Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N+:12]=[N-:13].[CH2:14]([OH:17])[C:15]#[CH:16]>CCOCC.C(O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:11])[N:12]3[N:13]=[C:15]([CH2:14][OH:17])[CH:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Solvent: CCO
Solvent: CCOCC
Product: O=c1[nH]c2ccc(F)cc2c2cc(CO)nn12
Reaction time: 0.25 h

Procedure:
2.0 g (0.0113 mole) of 5- fluoro-3-diazooxindole (part B9 and 13.1 g (0.226 mole of 20 equivalents) of 97% propargyl alcohol are refluxed under argon for 4 hours. The reaction mixture is cooled, diluted with ether (200 ml) and stirred for 15 minutes. The beige-colored precipitates are filtered off and dried in vacuo overnight. Yield: 2.3 g, mp 295°-297°, 87.5% crude yield. The crude produce is taken up in absolute ethanol (500 ml), treated with activated carbon, filtered through a Celite pad, the pad is washed with 50 ml of hot ethanol. The clear filtrate is concentrated down to a volume of 100 ml and cooled. The white precipitates are filtered off and dried in vacuo at 60° to yield the product (title compound) 1.16 g, mp 303°-304°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[C:16]=1[O:28][C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][N:30]=1)([O-:14])=[O:13].Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:31]1[C:32]([CH3:34])=[CH:33][C:29]([O:28][C:16]2[C:17]([C:24]([F:26])([F:27])[F:25])=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[N:30]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.6 %

Procedure:
Potassium carbonate (0.15 g, 1.1 mmol) and ethyl isocyanate (0.07 g, 1.0 mmol) were added to a solution of 3-(2,4-dinitro-6-trifluoromethylphenyloxy)-5-methylpyrazole (0.33 g, 1.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellowish solid of N-ethyl-3-(2,4-dinitro-6-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.20 g, yield: 49.6%). mp: 169-171° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.18 (t, J=7.2 Hz, 3H), 2.59 (d, J=0.4 Hz, 3H), 3.31 (dq, J=6.0 and 7.2 Hz, 2H), 5.95 (q, J=0.4 Hz, 1H), 6.25-6.50 (m, 1H), 8.85 (d, J=2.7 Hz, 1H), 9.02 (d, J=2.7 Hz, 1H).
Reaction SMILES: C1([C@H](NC([C:13]2[CH:14]=[C:15]([C:22](N3CCC[C@@H]3C(O)=O)=[O:23])[N:16]3CCOC[C:17]=23)=O)CC)C=CC=CC=1.[CH:32]([OH:35])([CH3:34])[CH3:33]>Cl>[CH:32]([O:35][C:22]([CH:15]1[CH2:14][CH2:13][CH2:17][NH:16]1)=[O:23])([CH3:34])[CH3:33]
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C(=O)O)n2c1COCC2)c1ccccc1
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)C1CCCN1

Procedure:
A solution of (R)-1-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid in isopropanol and 2 drops of concentrated aqueous hydrochloric acid was heated to reflux overnight. Solvents were evaporated. The residue was dissolved in a small amount of acetonitrile, excess water was added and the solution was freeze-dried to give 27 mg (49%) of (R)-1-[84(R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid isopropyl ester. LC/MS (method 4): Rt=1.27 min; m/z=468.35 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>O>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
1-(Diphenylmethyl)azetidin-3-ol (2.0 g) was dissolved in N,N-dimethyl sulfoxide (60 mL), and triethylamine (11.7 mL) was added. The reaction solution was cooled to 10° C., a solution of pyridine sulfur trioxide complex (10.6 g) in N,N-dimethyl sulfoxide (20 mL) was added, and the mixture was stirred for 1 hr. The mixture was warmed to room temperature and further stirred for 3 hr. The reaction solution was poured into cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (30% to 50% ethyl acetate/hexane) to give the object product as a white solid (1.83 g, 92.4%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:13](OCC)=O)=[C:7]([CH3:12])[C:8]=1[CH2:9][CH2:10][CH3:11])[CH2:2][CH3:3].[CH:18](=O)[CH2:19]C>>[CH2:1]([C:4]1[NH:5][C:6]([CH2:13][CH2:18][CH3:19])=[C:7]([CH3:12])[C:8]=1[CH2:9][CH2:10][CH3:11])[CH2:2][CH3:3]
Reactant: CCCc1[nH]c(C(=O)OCC)c(C)c1CCC
Reactant: CCC=O
Product: CCCc1[nH]c(CCC)c(CCC)c1C

Procedure:
2,3-Di(n-propyl)-4-methyl-5-carbethoxy-pyrrole was reductively alkylated with propionaldehyde to yield 2,3,5-tri(n-propyl)-4-methyl-pyrrole. ##STR106##
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH2:3]>[Pd].CO>[CH3:3][CH:2]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: C=C(C)c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Reaction time: 12 h
Yield: 68.2 %

