(1R)-1-(4-chlorophenyl)ethanamine

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 (1.255 g, 3.30 mmol) was added in one portion to 1-(tert-butoxycarbonyl)-4-cyanopiperidine-4-carboxylic acid (Intermediate 43) (0.763 g, 3 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.462 mL, 3.00 mmol) and DIPEA (1.572 mL, 9.00 mmol) in DMA (20 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (150 mL), and washed sequentially with 1M aqueous citric acid (50 mL), water (50 mL), and saturated sodium hydrogen carbonate (100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product thus obtained was concentrated, then purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to afford (R)-tert-butyl 4-(1-(4-chlorophenyl)ethylcarbamoyl)-4-cyanopiperidine-1-carboxylate (1.100 g, 94%) as a colourless gum which solidified on drying under high vacuum. This material was then redissolved in DCM (20.00 mL), and trifluoroacetic acid (2.311 mL, 30.00 mmol) was added. The solution was stirred at room temperature for 3 hours, after which the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyanopiperidine-4-carboxamide (0.720 g, 82%) as a colourless gum. This material was used directly in the next step without further purification. The reaction mixture was evaporated to dryness redissolved in DCM (150 mL) washed sequentially with 1M aqueous citric acid (50 mL), water (50 mL), and saturated sodium hydrogen carbonate (100 mL) The organic layer was dried over magnesium sulfate filtered evaporated to afford crude product The crude product thus obtained was concentrated purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane Pure fractions were evaporated

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, 1.10 mmol) 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, 1 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.156 g, 1.00 mmol) and DIPEA (0.524 mL, 3.00 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 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude material was treated with a 10% solution of TFA in DCM (5 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 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.211 g, 52.9%) as a white solid. The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness The crude material was treated with a 10% solution of TFA in DCM (5 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 The crude product was purified by preparative LCMS Fractions containing the desired compound were evaporated to dryness

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of K2CO3 (1.5 eq.) and (R)-1-(4-chloro-phenyl)-ethylamine (0.9 eq.) in MeCN was added 4-bromo-butyric acid methyl ester (1 eq.) and KI (0.1 eq.). The reaction was stirred for 15 h at 20° C., then heated to reflux until completion. The crude was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 99/1 to 90/10) to afford 4-[(R)-1-(4-chloro-phenyl)-ethylamino]-butyric acid methyl ester. heated to reflux until completion The crude was partitioned between water and EtOAc The organic layer was washed with brine dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 99/1 to 90/10)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Two 20 mL microwave vials were charged with a half portion of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.50 g, 13.5 mmol), (R)-1-(4-chloro-phenyl)-ethylamine (4.20 g, 27.0 mmol), N,N-diisopropylethylamine (4.7 mL, 27 mmol) and acetonitrile (20 mL); and the mixture was heated in a microwave at 200° C. for 2.5 h. The mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 (100 mL) and ethyl acetate (20 mL), washed with 0.5 M aq. NaH2PO4 (pH 4, 100 mL), dried (Na2SO4), and concentrated. The residue was purified on silica gel column (0-5% MeOH/CH2Cl2) to give a pale yellow foam (4.46 g). The mixture was concentrated in vacuo ethyl acetate (20 mL), washed with 0.5 M aq. NaH2PO4 (pH 4, 100 mL) dried (Na2SO4) concentrated The residue was purified on silica gel column (0-5% MeOH/CH2Cl2)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Two 20 mL microwave vials were charged with a half portion of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.50 g, 13.5 mmol), (R)-1-(4-chloro-phenyl)-ethylamine (4.20 g, 27.0 mmol), N,N-diisopropylethylamine (4.7 mL, 27 mmol) and acetonitrile (20 mL); and the mixture was heated in a microwave at 200° C. for 2.5 h. The mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 (100 mL) and ethyl acetate (20 mL), washed with 0.5 M aq. NaH2PO4 (pH 4, 100 mL), dried (Na2SO4), and concentrated. The residue was purified on silica gel column (0-5% MeOH/CH2Cl2) to give a pale yellow foam (4.46 g). The mixture was concentrated in vacuo ethyl acetate (20 mL), washed with 0.5 M aq. NaH2PO4 (pH 4, 100 mL) dried (Na2SO4) concentrated The residue was purified on silica gel column (0-5% MeOH/CH2Cl2)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A glass microwave reaction vessel was charged with 1-chloro-6-methyl-5-nitroisoquinoline (0.22 g, 1.0 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.31 g, 2.0 mmol), 2,2,2-trifluoroacetic acid (0.011 g, 0.10 mmol) and isopropanol (1 mL). The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 60 min. The reaction mixture was diluted with chloroform, washed with 10% sodium carbonate, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel eluting with 20% ethyl acetate/hexane to give (R)-N-(1-(4-chlorophenyl)ethyl)-6-methyl-5-nitroisoquinolin-1-amine as a solid. MS Found: (ESI pos. ion) m/z 342 (M+H+). A glass microwave reaction vessel washed with 10% sodium carbonate dried over sodium sulfate concentrated The crude product was chromatographed on silica gel eluting with 20% ethyl acetate/hexane

