Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:12])=[CH:8][C:9]=2O)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[CH3:24])=[N:3]1.P(Cl)(Cl)([Cl:27])=O>C(#N)C>[Cl:27][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]2[C:4]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][C:14]=3[CH3:24])=[N:3][N:2]([CH3:1])[C:10]=12
Reactant: Cc1cc(O)c2c(n1)c(-c1ccc(-n3cccn3)cc1C)nn2C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(Cl)c2c(n1)c(-c1ccc(-n3cccn3)cc1C)nn2C

Procedure:
To a solution of compound 3e (1.0 g) in anhydrous acetonitrile (10 mL) was added phosphorous oxychloride (0.60 mL). The reaction was refluxed under nitrogen for 2 hours. The reaction mixture was cooled and quenched on ice with H20. The mixture was basified to pH 8 with sodium bicarbonate. The product was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over magnesium sulfate and concentrated to afford 7-chloro-1,5-dimethyl-3-(2-methyl-4-pyrazol-1-yl-phenyl)-1H-pyrazolo[4,3-b]pyridine as a yellow oil. The compound was purified by silica gel chromatography, using 30% ethyl acetate/hexanes as eluent to provide 1.0 g (99%) of compound 4a as a white solid; LC/MS: [M+H]=338.2.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]=[CH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>CN(C=O)C.C(=O)([O-])O.[Na+]>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]=[CH:12]3)[CH2:2][CH2:3]1)=[O:29]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=c1ccc2cccc(N3CCNCC3)c2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Cl)N1CCN(c2cccc3ccc(=O)[nH]c23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
8-(1-Piperazinyl)carbostyril (0.7 g, 2.26 mmols) and sodium hydrogencarbonate (0.2 g) were suspended in 5 ml of DMF and the suspension was stirred at room temperature for 30 minutes. To the resulting mixture was added 0.4 ml of triethylamine, and further a solution of 0.47 g of 2-chlorobenzoyl chloride in 5 ml of DMF dropwise, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured in saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was washed with water and then with saturated aqueous sodium hydrogencarbonate and dried over sodium sulfate. After distilling off the solvent, ether was added to the residue to crystallize. The crystals thus obtained were recrystallized from ethanol to give 0.24 g of 8-[4-(2-chlorobenzoyl)-1-piperazinyl]carbostyril, m.p. 239°-240.5° C., colorless needles.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH3:29])[C:21]([CH3:28])=[C:22]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[C:16]=2[O:15]1.[OH-].[Na+]>CO>[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH3:29])[C:21]([CH3:28])=[C:22]([CH:23]3[CH2:3][C:4](=[O:5])[CH2:26][C:25](=[O:27])[CH2:24]3)[C:16]=2[O:15]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)c(C)c(C)c2c1OC(C)(C)C2
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c2c(c(C3CC(=O)CC(=O)C3)c1C)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.57 g of sodium in 68 ml of absolute methanol was added 10.35 ml of diethyl malonate. After stirring for 20 minutes, the mixture was added 8 g of the 4-(2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-yl)-3-buten-2-one in 17.5 g of absolute methanol, refluxed for 4 hours and added 150 g of 5% aqueous solution of sodium hydroxide. The reaction mixture was cooled to room temperature and washed three times with 50 ml of diethyl ether. 2N aqueous solution of hydrochloric acid was added dropwise into the aqueous layer until the bubble of carbon dioxide ceased. And then, solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 16.7 g of 5-(2,3-dihydro-2,2,4,5,6-pentamethyl-benzofuran-7-yl)cyclohexane-1,3-dione as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH2:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH:35]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.ClCCl.O.Cl>[C:1]([NH:4][C:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:9][N:8]([CH:11]([CH2:35][C:34]2[CH:37]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:39]=[C:32]([C:31]([F:30])([F:44])[F:45])[CH:33]=2)[CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH2:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(c2ccccc2)CCN(CCC(CN)c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C

Procedure:
To a solution of 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butylamine (0.30 g) in methanol (3 mL) was added 3,5-bis(trifluoromethyl)benzaldehyde (0.088 mL) and the mixture cooled to 0° C. To this stirred mixture was sequentially added acetic acid (0.046 mL) and a solution of sodium cyanoborohydride (0.50 g) in methanol (1 mL). The mixture was allowed to slowly warm to room temperature overnight and was diluted with dichloromethane (5 mL), water (5 mL), and hydrochloric acid (1N, 5 mL). The layers were separated, and the aqueous layer was extracted three times with dichloromethane (10 mL). The acidic aqueous layer was made basic with aqueous sodium hydroxide (1N, 5mL) and then extracted with 5:1 dichloromethane:methanol (3×10 mL). The combined organic layers were washed (brine), dried, filtered and evaporated to afford an oil which was purified by chromatography, with dichloromethane:methanol (40:1) as eluent. Evaporation of the appropriate fractions afforded a partial hydrate of the title compound as a white solid (0.154 g); mp 66-68° C.; NMR: 7.82 (s,3), 7.75 (s,1), 7.50 (m,2), 7.35-5.15 (m,6), 2.75 (m,1), 2.65-2.55 (m,2), 2.32-1.95 (m,6), 1.85 (s,3), 1.95-1.55 (m,6); MS: m/z=660(M+1, 100%); Rf =0.51 (10:1, dichloromethane:-methanol). Analysis for C32H33Cl2F6N3O.0.0.25 H2O: Calculated: C, 57.79; H, 5.08; N, 6.32; Found: C, 57.68; H, 5.07; N, 6.30.
