SUMMARY The current proposal is seeking funding to achieve the fundamental goal of systematically identifying processes that show promise during HHP activation. A broad range of reactions will be investigated by theoretical calculations to identify processes that are stimulated by HHP. Then the selected reactions will be studied experimentally confirm the results, and determined the extent of the pressure effect. Our own preliminary data indicate that even a serendipitous search of reactions can yield positive results, however the lack of systematic framework greatly inhibits progress. What makes the identification of such reaction networks especially worthwhile is the fact that HHP equipments capable of industrial scale syntheses are already available and commonly used in the food industry. Thus, any reaction identified in our project could be scaled-up to industrial scale in a short time. We intend to achieve these goals in two major steps: (1) Scanning a broad range of reactions by theoretical calculations based on the determination of the V‡ and V values. The first aim will focus on building a reaction network by selecting a broad range of transformations based on a literature search and carrying out the theoretical calculations to determine the favorability rating of those reactions, and identify reactions that are being enhanced under high pressure conditions. The second aim focuses on the experimental testing of the selected reactions as classified by the in-silico methods to confirm that HHP in fact improves these reactions. The combination of the data obtained in Aims 1-2, will aid us to make a more reasonable predictions regarding future applications of HHP. Finally in aim 3 we extend the application of the HHP-based protocol to currently known active pharmaceutical ingredients, such as pain killers (paracetamol, or Aspirin), benzodiazepines, pyrazoles, and hydrazones to illustrate the potential usefulness of the high pressure synthesis to the pharmaceutical industry.