SYLVIA
Estimation of the Synthetic Accessibility
of Organic Compounds
Version 1.4
Program Manual and Description
Molecular Networks GmbH April 2016
www.mn-am.com
Molecular Networks GmbH
Neumeyerstr. 28
90411 Nuremberg
Germany
Altamira LLC
1455 Candlewood Drive
Columbus, OH 43235-1623
USA
mn-am.com
This document is copyright © 2008-2018 by Molecular Networks GmbH Computerchemie and Altamira LLC. All rights reserved. Except as permitted under the terms of the Software Licensing Agreement of Molecular Networks GmbH Computerchemie or Altamira LLC, no part of this publication may be reproduced or distributed in any form or by any means or stored in a database retrieval system without the prior written permission of Molecular Networks GmbH Computerchemie or Altamira LLC.
The software described in this document is furnished under a license and this document may be used and copied only in accordance with the terms of such license. (Doc version: 1.0-2016-04-25)
Contents
Contents
1 Introducing SYLVIA 1
2 SYLVIA GUI Version 2
2.1 The Main Window 4
2.2 The Main Menus 4
2.3 The Wizard 8
2.4 Synthetic Accessibility Settings 11
2.5 Database Management 14
2.6 Total Synthetic Accessibility Score and Components Contributions 20
3 SYLVIA Batch Version and Associated Tools 21
3.1 SYLVIA Batch Version 21
3.2 extractSM 23
3.3 extractRCSS 25
4 Understanding SYLVIA – The Scientific Method 27
4.1 Overview 27
4.2 Starting Material Similarity Score 28
4.3 Reaction Center Substructure Score 33
4.4 Generation of Product Reaction Center Substructure Database 33
5 Technical Requirements 36
5.1 System Requirements 36
5.2 Program Scope and Known Limitations 36
6 Program Installation 37
6.1 Download from the Web Server of Molecular Networks 37
6.2 New Installation 37
6.3 Program Updates 40
7 Problems and Help! 41
8 Acknowledgements 42
9 References 43
10 Report Form 44
Introducing SYLVIA
1
1 Introducing SYLVIA
SYLVIA is a program to estimate the synthetic accessibility (or the ease of synthesis) of
organic compounds. SYLVIA is available in the following three different versions.
Graphical user interface application (GUI) for interactive usage
Batch version for automatic batch processing of large files
Daemon version for running calculations as background processes
All four versions perform the same calculation and give the same results. This
document is the manual for the GUI and batch version. The estimation of synthetic
accessibility provides a number between 1 for compounds that are very easy to
synthesize and a number of 10 for compounds that are very difficult to synthesize. The
method for calculating synthetic accessibility takes account of a variety of criteria such
as complexity of the molecular structure, complexity of the ring system, number of
stereo centers, similarity to commercially available compounds, and, potential for using
powerful synthesis reactions. These criteria have been individually weighted to provide
a single value for synthetic accessibility. Results of a survey of several medicinal
chemists have been considered in this weighting process. Major points of the
calculation method have been published in the Journal of Computer-Aided Molecular
Design and are briefly summarized in this manual.
Low synthetic accessibility scores, i.e., from compounds easier to synthesize than a
given numerical threshold, are shown with a green background, medium scores yield a
yellow background and those very difficult to synthesize obtain a red background.
However, these thresholds can be configured.
Release Notes
2
2 Release Notes
2.1 Version 1.0, October 2007
Version 1.0 is the first commercial release of SYLVIA (based on the software
technology platform MOSES, MOlecular Structure Encoding System, see
www.molecular-networks.com/moses, [1]).
Version 1.0 includes the GUI, batch and daemon version. It reads in SD and SMILES
files and displays and outputs the synthetic accessibility scores in the GUI version, as
SD data fields in SD output files or as system-wide available values of the daemon
version.
2.2 Version 1.2, December 2012
Besides several improvements and extensions, version 1.2 offers the output of the
individual structure- and reaction-based scores which contribute to the total synthetic
accessibility score, that are the following components.
Molecular graph complexity
Ring complexity
Stereochemical complexity
Starting material similarity
Reaction center substructure similarity
2.3 Version 1.4, November 2014
The following specific improvements, changes and new features have been
implemented into version 1.4.
New Database Manager in GUI version to create and administrate customized
starting material (SM-DB) and reaction center substructure databases (RCSS-
DB)
o Creation of new customized databases and extension of existing
databases
o Access to all options available
o Import of customized databases
o Renaming and deletion of databases
o Export of databases
o Information about content in databases
Improved command line tool "extractSM" in XT version to generate customized
SM-DBs
Release Notes
3
New command line tool "extractRCSS" in XT version to generate customized
RCSS-DBs for reaction fitness scores
Improved statistics about generation of RCSS-DBs and SM-DBs displayed after
generation of databases with Database Manager in GUI version or with
command line tools "extractSM" and "extractRCSS" in XT version
Improved configuration side bar in GUI version with field to change applied SM-
DB and RCSS-DB while compounds are loaded
In addition, the following general improvements have been implemented.
Zero-based counting of record numbers in input files changed to one-based
Automatic storing of all user settings of a session (GUI version)
Changes of connection table information in SMILES codes and SD records from
input to output file fixed, if input and output file format are identical
Improved handling of failed structures in GUI and XT version
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3 SYLVIA GUI Version
3.1 The Main Window
In this section, the main program window is described. Help on the individual
configuration options can be found by pressing the "Help" button of the configuration
dialog or in the navigation tab on the left hand side of this window.
When the program is started, it will usually open up a wizard that queries the wishes of
the user. However, if the name of an input file is provided as a command line
argument, this file will be loaded and no wizard will be shown.
