Pyrido[2,1-b][1,3]oxazines decorated with acetylenic, ester, aldehyde, ethyloxalyl functions, alkyl, aryl and heteroaryl substituents are readily assembled in up to 83% yield, mainly (∼90%) as 2S*,9aS*-diastereomers, by a mild (room temperature, no catalyst and solvent) one-pot procedure from pyridine and oxalylacetylenes (1:2 M ratio). The quantum chemical calculations (B3LYP/6-311G(d,p)) show that 2S*,9aS*-diastereomers of the pyrido[2,1-b][1,3]oxazines are more energetically preferred over 2S*,9aR*-diastereomers (by 2.9 kcal/mol for a modal example).