1-(chloromethyl)-2-iodobenzene

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: 8-Chlorotheophylline (8.5 g, 39.6 mmol) was dissolved in 400 ml of DMF and 2-iodobenzyl chloride (10.0 g, 39.6 mmol), potassium carbonate (5.47 g, 39.6 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 7 days. Water (2500 ml) and EtOAc (800 ml) were added and the layers were separated. The aqueous layer was extracted with 2×500 ml of EtOAc, and the combined organic layer was washed with 500 ml of water, 500 ml of brine, dried over sodium sulphate, and filtered. The solvent was evaporated and the crude product was crystallized from diethyl ether and petrol, to give compound (5A) as white crystals. The mother liquor was evaporated and resuspended in diethyl ether and petrol, to give a second crop of compound (5A). the layers were separated The aqueous layer was extracted with 2×500 ml of EtOAc the combined organic layer was washed with 500 ml of water, 500 ml of brine dried over sodium sulphate filtered The solvent was evaporated the crude product was crystallized from diethyl ether and petrol

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

Procedure: 8-Chlorotheophylline (8.5 g, 39.6 mmol) was dissolved in 400 ml of DMF and 2-iodobenzyl chloride (10.0 g, 39.6 mmol), potassium carbonate (5.47 g, 39.6 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 7 days. Water (2500 ml) and EtOAc (800 ml) were added and the layers were separated. The aqueous layer was extracted with 2×500 ml of EtOAc, and the combined organic layer was washed with 500 ml of water, 500 ml of brine, dried over sodium sulphate, and filtered. The solvent was evaporated and the crude product was crystallized from diethyl ether and petrol, to give compound (5A) as white crystals. The mother liquor was evaporated and resuspended in diethyl ether and petrol, to give a second crop of compound (5A). the layers were separated The aqueous layer was extracted with 2×500 ml of EtOAc the combined organic layer was washed with 500 ml of water, 500 ml of brine dried over sodium sulphate filtered The solvent was evaporated the crude product was crystallized from diethyl ether and petrol

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

Procedure: 3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Iodobenzyl chloride (61 mg, 0.24 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-iodo-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (1.4 mg, 1.3%). HRMS Calcd. for C17H14IN2O3 (M+H)+, 421.0044. Found: 421.0040. The solvent was evaporated the residue was purified by high-throughput purification

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

Procedure: A mixture of the dihydrochloride of 21c (250 mg, 0.67 mmol), DMF (10 mL), potassium carbonate (463 mg, 3.35 mmol) and 2-iodobenzyl chloride (1.00 mmol), 254 mg) was stirred at room temperature for 18 h. Water (25 mL) and dichloromethane (2×25 mL) were added and the organic layer was extracted, washed with brine (25 mL), dried (Na2SO4) and concentrated. The crude product was purified by chromatography (silica gel, hexanes/ethyl acetate, 50/50) to afford 13c as a yellow oil. The latter was converted to the corresponding hydrochloride in satd HCl/ether and recrystallized twice from 50% i-PrOH-hexanes to yield 0.20g (33%) of 13c; mp 258.8° C. 1H NMR (CDCl3) δ1.50-2.21 (2 m, 8, 2N--C H2 --C H2), 2.45-2.57 (m, 2H, Ar--C H2 --CH2, J=10.2 Hz), 2.60-2.76 (m, 2, C H2 --CHOH), 2.84 (m, 4, Ar--CH2 --C H2 --C H2), 2.88-3.00 (t, 2, C H2 --CH2 --CHOH, J=11.2 Hz), 3.09-3.13 (d, 2, N--C H2 --CHN, J=8.7 Hz), 3.50-3.64 (m, 3, Ar--CH2 --N+CH--N), 3.85 (s, 1, C H--OH), 4.67 (s, 1, OH), 6.96-7.49 (m, 8H, arom.), 7.83-7.87 (d, 1H, arom., J=6.8 Hz). the organic layer was extracted washed with brine (25 mL) dried (Na2SO4) concentrated The crude product was purified by chromatography (silica gel, hexanes/ethyl acetate, 50/50)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methanesulfonyl chloride (2.0 ml, 29 mmol) and triethylamine (3.6 ml, 26 mmol) were added to a solution of o-iodobenzyl alcohol (5.0 g, 21 mmol) in methylene chloride (50 ml) cooled to 0° C., and the mixture was stirred at that temperature for 19 hours. A 5% aqueous sodium hydrogencarbonate solution was added, and the resulting mixture was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (5.34 g). the resulting mixture was extracted with methylene chloride The methylene chloride layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure

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

Procedure: The title compound was prepared by the procedure described in the preparation of compound 8, except that 2-iodobenzyl chloride was used as the benzylating reagent. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.76 (d, J=7.6 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 6.89 (t, J=7.2 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 5.26 (s, 1H), 4.79-4.92 (ABq, J=34.1, 6.7.0 Hz, 2H), 3.27 (m, 1H), 3.13 (s, 1H), 2.85 (d, J=11.6 Hz, 1H), 2.70 (m, 1H), 2.41 (m, 1H), 2.02 (m, 1H), 1.60 (m, 1H), 1.45 (m, 2H). MS (ES) [m+H] calc'd for C16H20IN4O2, 427.1; found, 427.1.