Direct-to-Biology (D2B) in combination with high throughput screening streamlines the target discovery pipeline by obviating the need for separation and purification. Reactive chemical fragment and PROTAC design have both significantly benefitted from this style of HTS. However, D2B currently requires some careful experimental design to limit the noise of crude reactions. For example, reagent scavengers may be used to remove unwanted reaction components via filtration, but their application is limited to select reagents. For common chemistry such as peptide bond formation reactions, resins to remove residual coupling agent are commercially available, but this is not universal for all useful reactions. Alternatively, crude reaction mixtures can be used for biological investigation, however, the reagents utilized must not interfere with the assay to form false negatives or false positives. Likewise for any byproducts formed, reaction optimization should be performed to limit the number of side products. Often only higher yielding reactions are used in assays; lower yielding reactions are not further investigated due to the confounding effects of lower yielding reactions in the biological assay. A robust method to deconvolute the inherent noise of the crude reaction from the biological activity would increase the scope of high throughput D2B to a more diverse range of chemistries.