1-bromo-4-methylpentane

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

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

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

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

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

Procedure: Add NaH (60% oil suspension, 30 mg, 0.750 mmol) to a solution of [5-(5-cyanopyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester (Intermediate 22, 189 mg, 0.500 mmol) and DMF (5 ml) stirring at ambient temperature under nitrogen. After 20 minutes, add 1-bromo-4-methylpentane (247 mg, 1.50 mmol) and beat the mixture at 60° C. overnight. After cooling, pour the mixture into water and extract with EtOAc (2×). Wash the extract with water and brine before drying ((MgSO4) and concentrating. Purify on silica gel (20% EtOAc/Hexane) to obtain 111 mg of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)carbamic acid tert-butyl ester as a colorless glass. After cooling extract with EtOAc (2×) Wash the extract with water and brine before drying ((MgSO4) concentrating Purify on silica gel (20% EtOAc/Hexane)

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

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

Procedure: Under a protective gas, 20 g. (0.82 gram atom) of magnesium filings in 150 ml. of tetrahydrofuran is charged into a 1-liter three-necked flask. Within about 60 minutes, 120 g. (0.73 mole) of 1-bromo-4-methylpentane in 270 ml. of tetrahydrofuran is added dropwise to the reaction mixture so that a reaction temperature of 60° C. evolves. The agitation is continued for another 11/2 hours at 50° C. The thus-formed Grignard compound is separated from the unreacted magnesium by means of a glass pipette and transferred into a dropping funnel placed on top of a 2-liter three-necked flask. This flask is to be used for dissolving 84.0 g. (0.7 mole) of allyl bromide in 620 ml. of tetrahydrofuran and for combining this solution with 2.5 millimoles of Li2CuCl4 (as a 0.1-molar solution in THF). Within 60 minutes, the Grignard solution is to be dropped under stirring to this mixture, which latter has been cooled to -10° to -5° C. The reaction mixture is maintained at 0° C. for another 11/2 hours before Grignard compound is gently decomposed with saturated ammonium chloride solution (or about 50 ml. of water). The organic phase is separated, the residue is extracted repeatedly with ether, and the combined, olefin-containing phases are dried over sodium sulfate. After the solvents have been evaporated, 7-methyl-1-octene can be obtained in the pure form by fractionation over a Vigreux attachment or a column: 2 hours at 50° C The thus-formed Grignard compound is separated from the unreacted magnesium by means of a glass pipette transferred into a dropping funnel placed on top of a 2-liter three-necked flask This flask is for dissolving 84.0 g Within 60 minutes to be dropped has been cooled to -10° to -5° C The organic phase is separated the residue is extracted repeatedly with ether olefin-containing phases are dried over sodium sulfate After the solvents have been evaporated

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

Procedure: Under a protective gas, 20 g. (0.82 gram atom) of magnesium filings in 150 ml. of tetrahydrofuran is charged into a 1-liter three-necked flask. Within about 60 minutes, 120 g. (0.73 mole) of 1-bromo-4-methylpentane in 270 ml. of tetrahydrofuran is added dropwise to the reaction mixture so that a reaction temperature of 60° C. evolves. The agitation is continued for another 11/2 hours at 50° C. The thus-formed Grignard compound is separated from the unreacted magnesium by means of a glass pipette and transferred into a dropping funnel placed on top of a 2-liter three-necked flask. This flask is to be used for dissolving 84.0 g. (0.7 mole) of allyl bromide in 620 ml. of tetrahydrofuran and for combining this solution with 2.5 millimoles of Li2CuCl4 (as a 0.1-molar solution in THF). Within 60 minutes, the Grignard solution is to be dropped under stirring to this mixture, which latter has been cooled to -10° to -5° C. The reaction mixture is maintained at 0° C. for another 11/2 hours before Grignard compound is gently decomposed with saturated ammonium chloride solution (or about 50 ml. of water). The organic phase is separated, the residue is extracted repeatedly with ether, and the combined, olefin-containing phases are dried over sodium sulfate. After the solvents have been evaporated, 7-methyl-1-octene can be obtained in the pure form by fractionation over a Vigreux attachment or a column: 2 hours at 50° C The thus-formed Grignard compound is separated from the unreacted magnesium by means of a glass pipette transferred into a dropping funnel placed on top of a 2-liter three-necked flask This flask is for dissolving 84.0 g Within 60 minutes to be dropped has been cooled to -10° to -5° C The organic phase is separated the residue is extracted repeatedly with ether olefin-containing phases are dried over sodium sulfate After the solvents have been evaporated

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

Procedure: 4,5-Dimethylthiazol-2-ylamine, 1-bromo-4-methyl-pentane and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 0.87 (d, J=6.55 Hz, 6 H) 1.18-1.27 (m, 2 H) 1.54-1.62 (m, 1 H) 1.62-1.76 (m, 8 H) 1.84 (d, J=2.50 Hz, 6 H) 1.94-2.03 (m, 3 H) 2.15 (s, 3 H) 2.20 (s, 3 H) 3.98-4.11 (m, 2 H); MS (ESI) m/z 374 (M=H)+.

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

Procedure: 4,5-Dimethylthiazol-2-ylamine, 1-bromo-4-methyl-pentane and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 0.87 (d, J=6.55 Hz, 6 H) 1.18-1.27 (m, 2 H) 1.54-1.62 (m, 1 H) 1.62-1.76 (m, 8 H) 1.84 (d, J=2.50 Hz, 6 H) 1.94-2.03 (m, 3 H) 2.15 (s, 3 H) 2.20 (s, 3 H) 3.98-4.11 (m, 2 H); MS (ESI) m/z 374 (M=H)+.

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

Procedure: Add NaH (60% oil suspension, 30 mg, 0.750 mmol) to a solution of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester (Intermediate 22, 189 mg, 0.500 mmol) and DMF (5 ml) stirring at ambient temperature under nitrogen. After 20 minutes, add 1-bromo-4-methylpentane (247 mg, 1.50 mmol) and heat the mixture at 60° C. overnight. After cooling, pour the mixture into water and extract with EtOAc (2×). Wash the extract with water and brine before drying ((MgSO4) and concentrating. Purify on silica gel (20% EtOAc/Hexane) to obtain 111 mg of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester as a colorless glass. heat the mixture at 60° C. overnight After cooling extract with EtOAc (2×) Wash the extract with water and brine before drying ((MgSO4) concentrating Purify on silica gel (20% EtOAc/Hexane)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 55.6 mg, 0.20 mmol), K2CO3 (54.2 mg, 0.39 mmol), and 1-bromo-4-methylpentane (43 uL, 0.29 mmol) in DMF (1.0 mL). Heat at 80° C. overnight. Remove DMF azeotropically with xylenes. Purify by flash chromatography, eluting with 70:25:5 EtOAc/CH2Cl2/2.0 M NH3 in MeOH to afford the title compound (43.1 mg, 60%): MS ES+ 368.4 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2330, time 0.39 min; Anal. Calcd for C22H29N3O2.0.1CH2Cl2.0.1MeOH: C, 70.32; H, 7.87; N, 11.08. Found: C, 70.05; H, 7.52; N, 11.01. Purify by flash chromatography eluting with 70:25:5 EtOAc/CH2Cl2/2.0 M NH3 in MeOH