Venturing into the immensity of the small molecule universe to identify novel chemical structure is a much discussed objective of many methods proposed by the chemoinformatics community. To this end, numerous approaches using techniques from the fields of computational de novo design, virtual screening and reaction informatics, among others, have been proposed. Although in principle this objective is commendable, in practice there are several obstacles to useful exploitation of the chemical space. Prime among them are the sheer number of theoretically feasible compounds and the practical concern regarding the synthesizability of the chemical structures conceived using in silico methods. We present the Proximal Lilly Collection initiative implemented at Eli Lilly and Co. with the aims to (i) define the chemical space of small, drug-like compounds that could be synthesized using in-house resources and (ii) facilitate access to compounds in this large space for the purposes of ongoing drug discovery efforts. The implementation of PLC relies on coupling access to available synthetic knowledge and resources with chemo/reaction informatics techniques and tools developed for this purpose. We describe in detail the computational framework supporting this initiative and elaborate on the characteristics of the PLC virtual collection of compounds. As an example of the opportunities provided to drug discovery researchers by easy access to a large, realistically feasible virtual collection such as the PLC, we describe a recent application of the technology that led to the discovery of selective kinase inhibitors.