mixture is concentrated in vacuo, the residue is taken up in 200 ml of methylene chloride and the mixture is washed twice with 100 ml of water each time, dried over sodium sulphate and concentrated in vacuo. The oil which remains is purified by column chromatography (eluant: chloroform/acetone 9:1) and crystallised from petroleum ether. 8.0 g (66.6% of theory) of 4-cyano-1-(2-chloro-4-trifluoromethoxyphenyl)-5-(N-n-propyl-N-propionylamino)-pyrazole of melting point 83° C. are obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[C:21]([NH2:23])=[O:22])C1C=CC=CC=1.[H][H]>CO.C(O)C.[OH-].[OH-].[Pd+2]>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:21]([NH2:23])=[O:22])[CH2:10]1
Reactant: Cc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Cc1ccccc1N1CCNC(C(N)=O)C1

Procedure:
1-benzyl -4-(2-methylphenyl)piperazine-2-carboxamide (2.64 g, 8.53 mmol) and palladium hydroxide/carbon (430 mg) were combined in a mixture of methanol (35 ml) and ethanol (35 ml) and shaken in an atmosphere of hydrogen at 55 psi for 6 hours at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was reconcentrated in vacuo from ether three times to provide 4-(2-methylphenyl)piperazine-2-carboxamide.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([CH:15]1O[CH2:16]1)[Cl:14].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:14][CH2:13][C@H:15]1[O:11][CH2:10][C@H:9]([CH3:12])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16]1
Reactant: ClCC1CO1
Reactant: C[C@@H](CO)NCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CO[C@H](CCl)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2S)-2-[benzylamino]propan-1-ol (1 equivalent) and epichlorohydrin (1 equivalent) was stirred at room temperature overnight. The mixture was cooled down to 0° C. and cold trifluoromethanesulfonic acid (4 equivalents) was added. The flask was equipped with a reflux condenser and the mixture was stirred at 160° C. overnight. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 and quenched with ice water. The mixture was then made basic (pH=12) with a 30% NaOH solution. The two phases were separated, and the aqueous phase was extracted with CH2Cl2. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to afford a dark brown oil. The crude product contained an equimolar mixture of (2R,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine(cis diastereoisomer) and (2S,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine(trans diastereoisomer), which were separated by chromatography on silica gel (ethyl acetate/hexanes 1:20 to 1:8). (2S,5S)-2-(chloromethyl)-5-methyl-4-benzyl morpholine was obtained as the isomer with the lower Rf. GC/MS: 239 (15%, M+), Rt=15.08 minutes; LC/MS (m/z): 240.0 (MH+), Rt 1.56 minutes.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:32]3[CH:40]=[CH:39][C:35]4[O:36][CH2:37][O:38][C:34]=4[CH:33]=3)[CH:23]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>C1COCC1.C(O)C.C(#N)C>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 47.5 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of the 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (26.7 g, 39.1 mmol) in THF (200 mL) and ethanol (200 mL) was added aqueous 1.0 N sodium hydroxide (200 mL) at room temperature. The resulting suspension was heated to 45-50° C. and the mixture was stirred for 30 min and then cooled to room temperature and stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was concentrated and the residue was diluted with water (200 mL) and extracted with diethyl ether (150 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×200 mL). The combined ethyl acetate extracts were washed with brine solution (300 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent afforded the crude product which was dissolved in acetonitrile (270 mL) at hot condition and was stored in the refrigerator. The resulting white solids were collected by filtration and washed with acetonitrile. After air-drying, 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (19.7 g, 80.5%) was isolated as a white solid. ES(+)-HRMS m/e calcd for C33H38O10S (M+Na)+ 649.2078, found 649.2076.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: BrCCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: BrCCCCCCCCCCCCN1CCN(c2ccccc2)CC1
Yield: 50.1 %

Procedure:
A mixture of 6.56 g of 1,12-dibromododecane, 3.24 g of N-phenylpiperazine, 2.53 g of triethylamine, and 50 ml of toluene was heated under reflux for 2 hours. To the reaction mixture was added 100 ml of ethyl acetate, and the mixture was washed successively with water and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using a 1:2 mixture of ethyl acetate and hexane as a developing solvent to yield 4.1 g of 1-bromo-12-(4-phenylpiperazinyl)dodecane (m.p.=26.0°-28.0° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:14](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O.O>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
There was dissolved, in 200 mL of N,N-dimethylformamide, 20.0 g of 5-methyl-2-nitrobenzoic acid, 22.9 g of potassium carbonate and then 8.2 mL of methyl iodide were added to the resulting solution and the mixture was stirred at room temperature for 4 hours. To the reaction liquid, there were added 400 mL of water and 200 mL of a 1M hydrochloric acid solution, then extracted with 900 mL of ethyl acetate, the extract was washed with 200 mL of a saturated sodium hydrogen carbonate solution and 200 mL of a saturated common salt solution and the solvent was then distilled off under reduced pressure to thus give 20.6 g of the title compound as a crude product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]2[CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:9][CH:3]12.[C:17]([N:24]1[CH:28]=[CH:27]N=[CH:25]1)(N1C=CN=C1)=[O:18].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2CCNC[CH2:37]2)=[CH:32][CH:31]=1>>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]2[CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:24]4[CH2:25][CH2:37][CH:36]([C:33]5[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=5)[CH2:27][CH2:28]4)=[O:18])=[CH:12][CH:11]=3)[CH2:9][CH:3]12
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CN1CCC2CN(c3ccc(N)cc3)CC21
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CN1CCC2CN(c3ccc(NC(=O)N4CCC(c5ccc(Cl)cc5)CC4)cc3)CC21

Procedure:
4-(1-Methylhexahydropyrrolo[3,4-b]pyrrol-5-yl)phenylamine was reacted by method A initially with carbonyldiimidazole and then with 4-(4-chlorophenyl)piperidine. The product with the molecular weight of 439.01 (C25H31ClN4O); MS (ESI): 439 (M+H+) was obtained in this way.