The Molecular Industrial Revolution: Automated Synthesis of Small Molecules.

Today we are poised for a transition from the highly customized crafting of specific molecular targets by hand to the increasingly general and automated assembly of different types of molecules with the push of a button. Creating machines that are capable of making many different types of small molecules on demand, akin to that which has been achieved on the macroscale with 3D printers, is challenging. Yet important progress is being made toward this objective with two complementary approaches: 1) Automation of customized synthesis routes to different targets by machines that enable the use of many reactions and starting materials, and 2) automation of generalized platforms that make many different targets using common coupling chemistry and building blocks. Continued progress in these directions has the potential to shift the bottleneck in molecular innovation from synthesis to imagination, and thereby help drive a new industrial revolution on the molecular scale.

[1]  James M. B. Evans,et al.  End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. , 2013, Angewandte Chemie.

[2]  Gerlach,et al.  A Combinatorial Approach to Polyketide-Type Libraries by Iterative Asymmetric Aldol Reactions Performed on Solid Support We thank the European Commission (TMR Network ERB-FMR XCT 96-0011 and IHP Network HPRN-CT-2000-00014), EPSRC, Pfizer, and Merck for support. , 2000, Angewandte Chemie.

[3]  E. Corey,et al.  Computer-assisted analysis in organic synthesis. , 1985, Science.

[4]  T. Hansen,et al.  Synthesis of methyl (5Z,8Z,10E,12E,14Z)-eicosapentaenoate , 2011 .

[5]  Robert L. Woodward,et al.  Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor , 2016 .

[6]  K C Nicolaou,et al.  Constructing molecular complexity and diversity: total synthesis of natural products of biological and medicinal importance. , 2012, Chemical Society reviews.

[7]  T. M. Anderson,et al.  A Simple and General Platform for Generating Stereochemically Complex Polyene Frameworks by Iterative Cross-Coupling , 2010, Angewandte Chemie.

[8]  Wei Chen,et al.  3D printing of versatile reactionware for chemical synthesis , 2016, Nature Protocols.

[9]  Junzo Otera,et al.  Automated Synthesis: Development of a New Apparatus Friendly to Synthetic Chemists (MEDLEY) , 2000 .

[10]  Automated radiosynthesis of the Pittsburg compound-B using a commercial synthesizer , 2008, Nuclear medicine communications.

[11]  J. Spencer,et al.  Regioselective routes to orthogonally-substituted aromatic MIDA boronates. , 2016, Organic & biomolecular chemistry.

[12]  Alan H. Cherney,et al.  Stereoretentive Suzuki-Miyaura coupling of haloallenes enables fully stereocontrolled access to (-)-peridinin. , 2010, Journal of the American Chemical Society.

[13]  A. Campbell,et al.  Synthesis of 2-BMIDA 6,5-bicyclic heterocycles by Cu(i)/Pd(0)/Cu(ii) cascade catalysis of 2-iodoaniline/phenols. , 2016, Chemical communications.

[14]  M. Burke,et al.  A simple and modular strategy for small molecule synthesis: iterative Suzuki-Miyaura coupling of B-protected haloboronic acid building blocks. , 2007, Journal of the American Chemical Society.

[15]  Luca Cera,et al.  Iterative Synthesis of Oligo[n]rotaxanes in Excellent Yield. , 2016, Journal of the American Chemical Society.

[16]  M. Burke,et al.  A general solution for unstable boronic acids: slow-release cross-coupling from air-stable MIDA boronates. , 2009, Journal of the American Chemical Society.

[17]  V. Aggarwal,et al.  Lithiation-borylation methodology and its application in synthesis. , 2014, Accounts of chemical research.

[18]  Mitchell T. Ong,et al.  Force-induced activation of covalent bonds in mechanoresponsive polymeric materials , 2009, Nature.

[19]  Maneesh Yadav On the synthesis of machine learning and automated reasoning for an artificial synthetic organic chemist , 2017 .

[20]  Hans Schuler,et al.  Automation in Chemical Industry (Automatisierung in der Chemischen Industrie) , 2006, Autom..

[21]  Eric M. Woerly,et al.  Synthesis of most polyene natural product motifs using just twelve building blocks and one coupling reaction , 2014, Nature chemistry.

[22]  M. Burke,et al.  Simple, efficient, and modular syntheses of polyene natural products via iterative cross-coupling. , 2008, Journal of the American Chemical Society.

