The invention provides general methods for preparing 2,9-, 2,6,9-, O⁶-aryl- and O⁶-alkyl-substituted purines in a combinatorial and traceless fashion. The methods involve, in some embodiments, Mitsunobu alkylation of 2-fluoro-6-phenylsulfenylpurine at N9 with alcohols in solution, followed by C2-capture of the purine core with a resin-bound amine and subsequent oxidation and displacement of the C6 sulfonyl group with amines and anilines. In one aspect, the present invention provides a method of preparing a 2,6,9-substituded purine compounds of Formula I: ##STR1##

the method comprising:

• a) oxidizing a resin-bound compound of Formula II: ##STR2##
• to provide a resin-bound compound of Formula III: ##STR3##
• b) reacting the compound of Formula III with an amine of Formula IV

  to provide a resin-bound compound of Formula V ##STR4##

• c) cleaving the resin-bound compound of Formula V from the resin to provide the substituted purine compounds of Formula I.