(2-methylsulfanylphenyl)boronic acid

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

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

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

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

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

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

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

Procedure: 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (61 mg, 0.075 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 11) (354 mg, 0.75 mmol), sodium carbonate (239 mg, 2.25 mmol) and [2-(methylthio)phenyl]boronic acid (252 mg, 1.5 mmol) in N,N-dimethylformamide/water (2:1) (22.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylthio)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide. the reaction mixture was cooled extracted with diethyl ether The combined organic extracts were dried (magnesium sulfate) concentrated in vacuo

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(1-(3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione (0.9836 g, 2.470 mmol), 2-(methylthio)phenylboronic acid (0.623 g, 3.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.124 mmol), and potassium carbonate (1.024 g, 7.41 mmol) in DME (12.35 mL) was stirred at 85° C. After 25.5 h, to the mixture were added 2-(methylthio)phenylboronic acid (0.623 g, 3.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.124 mmol), and potassium carbonate (1.024 g, 7.41 mmol) and the mixture was stirred at 85° C. After 4 days 21 h, the mixture was cooled to rt. The insoluble solid was filtered off and the solid was washed with DCM (50 mL). The filtrate was cond under reduced pressure. The residue was dissolved in DCM (50 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and cond under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 20 min as eluent to give 2-(1-(3-(2-(methylthio)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (1 H, ddd, J=7.2, 1.6, 0.8 Hz), 7.98-8.05 (1 H, m), 7.77-7.84 (2 H, m), 7.68-7.75 (3 H, m), 7.43 (1 H, td, J=6.9, 1.5 Hz), 7.31 (1 H, dd, J=8.1, 0.9 Hz), 7.18-7.24 (1 H, m), 6.79-6.85 (1 H, m), 6.70-6.76 (1 H, m), 5.36-5.44 (1 H, m), 2.41 (3 H, s), 1.64 (3 H, d, J=7.2 Hz); Mass Spectrum (ESI) m/e=442.1 (M+1). the mixture was stirred at 85° C After 4 days 21 h the mixture was cooled to rt The insoluble solid was filtered off the solid was washed with DCM (50 mL) The residue was dissolved in DCM (50 mL) washed with brine (50 mL×2) dried over Na2SO4 filtered The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column over 14 min

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

Procedure: The mixture of 2-methylthiophenyl-dihydroxyborane (1.55 g) and 3-iodobenzoic acid (2.08 g) in water (30 ml) was stirred at room temperature, then sodium carbonate (2.67 g) and palladium(II) acetate (0.019 g) were added thereto. After stirring at 40° C. overnight, the reaction mixture was filtered and was washed with ether (2×20 ml). The aqueous layer was adjusted to pH 2 with 6N-hydrochloric acid. The crystalline was collected, washed with water, and dried to afford 3-(2-methylthiophenyl)benzoic acid. After stirring at 40° C. overnight the reaction mixture was filtered was washed with ether (2×20 ml) The crystalline was collected washed with water dried

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

Procedure: A solution of 1-methylthio-2-bromobenzene (5 g) in dry ether (30 ml) was stirred at 0° C. and 1.63M n-butyllithium in hexane solution (16.6 ml) was added dropwise over a period of 15 minutes. The reaction mixture was stirred at 0° C. for 1.5 hours and then transferred to a cold (-78° C.) solution of triisopropyl borate (7.4 ml) in tetrahydrofuran (40 ml) over 40 minutes. After stirring for 1 hour at -78° C., the reaction mixture was allowed to warm to room temperature overnight. The suspension was poured into dilute 2M hydrochloric acid (40 ml) and the layers were separated. The aqueous phase was extracted with ether (2×80 ml) and the combined organic phases were washed with brine, dried with magnesium sulfate, evaporated and washed with petroleum ether (2×20 ml) to afford 2-methylthiophenyldihydroxyborane. After stirring for 1 hour at -78° C. to warm to room temperature overnight The suspension was poured the layers were separated The aqueous phase was extracted with ether (2×80 ml) the combined organic phases were washed with brine dried with magnesium sulfate evaporated washed with petroleum ether (2×20 ml)

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

Procedure: 2-[Bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine (2.00 g, 5.3 mmol) was dissolved in benzene (130 mL). 2-methylthiophenylboronic acid (2.24 g, 13.3 mmol), aq. sodium carbonate (13 mL, 2.0 M, 26 mmol), tetrabutyl ammonium bromide (86 mg, 0.26 mmol), and bis(triphenylphosphine)palladium(II)chloride (190 mg, 0.27 mmol) were added, and the resulting mixture was first purged with vacuum and argon, then refluxed 17 hours. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organic was dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (50% EtOAc/hexanes), evaporated, and chromatographed a second time on silica gel (30-50% EtOAc/hexanes) to yield the desired product (2.13 g, 96%). 1H NMR (CDCl3): δ 8.81 (s, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 2.39 (s, 3H), 1.49 (s, 18H). the resulting mixture was first purged with vacuum and argon refluxed 17 hours The cooled mixture was diluted with EtOAc and water The layers were separated the organic was dried over Na2SO4 filtered evaporated The crude product was chromatographed on silica gel (50% EtOAc/hexanes) evaporated chromatographed a second time on silica gel (30-50% EtOAc/hexanes)

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

Procedure: 2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to −75° C. n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 minutes. After stirring 25 minutes, triisopropyl borate (46 mL, 199 mmol) was added over 35 minutes. The cold bath was removed and the reaction was stirred at room temp for 16 hours. The resulting solution was cooled in an ice bathours, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 hours and concentrated to about half of the original volume. The concentrated solution was partitioned between Et2O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et2O. These Et2O washes were dried over Na2SO4, filtered, and evaporated to yield a beige solid (20.4 g, 85%). 1H NMR (CDCl3): δ 8.01 (dd, 1H, J=7.3, J′=1.4), 7.53 (dd, 1H, J=7.7, J′=1.1), 7.43 (td, 1H, J=7.3, J′=1.8), 7.34 (td, 1H, J=7.3, J′=1.5), 6.22 (s, 2H), 2.50 (s, 3H). was added over 50 minutes The cold bath was removed the reaction was stirred at room temp for 16 hours The resulting solution was cooled in an ice bathours, and 6 M HCl (100 mL) was added This mixture was stirred at room temp 5 hours concentrated to about half of the original volume The concentrated solution was partitioned between Et2O and water The organic layer was extracted with 2 M NaOH, which extracted several times back into Et2O These Et2O washes were dried over Na2SO4 filtered evaporated