[23]  Claudio Battilocchio,et al.  Machine‐Assisted Organic Synthesis , 2015, Angewandte Chemie.

[24]  S. Katsumura,et al.  Stereocontrolled Synthesis of Paracentrone , 2016, Synlett.

[25]  Hong Tao Tang,et al.  Design of Holonic Manufacturing Execution System with Control Mechanism Based Stigmergy , 2010 .

[26]  Davidr . Evans,et al.  Diastereoselective aldol reactions using .beta.-keto imide derived enolates. A versatile approach to the assemblage of polypropionate systems , 1990 .

[27]  C. Crudden,et al.  Iterative protecting group-free cross-coupling leading to chiral multiply arylated structures , 2016, Nature Communications.

[28]  S. Ishibashi,et al.  A single-component molecular superconductor. , 2014, Journal of the American Chemical Society.

[29]  Takashi Takahashi,et al.  Solution-phase automated synthesis of an α-amino aldehyde as a versatile intermediate , 2017, Beilstein journal of organic chemistry.

[30]  V. Aggarwal,et al.  Synthesis of enantioenriched tertiary boronic esters from secondary allylic carbamates. Application to the synthesis of C30 botryococcene. , 2012, Journal of the American Chemical Society.

[31]  J. Molloy,et al.  Tandem Chemoselective Suzuki-Miyaura Cross-Coupling Enabled by Nucleophile Speciation Control. , 2015, Angewandte Chemie.

[32]  B. Feringa,et al.  Catalytic asymmetric synthesis of phthioceranic acid, a heptamethyl-branched acid from Mycobacterium tuberculosis. , 2007, Organic letters.

[33]  Klavs F. Jensen,et al.  Suzuki–Miyaura cross-coupling optimization enabled by automated feedback , 2016, Reaction chemistry & engineering.

[34]  Timothy F Jamison,et al.  A three-minute synthesis and purification of ibuprofen: pushing the limits of continuous-flow processing. , 2015, Angewandte Chemie.

[35]  Andreas Kirschning,et al.  Iterative Synthesen: das Tor zu neuen Automationsprotokollen , 2015 .

[36]  A. Suzuki,et al.  Construction of Iterative Tetrahydrofuran Ring Units and Total Synthesis of (+)-Goniocin. , 2016, Organic letters.

[37]  J. T. Njardarson,et al.  Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. , 2014, Journal of medicinal chemistry.

[38]  anastasia. khvorova,et al.  The chemical evolution of oligonucleotide therapies of clinical utility , 2017, Nature Biotechnology.

[39]  David H Phillips,et al.  Boronic acids-a novel class of bacterial mutagen. , 2011, Mutation research.

[40]  Riccardo Porta,et al.  Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products , 2016 .

[41]  Y. Lawryshyn,et al.  A Continuous-Flow Microwave Reactor for Conducting High-Temperature and High-Pressure Chemical Reactions , 2014 .

[42]  Daniel S. Palacios,et al.  Amphotericin primarily kills yeast by simply binding ergosterol , 2012, Proceedings of the National Academy of Sciences.

[43]  C. Papageorgiou,et al.  Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material , 2017 .

[44]  Qingjiang Li,et al.  Oxidative Difunctionalization of Alkenyl MIDA Boronates: A Versatile Platform for Halogenated and Trifluoromethylated α-Boryl Ketones. , 2016, Angewandte Chemie.

[45]  Matthew Burns,et al.  Assembly-line synthesis of organic molecules with tailored shapes , 2014, Nature.

[46]  Volker Hessel,et al.  A View Through Novel Process Windows , 2013 .

[47]  M. Burke,et al.  From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks. , 2015, Accounts of chemical research.

[48]  J. Pascual,et al.  Protection of excited spin states by a superconducting energy gap , 2013, Nature Physics.

[49]  M. Krische,et al.  Polyketide construction via hydrohydroxyalkylation and related alcohol C-H functionalizations: reinventing the chemistry of carbonyl addition. , 2014, Natural product reports.

[50]  M. Burke,et al.  Total Synthesis of Synechoxanthin through Iterative Cross-Coupling** , 2011, Angewandte Chemie.

[51]  A. Orita,et al.  Automated Synthesis: Utilization of MEDLEY in Synthetic Processes , 2000 .

