2-chloro-N-cyclopropylacetamide

Conditions: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-N-cyclopropylacetamide (20 g, 0.15 moles) was added in portions with stirring to triethyl phosphite (28 g, 0.17 moles, Aldrich) at 110° C. The solution was then heated to 155° C. for 30 minutes, cooled to 125° C., and the volatiles were removed by distillation under aspirator vacuum (15 mm Hg) at this temperature. The residual oil was stirred with pentane (200 mL) while cooling in an ice bath to induce crystallization. Filtration gave 5.2 g (14%) of diethyl((cyclopropylcarbamoyl)methyl)phosphonate as white crystals; m.p. 51°-56° C. The liquor was concentrated and cooled to give 25.3 g (71%) of a second crop; m.p. 50°-56° C. Recrystallization from dichloromethane/hexanes gave the analytical sample, m.p. 55°-57° C. cooled to 125° C. the volatiles were removed by distillation under aspirator vacuum (15 mm Hg) at this temperature while cooling in an ice bath crystallization Filtration

Conditions: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-N-cyclopropylacetamide (20 g, 0.15 moles) was added in portions with stirring to triethyl phosphite (28 g, 0.17 moles, Aldrich) at 110° C. The solution was then heated to 155° C. for 30 minutes, cooled to 125° C., and the volatiles were removed by distillation under aspirator vacuum (15 mm Hg) at this temperature. The residual oil was stirred with pentane (200 mL) while cooling in an ice bath to induce crystallization. Filtration gave 5.2 g (14%) of diethyl((cyclopropylcarbamoyl)methyl)phosphonate as white crystals; m.p. 51°-56° C. The liquor was concentrated and cooled to give 25.3 g (71%) of a second crop; m.p. 50°-56° C. Recrystallization from dichloromethane/hexanes gave the analytical sample, m.p. 55°-57° C. cooled to 125° C. the volatiles were removed by distillation under aspirator vacuum (15 mm Hg) at this temperature while cooling in an ice bath crystallization Filtration

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

Procedure: To a solution of 2-chloro-N-cyclopropyl-acetamide (58.1 g, 0.435 mol) in dichloromethane (700 ml) at 0° C. is added thiolactic acid (49.65 g, 0.652 mol). The mixture is stirred at 0° C. for 5 minutes, then TEA (88.0 g, 0.870 mol) is added very slowly (exothermic reaction). The mixture is stirred at 0° C. for 2 hours, then poured over 700 ml of water with stirring. The aqueous layer is acidified to pH2 with 5 N HCl, and the layers are shaken and separated. The aqueous layer is extracted with dichloromethane (2×400 ml). The combined organic layers are washed with brine, then dried (anhydrous magnesium sulfate), filtered, and concentrated to give the title compound as a yellow-orange solid (74.5 g, 99%). Mass (m/z): 174.1 (M++1). (exothermic reaction) The mixture is stirred at 0° C. for 2 hours with stirring the layers are shaken separated The aqueous layer is extracted with dichloromethane (2×400 ml) The combined organic layers are washed with brine dried (anhydrous magnesium sulfate) filtered concentrated

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

Procedure: To a solution of 2-chloro-N-cyclopropyl-acetamide (58.1 g, 0.435 mol) in dichloromethane (700 ml) at 0° C. is added thiolactic acid (49.65 g, 0.652 mol). The mixture is stirred at 0° C. for 5 minutes, then TEA (88.0 g, 0.870 mol) is added very slowly (exothermic reaction). The mixture is stirred at 0° C. for 2 hours, then poured over 700 ml of water with stirring. The aqueous layer is acidified to pH2 with 5 N HCl, and the layers are shaken and separated. The aqueous layer is extracted with dichloromethane (2×400 ml). The combined organic layers are washed with brine, then dried (anhydrous magnesium sulfate), filtered, and concentrated to give the title compound as a yellow-orange solid (74.5 g, 99%). Mass (m/z): 174.1 (M++1). (exothermic reaction) The mixture is stirred at 0° C. for 2 hours with stirring the layers are shaken separated The aqueous layer is extracted with dichloromethane (2×400 ml) The combined organic layers are washed with brine dried (anhydrous magnesium sulfate) filtered concentrated

