N,N-diethyl-2-piperazin-1-ylethanamine

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

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

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

Procedure: EDCI (166 mg, 0.87 mmol) and HOAt (11 mg, 0.08 mmol) were added at 0° C. to a reaction mixture of 4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrole-2-carboxylic acid (252 mg, 0.79 mmol) and 1-(2-diethylaminoethyl)-piperazine (146 mg, 0.79 mmol) in DCM (5 mL) and the reaction mixture was stirred for 30 min at 0° C. and overnight at RT. After removal of the solvent, purification proceeded by means of column chromatography and the desired product [4-(2-diethylamino-ethyl)-piperazin-1-yl]-[4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrol-2-yl]-methanone (148 mg, 38% of theoretical) was obtained. After removal of the solvent, purification

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

Procedure: EDCI (166 mg, 0.87 mmol) and HOAt (11 mg, 0.08 mmol) were added at 0° C. to a reaction mixture of 4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrole-2-carboxylic acid (252 mg, 0.79 mmol) and 1-(2-diethylaminoethyl)-piperazine (146 mg, 0.79 mmol) in DCM (5 mL) and the reaction mixture was stirred for 30 min at 0° C. and overnight at RT. After removal of the solvent, purification proceeded by means of column chromatography and the desired product [4-(2-diethylamino-ethyl)-piperazin-1-yl]-[4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrol-2-yl]-methanone (148 mg, 38% of theoretical) was obtained. After removal of the solvent, purification

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 14 mg (35 mol) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid and 22 μL (approx. 120 μmol; density unknown) of 1-(2-diethylaminoethyl)-piperazine were dissolved in a mixture of 1 mL of acetonitrile and 100 μL of DMF. 14 mg (55 μmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride was added and the mixture heated gently until all materials were dissolved. The resulting solution was left at ambient temperature for 4.5 h. 28 mg (110 μmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride was added and the resulting mixture left at ambient temperature for 3.5 h, then heated to 75° C. for 3.5 h. The resulting mixture was distributed between 1 mL of a saturated aqueous solution of sodium bicarbonate in water and 2 mL of ethyl acetate. The organic phase was evaporated and the residue directly purified by mass-triggered reverse-phase HPLC to afford 3.2 mg (5.7 μmol, 17%) of {3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.80 (s, br. 1H), 8.81 (d, 1H), 8.29 (d, 1H), 7.82 (d, 1H), 7.64 (dd, 1H), 7.49-7.44 (m, 2H), 7.21 (d, 1H), 7.10 (ddd, 1H), 3.83 (s, 3H), 3.40-3.30 (m, 4H), 2.49-2.35 (m, 8H), 0.94 (t, 6H), MS: m/z 563.2 (M+H+). the mixture heated gently until all materials were dissolved the resulting mixture left at ambient temperature for 3.5 h The organic phase was evaporated the residue directly purified by mass-triggered reverse-phase HPLC

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

Procedure: 300 mg (0.564 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid, 105 mg (0.564 mmol) of 1-(2-diethylaminoethyl)piperazine, and 279 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) were combined in 3.5 mL dimethyl formamide and stirred at room temperature for 48 hours. The reaction was extracted into ethyl acetate and washed with water. The water layer was back extracted three times with ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions containing the purified intermediate were evaporated to afford 230 mg (0.329 mmol, 58% yield) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone as a white solid. 1H NMR (500 MHz, CD3CN) δ 8.59 (d, 1H), 8.09 (s, 1H), 8.09 (d, 2H), 8.01 (s, 1H), 7.61 (dd, 1H), 7.43 (m, 4H), 7.23 (d, 1H), 7.18 (d, 1H), 7.11 (t, 1H), 4.67 (s, 2H), 3.88 (s, 3H), 3.60 (s, br., 4H), 2.52 (m, 12H), 0.99 (t, 6H); MS: m/z 699.3 (M+H+). The reaction was extracted into ethyl acetate washed with water The water layer was back extracted three times with ethyl acetate The layers were separated the organic layer was dried over sodium sulfate concentrated to dryness The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes The clean fractions containing the purified intermediate were evaporated

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

Procedure: 24 mg (0.05 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid, 8.4 mg (0.05 mmol) of 1-(2-diethylaminoethyl)piperazine, and 17 mg (0.05 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) were combined in 1.0 mL dimethyl formamide and stirred at room temperature for 48 hours. To the crude reaction was added 200 μL of a 50% w/v potassium hydroxide (aqueous) solution and the mixture was stirred for 24 hours at room temperature. The reaction was neutralized by adding a few drops of acetic acid, filtered through a 0.45 μm syringe filter, and then purified by mass-triggered reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 5.0 mg (0.01 mmol, 21% yield) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone as a orange glass. 1H NMR (500 MHz, MeOD) δ 8.40 (d, 1H), 8.17 (d, 1H), 7.65 (s, 1H), 7.58 (dd, 1H), 7.42 (dd, 1H), 7.31 (t, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 7.07 (t, 1H), 3.86 (s, 3H), 3.70 (s, br., 4H), 2.58 (m, 12H), 1.09 (t, 6H). MS: m/z 545.3 (M+H+). To the crude reaction the mixture was stirred for 24 hours at room temperature filtered through a 0.45 μm syringe filter purified by mass-triggered reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 14 mg (35 mol) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid and 22 μL (approx. 120 μmol; density unknown) of 1-(2-diethylaminoethyl)-piperazine were dissolved in a mixture of 1 mL of acetonitrile and 100 μL of DMF. 14 mg (55 μmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride was added and the mixture heated gently until all materials were dissolved. The resulting solution was left at ambient temperature for 4.5 h. 28 mg (110 μmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride was added and the resulting mixture left at ambient temperature for 3.5 h, then heated to 75° C. for 3.5 h. The resulting mixture was distributed between 1 mL of a saturated aqueous solution of sodium bicarbonate in water and 2 mL of ethyl acetate. The organic phase was evaporated and the residue directly purified by mass-triggered reverse-phase HPLC to afford 3.2 mg (5.7 μmol, 17%) of {3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.80 (s, br. 1H), 8.81 (d, 1H), 8.29 (d, 1H), 7.82 (d, 1H), 7.64 (dd, 1H), 7.49-7.44 (m, 2H), 7.21 (d, 1H), 7.10 (ddd, 1H), 3.83 (s, 3H), 3.40-3.30 (m, 4H), 2.49-2.35 (m, 8H), 0.94 (t, 6H), MS: m/z 563.2 (M+H+). the mixture heated gently until all materials were dissolved the resulting mixture left at ambient temperature for 3.5 h The organic phase was evaporated the residue directly purified by mass-triggered reverse-phase HPLC