Recursion Error in `reactions2route` function

[fredhastedt]

Description

The reactions2route function in rxnutils/routes/readers.py encounters a maximum recursion depth exceeded error when processing reaction sequences that involve changes in stereochemistry. This occurs because the smiles2inchikey function is called with ignore_stereo=True, which causes molecules with different stereo configurations to be treated as identical, leading to unintended cycles in the synthesis tree. As a result, the make_dict function is called infinitely.

Example

Consider the following sequence of reactions:

1. 'N#CCc1cnc[nH]1.[C-]#N>>N#CC(N)Cc1cnc[nH]1'
2. 'CI.N#CC(N)Cc1cnc[nH]1>>Cn1cncc1CC(N)C#N'
3. 'O=C[O-].Cn1cncc1CC(N)C#N>>Cn1cncc1C[C@@H](C#N)NC=O'
4. 'Cn1cncc1C[C@@H](C#N)NC=O>>Cn1cncc1C[C@H](N)C#N'
5. 'CC(C)C[C@H](N)C(=O)O.Cn1cncc1C[C@H](N)C#N>>CC(C)C[C@H](N)C(=O)N[C@H](C#N)Cc1cncn1C'
6. 'CC(C)C[C@H](N)C(=O)N[C@H](C#N)Cc1cncn1C.COc1cccc2[nH]c(C(=O)O)cc12>>COc1cccc2[nH]c(C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C#N)Cc3cncn3C)cc12'

In this sequence, Cn1cncc1CC(N)C#N (achiral) is the reactant of reaction 3, but Cn1cncc1C[C@H](N)C#N (chiral) is the product of reaction 4. The product of reaction 3 is the reactant of reaction 4 thus introducing the dependency. Since ignore_stereo=True, both the chiral/achiral molecule map to the same InChI key, causing the graph to loop back, resulting in recursion.

Steps to Reproduce

1. Call reactions2route with the above list of reaction SMILES.
2. Observe the recursion error: RecursionError: maximum recursion depth exceeded.

Possible Solution

Modify the key generation to account for stereochemistry by setting ignore_stereo=False in smiles2inchikey calls, or implement a stereo-aware comparison to prevent false matches.

Environment

• Python version: 3.12
• RDKit version: 2023.9.6
• rxnutils version: 2.0.0

[SGenheden]

Thanks for reporting this.

I have added ignore_stereo as an optional argument to reactions2route so to get it to work with the above SMILES, one can use

route = reactions2route(reaction_smiles, ignore_stereo=False)

This is on branch for now