3-(T-BUTYLDIMETHYLSILOXY)IODOBENZENE

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

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

Procedure: Methyl 4-[3-(tert-butyldimethylsilyloxy)phenyl]-2-oxo-butyrate was prepared as a yellow oil from 3-(tert-butyldimethylsilyloxy) iodobenzene and methyl 2-hydroxy-3-butenoate.

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

Procedure: Methyl 4-[3-(tert-butyldimethylsilyloxy)phenyl]-2-oxo-butyrate was prepared as a yellow oil from 3-(tert-butyldimethylsilyloxy) iodobenzene and methyl 2-hydroxy-3-butenoate.

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

Procedure: Methyl 4-[3-(tert-butyldimethylsilyloxy)phenyl]-2-oxo-butyrate was prepared as a yellow oil from 3-(tert-butyldimethylsilyloxy) iodobenzene and methyl 2-hydroxy-3-butenoate.

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

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

Procedure: 3-Iodophenoxy-tert-butyldimethylsilane (48.85 g, 146 mmol) was placed in a 250 mL flask with 180 mL of dry tetrahydrofuran at room temperature under nitrogen, Isopropylmagnesium chloride (73 mL, 146 mmol, 2.0 M solution in tetrahydrofuran) was added through an addition funnel to form a light yellow solution. The reaction was stirred at room temperature for 1 hour. In the meantime, 30 g of 4-formyl-N,N-diethylbenzamide was dissolved in 300 mL of dry tetrahydrofuran in another 1000 mL flask and cooled to −72° C. under nitrogen. The freshly prepared 3-phenoxy-tert-butyl-dimethylsilane magnesium chloride was slowly added into the 1000 mL flask. The transfer rate was monitored to maintain reaction temperature below −70° C. The reaction was allowed to warm to room temperature while stirring overnight. The mixture was quenched with 24 mL of saturated aqueous ammonium chloride, diluted with 600 mL of diethyl ether, and washed with 600 mL of water followed by 150 mL of saturated sodium chloride. The ethereal solution was dried over sodium sulfate and the solvent was removed to give crude 4-{[3-(tert-butyl-dimethylsilanyloxy)phenyl]hydroxymethyl}-N,N-diethylbenzamide as a yellow oil. Crude yield was˜100%. The crude product was slurried in a solution of 20% ethyl acetate in pentane. The resulting white precipitate was collected by filtration, washed with pentane, and dried overnight (30 mmHg, 40° C.). to form a light yellow solution cooled to −72° C. under nitrogen to maintain reaction temperature below −70° C to warm to room temperature while stirring overnight The mixture was quenched with 24 mL of saturated aqueous ammonium chloride diluted with 600 mL of diethyl ether washed with 600 mL of water The ethereal solution was dried over sodium sulfate the solvent was removed

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Iodophenol (110 g, 0.50 mol, 1 eq) and imidazole (93.6 g, 1.375 mol, 2.75 eq) were placed in a 2000 ml flask with dichloromethane (1150 mL) and cooled in an ice water bath to 15° C. under nitrogen. tert-Butyldimethylchlorosilane (82.9 g, 0.55 mol, 1.1 eq) in dichloromethane (200 mL) was added dropwise through an addition funnel and the reaction mixture was stirred overnight. The reaction solution was washed with 0.5 N sodium hydroxide solution (3×200 mL), water (3×200 mL) and brine (200 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure leaving 166.34 g of crude (3-iodo-phenoxy)-tert-butyl-dimethyl-silane. 1H NMR (300 MHz, CDCl3) δ 7.27 (ddd, J=8.0, 2.0, 1.0 Hz), 7.19 (dd, 1H, J=2.0, 2.0 Hz), 6.92 (dd, 1H, J=8.0, 8.0 Hz), 6.77 (ddd, 1H, J=8.0, 2.0, 1.0 Hz). The reaction solution was washed with 0.5 N sodium hydroxide solution (3×200 mL), water (3×200 mL) and brine (200 ml) dried over sodium sulfate The solvent was removed under reduced pressure

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Iodophenol (110 g, 0.50 mol, 1 eq) and imidazole (93.6 g, 1.375 mol, 2.75 eq) were placed in a 2000 ml flask with dichloromethane (1150 mL) and cooled in an ice water bath to 15° C. under nitrogen. tert-Butyldimethylchlorosilane (82.9 g, 0.55 mol, 1.1 eq) in dichloromethane (200 mL) was added dropwise through an addition funnel and the reaction mixture was stirred overnight. The reaction solution was washed with 0.5 N sodium hydroxide solution (3×200 mL), water (3×200 mL) and brine (200 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure leaving 166.34 g of crude (3-iodo-phenoxy)-tert-butyl-dimethyl-silane. 1H NMR (300 MHz, CDCl3) δ 7.27 (ddd, J=8.0, 2.0, 1.0 Hz), 7.19 (dd, 1H, J=2.0, 2.0 Hz), 6.92 (dd, 1H, J=8.0, 8.0 Hz), 6.77 (ddd, 1H, J=8.0, 2.0, 1.0 Hz). The reaction solution was washed with 0.5 N sodium hydroxide solution (3×200 mL), water (3×200 mL) and brine (200 ml) dried over sodium sulfate The solvent was removed under reduced pressure

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Iodophenol (110 g, 0.50 mol, 1 eq) and imidazole (93.6 g, 1.375 mol, 2.75 eq) were placed in a 2000 ml flask with dichloromethane (1150 mL) and cooled in an ice water bath to 15° C. under nitrogen. tert-Butyldimethylchlorosilane (82.9 g, 0.55 mol, 1.1 eq) in dichloromethane (200 mL) was added dropwise through an addition funnel and the reaction mixture was stirred overnight. The reaction solution was washed with 0.5 N sodium hydroxide solution (3×200 mL), water (3×200 mL) and brine (200 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure leaving 166.34 g of crude (3-iodo-phenoxy)-tert-butyl-dimethyl-silane. 1H NMR (300 MHz, CDCl3) δ 7.27 (ddd, J=8.0, 2.0, 1.0 Hz), 7.19 (dd, 1H, J=2.0, 2.0 Hz), 6.92 (dd, 1H, J=8.0, 8.0 Hz), 6.77 (ddd, 1H, J=8.0, 2.0, 1.0 Hz). The reaction solution was washed with 0.5 N sodium hydroxide solution (3×200 mL), water (3×200 mL) and brine (200 ml) dried over sodium sulfate The solvent was removed under reduced pressure

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

Procedure: Glacial acetic acid (190 μL, 3.3 mmoL) was added to a solution of tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-5-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(4-methoxybenzyl)thio]pentanoate (800 mg, 0.89 mmol, synthesised according to the procedure for Example 1, starting from tert-butyl(3-iodophenoxy)dimethylsilane) in dry THF (10 mL). Tetrabutylammonium fluoride trihydrate (489 mg, 1.5 mmol) was added and the mixture was stirred for 12 h at room temperature. EtOAc (150 mL) was added and the solution was washed with saturated aqueous NaHCO3, water and brine, dried and concentrated. Flash chromatography (CH2Cl2/EtOAc, 10:1) gave tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-5-(3-hydroxyphenyl)-3-[(4-methoxybenzyl)thio]pentanoate (660 mg, 98%). synthesised the solution was washed with saturated aqueous NaHCO3, water and brine dried concentrated

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

Procedure: Imidazole (7.8 g, 115 mmol) was added to a solution of 3-iodophenol (12.7 g, 58 mmol) and tert-butyl(chloro)dimethylsilane (9.9 g, 65 mmol) in dichloromethane (80 mL) at 0° C. The reaction mixture was stirred at rt overnight. The suspension was washed three times with water and once with brine, dried and concentrated to give crude tert-butyl(3-iodophenoxy)dimethylsilane (20 g, 93%). The suspension was washed three times with water once with brine, dried concentrated

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A deoxygenated mixture of tert-butyl 3-(5-chloro-2-fluorophenyl)-2,3dihydro-1H-pyrrole-1-carboxylate (3-1, 1.100 g, 3.69 mmol, 1 equiv), tert-butyl(3-iodophenoxy)dimethylsilane (1.85 g, 5.54 mmol, 1.50 equiv), tributylamine (1.76 mL, 7.39 mmol, 2.00 equiv), triphenylarsine (0.453 g, 1.48 mmol, 0.400 equiv), and palladium acetate (0.166 g, 0.739 mmol, 0.200 equiv) in DMF (10 mL) was heated at 65° C. for 20 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (2×85 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexanes initially, grading to 50% ethyl acetate in hexanes) to provide tert-butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3-2) as an orange oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ 7.11-6.53 (m, 7H), 6.11 (s, 1H), 5.32 (m, 1H), 4.53 (m, 2H), 1.09 (s, 9H), 0.79 (s, 9H), 0.00 (s, 6H). LRMS m/z (M+H) 504.1 found, 504.2 required. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (2×85 mL) The combined organic layers were dried over sodium sulfate concentrated The residue was purified by flash column chromatography (100% hexanes initially