(1R)-3-chloro-1-phenylpropan-1-ol

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

Procedure: Add sodium iodide (4.29 g, 29 mmol) to a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (0.5 g, 2.93 mmol) in acetone (9.75 mL), and heat to reflux overnight. Cool and filter the suspension, then remove the volatiles under reduced pressure. Resuspend the residue in ether, filter and evaporate to afford (R)-3-iodo-1-phenyl-1-propanol (0.71 g). Add (R)-3-iodo-1-phenyl-1-propanol (0.1 g, 0.4 mmol) to a solution of 7-phenyl-isoquinoline -5-sulfonic acid (2-amino-ethyl)-amide (0.087 g, 0.27 mmol) in DMF (0.5 mL) and DCE (0.27 mL) containing diisopropylethylamine (0.094 mL, 0.53 mmol), and warm to 80° C. for 30 minutes. Cool to ambient temperature, and apply to a cation exchange resin cartridge. Wash with methanol, and elute product from the resin with 2M methanolic ammonia. Evaporate and purify the residue by silica gel chromatography using a methanol-methylene chloride gradient, followed by treatment with aqueous hydrochloric acid and lyophylization to afford the title compound. 1H NMR (DMSO): δ9.71(s, 1H), 9.00-8.82 (m, 3H), 8.80-8.73(m, 2H), 8.69 (d, J=1.8 Hz, 1H), 8.59 (d, J=6.2 Hz, 1H), 7.95 (dd, J1=1.5 Hz, J2=8.5 Hz, 2H), 7.62 (t, J=6.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.38-7.29 (m, 4H), 7.28-7.21 (m, 1H), 5.50-4.67 (bs, 2H), 4.65 (dd, J1=4.5 Hz, J2=8.5 Hz, 1H), 3.23-3.10 (m, 2H), 3.06-2.86 (m, 4H), 2.00=−1.77(m, 2H). LCMS: m/z 462(M+H)+460(M−H)−. heat to reflux overnight Cool filter the suspension remove the volatiles under reduced pressure filter evaporate

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

Procedure: Add sodium iodide (4.29 g, 29 mmol) to a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (0.5 g, 2.93 mmol) in acetone (9.75 mL), and heat to reflux overnight. Cool and filter the suspension, then remove the volatiles under reduced pressure. Resuspend the residue in ether, filter and evaporate to afford (R)-3-iodo-1-phenyl-1-propanol (0.71 g). Add (R)-3-iodo-1-phenyl-1-propanol (0.1 g, 0.4 mmol) to a solution of 7-phenyl-isoquinoline -5-sulfonic acid (2-amino-ethyl)-amide (0.087 g, 0.27 mmol) in DMF (0.5 mL) and DCE (0.27 mL) containing diisopropylethylamine (0.094 mL, 0.53 mmol), and warm to 80° C. for 30 minutes. Cool to ambient temperature, and apply to a cation exchange resin cartridge. Wash with methanol, and elute product from the resin with 2M methanolic ammonia. Evaporate and purify the residue by silica gel chromatography using a methanol-methylene chloride gradient, followed by treatment with aqueous hydrochloric acid and lyophylization to afford the title compound. 1H NMR (DMSO): δ9.71(s, 1H), 9.00-8.82 (m, 3H), 8.80-8.73(m, 2H), 8.69 (d, J=1.8 Hz, 1H), 8.59 (d, J=6.2 Hz, 1H), 7.95 (dd, J1=1.5 Hz, J2=8.5 Hz, 2H), 7.62 (t, J=6.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.38-7.29 (m, 4H), 7.28-7.21 (m, 1H), 5.50-4.67 (bs, 2H), 4.65 (dd, J1=4.5 Hz, J2=8.5 Hz, 1H), 3.23-3.10 (m, 2H), 3.06-2.86 (m, 4H), 2.00=−1.77(m, 2H). LCMS: m/z 462(M+H)+460(M−H)−. heat to reflux overnight Cool filter the suspension remove the volatiles under reduced pressure filter evaporate

