(1S)-N-methyl-1-phenylethanamine

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Naphthaldehyde (2.7 mL, 20 mmol), (S)-(−)-N,α-dimetylbenzylamine (2.60 g, 19 mmol) and 2-naphthol (2.43 g, 16 mmol) are charged into a 25 mL flask with a magnetic stirring bar. The mixture is heated to 85° C. and stirred for 72 h. After the system is cooled to RT, MeOH (5 mL) is added and the precipitated product is collected by filtration, washed with MeOH (5 mL) and dried to afford 1-{(S)-[methyl-((S)-1-phenyl-ethyl)-amino]-naphthalen-1-yl-methyl}-naphthalen-2-ol as white crystals (about 51% yield): 1H NMR (500 MHz, CDCl3) δ 14.01 (br s, 1H), 7.77-7.02 (m, 18H), 6.45 (s, 1H), 4.40 (br s, 1H), 1.95 (s, 3H), 1.65 (br s, 3H); MS (EI) m/z (rel intensity) 418 (M++1), 283, 141, 136; HRMS (EI) Calcd for C30H28NO (M++1): 418.2171, found 418.2135. After the system is cooled to RT the precipitated product is collected by filtration washed with MeOH (5 mL) dried

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Naphthaldehyde (2.7 mL, 20 mmol), (S)-(−)-N,α-dimetylbenzylamine (2.60 g, 19 mmol) and 2-naphthol (2.43 g, 16 mmol) are charged into a 25 mL flask with a magnetic stirring bar. The mixture is heated to 85° C. and stirred for 72 h. After the system is cooled to RT, MeOH (5 mL) is added and the precipitated product is collected by filtration, washed with MeOH (5 mL) and dried to afford 1-{(S)-[methyl-((S)-1-phenyl-ethyl)-amino]-naphthalen-1-yl-methyl}-naphthalen-2-ol as white crystals (about 51% yield): 1H NMR (500 MHz, CDCl3) δ 14.01 (br s, 1H), 7.77-7.02 (m, 18H), 6.45 (s, 1H), 4.40 (br s, 1H), 1.95 (s, 3H), 1.65 (br s, 3H); MS (EI) m/z (rel intensity) 418 (M++1), 283, 141, 136; HRMS (EI) Calcd for C30H28NO (M++1): 418.2171, found 418.2135. After the system is cooled to RT the precipitated product is collected by filtration washed with MeOH (5 mL) dried

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

Procedure: According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (S)-N,α-dimethylbenzylamine: yield 54%.

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

Procedure: A solution of ethyl 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (1.5 g, 6.6 mmol) and (S)-N-methyl-1-phenylethanamine (3.6 g, 26.4 mmol) in 20 mL of CH3CN was heated to reflux and stirred for 36 h. When cooled to room temperature, the reaction mixture was concentrated in vacuum, and the residue was purified by flash chromatography eluting with DCM/EA=5:1 to give product (S)-ethyl 6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate as a yellow oil (0.7 g, 32%). LRMS (M+H+) m/z: calcd 326.16; found 326. 1H NMR (300 MHz, CDCl3): δ 8.02-7.99 (d, J=9 Hz, 1H), 7.36-7.26 (m, 5H), 7.09-7.06 (d, J=9 Hz, 1H), 5.82-5.75 (q, 1H), 4.57-4.50 (q, 2H), 2.94 (s, 3H), 1.68-1.65 (d, 3H), 1.48-1.44 (t, 3H). to reflux the reaction mixture was concentrated in vacuum the residue was purified by flash chromatography eluting with DCM/EA=5:1

