prop-2-yn-1-amine;hydrochloride

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

Procedure: The title compound was prepared from the product of Example 45A and commercially available propargylamine hydrochloride using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.44 (s. 6H), 1.48 (s, 6H), 3.06-3.08 (m, 1H), 3.90-3.93 (m, 2H), 7.65-7.81 (m, 3H), 8.55 (t, J=5.6 Hz, 1H), 11.58 (br s, 1H). MS (ESI+) m/z 469 (M+H)+. Anal. calcd. for C22H20F4N2O3S: C, 56.40; H, 4.30; N, 5.98. Found: C, 56.36; H, 4.27; N, 5.94.

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

Procedure: The title compound was prepared from the product of Example 45A and commercially available propargylamine hydrochloride using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.44 (s. 6H), 1.48 (s, 6H), 3.06-3.08 (m, 1H), 3.90-3.93 (m, 2H), 7.65-7.81 (m, 3H), 8.55 (t, J=5.6 Hz, 1H), 11.58 (br s, 1H). MS (ESI+) m/z 469 (M+H)+. Anal. calcd. for C22H20F4N2O3S: C, 56.40; H, 4.30; N, 5.98. Found: C, 56.36; H, 4.27; N, 5.94.

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

Procedure: 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoro-aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (47 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propargylamine hydrochloride (29 mg) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with chloroform to give 21 mg (yield 33%) of the title compound. the mixture was further stirred at room temperature overnight the mixture was extracted with chloroform The chloroform layer was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure The residue was washed with chloroform

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

Procedure: 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy)-aniline (50 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (45 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propargylamine hydrochloride (21 mg) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. The precipitated crystal was collected by filtration and was washed to give 38 mg (yield 61%) of the title compound. the mixture was stirred at room temperature for additional 30 min The precipitated crystal was collected by filtration was washed

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

Procedure: 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propargylamine hydrochloride (31 mg) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 26 mg (yield 41%) of the title compound. the mixture was stirred at room temperature overnight the mixture was purified by HPLC by development with chloroform/methanol

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

Procedure: 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propargylamine hydrochloride (31 mg) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 26 mg (yield 41%) of the title compound. the mixture was stirred at room temperature overnight the mixture was purified by HPLC by development with chloroform/methanol

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

Procedure: To a stirred solution of propargylamine hydrochloride (5.0 g, 54.6 mmol) and pyridine (7.8 g, 99.1 mmol) in tetrahydrofuran (30 mL) was added 4-nitro-benzoylchloride (9.2 g, 49.6 mmol) in tetrahydrofuran (20 mL) and the mixture was heated at reflux for 16 h. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The crude residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford 4-nitro-N-prop-2-ynyl-benzamide (7.74 g, 77%) as a solid. the mixture was heated at reflux for 16 h concentrated in vacuo The crude residue was dissolved in ethyl acetate washed with saturated aqueous sodium bicarbonate solution, water, brine dried over anhydrous sodium sulphate filtered concentrated in vacuo

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

Procedure: To a stirred solution of propargylamine hydrochloride (5.0 g, 54.6 mmol) and pyridine (7.8 g, 99.1 mmol) in tetrahydrofuran (30 mL) was added 4-nitro-benzoylchloride (9.2 g, 49.6 mmol) in tetrahydrofuran (20 mL) and the mixture was heated at reflux for 16 h. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The crude residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford 4-nitro-N-prop-2-ynyl-benzamide (7.74 g, 77%) as a solid. the mixture was heated at reflux for 16 h concentrated in vacuo The crude residue was dissolved in ethyl acetate washed with saturated aqueous sodium bicarbonate solution, water, brine dried over anhydrous sodium sulphate filtered concentrated in vacuo

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

Procedure: 5-Chloro-2-methylphenyl isothiocyanate (18.3 g; 0.1 mol) was added dropwise to the mixture of 2-propynylamine hydrochloride (9.2 g, 0.1 mol) and triethyl amine (20 mL) in methylene chloride (200 mL). The mixture was stirred for 18 hours at ambient temperature. The mixture was evaporated to dryness. The residue was stirred in water (200 mL) for 1 hour then filtered. The solid was dissolved in ethyl acetate (300 mL) and washed with 1N hydrochloric acid (2×200 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give 16.8 g of N-(5-chloro-2-methylphenyl)-N′-(2-propynyl)thiourea. The mixture was evaporated to dryness The residue was stirred in water (200 mL) for 1 hour then filtered The solid was dissolved in ethyl acetate (300 mL) washed with 1N hydrochloric acid (2×200 mL) The organic phase was dried over anhydrous magnesium sulfate evaporated to dryness

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

Procedure: Under a nitrogen atmosphere, a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (137.9 g, 0.624 mol) in anhydrous DMF (1.4 L) was cooled to 0° C., and anhydrous triethylamine (109 mL, 0.780 mol) was added. Propargyl amine hydrochloride (4.72 g, 51.6 mmol) and propargyl amine (38.4 g, 0.697 mol) were sequentially added dropwise, and the reaction was allowed to warm to room temperature and then heated at 40° C. for 22 hours. The volatiles were removed under reduced pressure, and water (1.5 L) and solid sodium carbonate (75 g) were added to the resulting oil. The mixture was then extracted with dichloromethane, and the combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 60:40 dichloromethane/hexane and dichloromethane) to provide 51.54 g of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine as a brown solid. heated at 40° C. for 22 hours The volatiles were removed under reduced pressure, and water (1.5 L) and solid sodium carbonate (75 g) were added to the resulting oil The mixture was then extracted with dichloromethane the combined extracts were washed sequentially with water and brine dried over sodium sulfate filtered concentrated under reduced pressure The crude product was purified by column chromatography on silica gel ( eluting sequentially with 60:40 dichloromethane/hexane and dichloromethane)

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

Procedure: 4′-Methyl-2,2′-bipyridine-4-carboxylic acid (0.22 g, 1 mmol), propargylamine hydrochloride (0.092 g, 1 mmol), HOBt (0.15 g, 1 mmol) and DIPEA (0.21 ml) were dissolved in dry DMF (15 ml) and cooled to 0° C. DCC (0.25 g, 1.2 mmol) was dissolved in DMF (3 ml) and added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. DCU was filtered off and solvent was removed by vacuum distillation. The remaining solid compound was dissolved in ethyl acetate and washed with NaHCO3(5%), 0.5 N HCl, brine and dried over sodium sulfate. Solvent was removed by rotary evaporator and the compound was purified by column chromatography using 2% methanol in chloroform as eluent afforded 0. 19 g (76%). FAB-MS: M.W. 251 [M+]; NMR assigned. added dropwise to the reaction mixture DCU was filtered off solvent was removed by vacuum distillation The remaining solid compound was dissolved in ethyl acetate washed with NaHCO3(5%), 0.5 N HCl, brine dried over sodium sulfate Solvent was removed by rotary evaporator the compound was purified by column chromatography afforded 0

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

Procedure: 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (47 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propargylamine hydrochloride (29 mg) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with chloroform to give 21 mg (yield 33%) of the title compound. the mixture was further stirred at room temperature overnight the mixture was extracted with chloroform The chloroform layer was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure The residue was washed with chloroform