Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:27]I.Cl>CN(C)C=O>[CH2:3]([O:10][C:11]([N:13]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CCOC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)C(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 44.2 %

Procedure:
0.29 g (6.83 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 1.50 g (4.55 mmol) of ethyl 4-(benzyloxycarbonylamino)phenoxyacetate (prepared as described in Preparation 14) in 9 ml of dimethylformamide, and the mixture was stirred for 20 minutes, after which 0.57 ml (9.10 mmol) of methyl iodide was added to the reaction mixture. The mixture was then stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was neutralized with 1N aqueous hydrochloric acid, and the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with ethyl acetate, and the resulting organic solution was washed with 1N aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate, with a 5% w/v aqueous solution of sodium thiosulfate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography, using a 3:2 by volume mixture of hexane and ethyl acetate as the developing solvent, to give 0.69 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([NH:15]C(OCC2C=CC=CC=2)=O)[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:15][C:10]1[C:9](=[O:26])[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[C:13]([CH3:14])=[CH:12][CH:11]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
tert-Butyl-2-[3-[(benzyloxy)carbonyl]amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (preparation 4) (5 g, 13 mmol) was dissolved in ethyl acetate (70 ml), treated with 10% Pd on carbon catalyst (400 mg) and stirred under a hydrogen atmosphere (2 psi, room temperature, 3 hr). The catalyst was removed by filtration, and the solvent evaporated to dryness to give the desired product as a cream solid (3.08 g, 99%). 1H NMR (CDCl3) δ 1.40 (s, 9H), 2.20 (s, 3H), 4.00 (s, br, 2H), 4.70 (s, 2H), 5.90 (d, 1H), 6.45 (d, 1H). LRMS m/z=239.5 (M+1)+.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[C:3]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cn1cc(Br)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(-c2ccccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of 4-bromo-3-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1-methyl-1H-pyrazole (88 mg, 022 mmol), 2-chlorophenylboronic acid (41 mg, 0.26 mmol), K2CO3 (91 mg, 0.66 mmol), Cl2Pd(dppf).DCM (18 mg, 10 mol %) and H2O (0.25 mL) in dioxane (2.5 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 4 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 30:70 to 40:60) to give the title compound (64 mg, 67%). Rf 0.14 (40% EtOAc/Hex); 1H NMR (CD2Cl2): δ 8.09 (1H, m), 7.85-7.76 m), 7.60-7.49 (2H, m), 7.45 (1H, s), 7.41-7.30 (3H, m), 7.21 (1H, d), 6.70 (1H, d), 3.97 (3H, s), 3.05 (3H, s); MS (ES): 429 [M+H]+.
Reaction SMILES: [O-]CC.[Na+].Cl[CH2:6][CH2:7][C:8]([N:10]([CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[CH3:18][N:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]1=[O:41]>C(O)C>[CH3:17][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8](=[O:9])[CH2:7][CH2:6][N:33]([CH2:32][CH2:31][CH2:30][O:29][C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[N:19]([CH3:18])[C:20](=[O:41])[CH:21]=[CH:22]2)[CH2:34][C:35]1[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=1
Reactant: Cn1c(=O)ccc2cc(OCCCNCc3ccncc3)ccc21
Reactant: CN(C(=O)CCCl)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C(=O)CCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1)c1ccccc1
Temperature: 60 °C
Reaction time: 8.5 h
Yield: 2.3 %