Figure 1 The main window of SYLVIA.
3.2 The Main Menus
In the following section the main menus (main menu bar) of SYLVIA are described see
Figure 2).
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Figure 2 The main menu bar of SYLVIA with menus File, View, Data, Extra
and Help.
3.2.1 The File Menu
The file menu provides a number of typical options for accessing data in files.
Command Description
New With the "New" command, the list of already loaded compounds is
cleared.
Start
Wizard...
This command restarts the Wizard, even if it has been deactivated in the
last page of the wizard. If applicable, the program will ask whether new
structures should be appended to the list of already existing (or loaded)
molecules.
Input
Structure...
Opens up a molecule editor for input of a new molecule. While the editor
runs, the application is otherwise blocked. If applicable, the program will
ask whether the new structure should be appended to the list of already
existing (or loaded) molecules.
Open... Open will open and load new structure files. The program will ask
whether these new structures should be appended to the list of already
existing (or loaded) molecules, if there are any.
Save The "Save" command will save the current view (structures as sorted
and filtered) together with the properties that are present in the input
files and those shown on the screen, i.e., the properties that are
selected for viewing.
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Command Description
Save As... Saves the structures as with the "Save" command but provides the
possibility to select a new file name first.
Exit The "Exit" command will close the program.
3.2.2 The View Menu
Using the View menu, the visual appearance of the structures can be changed.
Command Description
Structure Size With "Structure Size" the size of the structures in the table
can be changed. This value is retained in subsequent
program uses.
View First Row Jumps to the very first record in the file.
View Page Up Goes up one page.
View Page Down Goes down one page.
View Last Row Jumps to the last record of the file. If not yet done, the file will
then be completely scanned. Thus, for large files, delays may
be noticeable.
Goto... Allows the specification of a record number to jump to. If not
yet done, the file will then be fully scanned. For large files,
delays may be noticeable.
3.2.3 The Data Menu
In the Data menu properties (read in and calculated) can be activated for displaying
and used for filtering and sorting.
Command Description
Properties Opens up a sub menu where all calculable properties and all
properties from the input file can be selected for display. The
visible properties and the properties from the input file will be
written out to the output file upon "File → Save".
This menu is detachable by clicking on the dotted line at the
top of the menu strip - the menu will then become a window
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Command Description
of its own, stay on the screen and allow enabling and
disabling of properties by a single mouse click.
Filter… Use this function to filter out structures from the list. When
this command is selected, a dialog box will open up:
In the uppermost part, the logic how to connect filter
conditions can be selected, if there are more than one
filter condition. Filters can be connected that all filter
conditions have to be matched (logical AND, which is the
default), or that matching any filter condition (logical OR)
will suffice.
In the next line, the property to be used for filtering can be
selected. All calculable properties and the properties read
in from the input file are available. Once a property has
been selected, suitable comparison operators become
available. In the third column, the value (or threshold) for
the comparison has to be entered.
Pressing the More button adds new filter condition lines
to the dialog. They can be removed again by pressing the
Less button, which will in turn remove the last filter
condition. All rows set to "none (please select property)"
are automatically ignored in the filtering process.
For the deactivation of filters, open this dialog again and
either remove all filters using the Less button or set each
property selector to "none (please select property)".
Please be aware that properties read in from SMILES and
SD files are always treated as character strings and, thus,
never allow the use of operators like < or >. To allow these
numerical comparisons on properties read in from file, the
CTX file format for input should be used which allows the
qualification of properties as integers or real numbers.
Sort… The "Sort" command opens a dialog to select which property
should be used for sorting and to determine whether the
records should be sorted in ascending or descending order.
The sorting functionality is also available (for visible
properties) by clicking on the column headers of the record
table. The first click will start the sorting in ascending order,
the second click reverses the sorting to descending order
and a third click will apply the order of the structures as given
in the input file.
Comparisons for sorting are done numerically for numeric
properties. As mentioned in the section about "Filtering",
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Command Description
properties read in from SMILES and SD files are treated as
alpha-numeric data. Thus, please be aware that rows are
always sorted in alphabetic order and not numerical order.
3.2.4 The Extra Menu
In the Data menu, tools for customizing and manipulating the starting material and
reaction center sub-structures (reaction fitness) database can be started.
Command Description
Open Database
Manager
Start the database manager to customize and manipulate the
starting material and reaction center sub-structures (reaction
fitness) database.
3.2.5 The Help Menu
The Help menu opens additional information of SYLVIA.
Command Description
Index… The "Index" command opens the online help.
License… This function will open an information window with details
about the license governing the use of the program. Most
notably, it will detail when the license expires.
About… This command provides a list of the underlying technology of
the program as well as the third-party components employed.
3.3 The Wizard
The Wizard is started if the program is called without any file arguments. Its main
purpose is to make the selection of input easy also for the casual user.
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3.3.1 The Welcome Page
The "Welcome" page allows to select whether a structure should be input by means of
a chemical structure editor, or, if chemical structures should be read in from a file in a
standard chemical file format (e.g., SD file [2], SMILES [3]). Either way, without a
decision here, it is not possible to continue (see Figure 3).
Figure 3 The Welcome page of the SYLVIA wizard.
3.3.2 The Editor Page
The "Editor" page allows the start of an external structure editor, usually the JME
Molecular Editor. After input, the chemical structure is shown for direct visual inspection
(see Figure 4).
Figure 4 The Editor page of the SYLVIA wizard.
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3.3.3 The File Selection Page
Standard chemical structure files, e.g., Molfile, SD files [2], Daylight SMILES [3] files
and other files can be selected here. When a valid structure file is selected or input in
the field "Input file name", the next page of the Wizard can be called (see Figure 5).
