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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-chloro-3-chloromethyl-4-cyclopentyloxy-2-methyl-pyridine hydrochloride salt, (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (3.0 g, 18.6 mmol), N,N-diisopropylethylamine (4.0 mL, 22.9 mmol), and anhydrous acetonitrile (50 mL) is stirred for 5 hours at 80° C. The reaction is cooled to ambient temperature and concentrated in vacuo. The obtained residue is dissolved in a mixture of hexane and ethyl:acetate (4:1, 100 mL) and filtered over a small pad of silica gel (35 g), which is subsequently rinsed with additional 100 mL of the same mixture of hexane and ethyl acetate. The filtered solution is concentrated in vacuo and the resultant residue is chromatographed on silica gel (hexane/ethyl Acetate 4:1) to afford (S)-(6-chloro-4-cyclopentyloxy-2-methyl-pyridin-3-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. 1H NMR: (CDCl3) 7.53 (m, 1H), 7.09 (m, 2H), 7.02 (m, 1H), 6.63 (s, 1H), 4.77 (m, 1H), 3.83 (d, 1H), 3.73 (dd, 1H), 3.56 (d, 1H), 2.73 (m, 2H), 2.63 (s, 3H), 2.07 (m, 2H), 2.04 (s, 3H), 1.98 (m, 2H), 1.82 (m, 4H), 1.68 (m, 4H). The reaction is cooled to ambient temperature concentrated in vacuo The obtained residue is dissolved in a mixture of hexane and ethyl:acetate (4:1, 100 mL) filtered over a small pad of silica gel (35 g), which is subsequently rinsed with additional 100 mL of the same mixture of hexane and ethyl acetate The filtered solution is concentrated in vacuo the resultant residue is chromatographed on silica gel (hexane/ethyl Acetate 4:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-chloro-3-chloromethyl-4-cyclopentyloxy-2-methyl-pyridine hydrochloride salt, (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (3.0 g, 18.6 mmol), N,N-diisopropylethylamine (4.0 mL, 22.9 mmol), and anhydrous acetonitrile (50 mL) is stirred for 5 hours at 80° C. The reaction is cooled to ambient temperature and concentrated in vacuo. The obtained residue is dissolved in a mixture of hexane and ethyl:acetate (4:1, 100 mL) and filtered over a small pad of silica gel (35 g), which is subsequently rinsed with additional 100 mL of the same mixture of hexane and ethyl acetate. The filtered solution is concentrated in vacuo and the resultant residue is chromatographed on silica gel (hexane/ethyl Acetate 4:1) to afford (S)-(6-chloro-4-cyclopentyloxy-2-methyl-pyridin-3-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. 1H NMR: (CDCl3) 7.53 (m, 1H), 7.09 (m, 2H), 7.02 (m, 1H), 6.63 (s, 1H), 4.77 (m, 1H), 3.83 (d, 1H), 3.73 (dd, 1H), 3.56 (d, 1H), 2.73 (m, 2H), 2.63 (s, 3H), 2.07 (m, 2H), 2.04 (s, 3H), 1.98 (m, 2H), 1.82 (m, 4H), 1.68 (m, 4H). The reaction is cooled to ambient temperature concentrated in vacuo The obtained residue is dissolved in a mixture of hexane and ethyl:acetate (4:1, 100 mL) filtered over a small pad of silica gel (35 g), which is subsequently rinsed with additional 100 mL of the same mixture of hexane and ethyl acetate The filtered solution is concentrated in vacuo the resultant residue is chromatographed on silica gel (hexane/ethyl Acetate 4:1)

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

Procedure: A mixture of (2,6-dichloro-3-hydroxymethyl-pyridin-4-yl)-pyrrolidin-1-yl-methanone (400 mg, 1.45 mmol) and SOCl2 (1 mL) in CH2Cl2 (10 mL) is stirred at room temperature for 1 hour, and then concentrated. The residue is treated with K2CO3 (1.0 g, 7.2 mmol), CH3CN (10 mL) and (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (250 mg, 1.55 mmol). The resulting mixture is stirred at room temperature overnight. EtOAc (50 mL) and water (40 mL) are added to the residue. The organic layer is separated, washed once with brine, dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (4:1 hexane:EtOAc) to give the title compound. concentrated The resulting mixture is stirred at room temperature overnight The organic layer is separated washed once with brine dried (Na2SO4) concentrated The residue is chromatographed on silica gel (4:1 hexane:EtOAc)

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

Procedure: A mixture of (2,6-dichloro-3-hydroxymethyl-pyridin-4-yl)-pyrrolidin-1-yl-methanone (400 mg, 1.45 mmol) and SOCl2 (1 mL) in CH2Cl2 (10 mL) is stirred at room temperature for 1 hour, and then concentrated. The residue is treated with K2CO3 (1.0 g, 7.2 mmol), CH3CN (10 mL) and (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (250 mg, 1.55 mmol). The resulting mixture is stirred at room temperature overnight. EtOAc (50 mL) and water (40 mL) are added to the residue. The organic layer is separated, washed once with brine, dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (4:1 hexane:EtOAc) to give the title compound. concentrated The resulting mixture is stirred at room temperature overnight The organic layer is separated washed once with brine dried (Na2SO4) concentrated The residue is chromatographed on silica gel (4:1 hexane:EtOAc)

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

Procedure: A mixture of 3-bromomethyl-6-(2,6-diethyl-phenyl)-4-methoxy-pyridine-2-carbonitrile (40 mg), K2CO3 (50 mg) and (S)-methyl(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (40 mg) in CH3CN (2 mL) is stirred at room temperature overnight. Hexane (5 mL) and water (5 mL) are added to the mixture. The organic layer is separated, washed, once with brine, dried (Na2SO4), and concentrated. The crude is purified by PTLC (4.1 hexane/EtOAc) to give (S)-6-(2,6-diethyl-phenyl)-4-methoxy-3-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyridine-2-carbonitrile. 1H NMR (CDCl3) 7.72 (d, 1H), 7.35 (t, 1H), 7.07-7.17 (m, 5H), 6.92 (s, 1H), 4.05 (m, 1H), 3.97 (d, 2H), 3.89 (s, 3H), 2.75 (m, 2H), 2.32 (m, 4H), 2.2 (s, 3H), 2.09 (m, 2H), 2.70-2.95 (m, 2H), 1.08 (t, 6H). The organic layer is separated washed, once with brine dried (Na2SO4) concentrated The crude is purified by PTLC (4.1 hexane/EtOAc)

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

Procedure: A mixture of 3-bromomethyl-6-(2,6-diethyl-phenyl)-4-methoxy-pyridine-2-carbonitrile (40 mg), K2CO3 (50 mg) and (S)-methyl(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (40 mg) in CH3CN (2 mL) is stirred at room temperature overnight. Hexane (5 mL) and water (5 mL) are added to the mixture. The organic layer is separated, washed, once with brine, dried (Na2SO4), and concentrated. The crude is purified by PTLC (4.1 hexane/EtOAc) to give (S)-6-(2,6-diethyl-phenyl)-4-methoxy-3-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyridine-2-carbonitrile. 1H NMR (CDCl3) 7.72 (d, 1H), 7.35 (t, 1H), 7.07-7.17 (m, 5H), 6.92 (s, 1H), 4.05 (m, 1H), 3.97 (d, 2H), 3.89 (s, 3H), 2.75 (m, 2H), 2.32 (m, 4H), 2.2 (s, 3H), 2.09 (m, 2H), 2.70-2.95 (m, 2H), 1.08 (t, 6H). The organic layer is separated washed, once with brine dried (Na2SO4) concentrated The crude is purified by PTLC (4.1 hexane/EtOAc)

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

Procedure: (1,2,3,4-Tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH4 (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 hours. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 mL) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H). On cooling The resulting mixture is stirred at room temperature for 1 hour filtered through celite concentrated in vacuo 1 N HCl (20 mL) and ether (20 mL) are added to the residue The organic layer is separated extracted with CH2Cl2 (2×25 mL) The combined extract is washed with water (2×) dried (Na2SO4) concentrated

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

Procedure: (1,2,3,4-Tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH4 (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 hours. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 mL) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H). On cooling The resulting mixture is stirred at room temperature for 1 hour filtered through celite concentrated in vacuo 1 N HCl (20 mL) and ether (20 mL) are added to the residue The organic layer is separated extracted with CH2Cl2 (2×25 mL) The combined extract is washed with water (2×) dried (Na2SO4) concentrated

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

Procedure: To a flask containing 2,4-dichloro-5-chloromethyl-6-methyl-pyrimidine (107 mg, 0.51 mmol) in absolute ETOH (10 mL) is added K2CO3 (70 mg, 1.0 eq., 0.51 mmol) and the reaction is cooled to 0° C. with an ice bath. (1S)-Methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (82 mg, 1.0 equiv, 0.51 mmol) in 1.0 mL of EtOH is added via syringe in one portion and allowed to warm to ambient temperature over 3 h. Water (50 mL) and EtOAc (50 mL) is added and the EtOAc layer is washed with water (100 mL) and brine (50 mL) and dried over Na2SO4. Concentration and vacuum drying affords the title compound as a yellow gum. [mass expected (336.26); mass found (336.30)] to warm to ambient temperature over 3 h the EtOAc layer is washed with water (100 mL) and brine (50 mL) dried over Na2SO4 Concentration and vacuum drying

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

Procedure: To a flask containing 2,4-dichloro-5-chloromethyl-6-methyl-pyrimidine (107 mg, 0.51 mmol) in absolute ETOH (10 mL) is added K2CO3 (70 mg, 1.0 eq., 0.51 mmol) and the reaction is cooled to 0° C. with an ice bath. (1S)-Methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (82 mg, 1.0 equiv, 0.51 mmol) in 1.0 mL of EtOH is added via syringe in one portion and allowed to warm to ambient temperature over 3 h. Water (50 mL) and EtOAc (50 mL) is added and the EtOAc layer is washed with water (100 mL) and brine (50 mL) and dried over Na2SO4. Concentration and vacuum drying affords the title compound as a yellow gum. [mass expected (336.26); mass found (336.30)] to warm to ambient temperature over 3 h the EtOAc layer is washed with water (100 mL) and brine (50 mL) dried over Na2SO4 Concentration and vacuum drying

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

Procedure: (1,2,3,4-Tetrahydro-naphthalen-1-yl)carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 h. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 ML) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H). On cooling The resulting mixture is stirred at room temperature for 1 hour filtered through celite concentrated in vacuo 1 N HCl (20 mL) and ether (20 ML) are added to the residue The organic layer is separated extracted with CH2Cl2 (2×25 mL) The combined extract is washed with water (2×) dried (Na2SO4) concentrated

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

Procedure: (1,2,3,4-Tetrahydro-naphthalen-1-yl)carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 h. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 ML) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H). On cooling The resulting mixture is stirred at room temperature for 1 hour filtered through celite concentrated in vacuo 1 N HCl (20 mL) and ether (20 ML) are added to the residue The organic layer is separated extracted with CH2Cl2 (2×25 mL) The combined extract is washed with water (2×) dried (Na2SO4) concentrated