I have been traveling once 6 years ago from Skopje - Instabul and back to Skopje.
The trip lasts approx. 14-16 hours... Mine trip has started in 16:00 o'clock and finished in Istanbul main bus station in 07:00 o'clock in the next morning. Until Sophia (which I have been couple of time before it lasts some 6 hrs, including the time wasted on the Gjueshevo(BG)-Deve Bair(MK) border crossings.
We have made some brake in can you image KOSOVA, named restaurant in the middle of Buglaria
Some companies like Hisar Turizam (MK) & Vardar Tuyrizam (TR), IPEK Turizm (TR) have everuday line from Istanbul - via Skopje(MK)/Tetovo(MK)/Gostivar(MK)/Kicevo(MK) to Struga(MK).
If you can't find a direct bus to Skopje, than a direct bus to Sophia and then try looking for MATPU (BG) company which drives twice per week for Skopje.
The following Get in Skopje
page might be also of great help.
Hope it helps...
Regards from Skopje