Procedure:
Sodium ethoxide (34 mg) and 3-chloro-N-methyl-N-phenylpropionamide (148 mg) were added to a ethanol solution (5 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (161 mg), and stirred at 60° C. for 8.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (5.6 mg) as a colorless oil. 1H-NMR (CDCl3) δ ppm: 1.80-1.98 (2H, m), 2.26 (2H, t, J=7.3 Hz), 2.53 (2H, t, J=6.5 Hz), 2.81 (2H, t, J=7.3 Hz), 3.24 (3H, s), 3.44 (2H, s), 3.72 (3H, s), 3.98 (2H, t, J=6.0 Hz), 6.73 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.7 Hz), 7.00-7.19 (5H, m), 7.24-7.41 (4H, m), 7.60 (1H, d, J=9.5 Hz), 8.42 (2H, d, J=5.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].OS(O)(=O)=O.O.[CH3:21]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:21])=[O:13]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1F
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (1.0 g, 5.0 mmol) in CH3OH (20 mL) was added con. H2SO4 (0.50 mL), the reaction was warmed to 80° C. and stirred for about 3 hr. After cooling down to RT, the reaction was poured into water (20 mL) and concentrated to remove CH3OH. The aqueous was extracted with ethyl acetate (2×20 mL), the combined organic phases were washed brine (10 mL), dried over Na2SO4, filtered and concentrated to afford the product about 1.0 g (93.4%) as a colorless oil. MS (ESI) m/e [M+1]+ 214.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[C:12]2[CH2:17][O:16][C:15](=[O:18])[NH:14][C:13]=2[N:19]=1.[ClH:33]>O1CCOCC1>[ClH:33].[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[C:12]2[CH2:17][O:16][C:15](=[O:18])[NH:14][C:13]=2[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3O)nc3c2COC(=O)N3)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3c(O)cccc3O)cc(C3CCCNC3)c2CO1
Reaction time: 3 h
Yield: 46 %

Procedure:
A mixture of 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride (0.070 g, 0.160 mmol), which was obtained in Example 18-1, and 2.5N HCl in 1,4-dioxane (4 mL) was stirred at 80° C. overnight. After cooled to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (3 mL), and triethylamine (0.064 g, 0.497 mmol) was added. To the cooled (0° C.) mixture was added di-tert-butyl dicarbonate (0.047 g, 0.218 mmol) under an argon atmosphere. The stirring was continued at room temperature overnight. After quenched by water, the mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give tert-butyl 3-[7-(2,6-dihydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl]-1-piperidine-carboxylate (0.019 g, 19%). To a solution of tert-butyl 3-[7-(2,6-dihydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl]-1-piperidinecarboxylate in dioxane (1 mL) was added 4N HCl in dioxane (1 mL) at room temperature. The stirring was continued for 3 hrs. After the solvent was removed by evaporation, the resulting residue was washed with acetonitril, and dried under reduced pressure to give 7-(2,6-dihydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one hydrochloride as a brown solid (0.007 g, 46%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]3([CH3:12])[CH3:13])=[CH:4][CH:3]=2)[CH:28]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(-c3cccnc3)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (265 mg, 625 μmol, see Example 53), 3-pyridylboronic acid (115 mg, 937 μmol), and tetrakis(triphenylphosphine)palladium (72 mg, 62 μmol) were mixed in dioxane (4 mL) in a microwave tube under a nitrogen atmosphere. 2M Na2CO3 (937 μL, 1874 μmol) was added via syringe, and the reaction mixture was stirred at 75° C. for 15 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo to give the crude product as a yellow solid. The crude product was purified by silica flash chromatography (0-10% EtOAc/DCM) to give the desired compound as an off-white solid (190 mg). MS (m/e)=423.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[CH3:23][CH:24]1[CH2:28][CH2:27][C:26](=O)[CH2:25]1>>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][N:18]([CH:26]4[CH2:27][CH2:28][CH:24]([CH3:23])[CH2:25]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: CC1CCC(=O)C1
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC(C)C2)CC3)nc1

Procedure:
Example 253 (E253) was prepared from N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) and 3-methyl cyclopentanone using the method described for Example 223; MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: Cl[C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=[O:3].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([NH:29][C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=[O:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12

