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Title: Learning to Make Generalizable and Diverse Predictions for Retrosynthesis

Paper content:
We propose a new model for making generalizable and diverse retrosynthetic reaction predictions.
Given a target compound, the task is to predict the likely chemical reactants to produce the target.
This generative task can be framed as a sequence-to-sequence problem by using the SMILES representations of the molecules.
Building on top of the popular Transformer architecture, we propose two novel pre-training methods that construct relevant auxiliary tasks (plausible reactions) for our problem.
Furthermore, we incorporate a discrete latent variable model into the architecture to encourage the model to produce a diverse set of alternative predictions.
On the 50k subset of reaction examples from the United States patent literature (USPTO-50k) benchmark dataset, our model greatly improves performance over the baseline, while also generating predictions that are more diverse.
This paper proposes a novel approach for one-step retrosynthesis.
This task is crucial for material and drug manufacturing (Corey & Wipke, 1969; Corey, 1991) and aims to predict which reactants are needed to generate a given target molecule as the main product.
For instance, Figure 1 demonstrates that the input molecule "[N-]=[N+]=NCc1ccc(SCCl)cc1", expressed here as a SMILES string (Weininger, 1988) , can be generated using reactants "CSc1ccc(CN= [N+] =[N-])cc1" and "ClCCl".
For decades, this task has been solved using template-based approaches (Gelernter et al., 1990; Satoh & Funatsu, 1999) .
Templates encode transformation rules as regular expressions operating on SMILES strings and are typically extracted directly from the available training reactions.
The primary limitation of such templates is coverage, i.e., it is possible that none of the templates applies to a test molecule.
In order to better generalize to newer or broader chemical spaces, recently developed template-free approaches cast the problem as a sequence-to-sequence prediction task.
These approaches were first explored by Liu et al. (2017) using LSTM models; the current state-of-the-art performance on this task uses Transformer models (Lin et al., 2019; Karpov et al., 2019) .
Out-of-the-box Transformers nevertheless do not effectively generalize to rare reactions.
For instance, model accuracy drops by 25% on reactions with 10 or fewer representative instances in the Figure 1: An example prediction task: on the left is the input target SMILES, and on the right are the output reactants SMILES.
The input is a single molecule, while the output is a set of molecules separated by a period (".").
training set.
1 Another key issue is diversity.
Manufacturing processes involve a number of additional criteria -such as green chemistry (having low detrimental effects on the environment).
It is therefore helpful to generate a diverse collection of alternative ways of synthesizing the given target molecule.
However, predicted reactions are unlikely to encompass multiple reaction classes (see Figure 2 ) without additional guidance.
This is because the training data only provides a single reactant set for each input target, even if this is not the only valid reaction to synthesize the target.
Figure 2: For the input target compound shown on the left, three possible reactant predictions are shown on the right.
Prediction 1 suggestions a heterocycle formation reaction, while Predictions 2 and 3 both suggest substitution reactions.
The only difference between the latter two is the halide functional group (Cl vs Br) highlighted in red.
They share similar chemical properties and thus provide no additional insights for chemists.
We extend molecular Transformers to address both of these challenges.
First, we propose a novel pre-training approach to drive molecular representations to better retain alternative reaction possibilities.
Our approach is reminiscent of successful pre-training schemes in natural language processing (NLP) applications (Devlin et al., 2018) .
However, rather than using conventional token masking methods, we adopt chemically-relevant auxiliary tasks.
Each training instance presents a single way to decompose a target molecule into its reactants.
Here, we add alternative proxy decompositions for each target molecule by either
1) randomly removing bond types that can possibly break during reactions, or
2) transforming the target based on templates.
While neither of these two auxiliary tasks are guaranteed to construct valid chemical reactions, they are closely related to the task of interest.
Indeed, representations trained in this manner provide useful initializations for the actual retrosynthesis problem.
To improve the diversity of predicted reactions, we incorporate latent variables into the generation process.
Specifically, we merge the Transformer architecture with a discrete mixture over reactions.
The role of the latent variable is to encode distinct modes that can be related to underlying reaction classes.
Even though the training data only presents one reaction for each target molecule, our model learns to associate each reaction with a latent class, and in the process covers multiple reaction classes across the training set.
At test time, a diverse collection of reactions is then obtained by collecting together predictions resulting from conditioning on each latent class.
Analogous mixture models have shown promise in generating diverse predictions in natural language translation tasks (He et al., 2018; Shen et al., 2019) .
We demonstrate similar gains in the chemical context.
We evaluate our model on the benchmark USPTO-50k dataset, and compare it against state-ofthe-art template-free baselines using the Transformer model.
We focus our evaluation on top-10 accuracy, because there are many equally valuable reaction transformations for each input target, though only one is presented in the data.
Compared to the baseline, we achieve better performance overall, with over 13% increase in top-10 accuracy for our best model.
When we create a split of the data based on different reaction templates (a task that any template-based model would fail on), we similarly observe a performance increase for our model.
Additionally, we demonstrate that our model outputs exhibit significant diversity through both quantitative and human evaluations.
We explored the problem of making one-step retrosynthesis reaction predictions, dealing with the issues of generalizability and making diverse predictions.
Through pre-training and use of mixture models, we show that our model beats state-of-the-art methods in terms of accuracy and generates more diverse predictions.
Even on a challenging task, for which any template-based models would fail, our model still is able to generalize to the test set.

assistant: text: We propose a new model for making generalizable and diverse retrosynthetic reaction predictions.