6-bromo-2-methyl-3H-isoindol-1-one

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

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

Procedure: (S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 300 mg), 6-bromo-2-methylisoindolin-1-one (Example 30, step (i), 131 mg) and potassium acetate (171 mg) in a mixture of acetonitrile (15 mL) and water (5 mL) was stirred under nitrogen at 90° C. with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (378 mg). After 4 h the reaction mixture was cooled to room temperature and diluted with water (50 mL). The products were extracted with ethyl acetate (3×50 mL) and the combined extracts dried over magnesium sulfate and concentrated to afford the sub-titled compound (200 mg). The products were extracted with ethyl acetate (3×50 mL) the combined extracts dried over magnesium sulfate concentrated

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

Procedure: Methyl 5-bromo-2-methylbenzoate (3 g) in ethyl acetate (100 mL) was treated with N-chlorosuccinimide (1.749 g). The mixture was stirred and heated under reflux whilst being irradiated with a halogen lamp for 5 h. The reaction mixture was cooled and washed with 10% aqueous sodium metabisufite (100 mL) and water. The organic phase was dried over magnesium sulfate and concentrated to an oil. The crude product was treated with 8M methylamine in ethanol (20 mL) and the resulting mixture heated under reflux for 30 min. After cooling, the solution was concentrated to an oil, and the mixture purified on silica gel eluting with ethyl acetate to afford the sub-titled compound (0.300 g). heated under reflux whilst being irradiated with a halogen lamp for 5 h The reaction mixture was cooled washed with 10% aqueous sodium metabisufite (100 mL) and water The organic phase was dried over magnesium sulfate concentrated to an oil The crude product was treated with 8M methylamine in ethanol (20 mL) the resulting mixture heated under reflux for 30 min After cooling the solution was concentrated to an oil the mixture purified on silica gel eluting with ethyl acetate

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

Procedure: (S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 300 mg), 6-bromo-2-methylisoindolin-1-one (Example 30, step (i), 131 mg) and potassium acetate (171 mg) in a mixture of acetonitrile (15 mL) and water (5 mL) was stirred under nitrogen at 90° C. with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (378 mg). After 4 h the reaction mixture was cooled to room temperature and diluted with water (50 mL). The products were extracted with ethyl acetate (3×50 mL) and the combined extracts dried over magnesium sulfate and concentrated to afford the sub-titled compound (200 mg). The products were extracted with ethyl acetate (3×50 mL) the combined extracts dried over magnesium sulfate concentrated

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

Procedure: Methyl 5-bromo-2-methylbenzoate (3 g) in ethyl acetate (100 mL) was treated with N-chlorosuccinimide (1.749 g). The mixture was stirred and heated under reflux whilst being irradiated with a halogen lamp for 5 h. The reaction mixture was cooled and washed with 10% aqueous sodium metabisufite (100 mL) and water. The organic phase was dried over magnesium sulfate and concentrated to an oil. The crude product was treated with 8M methylamine in ethanol (20 mL) and the resulting mixture heated under reflux for 30 min. After cooling, the solution was concentrated to an oil, and the mixture purified on silica gel eluting with ethyl acetate to afford the sub-titled compound (0.300 g). heated under reflux whilst being irradiated with a halogen lamp for 5 h The reaction mixture was cooled washed with 10% aqueous sodium metabisufite (100 mL) and water The organic phase was dried over magnesium sulfate concentrated to an oil The crude product was treated with 8M methylamine in ethanol (20 mL) the resulting mixture heated under reflux for 30 min After cooling the solution was concentrated to an oil the mixture purified on silica gel eluting with ethyl acetate

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

Conditions: temp:60.01; pressure:0.00; stir:

Procedure: In an oven-dried RB flask was added Tris(dibenzylideneacetone)dipalladium(0) (0.046 g, 0.05 mmol) and rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (0.062 g, 0.10 mmol). The flask was evacuated and back-filled with nitrogen. Anhydrous toluene (3 mL) was added and the mixture was stirred at rt for 10 min to give a purple solution. 6-bromo-2-methylisoindolin-1-one (2.261 g, 10 mmol), 1-Boc-piperazine (1.863 g, 10.00 mmol) and Sodium tert-butoxide (1.714 mL, 14.00 mmol) were added in one portion followed by anhydrous toluene (15 mL). The flask was evacuated and back-filled with nitrogen and the resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 days. LCMS shows 10% conversion. Tris(dibenzylideneacetone)dipalladium(0) (0.183 g, 0.20 mmol) and 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.187 g, 0.40 mmol) (RuPhos) were added and the mixture was heated to 80 °C and stirred for 5 h. LCMS shows complete conversion. When cooled to rt the mixture was diluted with EtOAc (25 mL) and stirred for 1 h. The solid was filtered off and washed with EtOAc (50 mL). The filtrate was washed with saturated aqueous Na2CO3 (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude producr was purified on a silica gel column eluted with 20-100% EtOAc in Heptane to give a yellow solid; tert-butyl 4-(2-methyl-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (1.890 g, 57.0 %).

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 mL) was a solution of methylamine in THF (2M, 8.12 mL, 16.24 mmol). The reaction mixture was heated at 50° C. for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100%) as a yellow solid. concentrated under vacuum the organic layer was then washed with an aqueous 1M HCl solution, brine dried (Na2SO4) filtered concentrated under vacuum

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

Procedure: (S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 300 mg), 6-bromo-2-methylisoindolin-1-one (Example 30, step (i), 131 mg) and potassium acetate (171 mg) in a mixture of acetonitrile (15 mL) and water (5 mL) was stirred under nitrogen at 90° C. with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (378 mg). After 4 h the reaction mixture was cooled to room temperature and diluted with water (50 mL). The products were extracted with ethyl acetate (3×50 mL) and the combined extracts dried over magnesium sulfate and concentrated to afford the sub-titled compound (200 mg). The products were extracted with ethyl acetate (3×50 mL) the combined extracts dried over magnesium sulfate concentrated

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

Procedure: Methyl 5-bromo-2-methylbenzoate (3 g) in ethyl acetate (100 mL) was treated with N-chlorosuccinimide (1.749 g). The mixture was stirred and heated under reflux whilst being irradiated with a halogen lamp for 5 h. The reaction mixture was cooled and washed with 10% aqueous sodium metabisufite (100 mL) and water. The organic phase was dried over magnesium sulfate and concentrated to an oil. The crude product was treated with 8M methylamine in ethanol (20 mL) and the resulting mixture heated under reflux for 30 min. After cooling, the solution was concentrated to an oil, and the mixture purified on silica gel eluting with ethyl acetate to afford the sub-titled compound (0.300 g). heated under reflux whilst being irradiated with a halogen lamp for 5 h The reaction mixture was cooled washed with 10% aqueous sodium metabisufite (100 mL) and water The organic phase was dried over magnesium sulfate concentrated to an oil The crude product was treated with 8M methylamine in ethanol (20 mL) the resulting mixture heated under reflux for 30 min After cooling the solution was concentrated to an oil the mixture purified on silica gel eluting with ethyl acetate

Conditions: temp:60.01; pressure:0.00; stir: