2-chloro-1-iodo-4-methylbenzene

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

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

Procedure: A suspension of 40.4 g (160 mmol) of the compound from Example XXXI in 400 ml of carbon tetrachloride, 31.3 g of N-bromosuccinimide (176 mmol) and 2.63 g of azobisiso-butyronitrile (16 mmol) is heated under reflux overnight. After cooling, the precipitate is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are concentrated and the residue is further reacted in the crude state. is heated under reflux overnight After cooling the precipitate is filtered off with suction washed with carbon tetrachloride The combined filtrates are concentrated the residue is further reacted in the crude state

Conditions: temp:-2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 250 ml of concentrated hydrochloric acid and 75 g of 4-amino-3-chlorotoluene (0.53 mol) are introduced onto 166 g of ice, and a solution of 40.3 g of sodium nitrite (0.583 mol) in 170 ml of water is then added dropwise at 0° C. After the solution has been stirred for 15 minutes, it is filtered through glass wool, and the solution, which has been cooled to -2° C., is added dropwise to a solution, warmed to room temperature, of 455 g of potassium iodide (2.74 mol) in 1 l of water together with a batch prepared analogously with 0.30 mol of 4-amino-3-chloro-toluene. After the reaction mixture has been stirred overnight, it is extracted three times with ether and the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water. After drying over sodium sulphate, filtration and concentration, the residue of copper powder is distilled over a Vigreux column under 1 mm Hg. The fraction between 70° and 85° C. gives 149 g of a yellow oil [7% of theory, Rf =0.57 (hexane:ethyl acetate=9:1)]. it is filtered through glass wool is added dropwise to a solution After the reaction mixture has been stirred overnight it is extracted three times with ether the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water After drying over sodium sulphate, filtration and concentration the residue of copper powder is distilled over a Vigreux column under 1 mm Hg

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

Procedure: A suspension of 40.4 g (160 mmol) of the compound from Example XXXI in 400 ml of carbon tetrachloride, 31.3 g of N-bromosuccinimide (176 mmol) and 2.63 g of azobisisobutyronitrile (16 mmol) is heated under reflux overnight. After cooling, the precipitate is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are concentrated and the residue is further reacted in the crude state. is heated under reflux overnight After cooling the precipitate is filtered off with suction washed with carbon tetrachloride The combined filtrates are concentrated the residue is further reacted in the crude state

Conditions: temp:-2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 250 ml of concentrated hydrochloric acid and 75 g of 4-amino-3-chlorotoluene (0.53 mol) are introduced onto 166 g of ice, and a solution of 40.3 g of sodium nitrite (0.583 mol) in 170 ml of water is then added dropwise at 0° C. After the solution has been stirred for 15 minutes, it is filtered through glass wool, and the solution, which has been cooled to -2° C., is added dropwise to a solution, warmed to room temperature, of 455 g of potassium iodide (2.74 mol) in 11 of water together with a batch prepared analogously with 0.30 mol of 4-amino-3-chloro-toluene. After the reaction mixture has been stirred overnight, it is extracted three times with ether and the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water. After drying over sodium sulphate, filtration and concentration, the residue of copper powder is distilled over a Vigreux column under 1 mm Hg. The fraction between 70° and 85° C. gives 149 g of a yellow oil [7% of theory, Rf =0.57 (hexane:ethyl acetate=9:1)]. it is filtered through glass wool is added dropwise to a solution After the reaction mixture has been stirred overnight it is extracted three times with ether the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water After drying over sodium sulphate, filtration and concentration the residue of copper powder is distilled over a Vigreux column under 1 mm Hg

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00007 mol) which was prepared using procedures analogous to those described in the synthesis of example 472-a and followed by standard hydrogenation to remove the carbobenzyloxy (Cbz) protecting group and 2-chloro-1-iodo-4-methylbenzene (22.7 mg, 0.0000831 mol), potassium carbonate (20.1 mg, 0.000145 mol), copper(I) iodide (0.6 mg, 0.000003 mol), and (1S,2S)-cyclohexane-1,2-diol (16.1 mg, 0.000138 mol) in tert-butyl alcohol (1.0 mL, 0.010 mol) was heated at 100° C. for 18 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 377.1 (M+H)+. was prepared those described in the synthesis of example 472-a The crude product was purified by prep-HPLC

