A library of 25 novel 3,6-disubstituted and 3-substituted pyrazolo[1,5-a]pyrimidines were synthesized using a microwave chemical reactor in 3 steps with a total reaction time of 1 hour. The products were obtained in good to excellent yields (20-93%, ave. = 62%). The synthesis began with the reaction of aryl acetonitriles with dimethylformamide-dimethylacetal (120C, 20 min), followed by treatment of the resulting 2-arylacrylonitrile with H2NNH2 • HBr (120C, 20 min). The intermediate 4-arylpyrazol-5-amine obtained was finally reacted with either 2-aryl-substituted malondialdehydes or 1,1,3,3-tetramethoxypropane (120C, 20 min) to give the final products. The products were either collected directly on a Buchner funnel or purified via flash chromatography. The compounds were screened for anti-cancer activity against the A2780 Ovarian cancer cell line in vitro at 10 µM. The most active compound was the 2-(pyrazolo[1,5-a]pyrimidin-3-yl)benzothiazole, herein referred to as RD-I-53, which had an EC50 value of 0.9 µM nearly mirroring the experimental control, Dorsomorphin, which had an EC50 of 1.1 µM. RD-I-53 was screened against a panel of 453 kinases by DiscoverX in a KinomeScan™, a competitive binding inhibition assay wherein RD-I-53 selectively inhibited VPS34 kinase and JAK1-JH2 pseudokinase (Kd VPS34 = 0.4µM, Kd JAK-1 JH2 = 0.5µM). NCI-60 data revealed selective anticancer activity of RD-I-53 against the MCF-7 and MDA-MB-468 breast cancer cell lines. Virtual docking studies of RD-I-53 against the VPS34 active site and its derivatives resulted in the creation of a virtual library of new compounds with potentially improved anticancer activity. A highly convergent route was developed to facilitate the ease of access to derivatives of RD-I-53. In the process, new methodologies for the synthesis of 2-aminobenzothiazoles and the thiocyanation of non-C4-substituted anilines and heterocycles were investigated and reported. A library of derivatives of RD-I-53 has been synthesized to be screened for potentially improved kinase inhibitory and anti-cancer activity.