Large scale oligonucleotide synthesis is particularly challenging for a variety of reasons related obviously to synthesis scale. Novel high loading supports have had to be developed. The synthesis cycle is usually modified to accommodate chemicals which are less hazardous and more easily recycled rather than treated as solvent waste. For that latter reason, chlorinated solvents are usually avoided. Because of the larger synthesis scale, reaction times are generally greater and so the incidence of side reactions becomes more relevant. As always, controlling side reactions is the key to purification of the product oligonucleotide. The most common side reaction during deprotection of oligonucleotides on a large scale is the alkylation of dT residues by acrylonitrile, formed by ?-elimination of the cyanoethyl phosphate protecting groups, to generate N3-cyanoethyl-dT.