Isabella received the title of Catholic Monarch by Pope Alexander VI, a pope of whose behavior and involvement in matters Isabella did not approve. Along with the physical unification of Spain, Isabella and Ferdinand embarked on a process of spiritual unification, trying to bring the country under one faith (Roman Catholicism). As part of this process, the Inquisition became institutionalised. After a Muslim uprising in 1499, and further troubles thereafter, the Treaty of Granada was broken in 1502, and Muslims were ordered to either become Christians or to leave. Isabella's confessor, Cisneros, was named Archbishop of Toledo. He was instrumental in a program of rehabilitation of the religious institutions of Spain, laying the groundwork for the later Counter-Reformation. As Chancellor, he exerted more and more power. Isabella and her husband had created an empire and in later years were consumed with administration and politics; they were concerned with the succession and worked to link the Spanish crown to the other rulers in Europe. By early 1497, all the pieces seemed to be in place: The son and heir John, Prince of Asturias, married a Habsburg princess, Margaret of Austria, establishing the connection to the Habsburgs. The eldest daughter, Isabella of Aragon, married King Manuel I of Portugal, and the younger daughter, Joanna of Castile, was married to a Habsburg prince, Philip I of Habsburg. However, Isabella's plans for her eldest two children did not work out. Her only son, John of Asturias, died shortly after his marriage. Her daughter Isabella of Aragon, whose son Miguel da Paz died at the age of two, died in childbirth. Queen Isabella I's crowns passed to her third child Joanna and her son-in-law, Philip I. Isabella did, however, make successful dynastic matches for her three youngest daughters. The death of Isabella of Aragon created a necessity for Manuel I of Portugal to remarry, and Isabella's third daughter, Maria of Aragon, became his next bride. Isabella's youngest daughter, Catherine of Aragon, married England's Arthur, Prince of Wales, but his early death resulted in her being married to his younger brother, King Henry VIII of England. Isabella officially withdrew from governmental affairs on September 14, 1504 and she died that same year on 26 November at the Medina del Campo Royal Palace. It is said that she had truly already been in decline since the death of her son Prince John of Asturias in 1497. She is entombed in Granada in the Capilla Real, which was built by her grandson, Charles V, Holy Roman Emperor (Carlos I of Spain), alongside her husband Ferdinand, her daughter Joanna and Joanna's husband Philip I; and Isabella's 2-year-old grandson, Miguel da Paz (the son of Isabella's daughter, also named Isabella, and King Manuel I of Portugal). The museum next to the Capilla Real holds her crown and scepter.

Answer this question "Why didnt it work out?" by extracting the answer from the text above.
Her only son, John of Asturias, died shortly after his marriage. Her daughter Isabella of Aragon, whose son Miguel da Paz died at the age of two, died in childbirth.