Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[CH:4][C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH3:3].[C:10](OC)(=[O:13])[C:11]#[CH:12]>CN(C)C=O>[C:5]([C:4]1[CH:12]=[CH:11][C:10](=[O:13])[NH:1][C:2]=1[CH3:3])(=[O:9])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(=O)C=C(C)N
Reactant: C#CC(=O)OC
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C

Procedure:
C-7. 5-(n-Butanoyl)-6-methyl-2(1H)-pyridinone--A mixture containing 22.2 g of 3-methyl-5-n-propylisoxazole [Kashima et al., Bull. Chem. Soc. Japan 46, 310-313 (1973)], 500 mg of platinum dioxide and 200 ml of ethanol was hydrogenated under catalytic hydrogenation conditions for ninety minutes, the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator to yield 18.5 g of colorless residue which solidified on cooling. The residue containing 2-amino-2-hepten-4-one was dissolved in 50 ml of dimethylformamide and to the solution was added 14.8 g of methyl 2-propynoate. The resulting reaction solution was allowed to stand at ambient temperature for thirty minutes (exothermic) and then refluxed for three and one half hours. The dimethylformamide was removed on a rotary evaporator. The remaining dark brown liquid was heated in an oil bath at 195°-200° C. for four hours, cooled to room temperature, crystallized from isopropyl alcohol and dried at 80°-85° C. to produce, as pale yellow flakes, 9.4 g of 5-(n-butanoyl)-6-methyl-2(1H)-pyridinone, m.p. 167°-168° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH2:19])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2F)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH:19][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:2]1
Reactant: NC(=NOCC1CC1)c1c(F)cccc1C(F)(F)F
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)NC(=NOCC2CC2)c2ccccc2C(F)(F)F)cc1
Yield: 75.2 %

Procedure:
In 80 ml of benzene was dissolved 10.4 g of N'-cyclopropylmethyloxy-2-fluoro-6-trifluoromethylbenzamidine, and to the solution was added 8.9 g of 4-methoxyphenylacetylchloride. The solution was heated under refluxing for 3 hours. After cooling, ethyl acetate was added to the solution, followed by washing with water and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue obtained in crystal was washed with a mixed solvent hexane and ether to thereby obtain 13.7 g of crude crystal. The crystal was then re-crystallized in hexane, thereby affording 11.5 g of the objective compound.m.p. 88-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1/[CH:12]=[CH:13]/[C:14]([O:16]CC)=O>Cl.O1CCOCC1>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH:12]=[CH:13][C:14](=[O:16])[NH:1]2
Reactant: CCOC(=O)/C=C/c1c(N)cccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2c(C(F)(F)F)cccc2[nH]1
Temperature: 100 °C

Procedure:
To a stirring mixture of (E)-ethyl 3-(2-amino-6-(trifluoromethyl)phenyl)acrylate in 4N HCl in dioxane (25 mL) was added concentrated HCl (2 mL). The resulting mixture was warmed to 100° C. overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCO3 solution until pH>7. A normal aqueous extraction with EtOAc was followed. The crude mixture was taken directly to the next reaction without further purification. Retention time (min)=1.892, method [1], MS(ESI) 214.0 (M+H).
Reaction SMILES: [NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:11]=2[S:10][C:9]=1[C:23]([O:25]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCCO)C.[NH3:34]>>[NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:11]=2[S:10][C:9]=1[C:23]([NH2:34])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccsc2)c1Nc1ccccc1
Solvent: CCOCCO
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccsc2)c1Nc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of Example 64 (129 mg), 2-ethoxyethanol and liquid ammonia was placed in a sealed pressure vessel and heated at 80° C. and 400 p.s.i. for 24 h. The volatiles were removed in vacuo and the residue purified by column chromatography (silica, 50% to 100% EtOAc in hexane) to give the title compound (20 mg). δH (CDCl3) 8.75 (1H, br s), 7.36-7.34 (2H, m), 7.16-7.11 (2H, m), 7.03 (1H, d, J 9.7 Hz), 6.99-6.88 (4H, m), 6.17 (1H, d, J 9.7 Hz), 5.47 (2H, br s). LCMS (ES+) RT 2.927 minutes, 368 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[C:27]([C:34]([F:35])([F:36])[F:37])[CH:28]=5)=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5ccc(OC)c(C(F)(F)F)c5)o4)cc23)cc1
Yield: 91 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 91%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].Cl>C(#N)C>[ClH:25].[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:9]1[CH2:8][CH2:7][C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:11][CH2:10]1)[CH3:19]
Reactant: CCOCCCCCl
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOCCCCN1CCC(C(=O)OCC)(c2ccccc2)CC1
Reaction time: 72 h