[52]  Andreas Kirschning,et al.  Iterative Syntheses—The Gateway to New Automation Protocols. , 2015, Angewandte Chemie.

[53]  Nancy R. Sottos,et al.  Biasing reaction pathways with mechanical force , 2007, Nature.

[54]  E. Corey,et al.  The Logic of Chemical Synthesis , 1989 .

[55]  J. Sperry,et al.  Extending the Utility of the Bartoli Indolization: Synthesis of Marinoquinolines C and E , 2013, Synlett.

[56]  Hao Li,et al.  Photoacoustic Probes for Ratiometric Imaging of Copper(II). , 2015, Journal of the American Chemical Society.

[57]  Alán Aspuru-Guzik,et al.  A redox-flow battery with an alloxazine-based organic electrolyte , 2016, Nature Energy.

[58]  Steven V Ley,et al.  A fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles. , 2011, Organic & biomolecular chemistry.

[59]  Brahim Benyahia,et al.  Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical , 2014 .

[60]  T. Doi,et al.  An Efficient Synthesis of a Cyclic Ether Key Intermediate for 9-Membered Masked Enediyne Using an Automated Synthesizer , 2009 .

[61]  Peter H. Seeberger,et al.  Automated synthesis of oligosaccharides as a basis for drug discovery , 2005, Nature Reviews Drug Discovery.

[62]  H. Chao,et al.  Design of CGMP Production of 18F- and 68Ga-Radiopharmaceuticals , 2014, BioMed research international.

[63]  M. Legrand,et al.  A fully automatic apparatus for chemical reactions on the laboratory scale , 1985, The Journal of automatic chemistry.

[64]  Peter H. Seeberger,et al.  Automated Solid-Phase Synthesis of Oligosaccharides , 2001, Science.

[65]  Leroy Cronin,et al.  The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot , 2016, Beilstein journal of organic chemistry.

[66]  C. Butts,et al.  Synergy of synthesis, computation and NMR reveals correct baulamycin structures , 2017, Nature.

[67]  J. Elkins,et al.  Oxalyl Boronates Enable Modular Synthesis of Bioactive Imidazoles. , 2017, Angewandte Chemie.

[68]  Marcus Baumann,et al.  The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry , 2015, Beilstein journal of organic chemistry.

[69]  Magnus Rueping,et al.  Online monitoring and analysis for autonomous continuous flow self-optimizing reactor systems , 2016 .

[70]  M. Burke,et al.  Multistep synthesis of complex boronic acids from simple MIDA boronates. , 2008, Journal of the American Chemical Society.

[71]  Steven V Ley,et al.  Flow chemistry syntheses of natural products. , 2013, Chemical Society reviews.

[72]  M. Crimmins,et al.  Titanium enolates of thiazolidinethione chiral auxiliaries: versatile tools for asymmetric aldol additions. , 2000, Organic letters.

[73]  T Monaghan,et al.  Customisable 3D printed microfluidics for integrated analysis and optimisation. , 2016, Lab on a chip.

[74]  A. Yudin,et al.  Synthesis of Previously Inaccessible Borylated Heterocycle Motifs Using Novel Boron-Containing Amphoteric Molecules. , 2015, Angewandte Chemie.

[75]  B. W. King,et al.  Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. , 2001, The Journal of organic chemistry.

[76]  S. Zard,et al.  Radical Instability in Aid of Efficiency: A Powerful Route to Highly Functional MIDA Boronates. , 2015, Journal of the American Chemical Society.

[77]  Susumu Kobayashi,et al.  Concise total synthesis of (-)-myxalamide A. , 2012, Angewandte Chemie.

[78]  Alexander G Cioffi,et al.  Restored Physiology in Protein-Deficient Yeast by a Small Molecule Channel. , 2015, Journal of the American Chemical Society.

[79]  Claudio Battilocchio,et al.  Enabling Technologies for the Future of Chemical Synthesis , 2016, ACS central science.

[80]  Carl Schubert,et al.  Innovations in 3D printing: a 3D overview from optics to organs , 2013, British Journal of Ophthalmology.

[81]  Ryan L. Hartman,et al.  Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis. , 2011, Angewandte Chemie.

[82]  M. Burke,et al.  Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp3) Boronate Building Blocks , 2011, Journal of the American Chemical Society.

