(1S)-1-(4-chlorophenyl)ethanamine

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

Procedure: HATU (0.251 g, 0.66 mmol) was added in one portion to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (0.225 g, 0.6 mmol), (S)-1-(4-chlorophenyl)ethanamine (0.093 g, 0.60 mmol) and DIPEA (0.314 mL, 1.80 mmol) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using methanol. Residual HATU was removed by passing the methanol solution through a silica-supported carbonate column. The crude product thus obtained was evaporated to dryness to afford (S)-tert-butyl (4-(1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.257 g, 83%) as a colourless gum. This material was used directly in the next step without further purification. The crude product was purified by ion exchange chromatography The desired product was eluted from the column Residual HATU was removed The crude product thus obtained was evaporated to dryness

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

Procedure: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g), (S)-1-(4-chlorophenyl)ethanamine (0.140 mL) and DIPEA (0.524 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.281 g, 70.4%). 1H NMR (400.13 MHz, DMSO-d6) δ 1.37 (3H, d), 1.42-1.45 (2H, m), 1.88-2.01 (2H, m), 2.27 (2H, s), 3.49-3.59 (2H, m), 4.34-4.44 (2H, m), 4.83-4.90 (1H, m), 6.57-6.58 (1H, m), 7.14-7.16 (1H, m), 7.32-7.38 (4H, m), 8.12 (1H, s), 8.30 (1H, d), 11.62 (1H, s). The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness This crude material was then treated with a 20% solution of TFA in DCM (10 mL) stirred at room temperature The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness This material was purified by preparative LCMS Fractions containing the desired compound were evaporated to dryness

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

Procedure: A 2 L reaction flask equipped with mechanical stirring was charged with N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester (94 g, 0.244 mol), N-methyl-2-pyrrolidinone (1.0 L) and triethylamine (68 mL, 0.487 mol). To the clear solution was added drop wise (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol), keeping the internal reaction temperature below 30° C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L). After extensive mixing, the organic layer was separated, and washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL), before drying with anhydrous sodium sulphate. Solvent was removed, and the residual oil was evaporated once from acetonitrile. This product was sufficiently pure for further synthesis. Yield: 103 g (84%). A 2 L reaction flask equipped the internal reaction temperature below 30° C Stirring the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L) After extensive mixing, the organic layer was separated washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL) before drying with anhydrous sodium sulphate Solvent was removed the residual oil was evaporated once from acetonitrile This product was sufficiently pure for further synthesis

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(6-bromo-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (91, 100 mg, 0.0003 mol) and (S)-1-(4-chloro-phenyl)-ethylamine (92, 0.5 g, 0.003 mol) in N-methylpyrrolidine (3 mL) was stirred at 150° C. in microwave for 100 minutes. The reaction mixture was concentrated under vacuum and the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (P-0075, 0.03 g, 20%). MS (ESI) [M+H+]+=363.18. The reaction mixture was concentrated under vacuum the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane

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

Procedure: 8 g of tetrabutyl ortho-titanate are added to a solution of 116 g (0.72 mol) of (S)-1-(4-chlorophenyl)-ethylamine (65% ee) and 114.5 g (0.727 mol) of 4-chloroacetophenone in 500 ml of toluene at room temperature with stirring, and the mixture is then refluxed for 6 hours at the water separator. The reaction mixture is filtered, and the filtrate is evaporated under reduced pressure to give 191.3 g (91% of theory) of (S)-[1-(4-chlorophenyl)-ethyl]-[1-(4-chlorophenyl)-ethylidene]-amine. The reaction mixture is filtered the filtrate is evaporated under reduced pressure

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

Procedure: A 2 L reaction flask equipped with mechanical stirring was charged with N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester (94 g, 0.244 mmol), N-methyl-2-pyrrolidinone (1.0 L) and triethylamine (68 mL, 0.487 mol). To the clear solution was added drop wise (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol), keeping the internal reaction temperature below 30° C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L). After extensive mixing, the organic layer was separated, and washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL), before drying with anhydrous sodium sulphate. Solvent was removed, and the residual oil was evaporated once from acetonitrile. This product was sufficiently pure for further synthesis. Yield: 103 g (84%). A 2 L reaction flask equipped the internal reaction temperature below 30° C Stirring the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L) After extensive mixing, the organic layer was separated washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL) before drying with anhydrous sodium sulphate Solvent was removed the residual oil was evaporated once from acetonitrile This product was sufficiently pure for further synthesis