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of compound methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol) in anhydrous DMSO (20 mL) was stirred for 30 min at 130° C. under microwave condition. After cooled to room temperature, the mixture was diluted with EA (100 mL) and washed with H2O (100 mL*3). The organic layer was dried over Na2SO4, concentrated in vacuum and purified by flash column chromatography (silica-gel, DCM: MeOH=10:1) to give product (S)-methyl 3-methyl-6-(methyl (1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate as a yellow oil (400 mg, 14.5%). LRMS (M+H+) m/z: calcd 326; found 326. After cooled to room temperature washed with H2O (100 mL*3) The organic layer was dried over Na2SO4 concentrated in vacuum purified by flash column chromatography (silica-gel, DCM: MeOH=10:1)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of compound methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol) in anhydrous DMSO (20 mL) was stirred for 30 min at 130° C. under microwave condition. After cooled to room temperature, the mixture was diluted with EA (100 mL) and washed with H2O (100 mL*3). The organic layer was dried over Na2SO4, concentrated in vacuum and purified by flash column chromatography (silica-gel, DCM: MeOH=10:1) to give product (S)-methyl 3-methyl-6-(methyl (1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate as a yellow oil (400 mg, 14.5%). LRMS (M+H+) m/z: calcd 326; found 326. After cooled to room temperature washed with H2O (100 mL*3) The organic layer was dried over Na2SO4 concentrated in vacuum purified by flash column chromatography (silica-gel, DCM: MeOH=10:1)

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

Procedure: A solution of methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol; commercially available from Aldrich) in DMSO (20 mL) was heated at 130° C. in a microwave tube for 30 min. Water (100 mL) was added to the reaction mixture, and the product was extracted with EtOAc (3×100 mL). The combined EtOAc layers were concentrated and the residue was purified by flash chromatography (silica gel, 1% to 10% MeOH in CH2Cl2) to give the (S)-methyl 3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (400 mg, 15% yield). LRMS [M+H]+: 325 m/z. the product was extracted with EtOAc (3×100 mL) The combined EtOAc layers were concentrated the residue was purified by flash chromatography (silica gel, 1% to 10% MeOH in CH2Cl2)

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

Procedure: A solution of methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol; commercially available from Aldrich) in DMSO (20 mL) was heated at 130° C. in a microwave tube for 30 min. Water (100 mL) was added to the reaction mixture, and the product was extracted with EtOAc (3×100 mL). The combined EtOAc layers were concentrated and the residue was purified by flash chromatography (silica gel, 1% to 10% MeOH in CH2Cl2) to give the (S)-methyl 3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (400 mg, 15% yield). LRMS [M+H]+: 325 m/z. the product was extracted with EtOAc (3×100 mL) The combined EtOAc layers were concentrated the residue was purified by flash chromatography (silica gel, 1% to 10% MeOH in CH2Cl2)

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

Procedure: 6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.712 mmol; commercially available or prepared according to patent WO2006/039325A2), (S)-N-methyl-1-phenylethanamine (385 mg, 2.85 mmol) and anhydrous NMP (1 mL) were charged into a microwave tube equipped with a magnetic stirbar. After the vessel was sealed, the mixture was heated at 200° C. for 60 min using microwave irradiation. The reaction was purified by normal phase chromatography (10% CH2Cl2 in hexane then a gradient of 0% to 20% MeOH in CH2Cl2) and by reverse phase chromatography before being lyophilized to give the (S)-N,3-dimethyl-N-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (Compound 3) as an off-white solid (69 mg; 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=10.1 Hz, 1H), 7.25-7.39 (m, 6H), 5.71 (q, J=6.9 Hz, 1H), 2.84 (s, 3H), 2.54 (s, 3H), 1.58 (d, J=6.9 Hz, 3H). LRMS [M+H]+: 268 m/z. commercially available or prepared were charged into a microwave tube equipped with a magnetic stirbar After the vessel was sealed microwave irradiation The reaction was purified by normal phase chromatography (10% CH2Cl2 in hexane

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

Procedure: In an analogous fashion to example 1, N-methyl-N-[(1S)-1-phenylethyl]amine (0.27 g, 2.0 mmol) was condensed with 2,6-dichloropyrazine (0.36 g, 2.4 mmol), to furnish the desired product as a light brown solid (192 mg, 39%).

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

Procedure: In an analogous fashion to example 1, N-methyl-N-[(1S)-1-phenylethyl]amine (0.27 g, 2.0 mmol) was condensed with 2,6-dichloropyrazine (0.36 g, 2.4 mmol), to furnish the desired product as a light brown solid (192 mg, 39%).

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

Procedure: In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-methyl-N-((S)-1-phenyl-ethyl)amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C45H54Cl2N5O3 [(M+H)+] 782.3598, observed 782.3596.