2,2-dimethylpropanedioic acid

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

Procedure: To a 500 ml. one-necked flask equipped with reflux condenser with drying tube, is added 50 grams (0.38 mole) dimethylmalonic acid (Aldrich Chemical Co.) and 300 ml. thionyl chloride. The mixture is heated to reflux for about 1 hour during which time the dimethylmalonic acid is dissolved and hydrogen chloride and sulfur dioxide are evolved. The unreacted thionyl chloride is removed by distillation under reduced pressure. The residue is recrystallized twice from cyclohexane to yield a white solid, M.P. 186°-187° C. one-necked flask equipped with reflux condenser with drying tube The mixture is heated is dissolved The unreacted thionyl chloride is removed by distillation under reduced pressure The residue is recrystallized twice from cyclohexane to yield a white solid, M.P. 186°-187° C.

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

Procedure: To a 500 ml. one-necked flask equipped with reflux condenser with drying tube, is added 50 grams (0.38 mole) dimethylmalonic acid (Aldrich Chemical Co.) and 300 ml. thionyl chloride. The mixture is heated to reflux for about 1 hour during which time the dimethylmalonic acid is dissolved and hydrogen chloride and sulfur dioxide are evolved. The unreacted thionyl chloride is removed by distillation under reduced pressure. The residue is recrystallized twice from cyclohexane to yield a white solid, M.P. 186°-187° C. one-necked flask equipped with reflux condenser with drying tube The mixture is heated is dissolved The unreacted thionyl chloride is removed by distillation under reduced pressure The residue is recrystallized twice from cyclohexane to yield a white solid, M.P. 186°-187° C.

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

Procedure: Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:NMP 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in NMP for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and NMP (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtrered and 2-(Aminomethyl)pyridine (2 eq; 6 mmol; 659 mg), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and NMP (10 mL) was added. The resin was shaken for overnigth. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr, filtered and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in NMP for 20 mins filtered the resin was shaken for 90 min at RT The resin was shaken for overnigth The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr filtered concentrated in vacuo

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

Procedure: 2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtrered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in DMF for 20 mins filtered the resin was shaken for 90 min at RT The resin was shaken for 2 days The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) the combined filtrates were collected concentrated in vacuo

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

Procedure: A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), dimethylpropanedioic acid (156 mg, 1.18 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature overnight. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layers were dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 10% methanol in DCM. The product fractions were combined and concentrated to give 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-2,2-dimethyl-3-oxopropanoic acid as a solid (165 mg, 34%). LC-MS m/z 418 (M+H)+. It was quenched with saturated NaHCO3 extracted with DCM twice The combined organic layers were washed with water wash The organic layers were dried over sodium sulfate filtered concentrated purified with CombiFlash eluting with 10% methanol in DCM concentrated

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

Procedure: To a 500 ml. one-necked flask equipped with reflux condenser with drying tube, is added 50 grams (0.38 mole) dimethylmalonic acid (Aldrich Chemical Co.) and 300 ml. thionyl chloride. The mixture is heated to reflux for about 1 hour during which time the dimethylmalonic acid is dissolved and hydrogen chloride and sulfur dioxide are evolved. The unreacted thionyl chloride is removed by distillation under reduced pressure. The residue is recrystallized twice from cyclohexane to yield a white solid, M.P. 186°-187° C. one-necked flask equipped with reflux condenser with drying tube The mixture is heated is dissolved The unreacted thionyl chloride is removed by distillation under reduced pressure The residue is recrystallized twice from cyclohexane to yield a white solid, M.P. 186°-187° C.

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

Procedure: Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:NMP 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in NMP for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and NMP (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtrered and 2-(Aminomethyl)pyridine (2 eq; 6 mmol; 659 mg), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and NMP (10 mL) was added. The resin was shaken for overnigth. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr, filtered and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in NMP for 20 mins filtered the resin was shaken for 90 min at RT The resin was shaken for overnigth The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr filtered concentrated in vacuo

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

Procedure: 2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtrered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in DMF for 20 mins filtered the resin was shaken for 90 min at RT The resin was shaken for 2 days The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) the combined filtrates were collected concentrated in vacuo

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

Procedure: Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:NMP 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in NMP for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and NMP (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtered and 2-(Aminomethyl)pyridine (2 eq; 6 mmol; 659 mg), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and NMP (10 mL) was added. The resin was shaken for overnigth. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr, filtered and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in NMP for 20 mins filtered the resin was shaken for 90 min at RT The resin was filtered The resin was shaken for overnigth The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr filtered concentrated in vacuo

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

Procedure: 2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in DMF for 20 mins filtered the resin was shaken for 90 min at RT The resin was filtered The resin was shaken for 2 days The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) the combined filtrates were collected concentrated in vacuo

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

Procedure: 2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in DMF for 20 mins filtered the resin was shaken for 90 min at RT The resin was filtered The resin was shaken for 2 days The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) the combined filtrates were collected concentrated in vacuo

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

Procedure: 2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in DMF for 20 mins filtered the resin was shaken for 90 min at RT The resin was filtered The resin was shaken for 2 days The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) the combined filtrates were collected concentrated in vacuo