Multisite lambda dynamics (MS lambda D) is a powerful emerging method in free energy calculation that allows prediction of relative free energies for a large set of compounds from very few simulations. Calculating free energy differences between substituents that constitute large volume or flexibility jumps in chemical space is difficult for free energy methods in general, and for MS lambda D in particular, due to large free energy barriers in alchemical space. This study demonstrates that a simple biasing potential can flatten these barriers and introduces an algorithm that determines system specific biasing potential coefficients. Two sources of error, deep traps at the end points and solvent disruption by hard-core potentials, are identified. Both scale with the size of the perturbed substituent and are removed by sharp biasing potentials and a new soft-core implementation, respectively. MS lambda D with landscape flattening is demonstrated on two sets of molecules: derivatives of the heat shock protein 90 inhibitor geldanamycin and derivatives of benzoquinone. In the benzoquinone system, landscape flattening leads to 2 orders of magnitude improvement in transition rates between substituents and robust solvation free energies. Landscape flattening opens up new applications for MS lambda D by enabling larger chemical perturbations to be sampled with improved precision and accuracy.