[83]  Steve Edmondson,et al.  3D printed fluidics with embedded analytic functionality for automated reaction optimisation , 2017, Beilstein journal of organic chemistry.

[84]  E. Corey,et al.  Robert Robinson Lecture. Retrosynthetic thinking—essentials and examples , 1988 .

[85]  Frank F. Bier,et al.  Miniaturization for Point-of-Care Analysis: Platform Technology for Almost Every Biomedical Assay , 2012, EJIFCC.

[86]  F. Toste,et al.  Tandem Cycloisomerization/Suzuki Coupling of Arylethynyl MIDA Boronates. , 2011, Tetrahedron.

[87]  E. Carreira Classics in total synthesis: Targets, strategies, methods , 1996 .

[88]  DelaunayThierry,et al.  Sequential Suzuki-Miyaura Cross-coupling Reactions of 4-Halopyrazolyl MIDA 3-Boronates : A Modular Synthetic Entry to 3,4-Bis(hetero)aromatic Pyrazoles , 2011 .

[89]  A. Myers,et al.  Asymmetric Synthesis of 1,3-Dialkyl-Substituted Carbon Chains of any Stereochemical Configuration by an Iterable Process , 1997 .

[90]  Dima Kozakov,et al.  How Proteins Bind Macrocycles , 2014, Nature chemical biology.

[91]  Christopher A. Hone,et al.  Rapid multistep kinetic model generation from transient flow data† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6re00109b Click here for additional data file. , 2016, Reaction chemistry & engineering.

[92]  Sarah E Bohndiek,et al.  Contrast agents for molecular photoacoustic imaging , 2016, Nature Methods.

[93]  Keith Kirkpatrick Automating organic synthesis , 2015, Commun. ACM.

[94]  Martin D. Burke,et al.  Synthesis of many different types of organic small molecules using one automated process , 2015, Science.

[95]  Frank Schuhmacher,et al.  Automated glycan assembly using the Glyconeer 2.1 synthesizer , 2017, Proceedings of the National Academy of Sciences.

[96]  Yang Liu,et al.  Route Designer: A Retrosynthetic Analysis Tool Utilizing Automated Retrosynthetic Rule Generation , 2009, J. Chem. Inf. Model..

[97]  Alexander G. Godfrey,et al.  A remote-controlled adaptive medchem lab: an innovative approach to enable drug discovery in the 21st Century. , 2013, Drug discovery today.

[98]  A. Buchanan The Portsmouth Block Mills: Bentham, Brunel and the start of the Royal Navy's Industrial Revolution, by Jonathan Coad , 2006, The Antiquaries Journal.

[99]  T. Brocksom,et al.  Combining batch and continuous flow setups in the end-to-end synthesis of naturally occurring curcuminoids , 2017 .

[100]  C. E. Berkoff,et al.  Chemical process optimization by computer — a self-directed chemical synthesis system , 1978 .

[101]  S. Y. Wong,et al.  On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system , 2016, Science.

[102]  A. Yudin,et al.  Chemoselective palladium-catalyzed α-allylation of α-boryl aldehydes. , 2012, Organic & biomolecular chemistry.

[103]  Thomas H Segall-Shapiro,et al.  Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome , 2010, Science.

[104]  Alán Aspuru-Guzik,et al.  Use machine learning to find energy materials  , 2017, Nature.

[105]  Alán Aspuru-Guzik,et al.  From computational discovery to experimental characterization of a high hole mobility organic crystal , 2011, Nature communications.

[106]  S. Sadeghi,et al.  An automated synthesizer for electrochemical 18F-fluorination of organic compounds. , 2017, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[107]  Charles L. Wilkins,et al.  Phenylacetylene Dendrimers by the Divergent, Convergent, and Double-Stage Convergent Methods , 1994 .

[108]  M. Burke,et al.  Iterative Cross-Couplng with MIDA Boronates: Towards a General Platform for Small Molecule Synthesis. , 2010, Aldrichimica acta.

[109]  Bowen Liu,et al.  Retrosynthetic Reaction Prediction Using Neural Sequence-to-Sequence Models , 2017, ACS central science.

[110]  M. Garcia‐Garibay,et al.  Phosphine-Mediated Iterative Arene Homologation Using Allenes. , 2015, Journal of the American Chemical Society.

[111]  Hideho Okamoto,et al.  Design of a robotic workstation for automated organic synthesis , 2000 .

