2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

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

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

Procedure: To a mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 ml, 120 mmol) and tetrahydrofuran (150 ml) was added dropwise n-butyllithium (2.6 M n-hexane solution, 39 ml, 100 mmol) at −78° C. (external temperature) over 1.5 hours. Then, the reaction mixture was stirred at the same temperature for 1.5 hours, and at room temperature for 2 hours. After the mixture was cooled at 0° C. (external temperature), to the reaction mixture was added methanesulfonic acid (6.5 ml, 100 mmol), and then, the reaction mixture was stirred at room temperature for 1 hour. After the mixture was cooled at 0° C. (external temperature), to the reaction mixture was added pinacol (12 g, 100 mmol), and then, the reaction mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the resulting residue was distilled under reduced pressure (74-76° C., 8 mmHg) to obtain the title compound (16 g, 72 mmol, 68%). at room temperature for 2 hours the reaction mixture was stirred at room temperature for 1 hour After the mixture was cooled at 0° C. (external temperature) the reaction mixture was stirred at room temperature for 1 hour After the solvent was distilled off under reduced pressure the resulting residue was distilled under reduced pressure (74-76° C., 8 mmHg)

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

Procedure: To a mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 mL, 120 mmol), and tetrahydrofuran (150 mL) was added dropwise n-butyl lithium (2.6 M n-hexane solution, 39 mL, 100 mmol) over a period of 1.5 hours at −78° C., and then the reaction mixture was stirred for 1.5 hours at the same temperature. This mixture was then stirred for 2 hours at room temperature, after which it was cooled to 0° C., methanesulfonic acid (6.5 mL, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred for 1 hour at room temperature. The mixture was cooled to 0° C., pinacol (12 g, 100 mmol) was added to the reaction mixture, and the reaction mixture was then stirred for 1 hour at room temperature. The reaction mixture was concentrated under a reduced pressure, after which the residue thus obtained was distilled under a reduced pressure (74-76° C., 8 mmHg) to obtain the title compound (16 g, 68%). This mixture was then stirred for 2 hours at room temperature the reaction mixture was stirred for 1 hour at room temperature The mixture was cooled to 0° C. the reaction mixture was then stirred for 1 hour at room temperature The reaction mixture was concentrated under a reduced pressure after which the residue thus obtained was distilled under a reduced pressure (74-76° C., 8 mmHg)

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

Procedure: To the mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 ml, 120 mmol), and tetrahydrofuran (150 ml), n-butyllithium (a 2.6 M n-hexane solution, 39 ml, 100 mmol) was added dropwise at −78° C. (an outer temperature) for 1.5 hour, and then the reaction mixture was stirred at the same temperature for 1.5 hours. Subsequently, the obtained mixture was stirred at room temperature for 2 hours, and then was cooled to 0° C. (an outer temperature). To the reaction mixture, methanesulfonic acid (6.5 ml, 100 mmol) was added, and then the reaction mixture was stirred at room temperature for 1 hour. The obtained mixture was cooled to 0° C. (an outer temperature), pinacol (12 g, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated under reduced pressure from the reaction mixture, and then the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg), thereby obtaining the entitled compound (16 g, 72 mmol, 68%). was added dropwise at −78° C. (an outer temperature) for 1.5 hour Subsequently, the obtained mixture was stirred at room temperature for 2 hours the reaction mixture was stirred at room temperature for 1 hour was added to the reaction mixture the reaction mixture was stirred at room temperature for 1 hour The solvents were evaporated under reduced pressure from the reaction mixture the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg)