Figure 5 The File Selection page of the SYLVIA wizard.
3.3.4 The Property Selection Page
If the chemical structure file contains any properties, one of these properties can be
selected to serve as an identifier in the list of structures to be shown in the main
window of the program. Alternatively, all properties that are available in the input file
can be chosen to be displayed in the main window. In both cases, the selection of
visible properties can be modified later by means of the "Data" and "Properties" menu.
Figure 6 The Property Selection page of the SYLVIA wizard.
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3.3.5 The Good Bye Page
The "Good Bye" page wraps up the communication made with the application so far. It
also allows to de-activate the further use of the wizard by checking the shown box.
Even if de-activated, the Wizard can be activated again at any time by using the "Help"
menu of the Wizard.
Figure 7 The Good bye page of the SYLVIA wizard.
3.4 Synthetic Accessibility Settings
Once a structure or a structure file is loaded, on the right hand side of the SYLVIA
window, a detachable dialog is present that can be used to specify options for the
calculation and display of the synthetic accessibility values (see Figure 8).
Figure 8 The main window with loaded structures.
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3.4.1 Thresholds for Synthetic Accessibility
Threshold for Easy Compounds
Using this slider, the threshold for easy compounds can be set. Compounds
with a synthetic accessibility estimation below this threshold are considered to
be easy to synthesize and are displayed with a green background.
Threshold for Difficult Compounds
With this slider, the threshold for difficult compounds can be set, i.e., the
threshold above which compounds will be classified as difficult to synthesize.
These compounds are displayed with a red background in the synthetic
accessibility column.
Compounds where the synthetic accessibility estimation lies between these two
thresholds are generally shown with a yellow background color in the synthetic
accessibility value cell.
The dialog window also provides three buttons. The first button "Help" brings up this
help, the second "Reset" re-sets the parameter values to their initial (factory) values,
and the "Expert" button that enables additional options for experts.
3.4.2 Additional Options for Experts
A warning is given before the expert options are detailed here: the expert options can
easily lead to sub-optimal and sometimes misleading results, and should be used with
appropriate care. To stress this point, when the expert mode is entered, a dialog
window appears and asks for verification. This dialog can be suppressed for
subsequent program uses by choosing the middle button of the confirmation dialog.
Starting Material Database
Using this option, a customized starting material database can be loaded and
used for the calculation of the "starting material similarity score", e.g., generated
from compound collections or databases available in-house (see Figure 9). This
customized starting material database has to be generated from a structure file
available in a standard file format (SD, SMILES). The generation and import of
such a customized starting material database is described below in the section
"Generation of Customized Starting Material Databases".
The starting material database can be reset to the standard (factory) database
by pressing the "Reset" button or by selecting "Built-in Starting Materials" in
the drop-down menu (see Figure 9).
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Figure 9 Choosing a starting material database.
Reaction Center Substructure Database
Using this option, a customized reaction center substructure database can be
loaded used for the calculation of the "reaction center substructure similarity
score", e.g., generated from reaction collections or databases available in-
house (see Figure 10). This customized reaction center substructure database
has to be generated from a reaction file available in the RD file format. The
generation and import of such a customized reaction center substructure
database is described below in the section "Generation and Import of
Customized Reaction Center Substructure Databases".
The reaction center substructure database can be reset to the standard
(factory) database by pressing the "Reset" button or by selecting "Built-in
Reaction Center Substructures" in the drop-down menu (see Figure 10).
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Figure 10 Choosing a reaction center sub-structure database.
3.5 Database Management
In the following sections the management of the databases that are used by SYLVIA is
described. These databases can be managed using the Database Manager which is
opened by selecting "Open Database Manager" in the "Extra" menu (see Figure 11).
Figure 11 The Database Manager.
SYLVIA uses two different databases for the evaluation of the synthetic accessibility of
organic compounds.
Starting material database for calculating the starting material similarity score of
SYLVIA GUI Version
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a query compound.
Reaction center substructure database for calculating the reaction center (or
reaction fitness) score of a query compound.
The underlying scientific methods of the two database-dependent scores are described
in the section "Understanding SYLVIA – The Scientific Method" of this manual.
3.5.1 Generation and Import of Customized Starting Material Databases
SYLVIA can use any structure data to evaluate the starting material similarity of a
query compound. However, the data have to be converted from typical structure file
formats (SD, SMILES) into the native database format of SYLVIA (SMDB) and then
imported into SYLVIA to make it available in the "Expert" section of the UI (please see
above).
3.5.1.1 Generation of Customized Starting Material Databases
By selecting Open Database Manager from the Extra menu and switching to the tab
"Starting Material Databases" new starting material databases can be created and
managed. By default, the "Built-in Starting Materials" are selected (factory database
shipped with the SYLVIA product). By clicking the button "Create" the dialog to
generate customized starting material databases from any structure files (SD, SMILES)
is opened. The input structure file and the name of the generated (customized) starting
material database can be selected in the file dialog or directly entered into the editable
fields. A valid file name as input and a reasonable file name for a database file have to
be given in order to finish this dialog successfully (see Figure 12).
If an existing starting material database should be extended by new compounds, it can
be selected in the field "Extend Existing Starting Material Database". It is possible to
extend the standard (factory) starting material database (database file Built-in Starting
Materials). However, it is required to enter a new name in the field "New Database
Name" in order to keep a copy of the original standard (factory) starting material
database for back-up purposes (see Figure 12).
