1-iodo-2-(2-iodoethoxy)ethane

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

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

Procedure: Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.4 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1-iodo-2-(2-iodoethoxy)ethane (1.2 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg). The reaction mixture was stirred an additional 1 h at 0° C. The reaction mixture was extracted with EtOAc (3×20 mL) the combined organic phases were washed with water (3×20 mL) and brine (20 mL) dried over MgSO4 The volatiles were removed under reduced pressure the residue was purified by flash column chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product from Example 6 (17.2 mg, 0.027 mmol) in DMA (1 mL) was treated with cesium carbonate (63.3 mg, 0.194 mmol) and 2-iodoethyl ether (15.8 mg, 0.049 mmol) at rt. The mixture was heated at 110° C. for 16 h, then cooled to rt and filtered. The filtrate was directly purified by RP-HPLC (15 to 100% acetonitrile/water+0.05% TFA) to afford the title compound. HPLC/MS: 601.4/603.4 (M+1); Rt=2.92 min (LC4). cooled to rt filtered The filtrate was directly purified by RP-HPLC (15 to 100% acetonitrile/water+0.05% TFA)

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

Procedure: Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.4 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1-iodo-2-(2-iodoethoxy)ethane (1.2 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg). The reaction mixture was stirred an additional 1 h at 0° C. The reaction mixture was extracted with EtOAc (3×20 mL) the combined organic phases were washed with water (3×20 mL) and brine (20 mL) dried over MgSO4 The volatiles were removed under reduced pressure the residue was purified by flash column chromatography

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

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

Procedure: Cesium carbonate (20.7 g, 63.5 mmol) was added portionwise over a 20 minute period to a stirred solution of tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (preparation 6a, 6.0 g, 16.0 mmol) and 1-iodo-2-(2-iodoethoxy)ethane (6.58 g, 17.6 mmol) in N,N′-dimethylformamide (250 mL) at −20° C. under an argon atmosphere. After the addition the mixture was warmed to room temperature and stirred for 3 hours. Acetic acid (1.1 mL) followed by ethyl acetate and water were added to the reaction mixture and the organic layer was separated, washed with water, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (10:1 to 5:1 hexanes/ethyl acetate) gave the title compound (4.50 g, 61%) as a pale yellow solid. After the addition the mixture were added to the reaction mixture the organic layer was separated washed with water dried (MgSO4) evaporated Purification of the residue by flash chromatography (10:1 to 5:1 hexanes/ethyl acetate)

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

Procedure: Butyllithium (2.5 M in hexanes, 3.76 mL, 9.39 mmol) was added to a solution of oxindole (500 mg, 3.76 mmol) at −78° C. in THF (40 mL). After complete addition, N,N,N′,N′-tetramethylethane-1,2-diamine (1.48 mL, 9.76 mmol) was added, maintaining the internal temperature <−70° C. After 1 h at −78° C., 2-iodoethyl ether (4.90 g, 15.0 mmol) was added and the reaction warmed to ambient temperature. After 48 h the reaction was quenched with H2O (5 mL) and the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous solution was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 97:3, gave the title compound. MS: m/z=204 (M+1). was added maintaining the internal temperature <−70° C After 48 h the reaction was quenched with H2O (5 mL) the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL) The aqueous solution was extracted with EtOAc (3×50 mL) the combined organic layers were washed with brine (20 mL) dried over Na2SO4 filtered concentrated in vacuo Purification by silica gel chromatography eluting with a gradient of CH2Cl2

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

Procedure: To a solution of adriamycin hydrochloride (20 mg; 0.034 mmoles) in 1 ml of DMF were added 200 mg (0.614 mmoles) of bis(2-iodoethyl)ether and 0.014 ml (0.104 mmoles) of triethylamine, and the reaction was carried out for 36 hours at room temperature. The product was worked up in the same way as in the purification procedure of Example 1 to give 13 mg (yield 61%) of the title compound. The product was worked up in the same way as in the purification procedure of Example 1

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

Procedure: Butyllithium (2.5 M in hexanes, 3.76 mL, 9.39 mmol) was added to a solution of oxindole (500 mg, 3.76 mmol) at −78° C. in THF (40 mL). After complete addition, N,N,N′,N′-tetramethylethane-1,2-diamine (1.48 mL, 9.76 mmol) was added, maintaining the internal temperature <−70° C. After 1 h at −78° C., 2-iodoethyl ether (4.90 g, 15.0 mmol) was added and the reaction warmed to ambient temperature. After 48 h the reaction was quenched with H2O (5 mL) and the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous solution was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH-100:0 to 97:3, gave the title compound. MS: m/z=204 (M+1). was added maintaining the internal temperature <−70° C After 48 h the reaction was quenched with H2O (5 mL) the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL) The aqueous solution was extracted with EtOAc (3×50 mL) the combined organic layers were washed with brine (20 mL) dried over Na2SO4 filtered concentrated in vacuo Purification by silica gel chromatography eluting with a gradient of CH2Cl2

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

Procedure: Cesium carbonate (20.7 g, 63.5 mmol) was added portionwise over a 20 minute period to a stirred solution of tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (preparation 8a, 6.0 g, 16.0 mmol) and 1-iodo-2-(2-iodoethoxy)ethane (6.58 g, 17.6 mmol) in N,N′-dimethylformamide (250 mL) at −20° C. under an argon atmosphere. After the addition the mixture was warmed to room temperature and stirred for 3 hours. Acetic acid (1.1 mL) followed by ethyl acetate and water were added to the reaction mixture and the organic layer was separated, washed with water, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (10:1 to 5:1 hexanes/ethyl acetate) gave the title compound (4.50 g, 61%) as a pale yellow solid. After the addition the mixture were added to the reaction mixture the organic layer was separated washed with water dried (MgSO4) evaporated Purification of the residue by flash chromatography (10:1 to 5:1 hexanes/ethyl acetate)

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

Procedure: To a stirred solution of 800 mg (4.47 mmol) 4-methoxy-benzooxazole-2,7-diamine in 40 ml DMF at room temperature were added 2.47 g (17.9 mmol) potassium carbonate and 2.18 g (6.70 mmol) 1-iodo-2-(2-iodo-ethoxy)-ethane and the mixture heated at 60° C. for 48 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Flash chromatography (2/98 methanol/dichloromethane, then 10/90 methanol/dichloromethane) afforded 585 mg (53%) 4-methoxy-7-morpholin-4-yl-benzooxazol-2-ylamine as a light brown solid. ES-MS m/e (%): 250 (M+H+, 100). After cooling to room temperature the mixture was poured onto water extracted three times with ethyl acetate The combined organic phases were washed with brine dried over sodium sulphate concentrated in vacuo

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

Procedure: Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.4 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1-iodo-2-(2-iodoethoxy)ethane (1.2 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg). The reaction mixture was stirred an additional 1 h at 0° C. The reaction mixture was extracted with EtOAc (3×20 mL) the combined organic phases were washed with water (3×20 mL) and brine (20 mL) dried over MgSO4 The volatiles were removed under reduced pressure the residue was purified by flash column chromatography