3-cyclopropylprop-2-yn-1-ol

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

Procedure: To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g). to exceed 0° C the mixture was quenched with 10 mL of water The aqueous layer was extracted twice with 20 mL each of CH2Cl2 The organic layer was washed with 20% HCl and water to drying over anhydrous Na2SO4 The organic phase was concentrated the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g)

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

Procedure: To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g). to exceed 0° C the mixture was quenched with 10 mL of water The aqueous layer was extracted twice with 20 mL each of CH2Cl2 The organic layer was washed with 20% HCl and water to drying over anhydrous Na2SO4 The organic phase was concentrated the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g)

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

Procedure: To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g). to exceed 0° C the mixture was quenched with 10 mL of water The aqueous layer was extracted twice with 20 mL each of CH2Cl2 The organic layer was washed with 20% HCl and water to drying over anhydrous Na2SO4 The organic phase was concentrated the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g)

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

Procedure: To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3 h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g). to exceed 0° C the mixture was quenched with 10 mL of water The aqueous layer was extracted twice with 20 mL each of CH2Cl2 The organic layer was washed with 20% HCl and water to drying over anhydrous Na2SO4 The organic phase was concentrated the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g)

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

Procedure: To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3 h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g). to exceed 0° C the mixture was quenched with 10 mL of water The aqueous layer was extracted twice with 20 mL each of CH2Cl2 The organic layer was washed with 20% HCl and water to drying over anhydrous Na2SO4 The organic phase was concentrated the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g)

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

Procedure: To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3 h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g). to exceed 0° C the mixture was quenched with 10 mL of water The aqueous layer was extracted twice with 20 mL each of CH2Cl2 The organic layer was washed with 20% HCl and water to drying over anhydrous Na2SO4 The organic phase was concentrated the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g)

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

Procedure: 3-Cyclopropyl-prop-2-yn-1-ol (3.28 g, 34.1 mmol) was dissolved in 40 mL toluene, DPPA (11.26 g, 40.9 mmol) was added, followed with DBU (6.24 g, 40.9 mmol) while maintaining temperature with a water bath. The mixture was stirred at room temperature for one hour and was diluted with 100 mL hexane and 15 mL CH2Cl2. The mixture was washed with water four times and once with brine, dried over Na2SO4, filtered and concentrated under rotovap with cold water bath to remove most of organic solvent leaving some toluene (product volatile). The residual oil was used for the next step. while maintaining temperature with a water bath The mixture was washed with water four times and once with brine dried over Na2SO4 filtered concentrated under rotovap with cold water bath to remove most of organic solvent leaving some toluene (product volatile)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-cyclopropylprop-2-yn-1-ol (205 mg, 2.137 mmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil; 8.6 mg, 0.214 mmol) at rt. After 15 min N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropyrazine-2-carboxamide (Example 261, 88 mg, 0.214 mmol) was added and the reaction mixture was stirred at 60° C. for 50 min. Water (1.0 mL) and aqueous, saturated NaHCO3 solution (1 mL) were added. The resulting mixture was then extracted with EtOAc (2×10 mL). The combined organic extracts were washed with water and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (0%-20% MeOH/DCM) to give 58 mg of the title compound as an off-white solid. MS m/z=472 [M+H]+ The resulting mixture was then extracted with EtOAc (2×10 mL) The combined organic extracts were washed with water dried over MgSO4 The filtrate was concentrated under reduced pressure the residue was purified by silica gel flash column chromatography (0%-20% MeOH/DCM)

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

Procedure: The title compound was synthesized analogously according to Method KS starting from methyl 5-hydroxypicolinate (Molbridge) and 3-cyclopropylprop-2-yn-1-ol. MS m/z: 218 (M+H).

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

Procedure: To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3 h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g). to exceed 0° C the mixture was quenched with 10 mL of water The aqueous layer was extracted twice with 20 mL each of CH2Cl2 The organic layer was washed with 20% HCl and water to drying over anhydrous Na2SO4 The organic phase was concentrated the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g)

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

Procedure: To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g). to exceed 0° C the mixture was quenched with 10 mL of water The aqueous layer was extracted twice with 20 mL each of CH2Cl2 The organic layer was washed with 20% HCl and water to drying over anhydrous Na2SO4 The organic phase was concentrated the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g)