[112]  J. Cossy,et al.  Synthesis of the Acyclic Carbon Skeleton of Filipin III. , 2016, The Journal of organic chemistry.

[113]  E J Corey,et al.  Computer-assisted design of complex organic syntheses. , 1969, Science.

[114]  Julien Rossignol,et al.  Machine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatography , 2014 .

[115]  B. Gutmann,et al.  Kontinuierliche Durchflussverfahren: ein Werkzeug für die sichere Synthese von pharmazeutischen Wirkstoffen , 2015 .

[116]  J. Yoshida,et al.  A new iterative route to optically active polyols using .alpha.-alkoxy silanes as key intermediates , 1992 .

[117]  A. Livingston,et al.  Continuous Consecutive Reactions with Inter‐Reaction Solvent Exchange by Membrane Separation , 2016, Angewandte Chemie.

[118]  Jonathan M. Goodman,et al.  Dial-a-molecule workshop: computational prediction of reaction outcomes and optimum synthetic routes , 2015, Chemistry Central Journal.

[119]  S. Ley,et al.  Continuous Preparation and Use of Dibromoformaldoxime as a Reactive Intermediate for the Synthesis of 3-Bromoisoxazolines , 2017 .

[120]  Marco Ceccarelli,et al.  A Brief Illustrated History of Machines and Mechanisms , 2010 .

[121]  Lee Joon Kim,et al.  Concise, diastereoconvergent synthesis of endiandric-type tetracycles by iterative cross coupling , 2016 .

[122]  C. Oliver Kappe,et al.  Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles: Toward the Continuous Production of Daclatasvir , 2015 .

[123]  Richard Leslie Hills,et al.  Papermaking in Britain, 1488-1988: A Short History , 1988 .

[124]  Jian Guo Yu,et al.  Research on Design and Development for Intelligent Manufacturing Execution System of Tungsten Powder Processing , 2011 .

[125]  E. Gouaux,et al.  Glycine receptor mechanism elucidated by electron cryo-microscopy , 2015, Nature.

[126]  Ventola Cl Medical Applications for 3D Printing: Current and Projected Uses. , 2014 .

[127]  Geoffrey R Akien,et al.  Online quantitative mass spectrometry for the rapid adaptive optimisation of automated flow reactors , 2016 .

[128]  Klavs F Jensen,et al.  A fully automated flow-based approach for accelerated peptide synthesis. , 2017, Nature chemical biology.

[129]  K. Houk,et al.  MIDA boronates are hydrolysed fast and slow by two different mechanisms , 2016, Nature chemistry.

[130]  K. Shin‐ya,et al.  Total synthesis of spiruchostatin B aided by an automated synthesizer. , 2011, Organic & biomolecular chemistry.

[131]  Piotr Dittwald,et al.  Computergestützte Syntheseplanung: Das Ende vom Anfang , 2016 .

[132]  H. Roche,et al.  3.3-million-year-old stone tools from Lomekwi 3, West Turkana, Kenya , 2015, Nature.

[133]  E. Corey,et al.  The Logic of Chemical Synthesis: Multistep Synthesis of Complex Carbogenic Molecules (Nobel Lecture)† , 1991 .

[134]  K. Kurdziel,et al.  Automated synthesis of 18F analogue of paclitaxel (PAC): [18F]Paclitaxel (FPAC). , 2007, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[135]  C. Papageorgiou,et al.  Development and Scale-up of an Efficient Miyaura Borylation Process Using Tetrahydroxydiboron , 2017 .

[136]  J. Wegner,et al.  Flow Chemistry – A Key Enabling Technology for (Multistep) Organic Synthesis , 2012 .

[137]  David Cantillo,et al.  Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. , 2015, Angewandte Chemie.

[138]  S. Ley,et al.  A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly. , 2006, Chemical communications.

[139]  Eric M. Woerly,et al.  (1-bromovinyl)-MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis. , 2013, Tetrahedron.

[140]  Chinmay A Shukla,et al.  Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic , 2017, Beilstein journal of organic chemistry.

[141]  A A Lapkin,et al.  Automation of route identification and optimisation based on data-mining and chemical intuition. , 2017, Faraday discussions.

[142]  Claudio Battilocchio,et al.  Maschinengestützte organische Synthese , 2015 .

[143]  Timothy F. Jamison,et al.  Continuous flow multi-step organic synthesis , 2010 .

