3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine (0.100 g, 0.2162 mmol), 2-(tert-butoxycarbonyl)acetic acid (0.04544 g, 0.2594 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.06216 g, 0.3243 mmol), and N,N-dimethylpyridin-4-amine (0.002641 g, 0.02162 mmol) were dissolved in CH2Cl2 (5 mL). Triethylamine (0.04375 g, 0.4323 mmol) was added and the solution was stirred at ambient temperature for 3 hours. Water was added and the solution was extracted with CH2Cl2, dried, filtered, and concentrated. The residue was purified by silica gel (1-2% MeOH in CH2Cl2) to give the title compound (0.1116 g, 83.30% yield). 1H NMR (d6-DMSO) δ 12.35 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 6.73 (t, 1H), 4.29 (t, 1H), 3.81 (m, 3H), 3.20-3.02 (m, 2H), 2.81 (t, 1H), 2.01 (m, 2H), 1.76-1.53 (m, 2H), 1.38 (s, 9H). the solution was extracted with CH2Cl2 dried filtered concentrated The residue was purified by silica gel (1-2% MeOH in CH2Cl2)

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

Procedure: To a stirred solution of 3-tert-butoxy-3-oxopropanoic acid (680 mg, 4.25 mmol) and 2M dimethylamine in THF (3.18 mL, 6.37 mmol) in DMF (10 mL) was added diisopropyl-ethylamine (2.224 mL, 12.74 mmol), 4-(dimethylamino)pyridine (DMAP) (104 mg, 0.849 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (2421 mg, 6.37 mmol) and the resulting mixture was stirred at room temperature for 16 h. Water was then added and the resulting mixture was extracted with ethyl acetate (2×50 mL), washed with 1N HCl (20 mL), dried (Na2SO4), filtered and concentrated to give crude product which was dissolved in CH2Cl2 (5.00 mL), treated with trifluoroacetic acid (4.91 mL, 63.7 mmol) and stirred at room temperature for 16 h. The solvent was then removed under reduced pressure to afford the title compound (230 mg, 41% yield) as a light-yellow solid, which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ: 12.1 (1 H, br s), 3.4 (2 H, s), 2.9 (3 H, s), 2.8 (3 H, s). LCMS (M+H)=132.33. the resulting mixture was extracted with ethyl acetate (2×50 mL) washed with 1N HCl (20 mL) dried (Na2SO4) filtered concentrated to give crude product which stirred at room temperature for 16 h The solvent was then removed under reduced pressure

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

Procedure: 3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine (0.100 g, 0.2162 mmol), 2-(tert-butoxycarbonyl)acetic acid (0.04544 g, 0.2594 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.06216 g, 0.3243 mmol), and N,N-dimethylpyridin-4-amine (0.002641 g, 0.02162 mmol) were dissolved in CH2Cl2 (5 mL). Triethylamine (0.04375 g, 0.4323 mmol) was added and the solution was stirred at ambient temperature for 3 hours. Water was added and the solution was extracted with CH2Cl2, dried, filtered, and concentrated. The residue was purified by silica gel (1-2% MeOH in CH2Cl2) to give the title compound (0.1116 g, 83.30% yield). 1H NMR (d6-DMSO) δ 12.35 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 6.73 (t, 1H), 4.29 (t, 1H), 3.81 (m, 3H), 3.20-3.02 (m, 2H), 2.81 (t, 1H), 2.01 (m, 2H), 1.76-1.53 (m, 2H), 1.38 (s, 9H). the solution was extracted with CH2Cl2 dried filtered concentrated The residue was purified by silica gel (1-2% MeOH in CH2Cl2)

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

Procedure: 3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine (0.100 g, 0.2162 mmol), 2-(tert-butoxycarbonyl)acetic acid (0.04544 g, 0.2594 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.06216 g, 0.3243 mmol), and N,N-dimethylpyridin-4-amine (0.002641 g, 0.02162 mmol) were dissolved in CH2Cl2 (5 mL). Triethylamine (0.04375 g, 0.4323 mmol) was added and the solution was stirred at ambient temperature for 3 hours. Water was added and the solution was extracted with CH2Cl2, dried, filtered, and concentrated. The residue was purified by silica gel (1-2% MeOH in CH2Cl2) to give the title compound (0.1116 g, 83.30% yield). 1H NMR (d6-DMSO) δ 12.35 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 6.73 (t, 1H), 4.29 (t, 1H), 3.81 (m, 3H), 3.20-3.02 (m, 2H), 2.81 (t, 1H), 2.01 (m, 2H), 1.76-1.53 (m, 2H), 1.38 (s, 9H). the solution was extracted with CH2Cl2 dried filtered concentrated The residue was purified by silica gel (1-2% MeOH in CH2Cl2)

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

Procedure: 3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine (0.100 g, 0.2162 mmol), 2-(tert-butoxycarbonyl)acetic acid (0.04544 g, 0.2594 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.06216 g, 0.3243 mmol), and N,N-dimethylpyridin-4-amine (0.002641 g, 0.02162 mmol) were dissolved in CH2Cl2 (5 mL). Triethylamine (0.04375 g, 0.4323 mmol) was added and the solution was stirred at ambient temperature for 3 hours. Water was added and the solution was extracted with CH2Cl2, dried, filtered, and concentrated. The residue was purified by silica gel (1-2% MeOH in CH2Cl2) to give the title compound (0.1116 g, 83.30% yield). 1H NMR (d6-DMSO) δ 12.35 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 6.73 (t, 1H), 4.29 (t, 1H), 3.81 (m, 3H), 3.20-3.02 (m, 2H), 2.81 (t, 1H), 2.01 (m, 2H), 1.76-1.53 (m, 2H), 1.38 (s, 9H). the solution was extracted with CH2Cl2 dried filtered concentrated The residue was purified by silica gel (1-2% MeOH in CH2Cl2)

