2-AMINO-5-METHOXYPYRAZINE

General procedure: To a solution of 5-chloropyrazin-2-amine (0.2 g, 1.54 mmol) in MeOH (3 mL) was added Cu powder (0.13 g, 2.07 mmol), followed by a solution of sodium methoxide in MeOH (0.38 mL, 1.75 mmol). The reaction mixture was stirred at 150°C in a sealed tube for 24 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3percent) to afford the title compound (0.13 g, 67percent). LCMS (ES+) 126 (M+H)Intermediate 22 5-Methoxypyrazin-2-amine [0242] To a solution of 5-chloropyrazin-2-amine (0.2 g, 1.54 mmol) in MeOH (3 mL) was added Cu powder (0.13 g, 2.07 mmol), followed by a solution of sodium methoxide in MeOH (0.38 mL, 1.75 mmol). The reaction mixture was stirred at 150° C. in a sealed tube for 24 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica: 100-200 mesh, MeOH: DCM 2-3percent) to afford the title compound (0.13 g, 67percent). LCMS (ES+) 126 (M+H)In a sealed tube, sodium methoxide (25 wt. percent, 10 mL) was added to a suspension of 5-bromopyrazin-2-amine (1.12 g, 6.44 mmol) in MeOH (10 mL). The reaction was stirred at 100°C for 40 h. At 15 h reaction time, reaction is about 40 percent complete by LCMS. At 40 h reaction time, reaction is about 90percent complete. After concentration the residue was taken up in EtOAc and extracted with brine, dried over sodium sulfate, concentrated and purified by flash chromatography on a 120 g silica gel cartridge with 30 to 50percent EtOAc in hexane, 45 min, at 35 mL/min. Pure fractions were pooled, concentrated and dried under high vac to give 5-methoxypyrazin-2-amine (455 mg, 57 percent).5-Bromopyrazin-2-amine (0.11g, 0.63 mmol) was dissolved in NaOMe/MeOH (0.23g Na metal in 10 ml_ MeOH) and heated by microwave irradiation at 14O4.8mmol), Pd2(dba)3 (184mg, 0.20mmol), XantPhos (233mg, 0.40mmol) and Cs2C03 (2.6g, 8.0mmol) were added sequentially with continued degassing. The reaction mixture was degassed with Ar(g) for a further 15min then heated up to 90C overnight. Once cooled down to rt, the reaction mixture was poured into H20 (20ml_) and extracted with EtOAc (5 x 30ml_). The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography with hexane/EtOAc (1 :0-0: 1 ) then CH2CI2/EtOAc (1 :0-1 :1 ), then re-dissolved in CH2CI2/MeOH (4:1 , 50mL) and swirled with MP-TMT resin (1.2g, 1.1 mmol/g) at rt overnight. The solution was filtered, the resin washed with CH2CI2/MeOH (4:1 , 100ml_) and the filtrate concentrated in vacuo to yield (3) as an off-white solid (600mg, 73%). (0436) LCMS (ES): Found 204.1 [M+Hf. (0437) 1H NMR (300 MHz, DMSO-cf6), d: 10.05 (s, 1 H), 8.81 (d, J=1.3 Hz, 1 H), 8.65 (d, J=1.5 Hz, 1 H), 8.19 (dd, J= 2.6, 1.5 Hz, 1 H), 8.06 (d, J=1.3 Hz, 1 H), 8.03 (d, J= 2.6 Hz, 1 H), 3.88 (s, 3H).General procedure: A 0.5 - 2.0 mL microwave vessel was charged with carboxylic acid VII (251 mg, 0.534 mmol) and this was dissolved in NMP (2 mL). HATU (223 mg, 0.587 mmol) andDIPEA (0.102 mL, 0.587 mmol) were then added and the resultant mixture was stirred at room temperature for 30 min. 2-amino-5-trifluoromethylpyridine (130 mg, 0.801 mmol) was then added and the vessel was tightly sealed with a crimp top. The resultant mixture was heated thermally in a heating block to 110 C for 16 h. The mixture was then diluted with EtOAc and washed with successively with sat. NH4Cl (aq) (1X), sat. NaHCO3 (aq) (1X), H2O (1X) and brine (1X). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was then purified by FCC (12 g SiO2, gradient elution with 0-5% MeOH/DCM). The semi-pure material obtained was then further purified by FCC (12 g SiO2, gradient elution with 0-100% EtOAc/hexanes) and then purified further by FCC (12 g SiO2, gradient elution with 0-5% MeOH/EtOAc) to provide 170 mg (52%) of 11d.General procedure: To a flame-dried flask was added 8 (0.046g, 0.142mmol), xantphos (0.016g, 0.028mmol), potassium carbonate (0.392g, 2.83mmol), palladium(II) acetate (0.003g, 0.014mmol), and the respective amine (0.170mmol). The flask was purged with nitrogen three times and then anhydrous dioxane (1.5mL) was added under nitrogen. The reaction was refluxed at 105C for 12h while under nitrogen, maintaining a positive pressure. The mixture was concentrated under reduced pressure, separated by silica column chromatography (dichloromethane/isopropanol), and purified by reverse phase chromatography (water/acetonitrile).General procedure: Isoquinolin-3-amine (3.23 g, 22.4 mmol) was added to a solution of 1, 1'-thiocarbonyldipyridin-2(1H)-one (5.20 g, 22.4 mmol) in dichloromethane (50 mL) at room temperature. The reaction was stirred for 2 h, then purified by flash chromatography on silica gel (0-10% ethyl acetate in hexanes). Product fractions were combined and concentrated in vacuo to give 3-isothiocyanatoisoquinoline(3.9 g, 93 %) as a white solid.

Molecular Weight:125.13
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:125.058911855
Monoisotopic Mass:125.058911855
Topological Polar Surface Area:61
Heavy Atom Count:9
Complexity:88.3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes