Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:35][S:36]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1)(=[O:38])=[O:37]
Reactant: Nc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)Nc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Yield: 49 %

Procedure:
7-Amino-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (3 g, 8.6 mmol) was dissolved in dichloromethane (100 ml), and 2,6-lutidine (1.2 ml, 10.32 mmol) was added. To this methylsulfonyl chloride (0.73 ml, 9.46 mmol) was added dropwise. A further portion of 2,6-lutidine (0.6 ml, 5.16 mmol) and methylsulfonyl chloride (0.37 ml, 4.78 mmol) were later added. The mixture was partitioned between sodium bicarbonate solution (100 ml) and dichloromethane (3×50 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue on alumina with ethyl acetate +0-1% methanol gradient elution gave the title compound as an oil (1.8 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH2:25][CH2:26][CH3:27])=[CH:23][CH:24]=1)#N>C(O)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[C:2]([NH:1][C:32]2[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[N:21][C:20]=3[N:28]=[CH:29][N:30]=2)[CH:7]=1
Reactant: Cc1ccc(Sc2cccc(O)c2)c(N)c1
Reactant: CCCc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(O)c3)ncnc2n1
Temperature: 130 °C

Procedure:
3-(2-amino-4-methyl-phenylsulfanyl)-phenol (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to 130° C. for 1.5 hours. After cooling to room temperature a solid in the acetic acid solvent appeared which was collected by filtration to provide the title compound as an acetic acid salt (78 mg, 68%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.95 (t, J=7.3 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2.40 (s, 3H), 2.88 (t, J=7.6 Hz, 2H), 6.57 (m, 3H), 7.00 (t, J=7.7 Hz, 1H), 7.13 (m, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 8.50 (s, 1H), 8.70 (d, J=8.5 Hz, 1H); MS (ESI)+ m/z 403 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]2C(CC(O)C)=CC=C3C([NH:18][C:19](=O)[C:14]=23)=O)[CH2:9][CH2:8]1.NN.C[OH:31]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([OH:31])[CH2:19][NH2:18])[CH2:9][CH2:8]1
Reactant: CC(O)Cc1ccc2c(c1N1CCC(c3ccccn3)CC1)C(=O)NC2=O
Reactant: CO
Agent: NN
Product: NCC(O)CN1CCC(c2ccccn2)CC1
Yield: 98 %

Procedure:
A mixture of 3-[4-(2-pyridyl)- piperidin-1-yl](2-hydroxypropyl)phthalimide (1.35 g, 3.68 mmol) and hydrazine (0.588 g, 18.4 mmol) in methanol (15 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL). Evaporation of solvent from the filtrate gave the product as a viscous oil (0.85 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)[N:3]=1.B(Br)(Br)Br>ClCCl>[CH3:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[N:3]=1
Reactant: COc1ccccc1C=C1N=C(C)N(C)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=NC(=Cc2ccccc2O)C(=O)N1C
Temperature: -40 °C
Yield: 91.6 %

Procedure:
3,5-Dihydro-2,3-dimethyl-5-(2′-methoxybenzylidene) -imidazol-4-one (2 g) was dissolved in dichloromethane (30 ml) and boron tribromide (2 ml) was added dropwise while stirring the mixture at −40° C. Thereafter, the reaction mixture was stirred under ice-cooling for 1 hr, and the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3,5-dihydro-2,3-dimethyl-5-(2′-hydroxybenzylidene)imidazol-4-one (1.72 g) as red crystals. The crystals and (S)-glycidyl nosylate (2 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (2.2 g) was added. The mixture was heated at 50° C. for 3 hr, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product (2.27 g). This oily product and 4-(naphthalen-2-yl)piperidine were dissolved in methanol (20 ml) and the mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.25 g) as an oil.
Reaction SMILES: [O:1]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C@@:23]([CH2:30][O:31][C:32](=[O:48])[N:33]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:29])[CH2:24]2)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:40][C:37]1[CH:36]=[CH:35][C:34]([N:33]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[C:32]([O:31][CH2:30][C@@:23]2([OH:29])[CH2:22][CH2:21][C:20]3[C:25](=[CH:26][CH:27]=[CH:28][C:19]=3[OH:1])[CH2:24]2)=[O:48])=[CH:39][CH:38]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(COC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1)C2)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OC[C@@]1(O)CCc2c(O)cccc2C1)N(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a mixture of (2R)-5-t-butyldiphenylsiloxy-2-{[N,N-di(4-fluorophenyl)carbamoyloxy]methyl}-2-hydroxy-1,2,3,4-tetrahydronaphthalene in THF (1 ml) was added 1M-tetra-n-butylammonium fluoride solution in THF (0.77 ml) at room temperature. After stirring for 4 hours, the reaction mixture was partitioned between AcOEt and water. The organic layer was washed with 1N-HCl, water, and evaporated in vacuo. The residue was purified by chromatography on silica gel (25 ml) using a mixture of AcOEt and n-hexane (1:4) to give (2R)-2-{[N,N-di(4-fluorophenyl)carbamoyloxy]methyl}-2,5-dihydroxy-1,2,3,4-tetrahydronaphthalene (0.19 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(isopropyl-methyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example C10) (2.98 g, 7.90 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a orange oil (2.42 g, 88%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.CI>C1COCC1.O>[Cl:13][C:14]1[C:15]([CH3:1])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Clc1cncc(Cl)c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 91 %

