1-(chloromethyl)-4-iodobenzene

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

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

Procedure: A mixture of the hydrochloride of 21c (250 mg, 0.67 mmol), potassium carbonate (463 mg, 3.35 mmol) and 4-iodobenzyl chloride (298 mg, 1.00 mmol) in absolute ethanol (25 mL) was refluxed for 16 h. When the mixture had cooled, salts were filtered off and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and the solution was successively washed with water (25 mL) and brine (25 mL). The organic layer was then dried (Na2SO4) and concentrated. The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50) and (13e) was obtained as a colorless oil (226 mg, 52%). The hydrochloride was prepared in a satd HCl/ether soln and recrystallized twice from 50% isopropyl alcohol-hexanes to yield a yellow powder; mp 256.3° C.; 1H NMR (CDCl3) δ1.56-2.18 (2 m, 8, 2 N--C H2 --C H2), 2.40-2.45 (d, 2H, Ar--C H2 --CH2, J=10.1 Hz), 2.51-2.60 (m, 2, C H2 --CHOH), 2.72-2.78 (m, 4, Ar--CH2 -C H2 --C H2), 2.84-2.97 (t, 2, N--C H2 --CH2 --CHOH, J=11.9 Hz), 3.05-3.50 (d, 2, CHN--C H2 --N, J=10.4 Hz), 3.40-3.55 (m, 4, C H--OH+Ar--CH2 --N+CHN), 3.81 (s, 1, OH), 7.22-7.02 (m, 4, arom.), 7.42-7.46 (d, 2, arom., J=7.7 Hz), 7.63-7.67 (d, 2, arom., J=8.2 Hz). was refluxed for 16 h When the mixture had cooled salts were filtered off the volatiles were removed under reduced pressure The residue was dissolved in ethyl acetate (25 mL) the solution was successively washed with water (25 mL) and brine (25 mL) The organic layer was then dried (Na2SO4) concentrated The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50)

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

Procedure: A mixture of the hydrochloride of 21c (250 mg, 0.67 mmol), potassium carbonate (463 mg, 3.35 mmol) and 4-iodobenzyl chloride (298 mg, 1.00 mmol) in absolute ethanol (25 mL) was refluxed for 16 h. When the mixture had cooled, salts were filtered off and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and the solution was successively washed with water (25 mL) and brine (25 mL). The organic layer was then dried (Na2SO4) and concentrated. The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50) and (13e) was obtained as a colorless oil (226 mg, 52%). The hydrochloride was prepared in a satd HCl/ether soln and recrystallized twice from 50% isopropyl alcohol-hexanes to yield a yellow powder; mp 256.3° C.; 1H NMR (CDCl3) δ1.56-2.18 (2 m, 8, 2 N--C H2 --C H2), 2.40-2.45 (d, 2H, Ar--C H2 --CH2, J=10.1 Hz), 2.51-2.60 (m, 2, C H2 --CHOH), 2.72-2.78 (m, 4, Ar--CH2 -C H2 --C H2), 2.84-2.97 (t, 2, N--C H2 --CH2 --CHOH, J=11.9 Hz), 3.05-3.50 (d, 2, CHN--C H2 --N, J=10.4 Hz), 3.40-3.55 (m, 4, C H--OH+Ar--CH2 --N+CHN), 3.81 (s, 1, OH), 7.22-7.02 (m, 4, arom.), 7.42-7.46 (d, 2, arom., J=7.7 Hz), 7.63-7.67 (d, 2, arom., J=8.2 Hz). was refluxed for 16 h When the mixture had cooled salts were filtered off the volatiles were removed under reduced pressure The residue was dissolved in ethyl acetate (25 mL) the solution was successively washed with water (25 mL) and brine (25 mL) The organic layer was then dried (Na2SO4) concentrated The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50)

