Simple calculator (going H.A.M with defining functions)
Of the feedback on your earlier version of this programme, the most obvious thing that you haven't done yet is to use lower() on text inputs so that you only have to compare against lower case options. e.g.

    again = input("Again? Yes/No: ").lower()
    if again == "yes":
        break
    elif again == "no":
        sys.exit(0)


It might be useful to know that the operations you define already exist as methods of numeric variables in Python, called __mul__, __add__, etc., and are also available within the operator module. e.g. operator.add(3, 4) is equivalent to 3 + 4. So you could, for example, do this

import operator

OPTIONS = {
    'divide': operator.truediv,
    'multiply': operator.mul,
    'add': operator.add,
    'subtract': operator.sub
}

def user_input():
    while True:
        try:
            return int(input("Number: "))
        except ValueError:
            print("NOPE...")

def get_operation():
    while True:
        operation = input("Multiply/Divide/Add/Subtract: ").lower()
        try:
            return OPTIONS[operation]
        except KeyError:
            print("Not an option.")

def play_again():
    while True:
        again = input("Again? Yes/No: ").lower()
        if again == "yes":
            return True
        elif again == "no":
            return False
        else:
            print("Nope..")

while True:
    operation = get_operation()
    x = user_input()
    y = user_input()
    print(operation(x, y))
    if not play_again():
        break