1-ethoxy-4-iodobenzene

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

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

Procedure: Under inert gas atmosphere 88 mg (0.12 mmol) PdCl2(dppf)xCH2Cl2, 13.6 mL (27.2 mmol) 2N sodium carbonate solution and 1.64 g (13.3 mmol) pyridine-4-boronic acid are added to 3.00 g (12.1 mmol) 1-ethoxy-4-iodo-benzene in 18 mL 1,4-dioxane and 6 mL methanol. The mixture is stirred for 2 d at reflux. After that time, water is added. The precipitate is filtered off, taken up in DCM and extracted with water. The organic layer is dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; gradient DCM:MeOH 100:0->95:5) to yield the desired product which is directly used in the next reaction step. at reflux The precipitate is filtered off extracted with water The organic layer is dried over sodium sulphate the solvent is evaporated The residue is purified by column chromatography (silica gel; gradient DCM:MeOH 100:0->95:5)

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

Procedure: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-ethoxyphenyl)-1H-indol-3-yl)propanoic acid (1.11 g, 66%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-4-ethoxybenzene using the procedure described for (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid. 1H NMR (400 MHz, chloroform-d) δ 8.12 (s, 1H), 7.77 (d, J=7.5 Hz, 2H), 7.69 (d, J=7.8 Hz, 1H), 7.54-7.34 (m, 8H), 7.33-7.12 (m, 4H), 6.97-6.90 (m, 2H), 5.16 (d, J=7.8 Hz, 1H), 4.64 (d, J=6.3 Hz, 1H), 4.28-4.06 (m, 4H), 3.62-3.42 (m, 2H), 1.44-1.36 (t, J=8.0 Hz, 3H); [α]20D −10.68° (4.01 mg/mL, MeOH). LCMS retention time=1.898 min., m/z 547=(M+H), 98.2% purity. The LCMS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using The following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a flow rate of 1 mL/minute.

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

Procedure: Under inert gas atmosphere 88 mg (0.12 mmol) PdCl2(dppf)xCH2Cl2, 13.6 mL (27.2 mmol) 2N sodium carbonate solution and 1.64 g (13.3 mmol) pyridine-4-boronic acid are added to 3.00 g (12.1 mmol) 1-ethoxy-4-iodo-benzene in 18 mL 1,4-dioxane and 6 mL methanol. The mixture is stirred for 2 d at reflux. After that time, water is added. The precipitate is filtered off, taken up in DCM and extracted with water. The organic layer is dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; gradient DCM:MeOH 100:0->95:5) to yield the desired product which is directly used in the next reaction step. at reflux The precipitate is filtered off extracted with water The organic layer is dried over sodium sulphate the solvent is evaporated The residue is purified by column chromatography (silica gel; gradient DCM:MeOH 100:0->95:5)

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

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

Procedure: The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 1-ethoxy-4-iodo-benzene. MS (ESI) 322.2 (M•)+.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-iodophenol (2 g) and potassium carbonate (1.88 g) in DMF (20 ml) was added dropwise ethyl iodide (1.83 ml) at room temperature, and the mixture was stirred at 50° C. overnight. The resulting mixture was poured into water (50 ml), and extracted with diethyl ether (25 ml×3). The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give 2.06 g of 1-ethoxy-4-iodobenzene as a slightly brown solid. The product was used for the next reaction without further purification. extracted with diethyl ether (25 ml×3) The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine dried over MgSO4 The solvent was evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-iodophenol (2 g) and potassium carbonate (1.88 g) in DMF (20 ml) was added dropwise ethyl iodide (1.83 ml) at room temperature, and the mixture was stirred at 50° C. overnight. The resulting mixture was poured into water (50 ml), and extracted with diethyl ether (25 ml×3). The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give 2.06 g of 1-ethoxy-4-iodobenzene as a slightly brown solid. The product was used for the next reaction without further purification. extracted with diethyl ether (25 ml×3) The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine dried over MgSO4 The solvent was evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-iodophenol (2 g) and potassium carbonate (1.88 g) in DMF (20 ml) was added dropwise ethyl iodide (1.83 ml) at room temperature, and the mixture was stirred at 50° C. overnight. The resulting mixture was poured into water (50 ml), and extracted with diethyl ether (25 ml×3). The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give 2.06 g of 1-ethoxy-4-iodobenzene as a slightly brown solid. The product was used for the next reaction without further purification. extracted with diethyl ether (25 ml×3) The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine dried over MgSO4 The solvent was evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-iodophenol (2 g) and potassium carbonate (1.88 g) in DMF (20 ml) was added dropwise ethyl iodide (1.83 ml) at room temperature, and the mixture was stirred at 50° C. overnight. The resulting mixture was poured into water (50 ml), and extracted with diethyl ether (25 ml×3). The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give 2.06 g of 1-ethoxy-4-iodobenzene as a slightly brown solid. The product was used for the next reaction without further purification. extracted with diethyl ether (25 ml×3) The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine dried over MgSO4 The solvent was evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-iodophenol (2 g) and potassium carbonate (1.88 g) in DMF (20 ml) was added dropwise ethyl iodide (1.83 ml) at room temperature, and the mixture was stirred at 50° C. overnight. The resulting mixture was poured into water (50 ml), and extracted with diethyl ether (25 ml×3). The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give 2.06 g of 1-ethoxy-4-iodobenzene as a slightly brown solid. The product was used for the next reaction without further purification. extracted with diethyl ether (25 ml×3) The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine dried over MgSO4 The solvent was evaporated

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

Procedure: A solution of 1.0 g (5 mmol) of 6-bromo-1H-indole, 1.06 g (4.15 mmol) of 4-iodophenetole, 1.45 g of potassium carbonate, 38.1 mg of copper(I) iodide and 42 mg of L-proline in 15 ml of dimethyl sulfoxide is heated at 120° C. for 15 hours. The reaction mixture is then cooled to room temperature, 30 ml of water are added, and the mixture is extracted three times with 20 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate, the solvent is stripped off in a rotary evaporator, and the crude product is purified by column chromatography on silica gel (n-heptane/ethyl acetate 98:2), giving 0.74 g of 6-bromo-1-(4-ethoxyphenyl)-1H-indole as brownish resin; LC/MS: 317 (M+H). the mixture is extracted three times with 20 ml of ethyl acetate each time After the combined organic phases have been dried over sodium sulfate the solvent is stripped off in a rotary evaporator the crude product is purified by column chromatography on silica gel (n-heptane/ethyl acetate 98:2)