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

Procedure: The compound [S]-(-)-1-chloro-3-phenyl-3-(4-iodo-2-methylphenoxy)propane (Compound 12) was prepared in the same manner as Compound 2 in Example 1 but using [R]-3-chloro-1-phenylpropanol (1.0 g, 5.88 mmol), 4-iodo-2-methylphenol (1.38 g, 5.88 mmol), triphenylphosphine (1.54 g, 5.88 mmol) and ethyl azodicarboxylate (0.93 mL, 1.04 g, 5.88 mmol) in THF (15 mL) at room temperature for 15 hours. Workup and purification gave 1.58 g (69%) of Compound 12 as a thick pale yellow liquid: [α]25D +14.97 (c 10.73, CHCl3); 1H NMR (CDCl3, 250 MHz) δ 7.42-7.20 (m, 7H), 6.39 (d, J=8.8 Hz, 1H), 5.34 (dd, J=4.6, 8.8 Hz, 1H), 3.83-3.73 (m, 1H), 3.65-3.55 (m, 1H), 2.55-2.40 (m, 1H), 2.29-2.13 (m, 1H), 2.25 (s, 3H), FTIR (neat) 3050, 3015, 2950, 2900, 1600, 1480 (s), 1460, 1395, 1350, 1300, 1250(s), 1200, 1135 cm-1. Anal C17H20INO; C, H. The compound [S]-(-)-1-chloro-3-phenyl-3-(4-iodo-2-methylphenoxy)propane (Compound 12) was prepared in the same manner as Compound 2 in Example 1 at room temperature for 15 hours Workup and purification

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

Procedure: Add sodium iodide (4.29 g, 29 mmol) to a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (0.5 g, 2.93 mmol) in acetone (9.75 mL), and heat to reflux overnight. Cool and filter the suspension, then remove the volatiles under reduced pressure. Resuspend the residue in ether, filter and evaporate to afford (R)-3-iodo-1-phenyl-1-propanol (0.71 g). Add (R)-3-iodo-1-phenyl-1-propanol (0.1 g, 0.4 mmol) to a solution of 7-phenyl-isoquinoline -5-sulfonic acid (2-amino-ethyl)-amide (0.087 g, 0.27 mmol) in DMF (0.5 mL) and DCE (0.27 mL) containing diisopropylethylamine (0.094 mL, 0.53 mmol), and warm to 80° C. for 30 minutes. Cool to ambient temperature, and apply to a cation exchange resin cartridge. Wash with methanol, and elute product from the resin with 2M methanolic ammonia. Evaporate and purify the residue by silica gel chromatography using a methanol-methylene chloride gradient, followed by treatment with aqueous hydrochloric acid and lyophylization to afford the title compound. 1H NMR (DMSO): δ9.71(s, 1H), 9.00-8.82 (m, 3H), 8.80-8.73(m, 2H), 8.69 (d, J=1.8 Hz, 1H), 8.59 (d, J=6.2 Hz, 1H), 7.95 (dd, J1=1.5 Hz, J2=8.5 Hz, 2H), 7.62 (t, J=6.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.38-7.29 (m, 4H), 7.28-7.21 (m, 1H), 5.50-4.67 (bs, 2H), 4.65 (dd, J1=4.5 Hz, J2=8.5 Hz, 1H), 3.23-3.10 (m, 2H), 3.06-2.86 (m, 4H), 2.00=−1.77(m, 2H). LCMS: m/z 462(M+H)+460(M−H)−. heat to reflux overnight Cool filter the suspension remove the volatiles under reduced pressure filter evaporate

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

Procedure: using (R)-(+)-3-chloro-1-phenyl-1-propanol, thieno[3,2-b]pyridin-7-ol (commercially available from the Aldrich Chemical Company), PBu3, and ADPP gave the title compound (0.71 g, 54%); Mass spectrum (ion spray): m/z=304.06 (m+1).

