As examples, the challenge of designing sensors based on dynamic covalent chemistry coupled with weak NCIs is evident in the field of chiroptical sensing (Figure ). Many chiroptical sensors 1 feature a configurationally labile set of CD-active chromophores that interact via exciton coupling (e.g., + and -configurations, depicted in red and blue, respectively). In the absence of a chiral analyte, the (+)-1 and (-)-1 configurations are enantiomeric and exist in a 1:1 equilibrium ratio. As a result, the Cotton effects from each enantiomer of the sensors cancel with no net CD signal observed. However, upon binding an enantioenriched analyte, the NCIs between the analyte 2 stereocenter and the optically active chromophores (depicted with a grey arrow) can lead to a net CD signal, which in turn is used to determine the enantioenrichment of 2. When the stereocenter is adjacent to the binding functional group (2, n = 0), repulsive steric interactions influence the relative twist of the chromophores, often leading to a substantial CD-signal (e.g., > 10 mdeg). When the stereocenter is remote (2, n ≥1) the steric interactions necessarily diminish, and multiple weak NCIs (including attractive interactions) could presumably induce a measurable CD-signal. However, there are a dearth of reports for chiroptical sensing of remote stereocenters. 6 One of our groups has been particularly interested in developing chiroptical sensors of enantioenriched alcohols (Figure ). We have shown that 2-formylpyridine (4) can efficiently react with dipicolylamine (5) and Zn(OTf)2 in the presence of an acid catalyst (chloroethylmorpholine hydrochloride, CEM•HCl) to form hemiaminal 6 (Figure ). The pyridine rings in 6 adopt enantiomeric CD-active helical configurations (P and M, depicted in red and blue, respectively). Upon binding of a chiral alcohol 7, a series of diastereomers form by virtue of the pyridine helical twist, the chiral alcohol, and the newly formed point stereocenter of the hemiaminal ether functional group. If the alcohol is enantioenriched, one configuration at the hemiaminal ether group dominates, which induces a bias toward a P or M twist of the pyridines, leading to exciton coupling and thus an observable CD signal. The magnitude of the CD signal can be correlated through a linear free energy relationship to differences in steric size of the R-groups on the stereocenter of the alcohol. This sensor assembly has proven to be robust in detecting the enantioenrichment of a-stereogenic alcohols in many settings. More recently, we developed complex 8 that is capable of sensing the more challenging b-stereogenic alcohols (Figure ). The design strategy hinged on the incorporation of an "appendage" off the pyridine ring closest to the hemiaminal group that could interact with the more remote stereocenter. While the assembly formation is identical to 9, the chromophore responsible for sensing the chirality of the alcohols is an atropisomeric biaryl motif (depicted in red and blue). Importantly for the present work, however, designing sensors for the more challenging g-stereogenic alcohols 11 remains a tremendous challenge (Figure ). Merging the need to develop sensors for g-stereogenic alcohols with the challenges of identifying what structural features are required to achieve this goal, we sought to develop an integrated synthetic and data science-based workflow (Figure ). With such a remote stereocenter, significant steric interactions with the three pyridines or the atropisomeric chromophore were anticipated to be minimal, while the possibility of attractive NCIs could arise that would place a twist into either chromophore. Ideally, this workflow would allow one to simultaneously optimize, as well as understand, the performance of chiroptical sensors that require multiple weak NCIs to function effectively. Four key stages were envisioned: 1) a simple machine-learning (ML) enabled strategy would be used to carefully identify highly diverse appendages (blue in structure 10) that are synthetically accessible, 2) the selected compounds would then be synthesized and tested, 3) the resultant data would be used to train statistical models that correlate structural features to CD signal intensity, and 4) interrogation of the models would provide insight to inform next generation designs. This workflow is iterative in nature, wherein the mathematical model is applied to quantitatively predict the performance of new assemblies and ultimately deconvolute the noncovalent interactions critical to the success or failure of the chiroptical sensor. Herein, we present the successful application of this workflow to the identification and interrogation of chiroptical sensors of g-stereogenic alcohols. Further, we were able to bolster the insight acquired from statistical modelling with DFT-level calculations to probe the underlying NCIs responsible for the observed sensor performance.