1-(2-prop-2-ynoxyethyl)pyrrolidine

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Nitrogen gas was bubbled through a mixture of 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 4.06 mmol), 1-(2-prop-2-ynoxyethyl)pyrrolidine (1.53 g, 10 mmol), bistriphenylphosphine palladium (II) dichloride (180 mg, 0.25 mmol), triethylamine (3.5 mL, 25 mmol), copper (I) iodide (75 mg, 0.4 mmol) in THF (20 mL) for 5 minutes. The reaction was then heated at 100° C. for 60 minutes in a microwave. The reaction was then diluted with ethyl acetate (50 ml) and water (50 ml) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to a gum. The gum was chromatographed on silica in a gradient of 2-15% methanol in dichloromethane. A peak eluted in about 8-12% methanol in dichloromethane to give 5-phenyl-4-[3-(2-pyrrolidine-1-ylethoxy)prop-1-ynyl]thieno[2,3-d]pyrimidine as a gum. (55 mg, 0.15 mmol, 3.7%). LCMS [M+H]+=364; RT=3.04 min. The ethyl acetate layer was then separated dried over sodium sulphate concentrated in vacuum to a gum The gum was chromatographed on silica in a gradient of 2-15% methanol in dichloromethane A peak eluted in about 8-12% methanol in dichloromethane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Nitrogen gas was bubbled through a mixture of 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 4.06 mmol), 1-(2-prop-2-ynoxyethyl)pyrrolidine (1.53 g, 10 mmol), bistriphenylphosphine palladium (II) dichloride (180 mg, 0.25 mmol), triethylamine (3.5 mL, 25 mmol), copper (I) iodide (75 mg, 0.4 mmol) in THF (20 mL) for 5 minutes. The reaction was then heated at 100° C. for 60 minutes in a microwave. The reaction was then diluted with ethyl acetate (50 ml) and water (50 ml) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to a gum. The gum was chromatographed on silica in a gradient of 2-15% methanol in dichloromethane. A peak eluted in about 8-12% methanol in dichloromethane to give 5-phenyl-4-[3-(2-pyrrolidine-1-ylethoxy)prop-1-ynyl]thieno[2,3-d]pyrimidine as a gum. (55 mg, 0.15 mmol, 3.7%). LCMS [M+H]+=364; RT=3.04 min. The ethyl acetate layer was then separated dried over sodium sulphate concentrated in vacuum to a gum The gum was chromatographed on silica in a gradient of 2-15% methanol in dichloromethane A peak eluted in about 8-12% methanol in dichloromethane

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Propargyl alcohol (1.40 g, 25 mmol) in toluene (30 ml) was treated with 1-(2-chloroethyl)pyrrolidine hydrochloride (8.55 g, 50 mmol), 10 N aqueous sodium hydroxide solution (30 ml) and tetrabutylammonium bromide (150 mg, 1.2 mmol) and heated at 90° C. for 18 h. The layers were separated and the organic layer was dried over sodium sulphate and concentrated under reduced pressure to give a gum. The gum was distilled on a kugelrohr at 160° C. at 22 mbar to give two fractions. Fraction 1 (4.01 g, 25 mmol), the higher boiling, was found to be a mixture of the desired compound I-(2-prop-2-ynoxyethyl)pyrrolidine with some toluene and 2-pyrrolidine-lylethanol. Fraction 2 (2.7 g) was found to be mainly the 2-pyrrolidine-lylethanol and toluene and a trace of the desired compound I-(2-prop-2-ynoxyethyl)pyrrolidine. A portion of fraction 1 (1 g) was repurified by chromatography on silica in a gradient of 2-12% methanol in dichloromethane on a 100 g silica column collecting column volumes. 1-(2-Prop-2-ynoxyethyl)pyrrolidine was isolated as a yellow oil (0.419 g). The layers were separated the organic layer was dried over sodium sulphate concentrated under reduced pressure to give a gum The gum was distilled on a kugelrohr at 160° C. at 22 mbar to give two fractions

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Nitrogen gas was bubbled through a mixture of 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 4.06 mmol), 1-(2-prop-2-ynoxyethyl)pyrrolidine (1.53 g, 10 mmol), bistriphenylphosphine palladium (II) dichloride (180 mg, 0.25 mmol), triethylamine (3.5 mL, 25 mmol), copper (I) iodide (75 mg, 0.4 mmol) in THF (20 mL) for 5 minutes. The reaction was then heated at 100° C. for 60 minutes in a microwave. The reaction was then diluted with ethyl acetate (50 ml) and water (50 ml) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to a gum. The gum was chromatographed on silica in a gradient of 2-15% methanol in dichloromethane. A peak eluted in about 8-12% methanol in dichloromethane to give 5-phenyl-4-[3-(2-pyrrolidine-1-ylethoxy)prop-1-ynyl]thieno[2,3-d]pyrimidine as a gum. (55 mg, 0.15 mmol, 3.7%). LCMS [M+H]+=364; RT=3.04 min. The ethyl acetate layer was then separated dried over sodium sulphate concentrated in vacuum to a gum The gum was chromatographed on silica in a gradient of 2-15% methanol in dichloromethane A peak eluted in about 8-12% methanol in dichloromethane

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Propargyl alcohol (1.40 g, 25 mmol) in toluene (30 ml) was treated with 1-(2-chloroethyl)pyrrolidine hydrochloride (8.55 g, 50 mmol), 10 N aqueous sodium hydroxide solution (30 ml) and tetrabutylammonium bromide (150 mg, 1.2 mmol) and heated at 90° C. for 18 h. The layers were separated and the organic layer was dried over sodium sulphate and concentrated under reduced pressure to give a gum. The gum was distilled on a kugelrohr at 160° C. at 22 mbar to give two fractions. Fraction 1 (4.01 g, 25 mmol), the higher boiling, was found to be a mixture of the desired compound I-(2-prop-2-ynoxyethyl)pyrrolidine with some toluene and 2-pyrrolidine-lylethanol. Fraction 2 (2.7 g) was found to be mainly the 2-pyrrolidine-lylethanol and toluene and a trace of the desired compound I-(2-prop-2-ynoxyethyl)pyrrolidine. A portion of fraction 1 (1 g) was repurified by chromatography on silica in a gradient of 2-12% methanol in dichloromethane on a 100 g silica column collecting column volumes. 1-(2-Prop-2-ynoxyethyl)pyrrolidine was isolated as a yellow oil (0.419 g). The layers were separated the organic layer was dried over sodium sulphate concentrated under reduced pressure to give a gum The gum was distilled on a kugelrohr at 160° C. at 22 mbar to give two fractions