With a few detours, I have ridden Route S from Bedford east during a tour from PGH to PHL. Bedford to Cowan's Gap State Park (which is very nice) is hilly. The rest of Route S isn't that bad. You can cut out one hilly section by riding a portion of the abandoned stretch of PA Turnpike between Breezewood and Pump Station Road. From there, it's easy to get back on Route S. The turnpike is a great ride. It's got a sort of post-apocalyptic look, which is why it was used in the film "The Road," starring Viggo Mortensen. You will need good lights as there are two unlit tunnels. The western tunnel is about 3,800'. The second is about a mile long and has a crown near the east portal so you literally cannot see the light at the end of the tunnel until you get close to the end. You will also need more than 23c tires. I road it last September fully loaded using 32c tires and was fine. Another nice thing about the tunnels is that the air inside is cool. Give you a good break from the heat.
Route S has its problems in Lancaster and Chester Counties. The biggest one being that it uses PA 23 more than it needs to and, IMO, more than it should. I was just out that way last weekend. PA 23 can have heavy traffic, especially on spring and summer weekends. From Morgantown east through at least Elverson, the road is banged up. When traffic is heavy, getting through Elverson is scary as the road is relatively narrow and the shoulder disappears. PA's 4' passing law hasn't sunk into the brains of many people. I can give you a better way to get through that area that spends more time in the beautiful Conestoga Valley and takes you through French Creek State Park, which has a nice, albeit busy on the weekends, campground. I can also give you a few other detours off Route S that I prefer.
I have never ridden Route S all the way to New Hope, but I have ridden to New Hope plenty of times. I have a couple different way to get there from Conshohocken, PA if you are interested. Route S takes you by the Schuykill River Trail. You could take that to Conshohocken and take one of my route to New Hope.
If you do decide to go through PGH, it might make sense to ride the GAP all the way to Cumberland and then head north on U.S. 220 to pick up Route S in Beford. That's what I did. Route S uses the GAP for a while but leaves it at Rockwood. There is a private campground just outisde Bedford and down the street from the original Cannondale headquarters.
In any event, I believe it's Route V that gives you more of the Allegheny Forest experience. It passes through DuBois, where Pamaguahiker is. I may be doing Youngstown, OH (Avis allows one way rentals to that location) to PHL in September via Franlkin PA then the Allegheny River Trail to meet up with Route V at Emlenton. I will eventually have to get off Route V to get to PHL. The preliminary plan is to go through Centralia and eventually into Lancaster County.