1-(2-chloroethyl)piperidine;hydrochloride

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

Procedure: A mixture of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (1 g, 5.10 mmol), 1-(2-chloroethyl)piperidine hydrochloride (1.876 g, 10.19 mmol), and tetrabutylammonium bromide (0.082 g, 0.255 mmol) in dichloromethane (10 mL) and 50% NaOH solution (10 mL) was stirred at room temperature overnight (16 hours). The mixture was diluted with dichloromethane (5 mL) and water (20 mL), and the mixture was then transferred to a separatory funnel. The organic layer was removed, and the aqueous layer was extracted in dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The red crude material was subjected to column chromatography on silica gel using the Biotage purification system (80 g silicycle column; solvent gradient: dichloromethane 3CV, ramp to 6:94 (2M NH3 in methanol):CH2Cl2 over 15CV; 254 nm monitoring wavelength; flow=45 mL/minute), to give an orange solid (0.937 g, 59.8%). 1H-NMR (DMSO-d6) δ 7.85-7.81 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 3.82-3.79 (m, 2H), 3.58 (t, J=6.9 Hz, 2H), 3.08-3.04 (m, 2H), 2.50-2.45 (m, 2H), 2.44-2.34 (m, 4H), 1.49-1.46 (m, 4H), 1.40-1.37 (m, 2H); ESI-MS (m/z, %): 308 (MH+, 100). the mixture was then transferred to a separatory funnel The organic layer was removed the aqueous layer was extracted in dichloromethane (2×10 mL) The combined organic layers were dried (Na2SO4) filtered concentrated the Biotage purification system (80 g silicycle column; solvent gradient: dichloromethane 3CV, ramp to 6:94 (2M NH3 in methanol):CH2Cl2 over 15CV; 254 nm monitoring wavelength; flow=45 mL/minute)

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

Procedure: cis-{4-[N,N-Dibenzylamino]cyclohexyl}methan-1-ol (2.851 g, 9.21 mmol) and (2-chloroethyl)piperidine hydrochloride were suspended in 50 mL of dioxane. Potassium hydride (3.16 g, 35% by weight in mineral oil) was added dropwise in suspension in 20 mL of dioxane. The reaction mixture was stirred at room temperature for about 1 hour. The reaction mixture was then warmed to about 70° C. and one equivalent of potassium hydride (1.05 g, 35% by weight in mineral oil) was added dropwise. The temperature was maintained for about 2 hours, after which the conversion was complete. The reaction was cooled to room temperature and quenched with methanol. Solvents were removed under reduced pressure. Acetonitrile was added (200 mL) and the gray brown solid was removed by filtration. The crude was purified by column chromatography on silica gel using 3% (ethanol/ammonium hydroxide=8:1) in dichloromethane. The product was isolated as an orange oil that solidified under vacuum. (2.84 g, 72% yield): ES-MS (m/z) 421. The reaction mixture was then warmed to about 70° C. The temperature was maintained for about 2 hours The reaction was cooled to room temperature quenched with methanol Solvents were removed under reduced pressure Acetonitrile was added (200 mL) the gray brown solid was removed by filtration The crude was purified by column chromatography on silica gel using 3% (ethanol/ammonium hydroxide=8:1) in dichloromethane The product was isolated as an orange oil that solidified under vacuum

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

Procedure: A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxy-phenyl)-5,6,7,8-tetrahydro-naphth-1-yl-methane (330 mg, 0.001 mol), anhydrous. K2CO3 (2.0 gm, 0.14 mol), 1-(2-chloroethyl)piperidine hydrochloride (400 mg, 0.002 mol) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent to give the title compound of formula I. Yield 210 mg. (7.19%). K2CO3 was filtered off acetone was distilled off the residue was diluted with water The reaction mixture was extracted with ethyl acetate washed with water dried over sodium sulphate concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent

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

Procedure: A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane (300 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.014 mol), 1-(2-chloroethyl)piperidine hydrochloride (300 mg, 0.0015 mol) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off and residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent and concentrated to give the title compound of formula I. Yield 218 mg. (55.89%). was refluxed for 10 hrs K2CO3 was filtered off acetone was distilled off residue was diluted with water The reaction mixture was extracted with ethyl acetate washed with water dried over sodium sulphate concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent concentrated

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

Procedure: A mixture of (4-methoxyphenyl)(3-methyl-4-hydroxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (345 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.014 mol), and 1-(2-chloroethyl)piperidine hydrochloride (400 mg, 0.002 ml) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent and concentrated to give title compound of formula I. Yield 324 mg (72%). was refluxed for 10 hrs K2CO3 was filtered off acetone was distilled off the residue was diluted with water The reaction mixture was extracted with ethyl acetate washed with water dried over sodium sulphate concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent concentrated

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

Procedure: A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (400 mg 0.0011 mol), anhydrous K2CO3 (2.0 gm, 0.014 mol), 1-(2-chloroethyl)piperidine hydrochloride (400 mg, 0.002) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off acetone was distilled off and residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column by using benzene as eluent, and was concentrated. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and compound was crystallized with absolute alcohol and anhydrous ether, and filtered under anhydrous conditions to give title compound of formula I. Yield 310 mg. (58.6%). was refluxed for 10 hrs K2CO3 was filtered off acetone was distilled off residue was diluted with water The reaction mixture was extracted with ethyl acetate washed with water dried over sodium sulphate concentrated to give an oil which was filtered through basic alumina column was concentrated The oil thus obtained The solvent was evaporated compound was crystallized with absolute alcohol and anhydrous ether filtered under anhydrous conditions

