(E)-1,4-dibromobut-2-ene

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

Procedure: In a 100-ml two-necked flask with thermometer, magnet stirrer and CaCl2 tube, 36.8 g (0.2 mole) of 2-vinylcyclopropane-1,1-dicarboxylic acid dimethyl ester, which is accessible from malonic acid dimethyl ester and trans-1,4-dibromobut-2-ene (cf. U.S. Pat. No. 4,713,478 and U.S. Pat. No. 4,713,479) were dissolved in 65 ml of methanol and cooled to ca. 5° C. with ice water. 13.3 g (0.2 mole) of KOH were added portionwise to the mixture, so that the temperature did not rise above 15° C. To complete the reaction, stirring was carried out for a further 12 h and the mixture was then concentrated at a rotation evaporator in vacuum (50 mbar) at 50° C. The obtained oil (ca. 43 g) was dissolved in 50 ml of water and adjusted to about pH 2-3 with conc. hydrochloric acid accompanied by cooling. The organic phase was taken up in 100 ml of diethyl ether, the aqueous phase extracted twice more each time with 100 ml of diethyl ether and the combined ether phases dried over anhydrous Na2SO4. The solution was stabilized with 0.01 g of hydroquinone monomethyl ether, concentrated in vacuum and dried in fine vacuum. 28.2 g (83% yield) of a colourless liquid were obtained. did not rise above 15° C the reaction the mixture was then concentrated at a rotation evaporator in vacuum (50 mbar) at 50° C The obtained oil (ca. 43 g) was dissolved in 50 ml of water by cooling the aqueous phase extracted twice more each time with 100 ml of diethyl ether the combined ether phases dried over anhydrous Na2SO4 concentrated in vacuum dried in fine vacuum

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

Procedure: A mixture of 1.28 g of 4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazin-7-ol, 2.71 g of (E)-1,4-dibromo-2-butene and 1.74 g of potassium carbonate in 80 ml of acetone is stirred at 65° C. After cooling the reaction mixture is filtered and the filtrate is concentrated and purified by chromatography (silica gel, toluene/acetone 98:2). There are obtained 1.44 g of 7-(4-bromo-but-2-enyloxy)-4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazine, MS: m/e 437 (64%, M+, 2 Br). After cooling the reaction mixture is filtered the filtrate is concentrated purified by chromatography (silica gel, toluene/acetone 98:2)

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

Procedure: Analogously to Example 25, from 1-(4-bromo-phenyl)-3,4-dihydro-isoquinolin-6-ol and (E)-1,4-dibromo-2-butene and after reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[1-(4-bromo-phenyl)-3,4-dihydro-isoquinolin-6-yloxy]-but-2-enyl]-methyl-amine, which is converted into the fumarate, MS: m/e 425 (M+H+, 1 Br).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 0.5 g of 1-(4-bromo-phenyl)-isoquinolin-6-ol in 15 ml of DMF is cooled to 0° C. and treated with 0.15 g of ~55% sodium hydride. The mixture is stirred for 40 min., with a solution resulting. A solution of 0.39 g of (E)-1,4-dibromo-2-butene in 5 ml of DMF is added dropwise at -20° C. After stirring at -15° to -20° C. for 3 hrs. 0.8 ml of N-allyl-methyl-amine is added, the mixture is stirred overnight and warmed to room temperature. Subsequently, the reaction mixture is concentrated and the residue is treated with sodium hydrogen carbonate solution and extracted with methylene chloride. The organic extracts are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed with toluene/acetone/triethylamine (90:9:1 to 70:29:1). There is obtained 0.1 g of (E)-allyl-[4-[1-(4-bromo-phenyl)-isoquinolin-6-yloxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 423 (M+H+, 1 Br). resulting After stirring at -15° to -20° C. for 3 hrs the mixture is stirred overnight warmed to room temperature Subsequently, the reaction mixture is concentrated the residue is treated with sodium hydrogen carbonate solution extracted with methylene chloride The organic extracts are washed with saturated sodium chloride solution dried over sodium sulphate concentrated The residue is chromatographed with toluene/acetone/triethylamine (90:9:1 to 70:29:1)

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

Procedure: Analogously to Example 1, from 3-(4-bromo-phenyl)benzofuran-6-ol and (E)-1,4-dibromo-2-butene via (E)-6-(4-bromo-but-2-enyloxy)-3-(4-bromo-phenyl)-benzofuran and by reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 412 (M+H+, 1 Br).

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

Procedure: Analogously to Example 14d, from 4-(6-bromo-benzo[d]isoxazol-3-yl)-phenol and (E)-1,4-dibromo-2-butene via (E)-6-bromo-3-[4-(4-bromo-but-2-enyloxy)-phenyl]-benzo[d]isoxazole and by reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[4-(6-bromo-benzo[d]isoxazol-3-yl)-phenoxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 413 (M+H+, 1 Br).

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

Procedure: Analogously to Example 1, from 3-(4-bromo-phenyl)-benzo[d]isoxazol-6-ol and (E)-1,4-dibromo-2-butene via (E)-6-(4-bromo-but-2-enyloxy)-3-(4-bromo-phenyl)-benzo[d]isoxazole and by reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[3-(4-bromo-phenyl)-benzo[d]isoxazol-6-yloxy]-but-2-enyl-methyl-amine which is converted into the fumarate, MS: m/e 412 (M30 , 1 Br).