Procedure:
Reaction of 3-chlorocarbonyl-1-(phenylsulfonyl)-indole [XXIII] (Ketcha D. M., Gribble G. W., J. Org. Chem. 1985;50:5451-5457) with an excess of benzylamine in CH2Cl2) (method of Ketcha and Gribble) gave N-benzyl-1-(phenylsulfonyl) indole-3-carboxamide [XXIV: R8 =CH2Ph]; mp (MeOH) 188°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](N)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([S-:15])(=[S:14])OCC.[K+].O.Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:10]([SH:15])[S:14][C:4]=2[CH:3]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(F)cc1N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2nc(S)sc2c1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
4-Fluorobenzene-1,2-diamine (10.0 g, 0.077 mol) and potassium O-ethyl carbonodithioate (37.1 g, 0.234 mol) were dissolved in dry DMF (150 mL) under nitrogen and heated to 95° C. for 12 h. The reaction was cooled to RT and 200 mL water was added followed by addition of 5N HCl to get precipitates. After stirring for 1 h, the precipitates were collected by filtration, washed with water and dried under vacuum for 2 h. The crude compound was then washed with chloroform and dried to give 6-fluorobenzo[d]thiazole-2-thiol as yellow solid.
Reaction SMILES: Cl.[O:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([OH:13])[CH2:9][CH2:10][CH:11]=[CH2:12]>>[CH2:8]([O:13][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][O:2]1)[CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C1=COCCC1
Reactant: C=CCCCO
Agent: Cl
Product: C=CCCCOC1CCCCO1
Yield: 87.1 %

Procedure:
Concentrated HCl (0.03 ml) was added dropwise over 25 minutes (slightly exothermic) to a solution of dihydropyran (5.37 g, 64 mmol) and 4-penten-1-ol (5.0 g, 58 mmol) while stirring. At RT the reaction mixture was stirred for two hours. The solution was washed with a saturated sodium carbonate solution and dried over anhydrous potassium carbonate, thus affording 8.6 g (87% yield) of a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([CH3:18])([CH3:17])[C:12](=[O:19])[C:11]([C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[C:10]3[OH:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([CH3:18])([CH3:17])[C:12](=[O:19])[C:11]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[C:10]3[OH:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(-c3ccccc3)ccc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(-c3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
1,1-Dimethylethyl N-((6-phenyl-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (190 mg, 451 μmol) was dissolved in TFA (2 mL) at ambient temperature. The resulting mixture was then stirred for 30 minutes. The reaction mixture was concentrated, precipitated with ether, filtered, washed with ether, and dried in a vacuum oven to give the title compound (57 mg) as a white solid. MS (m/z)=366 (M+H)+. Calculated for C21H19NO5 365.13.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([Cl:10])[CH:3]=1.COC1C=CC([B:19]([OH:21])[OH:20])=C(C(F)(F)F)C=1>>[Cl:10][C:4]1[CH:3]=[C:2]([B:19]([OH:21])[OH:20])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: COc1ccc(Br)cc1Cl
Product: COc1ccc(B(O)O)cc1Cl
Yield: 62 %

Procedure:
Starting from 4-bromo-2-chloroanisole (5.0 g, 23 mmol) in place of 4-bromo-3-trifluoromethylanisole, the title compound (2.6 g, 62%) was synthesized in essentially the same manner as described above for 4-methoxy-2-trifluoromethylphenylboronic acid in Step 2, Scheme 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[N:20]=[CH:21][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:23]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Brc1ccccn1
Reactant: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1c[nH]cn1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cn(-c2ccccn2)cn1

