Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[NH2:14][C:15]1[C:20](C(O)=O)=[C:19]([CH3:24])[N:18]=[C:17]2[S:25][C:26]([Br:35])=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=3)[C:16]=12>C(Cl)Cl>[Br:35][C:26]1[S:25][C:17]2[N:18]=[C:19]([CH3:24])[CH:20]=[C:15]([NH2:14])[C:16]=2[C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1
Reactant: Cc1nc2sc(Br)c(-c3cccc(Br)c3)c2c(N)c1C(=O)O
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(N)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Temperature: 200 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
Diphenyl ether (20 mL, 126 mmol) was added to 4-amino-2-bromo-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridine-5-carboxylic acid (Description 48) (1.861 g, 4.21 mmol). The mixture was heated to 200° C. and stirred at 200° C. for 4 h. The mixture cooled to RT and was stirred overnight at RT. The mixture was then diluted with DCM and purified by chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane, to give the title compound (1.0 g). LCMS (A) m/z: 399 [M+1]+, Rt 0.94 min (acidic).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])=[C:24]([F:34])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])=[C:24]([F:34])[CH:23]=1
Reactant: CCCNC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Solvent: C1COCCO1
Product: CCCNC(=O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1F
Yield: 7.8 %

Procedure:
Use a method similar to the General Procedure 1-4 to deprotect 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (33.1 mg, 0.83 mmol) in 1,4-dioxane (1 mL). Purify by SCX chromatography eluting with dichloromethane and dichloromethane/2M ammonia in methanol (1:1) to afford 7-Chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (25.2 mg, 96%). MS (ES+) m/z: 390.1 (M+H)+. Use a method similar to the General Procedure 2-6, using 7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (25 mg, 0.064 mmol) to provide the title compound as a white foam (31.4 mg, 91%). MS (ES+) m/z: 390.1 (M+H)+.
Reaction SMILES: C(N)C.Cl.NO.[CH2:7]([OH:10])[C:8]#[CH:9].Br[C:12]#[C:13][C:14]([O:17][CH3:18])([CH3:16])[CH3:15]>CO.[Cu]Cl>[CH3:18][O:17][C:14]([CH3:16])([CH3:15])[C:13]#[C:12][C:9]#[C:8][CH2:7][OH:10]
Reactant: C#CCO
Reactant: COC(C)(C)C#CBr
Agent: Cl[Cu]
Agent: CCN
Agent: Cl
Solvent: CO
Product: COC(C)(C)C#CC#CCO
Yield: 89.6 %

