Can we pick up the car one place and return it to another?
Yes, though there might be a fee for this. Check with the rental company to find out how much.
Is there a website that is good for hotels?
I'm sure but I'm afraid I don't know any off the top of my head. Other members will, though.
How long is each leg of the drive and are there places to visit en route?
This is off the top of my head but:
Las Vegas to Los Angeles - 5 hours
Los Angeles to Yosemite - 5 to 6 hours
Yosemite to San Francisco - 5 hours
I could be a bit off... well, I know the Vegas to LA one is about right. The other two... I've never driven to be honest. The couple of times I've been to Yosemite weren't from LA. But I think my times aren't TOO far off. You can always go to Google Maps to double check too. Of course, I could that too but... that should be half the fun for your trip planning.
What is the best time to look at booking flights and do you book them all with the same airline to get the best deal?
I'm not sure about the first question. The second... I'm not 100% sure either but I doubt it. The flights are going to be independent of one another and it's entirely possible you could find a better deal with a different airline on, say, the return journey than on the inbound flight.