Reaction SMILES: [Mg].[C:2](OCC)(=O)CC(OCC)=O.Cl[C:14]([C:16]1[O:17][C:18]2[C:27]([CH:28]=[CH:29][CH3:30])=[CH:26][CH:25]=[CH:24][C:19]=2[C:20](=[O:23])[C:21]=1[CH3:22])=[O:15].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.O.C(Cl)(Cl)(Cl)Cl>[C:14]([C:16]1[O:17][C:18]2[C:27]([CH:28]=[CH:29][CH3:30])=[CH:26][CH:25]=[CH:24][C:19]=2[C:20](=[O:23])[C:21]=1[CH3:22])(=[O:15])[CH3:2]
Reactant: CC=Cc1cccc2c(=O)c(C)c(C(=O)Cl)oc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC=Cc1cccc2c(=O)c(C)c(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.051 g of magnesium turnings were suspended in 10 mL of anhydrous ethanol. 0.3 mL of carbon tetrachloride and 0.32 mL of diethyl malonate were added and the resulting mixture was stirred at room temperature (with spontaneous heating) for 1 hour, then at 60° C. for 2 hours and cooled to room temperature. A solution of 0.42 g of Compound 2A in 15 mL of toluene and chloroform (5 mL) was added dropwise and the resulting mixture was stirred at room temperature for 6 hours. After overnight resting, 0.12 mL of 98% sulphuric acid and 3 mL of water were added; the precipitated inorganic salts were filtered off and the filtrate was evaporated under vacuum to dryness.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[CH3:27][C:28]([N:31]1[C:35]([OH:36])=[CH:34][CH:33]=[N:32]1)([CH3:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.ClCCCl.O.ClCCl.CC(C)(O)C#N.C(N(CC)CC)C>[CH3:27][C:28]([N:31]1[C:35]([OH:36])=[C:34]([C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]=2[Cl:1])[CH:33]=[N:32]1)([CH3:30])[CH3:29]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1-c1ccccc1
Reactant: CC(C)(C)n1nccc1O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)n1ncc(C(=O)c2ccc(S(C)(=O)=O)c(-c3ccccc3)c2Cl)c1O
Reaction time: 8 h

Procedure:
2-Chloro-3-phenyl-4-methylsulfonylbenzoic acid (750 mg, 2.4 mmol), excess oxalyl chloride, and a few drops of N,N-dimethylformamide were dissolved in 1,2-dichloroethane and the mixture was allowed to react with stirring overnight. The mixture was then concentrated by evaporation under reduced pressure. The residue was taken up in about 10 mL of dichloromethane and the resulting solution was cooled with an ice bath. To this was added 410 mg (2.9 mmol) of 1-(1,1-dimethylethyl)-5-hydroxypyrazole and about 2 mL of triethylamine. After about 1 hour, the mixture was diluted with water and with more dichloromethane and the phases were separated. The organic phase was washed with dilute aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was dissolved in 10 mL of anhydrous 1,2-dimethoxyethane and 1.3 g (9.6 mmol) of sodium carbonate and then about 8 drops of acetone cyanohydrin were added. The mixture was allowed to react overnight and was then diluted with water. The phases were separated and the aqueous phase was extracted with ether, acidified with aqueous hydrochloric acid, and then twice extracted with dichloromethane. The dichloromethane extracts were combined and washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The 900 mg of residue was placed in 15 mL of ethanol and the mixture was heated and then cooled. The precipitate that formed was collected by filtration, washed with ether, and dried in a reduced pressure oven for 1 hour at 80° C. to obtain 682 mg (66 percent of theory) of the title compound as a tan solid melting at 262.5-264° C.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[C:3](=O)[CH3:4].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[CH3:4][C:3]1[N:15]=[C:16]([NH2:18])[S:17][C:2]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: CC(=O)C(Br)c1cccc([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1nc(N)sc1-c1cccc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
A stirred solution of 1-Bromo-1-(3-nitro-phenyl)-propan-2-one (98a) (2.4 g, 9.3 mmol) in ethanol (20 ml) at room temperature is treated with thiourea (0.71 g, 9.3 mmol). The reaction mixture is heated to 70° C. for 10 minutes. The resulting precipitate is removed by filtration and dried under vacuum to give the titled compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:24][NH:25][C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1n[nH]c(CC)c1Cc1cncn1Cc1ccccc1

Procedure:
