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This Small Business Research Phase I project will develop novel silyl protecting groups for RNA/DNA oligonucleotide synthesis. The synthesis of RNA is more difficult than DNA because a more complex protection scheme for nucleoside monomers is required. The 5-silyl-2-orthoester (2-ACE) strategy addresses this problem and provides RNA of excellent purity and yield. This achievement is invaluable to RNA scientists studying molecular biology or developing therapeutic strategies. Such research absolutely requires synthetic oligonucleotides that often incorporate modifications and are made by no other means. The goal of this SBIR Phase I proposal is to reduce the cost and increase the reliability of RNA synthesis so that amidites can be provided to the scientific community. The new silyl groups to be developed will facilitate nucleoside monomer preparation by improving selectivity for 5-protection and will promote economical purification strategies including crystallization. Nucleosides 5-protected with potential silyl candidates will be examined for their stability, ease of deprotection during solid phase synthesis, and amenability to incorporation of chromophores for real-time assays of coupling efficiency The commercial application of this project will be in the rapidly growing RNA synthesis market to support research endeavors in molecular biology and drug design.