I ned your advice in terms of posible routes, travel time and cost.
What concerns routes, in most cases fastest and most convenient way will be to go via Bavaria, Austria (Vienna) and Hungary (Budapest). Travel time between Frankfurt (Main) and Budapest is between 10 and 11 hours when you take daytime high-speed trains or 13+ hours when you rely on overnight travel option. Another 8 hours is for the journey from Budapest to Belgrade (daytime and overnight options available) and finally extra 4-5:30 by train from Serbian capital to Nis. Obviously all of the above are raw travel time, so in addition you'll have to account extra time for waiting between trains (depends on time you want to depart/arrive)
Imho, we would probably opt for an option of late morning departure from Frankfurt on daytime high-speed trains, evening arrival to Budapest and overnight train from Budapest to Belgrade, while then either morning train to Nis or even bus, which is a bit faster than train
Also, would it be possible to buy tickets online for this particular itinerary?
Not only possible, but preferable, especially on leg from Germany to Hungary. When buying in advance via official
German Railways (DB) website you can get ticket Frankfurt-Budapest for as low as 39 euro (daytime trains) or 49 euro (overnight), while on the day of the journey the same ticket will be already 170 euro. On legs from Budapest to Belgrade and from Belgrade to Nis there is no point to buy anything in advance, since ticket prices aren't dependable on time of the purchase. Budapest to Belgrade is 15 euro, while Belgrade to Nis is 800 or 900 RSD (depending on train category)
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