Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:22].[Br:23][C:24]1[N:32]2[C:27]([CH:28]=[N:29][C:30](S(C)=O)=[N:31]2)=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C.COCCO>>[Br:23][C:24]1[N:32]2[C:27]([CH:28]=[N:29][C:30]([NH:22][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:14][CH2:13][CH:12]([N:15]5[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]5)[CH2:11][CH2:10]4)=[CH:8][C:3]=3[O:2][CH3:1])=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: CS(=O)c1ncc2ccc(Br)n2n1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Temperature: 170 °C

Procedure:
A mixture of 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (1.25 g, 0.00411 mol) (For preparation see Example 251), 7-Bromo-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.75 g, 0.0029 mol) and N,N-Diisopropylethylamine (2.02 mL, 0.0116 mol) in 2-Methoxyethanol (10 mL, 0.1 mol) was heated in the microwave at 170° C. for 90 minutes. Purification by Isco chromatography gave (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine as a tan solid (0.36 g, 255). MP: 171-173° C.; LCMS (m/e) 500 (M); 1H-NMR (DMSO, 400 MHz) δ 8.83 (s, 1H), 8.02 (d, 1H, J=8.76 Hz), 7.74 (s, 1H), 6.89 (q, 2H, J=4.76 Hz), 6.67 (s, 1H), 6.51 (d, 1H, J=6.40 Hz), 3.85 (s, 3H), 3.70 (d, 2H, J=12.20 Hz), 2.64 (t, 2H, J=11.80 Hz), 2.31-2.28 (br s, 4H), 1.83 (s, 3H), 1.85 (m, 2H), 1.55-1.50 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br-:27].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][C:16]([Br:27])=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Br-]
Reactant: Cc1ccc(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Br)c(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a stirred solution of (R)-2-Benzyl-7-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (190 mg, 0.59 mmol) in dry CH2Cl2:methanol (4:2 mL), tetrabutylammonium tribromide (331 mg, 0.68 mmol) was added. The reaction was stirred for 1 h under Argon added more tetrabutylammonium tribromide (45 mg, 0.09 mmol). After 20 min removed solvent in rotavap and then diluted with dichloromethane (100 mL), washed with 5% Na2S2O3 (10 mL), saturated NaHCO3 (10 mL) and brine (15 mL). The organic layer was dried over MgSO4, and conc in vacuo and purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to yield 86 mg (36%) of the product as a faint brown oil. MS (ESI) 401, 403 (M+H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[NH2:8][C:7](=[C:11]([C:10](=[O:9])[CH2:16][CH:17]([OH:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]([NH:14][CH3:15])=[O:13])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)C(C(=O)CC(O)c1ccccc1)=C(N)c1ccccc1