[144]  T. Hoffmann,et al.  Peptide therapeutics: current status and future directions. , 2015, Drug discovery today.

[145]  Demis Hassabis,et al.  Mastering the game of Go with deep neural networks and tree search , 2016, Nature.

[146]  H. Yin,et al.  Strategien zur Modulation von Protein‐Protein‐Wechselwirkungen mit synthetischen Substanzen , 2005 .

[147]  Jeremy P. Scott,et al.  Polyketide library synthesis: Conformational control in extended polypropionates , 1997 .

[148]  Jeffrey S. Moore,et al.  Nanoarchitectures. 1. Controlled synthesis of phenylacetylene sequences , 1992 .

[149]  Daniel E. Fitzpatrick,et al.  Engineering chemistry for the future of chemical synthesis , 2017, Tetrahedron.

[150]  T. Sugawara,et al.  Computer-controlled reaction of substituted N-(carboxyalkyl)amino acids. , 1988 .

[151]  Ryan P. Adams,et al.  Design of efficient molecular organic light-emitting diodes by a high-throughput virtual screening and experimental approach. , 2016, Nature materials.

[152]  Tudor I. Oprea,et al.  Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes , 2015, Cell.

[153]  Shinji Kato,et al.  Development of fully-automated synthesis systems , 1994, The Journal of automatic chemistry.

[154]  W. Wernsdorfer,et al.  Electrically driven nuclear spin resonance in single-molecule magnets , 2014, Science.

[155]  S. Ohla,et al.  On-chip integration of organic synthesis and HPLC/MS analysis for monitoring stereoselective transformations at the micro-scale. , 2016, Lab on a chip.

[156]  Eric M. Woerly,et al.  A General Solution for the 2-Pyridyl Problem , 2012, Angewandte Chemie.

[157]  Peter H Seeberger,et al.  Applying flow chemistry: methods, materials, and multistep synthesis. , 2013, The Journal of organic chemistry.

[158]  T. Jamison,et al.  A Unified Continuous Flow Assembly Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines , 2017, Angewandte Chemie.

[159]  Ross D. King,et al.  Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases , 2015, Journal of The Royal Society Interface.

[160]  L. Hamann,et al.  One-pot C-N/C-C cross-coupling of methyliminodiacetic acid boronyl arenes enabled by protective enolization. , 2012, Organic letters.

[161]  M. Caruthers,et al.  Gene synthesis machines: DNA chemistry and its uses. , 1985, Science.

[162]  Klavs F Jensen,et al.  Feedback in Flow for Accelerated Reaction Development. , 2016, Accounts of chemical research.

[163]  Leroy Cronin,et al.  Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals , 2018, Science.

[164]  M. Burke,et al.  General method for synthesis of 2-heterocyclic N-methyliminodiacetic acid boronates. , 2010, Organic letters.

[165]  Yongxin Liao,et al.  Self-Aware Smart Products: Systematic Literature Review, Conceptual Design and Prototype Implementation , 2017 .

[166]  R. Mach,et al.  Automation of the Radiosynthesis of Six Different 18F-labeled radiotracers on the AllinOne , 2016, EJNMMI Radiopharmacy and Chemistry.

[167]  J. Ellman,et al.  Asymmetric Rh(I)-catalyzed addition of MIDA boronates to N-tert-butanesulfinyl aldimines: development and comparison to trifluoroborates. , 2010, The Journal of organic chemistry.

[168]  Lukasz Kowalik,et al.  Illuminating developmental biology through photochemistry. , 2017, Nature chemical biology.

[169]  M. Johnston,et al.  Procyanidin oligomers. A new method for 4→8 interflavan bond formation using C8-boronic acids and iterative oligomer synthesis through a boron-protection strategy , 2012 .

[170]  Christopher H. Bryant,et al.  Functional genomic hypothesis generation and experimentation by a robot scientist , 2004, Nature.

[171]  Erin E. Carlson,et al.  Progress and prospects for small-molecule probes of bacterial imaging. , 2016, Nature chemical biology.

[172]  Steven V. Ley,et al.  Organische Synthese: Vormarsch der Maschinen , 2015 .

[173]  D. Caro,et al.  TTF[Ni(dmit)2]2: From single-crystals to thin layers, nanowires, and nanoparticles , 2016 .

