Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18](O)=[O:19].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:19]
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1n[nH]c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a stirring solution of 3-aminopyridine (CXXV) (0.195 g, 0.2.07 mmol) in DMF (10 mL) was added 5-bromo-1H-indazole-3-carboxylic acid (CXV) (0.500 g, 0.2.07 mmol) and N,N-diisopropylethylamine (0.723 mL, 4.15 mmol). The reaction mixture was cooled to 0° C. and added with HATU (0.787 g, 2.07 mmol). The reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The solution was concentrated under vacuum. The residue was purified by column chromatography (1:99 MeOH[7N NH3]:CHCl3→4:96 MeOH[7N NH3]:CHCl3) to afford 5-bromo-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (CXXXV) (0.200 g, 0.63 mmol, 30% yield) as a white solid. ESIMS found for C13H9BrN4O m/z 318.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]1=[O:17].Cl[C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:21][C:20]=1[F:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:19]=1[C:6]1[CH:5]=[CH:4][C:3](=[O:17])[N:2]([CH3:1])[CH:7]=1)[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(F)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2F)ccc1=O
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 21-3 (78 mg, 0.33 mmol), tert-butyl 4-chloro-3-fluorobenzylcarbamate 21-5 (94 mg, 0.36 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol) and K3PO4 (140 mg, 0.66 mmol) in dioxane (1.2 mL) and water (0.1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography to give crude tert-butyl 3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzylcarbamate 21-6.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([NH:27][C:28]1[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:29]=1[C:30]([O:32]C)=[O:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C(=O)C>[C:19]([NH:27][C:28]1[CH:37]=[C:36]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:35]=[CH:34][C:29]=1[C:30]([OH:32])=[O:31])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(-c2cc3ccccc3o2)ccc1C(=O)O)c1ccccc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 14.7 %

Procedure:
51 mg of benzofuran-2-boronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 22 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.2 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1.0 mL of 1.0 mol/L aqueous sodium hydroxide and 2.0 ml, of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid was added to the reaction mixture and a solid substance was separated by filtration to obtain 11 mg of 2-(benzamido)-4-(benzofuran-2-yl)benzoic acid as whine solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][C:3]1=2.Br[C:19]1[CH:20]=[C:21]([CH:24]=[O:25])[S:22][CH:23]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:19]3[CH:20]=[C:21]([CH:24]=[O:25])[S:22][CH:23]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Reactant: O=Cc1cc(Br)cs1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C=O)c3)ccc21

Procedure:
In a similar manner to Example 3(b), by reaction of 4.3 g (18.7 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylboronic acid with 2.36 g (12.3 mmol) of 4-bromo-2-thiophenecarboxaldehyde, 2.3 g (63%) of the expected aldehyde derivative are obtained, with a melting point of 84-5° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[C:5]([CH3:16])[O:4][N:3]=1.[Sn].Cl>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Cc1noc(C)c1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of 3,5-dimethyl-4-(4-nitrophenyl)-isoxazole (50 mg, 0.22 mmol) in ethanol (10 ml) was added tin (52 mg, 0.44 mmol), followed by dropwise addition of concentrated hydrochloric acid (1 ml) and the reaction was stirred at room temperature for 2 hr. The reaction mixture was filtered and the filtrate evaporated to dryness. The resultant residue was diluted with water, basified with saturated bicarbonate solution, then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness to yield 4-(3,5-dimethyl-isoxazol-4-yl)-phenylamine (40 mg, 90%) as solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>O1CCCC1>[SH:1][C:2]1[S:3][C:4]([S:7][CH:10]2[CH2:9][C:8](=[O:14])[O:13][C:11]2=[O:12])=[N:5][N:6]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Sc1nnc(S)s1
Solvent: C1CCOC1
Product: O=C1CC(Sc2nnc(S)s2)C(=O)O1

Procedure:
A mixture of 95 grams (0.5 moles) of 2,5-dimercapto-1,3,4-thiadiazole and 49.0 grams (0.5 moles) of maleic anhydride in 500 ml. tetrahydrofuran was refluxed for six hours. After distilling off the solvent, a light tan solid (123 g.) was obtained (m.p. 194°-196° C.). Its infrared spectrum and elemental analysis appeared to be consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: OB(O)c1ccsc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3ccsc3)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-thiophen-3-yl-7-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=5)[NH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: COC(=O)c1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.8 g, 8.09 mmol), methyl 3-(piperidin-4-yl)-1H-indole-5-carboxylate (2.09 g, 8.09 mmol) and DIPEA (1.55 mL, 8.90 mmol) in DMF (25 mL) were stirred and heated at 80° C. for 1 hour. The resulting mixture was then cooled to ambient temperature and quenched in water (60 mL) to give a precipitate which was collected by filtration, washed sequentially with water, acetonitrile and ether and dried under vacuum to give methyl 3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxylate (3.29 g, 92%) as a cream solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](O)(=O)[C:12]1C(=CC=C[CH:20]=1)C(O)=O.[BH4-].[Na+]>CC(C)=O>[CH:12]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])([CH3:20])[CH3:11]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Nc1ccccc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)Nc1ccccc1C(=O)O

