Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#N)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([Mg]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.C([O:27]CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: CCOCC
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 17.5 °C
Reaction time: 0.75 h

Procedure:
A 31 double jacket reactor was charged with 4-Benzyl-morpholine-2-carbonitrile (135.05 g; 1 eq) and dry diethyl ether (1.4 l). Alternatively, toluene may be used in place of diethyl ether. When Tj=0° C. and Tm=1° C. (Tj=temperature of the jacket, Tm=temperature of the mass), phenyl magnesium chloride (2M sol. in tetrahydrofuran, 360 ml, 1.08 equiv., available from Aldrich Chemical Company) was added dropwise over 1 hour. Tm rose to 4° C. and came back to 2° C. at the end of the addition. Tm was progressively raised to 17.5° C. over 45 minutes and the mixture stirred at this temperature for another 45 minutes. The reactor was cooled down to Tm=2° C. and Tj=0° C. (75 minutes) and hydrochloric acid (700 ml of 5N solution) was added in two portions. Tm rose to 33° C. After some minutes, the hydrochloride salt of the ketone crystallised. When Tm=Tj=room temperature, the triphasic suspension was filtered. The organic layer of the mother liquors was eliminated. The filtration cake was then washed with methylene chloride (700 ml). This liquor was charged in the reactor with the acid aqueous layer. Treatment of the hydrochloride salt: After drying under vacuum, 164.4 g of the hydrochloride contaminated with MgCl2 were suspended in a biphasic mixture of water/methylenechloride (500 ml/800 ml). The suspension was basified with aqueous sodium hydroxide (75 ml of a 30% solution) under ice bath cooling. Mg(OH)2 precipitated and the aqueous layer was extracted with methylene chloride. The organic layers were filtered on a bed of Celite 512 after addition of Celite. The filtered organic phase was dried over magnesium sulphate and evaporated to dryness. The ketone crystallized readily on standing (132.4 g; 70%). Treatment of the mother liquors: The combined organic phases were washed with aqueous sodium hydroxide (750 ml of a 2N solution). Celite 512 (160 g) was added to the suspension which was then filtrated through a bed of Celite. The aqueous layer was separated and extracted with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to provide 35.8 g of the title compound enriched with unreacted nitrile. Chiral compound was obtained after separation using chiral HPLC on a Daicel chiralpak AD 20 μm column with 100% Ethanol/0.3% DMEA as eluent at a flow rate of 150 ml/min and UV-detection at 300 nm. Alternatively, the two enantiomers may be separated by fractional crystallization from acetonitrile using from 0.55 to 1 equivalent of dibenzoyltartaric acid to generate diastereoisomeric salts of the title compound. The crystals may be collected by filtration and neutralized with 30% NaOH to afford the optically enriched title compound.