The fire started in a Japanese restaurant and grocery store on 44th Street in the Sunnyside section just before 7:30 a.m. Thursday.
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It spread to four other businesses in the same structure and went to four alarms before crews got the upper hand.
Video from NewsCopter 7 overhead showed heavy smoke pouring from the building.
FDNY Chief of Operations John Hodgens said more than 200 fire and EMS personnel responded to the scene.
Three firefighters were injured while battling the blaze in extreme heat and humidity.
The injuries were described as non-life-threatening.
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The cause of the blaze is under investigation.
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