Accurate methods to estimate free energies play an important role for studying diverse condensed-phase problems in chemistry and biochemistry. The most common methods used in conjunction with molecular dynamics (MD) and Monte Carlo statistical mechanics (MC) simulations are free energy perturbation (FEP) and thermodynamic integration (TI). For common applications featuring the conversion of one molecule to another, simulations are run in stages or multiple "λ-windows" to promote convergence of the results. For computation of absolute free energies of solvation or binding, calculations are needed in which the solute is typically annihilated in the solvent and in the complex. The present work addresses identification of optimal protocols for such calculations, specifically, the creation/annihilation of organic molecules in aqueous solution. As is common practice, decoupling of the perturbations for electrostatic and Lennard-Jones interactions was performed. Consistent with earlier reports, FEP calculations for molecular creations are much more efficient, while annihilations require many more windows and may converge to incorrect values. Strikingly, we find that as few as four windows may be adequate for creation calculations for solutes ranging from argon to ethylbenzene. For a larger druglike molecule, MIF180, which contains 22 non-hydrogen atoms and three rotatable bonds, 10 creation windows are found to be adequate to yield the correct free energy of hydration. Convergence is impeded with procedures that use any sampling in the annihilation direction, and there is no need for postprocessing methods such as the Bennett acceptance ratio (BAR).