cyclopropylurea

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

Procedure: To a solution of 64 g (0.75 mol) cyanoacetic acid and 250 ml of acetic anhydride was added 70 g (0.7 mol) of cyclopropylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 76.7 g (66%) (I). This was suspended in 200 ml of hot water and 55 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals were filtered off. Yield 31.7 g (42%) (II) NMR. After cooling white crystals were filtered off washed with ethanol 55 ml of 5N NaOH was added in portions so the solution the whole time The reaction mixture was refluxed for 20 minutes After cooling white crystals were filtered off

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

Procedure: To a solution of 64 g (0.75 mol) cyanoacetic acid and 250 ml of acetic anhydride was added 70 g (0.7 mol) of cyclopropylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 76.7 g (66%) (I). This was suspended in 200 ml of hot water and 55 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals were filtered off. Yield 31.7 g (42%) (II) NMR. After cooling white crystals were filtered off washed with ethanol 55 ml of 5N NaOH was added in portions so the solution the whole time The reaction mixture was refluxed for 20 minutes After cooling white crystals were filtered off

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

Procedure: To a solution of 64 g (0.75 mol) cyanoacetic acid and 250 ml of acetic anhydride was added 70 g (0.7 mol) of cyclopropylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 76.7 g (66%) (I). This was suspended in 200 ml of hot water and 55 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals were filtered off. Yield 31.7 g (42%) (II) NMR. After cooling white crystals were filtered off washed with ethanol 55 ml of 5N NaOH was added in portions so the solution the whole time The reaction mixture was refluxed for 20 minutes After cooling white crystals were filtered off

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

Procedure: To a solution of 64 g (0.75 mol) cyanoacetic acid and 250 ml of acetic anhydride was added 70 g (0.7 mol) of cyclopropylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 76.7 g (66%) (I). This was suspended in 200 ml of hot water and 55 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals were filtered off. Yield 31.7 g (42%) (II) NMR. After cooling white crystals were filtered off washed with ethanol 55 ml of 5N NaOH was added in portions so the solution the whole time The reaction mixture was refluxed for 20 minutes After cooling white crystals were filtered off

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

Procedure: To a microwave tube was added 4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5 mmol), 1-cyclopropylurea (0.043 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature, solid was removed via filtration and the filtrate was concentrated under reduced pressure. The residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a yellow solid (0.017 g, 26% yield). 1H NMR (500 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.32 (d, J=7.5 Hz, 1H), 7.99 (br, 1H), 7.75-7.49 (m, 4H), 2.63 (m, 1H), 0.72-0.66 (m, 2H), 0.52-0.46 (m, 2H). LCMS (Method A): RT=5.63 min, m/z: 363.0 [M+H+]. The mixture was degassed with N2 for 10 minutes irradiated in a microwave reactor at 160° C. for 2 hours solid was removed via filtration the filtrate was concentrated under reduced pressure The residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3

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

Procedure: To a microwave tube was added 4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5 mmol), 1-cyclopropylurea (0.043 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature, solid was removed via filtration and the filtrate was concentrated under reduced pressure. The residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a yellow solid (0.017 g, 26% yield). 1H NMR (500 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.32 (d, J=7.5 Hz, 1H), 7.99 (br, 1H), 7.75-7.49 (m, 4H), 2.63 (m, 1H), 0.72-0.66 (m, 2H), 0.52-0.46 (m, 2H). LCMS (Method A): RT=5.63 min, m/z: 363.0 [M+H+]. The mixture was degassed with N2 for 10 minutes irradiated in a microwave reactor at 160° C. for 2 hours solid was removed via filtration the filtrate was concentrated under reduced pressure The residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3

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

Procedure: A solution of cyclopropyl urea (10 g, 100 mmol, 1 eq) and ethyl 3-amino-3-ethoxy-acrylate HCl (19.55 g, 100 mmol, 1 eq) in Ethanol (125 ml) was heated at 75° C. for 2 hours. To this solution was added 2 equivalents of NaOEt then heated for an additional one hour. Solvent was evaporated, water (50 ml) was added then acidified via concentrated HCl to pH of 4-5. The resulting precipitate was obtained by filtration and washed with cold water to give the desired product (9.35 g, 56%) after vacuum dried overnight at 40° C.: The desired isomer was determined via 2D-NMR; 1H NMR (400 MHz, DMSO-d6) δ 10.18 (1H), 6.10 (2H), 4.44 (1H), 2.38 (1H), 0.85 (2H), 0.62 (2H); m/z (ES+) 168.17 then heated for an additional one hour Solvent was evaporated water (50 ml) was added The resulting precipitate was obtained by filtration washed with cold water

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

Procedure: To a solution of 64 g (0.75 mol) cyanoacetic acid and 250 ml of acetic anhydride was added 70 g (0.7 mol) of cyclopropylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 76.7 g (66%) (I). This was suspended in 200 ml of hot water and 55 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals were filtered off. Yield 31.7 g (42%) (II) NMR. After cooling white crystals were filtered off washed with ethanol 55 ml of 5N NaOH was added in portions so the solution the whole time The reaction mixture was refluxed for 20 minutes After cooling white crystals were filtered off

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

Procedure: To a solution of 64 g (0.75 mol) cyanoacetic acid and 250 ml of acetic anhydride was added 70 g (0.7 mol) of cyclopropylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 76.7 g (66%) (I). This was suspended in 200 ml of hot water and 55 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals were filtered off. Yield 31.7 g (42%) (II) NMR. After cooling white crystals were filtered off washed with ethanol 55 ml of 5N NaOH was added in portions so the solution the whole time The reaction mixture was refluxed for 20 minutes After cooling white crystals were filtered off