Procedure:
200 ml of a 70% aqueous solution of ethyamine, 1 g of copper(I) chloride, 5 g of hydroxylamine hydrochloride and 25 g of propargyl alcohol were dissolved in 500 ml of methanol, and with ice cooling and stirring, a methanol solution (100 ml) of 74 g of 1-bromo-3-methoxy-3-methyl-1-butyne was added. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. Water and ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer separated was worked up in a customary manner, and the product was purified by vacuum distillation ( b.p. -97° C. / 2 mmHg ) to give 57 g of the captioned compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1Cc1cccc(OC)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1Cc1cccc(OC)c1)CCCC3
Yield: 57.3 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.327 g; 0.85 mmol), LHMDS 1N in THF (1.27 mL; 1.27 mmol), 1-iodopropane (0.166 mL; 1.7 mmol) in DMF (4.2 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.213 g (59%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.[N:19](OC(C)(C)C)=[O:20].Cl>C(O)C.C(O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])/[C:9](=[N:19]\[OH:20])/[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(CC(=O)c2ccc(F)cc2)n1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: CCCO
Solvent: CCO
Product: CSc1nccc(/C(=N/O)C(=O)c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-fluorophenyl)-2-(2-(methylthio)pyrimidin-4-yl)ethanone, 73 (1.0 g) in ethanol (20 mL) at −10° C., under an atmosphere of nitrogen, is added dropwise t-butyl nitrite (0.5 mL) followed by hydrogen chloride in n-propanol (2.5 to 3 N, 0.6 mL) while maintaining the temperature below −5° C. Once the addition is complete, the solution is allowed to warm to room temperature with stirring and after 2 h the solvent is evaporated and the residue partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The layers are separated; the aqueous phase is extracted with ethyl acetate and the combined organic phases dried over sodium sulfate. Filtration and evaporation of the solvent affords the title compound, 74 (1.0 g).
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[CH2:12]([NH:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.N>O.CO>[NH2:6][C:5]1[N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:20]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCc1ccccc1
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: Nc1c(N=O)cnn1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 3.43 g (21 mmol) of benzylhydrazine hydrochloride with a purity of 97% by weight, 1.4 ml of water, 6 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for 3 hours. After completion of the reaction, 5 ml of water was added to the mixture to cool the mixture up to 10° C. Then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 5 ml of cold water and dried under reduced pressure to obtain 3.89 g of 5-amino-1-benzyl-4-nitrosopyrazole (Isolation yield: 82.8%) as brown solid with a purity of 86.1% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[C:6]([CH:49]([CH3:51])[CH3:50])=[N:7][N:8]([CH3:48])[C:9]=1[N:10]1[CH2:47][CH2:46][C:13]2[N:14]=[C:15]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH3:45])=[CH:29][N:30]4S(C3C=CC(C)=CC=3)(=O)=O)[N:16]=[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[C:12]=2[CH2:11]1.[OH-].[K+].[OH-].[NH4+]>ClCCl.O>[Cl:4][C:5]1[C:6]([CH:49]([CH3:51])[CH3:50])=[N:7][N:8]([CH3:48])[C:9]=1[N:10]1[CH2:47][CH2:46][C:13]2[N:14]=[C:15]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH3:45])=[CH:29][NH:30]4)[N:16]=[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[C:12]=2[CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCCC(C)(C)C6)n4)CN(c4c(Cl)c(C(C)C)nn4C)CC5)cccc32)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1c[nH]c2cccc(-c3nc4c(c(N5CCCC(C)(C)C5)n3)CN(c3c(Cl)c(C(C)C)nn3C)CC4)c12
Temperature: 100 °C

Procedure:
Ethanol (1.8 mL) was added to 6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-(3,3-dimethylpiperidin-1-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (74 mg, 0.108 mmol) in a microwave vial. Next, KOH (61 mg, 1.08 mmol) was added followed by 28% aqueous ammonium hydroxide (0.6 mL, 4.35 mmol). The vessel was sealed and heated via microwave irradiation at 100° C. for 75 minutes. The reaction mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the organic layer was dried by passing through a phase separator. The eluent was concentrated and the resulting residue was purified by reverse phase HPLC (20-55% MeCN/Water (0.1% TFA)). The eluent from the HPLC was neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic extract was dried by passing through a phase separator and concentrating to provide 6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-(3,3-dimethylpiperidin-1-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1.ClCCl>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7])(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(=O)Cl
Reactant: N#Cc1ccc(N)cc1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ccc(C#N)c(C#N)c1
Reaction time: 2 h
Yield: 70.7 %

Procedure:
4-Aminophthalonitrile (3.60 g, 25.2 mmole) was dissolved in 8.6 mL of pyridine. Hexanoyl chloride (8.6 mL, 61.5 mmole) was added and the mixture was stirred under N2 for 2 hours. The pyridine was distilled under vacuum until a yellow-orange residue was obtained. This residue was dissolved in dichloromethane and washed with 0.1 M HCl (5×15 mL) and then neutralized with aqueous sodium bicarbonate (3×50 mL). The organic solution was separated and dried over magnesium sulfate. Purification by column chromatography (silica, dichloromethane: methanol 5%) afforded 4.3 g (71% yield) of 4-hexanamidophthalonitrile as a light yellow compound.
Reaction SMILES: [CH:1]([OH:3])=O.[N+:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[NH2:15])[CH:10]=[O:11])([O-:6])=[O:5].C(OC(=O)C)(=O)C>O>[N+:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[NH:15][CH:1]=[O:3])[CH:10]=[O:11])([O-:6])=[O:5]
Reactant: O=CO
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 79.7 %

