4-Boc-2-(broMoMethyl)Morpholine

To a solution of the compound of Example 2(c) (0.67 g, 3.1 mmol) in dichloromethane (35 mL) at -20 Step B: Sodium 5-((1, 2, 3, 5, 6, 7-hexahydro-s-indacen-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)- methyl)-1H-1, 2, 4-triazole-3-sulfinate (Intermediate B2) (200 mg, 0.438 mmol) was dissolved in DMF (2 mL) and tert-butyl 2-(bromomethyl)morpholine-4-carboxylate (123 mg, 0.438 mmol), Cs2CO3(143 mg, 0.438 mmol) and KI (7.3 mg, 0.044 mmol) were added. The reaction was warmed up to 50 C for 16 h and then to 100 C and stirred for 4 h. The reaction was diluted with 2 M NaOH (aq) (20 mL) and extracted with DCM (2 x 20 mL). The combined organic extracts were dried (phase separator) and concentrated in vacuo. The crude product was dissolved in HCl (4 M in 1, 4- dioxane, 2 mL) and stirred for 16 h at RT. The volatiles were evaporated and the product purified by acidic prep HPLC (35-65% MeOH in water) to afford the title compound (3 mg, 2% yield) as a white solid.LCMS m/z 404.4 (M+H)+(ES+).1H NMR (DMSO-d6) d 9.00 (s, 1H), 6.97 (s, 1H), 4.05 - 3.89 (m, 1H), 3.74 - 3.68 (m, 1H), 3.59 (dd, J = 14.8, 4.5 Hz, 1H), 3.54 - 3.43 (m, 3H), 3.04 - 2.98 (m, 1H), 2.83 (m, 5H), 2.76 - 2.69 (m, 1H), 2.64 (m, 5H), 1.98 (p, J = 7.4 Hz, 4H). One exchangeable proton not observed.Step C: 5-(2, 4-Difluorophenoxy)-1-isobutyl-6-(morpholin-2-ylmethoxy)-1H-indazole To a solution of 5-(2, 4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.035 g, 0.11 mmol) in DMA (3.5 mL) was added Cs2CO3 (0.11 g, 0.33 mmol). The mixture stirred at room temperature for 1 hour before the addition of 2-bromomethylmorpholine-4-carboxylic acid tert-butyl ester (0.062 g, 0.22 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ether and water and the layers were separated. The aqueous layer was extracted with ether (3*) and the combined organic layers were washed with water and brine, and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford the desired product. MS (APCI+) m/z 418 (M+1) detected; 1H NMR (400 mHz, CD3OD) delta 7.90 (s, 1H), 7.38 (s, 1H), 7.21 (s, 1H), 7.11 (m, 1H), 6.84 (m, 2H), 4.22 (m, 2H), 4.18 (d, 2H), 4.05 (m, 2H), 3.31 (m, 3H), 3.03 (m, 2H), 2.31 (m, 1H), 0.92 (d, 6H)Step B: The compound of intermediate VII (0.55 g, 1.95 mmol), the compound of Example 2(d) (0.546 g, 1.95 mmol) and cesium carbonate (1.92 g, 5.8 mmol) in DMF (35 ml_) were stirred at 35 0C for 22 h. The product mixture was partitioned between ethyl acetate and water. The organic extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 0.90 g (96%) of product that was used in the next step.To a solution of the compound of Example 2(c) (0.67 g, 3.1 mmol) in dichloromethane (35 mL) at -20 0C was added CBr4 (2.06 g, 6.17 mmol) followed by dropwise addition of a solution of PPh3 (1.70 g, 6.48 mmol) in dichloromethane (25 mL). The reaction mixture was held at -15 0C for18 h then stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, EtOAc/hexanes) gave 0.55 g (63%) of product that was used in the next step.

Molecular Weight:280.16
XLogP3:1.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:279.04701
Monoisotopic Mass:279.04701
Topological Polar Surface Area:38.8
Heavy Atom Count:15
Complexity:227
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes