(1S)-1,2,3,4-tetrahydronaphthalen-1-amine

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

Procedure: (S)-1,2,3,4-tetrahydro-1-naphthylamine (26.9 g.) is dissolved in 200 ml. of toluene and 36 g. of acetic anhydride is added while the temperature from the reaction exotherm is moderated at 50° C. to 60° C. with an ice-bath. The solution is heated to reflux for 0.5 hr. and then stirred at room temperature overnight. The mixture is then evaporated to dryness and the residue is washed well with ether. On drying, 26.1 g. of the title compound, m.p. 153° C. to 155° C., is obtained. is moderated at 50° C. to 60° C. with an ice-bath The solution is heated to reflux for 0.5 hr The mixture is then evaporated to dryness the residue is washed well with ether On drying

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

Procedure: Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×TO mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid. the mixture is extracted with ether (2×100 mL) The combined extract is washed with 1 N HCl (2×TO mL), water dried (Na2SO4) concentrated in vacuo

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

Procedure: Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×TO mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid. the mixture is extracted with ether (2×100 mL) The combined extract is washed with 1 N HCl (2×TO mL), water dried (Na2SO4) concentrated in vacuo

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

Procedure: Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×10 mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid. the mixture is extracted with ether (2×100 mL) The combined extract is washed with 1 N HCl (2×10 mL), water dried (Na2SO4) concentrated in vacuo

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

Procedure: Ethyl trifluoroacetate (24.2 mL, 204 mmol) was added dropwise to a solution of (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (Alfa Aesar; 25.0 g, 170 mmol) and triethylamine (35.5 mL, 255 mmol) in MeOH (250 mL) at RT and stirred for 18 h. The mixture was concentrated to approximately ⅓ of its volume and then partitioned between DCM (200 mL) and water (200 mL). The aqueous layer was extracted into DCM (3×) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound (41.1 g, 169 mmol, 99%). 1H NMR (400 MHz, CDCl3): 1.80-1.95 (3H, m), 2.05-2.15 (1H, m), 2.75-2.90 (2H, m), 5.18-5.25 (1H, q, J 5.0 Hz), 6.38-6.48 (1H, br s), 7.12-7.16 (1H, m), 7.20-7.26 (3H, m). The mixture was concentrated to approximately ⅓ of its volume partitioned between DCM (200 mL) and water (200 mL) The aqueous layer was extracted into DCM (3×) the combined organic layers were washed with brine dried (MgSO4) concentrated in vacuo

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

Procedure: Ethyl trifluoroacetate (24.2 mL, 204 mmol) was added dropwise to a solution of (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (Alfa Aesar; 25.0 g, 170 mmol) and triethylamine (35.5 mL, 255 mmol) in MeOH (250 mL) at RT and stirred for 18 h. The mixture was concentrated to approximately ⅓ of its volume and then partitioned between DCM (200 mL) and water (200 mL). The aqueous layer was extracted into DCM (3×) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound (41.1 g, 169 mmol, 99%). 1H NMR (400 MHz, CDCl3): 1.80-1.95 (3H, m), 2.05-2.15 (1H, m), 2.75-2.90 (2H, m), 5.18-5.25 (1H, q, J 5.0 Hz), 6.38-6.48 (1H, br s), 7.12-7.16 (1H, m), 7.20-7.26 (3H, m). The mixture was concentrated to approximately ⅓ of its volume partitioned between DCM (200 mL) and water (200 mL) The aqueous layer was extracted into DCM (3×) the combined organic layers were washed with brine dried (MgSO4) concentrated in vacuo

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

Procedure: A solution of 550 mg of 2-(2-(3-(methyl(2-morpholinoethyl)carbamoyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid, 142 mg of (S)-1,2,3,4-tetrahydronaphthalen-1-amine, and 497 mg of diisopropylethylamine in 6 mL of DMF was treated with 366 mg of HATU. After stirring for 2 h the product was isolated by reverse phase HPLC, eluting with 0.05% TFA in a water/acetonitrile gradient. The procedure gave 220 mg of product. was isolated by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient

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

Procedure: Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×10 mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid. the mixture is extracted with ether (2×100 mL) The combined extract is washed with 1 N HCl (2×10 mL), water dried (Na2SO4) concentrated in vacuo

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

Procedure: Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×10 mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid. the mixture is extracted with ether (2×100 mL) The combined extract is washed with 1 N HCl (2×10 mL), water dried (Na2SO4) concentrated in vacuo

Conditions: temp:23.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The ethyl acetate solution of racemic N-t-butyloxycarbonyl-3-azabicyclo[3.3.0]octane-2-carboxylic acid from Example 2, Method 2, was added to a solution of (S)-1,2,3,4-tetrahydro-1-naphthylamine (56.7 g, 0.385 mol) in ethyl acetate (300 mL). The mixture was stirred for 3-4 hours at 22-25° C., then filtered, and the solids washed with ethyl acetate (200 mL). The product was dried at 20-30° C. under vacuum for 4 hours to give the title compound. filtered the solids washed with ethyl acetate (200 mL) The product was dried at 20-30° C. under vacuum for 4 hours

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

Procedure: (S)-1,2,3,4-tetrahydro-1-naphthylamine (26.9 g.) is dissolved in 200 ml. of toluene and 36 g. of acetic anhydride is added while the temperature from the reaction exotherm is moderated at 50° C. to 60° C. with an ice-bath. The solution is heated to reflux for 0.5 hr. and then stirred at room temperature overnight. The mixture is then evaporated to dryness and the residue is washed well with ether. On drying, 26.1 g. of the title compound, m.p. 153° C. to 155° C., is obtained. is moderated at 50° C. to 60° C. with an ice-bath The solution is heated to reflux for 0.5 hr The mixture is then evaporated to dryness the residue is washed well with ether On drying

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

Procedure: Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×TO mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid. the mixture is extracted with ether (2×100 mL) The combined extract is washed with 1 N HCl (2×TO mL), water dried (Na2SO4) concentrated in vacuo