What directories can be safely moved to the non boot drive

I have a 100 GB SSD that has filled up. I moved /Applications to a separate (non-SSD) drive using ditto. The system is much slower including booting up. Does the bootup process use executables in /Applications? **Finder** is also slower; Finder is not in /Applications. Spotlight is far slower. Can it be forced to reindex the files? In short what folder or files can be safely or intelligently moved off the boot drive? And secondly off the boot drive onto a slower drive of the following: /Applications /Library /Users I thought of splitting up /Applications into Mac/System one and downloaded applications. Is it sensible to move the /Users directory onto the external drive in order to separate it from system files and folders? And finally, is rsync or ditto any better for moving?