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The Portuguese enter the Indian Ocean

The squadron of Vasco da Gama left Portugal in 1497, rounded the Cape and continued along the coast of East Africa, where a local pilot was brought on board who guided them across the Indian Ocean, reaching Calicut, the capital of the kingdom ruled by Zamorins, also known as Kozhikode) in south-western India in May 1498. The second voyage to India was dispatched in 1500 under Pedro Álvares Cabral. While following the same south-westerly route as Gama across the Atlantic Ocean, Cabral made landfall on the Brazilian coast. This was probably an accidental discovery, but it has been speculated that the Portuguese secretly knew of Brazil's existence and that it lay on their side of the Tordesillas line. Cabral recommended to the Portuguese King that the land be settled, and two follow up voyages were sent in 1501 and 1503. The land was found to be abundant in pau-brasil, or brazilwood, from which it later inherited its name, but the failure to find gold or silver meant that for the time being Portuguese efforts were concentrated on India. In 1502, to enforce its trade monopoly over a wide area of the Indian Ocean, the Portuguese Empire created the cartaz licensing system, granting merchant ships protection against pirates and rival states.

Profiting from the rivalry between the ruler of Kochi and the Zamorin of Calicut, the Portuguese were well-received and seen as allies, as they obtained a permit to build the fort Immanuel (Fort Kochi) and a trading post that was the first European settlement in India. They established a trading center at Tangasseri, Quilon (Coulão, Kollam) city in (1503) in 1502, which became the centre of trade in pepper, and after founding manufactories at Cochin (Cochim, Kochi) and Cannanore (Canonor, Kannur), built a factory at Quilon in 1503. In 1505 King Manuel I of Portugal appointed Francisco de Almeida first Viceroy of Portuguese India, establishing the Portuguese government in the east. That year the Portuguese also conquered Kannur, where they founded St. Angelo Fort, and Lourenço de Almeida arrived in Ceylon (modern Sri Lanka), where he discovered the source of cinnamon. Although Cankili I of Jaffna initially resisted contact with them, the Jaffna kingdom came to the attention of Portuguese officials soon after for their resistance to missionary activities as well as logistical reasons due to its proximity with Trincomalee harbour among other reasons. In the same year, Manuel I ordered Almeida to fortify the Portuguese fortresses in Kerala and within eastern Africa, as well as probe into the prospects of building forts in Sri Lanka and Malacca in response to growing hostilities with Muslims within those regions and threats from the Mamluk sultan.

A Portuguese fleet under the command of Tristão da Cunha and Afonso de Albuquerque conquered Socotra at the entrance of the Red Sea in 1506 and Muscat in 1507. Having failed to conquer Ormuz, they instead followed a strategy intended to close off commerce to and from the Indian Ocean. Madagascar was partly explored by Cunha, and Mauritius was discovered by Cunha whilst possibly being accompanied by Albuquerque. After the capture of Socotra, Cunha and Albuquerque operated separately. While Cunha traveled India and Portugal for trading purposes, Albuquerque went to India to take over as governor after Almeida's three-year term ended. Almeida refused to turn over power and soon placed Albuquerque under house arrest, where he remained until 1509.

Although requested by Manuel I to further explore interests in Malacca and Sri Lanka, Almeida instead focused on western India, in particular the Sultanate of Gujarat due to his suspicions of traders from the region possessing more power. The Mamlûk Sultanate sultan Al-Ashraf Qansuh al-Ghawri along with the Gujarati sultanate attacked Portuguese forces in the harbor of Chaul, resulting in the death of Almeida's son. In retaliation, the Portuguese fought and destroyed the Mamluks and Gujarati fleets in the sea Battle of Diu in 1509.

Along with Almeida's initial attempts, Manuel I and his council in Lisbon had tried to distribute power in the Indian Ocean, creating three areas of jurisdiction: Albuquerque was sent to the Red Sea, Diogo Lopes de Sequeira to South-east Asia, seeking an agreement with the Sultan of Malacca, and Jorge de Aguiar followed by Duarte de Lemos were sent to the area between the Cape of Good Hope and Gujarat. However, such posts were centralized by Afonso de Albuquerque after his succession and remained so in subsequent ruling.