DeletedUser29726
This guide is going to put together some basics about designing your city layout in an abstract manner so that it can be applied to a multitude of layout strategies. There will be some general advice along the way but primarily it's going to be focused on evaluating individual features of a layout such that you can look at your city and have an idea how much there is to potentially gain by changing things. This could be a nightmare if you have city design OCD as creating a 'perfect' city is nigh-impossible 
You still have to decide what's good enough for you
For the purpose of the model, we'll be evaluating the space a building takes up by comparing it to an imaginary city in which your townhall has two roads going out from it in the two perpendicular directions. All buildings are placed on either side of the road where their short side would touch and all expansions wrap tight around them creating no dead space. This is of course impossible for the most part, but it does serve to create a good median state to compare layouts. The nominal space for a building is Short * (Long + RoadWidth / 2).
Necessary features of a real city
1) The corner
A corner has an inside (where it creates waste because a building has road on two sides) and an outside (where it may save space by allowing a building to take less road than it otherwise would need). In the above example the inside corner building is an "ideal" 2x2 wasting 1 square of space (2 extra spaces of one side of a road at 0.5 each). The outside of the corner is a 5x6 that would normally take 2.5 squares of road, but in this case is only taking 1 square of road. Combined the corner has saved 0.5 squares over the normal amount of road for the buildings involved.
Savings = (ShortOutside - UsedOutside - LongInside) * RoadWidth / 2 (if negative the corner is actually wasting a bit of space compared to normal).
2) The termination point
Every good road has an end (loops are incredibly wasteful because they deprive you of termination points). A termination point may provide savings on space for up to two buildings if you're lucky. In the above image the pirate ship has some minor savings (minor because it's short side isn't that long so it's only saving 1 half-tile of road) but the Alcatraz by using the 3rd side of a road tile is effectively attached for 'free' - a savings of 7 half tiles of road for a total of 4 squares saved by this termination point.
Savings = (ShortA + ShortB - UsedA) * RoadWidth / 2
3) The intersection
An intersection creates only waste locally but does also make a termination point which as seen above can create a lot of savings. It both involves having road along the long side of the interior buildings and has one tile of road where only one side is usable.
Waste = (LongA + LongB + RoadWidthMain) * RoadWidthBranch / 2
Other sources of wasted space
4) Wrong orientation
This image in fact has a few examples of wrong orientation, the Terrace Farm is using its 6-length side instead of its 5-length side. A waste of one half-tile of road. The sunken treasures are also using their 3-length side instead of 2-length side, also a waste of one half tile of road.
5) Dead space and things you place just because they fit
This one is usually most noticeable by the areas you have plugged up with victory towers or watchfires (which i mean there's nothing better to be done with the deadest of space, but unless it's actually a design goal of your city to HAVE these buildings, you can consider that space wholly wasted). It may also include larger buildings that you see a space that'd be "just perfect" for without regard to whether that building is actually something you want! Extraneous road segments (like a 2x2 block of single lane road) are another example of dead space.
In this image I have 5 victory towers and 5 2x2 decorations that may fall into that category (I actually do need the decorations in this case to reach enthusiastic atm but if i didn't they would be dead space). One of the victory towers is also using up road space. As an aside there's a Shrine of Knowledge sitting on 2 lane road when it only needs 1 lane that's also a waste (The end of your 2 lane road section if you have one is often a mess like this).
6) Road along the edge of your town
I don't have an image for this one because it's one I avoid it like the plague. Essentially if only one side of your road is being used then you're wasting an extra half-tile of road every square along its length.
Waste = Length * (RoadWidth / 2)
7) Using 2 Lane Road where you don't need it
In my example for #5 I had a Shrine on the end of the 2LR as an example but sometimes it gets far worse
Waste = Length / 2
8) Placing a building such that it has roads on opposite sides
The common example would be where someone has two rows of 2x2s and in the middle of them plunks down a 4x4. This wastes an extra 4 half-tiles of road.
Waste = Length * Road Width / 2
9) Loops are bad!
I touched on this when discussing termination points but essentially when you close a loop your are wasting not just one but two termination points (as closing the loop also creates an intersection which should've made a termination point itself but is instead just eliminating the one you already had).
Other considerations
10) Don't place your Townhall flush to a corner
As seen in #2 termination points are one of your BEST sources of savings. Roads that leave perpendicular from your townhall create extra termination points without the waste you usually have to accept to make them using an intersection. As such you should endeavour to at least use all sides of your townhall even if not sending roads out from it.
11) Disconnected houses can be an additional source of savings
I do do this at times, but don't have any at this moment. If you don't need the coin and the houses are mostly there for population (they usually are) then after they're constructed they don't actually need road service. You can banish them to those funny shapes at the edge of your city that are likely to create dead space because you haven't got the expansions to flush them up yet thus killing two birds with one stone - you're using up your dead space without it being dead space, and you're saving the road space on your housing!