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

Procedure: A suspension of 40.4 g (160 mmol) of the compound from Example XXXI in 400 ml of carbon tetrachloride, 31.3 g of N-bromosuccinimide (176 mmol) and 2.63 g of azobisiso-butyronitrile (16 mmol) is heated under reflux overnight. After cooling, the precipitate is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are concentrated and the residue is further reacted in the crude state. is heated under reflux overnight After cooling the precipitate is filtered off with suction washed with carbon tetrachloride The combined filtrates are concentrated the residue is further reacted in the crude state

Conditions: temp:-2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 250 ml of concentrated hydrochloric acid and 75 g of 4-amino-3-chlorotoluene (0.53 mol) are introduced onto 166 g of ice, and a solution of 40.3 g of sodium nitrite (0.583 mol) in 170 ml of water is then added dropwise at 0° C. After the solution has been stirred for 15 minutes, it is filtered through glass wool, and the solution, which has been cooled to -2° C., is added dropwise to a solution, warmed to room temperature, of 455 g of potassium iodide (2.74 mol) in 1 l of water together with a batch prepared analogously with 0.30 mol of 4-amino-3-chloro-toluene. After the reaction mixture has been stirred overnight, it is extracted three times with ether and the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water. After drying over sodium sulphate, filtration and concentration, the residue of copper powder is distilled over a Vigreux column under 1 mm Hg. The fraction between 70° and 85° C. gives 149 g of a yellow oil [7% of theory, Rf =0.57 (hexane:ethyl acetate=9:1)]. it is filtered through glass wool is added dropwise to a solution After the reaction mixture has been stirred overnight it is extracted three times with ether the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water After drying over sodium sulphate, filtration and concentration the residue of copper powder is distilled over a Vigreux column under 1 mm Hg

Conditions: temp:-2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 250 ml of concentrated hydrochloric acid and 75 g of 4-amino-3-chlorotoluene (0.53 mol) are introduced onto 166 g of ice, and a solution of 40.3 g of sodium nitrite (0.583 mol) in 170 ml of water is then added dropwise at 0° C. After the solution has been stirred for 15 minutes, it is filtered through glass wool, and the solution, which has been cooled to -2° C., is added dropwise to a solution, warmed to room temperature, of 455 g of potassium iodide (2.74 mol) in 1 l of water together with a batch prepared analogously with 0.30 mol of 4-amino-3-chloro-toluene. After the reaction mixture has been stirred overnight, it is extracted three times with ether and the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water. After drying over sodium sulphate, filtration and concentration, the residue of copper powder is distilled over a Vigreux column under 1 mm Hg. The fraction between 70° and 85° C. gives 149 g of a yellow oil [7% of theory, Rf =0.57 (hexane:ethyl acetate=9:1)]. it is filtered through glass wool is added dropwise to a solution After the reaction mixture has been stirred overnight it is extracted three times with ether the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water After drying over sodium sulphate, filtration and concentration the residue of copper powder is distilled over a Vigreux column under 1 mm Hg

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

Procedure: A suspension of 40.4 g (160 mmol) of the compound from Example XXXI in 400 ml of carbon tetrachloride, 31.3 g of N-bromosuccinimide (176 mmol) and 2.63 g of azobisisobutyronitrile (16 mmol) is heated under reflux overnight. After cooling, the precipitate is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are concentrated and the residue is further reacted in the crude state. is heated under reflux overnight After cooling the precipitate is filtered off with suction washed with carbon tetrachloride The combined filtrates are concentrated the residue is further reacted in the crude state

Conditions: temp:-2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 250 ml of concentrated hydrochloric acid and 75 g of 4-amino-3-chlorotoluene (0.53 mol) are introduced onto 166 g of ice, and a solution of 40.3 g of sodium nitrite (0.583 mol) in 170 ml of water is then added dropwise at 0° C. After the solution has been stirred for 15 minutes, it is filtered through glass wool, and the solution, which has been cooled to -2° C., is added dropwise to a solution, warmed to room temperature, of 455 g of potassium iodide (2.74 mol) in 11 of water together with a batch prepared analogously with 0.30 mol of 4-amino-3-chloro-toluene. After the reaction mixture has been stirred overnight, it is extracted three times with ether and the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water. After drying over sodium sulphate, filtration and concentration, the residue of copper powder is distilled over a Vigreux column under 1 mm Hg. The fraction between 70° and 85° C. gives 149 g of a yellow oil [7% of theory, Rf =0.57 (hexane:ethyl acetate=9:1)]. it is filtered through glass wool is added dropwise to a solution After the reaction mixture has been stirred overnight it is extracted three times with ether the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water After drying over sodium sulphate, filtration and concentration the residue of copper powder is distilled over a Vigreux column under 1 mm Hg

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