Procedure:
A mixture of 30.0 grams (0.093 mole) of 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide, 600 milliliters of ethanol and 3.0 grams of 10 percent Palladium on carbon in hydrogenated at 50 p.s.i. until 1 equivalent of hydrogen is absorbed (about 5 hours). The mixture is filtered and the filtrate evaporated in vacuo. The residue is then crystallized from methylene chloride petroleum ether to give 2-(α-aminobenzylidene)-5-hydroxy-N-methyl-3-oxo-5-phenylvaleramide, m.p. 72° C. - 76° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][NH2:12]>O1CCOCC1>[NH:11]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
2-Chloro-5-nitropyridine (5 g, 31.5 mmol) and hydrazine (1.74 g, 34.7 mmol) were dissolved in 60 ml of dioxane, and the solution was stirred at room temperature for 16 hours. The precipitated yellow powder (m.p.: 198°-208°0 C.) was collected by filtration to obtain 502 mg of the intended product as a hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][S:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[C:25](=[O:28])(O)[O-:26].[Na+]>O1CCOCC1.C(OCC)(=O)C>[C:12]([O:26][C:25](=[O:28])[NH:21][C:17]1[S:18][CH2:19][CH2:20][C@@:13]2([N:16]=1)[C:12]1[CH:11]=[C:10]([O:22][CH3:23])[CH:9]=[C:8]([F:24])[C:7]=1[O:6][C:5]1[C:14]2=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:13])([CH3:11])[CH3:7]
Reactant: O=C([O-])O
Reactant: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(Br)ccc1O2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(F)c2c(c1)[C@]1(CCSC(NC(=O)OC(C)(C)C)=N1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
(S)-7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine (400 mg, 0.977 mmol) was dissolved in dioxane (48870. Saturated aqueous sodium bicarbonate solution (5 mL) was added, followed by addition of Boc-anhydride (681 μl, 2.93 mmol). The reaction mixture was stirred at room temperature for 2 hrs. Then it was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with MgSO4, filtered, and concentrated. The material was purified through column chromatography eluting with a gradient of 45% to 60% to 75% EtOAc in Hexane to afford (S)-tert-butyl(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-yl)carbamate (490 mg, 0.962 mmol, 98% yield) as a yellow solid.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1C1C=CC=CC=1O.CC(C[AlH]C[CH:27]([CH3:29])[CH3:28])C>C1COCC1>[OH:20][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:28]2[CH:27]=[CH:29][CH:6]=[CH:7][C:8]=2[OH:9])=[O:9])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1O
Reactant: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of (2-hydroxyphenyl)-terephthalamic acid methyl ester (1.31 g, 4.8 mmol) in THF (50 mL) at −78° C. was added a solution of DIBAL-H (27 mL, 1.0 M in THF). The reaction was allowed to warm to room temperature, stirred for 1 h and quenched with a saturated potassium sodium tartrate solution (15 mL). The biphasic mixture was stirred vigorously for 1 h, the phases separated and the organic layer dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-hydroxymethyl-N-(2-hydroxyphenyl)-benzamide (0.58 g, 50%). 1H NMR (CDCl3) δ 1.83 (t, 1H (OH)), 4.82 (d, 2H, J=6.0 Hz), 6.93 (t, 1H, J=7.8 Hz), 7.08 (t, 1H, J=7.8 Hz), 7.19 (d, 2H, J=7.8 Hz), 7.53 (d, 2H, J=6.0 Hz), 7.92 (d, 2H, J=7.8 Hz), 8.07 (br, 1H), 8.62 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:11][C:3]1[CH:4]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCc2ccccc2)cccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 174.7 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (1.52 g) in DMF (25 mL) were added benzyl bromide (3.40 g) and potassium carbonate (4.14 g), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, and dried to give the title compound (2.90 g) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH:6](C)[CH2:7][C:8](Cl)=[O:9].Cl.[CH2:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[CH2:27](Cl)Cl>>[Cl:5][CH2:6][CH:7]([CH3:27])[C:8]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:18]=1)=[O:9]
Reactant: c1ccc(Cc2cccnc2)cc1
Reactant: ClCCl
Reactant: CC(Cl)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(CCl)C(=O)c1ccc(Cc2cccnc2)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
In 25 ml of methylene chloride was suspended 13.3 g of anhydrous aluminum chloride, and 7.3 g of 3-chloro-3-methylpropionyl chloride was added to the suspension with ice-cooling, after which 8.2 g of 3-benzylpyridine hydrochloride was added in small portions to the suspension. The resulting mixture was subjected to reaction with ice-cooling for 2 hours and then at room temperature for one hour. The reaction mixture was added in small portions to a mixture of 246 ml of iced water and 49 ml of methylene chloride, and the organic layer was separated, while the aqueous layer was extracted with 40 ml of methylene chloride. The organic layers were combined and then 80 ml of water was added thereto after which the resulting mixture was neutralized with sodium hydrogencarbonate. The organic layer was separated, washed with 50 ml of water, and thereafter dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform:ethyl acetate (1:1 by volume)] to obtain 10.53 g (yield 96.0%) of colorless, oily 3-[p-(3-chloro-2-methylpropionyl)benzyl]pyridine.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)(Cl)Cl.CCOCC>[ClH:26].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:17]([CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: c1ccc(CCNCc2ccccc2OCCN2CCOCC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cl
Product: O=C(c1ccc(Cl)cc1)N(CCc1ccccc1)Cc1ccccc1OCCN1CCOCC1
Yield: 168.8 %

Procedure:
N-[[2-[2-(4-Morpholinyl)ethoxy]phenyl]methyl]benzeneethanamine (40 g) and 22 g of p-chlorobenzoyl chloride are reacted in 600 ml of chloroform following the procedure described in Example 1C. The residue from the chloroform evaporation is first triturated with ether (evaporation repeated) and then with 400 ml of warm acetone to give a crystalline product. After diluting with 500 ml of ether and cooling for about 16 hours, the solid is filtered under nitrogen, washed with ether and dried in vacuo to yield 54.7 g of material, melting point 147°-149° C (sintering at 145° C). Crystallization from 250 ml of warm methanol-1750 ml ether yield 52.9 g of the title compound, melting point 147°-149° C.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].O>CN(C)C=O>[C:3]([N:6]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CCCCN1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.9 %

Procedure:
Oily sodium hydride (60%, 2.45 g) was added to a solution of acetanilide (7.0 g) in N,N-diemthylformamide (50 ml), and the mixture was stirred at 0° C. for 15 minutes. Then a solution of N-(4-bromobutyl)phthalimide (15.3 g) in N,N-dimethylformamide (80 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then the solvent was distilled off. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate-chloroform (1:9, v/v) to obtain N-[4-(N-acetyl-N-phenylamino)butyl]phthalimide (9.21 g, 52.9%), which was then recrystallized from isopropyl ether. Colorless prism, mp: 83°-84° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:16][C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.[OH-:25].[Na+]>>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:16][C:15]2[CH:14]=[C:13]3[C:9]([C:10]([C:6]([C:7]4[CH:8]=[CH:9][CH:13]=[CH:14][CH:15]=4)=[O:25])=[CH:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH2:18][CH3:19]
Reactant: CCCN(CCC)C1Cc2cc3cc[nH]c3cc2C1
Reactant: [OH-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1Cc2cc3[nH]cc(C(=O)c4ccccc4)c3cc2C1
Temperature: 85 °C
Yield: 100 %

Procedure:
A mixture of dipropyl-(1,5,6,7-tetrahydro-1-aza-s-indacen-6-yl)amine (31 mg, 0.12 mmol) N,N-dimethylbenzamide (36 mg, 0.24 mmol) and phosphorous oxychloride (14 μL, 23 mg, 0.15 mmol) was heated at 85° C. overnight. After cooling, 3M sodium hydroxide (4 mL) was added and the resulting mixture was heated at 85° C. for 1 hour. The mixture was cooled and extracted (ethyl acetate) three times. The organic solution was dried (magnesium sulfate), filtered and evaporated to yield 46 mg (100%) of the desired material.: MS m/z (relative intensity, 70 eV) 360 (M+, 12), 331 (100), 105 (38), 260 (31).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15]([NH2:22])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].[CH3:23][N:24]=[C:25]=[S:26].[CH:27](O)(C)C>>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15]([NH:22][C:25]([NH:24][CH2:23][CH3:27])=[S:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(N)cc3c12
Reactant: CC(C)O
Reactant: CN=C=S
Product: CCNC(=S)Nc1ccc2[nH]c3cnc(C(=O)OC(C)C)c(CC)c3c2c1

Procedure:
297 mg of 6-amino-4-ethyl-β-carboline-3-carboxylic acid isopropyl ester and 88 mg of methyl isothiocyanate are refluxed for 2 hours in 20 ml of isopropanol. The solvent is distilled off in a vacuum, and the residue is recrystallized from ethyl acetate/ether. 257 mg of 4-ethyl-6-(3-ethyl-thioureido)-β-carboline-3-carboxylic acid-isopropyl ester with a melting point of 234-236° C. is obtained.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:16][C:17]1[C:18]([Cl:39])=[CH:19][C:20]([F:38])=[C:21]([CH:37]=1)[NH:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1.CCCC(C)C>C(Cl)Cl>[ClH:9].[F:38][C:20]1[CH:19]=[C:18]([Cl:39])[C:17]([NH:16][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:37][C:21]=1[NH:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1
Reactant: COc1cc2ncnc(Nc3cc(N)c(Cl)cc3F)c2cc1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cc(NC(=O)c4ccccc4)c(Cl)cc3F)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (0.025 ml) and pyridine (0.036 ml) were added to a suspension of 4-(5-amino-4-chloro-2-fluoroanilino)-6,7-dimethoxyquinazoline (125 mg) in dry methylene chloride (3 ml) and the resulting mixture was stirred at ambient temperature for 18 hours. Isohexane (3 ml) was added and the precipitated solid was isolated, washed with diethyl ether and dried under vacuum. The title compound was obtained as a solid (65 mg); NMR: 4.0 (s, 6H), 7.35 (s, 1H), 7.56 (m, 3H), 7.78 (d, 2H), 7.99 (d, 2H), 8.22 (s 1H), 8.81 (s, 1H), 10.2 (broad s, 1H); m/s: M+H+ 453, 455.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6])#[N:2].B(Br)(Br)Br>C(Cl)Cl.O>[C:1]([C:3]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6])#[N:2]
Reactant: COc1ccc(C#N)c(C(N)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(O)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-cyano-5-methoxybenzamide (5.2 g, 0.027 mol) in methylene chloride is cooled to 0° C., treated dropwise with boron tribromide (54 mL of a 1M solution in methylene chloride) , stirred at 0° C. for 30 minutes, stirred at room temperature for 1 hour, refluxed for 4 hours, cooled to 0° C., treated with additional boron tribromide (54 mL of a 1M solution in methylene chloride), refluxed for 17 hours, cooled to room temperature and diluted with water. The aqueous mixture is filtered to obtain a solid which is washed sequentially with water and ether and dried to give the title product as a beige solid, mp 268°-270° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[CH3:17][N:18]=[C:19]=[O:20].O>O1CCCC1>[CH3:17][NH:18][C:19]([N:3]1[CH2:4][C@@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[C@@H:2]1[CH3:1])=[O:20]
Reactant: CN=C=O
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1C[C@@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
A stirred solution of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of tetrahydrofuran was treated with 0.94 g (0.0165 mole) of methyl isocyanate added dropwise and stirred for 16 hr under a blanket of nitrogen. Dilution of the reaction mixture with water produced an oil which solidified. After decanting the aqueous tetrahydrofuran phase, the solid residue was recrystallized from ethanol-water to yield 3.95 g (91.4%) of fine white crystals, m.p. 104.5°-106° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:15]([NH2:16])=[CH:14][C:13]([C:12]([CH3:19])([CH3:18])[CH3:11])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Br)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(Br)c2)n1
Yield: 54 %

Procedure:
A mixture of 3-bromophenylhydrazine hydrochloride (5.00 g, 22.4 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (4.29 g, 33.6 mmol) in absolute ethanol (55 mL) was stirred at reflux for 18 h and cooled, then concentrated in vacuo. The residue was suspended in sat. aq. NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound (3.56 g, 54%). LCMS (Method 1): Rt 3.33 min, m/z 294, 296 [MH+].
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:41])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:39])(=[O:38])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:40])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:40][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:41])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:39])(=[O:38])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.39 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.038 g, 0.07 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxy-phenyl-sulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.031 g, 84%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1 H), 10.56 (br. s, 1 H), 7.99 (dd, J=9.00, 6.40 Hz, 1 H), 7.90 (m, J=8.30 Hz, 2 H), 7.88 (s, 1 H), 7.42 (m, J=8.30 Hz, 2 H), 7.37 (td, J=8.80, 2.40 Hz, 1 H), 7.21-7.31 (m, 4 H), 6.49 (dd, J=11.00, 2.60 Hz, 1 H), 3.82 (s, 2 H), 1.99 (s, 3 H). MS calcd. for C26H18F4NO5S [(M−H)−] 532, obsd. 532.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.CC(O)=O>CCO.[Fe]>[NH2:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(Cl)ncc1N
Temperature: 80 °C

Procedure:
2-Chloro-4-methyl-5-nitropyridine (1 g, 5.8 mmol) was dissolved in EtOH (60 mL). AcOH (4 mL) and Fe (5 eq.) were added and the mixture was refluxed at 80° C. overnight. The mixture was filtered through celite and reduced under vacuum to afford the crude 5-amino-2-chloro-4-methylpyridine which was used in the next step with no further purification. The amine was dissolved in conc. HCl (6 mL), transferred to a 3-neck round bottom flask, and cooled to −5° C. A solution of NaNO2/H2O (440 mgs/5 mL) was slowly added and the mixture was allowed to stir for 10 mins. To a second, separate 3-neck round bottom flask was added H2O (12 mL) and cooled to −5° C. Thionyl chloride (4.5 eq.) was then added dropwise. After complete addition the mixture was allowed to warm to room temp. whereupon CuCl (0.05 eq.) was added and the mixture was then cooled back down to −5° C. The first reaction mixture, containing the amine precursor, was slowly added to the second reaction mixture. A froth formed and was filtered off to afford 6-chloro-4-methylpyridine-3-sulfonyl chloride which was used in the next step with no further purification. The title compound was synthesized from 2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-(pyrid-4-yl)ethyl acetamide and 6-chloro-4-methylpyridine-3-sulfonyl chloride using Method G.