12) Your city will probably not be perfect
I think I've had two city layouts in the history of my playtime that would've come out with more savings than waste under this model. They both would've been iron age cities when you don't have quite so much stuff of so many different shapes and sizes to fit in. Awareness of where the waste is is often enough I find to avoid the worst of it.
You still have to decide what's good enough for you For the purpose of the model, we'll be evaluating the space a building takes up by comparing it to an imaginary city in which your townhall has two roads going out from it in the two perpendicular directions. All buildings are placed on either side of the road where their short side would touch and all expansions wrap tight around them creating no dead space. This is of course impossible for the most part, but it does serve to create a good median state to compare layouts. The nominal space for a building is Short * (Long + RoadWidth / 2).
Necessary features of a real city
1) The corner
A corner has an inside (where it creates waste because a building has road on two sides) and an outside (where it may save space by allowing a building to take less road than it otherwise would need). In the above example the inside corner building is an "ideal" 2x2 wasting 1 square of space (2 extra spaces of one side of a road at 0.5 each). The outside of the corner is a 5x6 that would normally take 2.5 squares of road, but in this case is only taking 1 square of road. Combined the corner has saved 0.5 squares over the normal amount of road for the buildings involved.
Savings = (ShortOutside - UsedOutside - LongInside) * RoadWidth / 2 (if negative the corner is actually wasting a bit of space compared to normal).
2) The termination point
Every good road has an end (loops are incredibly wasteful because they deprive you of termination points). A termination point may provide savings on space for up to two buildings if you're lucky. In the above image the pirate ship has some minor savings (minor because it's short side isn't that long so it's only saving 1 half-tile of road) but the Alcatraz by using the 3rd side of a road tile is effectively attached for 'free' - a savings of 7 half tiles of road for a total of 4 squares saved by this termination point.
Savings = (ShortA + ShortB - UsedA) * RoadWidth / 2
3) The intersection
An intersection creates only waste locally but does also make a termination point which as seen above can create a lot of savings. It both involves having road along the long side of the interior buildings and has one tile of road where only one side is usable.
Waste = (LongA + LongB + RoadWidthMain) * RoadWidthBranch / 2
Other sources of wasted space
4) Wrong orientation
This image in fact has a few examples of wrong orientation, the Terrace Farm is using its 6-length side instead of its 5-length side. A waste of one half-tile of road. The sunken treasures are also using their 3-length side instead of 2-length side, also a waste of one half tile of road.
5) Dead space and things you place just because they fit
This one is usually most noticeable by the areas you have plugged up with victory towers or watchfires (which i mean there's nothing better to be done with the deadest of space, but unless it's actually a design goal of your city to HAVE these buildings, you can consider that space wholly wasted). It may also include larger buildings that you see a space that'd be "just perfect" for without regard to whether that building is actually something you want! Extraneous road segments (like a 2x2 block of single lane road) are another example of dead space.
In this image I have 5 victory towers and 5 2x2 decorations that may fall into that category (I actually do need the decorations in this case to reach enthusiastic atm but if i didn't they would be dead space). One of the victory towers is also using up road space. As an aside there's a Shrine of Knowledge sitting on 2 lane road when it only needs 1 lane that's also a waste (The end of your 2 lane road section if you have one is often a mess like this).
6) Road along the edge of your town
I don't have an image for this one because it's one I avoid it like the plague. Essentially if only one side of your road is being used then you're wasting an extra half-tile of road every square along its length.
Waste = Length * (RoadWidth / 2)
7) Using 2 Lane Road where you don't need it
In my example for #5 I had a Shrine on the end of the 2LR as an example but sometimes it gets far worse
Waste = Length / 2
8) Placing a building such that it has roads on opposite sides
The common example would be where someone has two rows of 2x2s and in the middle of them plunks down a 4x4. This wastes an extra 4 half-tiles of road.
Waste = Length * Road Width / 2
9) Loops are bad!
I touched on this when discussing termination points but essentially when you close a loop your are wasting not just one but two termination points (as closing the loop also creates an intersection which should've made a termination point itself but is instead just eliminating the one you already had).
Other considerations
10) Don't place your Townhall flush to a corner
As seen in #2 termination points are one of your BEST sources of savings. Roads that leave perpendicular from your townhall create extra termination points without the waste you usually have to accept to make them using an intersection. As such you should endeavour to at least use all sides of your townhall even if not sending roads out from it.
11) Disconnected houses can be an additional source of savings
I do do this at times, but don't have any at this moment. If you don't need the coin and the houses are mostly there for population (they usually are) then after they're constructed they don't actually need road service. You can banish them to those funny shapes at the edge of your city that are likely to create dead space because you haven't got the expansions to flush them up yet thus killing two birds with one stone - you're using up your dead space without it being dead space, and you're saving the road space on your housing!
12) Your city will probably not be perfect
I think I've had two city layouts in the history of my playtime that would've come out with more savings than waste under this model. They both would've been iron age cities when you don't have quite so much stuff of so many different shapes and sizes to fit in. Awareness of where the waste is is often enough I find to avoid the worst of it.