2-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol

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

Procedure: Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (Intermediate 107) and replacing methyl 2-bromothiazole-4-carboxylate with methyl 6-bromo-5-fluoropicolinate (see US2012/225062) gave the title compound.

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

Procedure: Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with 2-(3,5-difluorophenyl)propan-2-ol (see US2012/225062) provided the title compound.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen purged mixture of 2-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (1.53 g, 5.13 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (1.20 g, 5.13 mmol) and DIPEA (2.7 mL, 15 mmol) in 1,4-dioxane (20 mL) and water (1.2 mL), bis(tri-tert-butylphosphine)palladium (262 mg, 0.513 mmol) was added. The reaction mixture was heated at 120° C. for 40 min., then cooled and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to give methyl 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylate as a white powder, which was used without further purification. To a nitrogen purged was added cooled filtered through a pad of diatomaceous earth The filtrate was concentrated under reduced pressure The crude residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes)

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

Procedure: To a mixture of 2-(3,5-difluorophenyl)propan-2-ol (2.00 g, 11.6 mmol) in THF (46 mL) at −78° C., n-BuLi in hexanes (1.6 M; 18.2 mL, 29.0 mmol) was slowly added through a dripping funnel. When the addition was complete, the mixture was kept at −78° C. for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.11 mL, 34.8 mmol) was then added in one portion. The mixture was allowed to warm up room temperature and stirred for 1 h, then the reaction was quenched with water and the solution was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the sub-title compound as a colorless oil. LCMS calc. for C15H21BF2O3Na (M+Na)+ m/z=321.2. found: 321.0. When the addition the reaction was quenched with water the solution was extracted with EtOAc The combined organic extracts were washed with brine dried over Na2SO4 concentrated under reduced pressure

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

Procedure: Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (Intermediate 107) and replacing methyl 2-bromothiazole-4-carboxylate with methyl 6-bromo-5-fluoropicolinate (see US2012/225062) gave the title compound.

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

Procedure: Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with 2-(3,5-difluorophenyl)propan-2-ol (see US2012/225062) provided the title compound.