A decoration reaction was deemed successful when the library compound was isolated in >10 mg and >90% purity (by LCMS, evaporative light scattering detection). Of the 124 reactions performed, only one failed to deliver any product while eleven reductive amination products were isolated in less than 10 mg. Four products did not satisfy our purity threshold but were deemed of sufficient purity (>80%) for inclusion (with a flag) in the library. These results translate to a 90% success rate for compound library synthesis. Table summarizes the composition of the assembled compound library; further details can be found in the Supporting Information. To assess its chemical space coverage, we compared our bis-morpholine spiroacetal library with the collection of small-molecule drugs (molecular weight <700 Da 53 ) that have been approved by the Food and Drug Administration (FDA), 54 in the fraction of sp 3 carbon atoms (Fsp 3 )lipophilicity (cLogP)molecular weight (MW) chemical space (Figure ). To evaluate the dissimilarity of our compound library from this set of FDA-approved drugs, each compound in both libraries was translated into its Morgan 2 (an Extended Connectivity Fingerprint (ECFP_4) like) fingerprint using the KNIME platform; this allowed the calculation of Tanimoto Scheme 3. Orthogonal deprotection and decoration of spirobis-morpholine 9 a a Reaction conditions: (i) CbzCl, CH2Cl2, rt, 24 h; (ii) H2, 10% Pd/C, THF/H2O 4/1, rt; (iii) HCl (4 M in 1,4-dioxane), THF/H2O 4/1, rt; (iv) 2,4-difluoro-1-isocyanatobenzene, Et3N, CH2Cl2, rt, 1 h or pyridine-3-sulfonyl chloride, Et3N, CH2Cl2, 0 C-rt, 16 h, or 1-methyl-1H-pyrazole-4-carboxylic acid, HATU, iPr2NEt, CH2Cl2, 0 °C-rt, 16 h. coefficients, which are represented in histogram form in Fig- . The 3D scatter plot in Figure indicates our library occupies a similar region of physicochemical space to compounds in the FDA-approved list of small-molecule drugs. Tanimoto scores of between 0.2-0.4 indicate significant dissimilarity between compounds in our library and those on the FDA list. 26a Thus, while our library compounds have similar physicochemical properties to clinically approved small-molecule drugs, they are structurally distinct. We hypothesize that they may act on new targets and therefore represent attractive starting points for drug discovery.