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The Melchites accepted Chalcedon. However, the Syriacs formally rejected the Chalcedonian doctrine during the Synod of Tyre (513-515) under the leadership of Severus, patriarch of Antioch (c. 465-538). The Byzantine saw that as a revolt and crushed it through ruthless persecution. In 518, at the Second Council of Constantinople, Byzantine deposed and anathematized Severus, who fled to Egypt. In 521 the decree to expel all non-Chalcedonian monks and clergy drove the Syriac church again into seclusion, leading to the renaissance of Syriac monasticism. In 542 Jacob Baradeus (c. 500-578) was ordained bishop though the influence of Harith Ibn Jabalah, king of the Arabs (c. 529-569), with support of empress Theodora, who was a Syriac, in Constantinople. Bishop Baradeus secretly ordained more than one hundred thousand persons, including two patriarchs, of Antioch and Alexandria, and four metropolitans, of Isauria, Taurus, Laodicea, and Mesopotamia. The Syriacs are also known to the West as the Jacobites after Jacob Baradeus.

In 540 the Syriacs suffered the first of the Persian invasions which were repeated in 614. By 616 Both Syria and Egypt had fallen to the Persian Sasanids. The Syriac church reorganized itself during that period and developed the great centers in Edessa and Seleucia-Ctesiphon. In 629 the Roman emperor Heraclius, who was an Edessan, drove out the Persians. The following conquest of Syria was that of the Muslim Arabs in 636. The new Islamic empire, seemed cultured and tolerant, especially after the Umayyad shifted its capital to Damascus, allowed the Syriacs to group into West Syriac church and East Syriac church. Marutha of Tagrit (629-649) became the first maphrian in the East. The scholar Jacob of Edessa (c. 640-708) restructured the Syriac language and retranslated the Bible into Syriac. The West Syriacs constituted the Syriac Orthodox church of Antioch while the East Syriacs or Persian church became known as the Nestorians.

In 750 the Abbasid caliphate replaced the Umayyad with Baghdad as capital. Both East and West Syriacs organized themselves separately around Seleucia-Ctesiphon. When the Fatimid caliphate ruled from Egypt between 969 and 1171 persecution of the Christians took place and many converted to Islam. In the eleventh century Seljuk Turks conquered Damascus and Jerusalem but collapsed in 1092. The European Crusaders occupied Jerusalem and Antioch during the period 1098-1124. It was in 1181 that the Maronites of Lebanon, as a result of the Crusades, broke away from the West Syriac church by defecting to join Rome.

The Syriac church regained its glory and reached a peak in the twelfth century with 20 metropolitan sees, 103 bishops, and millions of believers in Syria and Mesopotamia. One distinguished leader of that time was Michael the Great, catholicos of the West Syriacs. Sultan Saladin, who defeated the Crusaders and took over Palestine, was supportive of culture and encouraged learned Christians. Unfortunately, this progress was wrecked in the thirteenth century with the second invasion of the Crusaders from the West and the invasions of the Mamluk Turks and Mangols from the East. Nonetheless, the Syriac Orthodox church grew to more than 200 dioceses and outstanding leaders such as Gregory Bar Hebraeus (1226-1286), who was a philosopher and catholicos of the East, contributed to contribute to the Syriac heritage. This shining period in the history of the church was concluded by the attack of the conqueror Timur in 1401.
During the fifteenth and sixteenth centuries the Syriacs suffered enormously from persecution by occupying forces. Through that period the church had dwindled to about twenty bishops. A new era in the survival of the church started when the western missionaries with money and diplomacy worked on braking the ranks of the Syriac Orthodox church. They cooperated with the ruling Ottoman Turkish empire to install a Uniate, Andrew Akhijan, as bishop of Aleppo in 1656 and later as patriarch of all the Syriacs in 1662. Although repudiated by most Syriacs he was acknowledge by Pope Clement IX in 1667, thus establishing Catholicism in the Syriac church through uniatism with Rome.
The nineteenth century was considered a turbulent time in the history of the church as well. Protestant and other western missions to the Middle East continued to lure away many Syriac Orthodox. The Ottoman Turks and the Kurds assaulted Syriac Christians. Large massacres took place in 1843, 1846, and 1860. The French protection afterwards strengthened the hands of the Catholic Uniates. As the dying Turkish empire grew more hostile to non-Muslim elements, Syriacs along with Armenians were massacred in huge numbers. First, it was the massacre of 1894 that was followed with the genocide of 1915-1916, which is still bitterly remembered among the surviving Syriacs as “Sayfo”.
In the second half of the twentieth century, the church tried to revive itself. During World War I the patriarchate moved from Mardin to Monastery of Za’faran to preserve itself. Under the leadership of the illustrious scholar Patriarch Mar Ignatius Ephrem I the church moved to Homos in modern Syria, where it flourished and regained its identity. In 1959 Patriarch Mar Ignatius Yacoub III transferred the Patriarchal See to Damascus where it still exists. In 1980 Mar Ignatius Zakka I headed the church and was succeeded by Mar Ignatius Aphrem II in 2014 as patriarch of Antioch and all the East.
The twentieth century also witnessed the migration of large number of Syriac Orthodox to Europe and North America. While the church was found mainly in Syria, Lebanon, Jordan, Palestine, Iraq, and Turkey, presently there are Syriac Orthodox bishoprics in Sweden, Germany, Holland, Belgium, England, Australia, Brazil, Canada, and the United States of America. As the church continues to suffer atrocities in its home land in the Middle East, more of its followers are migrating to the West. It is estimated that the Syriac Orthodox Church of Antioch numbers around 1 million worldwide, with less than 300 thousands remaining in the Middle East. At present, the Syriac Orthodox church has more than 30 bishops in five continents.
The Syriac Orthodox Church of Antioch also spread to India during the seventeenth century. The Thomas Christians of Malabar, who were forcibly inducted into the Roman communion by the Portuguese colonial power, revolted and accepted Syriac Orthodox doctrine in 1653. Presently, the Syriac church in India includes about 3 million members. They are under the jurisdiction of Mar Baselius Thoma Mathews I, catholicos of the East, as head in Kerala, India.