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

Procedure: Similar to Production Example 132, 5.04 g of 2-[(2-nitrophenyl)amino]-3-chloropyrazine was treated with (E)-1,4-dibromo-2-butene to thereby give 0.34 g of the title compound.

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

Procedure: A mixture of trans-1,4-dibromo-2-butene (6.4 g, 30 mmol) and potassium phthalimide (5.6 g, 30 mmol) in anhydrous dimethyl formamide (200 ml) was heated at 50° C. for 24 h. Then the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with brine and the pure title product was obtained by flash chromatography on silica gel (ethyl acetate: hexane; 15:85) (3.2 g, 40%). Then the reaction mixture was concentrated in vacuo dissolved in ethyl acetate washed with brine

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

Procedure: A heterogenous mixture of 1.59 g (4.35 mmol) of trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide (example 5.1), 5.0 ml of dichloromethane , 37.2 g (174 mmol) of (E)-1,4-dibromo-2-butene, 15.0 ml of 50% w/w sodium hydroxide solution and 0.44 g (1.3 mmol) of tetrabutylammonium hydrogensulfate was stirred vigorously at room temperature for 3 days. Afterwards, 30 ml of deionized water were added and the reaction mixture was extracted with 3 portions of n-hexane. The combined organic phases were then washed with water (3 times), 1 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, brine and were finally dried over magnesium sulfate and evaporated under reduced pressure. The excess of the (E)-1,4-dibromo-2-butene was distilled off under reduced pressure (0.5 torr) at 100° C. The residue thus obtained was chromatographed on silicagel with a 3:1 v/v mixture of dichloromethane and hexane as the eluent giving 1.51 g (69.6%) of trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as pale yellow solid, MS: 515 (MNH4+, 1Br). the reaction mixture was extracted with 3 portions of n-hexane The combined organic phases were then washed with water (3 times), 1 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, brine were finally dried over magnesium sulfate evaporated under reduced pressure The excess of the (E)-1,4-dibromo-2-butene was distilled off under reduced pressure (0.5 torr) at 100° C The residue thus obtained was chromatographed on silicagel with a 3:1 v/v mixture of dichloromethane and hexane as the eluent

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of potassium tert-butoxide (11.55 g, 102.9 mmol) in THF (450 mL) at −78° C. was added the commercially available N,N-dibenzyl imine of glycine ethyl ester (25.0 g, 93.53 mmol) in THF (112 mL). The reaction mixture was warmed to 0° C., stirred for 40 min, and was then cooled back to −78° C. To this solution was added trans-1,4-dibromo-2-butene (20.0 g, 93.50 mmol), the mixture stirred for 1 h at 0° C. and was cooled back to −78° C. Potassium tert-butoxide (11.55 g, 102.9 mmol) was added, the mixture immediately warmed to 0° C., and was stirred one more hour before concentrating in vacuo. The crude product was taken up in Et2O (530 mL), 1N aq. HCl solution (106 mL, 106 mmol) added and the resulting biphasic mixture stirred for 3.5 h at rt. The layers were separated and the aqueous layer was washed with Et2O (2×) and basified with a saturated aq. NaHCO3 solution. The desired amine was extracted with Et2O (3×) and the combined organic extract was washed with brine, dried (MgSO4), and concentrated in vacuo to obtain the free amine. This material was treated with a 4N HCl solution in dioxane (100 mL, 400 mmol) and concentrated to afford (1R,2S)/(1S,2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride as a brown semisolid (5.3 g, 34% yield) identical to the material obtained from procedure A, except for the presence of a small unidentified aromatic impurity (8%). was then cooled back to −78° C the mixture stirred for 1 h at 0° C. was cooled back to −78° C the mixture immediately warmed to 0° C. was stirred one more hour before concentrating in vacuo the resulting biphasic mixture stirred for 3.5 h at rt The layers were separated the aqueous layer was washed with Et2O (2×) The desired amine was extracted with Et2O (3×) the combined organic extract was washed with brine dried (MgSO4) concentrated in vacuo

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

Procedure: A 100 mL flask is charged with acetonitrile (12 mL) and water (24 mL) and is degassed with argon for about 5 min. Linear peptide (0.01 mmole) and 200 mM ammonium bicarbonate (6 mL) are added followed by at least one peptide (0.012 mmole) such as, but not limited to, 1,3-bis(bromomethyl) benzene, 1,2-bis(bromomethyl)benzene, 1,4-bis(bromomethyl)benzene, 2,6-bis(bromomethyl)pyridine, (E)-1,4-dibromobut-2-ene. The reaction mixture is stirred under argon at room temperature for approximately 2 hours and monitored by LC-MS. After the reaction is complete, the reaction solution is frozen and lyophilized. HPLC purification of the crude lyophilized product followed by lyophilization of fractions containing pure peptide results in the final cyclized product as a white power. is degassed with argon for about 5 min the reaction solution is frozen HPLC purification of the crude lyophilized product containing pure peptide results in the final cyclized product as a white power