Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)(Cl)Cl>[O:18]1[C:2]2([CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:1]1
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2(CO2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.9 %

Procedure:
To a solution of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate (2.96 g, 17.5 mmol) in chloroform (180 mL) was added 3-chloroperoxybenzoic acid (77%, 13.9 g, 62.0 mmol), and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions. The organic portion was isolated, dried over sodium sulfate, filtered and concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes) to give 1,1-dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (1.65 g, 51%), GC-MS for C9H15NO3: 185.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([C:11]([F:13])([F:12])[F:14])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)F)cnc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.87 g) in ethyl acetate (40 mL) was added tin(II) chloride dihydrate (8.22 g), and the mixture was stirred at 80° C. for 2 hours. After cooling, to the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution, and the mixture was vigorously stirred at room temperature and filtered through a celite pad. The residue was washed with ethyl acetate. The filtrate was combined with the washings, washed successively with an aqueous saturated sodium hydrogencarbonate solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was triturated with n-hexane to give 3-amino-2-chloro-5-(trifluoromethyl)pyridine (0.99 g) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([O:1][S:35]([CH3:34])(=[O:37])=[O:36])([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc2n(CCC)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(OS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of 50 mg of 8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 13a) (0.14 mmol) in CH2Cl2 (5 ml) was added 20 μL of Et3N and the reaction mixture cooled in an ice bath. To this was added 20 μL of methanesulfonyl chloride (0.26 mmol) and the reaction mixture kept at 10° C. overnight. The reaction mixture was concentrated in vacuo and the residue taken up in EtOAc and washed 2× with dilute HCl (5 ml). The organic layer was dried over NaSO4 and conc'd. The residue was triturated in acetonitrile to afford 36 mg (59%) of pure white solid (MH+=439.4).
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[O-:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[C:19]1([I+]C2C=CC=CC=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:14][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:13])=[O:11].[C:19]1([S+:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH:3]=[C:2]2[CH3:1])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: Cc1cc2ccccc2s1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: Cc1cc2ccccc2[s+]1-c1ccccc1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
2-Methylthianaphthene (5 g 0.0327 mole), diphenyliodonium triflate (18.28 g, 0.0425 mole) and copper benzoate (0.1 g, 0.000327 mole) were heated without solvent for 0.5 hours at 140° C. under a nitrogen atmosphere. After cooling down, 150 ethyl ether was added to solidify the product. Filtration and washing with ethyl ether Yielded a brownish-grey solid, which was dissolved in 500 ml hot water, and the solution filtered and the water removed in vacuo. The resulting off-white solid was stirred in 50 ml ethyl ether for 1 hour, the mixture filtered and the residue washed with ethyl ether. The product was recrystallized from dichloromethane/t-butyl methyl ether to yield 8.97 g (76%) of 1-phenyl-2-methylbenzothiophenium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.I[CH3:19].[OH-].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:17][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: OC(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 193 %

Procedure:
A mixture of 1,2-di(p-bromophenyl)-hydroxyethane (40 g, 0.056 mol), iodomethane (150 g) and powdered potassium hydroxide (30 g) was stirred at room temperature of 3 days. The reaction mixture was transferred into a 500 mL separatory funnel and water (200 mL) was added. The resulting mixture was extracted with chloroform (150 mL×2). The combined organic phases were dried through sodium sulfate and concentrated to provide an oil which was distilled under vacuum to give the title compound (40 g, 85%). This oil solidified upon standing and was recrystallized from methanol to provide fine crystals (mp: 53-54° C.), which showed the expected proton NMR spectrum.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.CC1C=CC(S(O[CH2:46][CH:47]2[CH2:50][O:49][CH2:48]2)(=O)=O)=CC=1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH2:46][CH:47]6[CH2:50][O:49][CH2:48]6)[CH:5]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC2)cc1