Procedure:
N,N-diisopropylamine (65.6 ml) was dissolved in anhydrous THF (150 ml), to which was dropwise added n-butyl lithium (1.54 mols/liter hexane solution, 300 ml) in an argon atmosphere at −78° C., and directly stirred for 5 minutes. An anhydrous THF (600 ml) solution of 3,5-dichloropyridine (63 g) was dropwise added thereto and stirred for 1 hours, and thereafter methyl iodide (29.2 ml) was dropwise added thereto and further stirred for 1.5 hours. Water was added to the reaction mixture to stop the reaction, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried over magnesium sulfate, and distilled under reduced pressure. This was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the resulting residue was suspended in ether, and taken out therefrom through filtration to obtain 3,5-dichloropicoline (Compound IIbz-b, 62.8 g, 91%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14]C)=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:7]([O:20]C)[CH:6]=2.Br>C(O)(=O)C.O>[OH:20][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[C:3]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)=[N:4]2)=[CH:9][C:8]=1[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(C)(=O)=O)cc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(C)(=O)=O)cc2c1C(=O)O
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of methyl 3-methyl-7-(methyloxy)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (4.95 g, 10.92 mmol) and hydrobromic acid (30 mL, 552 mmol) in acetic acid (30 mL) was heated to reflux for 5 d. The mixture was cooled to room temperature and diluted with water. The solid precipitate was collected by filtration, washed with water, and air dried to afford 7-hydroxy-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.22 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ14.51 (br. s., 1H), 11.77 (s, 1H), 8.32 (s, 1H), 7.95-8.00 (m, 2H), 7.90 (d, J=7.78 Hz, 1H), 7.78 (t, J=7.78 Hz, 1H), 7.54 (s, 1H), 3.41 (s, 3H), 2.36 (s, 3H); MS (m/z) 426.0 (M+H+).
Reaction SMILES: C([O:9][CH2:10][CH:11]1[O:18][CH2:17][C:14]2([CH2:16][CH2:15]2)[CH2:13][O:12]1)(=O)C1C=CC=CC=1.[OH-].[Na+].[Cl-].[NH4+]>CO>[CH2:15]1[C:14]2([CH2:17][O:18][CH:11]([CH2:10][OH:9])[O:12][CH2:13]2)[CH2:16]1
Reactant: O=C(OCC1OCC2(CC2)CO1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: OCC1OCC2(CC2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a mixture of 5,7-dioxaspiro[2.5]oct-6-ylmethyl benzoate (25.1 g, 101 mmol) obtained in the step (84b) above and methanol (150 ml), a 2N aqueous sodium hydroxide solution (55.6 ml, 111 mmol) was added at an inner temperature of 0 to 4° C. After the mixture was stirred at room temperature for 3 hours, a saturated aqueous ammonium chloride solution was added to the mixture to adjust pH to about 9. The mixture was concentrated under reduced pressure by about the amount of methanol. Ethyl acetate was added to the residue and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and then sodium chloride was added to the obtained water layer. The mixture was extracted with ethyl acetate and then the organic layers were combined and washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was removed by distillation to obtain the title compound (10 g, yield: 68.6%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH2:10][NH:11][CH2:12][CH2:13][C:8]=2[C:7](=[O:14])[O:6]1)[CH:2]([CH3:4])[CH3:3].[CH:21](=[O:30])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>C1COCC1>[C:21]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:14])[O:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[CH2:10]1)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: O=C/C=C/c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)C=Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol) in THF (5 mL) was added trans-cinnamaldehyde (49 mg, 0.369 mmol) and the reaction mixture stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (117 mg, 0.553 mmol) was added and the reaction mixture stirred at room temperature for additional 2 hours. Ethyl acetate (10 mL) was added and the organic solution washed with sat. NaHCO3 (10 mL), brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (12 g, SiO2, 0 to 20% ethyl acetate in hexanes) to provide 5-cinnamoyl-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (45 mg, 63%) as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73-1.05 (m, 6H), 1.54-1.84 (m, 2H), 2.20-2.48 (m, 3H), 2.52-2.66 (m, 1H), 2.73-2.89 (m, 1H), 2.99-3.14 (m, 1H), 3.19-3.37 (m, 2H), 3.43 (d, J=17.71 Hz, 1H), 6.23 (dt, J=15.82, 6.59 Hz, 1H), 6.44-6.57 (m, 1H), 7.20-7.46 (m, 10H); MS m/z 388 (M+H)+, 410 (M+23)+, 386 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O)C.C1(C)C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=2)[CH:20]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To 3-bromoaniline (513.1 mg, 2.983 mmol) was added ethanol/toluene (1:1, 20 mL), 3-pyridinylboronic acid (397.3 mg, 3.232 mmol), sodium carbonate (1.85 g, 17.45 mmol) in 9 mL water, and tetrakis(triphenylphosphine)palladium (504.3 mg, 0.439 mmol). The resulting mixture is heated to 80° C. and stirred for 16 h. The reaction mixture is cooled, diluted with 10 mL of water and extracted with EtOAc (3×25 ml). The organics were combined and, washed with 10 mL of water and saturated aqueous NaCl (2×10 mL), then dried over magnesium sulfate and concentrated in vacuo to a brown oil. The oil is purified over silica (0-5% MeOH in CH2Cl2) to afford 345 mg (68% yield) of the desired compound. MS (ESI, pos. ion) m/z: 171 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl.O>C(O)C>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][NH2:5]
Reactant: Cc1cccc(C)c1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1CN
Reaction time: 3.5 h

