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The waters of the Aegean energetically licked the hull of the Venetian vessel. Henry de Asti, looking on pensively, might even have felt a comradeship with this sea, which was nearly as conflicted as he was.

He'd intended for his vessel and the massive fleet which trailed behind it to set sail for Smyrna. In 1342, five years ago, he'd negotiated with the Cypriot King and the Knights of Rhodes. They'd agreed to petition the pope for a crusade to Smyrna. Clement VI had given them their crusade, but directed it a little further north, to Pergamon. And so Henry and his fleet sailed on, with explicit instructions to retrieve the city of Nicaea from the local upstart Turk [1], who dared to use it as a base of operations for his meddlesome intrusions in the affairs of the Greeks...​

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Excerpt from The Crusade of Nicaea, by Geoffrey Godwin:

Although the exact details of the redirection of what would have been the First Smyrniote Crusade to Nicaea are uncertain, the general motives of the Pope can be inferred from contemporary data. Pope Clement VI appears to have earnestly wanted negotiation and eventual union between the Eastern and Western churches. However, the Eastern Church, along with the Byzantine Empire itself, was locked into an intense struggle over its very future. Throughout the 1340s, the parties of John Kantakouzenos, the Empire's chief minister, and Anna of Savoy, the mother of its child Emperor, tore the already struggling Empire apart in a succession war that contained within it religious controversy and outright class warfare. In this contentious environment, both sides reached out to allies. John Kantakouzenos allied with Umur Beg of the coastal Aydin Emirate and, notoriously, with Orhan Beg, the lord of northwestern Anatolia. Orhan had already done much to expand his control in the region, conquering the cities of Nicaea and Nicomedia in the 1330s. Orhan's expansionism did not discriminate: on a flimsy casus belli pertaining to succession, he conquered the fellow Turkish principality of Karesi and its port of Pergamon in 1345. In 1346, John Kantakouzenos allied with Orhan, and allowed Orhan's soldiers to intervene in the Byzantine civil war. Orhan's domain was closer to the Byzantine core than any other Turkish fiefdom, and from this location his soldiers launched devastating raids on Thrace.

Meanwhile, Anna redoubled on efforts to reach out to the Latins. She had extracted an offer of aid from the Venetian Senate as early as 1343. Her correspondence with Clement, meanwhile, made a simple proposal: ecclesiastical union in exchange for help against Kantakouzenos's Turkish allies. Henry de Asti, the bishop of Negroponte, was appointed by the pope to lead a new Crusade in the East. However, Henry and the Venetians (a vital part of the alliance) favored an attack on the Aydin Emirate, whose pirates harmed Christian shipping in the Aegean. However, the Pope grew to favor an attack on Orhan's domain for two reasons.
1. Orhan's success in reaching core Byzantine territories like Thrace demonstrated his strength and preeminence among the Anatolian beys. However, this success proved to Greek and Latin alike that he was the greatest threat to the Eastern Church's future security.
2. In official correspondence between 1345 and 1346, Anna promised the city of Nicaea, conquered by Orhan in the 1330s, to the Catholics. For the unionist Pope Clement, the promise of the city of the Nicene Creed made the decision clear.
The Venetians, at first reluctant to allow Aydin to maintain its piracy with impunity, gradually came to realize the value of Nicaea, with its close proximity to Constantinople, as an economic outpost.

By 1347, the Crusade of Nicaea had begun.

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The POD is that the Smyrna Crusade of OTL, whose only successes were short-term, is re-routed to the Ottoman Beylik, and ready to inflict some serious wounds on a still-fragile state.
The House of Osman drew the short stick in this timeline, and we'll get a chance to see how the Balkans and Anatolia fare in their absence.
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