If the structure file that was used to create the database is loaded into SYLVIA for
synthetic accessibility assessment, scores can be higher than expected. This can have
mainly two reasons. First, starting material similarity is only one out of five components
of the synthetic accessibility score and even if this score is low, the other scores might
be not. Secondly, molecules that contain mostly "non-standard" organic chemistry
elements are excluded during database generation. However, these molecules are not
excluded for the ranking. Therefore, such structures are usually predicted as more
difficult to synthesize than others.
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Figure 12 Generation of a customized starting material databases.
Advanced Options
In the "Advanced" section, additional options for generating a new starting material
database are available (see Figure 12).
Keep Identical Compounds
With this option, compounds that occur multiple times in the original compound
database are counted as often as they appear. This gives a stronger weight to
those compounds. By default, this option is de-activated.
Store Transformed Structures in File
The results of the transformation steps carried out during the conversion step
can be saved to a separate structure file. A file name for this structure file can
be selected or directly entered into the field below this option. However, the file
of transformed structures can be very large with about 10 times more records
(molecules) than in the original structure file. The transformed structures can
provide insight into the conversion process and can answer questions on why a
particular compound receives a synthetic accessibility score higher or lower
than expected.
Read Only Parts of the Input File
The range of records (structures) in the input file which should be used to
generate the new starting material database can be selected and specified the
by record numbers.
Database Generation Statistics
After the generation of a new (or the extension of an existing) starting material
database, the statistics about the generation process are summarized in a separate
window. The statistics summary lists
How many structures have been read in
How many structures have been considered for the database generation
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How many structures and why they have not been considered (or ignored)
CPU time to build the database
The number of how many structures have been considered to build up a database is
also shown in the lower right part of the "Database Manager" dialog for the database
that is currently selected.
Command Line Tool
In the XT version of SYLVIA, customized starting material databases can also be
generated with the command line tool "extractsSM" which is described in the section
"extractSM" of this manual.
3.5.1.2 Import of Customized Starting Material Databases
Once a customized starting material database has been created, it has to be imported
into SYLVIA by pressing the button "Import". A dialog box appears where the starting
material database file can be selected or directly entered into the field "New Starting
Material Database File". In addition, a name for the database is suggested, but can be
changed in the field Name of the dialog. Pressing the button "Import" in this dialog
finishes the import confirmed by a message box (see Figure 13).
Figure 13 Import of a customized starting material databases.
3.5.2 Generation and Import of Customized Reaction Center Substructure Databases
SYLVIA can use reaction data to evaluate the reaction fitness of query compounds.
However, the data have to be converted from a reaction file in the RD format into the
native database format of SYLVIA (RCDB) and then imported into SYLVIA to make it
available in the "Expert" section of the UI (please see above).
Generation of Customized Reaction Center Substructure Databases
By selecting Open Database Manager from the Extra menu and switching to the tab
Reaction Center Substructure Databases new reaction center substructure databases
can be created and managed. By default, the "Built-in Reaction Center
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Substructures" are selected (factory database shipped with the SYLVIA product). By
clicking the button "Create" the dialog to generate customized reaction center
substructure databases from any reaction file (in RD format) is opened. The input
reaction file and the name of the generated (customized) reaction center substructure
database can be selected in the file dialog or directly entered into the editable fields. A
valid file name as input and a reasonable file name for a database file have to be given
in order to finish this dialog successfully (see Figure 14).
If an existing reaction center substructure database should be extended by new
reactions, it can be selected in the field "Extend Existing Reaction Center
Substructure Database". It is possible to extend the standard (factory) reaction center
substructure database (database file "Built-in Reaction Center Substructures").
However, it is required to enter a new name in the field "New Database Name" in order
to keep a copy of the original standard (factory) starting material database for back-up
purposes (see Figure 14).
Figure 14 Generation of a customized reaction center sub-structure databases.
Advanced Options
In the "Advanced" section, additional options for generating a new reaction center
substructure database are available (see Figure 14).
Keep Identical Reactions
With this option, reactions (or reaction centers) that occur multiple times in the
original reaction database are counted as often as they appear. This gives a
stronger weight to those reactions. By default, this option is de-activated.
Store Transformed Structures in File
The results of the reaction center substructure extraction carried out during the
conversion step can be saved to a separate structure file. A file name for this
structure file can be selected or directly entered into the field below this option.
The extracted reaction center substructure can provide insight into the
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conversion process and can answer questions on why a particular compound
receives a synthetic accessibility score higher or lower than expected.
Read Only Parts of the Input File
The range of records (reactions) in the input file which should be used to
generate the new reaction center substructure database can be selected and
specified the by record numbers.
Database Generation Statistics
After the generation of a new (or the extension of an existing) reaction center
substructure database, the statistics about the generation process are summarized in a
separate window. The statistics summary lists
How many reactions have been read in
How many reactions have been considered for the database generation
How many reactions and why they have not been considered (or ignored)
CPU time to build the database
The number of how many reaction center substructures have been considered to build
up a database is also shown in the lower right part of the Database Manager dialog for
the database that is currently selected.
Command Line Tool
In the XT version of SYLVIA, customized reaction center sub-structure databases can
also be generated with the command line tool "extractRCSS" which is described in the
section "extractRCSS".
3.5.2.1 Import of Customized Reaction Center Substructure Databases
Once a customized reaction center substructure database has been created, it has to
be imported into SYLVIA by pressing the button "Import". A dialog box appears where
the starting material database file can be selected or directly entered into the field "New
Reaction Center Substructure Database File". In addition, a name for the database
is suggested, but can be changed in the field "Name" of the dialog. Pressing the button
"Import" in this dialog finishes the import confirmed by a message box.