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

Procedure: Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-cyclopropylacetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (3.9 mg) was obtained. purified by LC-MS

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

Procedure: Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (37 mg) and 2-chloro-N-cyclopropylacetamide (19 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (2.2 mg) was obtained. purified by LC-MS

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

Procedure: Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (37 mg) and 2-chloro-N-cyclopropylacetamide (19 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (2.2 mg) was obtained. purified by LC-MS

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

Procedure: Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 2-chloro-N-cyclopropylacetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (10 mg) was obtained. purified by LC-MS

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg), 2-chloro-N-cyclopropylacetamide (13 mg), cesium carbonate (32 mg), potassium iodide (5.0 mg) and tetrahydrofuran (2 ml) was stirred for 5 hours at 60° C. To the reaction solution was added dropwise borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (0.49 ml), and the solution was stirred at 60° C. for one day and one night. The reaction solution was cooled to room temperature, concentrated hydrochloric acid (0.08 ml) was added thereto, the solution was stirred for 1.5 hours at 60° C., then an aqueous solution of 5N sodium hydroxide (1 ml) was added thereto, and the solution was stirred for 8 hours at 60° C. The reaction solution was diluted with water, then extracted with ethyl acetate. The organic layer was concentrated under a nitrogen stream; purified from a solution of the resulting residue in N,N-dimethylformamide by LC-MS, the title compound (9.0 mg) was obtained. the solution was stirred at 60° C. for one day and one night The reaction solution was cooled to room temperature the solution was stirred for 1.5 hours at 60° C. the solution was stirred for 8 hours at 60° C extracted with ethyl acetate The organic layer was concentrated under a nitrogen stream purified from a solution of the resulting residue in N,N-dimethylformamide by LC-MS

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg), 2-chloro-N-cyclopropylacetamide (13 mg), cesium carbonate (32 mg), potassium iodide (5.0 mg) and tetrahydrofuran (2 ml) was stirred for 5 hours at 60° C. To the reaction solution was added dropwise borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (0.49 ml), and the solution was stirred at 60° C. for one day and one night. The reaction solution was cooled to room temperature, concentrated hydrochloric acid (0.08 ml) was added thereto, the solution was stirred for 1.5 hours at 60° C., then an aqueous solution of 5N sodium hydroxide (1 ml) was added thereto, and the solution was stirred for 8 hours at 60° C. The reaction solution was diluted with water, then extracted with ethyl acetate. The organic layer was concentrated under a nitrogen stream; purified from a solution of the resulting residue in N,N-dimethylformamide by LC-MS, the title compound (9.0 mg) was obtained. the solution was stirred at 60° C. for one day and one night The reaction solution was cooled to room temperature the solution was stirred for 1.5 hours at 60° C. the solution was stirred for 8 hours at 60° C extracted with ethyl acetate The organic layer was concentrated under a nitrogen stream purified from a solution of the resulting residue in N,N-dimethylformamide by LC-MS

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

Procedure: To (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (110 mg, 0.39 mM) in 5 mL DMF was added 48.2 uL (1.06 eq) 2,6-lutidine and N1-cyclopropyl-2-chloroacetamide (1.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 6.5 mg of 382 after RP-HPLC purification (40% yield). MS (Q1) 464.3 (M)+ Complete reaction the reaction was concentrated in vacuo

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

Procedure: To (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (110 mg, 0.39 mM) in 5 mL DMF was added 48.2 uL (1.06 eq) 2,6-lutidine and N1-cyclopropyl-2-chloroacetamide (1.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 6.5 mg of 382 after RP-HPLC purification (40% yield). MS (Q1) 464.3 (M)+ Complete reaction the reaction was concentrated in vacuo