Product: c1cc(N2CCCNCC2)nc(-n2ncc3cnc(-c4cnn(CC5COC5)c4)cc32)c1
Yield: 51 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and oxetan-3-ylmethyl 4-methylbenzenesulfonate, 158 was obtained as a yellow solid (38 mg, 51%) over two steps. 1H-NMR (500 MHz, CD3OD) δ (ppm): 9.16-9.19 (m, 1H), 8.86-8.77 (m, 3H), 8.43-8.47 (m, 1H), 7.66-7.73 (m, 1H), 7.18-7.26 (m, 1H), 6.63-6.66 (m, 1H), 4.81-4.83 (m, 2H), 4.60-4.64 (m, 2H), 3.75-3.97 (m, 7H), 3.61-3.64 (m, 1H), 3.46-3.48 (m, 1H), 3.10-3.12 (m, 1H), 2.88-2.90 (m, 1H), 1.98-2.07 (m, 2H); MS (ESI) m/z: 431 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:18][CH3:19])[C:8]2[C:9]([CH2:16][OH:17])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([CH2:6][N:7]([CH2:18][CH3:19])[C:8]2[C:9]([CH:16]=[O:17])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCN(CC1CCCC1)c1ccc(OC)nc1C=O
Temperature: 55 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
A solution of {3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methanol (2.0 g, 7.57 mmol) in chloroform (200 mL) was added with manganese dioxide (20 g, 230 mmol), and the mixture was stirred at 55° C. for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was washed with chloroform, and then concentrated under reduced pressure. The resulting residue was added with chloroform (200 mL) and manganese dioxide (20 g, 230 mmol), and the mixture was stirred at 55° C. for 6 hours. The reaction mixture was filtered through Celite, and the filtrate was washed with chloroform, and then concentrated under reduced pressure to obtain 3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypicolinaldehyde (1.68 g, 85%) as pale yellow oil.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20].[CH3:21][NH2:22].C(O)C>>[CH3:21][NH:22][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: CN
Solvent: CCO
Product: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 90 °C

Procedure:
A mixture of 3a (660 mg, 2.20 mmol) in 33% methylamine/ethanol solution (30 mL) in a steel bomb was heated for 2 days at 90° C. The reaction mixture was concentrated to dryness and purified by column chromatography (elution with 4:1:0.3 chloroform:methanol:NH4OH). The desired fractions were combined, concentrated and dried in vacuo: yield 294 mg (45%); MS m/z 295 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (bs, 1H, H-2), 7.14 (bs, 2H, 6-NH2), 5.72 (d, 1H, H-1′, J1′,2′=6.5 Hz), 5.30 (d, 1H, 2′-OH, J2′-2′OH=6.3 Hz), 5.17 (bd, 1H, 3′-OH, J3′-3′OH=3.5 Hz), 5.01 (ddd, 1H, H-2′, J1′,2′=6.5 Hz, J2′,3′=5.5 Hz, J2′-2′OH=6.3 Hz), 4.16 (bs, 1H, H-3′), 3.96-4.0 (m, 1H, H-4′), 2.64-2.77 (bm, 2H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.29 (s, 3H, 5′NH—CH3).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH:1]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:7])[OH:8])=[O:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Solvent: CC(=O)O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A process comprising reacting N-formyl-aspartic anhydride with l-phenylalanine in glacial acetic acid to form N-formyl-α-L-aspartyl-L-phenylalanine, removing the formyl group from N-formyl-α-L-aspartyl-L-phenylalanine by hydrolysis with an aqueous solution of hydrogen chloride and esterifying the resulting α-L-aspartyl-L-phenylalanine with methanol in the presence of hydrogen chloride to form α-L-aspartyl-L-phenylalanine methyl ester and recovering the α-L-asparatyl-L-phenylalanine methyl ester.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:16]=1[CH:26]([C:28]1[C:29]([Cl:39])=[N:30][C:31]([Cl:38])=[CH:32][C:33]=1[C:34]([F:37])([F:36])[F:35])[OH:27].[CH:40](=[O:42])[CH3:41]>O.O1CCCC1>[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:16]=1[CH:26]([C:28]1[C:29]([Cl:39])=[N:30][C:31]([Cl:38])=[C:32]([CH:40]([OH:42])[CH3:41])[C:33]=1[C:34]([F:35])([F:37])[F:36])[OH:27]
Reactant: CC=O
Reactant: COc1cc(C)c(C(O)c2c(C(F)(F)F)cc(Cl)nc2Cl)c(OC)c1OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(C(O)c2c(Cl)nc(Cl)c(C(C)O)c2C(F)(F)F)c(OC)c1OC
