2-(bromomethyl)-1-chloro-3-fluorobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 4,5-Dimethylthiazol-2-ylamine, 2-bromomethyl-1-chloro-3-fluorobenzene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.50-1.70 (m, 12 H) 1.80-1.93 (m, 3 H) 2.17 (s, 3 H) 2.22 (s, 3 H) 5.42 (s, 2 H) 7.11-7.22 (m, 1 H) 7.26-7.41 (m, 2 H); MS (ESI) m/z 433 (M+H)+.

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

Procedure: 4,5-Dimethylthiazol-2-ylamine, 2-bromomethyl-1-chloro-3-fluorobenzene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.50-1.70 (m, 12 H) 1.80-1.93 (m, 3 H) 2.17 (s, 3 H) 2.22 (s, 3 H) 5.42 (s, 2 H) 7.11-7.22 (m, 1 H) 7.26-7.41 (m, 2 H); MS (ESI) m/z 433 (M+H)+.

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry DMF (2 ml) was stirred with sodium carbonate (64 mg, 0.6 mmol) and 2-chloro-6-fluorobenzyl bromide (134 mg, 0.6 mmol) and heated at 45° C. for 18 h under nitrogen. After cooling to rt the mixture was degassed by evacuating and readmitting nitrogen, and stirred with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.303 mmol) and morpholine (0.13 ml) for 5.5 h. The mixture was partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated and the residue purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH and finally eluting with DCM-MeOH (1:1) containing 5% AcOH) to give the title compound (57 mg) as a solid. After cooling to rt the mixture was degassed by evacuating The mixture was partitioned between EtOAc and 2M HCl the organic phase separated evaporated the residue purified by aminopropyl SPE (5 g washing with THF-MeOH (1:1) neat MeOH and finally eluting with DCM-MeOH (1:1) containing 5% AcOH)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry DMF (2 ml) was stirred with sodium carbonate (64 mg, 0.6 mmol) and 2-chloro-6-fluorobenzyl bromide (134 mg, 0.6 mmol) and heated at 45° C. for 18 h under nitrogen. After cooling to rt the mixture was degassed by evacuating and readmitting nitrogen, and stirred with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.303 mmol) and morpholine (0.13 ml) for 5.5 h. The mixture was partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated and the residue purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH and finally eluting with DCM-MeOH (1:1) containing 5% AcOH) to give the title compound (57 mg) as a solid. After cooling to rt the mixture was degassed by evacuating The mixture was partitioned between EtOAc and 2M HCl the organic phase separated evaporated the residue purified by aminopropyl SPE (5 g washing with THF-MeOH (1:1) neat MeOH and finally eluting with DCM-MeOH (1:1) containing 5% AcOH)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(1H-Benzimidazol-4-yl)-5-hydroxy-2-methylpyridin-4(1H)-one (30 mg, 0.124 mmol) and 2-chloro-6-fluorobenzyl bromide (20 μï, 0.146 mmol) were combined in DMF (0.5 ml) then heated to 100° C. After 3 h LC/MS indicated the reaction was incomplete. The mixture was cooled to RT and 10 μL of 2-chloro-6-fluorobenzyl bromide was added. The mixture was heated to 100° C. After 1 hr the mixture was cooled to RT and purified directly by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-40% ACN/water over 20 min at 20 mL/min). Fractions containing the product were pooled then applied to a Phenomenex Strata-X-C ion exchange column. The column was washed with H20 and MeOH (discard) then with 10% concentrated NH4OH in MeOH (collect). The collected fraction was concentrated to give 1-[1-(2-Chloro-6-fluorobenzyl)-1H-benzimidazol-4-yl]-5-hydroxy-2-methylpyridin-4(1H)-one as an off-white solid. 1H NMR (500 MHz, d6-DMSO) δ 8.43 (s, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.52-7.29 (m, 6H), 6.24 (s, 1H), 5.70 (s, 2H), 1.90 (s, 3H). HRMS (ESI) calc (M+H)+=384.0910. found 384.0913. The mixture was cooled to RT The mixture was heated to 100° C After 1 hr the mixture was cooled to RT purified directly by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-40% ACN/water over 20 min at 20 mL/min) Fractions containing the product The column was washed with H20 and MeOH (discard) The collected fraction was concentrated