(5-fluoro-1-benzofuran-2-yl)boronic acid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a nitrogen atmosphere, to a solution of 2.0 g of 5-fluorobenzofuran in 150 ml tetrahydrofuran was added 18.5 ml of a 1.59 M solution of n-butyllithium in n-hexane at −78° C., and the mixture was stirred at the same temperature for 10 minutes and at 0° C. for further 10 minutes. At −78° C., 3.7 ml of triethoxyborane was added, and the mixture was stirred for 2 hours while elevating to 0° C. 30 ml of 1 N hydrochloric acid was added, stirred at room temperature for 1 hour, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1), to give 525 mg of the title compound as colorless crystals. the mixture was stirred for 2 hours while elevating to 0° C stirred at room temperature for 1 hour the mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a nitrogen atmosphere, to a solution of 2.0 g of 5-fluorobenzofuran in 150 ml tetrahydrofuran was added 18.5 ml of a 1.59 M solution of n-butyllithium in n-hexane at −78° C., and the mixture was stirred at the same temperature for 10 minutes and at 0° C. for further 10 minutes. At −78° C., 3.7 ml of triethoxyborane was added, and the mixture was stirred for 2 hours while elevating to 0° C. 30 ml of 1 N hydrochloric acid was added, stirred at room temperature for 1 hour, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1), to give 525 mg of the title compound as colorless crystals. the mixture was stirred for 2 hours while elevating to 0° C stirred at room temperature for 1 hour the mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a nitrogen atmosphere, to a solution of 2.0 g of 5-fluorobenzofuran in 150 ml tetrahydrofuran was added 18.5 ml of a 1.59 M solution of n-butyllithium in n-hexane at −78° C., and the mixture was stirred at the same temperature for 10 minutes and at 0° C. for further 10 minutes. At −78° C., 3.7 ml of triethoxyborane was added, and the mixture was stirred for 2 hours while elevating to 0° C. 30 ml of 1 N hydrochloric acid was added, stirred at room temperature for 1 hour, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1), to give 525 mg of the title compound as colorless crystals. the mixture was stirred for 2 hours while elevating to 0° C stirred at room temperature for 1 hour the mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a nitrogen atmosphere, to a solution of 2.0 g of 5-fluorobenzofuran in 150 ml tetrahydrofuran was added 18.5 ml of a 1.59 M solution of n-butyllithium in n-hexane at −78° C., and the mixture was stirred at the same temperature for 10 minutes and at 0° C. for further 10 minutes. At −78° C., 3.7 ml of triethoxyborane was added, and the mixture was stirred for 2 hours while elevating to 0° C. 30 ml of 1 N hydrochloric acid was added, stirred at room temperature for 1 hour, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1), to give 525 mg of the title compound as colorless crystals. the mixture was stirred for 2 hours while elevating to 0° C stirred at room temperature for 1 hour the mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (From Ex. 6, step 3, 200 mg, crude) in dioxane (5.0 mL) and three drops of water was added 5-fluorobenzofuran-2-ylboronic acid (210 mg, 1.07 mmol), K3PO4 (272 mg, 1.29 mmol) and Pd(PPh3)4 (25 mg, 0.02 mmol). The reaction was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified by a silica gel column with 1% to 5% ethyl acetate in petroleum to afford methyl 2-(5-fluoro-1H-inden-2-yl)-3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinoxaline-6-carboxylate as a light red solid (59 mg). The reaction mixture was concentrated under vacuum to give the residue, which was purified by a silica gel column with 1% to 5% ethyl acetate in petroleum

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-fluorobenzofuran-2-ylboronic acid (614.3 mg, 3.41 mmol) in dioxane (15 ml) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (500 mg, 1.70 mmol), K3PO4 (725 mg, 3.42 mmol), Pd(PPh3)4 (40.5 mg, 0.035 mmol) and water (1.0 ml), and the resulting mixture was stirred for 1 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (536 mg, 80%). The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-fluorobenzofuran-2-ylboronic acid (258.0 mg, 1.43 mmol) in dioxane (5.5 mL) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol) and Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column (1% ethyl acetate in petroleum ether) to afford methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (160.0 mg, 81%). maintained under an inert atmosphere of nitrogen The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column (1% ethyl acetate in petroleum ether)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-fluorobenzofuran (10 g, 73.53 mmol) in dry tetrahydrofuran (250 mL) was added tetramethylethylenediamine (10.2 g, 87.93 mmol). The solution was kept below −60° C. under nitrogen, while BuLi (93.75 mmol, 2.5M solution in hexane) was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (41.4 g, 220.21 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (70 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give 5-fluorobenzofuran-2-ylboronic acid (3.5 g, 26%) which was used for the next step without further purification. was added dropwise The mixture was cooled again below −60° C. After warming to room temperature the mixture was quenched with hydrochloric acid (70 mL, 2N) stirred for 1 h extracted with ethyl acetate (3×80 mL) dried over sodium sulfate concentrated in vacuo

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (240 mg, crude) in dioxane (5 mL) was added 5-fluorobenzofuran-2-ylboronic acid (337 mg, 1.87 mmol), K3PO4 (397 mg, 1.87 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 hour at 90° C. and then concentrated under vacuum to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(5-fluorobenzofuran-2-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (135.0 mg, 59% 2 steps). concentrated under vacuum to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (400 mg, crude) in dioxane (5 mL) was added 5-fluorobenzofuran-2-ylboronic acid (441 mg, 2.45 mmol), K3PO4 (620 mg, 2.94 mmol), and Pd(PPh3)4 (57 mg, 0.05 mmol). The resulting solution was stirred for 1 h at 90° C. and then quenched by the addition of dichloromethane (200 mL) and washed with water (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (R)-methyl 3-(sec-butylamino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylate as a yellow solid (100 mg, 24% 2 steps). quenched by the addition of dichloromethane (200 mL) washed with water (3×50 mL) The organic layer was dried over anhydrous sodium sulfate concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (390 mg, crude) in dioxane (6 mL) was added 5-fluorobenzofuran-2-ylboronic acid (353 mg, 1.96 mmol), K3PO4 (416 mg, 1.96 mmol), Pd(PPh3)4 (64 mg, 0.06 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. and then quenched by the addition of dichloromethane (100 mL). The resulting mixture washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 3.3% ethyl acetate in petroleum ether to afford (S)-methyl 3-(sec-butylamino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylate as a red solid (130.0 mg, 30% 2 steps). quenched by the addition of dichloromethane (100 mL) The resulting mixture washed with water (3×50 mL) dried over anhydrous sodium sulfate concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 3.3% ethyl acetate in petroleum ether

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-fluorobenzofuran-2-ylboronic acid (258.0 mg, 1.43 mmol) in dioxane (5.5 mL) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol) and Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (160.0 mg, 81%). maintained with an inert atmosphere of nitrogen The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether