Analysis Preferences

During the analysis, the search algorithm controls which retrosynthetic cuts are favored, and scores the pathways as it finds them. Penalties are assigned for undesirable variables, such as reaction steps, protecting group requirements, incompatibilities, or unrealistic intermediates. Consequently, the lowest scoring pathways are preferred, and will be featured in the search results.

The settings in Analysis Preferences allow you to adjust pathway scoring according to your preferences for various criteria, such as length of the pathway, price of starting materials, reaction selectivity, reaction robustness, protection group requirements, and pathway efficiency.

Price

Check this box to reduce the bias toward low-cost starting materials. This setting may be used to favor shorter pathways that may use more expensive, advanced intermediates. Increase the limit of the maximum price per gram of commercial compounds to find shorter pathways.

Reaction Selectivity

Check this box to allow to non-selective reactions when they help find better pathways. This setting may be used to find shorter pathways for complex molecules, such as natural products, when more complex purifications are acceptable.

Protecting Groups

Steps that require a protecting group are generally assigned an additional penalty to reflect the extra work needed to install and eliminate protecting groups. The inclusion of protecting group requirements in a pathway can be controlled by selecting one of the following options:

• None: Excludes pathways that require protecting groups
• Fewer: Favors pathways that require fewer protecting groups
• Balanced: Suggests protecting groups when they help keep pathways short
• More: Allows more protecting groups in results
• Unlimited: Shows pathways with an unlimited number of protecting groups

Balanced: Assigns a penalty worth twice as much as that for a single synthetic step. This reflects the two extra reaction steps needed to install and eliminate the protecting group. 

More or Unlimited: A smaller or no extra penalty is applied to steps that require protecting groups. This may return search results with shorter pathways, although with potentially several steps requiring protection. These options may be useful when the same functional group needs to be protected over many steps of a synthetic pathway. As the penalty for protection is removed, search results may return shorter pathways for which only two protective synthetic steps need to be added, since the protection group can be carried over the synthesis. 

Fewer or None: Any reaction step that requires a protecting group is assigned a heavier penalty. This may return search results with longer pathways. However, fewer, or no extra protective steps need to be accounted for in the actual total step count.

Options

‘Options’ are useful “synthetic tricks” that can help tailor your analysis.

Plan strategic two-step reaction sequences (Strategies)
Search through a collection of two-step reaction sequences, for which the product of the first step is more complex than that of the second step. These two-step sequences go through a higher complexity intermediate to make strategic and significant advances toward the structure of your target molecule. 
For example: when creating a highly functionalized cyclohexane ring, SYNTHIA™ will find efficient pathways using a Diels-Alder reaction to build a cyclohexene ring (more complex than a cyclohexane ring), followed by reduction to a cyclohexane ring. 
Use preferentially for natural products and complex molecules.
When this option is selected, search time may be longer due to the “deeper thinking” required to apply this filter.

Allow multiple identical retrosynthetic disconnections in one step (Multicut)
Look for multiple retrosynthetic disconnections that can be made in a single step. This option is useful when the target molecule contains symmetry, or multiple equivalent groups. For example, bis-alkylation of piperazine using ethyl iodide can be performed in one step, instead of sequentially. 
Use for symmetric molecules, and molecules with two or more identical motifs.
When this option is selected, search time may be longer due to the “deeper thinking” required to apply this filter.

Build heterocycles from scratch
Build aromatic heterocycles within the target structure from scratch, even when heterocyclic building blocks are known or commercially available.

Exclude diastereoselective reactions
Only show reactions that are enantioselective and eliminate any proposed reactions that are only diastereoselective. 
For example: Catalytic hydrogenations of double bonds, Diels-Alder reactions, cyclopropanations.
Use when only one enantiomer is exclusively wanted.

Power search: Simultaneous protection/deprotection steps 
Like Multicut, Simultaneous Reactions applies multiple reactions with matching reaction conditions to different functional groups at once (e.g., hydrogenolysis of benzyl ethers and benzyl amines, or deprotections of Boc-protected amines and TBDMS ethers).
Use when looking for explicit protection and deprotection steps.

Power search: Promote functional group interconversions
Functional group interconversions (FGIs) are series of up to three consecutive reactions that stabilize highly reactive functional groups along synthetic pathways and will find alternative precursors for a penalized reaction in pathways that could otherwise be excluded. Precursors that could cause a reaction to be ignored by the regular search algorithm, because they are non-selective, contain incompatible functional groups, or require protective groups, can be interchanged for ones that do not cause the issue, but may add an extra step to the pathway. FGIs were generated based on the analysis of several thousand reports of classical total syntheses.
Use preferentially for natural products and complex molecules, or when looking for explicit protection and deprotection steps.

Power search: Dynamic strategies 
Like strategies, dynamic strategies are a series of up to three consecutive reactions that allow SYNTHIA™ to strategize over multiple steps and reach commercial compounds that would otherwise not be found by the conventional search algorithm.
Use with simultaneous protection/deprotection steps and promote functional group interconversions for natural products and complex molecules.
When this option is selected, search time may be significantly longer due to the “deeper thinking” required to apply this filter.

Promote Robust Reactions
Promote reactions that are considered robust. Expert-coded rules for well-established chemistry such as Amide Couplings or Suzuki Reactions, have been designated as robust chemistry. When enabled, SYNTHIA™ will favor pathways using these reactions. Less popular reactions can still be proposed it they offer simplifications for the pathway that could not be achieved otherwise.
Use preferentially for finding routes with well-documented chemistry

Exclude Gaseous Substrates
Exclude reactions that use gaseous substrates. When enabled, SYNTHIA will eliminate reactions that have gases such as carbon monoxide, hydrogen fluoride or phosgene, listed in their typical reaction conditions. 
Use when handling potentially hazardous gases in the lab is not desirable.

Exclude Reactions Utilizing Metals
Exclude reactions that use metals as catalyst or reagent. When enabled, SYNTHIA will eliminate reactions that have metals, such as palladium, platinum, nickel or chromium, listed in their typical reaction conditions.
Use when the presence of metal residues in final product is a concern.

Tip: The ‘Allow multiple identical retrosynthetic disconnections in one step’ option can be used for global deprotection of a molecule if multiple protecting groups are required, for example in sugar chemistry.

Pathways

By default, SYNTHIA™ will consider both: retrosynthetic cuts that result in two approximately equal-sized fragments, leading to convergent pathways; and peripheral cuts that result in one larger fragment and one smaller fragment, creating more linear pathways. This will generate a greater diversity of pathways.

Favor more convergent pathways
Retrosynthetic cuts that result in two approximately equal-sized fragments will be favored. This may return search results with more convergent synthetic pathways.

Favor more linear pathways
Peripheral retrosynthetic cuts will be favored. This may return search results with more linear synthetic pathways.

Analysis Complexity

Analysis Complexity tells SYNTHIA™ how much effort it should take before completing an analysis, based on number of iterations. Each iteration represents one single expansion of the tree of synthetic possibilities. Increasing the number of iterations may increase the chances of finding more diverse pathways, or pathways with lower scores.

Analysis for a simple molecule will return valuable pathways after just a few iterations. However, when molecule or analysis complexity increase (e.g., larger molecule size, presence of chiral bonds, or complex ring systems), it may take several additional iterations to find viable pathways.

Quick Analysis (stops at 300 iterations)
Suitable for a simple molecule, or to quickly check what kind of results are returned for selected analysis parameters.

Standard Analysis (stops at 2,000 iterations)
This option will stop after 2,000 iterations and should return appropriate results for most analyses.

Long Analysis (stops at 10,000 iterations)
This option increases the probability of finding more diverse pathways, or pathways with lower scores. Use for complex molecules with several chiral centers, or natural products. Depending on server capacity at the time of the search, the analysis may take up to several hours to complete.

