tert-butyl 3-bromobenzoate

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-benzoic acid tert-butyl ester (6.7 g, 26 mmol), N-methyl piperizine (3.4 ml, 31.2 mmol), sodium t-butoxide (3.5 g, 36.4 mmol). 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.12 g, 0.195 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.067 g, 0.065 mmol) were combined in toluene (200 ml), then was heated to 80 degrees C. Argon gas was then bubbled through the solution for 5 minutes. The reaction mixture was heated and stirred for 5 h. The reaction was then cooled to RT, concentrated in vacuo, and chromatographed (silica gel, 4% MeOH: CH2Cl2) to yield the title compound (4.12 g, 58%). Argon gas was then bubbled through the solution for 5 minutes The reaction mixture was heated The reaction was then cooled to RT concentrated in vacuo chromatographed (silica gel, 4% MeOH: CH2Cl2)

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

Procedure: 2,4,6-Trichlorobenzoic acid (11.7 ml, 75 mmol) was added dropwise to a solution of 3-bromobenzoic acid (15 g, 75 mmol), triethyl amine (10.5 ml, 75 mmol) in THF (25 ml) at RT. The reaction was stirred 15 min. Then, t-butanol (7.1 ml, 150 mmol) and DMAP (18.3 g, 150 mmol) were added and the reaction was stirred overnight. The crude reaction was filtered through a pad of silica gel, concentrated, and was used in the next reaction without further purification. the reaction was stirred overnight The crude reaction was filtered through a pad of silica gel concentrated was used in the next reaction without further purification

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

Procedure: 2,4,6-Trichlorobenzoic acid (11.7 ml, 75 mmol) was added dropwise to a solution of 3-bromobenzoic acid (15 g, 75 mmol), triethyl amine (10.5 ml, 75 mmol) in THF (25 ml) at RT. The reaction was stirred 15 min. Then, t-butanol (7.1 ml, 150 mmol) and DMAP (18.3 g, 150 mmol) were added and the reaction was stirred overnight. The crude reaction was filtered through a pad of silica gel, concentrated, and was used in the next reaction without further purification. the reaction was stirred overnight The crude reaction was filtered through a pad of silica gel concentrated was used in the next reaction without further purification

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of tert-butyl 3-bromobenzoate (7.0 g, 27.2 mmol), sodium methanesulfinate (4.45 g, 43.6 mmol), copper(I) iodide (0.52 g, 2.72 mmol), L-proline (0.63 g, 5.44 mmol) and sodium hydroxide (0.22 g, 5.44 mmol) was purged with nitrogen and DMSO was added. The mixture was heated to 80° C. After 18 h, the mixture was cooled to ambient temperature. Additional sodium methanesulfinate (2.78 g, 27.2 mmol), copper(I) iodide (0.52 g, 2.72 mmol), L-proline (0.63 g, 5.44 mmol) were added and the mixture was stirred at 80° C. for another 18 h. The mixture was cooled to ambient temperature and filtered with Celite. Lithium chloride (3.0 M in water) was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with LiCl (3.0 M in water), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (5.05 g). was purged with nitrogen and DMSO was added the mixture was cooled to ambient temperature The mixture was cooled to ambient temperature filtered with Celite Lithium chloride (3.0 M in water) was added the mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with LiCl (3.0 M in water), brine dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate)

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

Procedure: In an oven dried, 1-L, 3-necked round bottom flask equipped with an addition funnel, a glass stopper, a magnetic stirbar, and a reflux condenser connected to a nitrogen inlet, potassium t-butoxide (23.6 g, 209.6 mmol) was combined with toluene (150 mL). A solution of 3-bromobenzoyl chloride (40 g, 182.3 mmol) in toluene (100 mL) was added dropwise to the potassium t-butoxide and the mixture was stirred for 16 h at room temperature. The viscous mixture was transferred to a 1-L separatory funnel, and the reaction flask was rinsed with toluene (50 mL) and added to the separatory funnel. The toluene mixture was extracted with water (200 mL), a potassium carbonate solution (10%, 250 mL), and again with water (3×200 mL). The toluene layer was dried over magnesium sulfate and filtered, and the toluene was removed in vacuo to yield the product as a yellow oil (45.1 g, 96%). HPLC: >99% pure. In an oven dried 1-L, 3-necked round bottom flask equipped with an addition funnel a glass stopper, a magnetic stirbar, and a reflux condenser connected to a nitrogen inlet The viscous mixture was transferred to a 1-L separatory funnel the reaction flask was rinsed with toluene (50 mL) added to the separatory funnel The toluene mixture was extracted with water (200 mL) The toluene layer was dried over magnesium sulfate filtered the toluene was removed in vacuo