Figure 15 Import of a customized reaction center sub-structure databases.
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3.6 Total Synthetic Accessibility Score and Components Contributions
The scientific method behind SYLVIA and how the total synthetic accessibility of a
compound is estimated is described in section "Understanding SYLVIA – The Scientific
Method" of this manual.
The individual contributions to the total synthetic accessibility score can be displayed
(and written out to an SD file) via the menu item "Properties" of the "Data" menu.
The following table lists the synthetic accessibility properties that are calculated by
SYLVIA and their name in the Data menu of the GUI as well as the data field under
which they are stored in output SD files.
Name in GUI and in exported SD file Description
M_SYN_ACCESSIBILITY Synthetic accessibility: total synthetic
accessibility score of a molecule
M_GRAPH_SCORE Molecular graph complexity score:
contribution to total synthetic accessibility
score based on molecular graph complexity
M_RING_SCORE Ring complexity score: contribution to total
synthetic accessibility score based on ring
complexity
M_STEREO_SCORE Stereochemical complexity score:
contribution to total synthetic accessibility
score based on stereochemical complexity
M_STARTING_MATERIAL_SCORE Starting material similarity score:
contribution to total synthetic accessibility
score based on similarity to available
starting materials
M_REACTION_CENTER_SCORE Reaction center substructure score:
contribution to total synthetic accessibility
score based on similarity to known reaction
center substructures
SYLVIA Batch Version and Associated Tools
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4 SYLVIA Batch Version and Associated Tools
4.1 SYLVIA Batch Version
The command line tool "sylvia" calculates the synthetic accessibility estimations for
organic molecules in batch mode by reading in a structure file and writing out a
structure file with the stored scores.
4.1.1 Description
Calculates synthetic accessibility values for given chemical structures given in a file (or
SMILES on standard-in).
4.1.2 Synopsis
sylvia [option]... inputfile outputfile
4.1.3 Supported File Formats
File File format File extension
Input file SD file (structure data file),
SMILES
sdf, smi or smiles
Output file SD file (structure data file),
SMILES
sdf, smi or smiles
4.1.4 Command Line Options
Short
option
Long option Description
--help Print this help on the screen
--rcssdb file Use the reaction center substructure database
file (default: use standard/factory reaction
center substructure database)
--smdb file Use the starting material database file (default:
use standard/factory starting material database)
SYLVIA Batch Version and Associated Tools
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Short
option
Long option Description
--discard-on-failure Remove records from the output file for which
the calculation failed or which are not readable
from the output file (default: write out original
record and "NULL" for not calculable properties;
if record is not readable and input and output
format are not equal, an empty compound
record is written)
--discard-read-properties Remove properties that were read from the
input file (default: write out all properties (SD
data fields and values) that are present in the
input file)
--trace-area area Restrict the output of trace message to defined
trace areas (area: All (default), App)
--trace-to file Write trace output to file (file: cout, cerr, or given
file)
--version Show the program version
-a --all-terms Write out all individual terms contributing to the
total synthetic accessibility score
-c --config-file file Read the configuration file file
-d --daemon Enable the daemon mode. In this mode, only
SMILES strings are accepted and read from
standard input and accessibility estimations are
written to standard out. If END is given instead
of a valid SMILES, the program is terminated. If
the given SMILES string cannot be read the
string ERROR is written out.
-e --errfile file Write out structures which cannot be read into
separate file file. If this option is not given,
unreadable records are copied verbatim into the
output file.
-m --molecular-complexity Write out molecular graph complexity score.
-n --stereochemical-
complexity
Write out stereochemical complexity score.
-o --ring-complexity Write out ring complexity score.
-p --propname name Use property name name in output file instead
of M_SYN_ACCESSIBILITY.
-r --reaction-center-similarity Write out reaction center similarity score.
SYLVIA Batch Version and Associated Tools
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Short
option
Long option Description
-s --starting-material-
similarity
Write out starting material similarity score.
-t --trace-level level Set the minimum importance of logged
messages to level (level: crit, fail, warn, or
verbose)
4.1.5 Examples
sylvia -e errors.sdf input.sdf output.sdf
sylvia --smdb myStartingMaterials.smdb --daemon
4.2 extractSM Batch Tool
The command line tool "extractSM" generates synthetic accessibility starting material
databases by reading in a structure file and writing out the transformed structures in a
database file that can be read in by SYLVIA.
4.2.1 Description
Extracts starting material similarity hash codes from a structure file and creates a
database.
4.2.2 Synopsis
extractSM [option]... inputStructures.sdf smDB.smdb
4.2.3 Supported File Formats
File File format File extension
Input file SD file (structure data file),
SMILES
sdf, smi or smiles
Output file Starting material database smdb
SYLVIA Batch Version and Associated Tools
24
File File format File extension
(SQLite-based)
4.2.4 Command Line Options
Short
option
Long option Description
--from no Start conversion from record no (inclusive)
--to no Stop conversion at record no (inclusive)
-i --include Include starting materials which are already
present in the database (multiplets)
-s --output-structure file Store the derived starting materials in the file file
(SD formatted, usually only used to better
understand database generation)
-t --trace-level level Set the importance of logged messages to level
(level: crit, fail, warn, verbose)
--trace-to file Write the trace output to file file (file: cout, cerr,
or filename)
--help Print help page to the screen
--version Print the program version to the screen
4.2.5 Examples
extractSM -s transformedStructs.sdf inhouseData.sdf inhouseData.smdb
extractSM --from 0 --to 100 myStructs.smi test.smdb
extractSM -i supplier1.sdf supplier-all.smdb
extractSM -i supplier2.sdf supplier-all.smdb
extractSM -i supplierN.sdf supplier-all.smdb
4.2.6 Remarks
If the output file already exist, entries are added to it. Structures already in the
database are usually ignored, but can be included by specifying the option "-i".
