Los Blancos cruised to a 4-0 win thanks to goals from Gonzalo Higuain, Angel di Maria, Michael Essien and Luka Modric.
Mourinho is only the fifth man to reach the milestone, and it was all the sweeter as rivals Atletico Madrid lost their unbeaten run to Valencia.
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Since Guus Hiddink arrived at the helm, Chelsea have improved considerably after a tricky start to the campaign.
Newcastle United are staring down the barrel of relegation to the Championship for the second time in the past eight years.