Manifold’s Library Enumeration tool offers users an interface to build multi-step libraries based on PostEra’s robust set of library-enabled reactions. With the addition of structure and property filters at any step of the enumeration tree, users have the tools to build virtual spaces which adhere strictly to the needs of their project.

To add even more flexibility to the tool, we now offer users the ability to define custom reaction templates to be used alongside the PostEra default set. This guide will walk you through an example of creating a custom reaction template, and combining it with the entire Manifold library enumeration workflow for library enumeration.

To follow along with this guide, you can create and view your own custom reactions from the Reactions tab of your Dashboard.

Figure 1 offers a high-level overview of the new interface for constructing custom reaction templates. The entry-point into the tool is to start drawing your chemical transformation (Figure 1A).

Figure 1. Overview of the custom reaction templates create and update page, with the key areas annotated. The key component you interact with is the drawing window (A), where you will construct your template visually, and map the reactant atoms to their corresponding positions in the product molecule. The reaction (B), reactants (C), and product (D) SMARTS (B) are auto-generated and updated as you draw. You can further customize your template with a description (E) and name (F).

There are 3 keys steps to creating a custom template, detailed in the following sections.

Click here to create a reaction on your account.

There are two suggested ways to draw your custom template: (1) directly in the Manifold drawing tool or (2) drawing the reaction in another drawing tool like ChemDraw, and pasting the reaction file into the Manifold drawing tool.

Figure 2 illustrates how to draw a reaction in Manifold, including adding the “+” sign and reaction arrow to differentiate reactants from one another and from the product. You can optionally use R-groups to define which parts of the template remain constant after the transformation. If you are finding the view too small, consider going full-screen (Figure 2E).

Figure 2. Annotation of the Manifold drawing tool, annotating the key functionality required to draw a custom template. Like any drawing tool, you can use the canvas to draw the skeleton of the reaction (A). After you have the outline, you can then polish off the reaction by adding an optional plus sign (B) for intermolecular reactions, a reaction arrow (C) to distinguish the reactants from the product, and optional R-groups (D) to illustrate vectors which are held constant. You can also use full-screen mode (E) if you’re looking for a little more real-estate to work with.

If preferable, you can also use the drawing tool of your choice, and when you’re ready to move over to Manifold, copy your drawing as a RXN file, and then simply paste it into the Manifold drawing tool. You should make sure everything was brought over as desired.

An important step in defining your custom templates is to map the reactant atoms to their corresponding product atoms to define how the transformation proceeds. Without this mapping, some more complex transformations will likely fail when applied to library enumeration, so we always recommend this step.

Figure 3. Example of how to use the Manifold drawing tool to perform atom mapping. To manually map the atoms, select the reaction mapping tool (A), and then draw a line from reactant atoms to product atoms (B) one at a time.

The last step is to give your transformation a name, and name each of your reactants and products (Figure 1F, 1C, 1D). These names are used to identify the reactant classes in the library enumeration tool.

Once you’re satisfied with your new custom template, you can then work with it from within the library enumeration tool anywhere you can use the default PostEra set of reactions.

There are many scenarios a user would want to use a custom reaction template within library enumeration.

One example would be to control the stereochemistry of transformations, as currently the PostEra default reactions do not consider the stereochemistry effects of the reaction center.

Another use case for custom reaction templates in library enumeration would be to account for selectivity of reactions. The PostEra default set of reactions has limited functionality for accounting for selectivity.

A third use case could be to allow for intramolecular reactions. We’ll dive into this use-case more deeply to illustrate a potential workflow.

The number of reactants for a given reaction in a library is strictly defined by the templates, and for the default PostEra reactions, this means intramolecular reactions are not supported.

For example, let’s pretend you want to perform a ring-closing step using an Amide Schotten-Baumann reaction. You might try to add the single reactant with both the amine and acyl chloride in both of the reactant nodes in the tree (Figure 4). If you then run this reaction, the coupling will only happen intermolecularly, and no ring-closing products will be formed.

Figure 4. An attempt to use an Amide Schotten-Baumann reaction to close a ring with an amide bond. The default PostEra reaction was chosen (A), and a bi-functional reactant was added in both reactant nodes. The enumeration produced 1 product (C), coupling the two reactants together intermolecularly instead of performing a ring-closing reaction.

This is obviously not the desired workflow, nor the desired product. Luckily, custom reaction templates can offer an improved mode of work to support intramolecular reactions.

Figure 5. Example visualization of the reaction description of the PostEra default Amide Schotten-Baumann with amine reaction, revealed by pressing the info button (A).

First, create a new custom reaction template on your account, and draw the intramolecular version of the Amide Schotten-Bauman reaction (Figure 6). Remember, you can view the reaction details of the intermolecular reaction for guidance on the reaction template (Figure 5). We ensure that the reaction acts intramolecularly by forming an "S-group" between the two components (Figure 6) Notice how there is only one reactant in the "Reactants" section after the S-group is formed; this ensures that the enumeration looks for both of the reactants in the same molecule.

Figure 6. Intramolecular version of the Amide Schotten-Baumann with amine reaction template. The reactant defined by two intramolecular groups (an amine and acyl-chloride in the same molecule) is defined by using an "S-group" in the drawing tool.

With our new intramolecular reaction in hand, we can return to our library and change out the reaction to it. After re-enumerating the products, we now successfully perform the ring-closing coupling as desired (Figure 7C).

Figure 7. An attempt to use an Amide Schotten-Baumann reaction to close a ring with an amide bond. The new custom intramolecular reaction was chosen (A), and a bi-functional reactant was added in the single reactant node. The enumeration produced a single product (C), closing the ring with an amide bond as desired.

This is just one example of how you can incorporate custom reaction templates into your Manifold Library Enumeration workflow. Some other example use-cases might include adding in a transformation not included in the PostEra default set, or perhaps including selectivity rules in the definition of a template.

For more information on how to use the library enumeration tool, you can reference the full library enumeration guide here.