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Istanbul is the largest city in Turkey (and in Europe), and the country's economic and cultural hub. The city has existed for millenia, formerly called Byzantium and Constantinople, and was the capital of the once-proud Byzantine Empire. Istanbul is the home of Madrigal agent Erasmus Yilmaz, and his cousin, Bartu Yilmaz, operates a hotel in the city.

Istanbul is dominated by the Janus branch of the Cahill family, who hid a Clue, Sulfur, on one of the columns of Istanbul's most famous landmark, the Hagia Sophia. The hidden Clue has attracted a great deal of attention from Clue hunters from other branches; for example, Lucian leader Vikram Kabra sent agent Irina Spasky to Istanbul to search for the Clue, without success. During the Clue Hunt, Team Six may have visited the Hagia Sophia, as Jonah Wizard gave the Clue Sulfur to Isabel Kabra when threatened in the Madrigal Gauntlet. Card 194: Sky Message suggests that Team Two may also have visited Istanbul.

Some time after the conclusion of the Clue Hunt, Isabel Kabra visited Istanbul with her charity, AidWorksWonders, in her capacity as Vesper Two to find a place in the city (which sits on a subduction zone) for the use of the Machina Fini Mundi. A team affiliated with the Madrigals (consisting of Amy and Dan Cahill, Atticus and Jake Rosenbloom, Jonah Wizard, Hamilton Holt, Ian Kabra, and Pony) flew into Istanbul while searching for an ingredient of the serum antidote, Anatolian Leopard Whiskers.

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