(Z)-1,2-dibromoethene

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

Procedure: In a nitrogen atmosphere, 5 ml of tetrahydrofuran and 0.1 ml of dibromoethylene were added to 3.4 g of metallic magnesium, the mixture was ice-cooled, and 30.0 g of 2,5,5-trimethyl-2-(2-bromoethyl)-1,3-dioxane and 75 ml of tetrahydrofuran were added dropwise to that mixture simultaneously over 1.5 hours. After completion of the dropping, the mixture was stirred for 1 hour with ice cooling and further at room temperature for 30 minutes to give bromo[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]magnesium (1.16 mol/l, tetrahydrofuran solution). cooled

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 8.50 g of dry magnesium shavings was added 100 ml of tetrahydrofuran and a small crystal of iodine. After 20 minutes, 0.5 ml of 1,2-dibromoethene was added using a syringe followed by the dropwise addition of 5 ml of a 70% solution of 1,1,1-tris(chloromethyl)propane in tetrahydrofuran with evolution of heat and gas. While stirring, additional 1,1,1-tris(chloromethyl)propane solution was added, to total 44.7 g at a rate to maintain reflux. The refluxing was continued for an additional 0.5 hour. Then, the reaction mixture was cooled to -62° to -43° C. and 15.0 g of 4H-pyran-4-one (Aldrich) in 20 ml of tetrahydrofuran was added dropwise. After 1 hour at -60° C., the reaction mixture was allowed to warm to -20° C. and then poured into a mixture of ice-cold diethyl ether (500 ml) and saturated ammonium chloride (350 ml). The aqueous fraction was extracted twice with 300 ml diethyl ether. The combined ether solutions were washed with saturated sodium chloride solution, dried and stripped to yield 16.52 g of the desired product as a pale yellow liquid. of heat to maintain reflux The refluxing was continued for an additional 0.5 hour Then, the reaction mixture was cooled to -62° to -43° C. After 1 hour at -60° C. The aqueous fraction was extracted twice with 300 ml diethyl ether The combined ether solutions were washed with saturated sodium chloride solution dried

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,2-dibromoethylene (1.7 mL, 21 mmol) in dry THF (25 mL) was treated with n-BuLi (16.8 mL, 2.5M in THF, 42 mmol) at -65° C. After stirring the mixture at -70° C. for 0.25 hr, a solution of 17β-methoxy-5α-androstan-3-one (2.128 g, 7 mmol) in THF (22 mL) was added and the mixture was stirred at -78° C. for 30 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3-hydroxy-17β-methoxy-5α-androstane (100 mg) as a colorless solid; mp 138-145° C.; TLC Rf (hexane:acetone 7:3)=0.45; and then 3β-ethynyl-3α-hydroxy-17β-methoxy-5α-androstane (1.6 g) as a colorless solid. the mixture was stirred at -78° C. for 30 min The cooling bath was then removed the mixture was quenched with NH4Cl solution (3 mL) The solvents were removed the residue was extracted with EtOAc The organic layer was washed with water, and brine After drying over anhyd MgSO4 the solution was filtered evaporated to yield the crude product poured on a column of silica gel Elution with toluene

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,2-dibromoethylene (1.7 mL, 21 mmol) in dry THF (25 mL) was treated with n-BuLi (16.8 mL, 2.5M in THF, 42 mmol) at -65° C. After stirring the mixture at -70° C. for 0.25 hr, a solution of 17β-methoxy-5α-androstan-3-one (2.128 g, 7 mmol) in THF (22 mL) was added and the mixture was stirred at -78° C. for 30 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3-hydroxy-17β-methoxy-5α-androstane (100 mg) as a colorless solid; mp 138-145° C.; TLC Rf (hexane:acetone 7:3)=0.45; and then 3β-ethynyl-3α-hydroxy-17β-methoxy-5α-androstane (1.6 g) as a colorless solid. the mixture was stirred at -78° C. for 30 min The cooling bath was then removed the mixture was quenched with NH4Cl solution (3 mL) The solvents were removed the residue was extracted with EtOAc The organic layer was washed with water, and brine After drying over anhyd MgSO4 the solution was filtered evaporated to yield the crude product poured on a column of silica gel Elution with toluene

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,2-dibromoethylene (1.6 mL, 3.7 g, 19.71 mmol) in dry THF (10 mL) was treated with n-BuLi (16.4 mL, 2.4M in THF, 39.4 mmol) at -75° C. After stirring the mixture at -78° C. for 0.25 hr, a solution of 17β-methoxy-5β-androstan-3-one (2 g, 6.57 mmol) in THF (20 mL) was added and the mixture was stirred at -78° C. for 15 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (1.70 g) as a colorless solid; mp 62-65° C.; TLC Rf (toluene:acetone 95:5)=0.23. the mixture was stirred at -78° C. for 15 min The cooling bath was then removed the mixture was quenched with NH4Cl solution (3 mL) The solvents were removed the residue was extracted with EtOAc The organic layer was washed with water, and brine After drying over anhyd MgSO4 the solution was filtered evaporated to yield the crude product poured on a column of silica gel Elution with toluene

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

Procedure: In a nitrogen atmosphere, 5 ml of tetrahydrofuran and 0.1 ml of dibromoethylene were added to 3.4 g of metallic magnesium, the mixture was ice-cooled, and 30.0 g of 2,5,5-trimethyl-2-(2-bromoethyl)-1,3-dioxane and 75 ml of tetrahydrofuran were added dropwise to that mixture simultaneously over 1.5 hours. After completion of the dropping, the mixture was stirred for 1 hour with ice cooling and further at room temperature for 30 minutes to give bromo[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]magnesium (1.16 mol/l, tetrahydrofuran solution). cooled