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

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

Procedure: A mixture of the hydrochloride of 21c (250 mg, 0.67 mmol), potassium carbonate (463 mg, 3.35 mmol) and 4-iodobenzyl chloride (298 mg, 1.00 mmol) in absolute ethanol (25 mL) was refluxed for 16 h. When the mixture had cooled, salts were filtered off and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and the solution was successively washed with water (25 mL) and brine (25 mL). The organic layer was then dried (Na2SO4) and concentrated. The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50) and (13e) was obtained as a colorless oil (226 mg, 52%). The hydrochloride was prepared in a satd HCl/ether soln and recrystallized twice from 50% isopropyl alcohol-hexanes to yield a yellow powder; mp 256.3° C.; 1H NMR (CDCl3)δ1.56-2.18 (2 m, 8, 2 N--CH2 --CH2 ), 2.40-2.45 (d, 2H, Ar--CH2CH2, J=10.1 Hz), 2.51-2.60 (m, 2, CH2 --CHOH), 2.72-2.78 (m, 4, Ar--CH2 --CH2 --CH2), 2.84-2.97 (t, 2, N--CH2 --CH2 --CHOH, J=11.9 Hz), 3.05-3.50 (d, 2, CHN-CH2--N, J= 10.4 Hz), 3.40-3.55 (m, 4, CH--OH+Ar--CH2 --N+CHN), 3.81 (s, 1, OH), 7.22-7.02 (m, 4, arom.), 7.42-7.46 (d, 2, arom., J=7.7 Hz), 7.63-7.67 (d, 2, arom., J=8.2 Hz). was refluxed for 16 h When the mixture had cooled salts were filtered off the volatiles were removed under reduced pressure The residue was dissolved in ethyl acetate (25 mL) the solution was successively washed with water (25 mL) and brine (25 mL) The organic layer was then dried (Na2SO4) concentrated The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50)

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

Procedure: A mixture of the hydrochloride of 21c (250 mg, 0.67 mmol), potassium carbonate (463 mg, 3.35 mmol) and 4-iodobenzyl chloride (298 mg, 1.00 mmol) in absolute ethanol (25 mL) was refluxed for 16 h. When the mixture had cooled, salts were filtered off and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and the solution was successively washed with water (25 mL) and brine (25 mL). The organic layer was then dried (Na2SO4) and concentrated. The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50) and (13e) was obtained as a colorless oil (226 mg, 52%). The hydrochloride was prepared in a satd HCl/ether soln and recrystallized twice from 50% isopropyl alcohol-hexanes to yield a yellow powder; mp 256.3° C.; 1H NMR (CDCl3)δ1.56-2.18 (2 m, 8, 2 N--CH2 --CH2 ), 2.40-2.45 (d, 2H, Ar--CH2CH2, J=10.1 Hz), 2.51-2.60 (m, 2, CH2 --CHOH), 2.72-2.78 (m, 4, Ar--CH2 --CH2 --CH2), 2.84-2.97 (t, 2, N--CH2 --CH2 --CHOH, J=11.9 Hz), 3.05-3.50 (d, 2, CHN-CH2--N, J= 10.4 Hz), 3.40-3.55 (m, 4, CH--OH+Ar--CH2 --N+CHN), 3.81 (s, 1, OH), 7.22-7.02 (m, 4, arom.), 7.42-7.46 (d, 2, arom., J=7.7 Hz), 7.63-7.67 (d, 2, arom., J=8.2 Hz). was refluxed for 16 h When the mixture had cooled salts were filtered off the volatiles were removed under reduced pressure The residue was dissolved in ethyl acetate (25 mL) the solution was successively washed with water (25 mL) and brine (25 mL) The organic layer was then dried (Na2SO4) concentrated The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Brown, Stephen; Grigg, Ronald; Hinsley, Joanne; Korn, Stewart; Sridharan, Visuvanathar; Uttley, Michael; Tetrahedron (2001), 57(52), 10347-10355.) A mixture of 4-iodobenzylchloride (40.0 g, 134.7 mmol), potassium phthalimide (26.20 g, 141.5 mmol) and dry DMF (150 mL) was heated overnight at 55° C. under Ar, and then the solvent was removed at reduced pressure. The solid residue was triturated with CHCl3 (200 mL), filtered, and washed with CHCl3 (3×200 mL). The combined organic extracts were successively washed with aqueous 0.2 M NaOH (200 mL) and H2O (400 mL), and then dried (MgSO4). The solvent was removed at reduced pressure to afford a crude solid, which was triturated with Et2O to obtain a white solid (37.00 g, 75%): Rf=0.75 (1/1 EtOAc/hexanes); mp 138-139° C.; 1H NMR (CDCl3) 4.77 (s, CH2), 7.17 (d, J=8.6 Hz, 2 ArH), 7.63 (d, J=8.6 Hz, 2 ArH), 7.78 (dd, J=3.0, 5.7 Hz, 2 PhtH), 7.83 (dd, J=3.0, 5.7 Hz, 2 PhtH); 13C NMR (CDCl3) 41.0 (CH2), 93.5 (Cl), 123.4, 130.6, 131.9, 134.1, 135.9, 137.7 (6 Ar), 167.2 (2C(O)); HRMS (ESI) 363.9831 [M+H+] (calcd for C17H13NO2H+ 363.9835). the solvent was removed at reduced pressure The solid residue was triturated with CHCl3 (200 mL) filtered washed with CHCl3 (3×200 mL) The combined organic extracts were successively washed with aqueous 0.2 M NaOH (200 mL) and H2O (400 mL) dried (MgSO4) The solvent was removed at reduced pressure to afford a crude solid, which was triturated with Et2O