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

Procedure: A suspension of 2-(tert-butoxycarbonyl)acetic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (38 μL, 0.22 mmol) in anhydrous CH2Cl2 (0.5 mL) was stirred at RT for 10 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and anhydrous CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1 h. Activated and added another 0.5 equivalent of the acid as described above and stirred for 1 h. Activated and added another 0.3 equivalents of the acid as described above. Stirred for and additional hour and diluted with CH2Cl2. Extracted with H2O (3×) and the organic layer was dried under Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (1:1 EtOAc:Hexanes) to give the desired product tert-butyl 5-(2-(3-(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (123 mg, 0.20 mmol, 90%). The reaction mixture was stirred at RT for 1 h stirred for 1 h Stirred for and additional hour Extracted with H2O (3×) the organic layer was dried under Na2SO4 concentrated in vacuo The residue was purified by flash chromatography on silica (1:1 EtOAc:Hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flask under argon was placed (S)-2-benzyloxycarbonylamino-succinic acid 1-methyl ester (3.0 g, 10.67 mmol) and tetrahydrofuran (50 mL). To this mixture was added carbonyldiimidazole (1.90 g, 11.74 mmol) and the resulting mixture was stirred at 25° C. for 6 h. In a separate round bottom flask was placed malonic acid mono t-butyl ester (1.98 g, 11.74 mmol), tetrahydrofuran (30 mL) and magnesium ethoxide (685 mg, 5.87 mmol) and the resulting mixture stirred at 25° C. for 1 h and then concentrated in vacuo. The residue was taken up in tetrahydrofuran (15 mL) and added to the flask containing the succinic acid and carbonyldiimidazole mixture and stirred at 25° C. for 16 h. The mixture was concentrated in vacuo and partitioned between diethyl ether (200 mL) and a 0.5N aqueous hydrochloric acid solution (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (150 mL), dried over sodium sulfate and concentrated. Purification by flash column chromatography (silica gel 60, 230-400 mesh; 40% ethyl acetate/hexanes) afforded (S)-2-benzyloxycarbonylamino-4-oxo-hexanedioic acid 6-t-butyl ester 1-methyl ester (3.04 g, 75%) as a pale yellow oil. In a flask under argon was placed In a separate round bottom flask was placed concentrated in vacuo added to the flask containing the succinic acid and carbonyldiimidazole mixture stirred at 25° C. for 16 h The mixture was concentrated in vacuo partitioned between diethyl ether (200 mL) The organic layer was washed with a saturated aqueous sodium bicarbonate solution (150 mL) dried over sodium sulfate concentrated Purification by flash column chromatography (silica gel 60, 230-400 mesh; 40% ethyl acetate/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A suspension of 2-(tert-butoxycarbonyl)acetic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (38 μL, 0.22 mmol) in anhydrous CH2Cl2 (0.5 mL) was stirred at RT for 10 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and anhydrous CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1 h. Activated and added another 0.5 equivalent of the acid as described above and stirred for 1 h. Activated and added another 0.3 equivalents of the acid as described above. Stirred for and additional hour and diluted with CH2Cl2. Extracted with H2O (3×) and the organic layer was dried under Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (1:1 EtOAc:Hexanes) to give the desired product tert-butyl 5-(2-(3-(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (123 mg, 0.20 mmol, 90%). The reaction mixture was stirred at RT for 1 h stirred for 1 h Stirred for and additional hour Extracted with H2O (3×) the organic layer was dried under Na2SO4 concentrated in vacuo The residue was purified by flash chromatography on silica (1:1 EtOAc:Hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flask under argon was placed (S)-2-benzyloxycarbonylamino-succinic acid 1-methyl ester (3.0 g, 10.67 mmol) and tetrahydrofuran (50 mL). To this mixture was added carbonyldiimidazole (1.90 g, 11.74 mmol) and the resulting mixture was stirred at 25° C. for 6 h. In a separate round bottom flask was placed malonic acid mono t-butyl ester (1.98 g, 11.74 mmol), tetrahydrofuran (30 mL) and magnesium ethoxide (685 mg, 5.87 mmol) and the resulting mixture stirred at 25° C. for 1 h and then concentrated in vacuo. The residue was taken up in tetrahydrofuran (15 mL) and added to the flask containing the succinic acid and carbonyldiimidazole mixture and stirred at 25° C. for 16 h. The mixture was concentrated in vacuo and partitioned between diethyl ether (200 mL) and a 0.5N aqueous hydrochloric acid solution (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (150 mL), dried over sodium sulfate and concentrated. Purification by flash column chromatography (silica gel 60, 230-400 mesh; 40% ethyl acetate/hexanes) afforded (S)-2-benzyloxycarbonylamino-4-oxo-hexanedioic acid 6-t-butyl ester 1-methyl ester (3.04 g, 75%) as a pale yellow oil. In a flask under argon was placed In a separate round bottom flask was placed concentrated in vacuo added to the flask containing the succinic acid and carbonyldiimidazole mixture stirred at 25° C. for 16 h The mixture was concentrated in vacuo partitioned between diethyl ether (200 mL) The organic layer was washed with a saturated aqueous sodium bicarbonate solution (150 mL) dried over sodium sulfate concentrated Purification by flash column chromatography (silica gel 60, 230-400 mesh; 40% ethyl acetate/hexanes)

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

Procedure: Into a 50 mL round-bottom flask, was placed a solution of 2-(tert-butoxycarbonyl)acetic acid (899 mg, 5.14 mmol, 1.00 equiv) in dichloromethane (20 mL), EDC.HCl (1 g, 5.21 mmol, 1.10 equiv), HOBt (756 mg, 5.60 mmol, 1.10 equiv), triethylamine (1.5 g, 14.85 mmol, 3.00 equiv) and 1-(3-aminocyclobutyl)-4-(thiazol-5-yl)piperidin-4-ol (as prepared in the previous step) (1.3 g, 5.14 mmol, 1.00 equiv). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue purified by chromatography over a silica gel column with EtOAc/petroleum ether (1:1-1:10). The title compound was obtained as a white solid. Into a 50 mL round-bottom flask, was placed The resulting mixture was concentrated under vacuum The residue purified by chromatography over a silica gel column with EtOAc/petroleum ether (1:1-1:10)