To a solution of 140 mg (0.47 mmol) 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione in 1.5 ml ethanol was added a solution of 24 mg (0.48 mmol) hydrazine monohydrate in 0.5 ml ethanol and the mixture heated to reflux for 10 min. The reaction mixture was evaporated under reduced pressure, the residue dissolved in 1N aqueous HCl solution and extracted three times with t-butyl methyl ether. The aqueous phase was adjusted to pH 12 and extracted three times with t-butyl methyl ether, the combined extracts washed with brine, dried over sodium sulfate, filtered and evaporated. Purification of the residue by flash-chromatography on silica gel with ethyl acetate as eluent provided 4-(3-benzyl-3H-imidazol-4-ylmethyl)-3,5-diethyl-1H-pyrazole as colourless viscous oil: MS (ISP): 295.3 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:9]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].O.[CH:37]([B-](F)(F)F)=[CH2:38].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.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:1][C:2]1[C:3]([CH:37]=[CH2:38])=[C:4]([CH:9]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[C:11]=1[C:12]([F:13])([F:15])[F:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c(Cl)c1OS(=O)(=O)C(F)(F)F
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Temperature: 90 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
To a solution of methyl 3-chloro-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (0.24 g) in THF (5.00 mL)-water (5.00 mL) were added potassium vinyltrifluoroborate (0.07 g), cesium carbonate (0.24 g) and tetrakis(triphenylphosphine)palladium(0) (0.01 g), and the mixture was stirred at 90° C. for 16 hr under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by prep-thin layer chromatography (ethyl acetate/petroleum ether) to give the title compound (0.08 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:22](=[O:27])[C:23](Br)([F:25])[F:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2I)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CS(C)=O.[Cu]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:23]([F:25])([F:24])[C:22]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)C(F)(F)Br)c2ccccc2I)CC1
Agent: [Cu]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(F)(F)c3ccccc32)CC1
Temperature: 70 °C
Yield: 93 %

Procedure:
A mixture of 4-[(2-bromo-2,2-difluoroacetyl)-(2-iodophenyl)amino]-piperidine-1-carboxylic acid tert-butyl ester (1.670 g, 2.98 mmol) and copper (bronze, 0.480 g, 7.55 mmol) in DMSO (15 mL) was heated at 70° C. overnight. The reaction mixture was quenched with water at 0° C. and then extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. Purification of the residue by flash chromatography to afford the title compound in 93% yield (0.976 g). 1H NMR (300 MHz, CDCl3) δ 7.52-7.40 (m, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.00 (t, J=8.1 Hz, 1H), 4.28-4.13 (m, 3H), 2.77 (t, J=12.9 Hz, 2H), 2.32-2.18 (m, 2H), 1.73 (d, J=12.9 Hz, 2H), 1.45 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 165.5, 165.0, 164.6, 154.5, 142.6, 142.5, 142.4, 133.4, 125.0, 123.6, 120.6, 120.3, 120.0, 113.6, 110.9, 110.3, 107.0, 80.0, 77.5, 77.0, 76.6, 51.0, 43.2, 28.3, 27.9. MS (ES+) m/z 375.3 (M+Na).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[C:5](=[O:17])[O:6][C:7]12[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:18]1([C:24]2[CH:25]=[N:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[C:5](=[O:17])[O:6][C:7]12[CH2:12][CH2:11][N:10]([C:31]([NH:30][C:27]2[N:26]=[CH:25][C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:29][N:28]=2)=[O:32])[CH2:9][CH2:8]1
Reactant: O=C1OC2(CCNCC2)c2cccc(F)c21
Reactant: O=C(Nc1ncc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1OC2(CCN(C(=O)Nc3ncc(-c4ccccc4)cn3)CC2)c2cccc(F)c21
Temperature: 60 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of 4-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60° C. for 3 hours. The concentration of the reaction mixture left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/methanol=1/1/0˜8/8/1˜6/6/1) followed by recrystallization from ethyl acetate-hexane to give the subject compound (190 mg) as colorless crystals (melting point 247-249° C.).