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Bartholomew Columbus founded the settlement and named it La Nueva Isabela, after an earlier settlement in the north named after the Queen of Spain Isabella I.

Expeditions which led to Ponce de León's colonization of Puerto Rico, Diego Velázquez de Cuéllar's colonization of Cuba, Hernando Cortes' conquest of Mexico, and Vasco Núñez de Balboa's sighting of the Pacific Ocean were all launched from Santo Domingo.

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Founded by Bartholomew Columbus in 1496, on the east bank of the Ozama River and then moved by Nicolás de Ovando in 1502 to the west bank of the river, the city is the oldest continuously inhabited European settlement in the Americas, and was the first seat of the Spanish colonial rule in the New World.Santo Domingo is the site of the first university, cathedral, castle, monastery, and fortress in the New World.From 1795 to 1822 the city changed hands several times along with the colony it headed.The city was ceded to France in 1795 after years of struggles, it was briefly captured by Haitian rebels in 1801, recovered by France in 1802, and was once again reclaimed by Spain in 1809.In 1512, Ferdinand established a Real Audiencia with Juan Ortiz de Matienzo, Marcelo de Villalobos, and Lucas Vazquez de Ayllon appointed as judges of appeal.

In 1514, Pedro Ibanez de Ibarra arrived with the Laws of Burgos.The city's harbor at the mouth of the Ozama River accommodates the largest vessels, and the port handles both heavy passenger and freight traffic.Temperatures are high year round, with a cool breeze around winter time.The city is coterminous with the boundaries of the Distrito Nacional ("D.N.", "National District"), itself bordered on three sides by Santo Domingo Province.The city and the colony lost much of their Spanish-born peninsular population as a result of these events which caused a great deal of instability and unrest.