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

Procedure: In a nitrogen atmosphere, 5 ml of tetrahydrofuran and 0.1 ml of dibromoethylene were added to 3.4 g of metallic magnesium, the mixture was ice-cooled, and 30.0 g of 2,5,5-trimethyl-2-(2-bromoethyl)-1,3-dioxane and 75 ml of tetrahydrofuran were added dropwise to that mixture simultaneously over 1.5 hours. After completion of the dropping, the mixture was stirred for 1 hour with ice cooling and further at room temperature for 30 minutes to give bromo[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]magnesium (1.16 mol/l, tetrahydrofuran solution). cooled

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,2-dibromoethylene (1.7 mL, 21 mmol) in dry THF (25 mL) was treated with n-BuLi (16.8 mL, 2.5 M in THF, 42 mmol) at −65° C. After stirring the mixture at −70° C. for 0.25 hr, a solution of 17β-methoxy-5α-androstan-3-one (2.128 g, 7 mmol) in THF (22 mL) was added and the mixture was stirred at −78° C. for 30 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (100 mg) as a colorless solid; mp 138-145° C.; TLC Rf (hexane:acetone 7:3)=0.45; and then 3α-ethynyl-3β-hydroxy-17β-methoxy-5β-androstane (1.6 g) as a colorless solid. the mixture was stirred at −78° C. for 30 min The cooling bath was then removed the mixture was quenched with NH4Cl solution (3 mL) The solvents were removed the residue was extracted with EtOAc The organic layer was washed with water, and brine After drying over anhyd MgSO4 the solution was filtered evaporated to yield the crude product poured on a column of silica gel Elution with toluene

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,2-dibromoethylene (1.6 mL, 3.7 g, 19.71 mmol) in dry THF (10 mL) was treated with n-BuLi (16.4 mL, 2.4M in THF, 39.4 mmol) at −75° C. After stirring the mixture at −78° C. for 0.25 hr, a solution of 17β-methoxy-5β-androstan-3-one (2 g, 6.57 mmol) in THF (20 mL) was added and the mixture was stirred at −78° C. for 15 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (1.70 g) as a colorless solid; mp 62-65° C.; TLC Rf (toluene:acetone 95:5)=0.23. the mixture was stirred at −78° C. for 15 min The cooling bath was then removed the mixture was quenched with NH4Cl solution (3 mL) The solvents were removed the residue was extracted with EtOAc The organic layer was washed with water, and brine After drying over anhyd MgSO4 the solution was filtered evaporated to yield the crude product poured on a column of silica gel Elution with toluene

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

Procedure: The title compound was prepared in analogy to Example 81 starting from 2-(2,6-dimethylmorpholino)ethanamine, dibromo ethylene (commercially available), (1R,2S) and (1S, 2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C26H32ClN3O2: 453, observed (M+H)+: 454.1 1HNMR (400 MHz, MeOD-d4) δppm 1.22 (dd, J=6.32, 2.27 Hz, 2 H) 1.26-1.37 (m, 6 H) 2.15-2.32 (m, 3 H) 2.43-2.67 (m, 1 H) 2.88 (br. s., 3 H) 3.26 (d, J=8.59 Hz, 2 H) 3.40-3.62 (m, 4 H) 3.70-3.96 (m, 1 H) 4.13 (br. s., 4 H) 6.05-6.21 (m, 1 H) 6.81 (t, J=7.58 Hz, 1 H) 7.06-7.18 (m, 1 H) 7.24 (d, J=8.34 Hz, 3 H) 7.29-7.38 (m, 2 H).

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

Procedure: The title compound was prepared in analogy to Example 81 starting from dibromo ethylene, 1-(pyridin-4-yl)piperazine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C27H27ClN4O: 458, observed (M+H)+: 459.2 1HNMR (400 MHz, MeOD-d4) δppm 1.32 (s, 2 H) 2.02-2.40 (m, 3 H) 3.26 (s, 1 H) 3.47 (d, J=9.09 Hz, 8 H) 4.02 (br. s., 4 H) 4.25 (s, 2 H) 6.11 (d, J=7.33 Hz, 1 H) 6.80 (s, 1 H) 7.12-7.18 (m, 1 H) 7.19-7.27 (m, 3 H) 7.32 (t, J=8.97 Hz, 4 H) 8.27 (d, J=7.83 Hz, 2 H).

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

Procedure: The title compound was prepared in analogy to Example 81 starting from dibromo ethylene, 2-morpholinoethanamine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H28ClN3O2: 425, observed (M+H)+: 426.2 1HNMR (400 MHz, MeOD-d4) δppm 2.09-2.34 (m, 3 H) 3.02 (br. s., 4 H) 3.17 (t, J=6.19 Hz, 2 H) 3.27 (t, J=8.72 Hz, 1 H) 3.44-3.61 (m, 4 H) 3.87 (t, J=4.67 Hz, 4 H) 4.12-4.45 (m, 2 H) 6.11 (d, J=7.83 Hz, 1 H) 6.80 (t, J=7.58 Hz, 1 H) 7.10-7.18 (m, 1 H) 7.20-7.27 (m, 3 H) 7.29-7.40 (m, 2 H).