Procedure:
To 56.6 ml (1.50 mol) of HCOOH was added 24.9 g (150 mmol) of 3-nitro-4-aminobenzaldehyde. The solution was heated to reflux, 28.4 ml (300 mmol) of acetic anhydride was added dropwise and the solution was refluxed for 30 minutes. The resulting suspension was cooled and poured into 400 ml of cold H2O with rapid stirring. The product was filtered, air dried, and recrystallized from isopropanol to yield 23.2 g (80%) of 3-nitro-4-formamidobenzaldehyde as a bright yellow powder: melting point=183°-191°.
Reaction SMILES: C(ON=O)(C)(C)C.[F:8][CH:9]([F:31])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12](N)[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].N#N.[ClH:34]>CC#N.[Cu](Cl)Cl>[F:8][CH:9]([F:31])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([Cl:34])[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: N#N
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl

Procedure:
To a mechanically stirred mixture of 11.52 g (0.087 mol) of copper (II) chloride, and 11.18 g (0.108 mol) of t-butylnitrite in 350 ml of CH3CN, was added a solution of 25.00 g (0.070 mol) of product of Example 100 in 25 ml of CH3CN in such a rate that a slow evolution of N2 was observed. After 18 hours the mixture was poured into 3.7% HCl, and extracted with diethyl ether. The ether phase was washed with H2O and dried (MgSO4). This was concentrated in vacuo to 24.03 g of a yellow oil. The crude product was purified by HPLC in 5% ethvl acetate/cyclohexane affording 13.2 g (50%) of product as a yellow solid; mp 35°-40° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([C:22](=O)[CH3:23])=[CH:13][C:14]([F:21])=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([CH:22]([NH2:31])[CH3:23])=[CH:13][C:14]([F:21])=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CCN(C2CCC2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(F)c2cccnc2c1N1CCN(C2CCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(4-cyclobutylpiperazin-1-yl)-5-fluoroquinolin-7-yl]ethanone (16 mg, 0.049 mmol) and ammonium acetate (37.7 mg, 0.489 mmol) in methanol (0.27 mL) and acetonitrile (0.28 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (6 mg, 0.01 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C19H26FN4 (M+H)+: m/z=329.2; Found: 329.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH2:26][CH2:27][C:28]#[N:29])[C:10]2=[O:30])=[CH:5][CH:4]=1.[OH-:31].[Na+].OO>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH2:26][CH2:27][C:28]([NH2:29])=[O:31])[C:10]2=[O:30])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(CCC#N)C2=O)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(CCC(N)=O)C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of 3-[-3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-1-yl]-propionitrile (60 mg, 0.15 mmol) (from Example 26 supra) in dimethyl sulfoxide (2 mL) at 0 C was added 1.0 N aqueous sodium hydroxide solution (0.42 mL, 0.42 mmol) followed by 35% aqueous hydrogen peroxide (0.35 mL) (Fisher). The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with water (3×20 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude solid (71 mg) which was purified by recrystallization from hexanes-ethyl acetate to give 3-[-3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-1-yl]-propionamide as a gray solid. (Yield 28.3 mg, 45.1%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:7]([Br:14])=[N:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19](N2C3C=CC=C(C(O)=O)C=3C=N2)=[CH:18][CH:17]=1>>[Br:14][C:7]1[C:6]2[C:5]([C:3]([OH:2])=[O:4])=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:8]=1
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: COC(=O)c1cccc2[nH]nc(Br)c12
Product: O=C(O)c1cccc2c1c(Br)nn2-c1ccc(F)cc1

Procedure:
3-Bromo-1H-indazole-4-carboxylic acid methyl ester was then subjected to the reaction conditions described in Example 2, for the synthesis of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid, to yield 3-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid. Using the methods described in Example 2,3-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid was used to provide the following compounds:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:12]1[C:16]([N:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)C(=O)OC(C)(C)C)=[CH:15][N:14]=[N:13]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:9]([C:5]1[CH:4]=[C:3]([N:12]2[C:16]([NH:17][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[CH:30][CH:31]=3)=[CH:15][N:14]=[N:13]2)[C:2]([OH:1])=[CH:7][C:6]=1[OH:8])([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(-n2nncc2N(Cc2ccc(N3CCOCC3)cc2)C(=O)OC(C)(C)C)c(O)cc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(-n2nncc2NCc2ccc(N3CCOCC3)cc2)c(O)cc1O
Yield: 50 %