The command line tool "extractSM" is only available in the SYLVIA XT version,
SYLVIA Batch Version and Associated Tools
25
however, the functionality is also available in the SYLVIA GUI program (Database
Manager).
4.3 extractRCSS Batch Tool
The command line tool "extractRCSS" generates a database of reaction center sub-
structures from an input reaction database that can be read in by SYLVIA.
4.3.1 Description
Calculates hash codes of reaction center sub-structures (rcss) from a reaction
database, records the occurrences of the reaction center sub-structures in the
reactions and creates a database.
4.3.2 Synopsis
extractRCSS [option]... inputReactions.rdf rcssDB.rcdb
4.3.3 Supported File Formats
File File format File extension
Input file RDfile (reaction data file) rdf
Output file Reaction center database
(SQLite-based)
rcdb
4.3.4 Command Line Options
Short
option
Long option Description
--from no Start conversion from record no (inclusive)
--to no Stop conversion at record no (inclusive)
-i --include Include reaction center substructures which are
already present in the database (multiplets)
SYLVIA Batch Version and Associated Tools
26
Short
option
Long option Description
-s --output-structure file Store the derived reaction center substructures
in the file file (SD formatted, usually only used to
better understand database generation)
-t --trace-level level Set the importance of logged messages to level
(level: crit, fail, warn, verbose)
--trace-to file Write the trace output to file file (file: cout, cerr,
or filename)
--help Print help page to the screen
--version Print the program version to the screen
4.3.5 Examples
extractRCSS -s rxn_substructures.sdf inhouse_rxns.rdf inhouse_rcss.rcdb
extractRCSS --from 0 --to 100 --include inhouse_rxns.rdf inhouse_rcss.rcdb
4.3.6 Remarks
If the output file (reaction center substructure database, e.g., "rcssDB.rcdb") already
exists, the hash-codes of the new substructures are added to this database file.
Structures already in the database are usually ignored, but can be included by
specifying the option "-i" (or "--include").
The command line tool extractRCSS is only available and shipped as part of the
SYLVIA XT version, however, the functionality is also available in the SYLVIA GUI
program (Database Manager).
Understanding SYLVIA – The Scientific Method
27
5 Understanding SYLVIA – The Scientific Method
5.1 Overview
The synthetic accessibility estimation consists of five components. The first three
components are based on structural features of the target structure only [4].
Molecular Graph Complexity Score
This score is based on graph and information theories and takes account of the
size, symmetry, branching, rings, multiple bonds and heteroatoms of the target
molecule.
The corresponding data field in SD output files is named "M_GRAPH_SCORE".
Ring Complexity
This score penalizes bridged and fused ring systems which might be more
difficult to be synthesized and thus increase the synthetic accessibility score.
The corresponding data field in SD output files is named "M_RING_SCORE".
Stereochemical Complexity
This score is a simple counter of tetrahedral stereo centers in the target
structure which make the synthesis of the target more difficult.
The corresponding data field in SD output files is named
"M_STEREO_SCORE".
The latter two components are data based, take up a larger portion of the calculation
time, but also provide more meaningful results.
Starting Material Similarity Score
Structures with complex structural motifs can still easily be synthesized if the
complex parts are covered by available starting materials. Therefore,
compounds with a high starting material similarity are searched in a
preprocessed database. The more similar compounds are identified and the
higher the coverage of the target molecule, the easier it is to synthesize a given
target compound.
The corresponding data field in SD output files is named
"M_STARTING_MATERIAL_SCORE".
Reaction Center Substructure Score
Synthesis design programs perform comprehensive retrosynthetic analysis in
order to transform the synthetic target structure to a sequence of progressively
simpler structures along a retrosynthetic pathway, which ultimately leads to
simple or commercially available starting materials. Accordingly, synthetic
accessibility can be approximated by analyzing structural motifs where the
target molecule can be decomposed into smaller components.
The corresponding data field in SD output files is named
"M_REACTION_CENTER_SCORE".
Understanding SYLVIA – The Scientific Method
28
Calculation of the Total Score
The overall synthetic accessibility score of a target structure is calculated by summing
the five weighted individual components.
In order to determine the weights of each component, five medicinal chemists
have manually evaluated a dataset of 100 structures according to their synthetic
accessibility on a scale between 1 (easy to synthesize) and 10 (difficult to
synthesize). The structures of the dataset were taken from the Journal of
Medicinal Chemistry and vary in size and complexity. Based on the average
scores of the medicinal chemists, a linear regression analysis was used to
calculate the weights of each component. Due to the method, a fixed increment
of 0.68 is added to the sum of the weighted components (intercept of y-axis).
The corresponding data field in SD output files is named
"M_SYN_ACCESSIBILITY".
In the following, the components "Starting Material Similarity Score" and "Reaction
Center Substructure Score" are described in more detail. For a full overview about the
method, reading of [4] is recommended.
5.2 Starting Material Similarity Score
The synthetic accessibility of a target structure highly depends on the degree of
resemblance between the target structure and available starting materials. However,
the concept of molecular similarity is application dependent - therefore a variety of
similarity measures are known in chemoinformatics. For the purpose required here,
similarity scores useful for the design of syntheses have been developed [5].
5.2.1 Similarity Search
Assessing synthetic proximity between a target structure and a set of starting materials
demands a different approach to similarity than biological activity. SYLVIA applies
transformation-based similarity criteria which have specifically been developed for
synthesis design and reaction planning. By definition, two compounds are considered
similar by a similarity search criterion if their transformed structures are identical. This
is shown in Figure 1.