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
9.6 ml (14 mmol) of n-butyllithium (1.5 M hexane solution) was dropwise added to a tetrahydrofuran (16 ml) solution of 2.0 ml (14 mmol) of diisopropylamine at 0° C., followed by stirring for 30 minutes. The solution was cooled to −50° C., a tetrahydrofuran (11 ml) solution of 2.9 g (7 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(2,6-dichloro-4-trifluoromethyl-3-pyridyl)methanol was added thereto, followed by stirring for 30 minutes, then the solution was cooled to −78° C., and acetaldehyde in an excess amount was added thereto, followed by stirring for 2 hours. 30 ml of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 2.5 g (yield 78%) of (2,3,4-trimethoxy-6-methylphenyl)(2,6-dichloro-5-(1-hydroxyethyl)-4-trifluoromethyl-3-pyridyl)methanol.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH3:30])[C:23]([CH:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[C:34]1[N:38]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([CH3:48])[CH:43]=[CH:42]3)[C:37](=[O:49])[NH:36][N:35]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.Cl>ClCCl.CO>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH3:30])[C:23]([CH:31]([CH3:32])[CH3:33])=[CH:22][C:21]=1[C:34]1[N:38]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([CH3:48])[CH:43]=[CH:42]3)[C:37](=[O:49])[N:36]([C:9]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[O:10])[N:35]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCOc1cc(OCc2ccccc2)c(-c2n[nH]c(=O)n2-c2ccc3c(ccn3C)c2)cc1C(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOCOc1cc(OCc2ccccc2)c(-c2nn(C(=O)OCc3ccccc3)c(=O)n2-c2ccc3c(ccn3C)c2)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cbz-Cl was added to the solution of 3-(2-(benzyloxy)-4-(ethoxymethoxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-1H-1,2,4-triazol-5(4H)-one and DIPEA in dichloromethane and reaction solution was stirred for 2 h at room temperature. Washed with water and extracted with dichloromethane and solvent was removed. The crude reaction mixture was carried over to the next reaction without further purification. The reaction mixture was diluted by methanol and treated with concentrated HCl and heated it up to 65° C. Column chromatogram produced the desired benzyl 3-(2-(benzyloxy)-4-(ethoxymethoxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylate.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].C1COCC1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([Mg]Br)[CH:42]=[CH:43][CH:44]=1.CO>ClC1C=CC=CC=1.C(Cl)Cl>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:12][CH:11]=2)=[O:9])[CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: COc1cccc([Mg]Br)c1
Solvent: Clc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)c1
Yield: 53.1 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.0 g, 2.29 mmol) in chlorobenzene (10 mL) was treated with a 0.64 M THF solution of 3-methoxyphenylmagnesium bromide (11.0 mL, 7.04 mmol) (prepared from 3-bromoanisole, catalytic iodide, and magnesium turnings in THF) to provide after chromatography (silica gel, 5-10% MeOH in CH2Cl2) 610 mg (53%) of the title compound as a dark oil: 1H NMR d 1.44 (m, 2H), 1.59 (m, 4H), 2.47 (m, 4H), 2.73 (t, J=6.0 Hz, 2H), 3.70 (s, 3H), 3.88 (s, 3H), 4.08 (t, J=6.0 Hz, 2H), 6.76 (m, 3H), 6.96-7.04 (m, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H); MS (FD) m/e 501 (M+); Anal. calc'd. for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79. Found: C, 71.68; H, 6.25; N, 2.66.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:2].[C:22]([N:30]1[CH2:34][CH2:33][C:32]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH2:35][CH2:36]OS(C)(=O)=O)[CH2:31]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([N:30]1[CH2:34][CH2:33][C:32]([CH2:35][CH2:36][N:19]2[CH2:18][CH2:17][CH:16]([NH:15][C:7]3[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:21][CH2:20]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:31]1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)CCN(C(=O)c2ccccc2)C1
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4ccccc4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using (1-(2-ethyoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine and 1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine to give the title compound.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].Cl[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNc1ccc(Cl)cc1