[174]  Flavien Susanne,et al.  Continuous flow synthesis. A pharma perspective. , 2012, Journal of medicinal chemistry.

[175]  Chyouhwa Chen,et al.  Building and refining a knowledge base for synthetic organic chemistry via the methodology of inductive and deductive machine learning , 1990, J. Chem. Inf. Comput. Sci..

[176]  R. B. Merrifield Automated synthesis of peptides. , 1965, Science.

[177]  A. Yudin,et al.  Amphoteric α-boryl aldehydes. , 2011, Journal of the American Chemical Society.

[178]  Marwin H. S. Segler,et al.  Neural-Symbolic Machine Learning for Retrosynthesis and Reaction Prediction. , 2017, Chemistry.

[179]  Ferenc Faigl,et al.  The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds. , 2017, Bioorganic & medicinal chemistry.

[180]  C. Oliver Kappe,et al.  Continuous flow organic synthesis under high-temperature/pressure conditions. , 2010, Chemistry, an Asian journal.

[181]  K C Nicolaou,et al.  Organic synthesis: the art and science of replicating the molecules of living nature and creating others like them in the laboratory , 2014, Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[182]  Martin D. Johnson,et al.  Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions , 2017, Science.

[183]  Ryan L. Hartman,et al.  Pro und kontra Strömungsreaktoren in der Synthese , 2011 .

[184]  Friedrich Wöhler,et al.  Ueber künstliche Bildung des Harnstoffs , 1828 .

[185]  A. Kirschning,et al.  Total synthesis of the antibiotic elansolid B1. , 2014, Organic letters.

[186]  Piotr Dittwald,et al.  Computer-Assisted Synthetic Planning: The End of the Beginning. , 2016, Angewandte Chemie.

[187]  M. Burke,et al.  B-protected haloboronic acids for iterative cross-coupling , 2009 .

[188]  F Lodi,et al.  Automation synthesis modules review. , 2013, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[189]  Richard J Ingham,et al.  A Systems Approach towards an Intelligent and Self-Controlling Platform for Integrated Continuous Reaction Sequences** , 2014, Angewandte Chemie.

[190]  Andrea M E Palazzolo,et al.  The natural productome , 2017, Proceedings of the National Academy of Sciences.

[191]  Mary M. Caruso,et al.  Evaluation of ruthenium catalysts for ring-opening metathesis polymerization-based self-healing applications , 2008 .

[192]  R. Noyori,et al.  Sulfonyl-stabilized oxiranyllithium-based approach to polycyclic ethers. Convergent synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin. , 2003, The Journal of organic chemistry.

[193]  Junji Kido,et al.  Solution-processed multilayer small-molecule light-emitting devices with high-efficiency white-light emission , 2014, Nature Communications.

[194]  Jeremy Straub,et al.  Initial Work on the Characterization of Additive Manufacturing (3D Printing) Using Software Image Analysis , 2015 .

[195]  S. Kent Total chemical synthesis of proteins. , 2009, Chemical Society reviews.

[196]  P. Phansavath,et al.  Heck coupling using a vinyliodo-MIDA boronate: an efficient and modular access to polyene frameworks. , 2015, Organic letters.

[197]  R. Mart,et al.  Azobenzene photocontrol of peptides and proteins. , 2016, Chemical communications.

[198]  Gregory W. Kauffman,et al.  Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects. , 2016, Journal of medicinal chemistry.

[199]  K. Nicolaou,et al.  Total synthesis of amphoteronolide B and amphotericin B. 1. Strategy and stereocontrolled construction of key building blocks , 1988 .

[200]  K. Jensen,et al.  A Rapid Total Synthesis of Ciprofloxacin Hydrochloride in Continuous Flow. , 2017, Angewandte Chemie.

[201]  Claudio Battilocchio,et al.  A machine-assisted flow synthesis of SR48692: a probe for the investigation of neurotensin receptor-1. , 2013, Chemistry.

[202]  Zhanmin Lin,et al.  Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474 , 2017, Science.

[203]  Richard J Ingham,et al.  Organic synthesis: march of the machines. , 2015, Angewandte Chemie.

[204]  Bruno G. Nicolau,et al.  Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals , 2017, Science.

[205]  Paulo Cézar Stadzisz,et al.  Manufacturing execution systems for customized production , 2006 .