Procedure:
A mixture of tert-butyl 9-(1-methylethenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (480 mg, 1.66 mmol) and 10% palladium on carbon (30.0 mg) in methanol (10 ml) was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (330 mg, 68.1%) as an oil.
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12](OC)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4C)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>CN(C=O)C.CCOC(C)=O>[N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCNCC
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 115 °C

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (1.44 g, 3.33 mmol, Intermediate 6, step c) and diethylamine (6.91 mL, 66.5 mmol) in DMF (10 mL) in a sealed tube was heated in a 115° C. oil bath for 23 hours. The mixture was diluted with EtOAc and extracted with water (5×, saturated aqueous NaCl added as needed to achieve phase separation). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dry loading, 2-10% EtOAc-Heptane first column, 0-4% EtOAc-Heptane second column) to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.N1CCNCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 195.1 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) and piperazine (7.3 ml) are added to the bottle within 20 min, the above mixture is reacted at the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.4 g). The yield is about 72.7%.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[N:6](CC(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[CH:24](C1NC2C(C=1)=C([N+]([O-])=O)C=CC=2)([CH3:26])[CH3:25]>>[CH:24]([C:5]1[NH:6][C:7]2[C:12]([C:4]=1[CH2:3][C:1]#[N:2])=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c([N+](=O)[O-])cccc21
Reactant: CC(C)c1cc2c([N+](=O)[O-])cccc2[nH]1
Product: CC(C)c1[nH]c2cccc([N+](=O)[O-])c2c1CC#N

Procedure:
Essentially following the procedures described for Intermediate 11, but using 2-isopropyl-4-nitro-1H-indole from Step B in place of 4-nitroindole, the title compound was prepared. MS: m/z=244 (M+1).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl.OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)([C:52]1[N:53]=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.CN.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O.CO>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:53][CH3:52])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Reaction time: 1.5 h