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

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

Procedure: To the mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 ml, 120 mmol), and tetrahydrofuran (150 ml), n-butyllithium (a 2.6 M n-hexane solution, 39 ml, 100 mmol) was added dropwise at −78° C. (an outer temperature) for 1.5 hour, and then the reaction mixture was stirred at the same temperature for 1.5 hours. Subsequently, the obtained mixture was stirred at room temperature for 2 hours, and then was cooled to 0° C. (an outer temperature). To the reaction mixture, methanesulfonic acid (6.5 ml, 100 mmol) was added, and then the reaction mixture was stirred at room temperature for 1 hour. The obtained mixture was cooled to 0° C. (an outer temperature), pinacol (12 g, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated under reduced pressure from the reaction mixture, and then the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg), thereby obtaining the entitled compound (16 g, 72 mmol, 68%). was added dropwise at −78° C. (an outer temperature) for 1.5 hour Subsequently, the obtained mixture was stirred at room temperature for 2 hours the reaction mixture was stirred at room temperature for 1 hour was added to the reaction mixture the reaction mixture was stirred at room temperature for 1 hour The solvents were evaporated under reduced pressure from the reaction mixture the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg)

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

Procedure: To the mixture of sodium hydride (61%, 250 mg, 6.4 mmol) and tetrahydrofuran (25 ml), (2-chloro-6-methoxy-quinolin-3-yl)-methanol (1.4 g, 6.4 mmol) synthesized in Example 16 was added at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at room temperature for 40 minutes. To the reaction mixture, 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92%, 700 mg, 2.9 mmol) synthesized in Production Example 2 was added at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at 50° C. (an outer temperature) for 5 hours. After cooling the reaction mixture to 0° C. (an outer temperature), sodium hydrogen fluoride (580 mg, 9.3 mmol) was added to the reaction mixture at the same temperature, followed by the dropwise addition of water (20 ml) at the same temperature. After stirring the reaction mixture for 15 minutes at room temperature, the solvents were evaporated under reduced pressure. Acetone was added to the obtained residue, followed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Ethyl acetate was then added to the obtained residue, followed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. The mixed solvent of ethyl acetate-diethyl ether (1:4) was added to the obtained residue, followed by filtration. The crystals precipitated in the filtrate were collected, thereby obtaining the entitled compound (260 mg). The solvents were evaporated under reduced pressure from the filtrate, and ethyl acetate was added to the obtained residue and then heated to 60° C., resulting in the precipitation of crystals. The crystals were collected, thereby obtaining the entitled compound (250 mg (510 mg in total), 53%). was added at 0° C. (an outer temperature), and the obtained reaction mixture was added at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at 50° C. (an outer temperature) for 5 hours was added to the reaction mixture at the same temperature After stirring the reaction mixture for 15 minutes at room temperature the solvents were evaporated under reduced pressure Acetone was added to the obtained residue followed by filtration the solvents were evaporated under reduced pressure from the filtrate Ethyl acetate was then added to the obtained residue followed by filtration the solvents were evaporated under reduced pressure from the filtrate The mixed solvent of ethyl acetate-diethyl ether (1:4) was added to the obtained residue followed by filtration The crystals precipitated in the filtrate were collected

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

Procedure: To the mixture of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 g, 8.3 mmol) synthesized in Production Example 2 and acetone (17 ml), sodium iodide (1.9 g, 13 mmol) was added at room temperature, and the obtained reaction mixture was stirred at room temperature for 2 hours. Impurities were removed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Hexane was added to the obtained residue, and insoluble matter was removed by filtration. The solvents were evaporated under reduced pressure from the filtrate, thereby obtaining the entitled compound (2.2 g, 97%). was added at room temperature the obtained reaction mixture Impurities were removed by filtration the solvents were evaporated under reduced pressure from the filtrate Hexane was added to the obtained residue, and insoluble matter was removed by filtration The solvents were evaporated under reduced pressure from the filtrate

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

Procedure: To the mixture of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 g, 8.3 mmol) synthesized in Production Example 2 and acetone (17 ml), sodium iodide (1.9 g, 13 mmol) was added at room temperature, and the obtained reaction mixture was stirred at room temperature for 2 hours. Impurities were removed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Hexane was added to the obtained residue, and insoluble matter was removed by filtration. The solvents were evaporated under reduced pressure from the filtrate, thereby obtaining the entitled compound (2.2 g, 97%). was added at room temperature the obtained reaction mixture Impurities were removed by filtration the solvents were evaporated under reduced pressure from the filtrate Hexane was added to the obtained residue, and insoluble matter was removed by filtration The solvents were evaporated under reduced pressure from the filtrate