Procedure:
The title compound was synthesized from 1H-Imidazole-4-carboxylic acid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide of Example 15 and 2-bromopyridine by the method described by A. K. Verma et al. Tetrahedron Lett. 48 (2007) 4207. Purification by flash chromatography using CH2Cl2/MeOH as a gradient eluent (100:0-99.9:0.1) gave a product which was triturated in EtOAc at RT to afford the desired product. 1H NMR (400 MHz, DMSO-d6): 2.96 (2H, t), 3.59 (2H, m), 6.35 (1H, d), 7.03 (1H, d), 7.44 (1H, m), 7.63 (2H, s), 7.84 (1H, s), 7.95 (1H, distorted d), 8.05 (1H, m), 8.33 (1H, t), 8.43 (1H, d), 8.54 (1H, m), 8.64 (1H, d, 4J=1.1 Hz).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:31][C:32]([NH2:34])=[O:33]>>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:31][C:32]([NH2:34])=[O:33])[C@@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC(=O)CI
Product: C[C@@H](O[C@H]1CC[C@@H](NCC(N)=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared using the amine from Example 28 and iodoacetamide using essentially the same procedure as Example 10. Mass spec (NH3 /CI): 475 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:26][CH3:27])=[CH:4][C:5]([O:21][CH2:22][CH:23]([F:25])[F:24])=[C:6]([CH:20]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]1)=[O:8].[N:28]([C:31]1[CH:32]=[C:33]([CH:42]=[CH:43][C:44]=1[C:45]([F:48])([F:47])[F:46])[CH2:34][N-:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[C:29]=S>>[F:17][C:16]([F:18])([F:19])[C@H:13]1[CH2:14][CH2:15][C@H:10]([NH:9][C:7]([C:6]2[C:5]([O:21][CH2:22][CH:23]([F:24])[F:25])=[CH:4][C:3]3[N:26]([CH3:27])[C:29]([NH:28][C:31]4[CH:32]=[C:33]([CH2:34][NH:35][C:36]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH:42]=[CH:43][C:44]=4[C:45]([F:48])([F:47])[F:46])=[N:1][C:2]=3[CH:20]=2)=[O:8])[CH2:11][CH2:12]1
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)[N-]Cc1ccc(C(F)(F)F)c(N=C=S)c1
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2C(F)(F)F)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The sub-title compound was prepared from 5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide and N-(3-isothiocyanato-4-trifluoromethyl-benzyl)-pivaloylamide in analogy to example 72a.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[C:12]([Cl:20])[CH:11]=1>N1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:17])=[O:18])=[C:12]([Cl:20])[CH:11]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 5-bromopyridin-3-amine (0.300 g, 1.73 mmol) in pyridine (8.67 ml) was slowly added 4-bromo-2-chlorobenzene-1-sulfonyl chloride (0.600 g, 2.08 mmol) at 0° C. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with 1 N aq. HCl, and then extracted with DCM (2×50 mL). The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was recrystallized from EtOAc-hexanes to give 4-bromo-N-(5-bromopyridin-3-yl)-2-chlorobenzenesulfonamide (0.530 g, 72%) as a red solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.53-7.55 (1H, m), 7.71 (1H, d, J=1.6 Hz), 7.78 (1H, t, J=2.2 Hz), 7.89 (1H, d, J=8.4 Hz), 8.26 (1H, d, J=2.0 Hz). 8.44 (1H, d, J=2.4 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]4)=[CH:31][CH:30]=3)[N:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: Nc1cc(-c2ccc(F)c(Cl)c2)nc(Cl)n1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3nc(N)cc(-c4ccc(F)c(Cl)c4)n3)cc2)CC1
Yield: 84 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-6-(3-chloro-4-fluorophenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 84% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). MS (ESI): 214.2 [M+2H]2+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[C:3]([OH:9])[CH:2]=1.Cl.Cl.[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23](O)=O.[OH-].[Na+]>>[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]1[O:9][C:3]2[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][C:4]=2[N:8]=1
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: Nc1ccc(O)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2oc(-c3cccc4c(Cl)cccc34)nc2c1
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 79.3 %

Procedure:
80 μmol of 2,4-diaminophenol.2HCl and 80 μmol of 5-chloro-naphthalene-1-carboxylic acid were dissolved in 100 mg of PPA, and then, the mixed solution was stirred at a temperature of 180° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was cooled, neutralized with 10% NaOH, and filtered by using distilled water for recrystallization in a slow manner, thereby obtaining 18.7 mg of 2-(5-chloronaphthalene-1-yl)benzo[d]oxazole-5-amine (Derivative #5) (yield: 79%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:13]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=[O:15])[NH2:14]>CN1C(=O)N(C)CCC1>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[O:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(C(=O)CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Solvent: CN1CCCN(C)C1=O
Product: CSc1ccc(-c2coc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 145 °C
Yield: 25.1 %

Procedure:
2-Bromo-1-[4-(methylsulfanyl)phenyl]ethanone (5 g, 19.15 mmol) and tert-butyl 4-carbamoylpiperidine-1-carboxylate (4.37 g, 19.15 mmol) were dissolved in DMPU (40.8 mL) and heated to 145° C. for 15 min. The resulting solution was then cooled to room temperature, partitioned between aqueous LiCl and ethyl acetate. The combined organics were dried over sodium sulfate and concentrated in vacuo. The resulting crude oil was purified using silica gel chromatography (300 g, using 20-80% ethyl acetate in hexane gradient) to yield 1.8 g of the desired product as a yellow oil. LCMS (M+1)=375.40