1-aminopropan-2-one;hydrochloride

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.800 g, 1.90 mmol), HOBT-H2O (0.437 g, 2.86 mmol), DIEA (1.36 mL, 7.80 mmol), EDCI (0.547 g, 2.86 mmol), and 1-aminopropan-2-one hydrochloride (0.834 g, 7.61 mmol) in 50 mL THF was stirred at 50° C. for 2 days. The mixture was concentrated and diluted with CH2Cl2 and washed with water, dried over sodium sulfate and concentrated to a residue that was carried on to the next step without further purification. The mixture was concentrated diluted with CH2Cl2 washed with water dried over sodium sulfate concentrated to a residue that was carried on to the next step without further purification

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

Procedure: Crushed potassium hydroxide (5.7 g, 0.1 mol) was added portionwise to a refluxing solution of 1-nitro-2-methylthio-2-methylsulphinylethylene (9.3 g, 0.05 mol) and aminoacetone hydrochloride (5.6 g, 0.05 mol) in methanol (100 ml). Reflux was continued for 5 minutes, and then the mixture was cooled and the solvent removed in vacuo. Water was added to the residue, and the solid was recrystallised from chloroform/methanol/petroleum ether to give 2-methylthio-3-nitro-4-methylpyrrole (1.45 g, 16%) m.p. 216-216-5. Reflux the mixture was cooled the solvent removed in vacuo Water was added to the residue the solid was recrystallised from chloroform/methanol/petroleum ether

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.800 g, 1.90 mmol), HOBT-H2O (0.437 g, 2.86 mmol), DIEA (1.36 mL, 7.80 mmol), EDCI (0.547 g, 2.86 mmol), and 1-aminopropan-2-one hydrochloride (0.834 g, 7.61 mmol) in 50 mL THF was stirred at 50° C. for 2 days. The mixture was concentrated and diluted with CH2Cl2 and washed with water, dried over sodium sulfate and concentrated to a residue that was carried on to the next step without further purification. The mixture was concentrated diluted with CH2Cl2 washed with water dried over sodium sulfate concentrated to a residue that was carried on to the next step without further purification

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.800 g, 1.90 mmol), HOBT-H2O (0.437 g, 2.86 mmol), DIEA (1.36 mL, 7.80 mmol), EDCI (0.547 g, 2.86 mmol), and 1-aminopropan-2-one hydrochloride (0.834 g, 7.61 mmol) in 50 mL THF was stirred at 50° C. for 2 days. The mixture was concentrated and diluted with CH2Cl2 and washed with water, dried over sodium sulfate and concentrated to a residue that was carried on to the next step without further purification. The mixture was concentrated diluted with CH2Cl2 washed with water dried over sodium sulfate concentrated to a residue that was carried on to the next step without further purification

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: T3P (591 mg, 553 μL of 50% w/w, 0.93 mmol) was added to a mixture of 9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (142 mg, 0.37 mmol), 1-aminopropan-2-one hydrochloride salt (41 mg, 0.37 mmol) and Et3N (188 mg, 259 μL, 1.86 mmol) in 2-methyltetrahydrofuran (706 μL). The reaction mixture was then heated at 45° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 0-50% EtOAC in DCM as eluent to afford tert-butyl 10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 49%) as a yellow solid. ESI-MS m/z calc. 437.5. found 438.7 (M+1)+; Retention time: 1.01 minutes (3 min run). The reaction mixture was cooled to room temperature partitioned between EtOAc/saturated aq. NaHCO3 The layers were separated the aqueous layer was extracted with EtOAc (2×) The combined organics were dried over Na2SO4 filtered concentrated in vacuo to a dark foam The crude product was purified by silica gel column chromatography

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

Procedure: Crushed potassium hydroxide (5.7 g, 0.1 mol) was added portionwise to a refluxing solution of 1-nitro-2-methylthio-2-methylsulphinylethylene (9.3 g, 0.05 mol) and aminoacetone hydrochloride (5.6 g, 0.05 mol) in methanol (100 ml). Reflux was continued for 5 minutes, and then the mixture was cooled and the solvent removed in vacuo. Water was added to the residue, and the solid was recrystallised from chloroform/methanol/petroleum ether to give 2-methylthio-3-nitro-4-methylpyrrole (1.45 g, 16%) m.p. 216-216-5. Reflux the mixture was cooled the solvent removed in vacuo Water was added to the residue the solid was recrystallised from chloroform/methanol/petroleum ether

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

Procedure: Crushed potassium hydroxide (5.7 g, 0.1 mol) was added portionwise to a refluxing solution of 1-nitro-2-methylthio-2-methylsulphinylethylene (9.3 g, 0.05 mol) and aminoacetone hydrochloride (5.6 g, 0.05 mol) in methanol (100 ml). Reflux was continued for 5 minutes, and then the mixture was cooled and the solvent removed in vacuo. Water was added to the residue, and the solid was recrystallised from chloroform/methanol/petroleum ether to give 2-methylthio-3-nitro-4-methylpyrrole (1.45 g, 16%) m.p. 216-216-5. Reflux the mixture was cooled the solvent removed in vacuo Water was added to the residue the solid was recrystallised from chloroform/methanol/petroleum ether

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.800 g, 1.90 mmol), HOBT-H2O (0.437 g, 2.86 mmol), DIEA (1.36 mL, 7.80 mmol), EDCI (0.547 g, 2.86 mmol), and 1-aminopropan-2-one hydrochloride (0.834 g, 7.61 mmol) in 50 mL THF was stirred at 50° C. for 2 days. The mixture was concentrated and diluted with CH2Cl2 and washed with water, dried over sodium sulfate and concentrated to a residue that was carried on to the next step without further purification. The mixture was concentrated diluted with CH2Cl2 washed with water dried over sodium sulfate concentrated to a residue that was carried on to the next step without further purification

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

Procedure: t-Butyloxycarbonyl-p-nitrophenylalanine (4.42 g, 14.26 mmol, aminoacetone hydrochloride (1.56 g, 14.26 mmol), triethylamine (1.44 g, 14.26 mmol), 1-hydroxybenzotriazole (1.69 g, 12.55 mmol), were dissolved in ethyl acetate (400 ml). 1,3-Dicyclohexylcarbodiimide (3.23 g, 15.68 mmol) in ethyl acetate (25 ml) was added and the solution allowed to stir for 18 hours. Glacial acetic acid (0.2 ml) was added and the solution was filtered. The filtrate was extracted with saturated salt solution (100 ml), 1N HCl solution (3×100 ml), saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml). The organic phase was dried over MgSO4, filtered and concentrated to 50 ml. Petroleum ether (50 ml) was added and the solution was cooled to 0° C. for 12 hours. The precipitated product was collected and dried under vacuum. the solution was filtered The filtrate was extracted with saturated salt solution (100 ml), 1N HCl solution (3×100 ml), saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml) The organic phase was dried over MgSO4 filtered concentrated to 50 ml Petroleum ether (50 ml) was added The precipitated product was collected dried under vacuum

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

Procedure: t-Butyloxycarbonyl-p-nitrophenylalanine (4.42 g, 14.26 mmol, aminoacetone hydrochloride (1.56 g, 14.26 mmol), triethylamine (1.44 g, 14.26 mmol), 1-hydroxybenzotriazole (1.69 g, 12.55 mmol), were dissolved in ethyl acetate (400 ml). 1,3-Dicyclohexylcarbodiimide (3.23 g, 15.68 mmol) in ethyl acetate (25 ml) was added and the solution allowed to stir for 18 hours. Glacial acetic acid (0.2 ml) was added and the solution was filtered. The filtrate was extracted with saturated salt solution (100 ml), 1N HCl solution (3×100 ml), saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml). The organic phase was dried over MgSO4, filtered and concentrated to 50 ml. Petroleum ether (50 ml) was added and the solution was cooled to 0° C. for 12 hours. The precipitated product was collected and dried under vacuum. the solution was filtered The filtrate was extracted with saturated salt solution (100 ml), 1N HCl solution (3×100 ml), saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml) The organic phase was dried over MgSO4 filtered concentrated to 50 ml Petroleum ether (50 ml) was added The precipitated product was collected dried under vacuum

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

Procedure: t-Butyloxycarbonyl-p-nitrophenylalanine (4.42g, 14.26 mmol, aminoacetone hydrochloride (1.56 g, 14.26 mmol), triethylamine (1.44 g, 14.26 mmol), 1-hydroxybenzotriazole (1.69 g, 12.55 mmol), were dissolved in ethyl acetate (400 ml). 1,3-Dicyclohexylcarbodiimide (3.23 g, 15.68 mmol) in ethyl acetate (25 ml) was added and the solution allowed to stir for 18 hours. Glacial acetic acid (0.2 ml) was added and the solution was filtered. The filtrate was extracted with saturated salt solution (100 ml), lN HCl solution (3×100 ml), and saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml). The organic phase was dried over MgSO4 , filtered and concentrated to 50 ml. Petroleum ether (50 ml) was added and the solution was cooled to 0° C. for 12 hours. The precipitated product was collected and dried under vacuum. the solution was filtered The filtrate was extracted with saturated salt solution (100 ml), lN HCl solution (3×100 ml), and saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml) The organic phase was dried over MgSO4 filtered concentrated to 50 ml Petroleum ether (50 ml) was added The precipitated product was collected dried under vacuum

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

Procedure: t-Butyloxycarbonyl-p-nitrophenylalanine (4.42g, 14.26 mmol, aminoacetone hydrochloride (1.56 g, 14.26 mmol), triethylamine (1.44 g, 14.26 mmol), 1-hydroxybenzotriazole (1.69 g, 12.55 mmol), were dissolved in ethyl acetate (400 ml). 1,3-Dicyclohexylcarbodiimide (3.23 g, 15.68 mmol) in ethyl acetate (25 ml) was added and the solution allowed to stir for 18 hours. Glacial acetic acid (0.2 ml) was added and the solution was filtered. The filtrate was extracted with saturated salt solution (100 ml), lN HCl solution (3×100 ml), and saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml). The organic phase was dried over MgSO4 , filtered and concentrated to 50 ml. Petroleum ether (50 ml) was added and the solution was cooled to 0° C. for 12 hours. The precipitated product was collected and dried under vacuum. the solution was filtered The filtrate was extracted with saturated salt solution (100 ml), lN HCl solution (3×100 ml), and saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml) The organic phase was dried over MgSO4 filtered concentrated to 50 ml Petroleum ether (50 ml) was added The precipitated product was collected dried under vacuum