Understanding SYLVIA – The Scientific Method
29
Figure 1 Concept of transformation-based similarity search; (a) similarity
criterion based on generalized reaction; (b) similarity criterion based on
structural features.
23 of such similarity criteria are implemented in SYLVIA. Some similarity search
transformations are based on generalized reactions (such as oxidation, reduction),
others are based on topological characteristics of the structure. The latter ones often
simply yield substructures, for example, taking the largest ring system of a query
structure.
Furthermore, there are similarity definitions that combine reaction type and
substructure characteristics (such as ring system with substitution pattern).
Figure 2 shows examples for such similarity search transformations in order of their
specificity.
Figure 2 Specificity of various similarity search transformations.
Within the similarity search process the target structure is modified according to
transformation rules associated with a certain similarity criterion. The transformed
structure is then compared with each transformed compound from the catalogs of
starting materials which was derived in advance for each transformation rule. This
process is illustrated in Figure 3 where the aromatic ring system including alpha atoms
Understanding SYLVIA – The Scientific Method
30
criterion is applied. If the transformed target structure and the transformed catalog
compound are identical, then the unchanged compound from the catalog of chemicals
is a potential starting material for the target compound according to this criterion.
Figure 3 Similarity search process applying the "aromatic ring system
including alpha atoms" transformation. The target (query) and all catalog
compounds are transformed by the same criterion.
5.2.2 Generation of Starting Material Databases
The necessary transformations are performed in advance for the entire starting
materials catalog. The transformed structures are stored in a database in the form of
hash codes along with counters that store the frequency of occurrence of hash-codes
for a specific transformation. By this means, only the target structure has to be
subjected to various transformations at run time, achieving rapid identification of
possible precursors.
A starting material similarity database was constructed from the combined Fluka, Acros
and Maybridge catalogs. If a starting material occurred more than once in this united
data set, then only one instance was considered. The starting materials were then
subjected to all available similarity search transformations, followed by generating hash
codes and keeping account of the frequency of occurrences.
This database generation from any chemical structure file is directly available in the
SYLVIA program - see the section on "Generation of Customized Starting Material
Databases" in this manual.
Understanding SYLVIA – The Scientific Method
31
Figure 4 Examples of similarity search transformations. Transformation steps:
(1) intact starting material
(2) taking atoms that are part of any aromatic ring system
(3) taking carbon atom side chains of aromatic ring systems
(4a) considering alpha heteroatoms
(4b) considering substitution pattern (heteroatoms are substituted by chlorine
atoms)
(5) selecting the largest fragment
Two examples for similarity search transformation are illustrated in Figure 4. The
transformation of a starting material (1) by similarity search criterion A starts with
identifying the aromatic atoms (2) and then taking carbon atom side chains that are
attached to aromatic ring systems (3). This is followed by taking into consideration of
the alpha heteroatoms (4a). Because this process can break the starting material into
smaller unconnected fragments, the largest of these fragments is selected as a result
of the similarity search transformation (5) for which a hash code is generated. The
similarity transformation B is differs from A by converting the alpha heteroatoms into
chlorine atoms (4b) thereby marking the possible substitution sites. The distribution of
structures generated by the first transformation is shown in Figure 5.
Understanding SYLVIA – The Scientific Method
32
Figure 5 Distribution of frequency of occurrences of structures resulting from
similarity search transformations: "aromatic ring + carbon skeleton with alpha-
atoms" (shown in Figure 3). The eight most frequent structures occurring are
shown with their frequency.
5.2.3 Evaluating Similarity to Starting Materials
After processing all transformations for the starting material databases, a similarity
score is calculated by mapping transformed structures back onto the target structure.
Each atom of the target structure receives an atom score that is initially set to 1.0.
These atom scores are then reduced by degrees as more and more potential
precursors are identified for the target structure. In this way, the atom scores reflect the
possible coverage of starting materials on the target structure.
If a similarity search transformation identifies potential precursors for the target
structure, then a transformation score is calculated.
The transformation score ranges between 0.0 and 1.0, and is devised to penalize
structural motifs that are infrequent in the similarity database. The larger the set of
potential precursors retrieved by a similarity search criterion, the smaller is the
corresponding transformation score. However, as the similarity criteria differ strongly in
specificity, an additional weight representing this circumstance is stored for each
transformation in the database and applied in the scoring.
The molecular starting material similarity score is finally calculated by summing up the
individual atom scores and normalizing the value.
Understanding SYLVIA – The Scientific Method
33
5.3 Reaction Center Substructure Score
The estimation of retrosynthetic reaction fitness is based on the determination of how
prone each bond in a target compound is to be built. By definition, a bond - or rather, a
structural motif consisting of a specific bond at its center and a neighborhood of varying
detail - is prone to retro-synthesis if it can be found on the product side of reactions in a
database.
To put it into other words: if the same bond that is present in a target structure can also
be found as part of the product reaction center in a database, the bond provides a
potential cutting-point for retro-synthesis. In SYLVIA, no real retro-synthesis is
undertaken, instead the bond receives a score indicating that it is easier to synthesize.
Figure 6 Extracting product reaction center substructures from synthetic
reaction.
In reaction databases, transformation characteristics of reactions are automatically
identified by marking the bonds directly involved in a reaction either as "change bond
order" or "make/break" bond (see example in Figure 6). Such bonds are called reaction
centers. This reaction center information (RC) is utilized to define a reaction center
substructure (RCSS) that consists of the atoms belonging to product reaction centers
along with their direct neighbors, i.e., alpha atoms. By considering the alpha atoms, the
influence of the chemical environment of the reaction center can be taken into account.
