1,4-diiodobutane

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: To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of anhydrous THF under N2 was added n-butyllithium (1.6 M in hexanes, 19.7 cm3, 31.5 mmol) drop-wise. To the resulting milky solution was added N,N,N′,N′-tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), then the combined organic layers were washed with dil. HCl (pH 1), water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:4) to afford the subtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: 1H NMR (CDCl3) δ 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J=7.5, 1.0 Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H). extracted with EtOAc (×2) the combined organic layers were washed with dil. HCl (pH 1), water (×2) dried (MgSO4) evaporated The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:4)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To N,N-dimethylformamide (400 ml) were added ethyl benzoylacetate (25.1 g, 0.13 mol), 1,4-diiodobutane (40.47 g) (0.13 g) and anhydrous sodium carbonate (82.7 g, 0.78 mol) and the mixture was stirred at 60° C. for 15.5 h. The reaction mixture was poured into 1 L of water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dehydrated over anhydrous sodium sulfate and concentrated. A red residual solution (33.5 g) was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to give the title compound (24.67 g) as a colorless oil (yield 77%). the mixture was extracted with ethyl acetate The extract was washed with saturated brine concentrated A red residual solution (33.5 g) was purified by silica gel column chromatography (ethyl acetate/hexane=1/4)

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

Procedure: Boc-2(S)-amino-4-keto-1,6-hexanedioic acid 1-benzyl ester 6-(4-nitrophenyl)methyl ester (4.8 g, 9.6 mmol) was dissolved in DMF (100 ml). Na2CO3 (4.07 g, 38.4 mmol) and 1,4-diiodobutane (3.59 g, 11.6 mmol) were added to the solution. The mixture was stirred 18 h at room temperature and then heated at 50 ° for 3 h. Evaporation of the solvent, dissolution of the resulting residue with EtOAc, washing of the resulting solution with 1N aqueous HCl and water, followed by drying (MgSO4) and evaporation gave a crude product. The crude product was purified by chromatography eluent: hexane-EtOAc (4:1)] to give the corresponding benzyl ester of the title compound (4.3 g). The benzyl ester was subjected to hydrogenolysis [20% Pd(OH2)/C in MeOH, 18 h] and worked up (see example 1 ) to give the title compound (140 mg). NMR and MS of the product were in agreement with the expected structure. heated at 50 ° for 3 h Evaporation of the solvent, dissolution of the resulting residue with EtOAc washing of the resulting solution with 1N aqueous HCl and water by drying (MgSO4) and evaporation gave a crude product The crude product was purified by chromatography eluent

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

Procedure: A mixture of 4-(1',1'-dioxothiomorpholino)phenol (10 g, 44 mmol), 1,4-diiodobutane (40.9 g, 132 mmol) and cesium carbonate (42.9 g, 132 mmol) was heated at 50° C. in acetonitrile (400 ml). After 4 hours, the reaction mixture was cooled, filtered and the solid salts washed with acetonitrile. The filtrate was poured into dilute HCl/ice water (1.2 l) and the resultant cream colored solid was isolated by filtration and washed with water. Chromatography on silica gel, with 97:3; dichloromethane:ether, afforded 1-iodo-4-[4'-(1,1-dioxothiomorpholino)phenoxy] butane, II (13.4 g, 74%). Mp. 119-121° C. the reaction mixture was cooled filtered the solid salts washed with acetonitrile The filtrate was poured into dilute HCl/ice water (1.2 l) the resultant cream colored solid was isolated by filtration washed with water

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

Procedure: Boc-2(S)-amino-4-keto-1,6-hexanedioic acid 1-benzyl ester 6-(4-nitrophenyl)methyl ester (4.8 g, 9.6 mmol) was dissolved in DMF (100 mL). Na2CO3 (4.07 g, 38.4 mmol) and 1,4-diiodobutane (3.59 g, 11.6 mmol) were added to the solution. The mixture was stirred 18 h at room temperature and then heated at 50° for 3 h. Evaporation of the solvent, dissolution of the resulting residue with EtOAc, washing of the resulting solution with 1N aqueous HCl and water, followed by drying (MgSO4) and evaporation gave a crude product. The crude product was purified by chromatography {SiO2, eluent: hexane-EtOAc (4:1)} to give the corresponding benzyl ester of the title compound (4.3 g). The benzyl ester was subjected to hydrogenolysis {20% Pd(OH2)/C in MeOH, 18 h} and worked up (see section (d) of example 8 hereinafter) to give the title compound (140 mg). NMR and mass spectrum of the product were in agreement with the expected structure. heated at 50° for 3 h Evaporation of the solvent, dissolution of the resulting residue with EtOAc washing of the resulting solution with 1N aqueous HCl and water by drying (MgSO4) and evaporation gave a crude product The crude product was purified by chromatography {SiO2, eluent

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

Procedure: To a solution of 5-(3,4,5-trimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (Compound BN, 43 mg, 0.10 mmol) in DMF (2 mL) was added cesium carbonate (0.17 g, 0.50 mmol) and 1,4-diiodobutane (13 μL, 0.10 mmol). The resulting solution was stirred for 4 hr at room temperature, after which it was partitioned between EtOAc and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 6 N HCl (10 mL) and MeOH (5 mL), and the resulting mixture was stirred at room temperature overnight, after which it was partitioned between EtOAc and H2O. The organic layer was concentrated in vacuo, and the residue was dissolved in EtOH (2 mL). Potassium acetate (100 mg) was then added, and the reaction was stirred for 2 hr. The resulting solution was purified via preparatory HPLC to give the title compound (18 mg, 51%). 1H NMR (CDCl3, 300 MHz): δ 9.53 (s, 1H), 8.32 (d, J=2.1 Hz, 1H), 7.56 (s, 1H), 6.69 (s, 2H), 3.95 (s, 6H), 3.90 (s, 3H), 2.28 (m, 2H), 2.24 (m, 2H), 1.97 (m, 4H). HPLC retention time: 2.00 minutes; MS ESI (m/z): 355.4 (M+1)+, calc. 354. after which it was partitioned between EtOAc and H2O The organic layer was separated dried over MgSO4 filtered concentrated in vacuo The residue was dissolved in 6 N HCl (10 mL) MeOH (5 mL), and the resulting mixture was stirred at room temperature overnight after which it was partitioned between EtOAc and H2O The organic layer was concentrated in vacuo the residue was dissolved in EtOH (2 mL) Potassium acetate (100 mg) was then added the reaction was stirred for 2 hr The resulting solution was purified via preparatory HPLC

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

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