but-3-yn-1-amine;hydrochloride

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

Procedure: To a suspension of but-3-yn-1-amine hydrochloride (200 mg, 1.89 mmol) and triethylamine (425 μL, 3.78 mmol) in DCM (60 mL) was added morpholine-4-carbonyl chloride (218 μL, 1.89 mmol). The reaction was stirred at RT overnight and then washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL), dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0-100% ethyl acetate in heptane, to afford the title compound (13) (164 mg, 48%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ: 2.28 (2H, td), 2.82 (1H, t), 3.09-3.18 (2H, m), 3.20-3.27 (4H, m), 3.48-3.57 (4H, m), 6.74 (1H, t). washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL) dried filtered evaporated in vacuo The residue was purified by flash column chromatography eluting with 0-100% ethyl acetate in heptane

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

Procedure: To a mixture of potassium carbonate (40.2 g, 296 mmol) in water (50 mL) and THF (50 mL) at 15–20° C. was added but-3-ynylamine hydrogen chloride (10.4 g, 98.5 mmol). Then, (3,4-dichlorophenyl)methanesulfonyl chloride (5, 30.7 g, 118 mmol) was added in portions during of a period of 30 min. The mixture was stirred for 4 h at rt. THF is evaporated. The mixture is extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na2SO4. The solvent is evaporated to give a white solid (20.5 g, 71%). 1H NMR (CDCl3): δ7.53 (d, 1H, J=2.0 Hz), 7.47 (d, 1H, J=4.2 Hz), 7.27 (m, 1H), 4.52 (t, 1H, J=6.2 Hz), 4.22 (s, 2H), 3.17 (dd, 2H, J=6.2 Hz, 12.5 Hz), 2.41 (m, 2H), 2.07 (m, 1H) THF is evaporated The mixture is extracted with EtOAc (2×200 mL) The combined organic extracts were dried over Na2SO4 The solvent is evaporated

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

Procedure: To a suspension of but-3-yn-1-amine hydrochloride (200 mg, 1.89 mmol) and triethylamine (425 μL, 3.78 mmol) in DCM (60 mL) was added morpholine-4-carbonyl chloride (218 μL, 1.89 mmol). The reaction was stirred at RT overnight and then washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL), dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0-100% ethyl acetate in heptane, to afford the title compound (13) (164 mg, 48%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ: 2.28 (2H, td), 2.82 (1H, t), 3.09-3.18 (2H, m), 3.20-3.27 (4H, m), 3.48-3.57 (4H, m), 6.74 (1H, t). washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL) dried filtered evaporated in vacuo The residue was purified by flash column chromatography eluting with 0-100% ethyl acetate in heptane

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

Procedure: To a suspension of but-3-yn-1-amine hydrochloride (200 mg, 1.89 mmol) and triethylamine (425 μL, 3.78 mmol) in DCM (60 mL) was added morpholine-4-carbonyl chloride (218 μL, 1.89 mmol). The reaction was stirred at RT overnight and then washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL), dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0-100% ethyl acetate in heptane, to afford the title compound (13) (164 mg, 48%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ: 2.28 (2H, td), 2.82 (1H, t), 3.09-3.18 (2H, m), 3.20-3.27 (4H, m), 3.48-3.57 (4H, m), 6.74 (1H, t). washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL) dried filtered evaporated in vacuo The residue was purified by flash column chromatography eluting with 0-100% ethyl acetate in heptane

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

Procedure: To a suspension of but-3-yn-1-amine hydrochloride (200 mg, 1.89 mmol) and triethylamine (425 μL, 3.78 mmol) in DCM (60 mL) was added morpholine-4-carbonyl chloride (218 μL, 1.89 mmol). The reaction was stirred at RT overnight and then washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL), dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0-100% ethyl acetate in heptane, to afford the title compound (13) (164 mg, 48%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ: 2.28 (2H, td), 2.82 (1H, t), 3.09-3.18 (2H, m), 3.20-3.27 (4H, m), 3.48-3.57 (4H, m), 6.74 (1H, t). washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL) dried filtered evaporated in vacuo The residue was purified by flash column chromatography eluting with 0-100% ethyl acetate in heptane

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

Procedure: To a suspension of but-3-yn-1-amine hydrochloride (200 mg, 1.89 mmol) and triethylamine (425 μL, 3.78 mmol) in DCM (60 mL) was added morpholine-4-carbonyl chloride (218 μL, 1.89 mmol). The reaction was stirred at RT overnight and then washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL), dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0-100% ethyl acetate in heptane, to afford the title compound (13) (164 mg, 48%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ: 2.28 (2H, td), 2.82 (1H, t), 3.09-3.18 (2H, m), 3.20-3.27 (4H, m), 3.48-3.57 (4H, m), 6.74 (1H, t). washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL) dried filtered evaporated in vacuo The residue was purified by flash column chromatography eluting with 0-100% ethyl acetate in heptane

