To a suspension of NaH (17.6 g, 60%) in DMF (150 mL) at ice-bath temperature with mechanical stirring was added over a one hour period a mixture of 4-chlorobenzyl cyanide (30.3 g) and 1,3-dibromopropane (22.3 mL, 44.5 g). The reaction mixture was stirred for an additional 1 hour, and isopropyl alcohol (10 mL) was added slowly to quench excess NaH. Water (150 mL) was added. The reaction mixture was extracted with MTBE (2 × 200 mL), and the combined extracts were washed with water (3 × 200 mL), brine, and dried over MgSO₄. The solvent was removed in rotavapor and the final product was purified by column chromatography to give 1-(4-chlorophenyl)cyclobutanecarbonitrile (32.6 g, 85%) as a pale yellow oil. NMR complies.

Note: 1. The procedure was taken from US patent 6,974,838 B2. But we found anhydrous DMF (stored over molecular sieves) is a better solvent than DMSO in this case. 2. The reaction is very exothermic when the starting materials were added to NaH in DMF at 0 oC. The addition should be very slow in order to avoid foaming and overflow.

Morpholine (1.1 mL, 0.012 mol) was added to a solution of ethyl 4-(6-acetoxy-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)butanoate in 10 mL THF and the resulting mixture was refluxed for 1 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated, diluted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated under reduced pressure to give ethyl 4-(6-hydroxy-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)butanoate, isolated as a brown oil (1.2 g, 99% yield, NMR complies).

To a mixture of 4-(6-acetyl-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)butanoate (1.3 g, 0.003 mol), urea hydrogen peroxide (0.85 g, 0.009 mol) and sodium bicarbonate (0.76 g, 0.009 mol) in anhydrous dichloromethane (10 mL) under nitrogen atmosphere at ice-bath temperature was added trifluoroacetic anhydride (0.8 mL, 0.006 mol) drop-wise over a period of 10 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 24 h. The reaction mixture was diluted with 50 mL dichloromethane and washed with saturated sodium bicarbonate solution (50 mL), dried over sodium sulfate and evaporated under reduced pressure to give ethyl 4-(6-acetoxy-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)butanoate, isolated as a pale yellow oil (1.36 g, 99% yield, NMR complies).

A mixture of 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (3.4 g, 0.009 mol), sodium ethanethiolate (3.8 g, 0.045 mol) in 34 mL DMF was heated at 50 oC for overnight (12 h). The reaction mixture was cooled to rt and diluted with water (100 mL) and ethyl acetate (100 mL). The unreacted starting material was separated by extracting into the organic layer  using 2 x 100 mL ethyl acetate. The pH of the aqueous layer was adjusted to pH = 7 by carefully adding 1 mL of saturated aqueous citric acid solution. A oil gets separated which soon becomes a white solid. The solid was filtered off, washed with water, redissolved in dichloromethane, dried over sodium sulfate to give 2-((1-benzylpiperidin-4-yl)methyl)-6-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one as a white solid (2.4 g, 74% yield). NMR complies.

Ref. WO 2008/073452 A1, US 2008/0153878 A1

A mixture of 1-phenylethanol (1.21 mL) and 48% HBr in water (12 mL) was stirred at room temperature for overnight (12 h). The reaction mixture was diluted with 50 mL ethyl acetate, washed with 50 mL aqueous saturated NaHCO₃ solution, dried over Na₂SO₄ and evaporated under reduced pressure to give (1-bromoethyl)benzene as a light brown oil (1.5 g, 83% yield). NMR complies.

This material was prepared to protect the N atom of an amide so that after a sequence of reactions it can be cleaved off easily using MsOH. [06TL1813]

A 1.6 M solution of n-butyllithium in hexane (9.36 mL) was added to a stirred solution of diisopropylamine (2.22 mL) in THF (15 mL) at -5 to 0 ^oC. After being stirred at -5 to 0 ^oC for 30 min, the reaction mixture was cooled to -78 ^oC and ethyl isobutyrate (1.9 mL) was added. Stirring was continued at -78 ^oC for 45 min. A solution of 1-bromo-2-chloroethane (1.19 mL) in THF (1 mL) was then added dropwise to the mixture. The whole was further stirred at -78 ^oC for 1 h and at room temperature for 2 h, then poured into an excess of aqueous NH₄Cl solution and extracted with ethyl acetate, the extract was washed with brine, dried over MgSO₄, and evaporated in vacuum to give a residue, which was distilled to give ethyl 4-chloro-2,2-dimethylbutanoate isolated as a colorless oil, 2.1 g. NMR complies.

Ref: Chem. Pharm. Bull. 1997, 45, 1447-1457.

To a suspension of compound containing an acetyl (-COCH₃) group (0.01 mol) in 50 mL of dichloromethane was added m-chloroperbenzoic acid (0.03 mL) in three small portions at room temperature. The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with 50 mL dichloromethane and washed successively with 2% aqueous sodium thiosulfate (50 mL), saturated aqueous NaHCO₃ solution (2 × 50 mL) and brine (50 mL), dried over MgSO₄ and evaporated to give the corresponding Baeyer-Villager oxidation product (-OCOCH₃) which was purified by triturating with ether. White solid (60%).

Reference: Baeyer-Villager Oxidation

Sosnowski, J. J.; Danaher, E. B.; Murray, R. K. J. Org. Chem. 1985, 50, 2759-2763.

To a suspension of the acetate obtained in the previous step (0.0024 mol) in 4 mL ethanol was added 2 mL 2N aq. NaOH solution. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated on rotavapor under reduced pressure and the residue was cooled in ice bath. A few pieces of crushed ice were introduced into the flask and then acidified with 1N HCl solution. The precipitate formed was filtered and washed with water and air dried to give the corresponding phenol. Brown solid (73%).

To a suspension of sodium hydride (0.0004 mol) and alkyl methanesulfonate (0.0004 mol) in 5 mL THF at ice-bath temperature was added benzyl alcohol (0.0004 mol) in 5 mL THF dropwise. After the addition was complete, the resulting reaction mixture was allowed to warm to room temperature and then heated at 50 ^oC for 12 h. The reaction mixture was evaporated, diluted with 50 mL ethyl acetate, washed with saturated aq. NaHCO₃ solution and brine, dried (Na₂SO₄) and evaporated to give the corresponding benzyl alkyl ether  which was purified by silica gel column chromatography using ethyl acetate (75% yield, NMR and MS complies).

Procedure was taken from Bhatia S. K.; Hajdu, J. J. Org. Chem. 1988, 53, 5034-5039.

Note: This procedure worked in the presence of lactam and piperazine moieties.

To chlorosulfonic acid (0.9 mol) at 0 ^oC was slowly added salicylic acid (0.09 mol) with constant stirring. After all the salicylic acid was dissolved, the mixture was heated at 75 ^oC for 1 h. The mixture was cooled to room temperature and then carefully added to 250 g of crushed ice. The white solid precipitated was filtered, dissolved in ethyl acetate, washed with water, dried (Na₂SO₄) and evaporated under reduced pressure to give the corresponding chlorosulfonylated product (47% yield).

Source Literature: Coburn R. A. US Patent 4,939,132.

Note: Recently chlorosulfonic acid has been used as a reagent for cyclization of electron-withdrawing arenes in the synthesis of haloindanones. Sharma, A. K.; Subramani, A. V.; Gorman, C. B. Tetrahedron 2007, 63, 389-395.