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

Procedure: Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-iodobenzyl chloride

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product of Step 1 (536.2 mg, 2 mmol) and 4-iodobenzyl chloride (504 mg, 2 mmol) in dry DMF (10 mL) at 0° C. was added sodium hydride (80 mg, 2 mmol, 60% in oil). The mixture was stirred at 20° C. for 20 hours and a saturated NH4Cl solution (10 mL) was added. The mixture was extracted with EtOAc, the extracts were dried over MgSO4 and concentrated to an oil. The oil was purified by flash chromatography on silica gel, eluting with 20% EtOAc in hexane to afford 704 mg (69%) of the title compound. 1H NMR (CDCl3) 1.23 (3H, t, J=7.1 Hz), 2.28 (3H, s), 3.65 (2H, s), 4.12 (2H, q, J=7.1 Hz), 5.19 (2H, s), 6.64 (2H, d, J=8.3 Hz), 6.98 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=8.6 Hz, 1.8 Hz), 7.56 (2H, d, J=8.3 Hz), 7.68 (1H, d, 1.8 Hz). The mixture was extracted with EtOAc the extracts were dried over MgSO4 concentrated to an oil The oil was purified by flash chromatography on silica gel eluting with 20% EtOAc in hexane

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

Procedure: Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-iodobenzyl chloride

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Brown, Stephen; Grigg, Ronald; Hinsley, Joanne; Korn, Stewart; Sridharan, Visuvanathar; Uttley, Michael; Tetrahedron (2001), 57(52), 10347-10355.) A mixture of 4-iodobenzylchloride (40.0 g, 134.7 mmol), potassium phthalimide (26.20 g, 141.5 mmol) and dry DMF (150 mL) was heated overnight at 55° C. under Ar, and then the solvent was removed at reduced pressure. The solid residue was triturated with CHCl3 (200 mL), filtered, and washed with CHCl3 (3×200 mL). The combined organic extracts were successively washed with aqueous 0.2 M NaOH (200 mL) and H2O (400 mL), and then dried (MgSO4). The solvent was removed at reduced pressure to afford a crude solid, which was triturated with Et2O to obtain a white solid (37.00 g, 75%): Rf=0.75 (1/1 EtOAc/hexanes); mp 138-139° C.; 1H NMR (CDCl3) □4.77 (s, CH2), 7.17 (d, J=8.6 Hz, 2 ArH), 7.63 (d, J=8.6 Hz, 2 ArH), 7.78 (dd, J=3.0, 5.7 Hz, 2 PhtH), 7.83 (dd, J=3.0, 5.7 Hz, 2 PhtH); 13C NMR (CDCl3) δ 41.0 (CH2), 93.5 (Cl), 123.4, 130.6, 131.9, 134.1, 135.9, 137.7 (6 Ar), 167.2 (2 C(O)); HRMS (ESI) 363.9831 [M+H+] (calcd for C17H13NO2H+ 363.9835). the solvent was removed at reduced pressure The solid residue was triturated with CHCl3 (200 mL) filtered washed with CHCl3 (3×200 mL) The combined organic extracts were successively washed with aqueous 0.2 M NaOH (200 mL) and H2O (400 mL) dried (MgSO4) The solvent was removed at reduced pressure to afford a crude solid, which was triturated with Et2O

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

Procedure: Zinc powder (70 mg, 1.06 mmol) was dried at 70° C. for 30 min in a sealed tube, then DMA (0.4 ml) and solid 12 (9 mg, 0.04 mmol) were added. After stirring for 10 min, a solution of ethyl 17-iodo-heptadecanoate 80 (300 mg, 0.71 mmol) in DMA (1.5 ml) was added and the reaction mixture was stirred in the sealed tube for 11 h at 70° C. In a 10-ml flask, Ni(COD)2 (10 mg, 0.04 mmol), (R)-(s-Bu)-Pybox (or (S)-(s-Bu)-Pybox) (23 mg, 0.07 mmol) and p-iodobenzyl chloride 82 (252 mg, 1 mmol) were dissolved in DMA (1.5 ml), then organozinc solution 81 was added via cannula. The mixture was stirred at room temperature for 15 h, and the reaction was quenched by addition of aqueous NH4Cl, extracted with EtOAc, the extract was dried over Na2SO4 and evaporated. Chromatography of the crude product in hexane-ether (97:3) yielded the compound 37 (276 mg, 76%). the reaction mixture was stirred in the sealed tube for 11 h at 70° C The mixture was stirred at room temperature for 15 h the reaction was quenched by addition of aqueous NH4Cl extracted with EtOAc the extract was dried over Na2SO4 evaporated