2-Chloro-6-methoxy-4-trifluoromethyl-pyridine

To a solution of 2, 6-dichloro-4-(trifluoromethyl)pyridine (2.0 g) in dry methanol (40 ml) was added a solution of sodium hydroxide (1.85 g) in dry methanol (7ml) and the reaction mixture stirred at 50°C under nitrogen for two hours then allowed to cool. The reaction mixture was extracted with pentane (2 x 100 ml), and the extract combined and evaporated to afford the title compound (1.69 g) as a colourless oil. LCMS: Rt 1.75 min, m/z 212/214 [M+H]To a solution of 2, 6-dichloro-4-(trifluoromethyl)pyridine (2 g, 9.26 mmol) in MeOH (15 mL)was added NaOMe (7 mL, 13.89 mmol, 2M in MeOH). The resultant mixture was stirred at 50 °C for 2 h. The reaction mixture was extracted with pentane, and the extract wasconcentrated in vacuo to give desired compound (1.3 g) as a colorless oil which was directlyused in the next step. LC-MS (ESI+): m/z 212.0 (M+Ht.Example 46C (50 mg, 0.120 mmol), A mixture of To a solution of 2, 6-dichloro-4-(trifluoromethyl)pyridine (2 g, 9.26 mmol) in MeOH (15 mL)was added NaOMe (7 mL, 13.89 mmol, 2M in MeOH). The resultant mixture was stirred at 50 C for 2 h. The reaction mixture was extracted with pentane, and the extract wasconcentrated in vacuo to give desired compound (1.3 g) as a colorless oil which was directlyused in the next step. LC-MS (ESI+): m/z 212.0 (M+Ht.Example 2B (300 mg, 0.686 mmol), cesium carbonate (671 mg, 2.059 mmol), 4, 5-bis(diphenylphosphino)-9, 9-dimethylxanthene (Xantphos) (79 mg, 0.137 mmol), and Pd2dba3 (tris(dibenzylideneacetone)dipalladium(0), 62.9 mg, 0.069 mmol) were weighed into a microwave vial. Xylene (1961 muL) was added, followed by A mixture of rac-(4aR*, 7aS*)-7a-(2-fluorophenyl)-4, 4a, 5, 6, 7, 7a- hexahydropyrrolo[3, 4-d][l , 3]thiazin-2-amine (0.1 g), 2-chloro-6-methoxy-4- (trifluoromethyl)pyridine (0.17 g) and triethylamine (0.083 ml) in anhydrous acetonitrile (1 ml) was stirred at 120C for thirty minutes under microwave conditions. The reaction mixture was evaporated, purified by preparative HPLC and isolated by SCX (10 g) to afford the title compound (0.031 g) as a pale pink solid. LCMS: Rt 1.31 min, m/z 427 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) delta (ppm): 2.88 (dd, J=13.20, 3.91 Hz, 1 H) 3.03 (dd, J=13.20, 4.40 Hz, 1 H) 3.07 - 3.20 (m, 1 H) 3.41 - 3.79 (m, 3 H) 3.84 (s, 3 H) 4.03 - 4.20 (m, 1 H) 6.00 - 6.28 (m, 4 H) 7.14 - 7.28 (m, 2 H) 7.30 - 7.44 (m, 2 H)Preparation 11. 2-Methoxy-6-chloro-4-trifluoromethylpyridine. To a solution of 2, 6-dichloro-4-trifluoromethylpyridine (10 g, 46.3 mmol) in methanol (200 mL) was added 25% NaOH/MeOH (12.5 g, 13.2 mL, 231 mmol), which was then stirred at 50 C. for 2 h and then at room temperature overnight. The reaction mixture was extracted with pentane, and the extract was concentrated in vacuo to afford To a solution of 2, 6- dichloro-4-trifluoromethylpyridine (10 g , 46.3 mmol) in methanol (200 mL) was added 25% NaOH/MeOH (12.5 g, 13.2 mL, 231 mmol), which was then stirred at 500C for 2 h and then at room temperature overnight. The reaction mixture was extracted with pentane, and the extract was concentrated in vacuo to afford To a solution of 2, 6-dichloro-4-(trifluoromethyl)pyridine (2.0 g) in dry methanol (40 ml) was added a solution of sodium hydroxide (1.85 g) in dry methanol (7ml) and the reaction mixture stirred at 50C under nitrogen for two hours then allowed to cool. The reaction mixture was extracted with pentane (2 x 100 ml), and the extract combined and evaporated to afford the title compound (1.69 g) as a colourless oil. LCMS: Rt 1.75 min, m/z 212/214 [M+H]+. 1H-NMR (400 MHz, CDC13) delta (ppm): 4.00 (s, 3 H) 6.89 (s, 1 H) 7.12 (s, 1 H)

Molecular Weight:211.57
XLogP3:3
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:211.0011760
Monoisotopic Mass:211.0011760
Topological Polar Surface Area:22.1
Heavy Atom Count:13
Complexity:176
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes