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| 1516 |
| | | The death of Ferdinand II results in Spain becoming part of the Habsburg empire, under the rule of Charles V (as Charles I of Spain) | |
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| 1519 |
| | | Ferdinand Magellan and a small fleet depart from Seville, attempting to sail round the world | |
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| 1521 |
| | | Ignatius of Loyola, recovering from a wound received as a soldier at Pamplona, is inspired by reading the lives of the saints | |
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| 1522 |
| | | One surviving ship of Magellan's fleet, the Victoria, returns to Sanlucar, in Spain, with Sebastian Cano in command | |
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| 1525 |
| | | Muslims throughout Spain are ordered to convert to Christianity or to leave the kingdom | |
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| 1533 |
| | | The Holy Roman Emperor, Charles V, makes Titian his court painter (an arrangement continued by Philip II) | |
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| 1542 |
| | | New Laws are passed in Spain, in an attempt to protect the Indians on the encomiendas of Spanish America | |
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| 1547 |
| | | The first book describing the game of draughts, or checkers, is published in Spain | |
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| 1554 |
| | | Mary I causes grave offence in England by her marriage to the Catholic heir to the king of Spain | |
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| 1556 |
| | | Charles V abdicates, handing the Netherlands and Spain to his son Philip and the title of Holy Roman emperor to his brother Ferdinand | |
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