ethyl 3-trimethylsilylprop-2-ynoate

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

Procedure: To a solution of 5-bromo-2-(2,6-difluorobenzyl)pyridine (5.6 g) in THF was added ethyl 3-(trimethylsily)propynoate (4.2 mL) and LHMD (42 mL, 1N in THF) at −78° C. The mixture was warmed to 0° C. and stirred in additional 2 h. The reaction was complete by TLC and quenched with NH4Cl, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and condensed in vacuo. The crude compound was purified by silica gel (hexanes/methylene chloride) to give the desired product. quenched with NH4Cl extracted with ethyl acetate The organic layer was washed with water, brine dried over MgSO4 and condensed in vacuo The crude compound was purified by silica gel (hexanes/methylene chloride)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-chloro-6-(2,6-difluorobenzyl)pyridazine (5.7 g, 23.7 mmol) in THF (300 mL) was added LHMDS (71.2 mL, 71.2 mmol, 1M solution in THF) via cannula at −78° C. After stirring for 0.5 hr at −78° C., ethyl 3-(trimethylsilyl)propynoate (6.66 mL, 35.5 mmol) was added. The reaction was allowed to warm from −78° C. to −10° C. over 3 hours. The reaction was known to be complete by LCMS analysis; and then quenched with aqueous NH4Cl, extracted with ethyl acetate. The organic layers were combined, washed with 0.5 N HCl, water, brine, dried over MgSO4, and condensed in vacuo to yield an oil. The crude material was purified via silica gel chromatography (EtOAc/Hex) to yield the title compound (9.6 g). to warm from −78° C. to −10° C. over 3 hours and then quenched with aqueous NH4Cl extracted with ethyl acetate washed with 0.5 N HCl, water, brine dried over MgSO4, and condensed in vacuo to yield an oil The crude material was purified via silica gel chromatography (EtOAc/Hex)

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

Procedure: To a solution of methyl 3-[(6-chloropyridazin-3-yl)methyl]-4-methoxybenzoate (10.03 g, 34.2 mmol) in THF (400 mL) was added LHMDS (100 mL, 1M solution in THF) and ethyl 3-(trimethylsilyl)propynoate (6.66 mL, 35.5 mmol) at −78° C. The reaction was warmed to 0° C. and stirred for 0.5 hr until the reaction was complete by LCMS analysis. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with 0.5 N HCl, brine, dried over MgSO4, and condensed in vacuo to yield an oil. The crude material was purified via silica gel chromatography (CH2Cl2) to yield the title compound. The reaction was quenched with aqueous NH4Cl extracted with ethyl acetate The combined organic layers were washed with 0.5 N HCl, brine dried over MgSO4, and condensed in vacuo to yield an oil The crude material was purified via silica gel chromatography (CH2Cl2)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-(2,6-difluorobenzyl)-2-(2,4-difluorophenyl)pyridine (from Step D above, 4.63 g) in THF was added lithium bis(trimethylsilyl)amide (22.0 mL, 1.0 M in THF) at −78° C. After stirring ½ h at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (2.2 mL) was added. The mixture was warmed to 0° C. and stirred for a couple of hours until reaction complete. The reaction was quenched with 0.1 N HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue in THF was added TBAF (25 mL, 1N in THF) at 0° C. and stirred for 1 h. The solution was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (100% methylene chloride) to give title compound (1.08 g). The mixture was warmed to 0° C. stirred for a couple of hours until reaction complete The reaction was quenched with 0.1 N HCl extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 concentrated The residue in THF was added TBAF (25 mL, 1N in THF) at 0° C. stirred for 1 h The solution was washed with water, brine dried over MgSO4 concentrated The residue was purified by silica gel (100% methylene chloride)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-{[6-(2,4-difluorophenyl)pyridin-2-yl]methyl}-3,5-difluorobenzonitrile (from Step E above, 6.10 g, 17.83 mmol) in THF (200 mL) was added lithium bis(trimethylsilyl)amide (53.49 mL, 1.0 M in THF) at −78° C. After stirring 1¼ h at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (4.01 mL, 21.37 mmol) was added to the reaction mixture. The reaction continued to stir at −78° C. for 1 hr and was warmed to −20° C. until the reaction was complete via LMCS. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with 1N HCl (1×), water, brine, dried over MgSO4, and condensed. The crude material was purified via silica gel chromatography (hexanes/methylene chloride) to give the title compound (7.0 g). to stir at −78° C. for 1 hr was warmed to −20° C. until the reaction The reaction was quenched with aqueous NH4Cl extracted with EtOAc (3×) The combined organic layers were washed with 1N HCl (1×), water, brine dried over MgSO4, and condensed The crude material was purified via silica gel chromatography (hexanes/methylene chloride)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-{[6-(2,4-difluorophenyl)pyridin-2-yl]methyl}-4-fluorobenzonitrile (from Step C above, 30.0 g, 92.3 mmol) in THF (700 mL) was added LiHMDS (276 mL, 276 mmol, 1M solution in THF) via cannula at −78° C. After stirring for 1 hr and 15 min at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (4.01 mL, 21.37 mmol) was added. The reaction was allowed to stir at −78° C. for 1 hr and was allowed to warm to 0° C. over 3 hours. The reaction was quenched with aqueous NH4Cl, extracted with ethyl acetate (2×). The organic layers were combined, washed with 0.5 N HCl, water, brine (2×), dried over MgSO4, and condensed in vacuo to yield a black oil. The crude material was purified via silica gel chromatography (100% CH2Cl2) to give the title compound (40.0 g). to stir at −78° C. for 1 hr to warm to 0° C. over 3 hours The reaction was quenched with aqueous NH4Cl extracted with ethyl acetate (2×) washed with 0.5 N HCl, water, brine (2×) dried over MgSO4, and condensed in vacuo to yield a black oil The crude material was purified via silica gel chromatography (100% CH2Cl2)