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

Procedure: To a mixture of potassium carbonate (40.2 g, 296 mmol) in water (50 mL) and THF (50 mL) at 15-20° C. was added but-3-ynylamine hydrogen chloride (10.4 g, 98.5 mmol). Then, (3,4-dichlorophenyl)methanesulfonyl chloride (5, 30.7 g, 118 mmol) was added in portions during of a period of 30 ml. The mixture was stirred for 4 h at rt. THF is evaporated. The mixture is extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na4SO4. The solvent is evaporated to give a white solid (20.5 g, 71%%). 1H NMR (CDCl3): δ7.53 (d, 1H, J=2.0 Hz), 7.47 (d, 1H, J=4.2 Hz), 7.27 (m, 1H), 4.52 (t, 1H, J=6.2 Hz), 4.22 (s, 2H), 3.17 (dd, 2H, J=6.2 Hz, 12.5 Hz), 2.41 (m, 2H), 2.07 (m, 1H) THF is evaporated The mixture is extracted with EtOAc (2×200 mL) The combined organic extracts were dried over Na4SO4 The solvent is evaporated to give a white solid (20.5 g, 71%%)

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

Procedure: Add triethylamine (3 mL) to a suspension of but-3-ynylamine hydrochloride (200 mg, 2.1 mmol) in DCM (10 mL) and stir for 10 min at room temperature under nitrogen. Add then neat pivaloyl chloride (284.9 μL, 2.31 mmol) and stir at room temperature overnight under nitrogen. Concentrate in vacuo, take up the residue in methanol and filter through a SCX-2 cartridge eluting with methanol to obtain the title compound (265 mg, 65%). Add Concentrate in vacuo filter through a SCX-2 cartridge eluting with methanol

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

Procedure: A mixture of 5 (2.67 g, 13.1 mmol), but-3-ynylamine HCl salt (2.76 g, 26.2 mmol) and potassium carbonate (3.62 g) in 40 ml of methanol was refluxed for 5 h. After the workup, the residue was purified by column chromatography (THF-EtOH=9:0.5) to give 2.2 g of yellow solid (6, 70% yield). 1H NMR (DMSO-d6, δppm): 2.26 (dt, 2H, ≡C—CH2—, J=7.2 Hz, 2.7 Hz), 2.50 (d, 2H, J=5.7 Hz), 2.63 (t, 2H, J=7.2 Hz), 2.78 (t, 1H, CH≡C—, J=2.7 Hz), 3.82 (m, 1H, HO—CH—), 4.25 (dd, 1H, imidazole-CHa—, J=13.8 Hz, 8.4 Hz), 4.54 (dd, 1H, imidazole-CHb—, J=13.8 Hz, 3.6 Hz), 5.13 (d, 1H, OH, J=5.1 Hz), 7.13 (s, 1H, —CH═), 7.55 (s, 1H, —CH═). 13C NMR (DMSO-d6, δppm): 18.80, 47.79, 52.04, 52.89, 68.09, 71.60, 82.87, 126.98, 128.19, 144.83. was refluxed for 5 h After the workup, the residue was purified by column chromatography (THF-EtOH=9:0.5)

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

Procedure: To a solution of but-3-yn-1-amine hydrochloride (4.88 g) and triethylamine (6.44 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.08 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.95 g). The reaction mixture was concentrated water was added to the residue the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was washed with ethyl acetate

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

Procedure: A mixture of but-3-yn-1-amine hydrochloride (26.4 g, 0.25 mol), K2CO3 (17.4 g, 0.13 mol), and tert-butyl 4-oxopiperidine-1-carboxylate (41.8 g, 0.21 mol) in MeOH (500 mL) was stirred at rt for 5 hrs. Then, NaBH(OAc)3 (133.6 g, 0.63 mol) was added and the suspension was stirred at rt for 17 hrs. The crude reaction mixture was used directly in the next step. ESI-MS (EI+, m/z): 253.2 [M+H]+. the suspension was stirred at rt for 17 hrs The crude reaction mixture

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

Procedure: To a 5-10° C. solution of tert-butyl but-3-yn-1-ylcarbamate (115 g, 0.675 mol) in dichloromethane (500 mL) was added 4N hydrochloric acid in dioxane (650 mL, 2.60 mol). After 3 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was washed with dichloromethane, then with diethyl ether, and then dried in vacuo to afford but-3-yn-1-amine hydrochloride as an intermediate. To a −5 to −10° C. solution of but-3-yn-1-amine hydrochloride and triethylamine (206 mL, 1.47 mol) in dichloromethane (500 mL) was added methanesulfonyl chloride (68.4 mL, 0.88 mol). After 3 hours at ambient temperature, the reaction mixture was diluted with 1N hydrochloric acid (150 mL). The organics were separated, washed with saturated aqueous sodium bicarbonate (150 mL) and with brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford N-but-3-yn-1-ylmethanesulfonamide. The organics were separated washed with saturated aqueous sodium bicarbonate (150 mL) and with brine dried over magnesium sulfate filtered concentrated in vacuo