My initial response was only in relation to the failure to generate a layout for more than 12 diffusers per your initial question.
On the wider issue now raised, personally I've never been reliant on auto-generation of network layouts - it never seems to get it quite right and then you're left with having to modify what it produces, e.g. branches reversed or main runs split into short sections between take-offs etc. Often I think its easier/quicker to sketch out the bones of the system and then use the "Connects into" option for diffusers.
I assume you've noticed that you can scroll through various possible system layouts before you commit to the one closest to what you want:

Regarding the diagonal layout problem, I would suggest breaking the systems down into chunks, then join them later:

However the diagonal layout doesn't seem to generate if you use the "Place Base" option to define the source end of the system, unless you play about with the view rotation by rotating the crop region or by changing the true north settings.
You've also got the option of generating a layout with placeholders which you can then edit/modify before converting to ducts.
So really its a bit of trial and error to see what works for you but if you think that you can automatically generate a layout for a substantial system and it won't require any manual input from yourself then I think you're going to be disappointed (despite what you might have seen in sales videos or in simplistic training tutorials).
Hope this helps. Other users on the forum might have different experiences of layout generation so maybe they can make other suggestions.