My graduate school mentor use to say that you could synthesize anything if you had the right precursors. With enough clever reagent artistry, most small molecules can be assembled, though if only enough for an NMR spectrum. With chromatography and small glassware, it is not unreasonable to do a few reactions on 1 mg of material and recover enough mass to get a proton and carbon NMR. Yes, I know that with microfluidics and labs on a chip, much lower quantities can be handled. But I refer to getting your hands on enough material to see.
What most of us who came through graduate chemistry have learned is that there are enough acids, bases, protecting groups, oxidants, reducers, latent functionalities, and catalysts out there to choose from so that some combination should get you to an endpoint in your synthesis. If not, then NMR, mass spec, IR, and imagination (with ample hand waving) should at least give an idea of why something won’t work.
Reaction chemistry (not including biochemical transformations!!) can be thought to occupy two broad domains- 1) low temperature, ambient pressure transformations with highly reactive species (preferably named after dead chemists), and 2) high pressure, high temperature transformations with lower reactive species. Most chemists fresh out of school know the former better than the latter. And that drives our problem solving strategies: Finding reactive intermediates that will react between -30 C and 150 C with a 5 lb nitrogen sweep in a kettle reactor.
Sometimes, the dumber brute force approach is worth considering. What can be done under pressure and at elevated temperature? Or, what can be done at high temperature and short contact time? That dusty Parr reactor sitting in the corner may be capable of a goodly bit of magic. Behind a shield. It is good to visit the high temperature, high pressure world now and then. Of course, our engineering friends already know this.
As far as the search for simplicity goes, consider what merits there may be in thermally driven transformations. Every once in a while it may be a viable avenue for something useful. Try thinking of heat as a kind of reagent. Chemical plants are good at producing heat.
Lamentations on Chemistry 
This is really great — thanks for inspiring my Process Wednesday post!
I wish I could give some good examples, but I’m not at liberty to give juicy examples. One class of transformations to consider at elevated temp are elimination reactions. We tend to think of elimination reactions as synchronous or stepwise reactions using an acid or base, but what happens at elevated temp with no acid or base? Perhaps silica or alumina at elevated temperature is acidic or basic enough. Decarboxylation offers the possibility of activation by an adjacent carbonyl followed by extrusion of CO2 at a later point in the scheme.
We should all try to do transformations with good atom efficiency. Exotic PGM catalysts with wild heteroatom ligandry adds costs that may or may not be easily made up by the catalysis step. The economics of using a PGM catalyst should always be closely scrutinized. It’s worth paddling into the brackish waters of early 20th century chem abstracts to see what people were doing from 1900 to 1950. It’s hard to believe, but they were just as smart as we are.
“It’s worth paddling into the brackish waters of early 20th century chem abstracts to see what people were doing from 1900 to 1950. It’s hard to believe, but they were just as smart as we are.”
Certainly true, especially considering the instrumentation constraints.