Procedure:
To a stirred solution of N-(2,6-Dimethylbenzyl)phthalimide (Step B, 7.77 g, 29.3 mmol) in ethanol (80 ml) was added hydrazine monohydrate (2.16 ml, 44.52 mmol) and the reaction mixture was refluxed for 3.5 hours. To this reaction mixture was added c HCl to bring pH to 1 and refluxing continued for another 3.5 hours, water was added and reaction mixture was filtered, the filtrate was concentrated and pH was adjusted to 10 with 2 N NaOH. The residue was taken in methylene chloride and washed with brine, dried over Na2SO4, filtered and concentrated to give an oil which was used without further purification.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[N:13][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25]Br)=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2=[CH:12][N:13]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([C:20](=[O:21])[C:19]4[CH:30]=[CH:31][C:16]([Cl:15])=[CH:17][CH:18]=4)[CH:23]=3)[N:14]=[C:8]2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc2[nH]ncc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc2nn(Cc3cccc(C(=O)c4ccc(Cl)cc4)c3)cc2c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (5 ml) was dissolved 5-t-butyl-1H-pyrazolo-[3,4-d]pyridazin-4(5H)-one (288 mg) followed by addition of 3-(4-chlorobenzoyl)benzyl bromide (712 mg) and potassium carbonate (318 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with ethyl acetate and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=1:1), washed with the following solvent, and dried. As the washing solvent, diethyl ether was used for 5-t-butyl-1-[3-(4-chlorobenzoyl) benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one and n-hexane-diethyl ester was used for 5-t-butyl-2-[3-(4-chlorobenzoyl)benzyl]-2H-pyrazolo [3,4-d]pyridazin-4(5H)-one.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]1([S:16]([NH:19][C:20]([C:22]2[N:27]=[C:26]3[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39]OS(C)(=O)=O)=[CH:35][C:34]=4[Cl:45])[C:29]([CH3:31])=[N:30][C:25]3=[CH:24][CH:23]=2)=[O:21])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C)C=O.O>[C:10]1([S:16]([NH:19][C:20]([C:22]2[N:27]=[C:26]3[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][O:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:35][C:34]=4[Cl:45])[C:29]([CH3:31])=[N:30][C:25]3=[CH:24][CH:23]=2)=[O:21])(=[O:17])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(COS(C)(=O)=O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(COc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
To a solution of phenol (12 mg, 0.13 mmol) in N,N-dimethylformamide (0.5 ml) was added sodium hydride (60% in mineral oil, 5.2 mg) under ice-cooling. Thirty minutes later, a solution of 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (68 mg, 0.12 mmol) in N,N-dimethylformamide (1 ml) was dropwise added, which was followed by stirring at room temperature for 3 hr. The reaction mixture was cooled with ice and water was added. Its pH was adjusted to 4 by dropwise addition of 1N hydrochloric acid. The resulting product was extracted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel thin layer chromatography (eluent: chloroform/methanol=20/1) and crystallized from ethyl acetate to give 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((phenyloxy)methyl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (30 mg) as colorless crystals.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].O.NN>C(O)C>[NH2:3][CH:12]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(N)CNC(=O)OC(C)(C)C
Temperature: 5 °C
Yield: 44.4 %

