A microwave-assisted protocol for the synthesis of 4-oxo and 4-chloropyrido [2,3-d]pyrimidin-7(8H)-ones, 13 and 9 respectively, bearing a carbon substituent at C2 and a chlorine atom at C4 is reported. The introduction of a wide range of substituents at C2 renders this methodology easily amenable to combinatorial chemistry applications. Two examples of further derivatization of compounds 9, substitution by amine and Suzuki coupling, under microwave irradiation are also described. IntroductionPyrido [2,3-d] Our group has actively been working in the development of synthetic strategies for the preparation of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a,b-unsaturated esters (3) (Scheme 1). Thus, in the so called cyclic strategy 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitriles (5) are obtained by reaction of an a,b-unsaturated ester (3) and malononitrile (4, G CN) in NaOMe/MeOH [11]. Treatment of pyridones 5 with guanidine or amidine systems (6, R 5 NH 2 , H, alkyl, aryl, heteroaryl) affords 4-aminopyrido[2,3-d]pyrimidines (2, R 4 NH 2 ) [12]. The 1,5-dinitrile systems 7 were obtained by reaction of the corresponding pyridine-3-carbonitriles (5) with sodium cyanamide [13]. Treatment of 7 with hydrogen bromide afforded both positional bromo-substituted isomers depending on the thermal level employed. Thus, when the reaction was carried out at low temperature the 2-amino-4-bromo-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (2, R 5 NH 2 , R 4 Br) were selectively formed, but when the process was run at high temperature the 4-amino-2-bromo-substituted compounds (2, R 5 Br, R 4 NH 2 ) were predominantly obtained [14]. This behaviour was found to be independent of the nature and position of the substituents present on the pyridone ring. On the other hand, we described an acyclic variation of the above protocol for the synthesis of pyridopyrimidines (2, R 4 NH 2 ) based on the isolation of the corresponding Michael adduct (8, G CN) [15], that also allowed us to obtain 4-oxopyrido [2,3-d] From the preceding discussion it is clear that, so far, we were only capable to synthesize 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (2) with a carbon substituent at position C2 by using an amidine (6), which causes the presence of an amino group or a carbonyl group at C4 of the resulting pyrido [2,3-d]pyrimidine. Now, as a part of our ongoing research in the area of combinatorial chemistry focused on the preparation of random libraries for High Throughput Screening (HTS), we decided to devise a strategy to synthesize 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (9) bearing a carbon substituent at C2 and a chlorine atom at C4 (R 4 Cl), susceptible of subsequent decoration chemistry (reduction, nucleophilic displacement with amines, C À C bond formation). The present paper deals with the results of this study. Results and discussionIn order to synthesize pyridopyrimidines (9) with a carbon substituent at position C2 and a chlorine atom at C4, we have developed a synthetic strategy based on the cyclization with anhydro...