Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[NH:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:20]=[C:18]([NH2:19])[CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:21])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:44])[CH3:43]
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=N)N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N=C(N)C(CCC(C)(C)F)CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide in methylene chloride is added 1.0 equivalents of triethylamine followed by 1.0 equivalents of acetyl chloride. The reaction is stirred at ambient temperature for approximately 5 hours. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C>[Br:46][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one (1.20 g, 3.52 mmol) in anhydrous DMF (15 mL) were added triphenylphosphine (1.00 g, 3.80 mmol) and carbontetrabromide (1.27 g, 3.80 mmol). The reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give 2-[4(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy3H-quinazolin-4-one as an off-white solid. Yield: 0.37 g (26%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.S([N:30]=[N+:31]=[N-:32])(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[N:30]([C:13]1[CH:12]=[C:11]([Cl:14])[S:10][C:9]=1[S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:8])=[N+:31]=[N-:32]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 311A (1.01 g, 3.99 mmol) in tetrahydrofuran (32 mL) at −78° C. was treated with dropwise addition of sec-BuLi (1.4 M in hexane, 2.1 equivalents). The reaction was warmed to −20° C. and stirred for 30 minutes, treated with a solution of tosyl azide (1.1 equivalent) in tetrahydrofuran (7 mL) at −20° C., stirred at 25° C. for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 30% dichloromethane in hexane to 100% dichloromethane to give approximately a 2:1 mixture of starting material to the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][N:27]([CH3:26])[C:28]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCN(C)C4=O)cc3F)CC2)c(C)c1
Yield: 85.5 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 111 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (367 mg) was obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N+:7]=1[O-:13].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([CH3:12])=[CH:8][N+:7]=1[O-:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)[n+]([O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
260 ml of fuming nitric acid (d =1.5) were added dropwise to 840 ml of concentrated sulphur-ic acid while cooling. 348,2 g of 2,5-dimethy1pyridine 1-oxide were subsequently added portionwise at 0-5° . The mixture was stirred at room temperature for 1 hour, then heated to 90° within 3 hours, left at this temperature overnight and, after cooling, poured on to 6 kg of ice. The mixture was adjusted to pH 3 with concentrated sodium hydroxide solution and extracted three times with 2 1 of methylene chloride. The combined organic phases were washed with 4 1 of water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from methylene chloride/petroleum ether and there was obtained 2,5-dimethyl-4-nitropyridine 1-oxide of melting point 142-144° .
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[CH:22]([CH:24]([CH:30]=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=O>CCO.CC(O)=O>[C:20]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[N:5][N:6]2[CH:30]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:1][C:2]=12)#[N:21]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (276 mg, 1.0 mmol) in EtOH (10 mL) was added ethyl 2-formyl-3-oxopropanoate (144 mg, 1.0 mmol) and HOAc (5 drops). After stirring at RT for 16 hr, the mixture was filtered. The cake was washed with H2O (10 mL×2) and dried to afford 250 mg (65%) of ethyl 3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate as a yellow solid. MS (ESI) m/e [M+1]+ 384.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[N:13]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([Cl:22])=[O:18])[N:13]=1
Reactant: O=C(O)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a suspension of (E)-3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acrylic acid (5.4 g, 19 mmol) in DCM (20 mL) was added oxalyl chloride (4.8 g, 38 mmol) and 2 drops of DMF. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the crude product (5.7 g, 100% yield), which was used in the next step without purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5](C2CCCCO2)[CH2:4][N:3]1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([OH:21])C>>[OH:21][CH:5]1[CH2:4][N:3]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2](=[O:1])[CH2:6]1
Reactant: CCO
Reactant: CCOC(=O)CN1CC(C2CCCCO2)CC1=O
Product: CCOC(=O)CN1CC(O)CC1=O
Yield: 62 %