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

Procedure: A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-naphth-1-yl-methane of formula 1 (0.3 gm, 0.001 mol), anhydrous K2CO3 (1.5 gm), 1-(2-chloroethyl)piperidine hydrochloride (0.276 gm, 0.002 mol) and dry acetone (100 ml) was refluxed for 810 hrs K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate washed with water dried over Na2SO4 and concentrated to give an oil. This oil was purified by column chromatography over basic alumina using benzene as the eluent. Solvent was distilled off to give the title compound of general formula I as an oil. Yield 0.3 gm(67%). was filtered off acetone was distilled off the residue was diluted with water The reaction mixture was extracted with ethyl acetate washed with water dried over Na2SO4 concentrated to give an oil This oil was purified by column chromatography over basic alumina Solvent was distilled off

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.120 g, 0.55 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.100 g, 0.54 mmol), potassium carbonate (0.226 g, 1.64 mmol) and 18-crown-6 (0.072 g, 0.27 mmol) in MeCN (3 mL) was heated in the microwave at 180° C. for 10 minutes. The mixture was diluted with MeOH and a small amount of water and purified by SPE using a MP-TsOH resin (1000 mg) cartridge. The solvent was removed in vacuo to afford 4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid (0.129 g, 0.52 mmol, 95%) which was used without further purification. LCMS (1) Rt: 1.55; m/z (ES+) 250. a small amount of water and purified by SPE The solvent was removed in vacuo

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

Procedure: A mixture of tert-butyl 2-(2-chloro-3-quinolinyl)-5-hydroxy-1H-indole-1-carboxylate 1-8 (395 mg, 1.00 mmol, 1 equiv), 1-(2-chloroethyl)-piperidine hydrochloride (276 mg, 1.50 mmol, 1.50 equiv), and cesium carbonate (978 mg, 3.00 mmol, 3.00 equiv) in N,N-dimethylformamide (5 mL) was heated at 50° C. for 2 h. The reaction mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water then brine, dried over magnesium sulfate, and concentrated to give a pale-yellow foam. The foam was dissolved in a 1:1 mixture of water and acetic acid (60 mL), and the resulting solution was heated at 110° C. for 12 h. The reaction mixture was concentrated, and the residue was stirred in aqueous saturated sodium bicarbonate solution which yielded a tan solid. The tan solid was filtered, then suspended in warm ethanol (2×20 mL) and filtered to give 3-[5-(2-piperidin-1-yl-ethoxy)-1H-indol-2-yl]-1H-quinolin-2-one (1-9) as a yellow solid. The ethanolic filtrate was concentrated and the residue purified by flash column chromatography (5% ethanol saturated with ammonia in ethyl acetate to afford additional 1-9. 1H NMR (400 MHz, (CD3)2SO) δ12.14 (s, 1H), 11.41 (s, 1H), 8.50 (s, 1H), 7.73 (br d, 1H, J=7.9 Hz), 7.51 (br t, 1H, J=7.6 Hz), 7.41 (d, 1H, J=8.6 Hz), 7.37 (br d, 1H, J=8.2 Hz), 7.24 (br t, 1H, J=7.7 Hz), 7.21 (br s, 1H), 7.06 (br s, 1H), 6.76 (dd, 1H, J=8.6,2.2 Hz), 4.06 (t, 2H, J=5.9 Hz), 2.67 (t, 3H, J=5.5 Hz), 2.45 (br m, 4H), 1.51 (br m, 4H), 1.39 (br m, 2H). The reaction mixture was concentrated the residue was partitioned between water and ethyl acetate The organic layer was washed with water brine, dried over magnesium sulfate concentrated to give a pale-yellow foam the resulting solution was heated at 110° C. for 12 h The reaction mixture was concentrated yielded a tan solid The tan solid was filtered filtered

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

Procedure: The title compound was prepared by reacting the compound of Example 104 with 1-(2-chloroethyl)piperidine hydrochloride essentially as previously described. mp 167° C., NMR, IR, MS 570.

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

Procedure: The title compound was prepared by reacting the compound of Example 104 with 1-(2-chloroethyl)piperidine hydrochloride essentially as previously described. mp 167° C., NMR, IR, MS 570.

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

Procedure: A mixture of 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol (prepared according to Example 57; 70.0 mg, 0.172 mmol), potassium carbonate (71.2 mg, 0.515 mmol), 1-(2-chloroethyl)piperidine hydrochloride (31.6 mg, 0.172 mmol), and DMF (2 mL) was stirred at room temperature for 30 minutes and heated to 50° C. overnight. The reaction was cooled to room temperature and water (15 mL) was added and extracted with ether. A white precipitate formed in the ether layer and was filtered to afford N-(4-methylthiazol-2-yl)-3-phenoxy-5-(3-(2-(piperidin-1-yl)ethoxy)phenylthio)pyridin-2-amine (34.2 mg, 38.4% yield) as a white solid. 1H NMR (d6-DMSO) δ 9.56 (s, 1H), 8.29 (dd, 1H), 7.50 (dd, 1H), 7.28 (m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.82 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.35 (m, 1H), 3.79 (t, 2H), 2.23 (s, 3H), 2.17 (m, 4H), 2.12 (t, 2H), 1.38 (m, 4H), 1.31 (m, 2H); Mass spectrum (esi) m/z=519.1 (M+H). heated to 50° C. overnight The reaction was cooled to room temperature extracted with ether A white precipitate formed in the ether layer was filtered