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:21]1([CH2:3][C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(CCBr)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)c(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 50 ml of DMF was dissolved 13.6 g of ethyl 2-(bromoethyl)biphenyl-4-carboxylate, and then a suspension of 50 ml of DMF, 6.2 ml of piperidine, and 9.2 g of potassium carbonate were added thereto under ice cooling, followed by 3 hours of stirring at room temperature. Water was added to the reaction solution, the whole was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate, followed by removal of the solvent by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain 12.6 g of ethyl 2-(piperidin-1 -ylmethyl)biphenyl-4-carboxylate as a pale yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].CO.Cl>O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:12][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cnc2ncc(C3(c4ccc5ncccc5c4)CC3)n2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc2ncc(C3(c4ccc5ncccc5c4)CC3)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxylate (14 mg, 0.040 mmol, isomer-I from Step 1), 1M lithium hydroxide in water (0.16 mL), and methanol (1.0 mL) was stirred overnight at RT. The mixture was neutralized with 1N HCl (0.16 mL) and concentrated under reduced pressure. The residue was dried to yield the desired product which was directly used in next step. LCMS: (M+H)=331.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1cnccc1N1CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 500 ml Parr hydrogenation bottle was suspended 1.0 g of 5% Pd/C in 25 ml ethanol, followed by a suspension of 2,3-dihydro-1-(3-nitro-4-pyridinyl)-1H-indole (4.7 g) in 125 ml ethanol. After shaking at 50 psi H2 at ambient temperature for five hours, the mixture was filtered and the filtrate concentrated to an oil (4.2 g). This oil was eluted on a silica gel column with ethyl acetate via HPLC and the desired fractions were combined and concentrated to give a solid, 4.0 g, m.p. 89-90° C. This material was recrystallized from ether/hexanes (4:1) to give a solid, 2.9 g, m.p. 90°-92° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C[O:18][C:19]([C@@H:21]1[C@@H:26]2[CH2:27][C@@H:23]([CH2:24][CH2:25]2)[N:22]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:31]([O:30][C:28]([N:22]1[C@H:21]([CH2:19][OH:18])[C@@H:26]2[CH2:27][C@H:23]1[CH2:24][CH2:25]2)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CO
Reaction time: 1.33 h

Procedure:
At −78° C. a solution of DIBAL in toluene (1.7M, 137 mmol) is added dropwise to a solution of (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (61.0 mmol) in THF (180 mL). After 80 min the solution is allowed to reach rt, stirred for additional 2 h and poured into a mixture of aq. NaOH solution (1.0M, 200 mL) and ice. EtOAc (150 mL) is added, the layers are separated and the aq. layer is extracted three times with EtOAc (150 mL each). The combined organic layers are washed with aq. NaOH solution (1.0M) and brine, dried over Na2SO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.78 min; [M+H]+=228.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:13]Br>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 1-(3-nitrophenyl)ethanone (50 g, 303.03 mmol, 1.00 equiv) in acetic acid (300 mL), Br2 (53.5 g, 331.6 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 60° C. in an oil bath. The reaction was then quenched by the addition of ice and the solids were collected by filtration. The crude product was re-crystallized from ethyl acetate/petroleum ether in the ratio of 1:10. This resulted in 25 g (34%) of 2-bromo-1-(3-nitrophenyl)ethanone as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.O>[I:7][C:8]1[CH:9]=[N:10][N:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=1
Reactant: BrCCOC1CCCCO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of cesium carbonate (20.7 g, 63.4 mmol) and 4-iodopyrazole (10.00 g, 51.6 mmol) in DMF (100 mL) was allowed to stir for 10 min. To the mixture was added 2-(2-bromoethoxy)tetrahydro-2 h-pyran (9.98 ml, 63.4 mmol) and heated at 80° C. overnight. The mixture was diluted with water and extracted with EtOAc (3×50 mL), and subsequently washed with water (2×50 mL) and brine, dried over sodium sulfate, and filtered. The crude mixture was evaporated onto silica gel and purified via MPLC (0% to 50%; EtOAc in hexanes). Isolated 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (15.3 g, 92%) as a clear oil. MS m/z=323.0 [M+1]+. Calc'd for C10H15IN2: 322.1.