Custom Analysis (use your own limit)
Set your own number of iterations by selecting a number between 1 and 50,000. Number of iterations over 5,000 will increase the probability of finding more diverse pathways, or pathways with lower scores. Depending on server capacity at the time of the search, the analysis may take up to several hours to complete.

You may also choose a time-based option to complete your analysis. Select ‘Autostop after’, and set your desired time in the format hh:mm. Depending on server capacity at the time of the search, results may vary for the same analysis set with the same time limit.

You can start reviewing pathways as soon as they are found, and the search can be manually terminated at any time.

Note: The time it takes to complete an analysis will depend on server resources available at the time of the search. Each running analysis will take up memory on the server, thus reducing searching capacity. An iteration may also take longer to complete for a complex analysis. Therefore, you may see significant variations in completion time for the same selected analysis complexity.

Note: The maximum number of iterations for Batch Analyses is limited to 2000, and time limits cannot be used.

Advanced Analysis Preferences – Databases 

SYNTHIA™ is built on our expert-coded rules database, which consists of over 100,000 reaction rules. These rules are based on transformations you would find in organic chemistry textbooks or in the literature and are written in a general way, so that they can be applied to any molecules, including novel ones. They consider full stereo- and regio-chemistry, and include protection information, reactivity conflicts, literature sources, and reaction conditions. By applying these rules to potential retrosynthetic disconnections, SYNTHIA™ will suggest reactions that are possible based on the chemistry that we know, and compatible with the rest of the molecule structure.

There is an additional subset of expert-coded rules based uniquely on enzymatic reactions, that can suggest enzymatic reactions as a green alternative to traditional chemistry.

Moreover, you can find five additional rules databases. They consist of machine-extracted rules, which cover specialized chemistries. They may be used to supplement the expert-coded rules database, particularly if your structure contains stereochemistry, complex aromatic systems, or unusual heterocycles. These rules were automatically extracted from the literature and may not contain all possible reaction condition incompatibilities, reactivity conflicts or protection requirements.

• Uncommon chemistry: Reaction rules for uncommon transformations that have a minimum of 10 examples.
• Rare chemistry: Reaction rules for rare transformations that have a minimum of 3 examples.
• Stereoselective chemistry: Reaction rules for stereoselective transformations.
• Heterocyclic chemistry: Reaction rules for the synthesis of aromatic heterocycles.
• Rhea reactions rules: Reaction rules extracted from the Rhea database of chemical and transport reactions of biological interest, which includes enzymatic reactions and transport reactions as well as reactions that occur spontaneously in biological systems, such as metabolic reactions.

In addition to reaction rules databases, SYNTHIA™ also includes several databases of reactions that have been published in the literature.

• SPRESI by DeepMatter covers organic synthesis literature from 1974 to 2014, and contains 4.6 million chemical reactions abstracted from 700,000 references.
• USPTO includes reactions from United States patents published between 1976 and 2016.
• Rhea is an expert-curated database of biochemical reactions, that includes enzymatic reactions and transport reactions as well as reactions that occur spontaneously in biological systems, such as metabolic reactions. 
  
• >> Rhea
• Science of Synthesis provides full-text descriptions of organic transformations and synthetic methods as well as experimental procedures, that review synthetic methodology developed from the early 1800s to-date for the entire field of organic and organometallic chemistry. World-renowned experts have chosen the most important molecular transformations for a class of organic compounds and elaborated on their scope and limitations.
  >> Science of Synthesis

By default, all Expert-Coded Rules, and SPRESI, USPTO, Enzyme-Catalyzed Reactions and Science of Synthesis databases are enabled.

Advanced Analysis Preferences – Advanced Options

Exclude highly strained intermediates
Eliminate highly strained intermediates, based on SYNTHIA™’s energy calculations.  Only use if the initial analysis yields strained intermediates that you wish to exclude.

Exclude ring contractions from macrocycles
Prevent ring contractions from macrocycles.  Only use if the initial analysis yields macrocyclic intermediates that you wish to exclude.