Yield: 55.9 %

Procedure:
Sodium acetate trihydrate (6 g) was added to a solution of commercial ethyl chloroacetate (6.2 g) and commercial 4-chloroaniline (6.4 g) in ethanol (5 ml). The mixture was heated to reflux for 5 h. After cooling in an ice bath the product precipitates. The solid was collected by suction filtration and washed with water. The still wet product was recrystallised from ethanol to give ethyl N-(4-chlorophenyl)glycinate (5.99 g) as greyish crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[N:12][CH:11]=1.O.[OH-].[Na+]>O1CCCC1>[O:16]([C:14]1[CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=[N:12][CH:13]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cncc(Oc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cncc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.6 %

Procedure:
To a suspension of lithium aluminum hydride (689 mg, 14.5 mmol, purity: 80%) in tetrahydrofuran (20 mL) was added 5-phenoxy-nicotinic acid methyl ester (1.11 g, 4.84 mmol) described in Manufacturing Example 145-1-1 at 0° C., which was stirred for 20 minutes at room temperature. First water (689 μL), then a 5 N sodium hydroxide aqueous solution (689 μL), and then water (2.07 mL) were added at 0° C. to the reaction mixture, which was filtered through a Celite pad. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (756 mg, 78%).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:34])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[NH:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1.[NH3:35]>C(O)C>[NH2:35][C:5]1[C:4](=[O:34])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[NH:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1
Reactant: COc1ccc(C(NCCCc2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(C(NCCCc2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(3-phenylpropylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 8 ml) were reacted, to afford the title compound (1.58 g) as a yellow solid.
Reaction SMILES: [H-].[Na+].C1(S)C=CC=CC=1.BrC1C(C)=[N+]([O-])C=CC=1.[CH3:19][C:20]1[C:25]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=[CH:22][N+:21]=1[O-].[CH3:34][C:35]([O:37]C(C)=O)=[O:36]>CN(C=O)C.C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[C:27]1([S:26][C:25]2[C:20]([CH2:19][O:37][C:35](=[O:36])[CH3:34])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1c(Sc2ccccc2)ccc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Agent: Cc1c(Br)ccc[n+]1[O-]
Agent: O=C([O-])O
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1ncccc1Sc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
To a suspension of 60% NaH (577 mg, 14.4 mmol) in DMF (15 mL) at 0° C. was added thiophenol (1.47 mL, 14.4 mmol) and the resultant mixture was warmed to room temperature and stirred for 1.5 h. To this mixture was added the 3-Bromo-2-methyl-pyridine 1-oxide (900 mg, 4.79 mmol) and the resultant yellow solution was heated to 80° C. for 96 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with EtOAc (100 mL), washed with brine (4×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (EtOAc/MeOH, 100:0 then 95:5) gave a mixture of 2-methyl-3-phenylsulfanyl-pyridine 1-oxide and a di-substituted thiophenol by-product. The mixture was treated with Ac2O (3 mL) and heated at 80° C. overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 (40 mL), H2O (10 mL) and saturated aqueous NaHCO3 (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30) gave Acetic acid 3-phenylsulfanyl-pyridin-2-ylmethyl ester (259 mg, 25% over 2 steps) as a yellow oil. 1H NMR (CDCl3) δ 2.11 (s, 3H), 5.37 (s, 2H), 7.18 (dd, 1H, J=7.9, 4.9 Hz), 7.27-7.38 (m, 5H), 7.53 (dd, 1H, J=7.9, 1.7 Hz), 8.50 (dd, 1H, J=4.7, 1.8 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.OS(O)(=O)=O.[CH3:19]O>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[CH:5][N:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)F)nc1
Yield: 100 %

Procedure:
To a solution of 6-(trifluoromethyl)nicotinic acid (3.82 g, 20 mmol) in 120 mL of methanol was added 5 mL of concentrated H2SO4 and the mixture was refluxed for 5 hours. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to about 7 by 1N HCl. The mixture was extracted with ethyl acetate (100 mL×3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound (4.1 g, 100%).