Procedure:
Norpethidine (15.63 g, 67 mmol), 4-ethoxybutylchloride (10.67 g, 70 mmol), Na2CO3 (7.77 g, 73 mmol), KI (0.6 g) and acetonitrile (150 ml) were heated under reflux and stirring for 72 h. The mixture was filtered and the solvent removed. The residue was dissolved in diethyl ether, and the solution washed with water and dried (MgSO4). Destillation yielded 17.9 g of base boiling at 160°-163° C./0.05 mm Hg. B.p. acc. to J. Chem. Soc. 3062 (1958) 180° C./1 mm Hg. Hydrochloride m.p. 143°-145° C.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:9].[OH2:10]>>[ClH:9].[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:10]
Reactant: O
Reactant: O=C1CCCCCN1
Agent: Cl
Product: NCCCCCC(=O)O
Temperature: 25 °C

Procedure:
ε-Caprolactam (750.00 g, 6.63 mol), water (1500 mL), and concentrated HCl (675 mL, 36-38%) are combined in a 5000 mL three-necked round bottomed flask fitted with a mechanical stirrer and condenser. The mixture is heated for 4 h at reflux, cooled to room temperature, and concentrated by rotary evaporation at 50° C. (water aspirator vacuum) to give 1 as a white solid. The absence of ε-caprolactam by TLC (Rf =0.21, THF) indicates the reaction is complete.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]#[N:14].[OH:15]S(O)(=O)=O>>[OH:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]([NH2:14])=[O:15]
Reactant: Cc1nn(C)c2nc(O)c(C#N)cc12
Reactant: O=S(=O)(O)O
Product: Cc1nn(C)c2nc(O)c(C(N)=O)cc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
6-Hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carbonitrile (0.91 g) was dissolved in concentrated H2SO4 (3 mL) and stirred at 40° C. for 24 hours. The solution was poured into ice water and the precipitate was filtered, washed with water, and dried under high vacuum to give 6-hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxamide as a white solid. A portion of this material (0.12 g) was dissolved in DMF (2 mL) and treated with 1-(2-chloroethyl)pyrrolidine hydrochloride (0.12 g) and potassium carbonate (0.30 g). The reaction mixture was stirred at 60° C. for 18 h, poured into water, and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure to give 1,3-dimethyl-6-[2-(pyrrolidin-1-yl)-ethoxy]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide. A portion of this material (0.06 g) was dissolved in toluene and treated with 3-isopropoxyphenyl isocyanate (0.1 g). The mixture was heated at reflux for 23 hours, and then cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (methanol/ethyl acetate). A portion of this material was dissolved in tetrahydrofuran and treated with 4M HCl/dioxane. The solid material obtained was recrystallized from acetonitrile to give 1-{1,3-dimethyl-6-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolo[3,4-b]pyridine-5-carbonyl}-3-(3-isopropoxyphenyl)urea hydrochloride (1), as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[Br:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Br)CC1
Reaction time: 14 h
Yield: 36 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0025 mole) in dry 1,2-dichloroethane (5 mL) under an atmosphere of nitrogen was added 2-bromoaniline (0.474 g, 0.00276 mole), acetic acid (0.18 g, 0.00301 mole) and sodium triacetoxyborohydride (0.638 g, 0.00301 mole). Stirring was continued at ambient temperature for 14 hours. The reaction mixture was quenched in cold aqueous 1N NaOH solution and the product extracted with ether. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as transparent viscous liquid. Purification by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) afforded 0.320 g (35%) of desired 4-(2-bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSO-d6): δ 7.44-7.38 (m, 1H), 7.2-7.12 (m, 1H), 6.84-6.78 (m, 1H), 6.58-6.48 (m, 1H), 4.65 (d, 1H), 3.9 (m, 2H), 3.5 (m, 1H), 3.0-2.8 (m, 2H), 2.0-1.8 (m, 2H), 1.4 (s, 9H). To a cooled solution (0° C.) of 4-(2-bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 0.00087 mole) in dioxane (0.5 mL) was added dioxane.HCl (2.5 mL). The mixture was stirred at the same temperature for 10 minutes, then gradually brought to ambient temperature with continued stirring for a further 15 minutes. The reaction mixture was evaporated under reduced pressure to afford a residue which was washed with dry ether to afford 0.106 g (42%) of 2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride.
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:24][NH2:25]>CS(C)=O.O>[CH3:21][CH:18]1[CH2:17][NH:16][C:15](=[O:22])[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:11]=[C:2]([NH:25][CH3:24])[C:3]([CH3:23])=[N:4]4)[NH:20][C:19]1=2
Reactant: CN
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Solvent: O
Solvent: CS(C)=O
Product: CNc1nc2c(-c3cc4c([nH]3)C(C)CNC4=O)cccc2nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 32.7 mg, 0.105 mmol) and methylamine (2.0M in THF; 0.158 mL, 0.316 mmol) in DMSO (0.8 mL) was stirred under argon in a sealed flask at 25° C. for 10 min, then at 60° C. for 1 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-7-methyl-2-(2-methyl-3-(methylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (21.0 mg, 0.065 mmol, 62% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.24 (1H, br. s.), 7.93 (1H, d, J=7.4 Hz), 7.57 (1H, d, J=7.8 Hz), 7.45 (1H, d, J=4.3 Hz), 7.32 (1H, t, J=7.8 Hz), 7.04 (1H, s), 6.99 (1H, br. s.), 3.43 (1H, dt, J=11.0, 4.0 Hz), 3.09-3.21 (2H, m), 3.07 (3H, s), 2.52 (3H, s), 1.30 (3H, d, J=6.5 Hz). m/z (ESI, +ve) 322.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:12]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[CH:24]=3)[C:20]3[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:22])=[N:13]2)[CH:6]=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10].[C-:35]#[N:36].[K+]>CC#N>[NH2:22][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:12]([C:5]2[CH:6]=[C:7]([CH3:11])[C:8]([O:9][CH3:10])=[C:3]([CH2:2][C:35]#[N:36])[CH:4]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)[CH:24]=2)[N:13]=1
Reactant: [C-]#N
Reactant: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CBr
Agent: [K+]
Solvent: CC#N
Product: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CC#N
Temperature: 25 °C
Yield: 13.8 %

