I love little thought experiments like this, so heres my 2 cents:

1. Targeting a modern architecture is good, but if I were being this ambitious, I would wager having such a backwards compatable burdened architecture like x86_64 (even when it is highly performant just through raw funding dollars) I would still rather start at square 1 on some risc 64 bit virtual 48 bit physical word system. Go even further, and design such a hardware ecosystem with heterogeneous computing built into the foundations - have arbitrary numbers of ALUs and FPUs and have different pipeline structures allowing for various degrees of SIMD parallelism across some tightly integrated weak cores and more heavily pipelined and bulkier serial cores, and have an intelligent enough instruction set to allow for scheduling (or even better, the hardware itself) to recognize parallel tasks and execute them with varying degrees of parallelism. Take AMD Fusion or Tegra to the next level and instead of having a discrete gpu and cpu on one die mash them together and share all the resources.

2. I'd kick C out. If I'm going with a new architecture, I need to write the compiler from scratch anyway. I might consider LLVM for such a system, just because the intermediary assembly layer is intentionally lossless and allows for backwards language compatability with everything under the sun right now. But ditch C, take modern language concepts from C++, Python etc, and cut down on the glyphic syntax and try rethinking the distribution of special characters (I think pointer<int> c makes more sense than int (star)c, for example - go even further, and provide 3 levels of verbosity for each concept, like pointer<int32> c, ptr<int32> c, and &:i32 c). I would definitely want to fix standard type sizes at the least, having things like i32 integers instead of the int type being 16 or 32 bit, etc, with some more modern niceities like the D style real float that uses the architecture restricted maximum FPU register size).

3. Screw UEFI, mainly because it is a design by consortium concept - it is inherently cumbersome because it was a commitee project between industry giants rather than a revolution in booting. I do like cutting down on legacy interfaces, I'd go even further and try to minimize my system to (in theory) one serial transport and one digital, maybe 4, with unidirectional and bidirectional versions of both, and maybe support for some classic analog busses (like audio, which doesn't make much sense to transport in digital format, although I haven't looked into it much). Everything plug and play, everything attempting to provide power over a channel so you don't need additional power connectivity if you can avoid it. For the BIOS, I would replace it with some metric of scan busses for profiles -> incite some kind of device-wise self test -> provide device information in memory to the payload binary, to allow memory mapping and all the other goodness. Maybe even have the bios itself act as a sub-kernel and provide the mapping itself. Maybe even fork the kernel, and treat it like some kind of paravirtualized device environment where the bios never overrides itself with the payload but instead stays active as a device interface. Saves a lot of code redundancy between the two then. It would of course have an integrated bootloader and the ability to parse storage device trees for some bootable material. Maybe have file system standards where each partition has a table of pointers to loadable binaries somewhere, or maybe stick them in some partition table entry (obviously not a FS expert here).

4. Screw URIs, go straight for a kernelwise VFS that can reference everything. I'd love to see /net/<IP address>/ referening the top level of some remote servers public resources. You could have a universal network protocol where each connection is treated as a virtual mount, and individual files (and everything is a file, of course) can dictate if they use streamed or packet based data off some network transaction about the base protocol. So instead of having http://google.com, you could use /net/google.com/ which when opened does DNS resolution in the VFS to 74.125.224.72 (well, ipv6, obviously - we are talking about a new OS here, so 2001:4860:8006::62 - and as a side note, I would never try to get rid of IP as the underlying transport protocol - as insane I might be about redesigning hardware and rethinking stuff people much smarter than myself came up with, I know you will never ursurp IP as the network trasport everyone uses to connect the world ever). And then when you open google.com/search, you open a remote file that interprets the "arguements" of ?q=baconatorextreme on the extension into the returned page file that you access.

I agree with getting rid of Unix directories, they are outdated crappy, and all their names make no sense. However, /bin is meant to be system required binaries to boot, where sbin is root utility binaries, /usr/bin is general purpose executables that might not be local to the machine and might be a remote mount, and /usr/local/bin is the local machines installed binaries. Of course these polcies are never abided by, and they still have /etc, /usr/games, and a bunch of other folders to make life a hassle.

That's enough rates for a HN comment thread though, I'll stop and spare y'all :P