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A glass microwave reaction vessel was charged with 1-chloro-6-methyl-5-nitroisoquinoline (0.22 g, 1.0 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.31 g, 2.0 mmol), 2,2,2-trifluoroacetic acid (0.011 g, 0.10 mmol) and isopropanol (1 mL). The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 60 min. The reaction mixture was diluted with chloroform, washed with 10% sodium carbonate, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel eluting with 20% ethyl acetate/hexane to give (R)-N-(1-(4-chlorophenyl)ethyl)-6-methyl-5-nitroisoquinolin-1-amine as a solid. MS Found: (ESI pos. ion) m/z 342 (M+H+). A glass microwave reaction vessel washed with 10% sodium carbonate dried over sodium sulfate concentrated The crude product was chromatographed on silica gel eluting with 20% ethyl acetate/hexane

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

Procedure: 0.3 g of zinc chloride is added to a solution of 20 g (0.128 mol) of (R)-1-(4-chlorophenyl)-ethylamine (97% ee) and 15.6 g (0.13 mol) of acetophenone in 70 ml of toluene at room temperature with stirring, and the mixture is then refluxed for 74 hours at the water separator. The reaction mixture is then filtered. The filtrate is evaporated under reduced pressure to give 15.56 g (47% of theory) of (R)-[1-(4-chlorophenyl)-ethyl]-[1-phenyl-ethylidene]-amine. The reaction mixture is then filtered The filtrate is evaporated under reduced pressure

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

Procedure: 3 g of tetrabutyl ortho-titanate are added to a solution of 52 g (0.35 mol) of (R)-1-(4-chlorophenyl)-ethylamine (97% ee) and 51.7 g (0.353 mol) of 4-chloroacetophenone in 300 ml of toluene at room temperature with stirring, and then the mixture is refluxed for 2 hours at the water separator. A further 2 g of tetrabutyl ortho-titanate are added, and the mixture is refluxed for a further 6 hours. A further 2 g of tetrabutyl ortho-titanate are then added, and the mixture is then refluxed for 3 hours. The reaction mixture is then filtered. The filtrate is evaporated under reduced pressure to give 67.3 g (66% of theory) of (R)-[1-(4-chlorophenyl)-ethyl]-[1-(4-chlorophenyl)-ethylidene]-amine. the mixture is refluxed for a further 6 hours the mixture is then refluxed for 3 hours The reaction mixture is then filtered The filtrate is evaporated under reduced pressure

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

Procedure: In a manner similar to that described previously (Example 1), 2-amino-5-bromopyridine-3-carboxaldehyde was sequentially reacted with 7-(4-fluorophenyl)-7-oxoheptanoic acid and TFAA-tBuOH. The resulting ester 6B was converted to 6C, coupled with (R)-1-(4-chlorophenyl)ethanamine, and deprotected with TFA to provide the title compound, 6-[[[1(R)-(4-chlorophenyl)ethyl]amino]carbonyl]-2-(4-fluorophenyl)-1,8-naphthyridine-3-pentanoic acid, 6. LCMS (M+H)=506.

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

Procedure: In a manner similar to that described previously (Example 1), 2-amino-5-bromopyridine-3-carboxaldehyde was sequentially reacted with 7-(4-fluorophenyl)-7-oxoheptanoic acid and TFAA-tBuOH. The resulting ester 6B was converted to 6C, coupled with (R)-1-(4-chlorophenyl)ethanamine, and deprotected with TFA to provide the title compound, 6-[[[1(R)-(4-chlorophenyl)ethyl]amino]carbonyl]-2-(4-fluorophenyl)-1,8-naphthyridine-3-pentanoic acid, 6. LCMS (M+H)=506.

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

Procedure: In a manner similar to that described previously (Example 1), 2-amino-5-bromobenzaldehyde was sequentially reacted with 7-(4-fluorophenyl)-7-oxoheptanoic acid and TFAA-tBuOH. The resulting ester 5B was converted to 5C (Pd(OAc)2, dcpp-2(HBF)4, K2CO3, 5 atm CO, H2O-DMF, 100° C. overnight), coupled with (R)-1-(4-chlorophenyl)ethanamine (HATU, DIPEA) and deprotected with TFA to provide the title compound, 6-[[[1(R)-(4-chlorophenyl)ethyl]amino]carbonyl]-2-(4-fluorophenyl)-3-quinolinepentanoic acid, 5. LCMS (M+H)=505.