Procedure:
To a solution of methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.80 g) in THF (20 mL) was added methanol (4 mL) and 4N-NaOH (20 mL) at 50° C. The mixture was stirred for 90 min, neutralized with conc. HCl. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The extract was concentrated to give crude mixture of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid. To a solution of the crude mixture was added methylamine in THF (2.0M:3.50 mL), 1-hydroxybenzotriazole (536 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (671 mg) under ice cooling. The mixture was stirred at room temperature for 20 h, diluted with water and extracted with ethyl acetate. The extract was concentrated and purified by column chromatography (eluent; hexane:THF=1:2) followed by crystallization from hexane-ethyl acetate to give the titled compound (1.55 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33].C(N(CC)CC)C>C(#N)C.CC(O)=O.CC(O)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:11]2[CH:16]=[CH:15][C:14](/[CH:33]=[CH:32]/[C:31]([O:35][CH3:36])=[O:34])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(I)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(/C(Nc2ccc(OC)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
257 mg (0.5 mmol) of (Z)-3-[1-(4-methoxyphenylamino)-1-(4-iodophenyl)-methylidene]-5-nitro-2-indolinone (Example 434), 0.06 ml (0.75 mmol) of methyl acrylate, 4.5 mg (0.02 mmol) of palladium-II-acetate and 1 ml of (7.2 mmol) of triethylamine are dissolved in 20 ml of acetonitrile under a nitrogen atmosphere. The solution is heated for 10 hours to 80° C. Then the reaction solution is filtered through Celite and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol=20:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[BH4-].[Na+].[BH4-]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: OCCCN=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCCNC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
179.0 g (0.5737 mole) of 1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylimino)ethyl)-1H-imidazole are dissolved in 300 ml of methanol, the solution is cooled to 0° C., and 50.0 g (1.322 mole) of sodium borohydride are added in portions in such a way that the temperature does not rise above 5° C. After the borohydride has been added, the reaction mixture is stirred at room temperature for a further 2 hours, then evaporated to dryness, and the pH is adjusted to 1 with half-concentrated hydrochloric acid. Subsequently, the reaction solution is adjusted to a pH of about 12 with 40% strength sodium hydroxide solution, and is extracted several times with dichloromethane. After the combined organic extracts have been washed with water and dried, and the solvent has been removed in vacuo, 169 g of crude product are obtained as an oil. Recrystallization of the oil from acetone results in 107 g of pure 1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylamino)ethyl)-1H-imidazole of melting point 77°-79° C. (Yield: 51%).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)([O-:5])=[O:4].[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>O.CO>[Br:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=2)[NH:11][N:10]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: [Br-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
A mixture of NaOH (2.0 g) in H2O (60 mL) was added 5-nitroindazole (2.0 g, 12 mmol), and the mixture was heated until a red solution formed. The mixture was placed in an ice-water bath for 15 minutes after which pyridinium tribromide (4.7 g, 15 mmol) in methanol (15 mL) was added. The mixture was stirred at 0° C. for 5 hours, the pH adjusted to 7 with diluted HCl and the mixture extracted with ethyl acetate. The combined organic layers were washed with H2O, concentrated under reduced pressure and purified by flash chromatography to provide the title compound (1.6 g, 55% yield). 1H NMR (300 MHz, DMSO-d6) ppm 7.80 (m, 1H), 8.28 (m, 1H), 8.50 (m, 1H), 14.09 (s, 1H), MS (DCI/NH3) m/z 243[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16](=O)[N:17]([CH3:19])[NH:18][C:11]1=2.P(Br)(Br)([Br:23])=O>ClCCl>[Br:23][C:16]1[N:17]([CH3:19])[N:18]=[C:11]2[C:12]=1[CH2:13][CH2:14][CH2:15][N:10]2[C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one (3.16 g) and phosphorus oxybromide (15.5 g) were combined and stirred in a 110° C. oil bath for 4 h. After the reaction mixture had cooled to room temperature, it was dissolved in dichloromethane and added to 200 mL of ice/water. This mixture was stirred vigorously for 30 min. The phases were then separated and the aqueous phase was washed with additional dichloromethane. The combined organic phases were washed with aqueous sodium bicarbonate, dried with magnesium sulfate, and concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to afford 1.16 g of 3-bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (1-1): mp 106-107° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(OCC)(=O)C>CS(C)=O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CN(C)CCN
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)CCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a stirred solution of 2,4-difluoronitrobenzene (3.18 g., 20 mmole) In DMSO (5 ml) was added portion-wise N,N-dimethylethylene-diamine (3.52 g., 40 mmole). The mixture was stirred at 23° C. for 1 hour and poured into crushed ice. Ethyl acetate (200 ml) was added to dissolve the orange-yellow solid. The organic phase separated was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on a silica gel column eluting with CH2Cl2 /MeOH (20:1) to afford the compound (15) (2.8 g., 62%) which solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][CH2:9]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:30][CH2:9][CH2:8][CH2:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(CCCO)s1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCCBr)s1
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Compound 48-2 (1.23 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (2.27 g) and N-bromosuccinimide (1.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (650 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@H:15]([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[S:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+].CI>CC#N.CCOCC>[C:23](/[N:22]=[C:20](\[S:21][CH3:32])/[NH:19][C@H:15]([CH:16]([CH3:17])[CH3:18])[C:14]([N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)=[O:31])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)[C@@H](NC(=S)NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CI
Product: CS/C(=N\C(=O)c1ccccc1)N[C@@H](C(=O)N1CCC(c2ccc(Cl)cc2)CC1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of (R)—N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamothioyl)benzamide (300 mg, crude) in CH3CN (2 mL) was added K2CO3 (275 mg, 2 mmol) followed by MeI (75 μL, 2 mmol). The reaction was stirred for 4 h at rt., diluted with Et2O (10 mL) and the solids were filtered through a plug of celite. The filtrate was condensed in vacuo to give (R,Z)-methyl N′-benzoyl-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamimidothioate (300 mg, m/z 473, M+1) as a foam, which was used in subsequent steps without purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH3:13].[OH:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH2:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[C:19]1[CH:20]=[C:15]([OH:14])[CH:16]=[CH:17][CH:18]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Cc1cnc2c(Cl)cccc2c1Br
Product: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 4-bromo-8-chloro-3-methyl-quinoline and 3-hydroxyphenyl boronic acid according to the procedure of Example 1. MS (ES) m/z 343.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2ccccn2)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2f (5.6g, 32.9mmol) and acetic anhydride (20ml) is stirred at ambient temperature for 1 hour. The mixture is poured into ice-water and rendered alkaline with 10M sodium hydroxide. The product is filtered off, washed with water and dried. Yield:
Reaction SMILES: [CH3:1][O:2][CH:3](O)[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[NH2:12][C@H:13](CO)[CH2:14][CH:15]([CH3:17])[CH3:16]>C1C=CC=CC=1>[CH2:14]([C@H:13]1[CH2:1][O:2][CH:3]([C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])[NH:12]1)[CH:15]([CH3:17])[CH3:16]
Reactant: COC(O)C(F)(F)C(F)(F)F
Reactant: CC(C)C[C@H](N)CO
Solvent: c1ccccc1
Product: CC(C)C[C@H]1COC(C(F)(F)C(F)(F)F)N1

Procedure:
Pentafluoropropanal methyl hemiacetal (14.9 g, 82.8 mmol) and L-leucinol (9.7 g, 82.8 mmol) were dissolved in 100 mL of benzene and heated to reflux overnight in a flask equipped with a Dean-Stark tube. The resulting solution was cooled and concentrated to provide the title compound as an oil which was used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[CH:17][CH:16]=1
Reactant: CN1CCNCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)CC1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.053 g; 0.153 mmol) and N-methylpiperazine (0.0684 mL; 0.610 mmol) in THF (3 mL). The mixture was heated at 80° C. for 5 hours. Flash chromatography on silica gel (eluent 1 to 15% methanol in dichloromethane) furnished 0.028 g (44%) of the title compound as a white solid.