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

Procedure: NEt3 (60 mL) followed by (S)-1-(4-chloro-phenyl)-ethylamine (20.5 g) was added to a solution of 3-chloro-1-phenyl-propan-1-one (23.2 g) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature overnight. Then, the solution was concentrated, water (100 mL) was added to the residue, and the resulting mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with water and brine and dried (MgSO4). The title compound was obtained after removal of the solvent. Then, the solution was concentrated water (100 mL) was added to the residue the resulting mixture was extracted with tert-butyl methyl ether The combined organic extracts were washed with water and brine dried (MgSO4)

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

Procedure: NEt3 (60 mL) followed by (S)-1-(4-chloro-phenyl)-ethylamine (20.5 g) was added to a solution of 3-chloro-1-phenyl-propan-1-one (23.2 g) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature overnight. Then, the solution was concentrated, water (100 mL) was added to the residue, and the resulting mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with water and brine and dried (MgSO4). The title compound was obtained after removal of the solvent. Then, the solution was concentrated water (100 mL) was added to the residue the resulting mixture was extracted with tert-butyl methyl ether The combined organic extracts were washed with water and brine dried (MgSO4)

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

Procedure: HATU (0.251 g, 0.66 mmol) was added in one portion to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (0.225 g, 0.6 mmol), (S)-1-(4-chlorophenyl)ethanamine (0.093 g, 0.60 mmol) and DIPEA (0.314 mL, 1.80 mmol) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using methanol. Residual HATU was removed by passing the methanol solution through a silica-supported carbonate column. The crude product thus obtained was evaporated to dryness to afford (S)-tert-butyl (4-(1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.257 g, 83%) as a colourless gum. This material was used directly in the next step without further purification. The crude product was purified by ion exchange chromatography The desired product was eluted from the column Residual HATU was removed The crude product thus obtained was evaporated to dryness

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

Procedure: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g), (S)-1-(4-chlorophenyl)ethanamine (0.140 mL) and DIPEA (0.524 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.281 g, 70.4%). 1H NMR (400.13 MHz, DMSO-d6) δ 1.37 (3H, d), 1.42-1.45 (2H, m), 1.88-2.01 (2H, m), 2.27 (2H, s), 3.49-3.59 (2H, m), 4.34-4.44 (2H, m), 4.83-4.90 (1H, m), 6.57-6.58 (1H, m), 7.14-7.16 (1H, m), 7.32-7.38 (4H, m), 8.12 (1H, s), 8.30 (1H, d), 11.62 (1H, s). The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness This crude material was then treated with a 20% solution of TFA in DCM (10 mL) stirred at room temperature The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness This material was purified by preparative LCMS Fractions containing the desired compound were evaporated to dryness

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

Procedure: A 2 L reaction flask equipped with mechanical stirring was charged with N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester (94 g, 0.244 mol), N-methyl-2-pyrrolidinone (1.0 L) and triethylamine (68 mL, 0.487 mol). To the clear solution was added drop wise (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol), keeping the internal reaction temperature below 30° C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L). After extensive mixing, the organic layer was separated, and washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL), before drying with anhydrous sodium sulphate. Solvent was removed, and the residual oil was evaporated once from acetonitrile. This product was sufficiently pure for further synthesis. Yield: 103 g (84%). A 2 L reaction flask equipped the internal reaction temperature below 30° C Stirring the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L) After extensive mixing, the organic layer was separated washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL) before drying with anhydrous sodium sulphate Solvent was removed the residual oil was evaporated once from acetonitrile This product was sufficiently pure for further synthesis

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

Procedure: A 2 L reaction flask equipped with mechanical stirring was charged with N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester (94 g, 0.244 mol), N-methyl-2-pyrrolidinone (1.0 L) and triethylamine (68 mL, 0.487 mol). To the clear solution was added drop wise (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol), keeping the internal reaction temperature below 30° C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L). After extensive mixing, the organic layer was separated, and washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL), before drying with anhydrous sodium sulphate. Solvent was removed, and the residual oil was evaporated once from acetonitrile. This product was sufficiently pure for further synthesis. Yield: 103 g (84%). A 2 L reaction flask equipped the internal reaction temperature below 30° C Stirring the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L) After extensive mixing, the organic layer was separated washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL) before drying with anhydrous sodium sulphate Solvent was removed the residual oil was evaporated once from acetonitrile This product was sufficiently pure for further synthesis