Procedure:
To stirred mixture of 2.7 g. of anthranilic acid and 5.4 g. of phthalic acid in 23 ml. of acetone is added 0.7 g. of powdered sodium borohydride over a period of 30 minutes at 20° C.-30° C. The resulting slurry is then stirred at 35°-40° C. for 4 hours, diluted with 25 ml. of chloroform and filtered. The filtrate is concentrated in vacuo and the residue dissolved in 20 ml. of chloroform and treated with 30 ml. of hexane, filtered and the filtrate concentrated in vacuo to obtain a crude solid product which is recrystallized 5 times from cyclohexane to obtain (second crop of fifth recrystallization) N-isopropylanthranilic acid, m.p. 109°-109.5° C.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13].O>C(O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:15][CH2:14][CH2:12][OH:13])[N:4]([CH3:11])[N:3]=1
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: NCCO
Solvent: CCO
Solvent: O
Product: Cn1nc(Br)c([N+](=O)[O-])c1NCCO
Temperature: 5 °C
Yield: 81 %

Procedure:
3 g (10.5 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in a solution of 30 ml ethanolamine in 30 ml ethanol for 15 hours at boiling temperature. The reaction mixture is then poured on 200 ml water, the separated product is filtered, washed with water (20 ml) and vacuum dried. Additional product crystallizes from the filtrate when cooled (5° C.). 2.25 g (81 percent of theory) of 3-bromo-5-(2'-hydroxyethyl)amino-1-methyl-4-nitropyrazole are obtained in the form of yellow crystals with a melting point of 150° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:19][O:20][C:21]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:25]2[CH2:24][CH2:23][C:22]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[C:30]([O:31][CH3:32])[C:21]=3[O:20][CH3:19])[CH2:26]2)[N:3]=1
Reactant: COc1cc2c(c(OC)c1OC)CCNC2
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Product: COc1cc2c(c(OC)c1OC)CCN(c1nc(N)c3cc(OC)c(OC)c(OC)c3n1)C2

Procedure:
The procedure described in Example 1 was followed to prepare the above compound, starting from 4-amino-2-chloro-6,7,8-trimethoxyquinazoline and using 5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline as the reagent of choice on the same molar basis as before. In this particular instance, the final product was obtained as the free base compound, m.p. 193°-195°C.
Reaction SMILES: [CH:1]1([C@H:4]([NH2:26])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:6])[CH2:3][CH2:2]1.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].C(O)C>O1CCOCC1>[CH:1]1([C@H:4]([NH:26][CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: C=CC(=O)OC
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)CCN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Temperature: 85 °C

Procedure:
A solution of {(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amine (16-7, 100 mg, 0.282 mmol, 1 equiv) and methyl acrylate (0.076 mL, 0.85 mmol, 3.0 equiv) in a 1:1 mixture of ethanol and dioxane (10 mL) was heated at 85° C. for 20 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography (100% EtOAc) to provide methyl N-{(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}-β-alaninate (41-1) as a colorless oil that solidified to a white solid over time. LRMS m/z (M+H) 441.4 found, 441.2 required.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][C@@H:30]2[CH2:32][C@H:27]1[CH2:28][NH:29]2)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CC#N>[C:19]([O:23][C:24]([N:26]1[CH2:31][C@@H:30]2[CH2:32][C@H:27]1[CH2:28][N:29]2[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: ClCc1ccc(Oc2nc3ccccc3s2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a stirred solution of 2-(4-chloromethyl-phenoxy)-benzothiazole (15.3 g, 55.3 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (13.2 g, 66.4 mmol) in CH3CN (200 mL) was added triethylamine (Et3N) (11.5 mL, 82.9 mmol). The resulting solution was stirred at rt for 24 h and then concentrated. The crude residue was then partitioned between CH2Cl2 (800 mL) and saturated (satd.) aqueous (aq.) NaHCO3 (200 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (10% to 40% ethyl acetate (EtOAc) in hexanes) afforded the title compound as a white foam (17.2 g, 71%). MS (ESI): mass calcd. for C24H27N3O3S, 437.18; m/z found, 438.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=7.1 Hz, 1H), 7.66 (d, J=7.1 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.38 (m, 1H), 7.32-7.24 (br m, 3H), 4.40 (br m, 0.5H), 4.26 (br m, 0.5H), 3.76 (br d, J=9.7 Hz, 2H), 3.63 (br d, J=10.5 Hz, 0.5H), 3.50 (br m, 1H), 3.46 (m, 0.5H), 3.18 (br m, 1H), 2.93 (br d, J=8.8 Hz, 0.5H), 2.88 (br d, J=9.4 Hz, 0.5H), 2.73 (br d, J=9.2 Hz, 0.5H), 2.55 (br d, J=9.2 Hz, 0.5H), 1.87 (br t, J=8.8 Hz, 1H), 1.74 (br d, J=9.3 Hz, 0.5H), 1.68 (br d, J=9.3 Hz, 0.5H), 1.47 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:27]([F:30])([F:29])[F:28])[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH3:24])=[C:21]([CH2:25][NH2:26])[CH:20]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:27]([F:29])([F:28])[F:30])[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH3:24])=[C:21]([CH2:25][NH:26][C:1](=[O:4])[CH2:2][CH3:3])[CH:20]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: CCC(=O)Cl
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C
Reaction time: 3 h