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

Procedure: To a mixture of tert-butyl-3-bromobenzoate (65 g, 0.25 mol), 4-tolyl boronic acid (41.3 g, 0.30 mol) and sodium carbonate (150 g) in a mixture of toluene (500 mL) and water (50 mL), tetrakis-triphenylphosphine palladium(0) (14.5 g, 0.05 mol) was added and the reaction mixture was refluxed overnight. Cooled to RT, toluene layer was separated. The organic layer was washed with water, brine, dried. The solvent was removed under vacuum to give tert-butyl-3-(4-tolyl)benzoate (62 g, 90%). was added the reaction mixture was refluxed overnight toluene layer was separated The organic layer was washed with water, brine dried The solvent was removed under vacuum

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

Procedure: To a mixture of tert-butyl-3-bromobenzoate (65 g, 0.25 mol), 4-tolyl boronic acid (41.3 g, 0.30 mol) and sodium carbonate (150 g) in a mixture of toluene (500 mL) and water (50 mL), tetrakis-triphenylphosphine palladium(0) (14.5 g, 0.05 mol) was added and the reaction mixture was refluxed overnight. Cooled to RT, toluene layer was separated. The organic layer was washed with water, brine, dried. The solvent was removed under vacuum to give tert-butyl-3-(4-tolyl)benzoate (62 g, 90%). was added the reaction mixture was refluxed overnight toluene layer was separated The organic layer was washed with water, brine dried The solvent was removed under vacuum

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

Procedure: To a mixture of 3-bromo benzoic acid (10 g, 0.5 mol), silver carbonate (276 g, 1 mol) and dry molecular sieves (100 g) taken in dry CH2Cl2 (2 L), tert-butylbromide (115 mL, 1 mol) was added dropwise at 0° C. and the reaction mixture was stirred overnight at RT. The solid was filtered and washed with dichloromethane. Organic layer was washed with 10% aqueous solution of NaHCO3 (2×500 mL), water (2×500 mL), brine and dried. The solvent was removed under vacuum to give tert-butyl-3-bromobenzoate (70 g, 57%). dry molecular sieves (100 g) The solid was filtered washed with dichloromethane Organic layer was washed with 10% aqueous solution of NaHCO3 (2×500 mL), water (2×500 mL), brine dried The solvent was removed under vacuum

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 3-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)benzoate (2.5 g, 4.96 mmol, prepared using A from tert-butyl 3-bromobenzoate [Frontier Scientific] with trimethylsilylacetylene, Q with K2CO3, A with 3,5-dibromopyrazin-2-amine, B and C) and K2CO3 (0.685 g, 4.96 mmol) in MeOH (20 mL) were added to a flask. The mixture was heated to about 60° C. for about 17 h. An aqueous 40% NaOH solution (2 mL) was added and the mixture was heated to about 60° C. for about 17 h. The mixture was cooled to rt and acidified with about 3 mL of 5 N aqueous HCl and then extracted with EtOAc (100 mL). The solids were removed by filtration then the filtrate was dried over anhydrous MgSO4 and concentrated under reduced pressure to provide 3-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)benzoic acid (2.01 g, 90%): LC/MS (Table 2, Method b) Rt=2.80 min; MS m/z 448 (M+H)+. the mixture was heated to about 60° C. for about 17 h The mixture was cooled to rt extracted with EtOAc (100 mL) The solids were removed by filtration the filtrate was dried over anhydrous MgSO4 concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-benzoic acid tert-butyl ester (6.7 g, 26 mmol), N-methyl piperizine (3.4 ml, 31.2 mmol), sodium t-butoxide (3.5 g, 36.4 mmol). 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.12 g, 0.195 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.067 g, 0.065 mmol) were combined in toluene (200 ml), then was heated to 80 degrees C. Argon gas was then bubbled through the solution for 5 minutes. The reaction mixture was heated and stirred for 5 h. The reaction was then cooled to RT, concentrated in vacuo, and chromatographed (silica gel, 4% MeOH: CH2Cl2) to yield the title compound (4.12 g, 58%). Argon gas was then bubbled through the solution for 5 minutes The reaction mixture was heated The reaction was then cooled to RT concentrated in vacuo chromatographed (silica gel, 4% MeOH: CH2Cl2)