Procedure:
A solution of 0.16 g ethyl 2-oxo-4-(tetrahydropyran-2-yl)-1-pyrrolidineacetate is dissolved in 5 ml ethanol containing 16 mg pyridinium p-toluenesulphonate. The mixture is heated 4 h at 35° , the ethanol is evaporated and the residue chromatographed on silica. The title compound is obtained as a colourless oil in 62% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[Mg].[C:19](=[O:21])=[O:20]>O1CCCC1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:19]([OH:21])=[O:20])=[CH:3][CH:4]=3)[C:12]=2[CH:13]=1
Reactant: Cc1ccc2occ(-c3ccc(Br)cc3)c2c1
Reactant: O=C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2occ(-c3ccc(C(=O)O)cc3)c2c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
The product of Step B is reacted in a Grignard reaction with 5 g. of magnesium turnings in 25 ml. of tetrahydrofuran (by adding the product of Step B in 150 ml. of tetrahydrofuran at a rate sufficient to sustain refluxing). Refluxing is continued for an additional 3 hours, after which the mixture is stirred overnight at about 20° C. To this reaction mixture is added gaseous carbon dioxide over a period of 1 hour, the mixture being maintained at reflux during the second half of the hour. The reaction mixture is cooled and cautiously added to 50 ml. of 6N hydrochloric acid, then evaporated to provide a residue which is recrystallized from acetic acid to provide tan crystals of 4-(5-methyl-3-benzofuranyl)benzoic acid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][N:3]1[CH2:15][C:16]#[N:17].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[C:16]([CH2:15][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:10][CH2:9]2)=[CH:4]1)#[N:17]
Reactant: N#CCn1cc(C2CCC(=O)CC2)ccc1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: N#CCn1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)ccc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of [2-oxo-5-(4-oxo-cyclohexyl)-2H-pyridin-1-yl]-acetonitrile (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])O[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][NH2:25]>CO>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])[N:25]([CH3:24])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Solvent: CO
Product: Cn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Reaction time: 4 h

Procedure:
To a solution of 3.035 g of 3-diphenylmethoxy-6-hydroxymethyl-4-pyrone in 20 ml of methanol is added 50 ml of 40% aqueous methylamine solution, and the mixture is stirred for 4 hours. The reaction mixture is condensed under reduced pressure to a volume of 15 ml, and the resulting crystal is collected by filtration, washed with a small amounts of water and ethyl acetate in this sequence, and dried under reduced pressure to give 2.04 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].N1CCCCC1>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 77.1 %

Procedure:
A mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (5.0 g), 2,4-thiazolidinedione (3.8 g), piperidine (0.32 ml) and ethanol (100 ml) was stirred under reflux for 5 hours. After cooling, the crystals which separated out were collected by filtration to give 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene}-2,4-thiazolidinedione (5.1 g, 76.8%). Recrystallization from chloroform-ethanol afforded colorless needles, m.p. 213°-214° C. Elemental analysis for C22H18N2O4S, Calcd.: C, 65.01; H, 4.46; N, 6.89. Found: C, 64.81; H, 4.55; N, 6.78.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][S:12][C:13]2[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O>C(Cl)Cl>[OH:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][S:12][C:13]2[S:17][C:16]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(CSc2ccc(S(N)(=O)=O)s2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(SCc2ccc(O)cc2)s1
Reaction time: 4 h
Yield: 2.9 %

Procedure:
A solution of boron tribromide (3.12 ml, 8.27g, 0.033 mol) in methylene chloride (30 ml) was added dropwise to a stirred solution of 5-(4-methoxybenzylthio)thiophene-2-sulfonamide (3.4 g, 0.11 mol) in methylene chloride (100 ml). The dark reaction mixture was stirred four hours, treated with water (125 ml) and extracted with ethyl acetate (500 ml). The organic layer was separated, washed with water (2×100 ml), saturated NaCl solution (100 ml) and dried (Na2SO4). The filtrate was evaporated to dryness, the residue slurried with ether and filtered to give 0.95 g off-white solid. Recrystallization from dichloroethane gave material with m.p., 167°-168.5° C.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:45]=[CH:44][C:17]([C:18]([N:20]([CH3:43])[C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=4[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[O:35])=[O:19])=[CH:16][C:15]=3[O:46][CH3:47])=[O:12])[C:4]=2[N:3]=1.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[CH3:47][O:46][C:15]1[CH:16]=[C:17]([CH:44]=[CH:45][C:14]=1[NH:13][C:11]([C:10]1[C:4]2[N:3]=[C:2]([N:52]3[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]3)[NH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)=[O:12])[C:18]([N:20]([CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35])=[O:19]
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(Cl)nc12
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(N3CCN(C)CC3)nc12
Yield: 86 %

Procedure:
A solution of 4-[2-chloro-1H-benzimidazol-4-yl]carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (70 mg) and N-methylpiperazine (106 mg) was heated at 80° C. for 2.5 hours. The excess of N-methylpiperazine was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-methylpiperazin-1-yl)-1H-benzimidazol-4-yl]carbonylaminobenzamide (66 mg).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1>C(Cl)Cl>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1
Reactant: Cc1ccc(N)nc1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cnc(N)c(Br)c1
Reaction time: 2 h

Procedure:
Bromine (3.19 g) was added dropwise at 0° C. to a solution of amino-5-picoline in 75 mL CH2Cl2. After about two hours at room temperature, the reaction was extracted with saturated sodium carbonate solution, then sodium thiosulfate solution. The combined aqueous extracts were washed with CH2Cl2, and the combined organic extracts washed with saturated NaCl, dried (Na2SO4) and concentrated giving 3.59 g crude material. The product was purified by flash chromatography on silica gel, eluting with petroleum ether with increasing amounts of CH2Cl2 (0-40%), giving 3.05 g 2-amino-3-bromo-5-picoline, m.p. 68°-70° C.
Reaction SMILES: C([C:3]1[N:4]([CH:27]2[CH2:29][CH2:28]2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[CH:9][C:8]([F:17])=[C:7]([C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([CH2:25]Cl)[CH:19]=1)[CH:6]=2)C.[CH3:30][O-:31].[Na+]>CO>[CH:27]1([N:4]2[C:5]3[C:10](=[CH:9][C:8]([F:17])=[C:7]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([CH2:25][O:31][CH3:30])[CH:19]=4)[CH:6]=3)[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3]2)[CH2:29][CH2:28]1
Reactant: CCc1c(C(=O)O)c(=O)c2cc(F)c(-c3cc(C)nc(CCl)c3)cc2n1C1CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)cc(C)n1
Yield: 65 %

Procedure:
A solution of 1.52 g ethyl 1-cyclopropyl-7-[2-(chloromethyl)-6-methyl-4-pyridinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example 18b) in 125 ml methanol was treated with 1.5 g of powdered sodium methoxide, and the reaction mixture was heated at reflux for about 16 hours. The mixture was quenched in ice containing acetic acid and extracted with methylene dichloride. The extracts were concentrated and the residue treated with water. The solid product was collected and dried (1.11 g) and was recrystallized from ethyl acetate/hexane to give 0.91 g 1-cyclopropyl-6-fluoro-7-[2-(methoxymethyl)-6-methyl-4-pyridinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 192°-193° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[N+]([O-])=O)[C:12]([N+:20]([O-])=O)=[CH:11][C:10]=1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])C1C=CC=CC=1>CO.[C].[Pd]>[CH2:27]([O:26][CH2:25][CH2:24][O:23][C:10]1[CH:11]=[C:12]2[C:13]([CH:15]=[CH:16][NH:20]2)=[CH:14][C:9]=1[OH:8])[CH3:28]
Reactant: CCOCCOc1cc([N+](=O)[O-])c(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOCCOc1cc2[nH]ccc2cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 33 %