Procedure:
Propionyl chloride (0.17 ml) is added to a solution of C-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-yl}-methylamine (816 mg) and DIPEA (1 ml) in dichloromethane (10 ml) at room temperature. After 3 hours at RT, the reaction is quenched with water. The aqueous phase is separated and further extracted two times with dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC and by crystallization in a diethylether/petroleum ether mixture to yield N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-ylmethyl}-propionamide (compound 1.6, 122 mg) as white crystals. MS (HPLC/MS): 465 (MH+). Retention time: 1.96 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:26][C:27](N)=[O:28])=[O:25].O>N1C=CC=CC=1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:27]([NH:26][C:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:25])=[O:28])[CH2:7][CH2:6]1
Reactant: NC(=O)NC(=O)c1ccco1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC(=O)c1ccco1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Yield: 17.5 %

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.2 g, 0.005 m) and 2-furoylurea (0.7 g) in pyridine (5 ml) was refluxed for 6 hours, then cooled. Water was added and the precipitate collected by filtration. The solid was dissolved in chloroform with a little methanol and filtered. The solvent was removed under reduced pressure and the residue was purified by medium pressure liquid chromatography on silica using CHCl3 : MeOH (9:1 v/v) as eluent. The isolated product (1st component eluted) was dissolved in ethyl acetate and acidified with ethanolic HCl to give a precipitate. This was filtered and dried to give 0.3 g of the title compound as the HCl, 3/4 H2O salt, mp. 157°-159° C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].N([O-])=O.[Na+].[BrH:15]>O>[Br:15][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Br
Reactant: Cc1ccc(N)cc1C#N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1C#N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Water (13.5 mL), HBr (74%, 14.4 mL) and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) was added to a flask and heated to 50° C. for 20 min. Then the mixture was cooled to 0˜5° C., and a solution of NaNO2 (1.2 g, 17.4 mmol) in water was added. The reaction mixture was stirred for 10 min at 0˜5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and refluxed for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed by saturated NaHCO3 solution and brine, and dried over Na2SO4. The crude product was purified by flask chomatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77%). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.51 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C1C=CC=CC=1>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: CC(=O)CCC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 39 %

Procedure:
A mixture of 1-(4-chlorophenyl)pentane-1,4-dione (5.0 g., 0.024 mol, as obtained in Step-1) and 4-chloroaniline (3.33 g, 0.026 mol) in benzene (5.0 ml) was refluxed either over molecular sieves or using a Dean Stark apparatus. After three hours, benzene was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water (2×100 ml.) and brine (1×50 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent evaporated off. The solid so obtained was washed with hexane to give 2.83 g (39.45%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>O1CCCC1>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7])=[CH:20][CH:19]=1)#[N:28]
Reactant: COCC(=O)CC(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A solution of methyl 4-methoxy-3-oxobutyrate (10.7 g) in tetrahydrofuran (150 mL) was added to a mixture of sodium hydride (1.91 g) and tetrahydrofuran (150 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. 4′-(Bromomethyl)biphenyl-2-carbonitrile (10 g) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated. To the residue were added 5% aqueous potassium hydrogen sulfate solution and then ethyl acetate, and the mixture was extracted. The ethyl acetate layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (12.1 g, 98%).
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][CH2:10][C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]=[CH2:13])=CC=1.C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[OH:8][CH2:9][CH2:10][C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:12]=[CH2:13]
Reactant: C=C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C=C=C(CCO)COC(=O)c1ccccc1

Procedure:
Combine 5-(p-methoxybenzyloxy)-3-benzoyloxymethylpent-1,2-diene (12.0 mmol), methylene chloride (25 mL) and water (1.25 mL). Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (12.5 mmol) with rapid stirring. After 1.5 hours filter the reaction mixture and extract the filtrate three times with water, dry over MgSO4 and concentrate in vacuo. Chromatograph on silica gel to give the title compound.