Reaction Enumeration

Generate virtual compound libraries using reaction SMARTS.

Reaction SMARTS Basics

from rdkit import Chem
from rdkit.Chem import AllChem

# Define reaction (reactants >> products with atom mapping)
# Amide coupling: carboxylic acid + amine -> amide
amide_rxn = AllChem.ReactionFromSmarts(
    '[C:1](=[O:2])O.[N:3]>>[C:1](=[O:2])[N:3]'
)

# Validate reaction definition
n_errors = amide_rxn.Validate()
if n_errors[0] == 0:
    print('Reaction is valid')

# Run reaction
acid = Chem.MolFromSmiles('CC(=O)O')
amine = Chem.MolFromSmiles('CCN')

products = amide_rxn.RunReactants((acid, amine))
# products is a tuple of tuples: ((product1,), (product2,), ...)
for prod_set in products:
    for prod in prod_set:
        Chem.SanitizeMol(prod)
        print(Chem.MolToSmiles(prod))

Common Reaction SMARTS

REACTIONS = {
    'amide_coupling': '[C:1](=[O:2])O.[N:3]>>[C:1](=[O:2])[N:3]',
    'reductive_amination': '[C:1]=O.[N:2]>>[C:1][N:2]',
    'suzuki': '[c:1][Br].[c:2][B](O)O>>[c:1][c:2]',
    'buchwald': '[c:1][Br].[N:2]>>[c:1][N:2]',
    'ester_formation': '[C:1](=[O:2])O.[O:3]>>[C:1](=[O:2])[O:3]',
    'michael_addition': '[C:1]=[C:2]C(=O).[C:3]>>[C:1][C:2]([C:3])C(=O)',
}

Combinatorial Library Enumeration

from rdkit import Chem
from rdkit.Chem import AllChem
from itertools import product

def enumerate_library(rxn_smarts, reactant_lists, deduplicate=True):
    '''
    Enumerate products from combinatorial reaction.

    Args:
        rxn_smarts: Reaction SMARTS string
        reactant_lists: List of lists of SMILES for each reactant position
        deduplicate: Remove duplicate products

    Returns:
        List of unique product SMILES
    '''
    rxn = AllChem.ReactionFromSmarts(rxn_smarts)

    # Validate reaction
    if rxn.Validate()[0] != 0:
        raise ValueError('Invalid reaction SMARTS')

    products = []
    seen = set()

    # Generate all combinations
    for reactants in product(*reactant_lists):
        mols = [Chem.MolFromSmiles(s) for s in reactants]
        if None in mols:
            continue

        try:
            prods = rxn.RunReactants(tuple(mols))
            for prod_set in prods:
                for prod in prod_set:
                    try:
                        Chem.SanitizeMol(prod)
                        smiles = Chem.MolToSmiles(prod)

                        if deduplicate:
                            if smiles not in seen:
                                seen.add(smiles)
                                products.append(smiles)
                        else:
                            products.append(smiles)
                    except Exception:
                        continue  # Skip invalid products
        except Exception:
            continue

    return products

# Example: Amide library
acids = ['CC(=O)O', 'c1ccccc1C(=O)O', 'OC(=O)CC(=O)O']
amines = ['CCN', 'c1ccc(N)cc1', 'NCCN']

products = enumerate_library(
    '[C:1](=[O:2])O.[N:3]>>[C:1](=[O:2])[N:3]',
    [acids, amines]
)
print(f'Generated {len(products)} unique products')

Multi-Step Synthesis

def multi_step_enumeration(building_blocks, reaction_sequence):
    '''
    Enumerate products from multi-step synthesis.

    Args:
        building_blocks: Dict of {step: [smiles_list]}
        reaction_sequence: List of reaction SMARTS
    '''
    current = building_blocks[0]

    for step, rxn_smarts in enumerate(reaction_sequence):
        next_bbs = building_blocks.get(step + 1, [])
        if not next_bbs:
            break

        current = enumerate_library(rxn_smarts, [current, next_bbs])
        print(f'Step {step + 1}: {len(current)} intermediates')

    return current

Product Validation

from rdkit import Chem
from rdkit.Chem import AllChem, Descriptors

def validate_products(smiles_list, mw_max=500, remove_reactive=True):
    '''
    Validate and filter enumerated products.
    '''
    valid = []

    reactive_smarts = [
        '[N+]([O-])=O',  # Nitro
        '[Cl,Br,I]',     # Halogens (optional)
        'C#N',           # Nitrile
    ]
    reactive_patterns = [Chem.MolFromSmarts(s) for s in reactive_smarts]

    for smiles in smiles_list:
        mol = Chem.MolFromSmiles(smiles)
        if mol is None:
            continue

        # Check MW
        if Descriptors.MolWt(mol) > mw_max:
            continue

        # Check reactive groups
        if remove_reactive:
            has_reactive = any(mol.HasSubstructMatch(p) for p in reactive_patterns)
            if has_reactive:
                continue

        # Check valence
        try:
            Chem.SanitizeMol(mol)
        except Exception:
            continue

        valid.append(smiles)

    return valid

Reaction Templates

def apply_template(core_smiles, r_groups, attachment_smarts='[*:1]'):
    '''
    Apply R-group decoration to a core scaffold.

    Args:
        core_smiles: Core with attachment point (e.g., '*c1ccccc1')
        r_groups: List of R-group SMILES
        attachment_smarts: SMARTS for attachment point
    '''
    products = []

    for rg in r_groups:
        # Simple string replacement for single attachment
        product_smiles = core_smiles.replace('*', rg, 1)
        mol = Chem.MolFromSmiles(product_smiles)
        if mol:
            try:
                Chem.SanitizeMol(mol)
                products.append(Chem.MolToSmiles(mol))
            except Exception:
                continue

    return products

# Example: Decorate benzene core
core = '*c1ccccc1'
r_groups = ['C', 'CC', 'C(=O)O', 'O']
decorated = apply_template(core, r_groups)

Related Skills

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