Procedure:
10% Palladium-carbon (water content, 50%) (6 g) was added to a solution of (E)-1-(benzyloxy)-2-(2-ethoxyethoxy)-4-nitro-5-(2-nitrovinyl)benzene described in Production Example 24-4 (17.5 g, 44.9 mmol) in methanol (180 mL) at room temperature. The reaction liquid was stirred under hydrogen atmosphere at room temperature. After 6 hours, the catalyst was filtered off with celite. The filtrate was concentrated under vacuum and then the residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=2:1-1:1) to obtain the title compound (3.28 g, 33%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12](O)=[O:13])[CH2:6]2.B.O>C1COCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][OH:13])[CH2:6]2
Reactant: O=C(O)C1Cc2ccc(C(F)(F)F)cc2C1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCC1Cc2ccc(C(F)(F)F)cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
The above 5-trifluoromethyl-indan-2-carboxylic acid (1.03 g, 4.47 mmol) was dissolved in THF (25 mL) and cooled to 0° C. To this solution was added a solution of borane in THF (1M, 6.5 mL). The mixture was warmed to room temperature and stirred for 1 hr. The mixture was treated with water (5 mL) and solvents were evaporated. The residue was extracted with ether and hydrochloric acid (1M). The organic phase was washed with brine and sodium bicarbonate solution. The ether solution was dried and solvents were evaporated to give oily material as 5-trifluoromethyl-indan-2-yl-methanol (0.98 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5](O)=[O:6].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)c1cc(Br)cc(Br)c1
Yield: 70.4 %

Procedure:
In a flask equipped with a reflux condenser, 84 g (0.3 mole) of 3,5-dibromobenzoic acid and 68 g (0.33 mole) of phosphorus pentachloride were reacted under reflux for one hour. After removal of phosphorus oxychloride under reduced pressure by means of an aspirator, the reaction product was subjected to vacuum distillation under 8 mm Hg to obtain 63 g of 3,5-dibromobenzoic acid chloride, melting at 125° to 130° C., in the form of a colorless transparent liquid (yield: 70%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:48])[CH2:14][CH2:13][CH:12]([C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23](C2CCCCO2)[N:22]=[C:21]3[C:33]2[NH:37][C:36]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:41][C:35]=3[N:34]=2)=[O:16])[CH2:11][CH2:10]1>C(Cl)Cl>[F:48][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:33]2[NH:37][C:36]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:41][C:35]=3[N:34]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4cc(N5CCOCC5)ccc4[nH]3)c2c1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
TFA (0.082 mL, 1.063 mmol) was added to a solution of 4,4-difluoro-N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclohexanecarboxamide (6 mg, 10.63 μmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and the solvent was removed in vacuo. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (4 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.46 (s, 1H), 7.69 (m, 1H), 7.57 (m 2H), 7.18 (d, 1H, J=1.6 Hz), 7.07 (dd, 1H, J=2.0 and 8.8 Hz), 3.88 (m, 4H), 3.18 (m, 4H), 2.55 (m, 1H), 2.17 (m, 2H), 2.01 (m, 2H), 1.96-1.83 (m, 4H); ESI-MS [M+H]+: 481.28.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH2:9][C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=2)=[N:3]1.[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH:9]([C:10]2[N:11]=[C:12]([O:18][CH3:19])[CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[Br:25])=[N:3]1
Reactant: COc1cc(OC)nc(Cc2ccccc2C2=NC(C)(C)CO2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)nc(C(Br)c2ccccc2C2=NC(C)(C)CO2)n1
Temperature: 75 °C

Procedure:
0.55 g of 2-(2-(4,4-dimethyl-oxazolin-2-yl)-benzyl)-4,6-dimethoxypyrimidine, 0.30 g of a N-bromosuccinimide, 0.03 g of benzoyl peroxide are dissolved in 60 ml of CCl4 and heated under reflux overnight at 75° C. The reaction mixture is filtered and the filtrate washed with 5% NaHCO3 solution (50 ml), 50 ml of water and the organic phase separated and concentrated to give the title compound.