Procedure:
To a solution of 1-(3-(bromomethyl)-4-methoxy-5-methylphenyl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine (185 mg, 0.36 mmol) in MeCN (5 mL) was added potassium cyanide (69.8 mg, 1.07 mmol) and the reaction mixture was stirred at rt over night. The mixture was filtered and the filtrate was concentrated in vacuo and purified by preparative HPLC to give 23 mg (12%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:34])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15]([F:26])=[CH:14][C:13]=1[F:27])[CH:9]=[C:8]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:7]2=[O:33].[N-:36]=[N+:37]=[N-:38].[Na+].CN(C)C=O>C(OCC)(=O)C>[N:36]([C:3]1[C:2]([Br:1])=[C:11]2[C:6]([C:7](=[O:33])[C:8]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:9][N:10]2[C:12]2[CH:17]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C:15]([F:26])=[CH:14][C:13]=2[F:27])=[CH:5][C:4]=1[F:34])=[N+:37]=[N-:38]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N=[N+]=[N-])c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
Ethyl 8-bromo-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1,000 mg) and sodium azide (180 mg) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 60° C. After the reaction mixture was cooled back to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (428 mg) as an amorphous substance.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([CH2:22][CH2:23][CH2:24][O:25][C:26]1[C:31]2[C:32]([CH3:43])=[C:33]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(C)(C)C.ClCCl>ClCCl>[CH3:43][C:32]1[C:31]2[C:26]([O:25][CH2:24][CH2:23][CH2:22][NH:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:27][CH:28]=[CH:29][C:30]=2[O:34][C:33]=1/[CH:35]=[CH:36]/[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1c(C=Cc2ccccc2)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(/C=C/c2ccccc2)oc2cccc(OCCCNCc3cccnc3)c12
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of 10% trifluoroacetic acid in dichloromethane [3-(3-methyl-2-styryl-benzofuran-4-yloxy)-propyl]-pyridin-3-ylmethyl-carbamic acid tert-butyl ester (15 mg) in dichloromethane (1 ml) was added with ice-cooling. After 3 hours, the mixture was quenched with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane-MeOH) to give a colorless solid (7 mg, 58%). ESI-MS: m/z 399 (MH+); 1H-NMR (CDCl3): δ 2.12 (2H, s), 2.37 (3H, s), 2.94 (2H, t, J=6.9 Hz), 3.91 (2H, s), 4.14 (2H, t, J=5.9 Hz), 6.57 (1H, d, J=7.6 Hz), 7.02-7.28 (5H, m), 7.37 (2H, t, J=7.6 Hz), 7.53 (2H, d, J=7.6 Hz), 7.73 (2H, d, J=7.9 Hz), 8.52 (1H, d, J=4.6 Hz), 8.61 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.CN.Cl.[CH3:23][N:24](C)CCCC(N=C=N)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH:24][CH3:23])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CC(CCCN(C)C)N=C=N
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-prop ionic acid (0.25 g, 0.74 mmol) and 1-hydroxybenatriazole (0.12 g, 0.88 mmol) in dichloromethane (3 ml) was stirred for 15 minutes before addition of methylamine (40% solution in water, 0.11 μl, 1.47 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.17 g, 0.88 mmol). The reaction mixture was stirred for 16 hours, solvent removed under reduced pressure and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated sodium hydrogen carbonate, brine, dried (MgSO4), filtered and concentrated to yield the title compound which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 353.95.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[N:5]2.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:12])[CH:6]=[N:5]2
Reactant: O=c1cnc2cc(Br)ccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)cnc2cc(Br)ccc21
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Under a nitrogen atmosphere 6-bromoquinoxalin-2(1H)-one (2.03 g, 9 mmol) (J.Med.Chem., 24, (1981), 93) was dissolved in 22 ml of dry DMF and sodium hydride (0.44 g, 10.8 mmol (60% mineral oil dispersion)) was added. After stirring for 2 h, ethyl bromoacetate (1.25 ml, 11.3 mmol) was added and the mixture was stirred for 3.5 h. The reaction mixture was poured onto crushed ice and acidified (pH=4.5) by addition of dilute hydrochloric acid. The precipitate was filtered off, washed with water and air dried. The crude product (containing a minor fraction of O-alkylated product) was triturated with ether (100 ml), the precipitate filtered off, washed with ether and dried to afford 1.95 g (80%) of pure 6-bromo-1-ethoxycarbonylmethylquinoxalin-2(1H)-one. 1H-NMR (DMSO-d6):δ1.22 (t, 3H), 4.17 (q, 2H), 5.08 (s, 2H), 7.56 (d, 1H), 7.83 (dd, 1H), 8.09 (dd, 1H), 8.37 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: Cc1ccc2ncnc(O)c2c1
Product: Cc1ccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1