Procedure:
Di-tert-butyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,3-propanediyl]biscarbamate (144 g) was suspended in ethanol (1.5 L), and hydrazine monohydrate (19.8 ml) was added dropwise to the suspension under cooling on an ice-water bath. The mixture was refluxed for 5 hours, and cooled to 5° C. on an ice-water bath. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure and recrystallized from hexane (500 ml)—ethyl acetate (100 ml) to give di-tert-butyl (2-amino-1,3-propanediyl)biscarbamate (44.1 g) as crystals. The mother liquor (31.3 g), which proved to be satisfactorily pure by thin layer chromatography, was also used for the next reaction.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([O:13][C@@H:47]2[CH:48]3[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]3)[CH2:46]2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[NH2:2]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: NC(=O)C1CCN(C(C(=O)O)c2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)C1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.2 %

Procedure:
2-(4-Carbamoylpiperidin-1-yl)-2-phenylacetic acid (145 mg, 0.55 mmol) was suspended in dry THF (5.5 ml) and DCC (240 mg, 1.16 mmol), HOBT (157 mg, 1.16 mmol) and (R)-quinuclidin-3-ol (148 mg, 1.16 mmol) were sequentially added. The mixture was stirred at room temperature under nitrogen atmosphere for 24 hours. The white solid was filtered off and the solution was evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.5) to obtain (R)-quinuclidin-3-yl 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetate (78 mg, 38% yield) as an off-white spongy solid.
Reaction SMILES: C[O-].[Na+].[N+:4]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([N+]([O-])=O)=[CH:14][CH:15]=3)[CH:10]([CH:23]3[O:27][CH2:26][CH2:25][O:24]3)[C:9]=2[CH:8]=1)([O-:6])=[O:5].CN(C)[CH:30]=[O:31]>O>[CH3:30][O:31][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[C:9](=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:19][CH:18]=3)[CH:10]([CH:23]3[O:24][CH2:25][CH2:26][O:27]3)[C:11]=2[CH:12]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2
Reaction time: 2 h
Yield: 86 %

Procedure:
For a period of two hours, 8 parts of sodium methoxide was added to a solution of 10 parts of 2-(2,7-dinitro-9-fluorenyl)-1,3-dioxolane in 300 parts of dimethylformamide contained within a 5 liter flask at room temperature. The mixture was magnetically stirred for 20 hours. All of the mixture was then diluted with 1800 parts of water. A yellow solid was precipitated therefrom, collected on a filter, washed with water and dried under vacuum. The dried filtered product was further purified in a chromatography column packed with silica gel (Merck Grade 60) and developed by methylene chloride to provide 8.2 parts of product (86% yield).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O.Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>CN(C1C=CN=CC=1)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Reactant: NNc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(-c2nn(-c3ccc(Br)cc3)c3c(C(F)(F)F)cccc23)cc1

Procedure:
Prepared according to Method C step A from (2-fluoro-3-trifluoromethyl-phenyl)-(4-methoxyphenyl)-methanone (0.149 g, 0.5 mmol), 4-bromophenylhydrazine hydrochloride (0.134 g, 0.6 mmol) and DMAP (0.061 g, 0.5 mmol) to give the title compound.