Procedure:
A solution of the intermediate from Step D in DCM/TFA (1/1, 5 ml) was stirred for 12 hours at RT. The reaction mixture was concentrated under reduced pressure and the crude reaction mixture was purified by column chromatography (DCM/MeOH: 95/5). The title compound was obtained as slightly brown solid.
Reaction SMILES: F[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:13])[CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:6]([C:5]1[C:4]([CH3:13])=[CH:3][C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1C#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C#N
Temperature: 80 °C
Yield: 110 %

Procedure:
A solution of 4-fluoro-2-methyl-5-nitrobenzonitrile (D90) (3 mmol, 540.3 mg) in dimethylformamide (20 mL) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (3 mmol, 600.9 mg, 1 eq) and diisopropylethylamine (3 mmol, 387.6 mg, 1 eq) under argon at room temperature and then heated at 80° C. overnight. The mixture was then concentrated under reduced pressure then treated with 10% aqueous sodium carbonate solution and extracted with ether/ethyl acetate. The organics were dried and concentrated under reduced pressure to give the title compound as a solid (3.3 mmol, 1.19 mg, >100% yield). M+H 304.97 for main fragment (loss of tert-butyl group).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:15]=[CH:16][C:3]1=2.[OH-].[K+].O.C([OH:27])C>C(O)(=O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:27])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CC(C(N)=O)c1ccc2c(c1)Oc1ncccc1CC2=O
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)Oc1ncccc1CC2=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
The mixture of 40 mg of 2-(5,6-dihydro-6-oxo benzo[b]-pyrido[3,2-f]oxepin-9-yl)-propionamide, 180 mg of potassium hydroxide, 1.5 ml of water and 5 ml of ethanol was refluxed with stirring for 5 hours. After cooling, the solvent was distilled off to obtain the residue, to this was added ice-water and the mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the oil, which was chromatographed over silica gel, eluted with chloroform-ethanol, and there was obtained 20 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-9-yl)-propionic acid as pale yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[CH2:12]Br.C(=O)([O-])[O-:16].[Ca+2].Cl>O1CCOCC1>[OH:16][CH2:10][C:8]1[CH:9]=[C:4]2[C:5]([CH2:12][O:2][C:3]2=[O:14])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(CBr)ccc1CBr
Agent: Cl
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=C1OCc2ccc(CO)cc21
Temperature: 100 °C
Reaction time: 16.5 h

Procedure:
The compound (1.1274 g) obtained in Example 102-1 was dissolved in carbon tetrachloride (19.2 ml). The reaction solution was added with N-bromosuccinimide (2.417 g) and benzoyl peroxide (147.2 mg), and the whole was refluxed under heating for 6.5 hours. After having been cooled to room temperature, the reaction solution was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining a mixture (2.4003 g) containing 2,5-bis-bromomethyl-benzoic acid methyl ester. The resultant mixture was dissolved in a 50% 1,4-dioxane aqueous solution (48 ml). The reaction solution was added with calcium carbonate (3.4823 g) and the whole was stirred at 100° C. for 16.5 hours. After having been cooled to room temperature, the reaction solution was cooled to 0° C. and concentrated hydrochloric acid was gradually added thereto to make the pH of the solution to 2. After that, the whole was stirred at room temperature for 20 minutes. The reaction solution was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution and then dried with anhydrous sodium sulfate. After the drying agent was filtrated out, the filtrate was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (372.0 mg) as a white crystal.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]1[O:55][N:54]=[CH:53][C:52]=1[C:56](O)=[O:57]>CN(C=O)C>[C:1]1([C@@H:7]2[CH2:11][N:10]([C:56]([C:52]3[CH:53]=[N:54][O:55][C:51]=3[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=3)=[O:57])[CH2:9][CH:8]2[CH2:12][OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CNCC1c1ccccc1
Reactant: O=C(O)c1cnoc1-c1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1-c1ccccn1)N1CC(CO)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-pyridin-2-ylisoxazole-4-carboxylic acid (6 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O3: 349.1426, found 349.1427.