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

Procedure: To the mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 ml, 120 mmol), and tetrahydrofuran (150 ml), n-butyllithium (a 2.6 M n-hexane solution, 39 ml, 100 mmol) was added dropwise at −78° C. (an outer temperature) over 1.5 hours, and then the reaction mixture was stirred at the same temperature for 1.5 hours. Subsequently, the obtained mixture was stirred at room temperature for 2 hours, and then was cooled to 0° C. (an outer temperature). To the reaction mixture, methanesulfonic acid (6.5 ml, 100 mmol) was added, and then the reaction mixture was stirred at room temperature for 1 hour. The obtained mixture was cooled to 0° C. (an outer temperature), pinacol (12 g, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated under reduced pressure from the reaction mixture, and then the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg), thereby obtaining the entitled compound (16 g, 72 mmol, 68%). was added dropwise at −78° C. (an outer temperature) over 1.5 hours Subsequently, the obtained mixture was stirred at room temperature for 2 hours the reaction mixture was stirred at room temperature for 1 hour was added to the reaction mixture the reaction mixture was stirred at room temperature for 1 hour The solvents were evaporated under reduced pressure from the reaction mixture the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg)

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

Procedure: To the mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 ml, 120 mmol), and tetrahydrofuran (150 ml), n-butyllithium (a 2.6 M n-hexane solution, 39 ml, 100 mmol) was added dropwise at −78° C. (an outer temperature) over 1.5 hours, and then the reaction mixture was stirred at the same temperature for 1.5 hours. Subsequently, the obtained mixture was stirred at room temperature for 2 hours, and then was cooled to 0° C. (an outer temperature). To the reaction mixture, methanesulfonic acid (6.5 ml, 100 mmol) was added, and then the reaction mixture was stirred at room temperature for 1 hour. The obtained mixture was cooled to 0° C. (an outer temperature), pinacol (12 g, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated under reduced pressure from the reaction mixture, and then the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg), thereby obtaining the entitled compound (16 g, 72 mmol, 68%). was added dropwise at −78° C. (an outer temperature) over 1.5 hours Subsequently, the obtained mixture was stirred at room temperature for 2 hours the reaction mixture was stirred at room temperature for 1 hour was added to the reaction mixture the reaction mixture was stirred at room temperature for 1 hour The solvents were evaporated under reduced pressure from the reaction mixture the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-(N-(3-chloro-4-hydroxyphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (65.0 mg, 0.123 mmol), potassium carbonate (85.0 mg, 0.614 mmol), and 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.109 g, 0.492 mmol) in 4 mL of anhydrous MeCN in a sealed tube was heated to 65° C. with stirring. After 2 hours the mixture was cooled to RT, filtered to remove solids, and the filtrate concentrated to dryness at reduced pressure. The residue was subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid) followed by lyophilization from MeCN/water to afford the title compound (43 mg, 60%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40-8.47 (m, 1H) 8.20 (s, 1H) 8.05 (s, 2H) 7.97 (dd, J=8.7, 5.5 Hz, 2H) 7.65 (d, J=2.5 Hz, 1H) 7.53 (dd, J=8.9, 2.6 Hz, 1H) 7.40 (t, J=8.8 Hz, 2H) 7.14 (s, 1H) 7.00 (d, J=9.1 Hz, 1H) 3.73 (s, 2H) 3.32 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.20-2.35 (m, 1H) 0.90 (br. s., 3H) 0.45 (br. s., 1H). LCMS (m/z, ES+)=587 (M+H+). After 2 hours the mixture was cooled to RT filtered to remove solids the filtrate concentrated to dryness at reduced pressure The residue was subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid)