4-bromo-1-chloro-2-methylbenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol), 4-bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8 mmol), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g, 7 mmol) were suspended in dioxane (9 mL) microwaved at 160° C. for 20 min. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as yellow solids (0.24 g, 38%). microwaved at 160° C. for 20 min Solvents were then decanted evaporated Resulting residue was purified by flash chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol), 4-bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8mmol), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g, 7 mmol) were suspended in dioxane (9 mL) microwaved at 160° C. for 20 min. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated. Resulting residue was purified by Hash chromatography on silica gel to afford title compound as yellow solids (0.24 g, 38%). microwaved at 160° C. for 20 min Solvents were then decanted evaporated Resulting residue was purified by Hash chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol), 4-bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8mmol), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g, 7 mmol) were suspended in dioxane (9 mL) microwaved at 160° C. for 20 min. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated. Resulting residue was purified by Hash chromatography on silica gel to afford title compound as yellow solids (0.24 g, 38%). microwaved at 160° C. for 20 min Solvents were then decanted evaporated Resulting residue was purified by Hash chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-1-chloro-2-methylbenzene (5.0 g, 24.0 mmol), N-bromosuccinimide (4.4 g, 25.0 mmol), and benzoyl peroxide (700 mg, 2.9 mmol) in anhydrous carbon tetrachloride (85 mL) was stirred at reflux for 4 hours. Dichloromethane (50 mL) was added. The mixture was extracted with 1 N NaOH (1×150 mL) and brine (1×150 mL). The organic extract was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-5% EtOAc/hexanes), affording 4-bromo-2-(bromomethyl)-1-chlorobenzene (4.76 g, 70% yield). The product was used without further purification. at reflux for 4 hours The mixture was extracted with 1 N NaOH (1×150 mL) and brine (1×150 mL) The organic extract was recovered dried over MgSO4 filtered evaporated dried in vacuo The crude product was purified by flash chromatography (0-5% EtOAc/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-1-chloro-2-methylbenzene (5.0 g, 24.0 mmol), N-bromosuccinimide (4.4 g, 25.0 mmol), and benzoyl peroxide (700 mg, 2.9 mmol) in anhydrous carbon tetrachloride (85 mL) was stirred at reflux for 4 hours. Dichloromethane (50 mL) was added. The mixture was extracted with 1 N NaOH (1×150 mL) and brine (1×150 mL). The organic extract was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-5% EtOAc/hexanes), affording 4-bromo-2-(bromomethyl)-1-chlorobenzene (4.76 g, 70% yield). The product was used without further purification. at reflux for 4 hours The mixture was extracted with 1 N NaOH (1×150 mL) and brine (1×150 mL) The organic extract was recovered dried over MgSO4 filtered evaporated dried in vacuo The crude product was purified by flash chromatography (0-5% EtOAc/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol), 4-bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8mmol), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g, 7 mmol) were suspended in dioxane (9 mL) microwaved at 160° C. for 20 min. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as yellow solids (0.24 g, 38%). microwaved at 160° C. for 20 min Solvents were then decanted evaporated Resulting residue was purified by flash chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The solution of 1.0 g (4.9 mmol) 5-bromo-2-chlorotoluene in 10 mL toluene was cooled down to −70° C. and treated dropwise with 3.6 mL (5.4 mmol; 1.5M solution in toluene) tert-butyllithium. After 30 min. 0.42 mL (5.3 mmol) (R)-(−)-epichlorohydrin was added and the temperature was allowed to rise to 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and extracted with 10% aqueous sodium bicarbonate solution followed by brine. The organic layer was dried over magnesium sulfate, filtered and evaporated and the residue was purified by column chromatography on silica gel with n-hexane:ethyl acetate (1:1) as eluant to give the title compound as a colorless oil (44.8%). to rise to 0° C extracted with 10% aqueous sodium bicarbonate solution The organic layer was dried over magnesium sulfate filtered evaporated the residue was purified by column chromatography on silica gel with n-hexane:ethyl acetate (1:1) as eluant

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The solution of 1.0 g (4.9 mmol) 5-bromo-2-chlorotoluene in 10 mL toluene was cooled down to −70° C. and treated dropwise with 3.6 mL (5.4 mmol; 1.5M solution in toluene) tert-butyllithium. After 30 min. 0.42 mL (5.3 mmol) (R)-(−)-epichlorohydrin was added and the temperature was allowed to rise to 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and extracted with 10% aqueous sodium bicarbonate solution followed by brine. The organic layer was dried over magnesium sulfate, filtered and evaporated and the residue was purified by column chromatography on silica gel with n-hexane:ethyl acetate (1:1) as eluant to give the title compound as a colorless oil (44.8%). to rise to 0° C extracted with 10% aqueous sodium bicarbonate solution The organic layer was dried over magnesium sulfate filtered evaporated the residue was purified by column chromatography on silica gel with n-hexane:ethyl acetate (1:1) as eluant

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 4-bromo-1-chloro-2-methylbenzene (308 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 60 mg (yield 15%).

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-amino-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 3(1); 150 mg), 5-bromo-2-chlorotoluene (321 mg), copper(I) iodide (37 mg), potassium carbonate (216 mg), N,N′-dimethylethylenediamine (40 μL) and toluene (8 mL) was heated at 110° C. overnight under argon atmosphere. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=4/1→1/1) to give 7-amino-4-(4-chloro-3-methylphenyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (98 mg) as a pale orange powder. After cooling, to the reaction mixture the mixture was extracted with ethyl acetate The organic layer was washed with brine dried over magnesium sulfate concentrated in vacuo The residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=4/1→1/1)