Procedure:
The title compound was prepared using 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (83 mg, 0.3 mmol) and 4-hydroxy-6-methylquinazoline from the previous step (53 mg, 0.3 mmol) according to the procedure described in Example 1B Step 1 to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methylquinazolin-4-yloxy)phenyl)urea.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([O:32]CCCC)=[O:31].C(=O)([O-])[O-].[K+].[K+]>>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:29][C:30]([OH:32])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCOC(=O)CBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)n(C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCC(=O)O)n(C)c2c1
Reaction time: 72 h
Yield: 90.6 %

Procedure:
A solution of intermediate 4 (4.00 g, 11.0 mmol), tent-butyl 2-bromoacetate (2.36 g, 12.1 mmol) and potassium carbonate (3.04 g, 22.0 mmol) was stirred at room temperature. After 72 h, the reaction mixture was concentrated under vacuum and the residue was partitioned between CH2Cl2 and water. The organic layer was dried and the residue was reconstituted in CH2Cl2 (20 mL) and TFA (20 mL) was added. After 2 h at room temperature, the reaction mixture was evaporated under vacuum to yield 4.2 g (90%) of {2-[3-cyclohexyl-6-(methoxycarbonyl)-1-methyl-1H-indol-2-yl]phenoxy}acetic acid 5: m/z=422 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[I:13]I.ClC1C=CC=CC=1.OO>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[I:13]
Reactant: II
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: OO
Solvent: Clc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(N)c(I)c1
Temperature: 90 °C

Procedure:
Ethyl 4-aminobenzoate (15.00 g, 91 mmol) and iodine (11.80 g, 46.5 mmol) were mixed with water (80 mL) and chlorobenzene (4.60 g, 41 mmol). The mixture was stirred while the temperature was gradually raised to 90° C. over 30 min. Hydrogen peroxide (30%, 50 mL) was added over 10 h at 90° C. After stirring at that temperature for an additional 6 h, the mixture was cooled and the solution decanted from the residual solids. The solids were dissolved in DCM and the solution washed successively with sodium thiosulfate and brine. After drying (MgSO4), the solvent was removed under reduced pressure and the resulting brown solid was triturated with hexane to remove di-iodinated by-products. The desired compound was obtained as a brown solid (22.85 g, 86% yield).