[206]  Steven V Ley,et al.  Accelerating spirocyclic polyketide synthesis using flow chemistry. , 2014, Angewandte Chemie.

[207]  Leroy Cronin,et al.  Towards dial-a-molecule by integrating continuous flow, analytics and self-optimisation. , 2016, Chemical Society reviews.

[208]  H. G. Khorana Total synthesis of a gene , 2012, Die Naturwissenschaften.

[209]  T. Doi,et al.  A formal total synthesis of taxol aided by an automated synthesizer. , 2006, Chemistry, an Asian journal.

[210]  A. Anzellotti,et al.  A "dose on demand" Biomarker Generator for automated production of [(18)F]F(-) and [(18)F]FDG. , 2014, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[211]  内田 星美 From the American System to Mass Production 1800〜1932/David A.Hounshell(1984) , 1988 .

[212]  Julien C. Vantourout,et al.  One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented Synthesis. , 2015, Organic letters.

[213]  H. Brown,et al.  Chiral synthesis via organoboranes. 7. Diastereoselective and enantioselective synthesis of erythro- and threo-.beta.-methylhomoallyl alcohols via enantiomeric (Z)- and (E)-crotylboranes. , 1986, Journal of the American Chemical Society.

[214]  Jeffrey S. Moore,et al.  Geometrically-Controlled and Site-Specifically-Functionalized Phenylacetylene Macrocycles , 1994 .

[215]  T. Sugawara,et al.  Computer-assisted automated synthesis I: computer-controlled reaction of substituted N-(carboxyalkyl)amino acids , 1988 .

[216]  David A. Nicewicz,et al.  Organic Photoredox Catalysis. , 2016, Chemical reviews.

[217]  Christopher J Chang,et al.  Reaction-based small-molecule fluorescent probes for chemoselective bioimaging. , 2012, Nature chemistry.

[218]  P. Seeberger,et al.  The Hitchhiker's Guide to Flow Chemistry ∥. , 2017, Chemical reviews.

[219]  H. Dodziuk,et al.  Applications of 3D printing in healthcare , 2016, Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery.

[220]  A. Hamilton,et al.  Strategies for targeting protein-protein interactions with synthetic agents. , 2005, Angewandte Chemie.

[221]  Tohru Sugawara,et al.  Development and application of a solution-phase automated synthesizer, 'ChemKonzert'. , 2010, Chemical & pharmaceutical bulletin.

[222]  V. Aggarwal,et al.  Short Enantioselective Total Synthesis of Tatanan A and 3‐epi‐Tatanan A Using Assembly‐Line Synthesis , 2016, Angewandte Chemie.

[223]  William H. Green,et al.  Computer-Assisted Retrosynthesis Based on Molecular Similarity , 2017, ACS central science.

[224]  Kimito Funatsu,et al.  A Novel Approach to Retrosynthetic Analysis Using Knowledge Bases Derived from Reaction Databases , 1999, J. Chem. Inf. Comput. Sci..

[225]  Lin-Li Li,et al.  RASA: A Rapid Retrosynthesis-Based Scoring Method for the Assessment of Synthetic Accessibility of Drug-like Molecules , 2011, J. Chem. Inf. Model..

[226]  Kelly J Kilpin,et al.  Chemistry Central Journal themed issue: Dial-a-Molecule , 2015, Chemistry Central Journal.

[227]  C. Solbach,et al.  Preparation of the hypoxia imaging PET tracer [18F]FAZA: reaction parameters and automation. , 2005, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[228]  E. J. Corey,et al.  Die Logik der chemischen Synthese: Vielstufige Synthesen komplexer „carbogener”︁ Moleküle (Nobel‐Vortrag) , 1991 .

[229]  Daniel E. Fitzpatrick,et al.  Engineering chemistry: integrating batch and flow reactions on a single, automated reactor platform , 2016 .

[230]  Ken E. Whelan,et al.  The Automation of Science , 2009, Science.

[231]  Stephen P. Thomas,et al.  Homologation and alkylation of boronic esters and boranes by 1,2-metallate rearrangement of boronate complexes. , 2009, Chemical record.

[232]  Matthew Burns,et al.  Toward ideality: the synthesis of (+)-kalkitoxin and (+)-hydroxyphthioceranic acid by assembly-line synthesis. , 2015, Journal of the American Chemical Society.

[233]  S. Schreiber,et al.  A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. , 2017, Nature chemical biology.