Ortho esters can be prepared by the Pinner reaction, in which nitriles react with alcohols in the presence of one equivalent of hydrogen chloride.  The reaction proceeds by formation of imido ester hydrochloride:
:RCN + R′OH +  HCl → [RC(OR′)=NH]Cl
Upon standing in the presence of excess alcohol, this intermediate converts to the ortho ester:
:[RC(OR′)=NH]Cl +  2R′OH → RC(OR′) + NHCl
The reaction requires anhydrous conditions.
Although a less common method, ortho esters were first produced by reaction of 1,1,1-trichloroalkanes with sodium alkoxide:
:RCCl +  3NaOR′ → RC(OR′) + 3NaCl