4-Bromo-1-(1-methylethyl)-1H-imidazole

A mixture of 4-bromo-1H-imidazole (1.0 g, 6.80 mmol) in dimethylformamide (5 mL) was stirred at 0°C, to which was added sodium hydride, 60percent suspension in oil, (326 mg, 8.20 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes, followed by dropwise addition of 2-bromopropane (0.70 mL, 7.48 mmol). The reaction mixture was stirred at room temperature for 15 hours under nitrogen, then quenched with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with water (20 mL) and extracted with 1M hydrochloric acid (3 x 20 mL). The combined acidic extracts were washed with ethyl acetate (20 mL), then basified with ammonium hydroxide (pH 12), and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Preparative HPLC, eluting with an ethyl acetate- isohexane gradient, gave the product as a pale brown oil (380 mg, 30percent) 8 (1H, 400MHz, CDCl3) 1.47 (6H, d, J = 6.8Hz), 4.28-4. 32 (1H, m), 6.92 (1H, d, J = 1.5 Hz), 7.40 (1H, d, J = 1.5 Hz). MS (ES+) 189, 191 ([MH]+).A mixture of compound 55-a (300 mg, 1.02 mmol), 4-bromo-l-(propan-2-yl)-lH-imidazole (230 mg, 1.22 mmol), Pd(PPh3)4 (117.7 mg, 0.10 mmol), and K2CO3 (422 mg, 3.06 mmol) in l, 4-dioxane (2 mL) was stirred at 100 C overnight. Solvent was removed in vacuo and the 56 residue was purified on a silica gel column with 30% EtOAc in PE to afford 130 mg (46%) of compound 6l-a as a yellow solidA mixture of methyl 5-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridine-2- carboxylate (300 mg, 1.08 mmol), 4-bromo-l -(propan-2 -yl)-lH-imidazole (307.0 mg, 1.62 mmol), Pd(PPh3)4 (250.2 mg, 0.22 mmol), K2CO3 (448.8 mg, 3.25 mmol) in dioxane (5 ml) was stirred at 100 C under nitrogen atmosphere overnight. The resulting mixture was 39 concentrated under vacuum and purified by reverse phase flash chromatography with 0-37% MeCN/fhO to afford compound 23-a (180 mg, 64.12%) as yellow oil.To the solution of compound 113-lc (500 mg, 3.4 mmol, 1 eq) in DMF (2.5 mL) was added NaH (163 mg, 4.1 mmol, 60% purity, 1.2 eq) at 0 C. The mixture was stirred at 0 C for 30 min. Then compound 113-lb (460 mg, 3.7 mmol, 351 uL, 1.1 eq) was added to the mixture. The solution was warmed up to 20 C and stirred for 16 hr. The reaction was monitored by LCMS. LCMS showed that the starting material remained and the desired MS was observed. H20 (20 mL) was added to the solution. The mixture was extracted with EtOAc (20 mL*3). The combined organic layer was dried with Na2SC>4 and concentrated under reduced pressure. The residue was purified by to give compound 113-la (100 mg, 528.95 umol, 15.55% yield). It was confirmed by HNMR and HMBC. lH NMR (400MHz, CDC13) delta 7.41 (d, J= 1.3 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 4.37 - 4.27 (m, 1H), 1.48 (d, J= 6.8 Hz, 6H).To the solution of compound 113-lc (500 mg, 3.4 mmol, 1 eq) in DMF (2.5 mL) was added NaH (163 mg, 4.1 mmol, 60% purity, 1.2 eq) at 0 C. The mixture was stirred at 0 C for 30 min. Then compound 113-lb (460 mg, 3.7 mmol, 351 uL, 1.1 eq) was added to the mixture. The solution was warmed up to 20 C and stirred for 16 hr. The reaction was monitored by LCMS. LCMS showed that the starting material remained and the desired MS was observed. H20 (20 mL) was added to the solution. The mixture was extracted with EtOAc (20 mL*3). The combined organic layer was dried with Na2SC>4 and concentrated under reduced pressure. The residue was purified by to give compound 113-la (100 mg, 528.95 umol, 15.55% yield). It was confirmed by HNMR and HMBC. lH NMR (400MHz, CDC13) delta 7.41 (d, J= 1.3 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 4.37 - 4.27 (m, 1H), 1.48 (d, J= 6.8 Hz, 6H).To the solution of compound 113-la (50 mg, 0.26 mmol, 1 eq) in dioxane (2 mL) was added compound 113-1 (125 mg, 0.32 mmol, 1.2 eq), Pd(PPh3)4 (31 mg, 26.5 umol, 0.1 eq), Cs2C03 (172 mg, 0.53mol, 2 eq) and H20 (0.4 mL). The mixture was stirred at 100 C for 16 hr. The reaction was monitored by LCMS. LCMS showed that the starting material was consumed and the desired MS was observed. The reaction solution was filtered. The residue was purified by HPLC to give Compound 113 (9.07 mg, 23.61 umol, 8.9% yield). LCMS (ESI): RT = 0.649 min, mass calcd. for C19H23N9O 376.19, m/z found 377.0 [M+H]+, Ti NMR (400MHz, CDCI3) delta 8.71 (br , 1H), 7.89 (d, J= 2.5 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.36 (d, J = 1.0 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.52 (q, J = 5.4 Hz, 1H), 4.41 - 4.30 (m, 1H), 3.44 (br , 1H), 2.61 (d, J=5.5 Hz, 3H), 2.10 - 2.02 (m, 2H), 1.84 - 1.75 (m, 2H), 1.69 - 1.60 (m, 1H), 1.51 (d, J = 6.8 Hz, 6H), 1.46 - 1.27 (m, 5H).A mixture of 4-bromo-1H-imidazole (1.0 g, 6.80 mmol) in dimethylformamide (5 mL) was stirred at 0C, to which was added sodium hydride, 60% suspension in oil, (326 mg, 8.20 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes, followed by dropwise addition of 2-bromopropane (0.70 mL, 7.48 mmol). The reaction mixture was stirred at room temperature for 15 hours under nitrogen, then quenched with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with water (20 mL) and extracted with 1M hydrochloric acid (3 x 20 mL). The combined acidic extracts were washed with ethyl acetate (20 mL), then basified with ammonium hydroxide (pH 12), and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Preparative HPLC, eluting with an ethyl acetate- isohexane gradient, gave the product as a pale brown oil (380 mg, 30%) 8 (1H, 400MHz, CDCl3) 1.47 (6H, d, J = 6.8Hz), 4.28-4. 32 (1H, m), 6.92 (1H, d, J = 1.5 Hz), 7.40 (1H, d, J = 1.5 Hz). MS (ES+) 189, 191 ([MH]+).

Molecular Weight:189.05
XLogP3:1.7
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:187.99491
Monoisotopic Mass:187.99491
Topological Polar Surface Area:17.8
Heavy Atom Count:9
Complexity:95.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes