# SynCoGen: Synthesizable 3D Molecule Generation via Joint Reaction and Coordinate Modeling

arXiv: https://arxiv.org/abs/2507.11818 · HTML: https://mlsanity.com/paper/2507.11818/

## Key facts

- Cited by 5 papers in the map (data through 14 Oct 2026).
- Builds on 47 of its 72 references that are in the map.
- First posted on arXiv 16 Jul 2025.

## Builds on (most cited first, 30 of 47)

- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Flow Straight and Fast: Learning to Generate and Transfer Data with Rectified Flow](https://mlsanity.com/paper/2209.03003/) (2022)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [Stochastic Interpolants: A Unifying Framework for Flows and Diffusions](https://mlsanity.com/paper/2303.08797/) (2023)
- [Chameleon: Mixed-Modal Early-Fusion Foundation Models](https://mlsanity.com/paper/2405.09818/) (2024)
- [Improving and generalizing flow-based generative models with minibatch optimal transport](https://mlsanity.com/paper/2302.00482/) (2023)
- [Simple and Effective Masked Diffusion Language Models](https://mlsanity.com/paper/2406.07524/) (2024)
- [Show-o: One Single Transformer to Unify Multimodal Understanding and Generation](https://mlsanity.com/paper/2408.12528/) (2024)
- [Simplified and Generalized Masked Diffusion for Discrete Data](https://mlsanity.com/paper/2406.04329/) (2024)
- [Generative Flows on Discrete State-Spaces: Enabling Multimodal Flows with Applications to Protein Co-Design](https://mlsanity.com/paper/2402.04997/) (2024)
- [Unified-IO 2: Scaling Autoregressive Multimodal Models with Vision, Language, Audio, and Action](https://mlsanity.com/paper/2312.17172/) (2023)
- [Torsional Diffusion for Molecular Conformer Generation](https://mlsanity.com/paper/2206.01729/) (2022)
- [GEOM: Energy-annotated molecular conformations for property prediction and molecular generation](https://mlsanity.com/paper/2006.05531/) (2020)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Fr'echet ChemNet Distance: A metric for generative models for molecules in drug discovery](https://mlsanity.com/paper/1803.09518/) (2018)
- [One Transformer Fits All Distributions in Multi-Modal Diffusion at Scale](https://mlsanity.com/paper/2303.06555/) (2023)
- [Mixed-Type Tabular Data Synthesis with Score-based Diffusion in Latent Space](https://mlsanity.com/paper/2310.09656/) (2023)
- [SE(3)-Stochastic Flow Matching for Protein Backbone Generation](https://mlsanity.com/paper/2310.02391/) (2023)
- [Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design](https://mlsanity.com/paper/2210.05274/) (2022)
- [MiDi: Mixed Graph and 3D Denoising Diffusion for Molecule Generation](https://mlsanity.com/paper/2302.09048/) (2023)
- [Diffusion Bridge Mixture Transports, Schr"odinger Bridge Problems and Generative Modeling](https://mlsanity.com/paper/2304.00917/) (2023)
- [CoDi: Co-evolving Contrastive Diffusion Models for Mixed-type Tabular Synthesis](https://mlsanity.com/paper/2304.12654/) (2023)
- [The Synthesizability of Molecules Proposed by Generative Models](https://mlsanity.com/paper/2002.07007/) (2020)
- [Learning To Navigate The Synthetically Accessible Chemical Space Using Reinforcement Learning](https://mlsanity.com/paper/2004.12485/) (2020)
- [Mixed Continuous and Categorical Flow Matching for 3D De Novo Molecule Generation](https://mlsanity.com/paper/2404.19739/) (2024)
- [Navigating the Design Space of Equivariant Diffusion-Based Generative Models for De Novo 3D Molecule Generation](https://mlsanity.com/paper/2309.17296/) (2023)
- [Amortized Tree Generation for Bottom-up Synthesis Planning and Synthesizable Molecular Design](https://mlsanity.com/paper/2110.06389/) (2021)
- [ET-Flow: Equivariant Flow-Matching for Molecular Conformer Generation](https://mlsanity.com/paper/2410.22388/) (2024)
- [SemlaFlow -- Efficient 3D Molecular Generation with Latent Attention and Equivariant Flow Matching](https://mlsanity.com/paper/2406.07266/) (2024)
- [RGFN: Synthesizable Molecular Generation Using GFlowNets](https://mlsanity.com/paper/2406.08506/) (2024)

## Built on by (most cited first, 5 of 5)

- [Efficient and Programmable Exploration of Synthesizable Chemical Space](https://mlsanity.com/paper/2512.00384/) (2025)
- [SynLaD: Latent Diffusion for Generating Synthesizable Molecules Conditioned on 3D Pharmacophore Profiles](https://mlsanity.com/paper/2607.01105/) (2026)
- [On the Design Space of Discrete Diffusion Online Adaptation for Molecular Optimization](https://mlsanity.com/paper/2607.02834/) (2026)
- [DBMol: Design of High-Affinity, Target-Specific Small Molecules through Structure Prediction Models](https://mlsanity.com/paper/2607.19237/) (2026)
- [Fraglingo: Molecular Design via Attachment-Aware Autoregressive Fragment Generation](https://mlsanity.com/paper/2609.13519/) (2026)

## Abstract (arXiv)

Synthesizability remains a critical bottleneck in generative molecular design. While recent advances have addressed synthesizability in 2D graphs, extending these constraints to 3D for geometry-based conditional generation remains largely unexplored. In this work, we present SynCoGen (Synthesizable Co-Generation), a single framework that combines simultaneous masked graph diffusion and flow matching for synthesizable 3D molecule generation. SynCoGen samples from the joint distribution of molecular building blocks, chemical reactions, and atomic coordinates. To train the model, we curated SynSpace, a dataset family containing over 1.2M synthesis-aware building block graphs and 7.5M conformers. SynCoGen achieves state-of-the-art performance in unconditional small molecule graph and conformer co-generation. For protein ligand generation in drug discovery, the amortized model delivers superior performance in both molecular linker design and pharmacophore-conditioned generation across diverse targets without relying on any scoring functions. Overall, this multimodal non-autoregressive formulation represents a foundation for a range of molecular design applications, including analog expansion, lead optimization, and direct de novo design.