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

Procedure: To a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (5 g, 29.3 mmol) in acetone (50 mL) was added sodium iodide (4.83 g, 32.2 mmol). The resulting solution was heated at reflux for 16 h. The solution was cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane: ethyl acetate [100:0 to 3:1] to yield the title compound as a white solid (7.51 g, 98%); δH (300 MHz, CDCl3) 7.36 (5H, m, Ar), 4.83 (1H, m, O—CH), 3.34-3.15 (2H, m, CH2), 2.28-2.15 (2H, m, CH2). The resulting solution was heated at reflux for 16 h The solution was cooled filtered concentrated in vacuo The residue was purified by flash chromatography eluting silica gel with hexane

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

Procedure: This was prepared by the method of Example 43(a) using 4-bromo-2,5-difluorobenzonitrile and (R)-α-(2-chloroethyl)benzenemethanol. This was prepared by the method of Example 43(a)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-α-(2-Chloroethyl)benzenemethanol (0.73 g, 4.3 mmol) and sodium azide (417 mg, 1.5 eq.) in DMSO (3 ml) was stirred and heated at 40° C. for 1.5 h. The reaction mixture was diluted with water (50 ml) and the products extracted into ethyl acetate(2×75 ml). The combined extracts were dried (magnesium sulphate) and concentrated to an oil. Purification was achieved on silica gel eluting with 50% diethyl ether/isohexane to afford the azide as a colourless oil (0.6 g, 79%). the products extracted into ethyl acetate(2×75 ml) The combined extracts were dried (magnesium sulphate) concentrated to an oil Purification

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

Procedure: (R)-α-(2-Chloroethyl)benzenemethanol (341 mg, 2 mmol) was dissolved in tetrahydrofuran (10 ml) and treated with sodium hydride as a 60% suspension in mineral oil (480 mg, 3 mmol) followed after 10 minutes by 4-chloro-2,5-difluorobenzonitrile (347 mg, 2 mmol). The mixture was stirred at room temperature for 18 h before being treated with methanol (1 ml) and then water (10 ml). The tetrahydrofuran was then removed via heating the vessel to 80° C. and applying a nitrogen stream. Once the tetrahydrofuran was evaporated the residue was extracted into dichloromethane, dried over magnesium sulphate and concentrated in vacuo. The resultant material was re-dissolved into dimethylformamide (8 ml) and treated with sodium iodide (305 mg, 2.03 mmol), triethylamine (565 μl, 4.06 mmol) and cyclopropylamine (114 mg, 2 mmol) before being heated to 60° C. for 5 days. The mixture was filtered and purified via RPHPLC on the crude reaction material. The purified compound was then treated with 50% saturated oxalic acid in ether to produce 74 mg of a white powder that was collected via filtration. The tetrahydrofuran was then removed via heating the vessel to 80° C. Once the tetrahydrofuran was evaporated the residue was extracted into dichloromethane dried over magnesium sulphate concentrated in vacuo The resultant material was re-dissolved into dimethylformamide (8 ml) before being heated to 60° C. for 5 days The mixture was filtered purified via RPHPLC on the crude reaction material

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

Procedure: Prepared by Procedure A using 3,4-dichlorophenol and (1R)-3-chloro-1-phenyl-1-propanol.

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

Procedure: Prepared by Procedure G and Scheme B1 using (1R)-3-chloro-1-phenyl-1-propanol and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 379.2 (M+H)+. Prepared by Procedure G and Scheme B1

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

Procedure: (1R)-3-Chloro-1-phenyl-1-propanol (1.000 g, 5.86 mmol), 1-(3-hydroxyphenyl)ethanone (0.797 9, 5.86 mmol), triphenylphosphine (1.54 g, 5.86 mmol) and diethylazodicarboxylate (1.53 g, 8.79 mmol) were combined in a flask, which was immediately flushed with argon. THF (20 mL) was added and the mixture was stirred overnight under argon. THF was removed in vacuo, the crude product was dissolved in 50 mL of CH2Cl2/H2O (1:1) and the organic layer was separated and dried over MgSO4. After removing the solvent in vacuo, the residue was purified by flash chromatography using 10% ethyl acetate/hexane to yield the desired product (900 mg, 76.0%): 1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.40-7.26 (m, 6H), 7.07-7.04 (m, 1H), 5.46-5.43 (dd, 1H, J=4.4 Hz, 8.8 Hz), 3.84-3.78 (m, 1H), 3.64-3.59 (m, 1H), 2.52 (s, 3H), 2.51-2.46 (m, 1H), 2.29-2.22 (m, 1H). which was immediately flushed with argon THF (20 mL) was added THF was removed in vacuo the crude product was dissolved in 50 mL of CH2Cl2/H2O (1:1) the organic layer was separated dried over MgSO4 After removing the solvent in vacuo the residue was purified by flash chromatography