A hash code is generated for each identified product RCSS, that is then inserted into a
database keeping account of frequency of occurrences of unique reaction center
substructures.
5.4 Generation of Product Reaction Center Substructure Database
For database generation one has to clean up the reaction data first. Reactions with
inconsistent reaction center information or multiple product reaction centers have to be
removed. The latter is required in order to avoid the retrieval of unconnected reaction
center substructures (see example in Figure 7). Furthermore, reactions are also
eliminated when having undesired atom types at the product reaction center.
Understanding SYLVIA – The Scientific Method
34
Figure 7 Example for multiple product reaction center sites.
For each RCSS a hash code is generated by considering the topology of the bonds at
the reaction center (along with atom type, atom connection and bond order). The
topology of a bond is either acyclic, aromatic or cyclic non-aromatic.
The distribution of the 14,112 unique RCSS retrieved from the Theilheimer reaction
database is shown in Figure 8. It reveals that a significant number of RCSS occur very
infrequently. Three quarters of the unique RCSS are present only once and only 2.9%
of the unique RCSS occur more than 10 times.
Figure 8 Distribution of the frequency of unique reaction center substructures
retrieved from the Theilheimer reaction database. The eight most frequent
reaction center substructures with their frequency of occurrence are displayed.
Figure 9 illustrates the distribution of the number of heavy atoms of the retrieved
substructures along with the maximum frequency of occurrences for the given size.
The majority of reaction center substructures fell into the range of four to twelve heavy
atoms. The line representing the maximum frequency of occurrence peaks at a size of
four heavy atoms, and reaction center substructures exceeding a size of seven heavy
atoms have a low frequency of occurrence.
Understanding SYLVIA – The Scientific Method
35
Figure 9 Distribution of the number of heavy atoms of unique reaction center
substructures retrieved from the Theilheimer database. The green line
represents the maximum frequency of occurrence for the given heavy atom
size.
5.4.1 Evaluating retrosynthetic reaction fitness
The process of calculating the retrosynthetic reaction fitness is analogous to the
calculation of the starting material similarity score.
Each atom of the target structure is associated with an atom score that is initialized to
1.0 and gradually reduced as substructures from the RCSS database are mapped onto
the target structure.
For this, substructures, which can coincide with real RCSS, are exhaustively
enumerated in the target structure. By definition, a RCSS consists of at least one
reacting bond with its alpha atoms. The size of the enumerated RCSS is restricted to 4
in order to avoid the identification of those RCSS which have negligible effect to the
overall retrosynthetic reaction fitness score due to their low frequency of occurrences.
After the enumeration process, for each enumerated substructure it has to be
confirmed whether it corresponds to a genuine product RCSS stored in the database.
Therefore, a hash code is generated for each potential RCSS. If the hash code is
present in the database, a score is calculated based on the retrieved frequency of
occurrences on the matched RCSS and the most frequent RCSS in the database.. By
considering the frequency of occurrence of the verified RCSS, privilege is given to
structural motifs that correspond to common retrosynthetic retrons.
At the end of the process, the overall retrosynthetic reaction fitness score is calculated
by totaling up the individual atom scores and normalizing the sum with the number of
heavy atoms. The overall retrosynthetic reaction fitness ranges between 0.0 and 1.0. A
smaller value indicates that the target structure can be more easily synthesized,
because of the identification of more fitting retrosynthetic reactions can be found for the
target structure with high frequency of occurrences.
Technical Requirements
36
6 Technical Requirements
6.1 System Requirements
SYLVIA and its associated command line tools support the following hardware
platforms and operating systems.
x86 platforms running Microsoft® Windows® XP/7 (win32, it is recommended to have installed the latest service pack)
x86 platforms (32bit, 64bit) running Linux®, Kernel 2.4/2.6
6.2 Program Scope and Known Limitations
SYLVIA has been designed to process a broad range of organic chemistry.
There are no limitations concerning the number of atoms or bonds of a molecule. Note.
Some structure file formats that are supported might have such limitations.
Metal atoms and, especially transition metal atoms, can be processed but might cause
problems in certain atom descriptor calculation routines due to the lack of
parameterization.
For multi-fragment records (e.g., salts) only the largest fragment is taken into account
and smaller fragments (e.g., counter ions) are discarded.
The conversion from SD into SMILES format (and vice versa) may result in unexpected
atom types, resonance structures and missing stereo information (if available in input
file), however, the output structures are formally correct.
In special cases, the perception of aromaticity of charged, aromatic compounds may
behave non-deterministic if a charged atomic center is conjugated to aromatic system.
In case of doubt, the aromaticity perception and realization by SYLVIA can be checked
interactively by browsing the structure depictions (diagrams) in the GUI version.
Program Installation
37
7 Program Installation
7.1 Download from the Web Server of Molecular Networks
SYLVIA is available for electronic download via the Internet on the web server of
Molecular Networks (Download Area). At
www.mn-am.com/php/profile.php
an account can be created that provides access to licensed software, evaluation
copies, program manuals, example files, and tutorials as well as to test copies of a
variety of chemoinformatics applications offered by Molecular Networks.
The software packages are submitted electronically to the user as compressed files in
order to increase the download speed. The downloaded files can be easily
uncompressed with standard software tools for file compressing and archiving, such as
WinZip, FileZip (www.filezip.com), or gzip (www.gzip.org).
7.2 New Installation
7.2.1 Installation on x86 Linux Platforms
Please note. Administrator rights are required to install SYLVIA.
1) Download the distribution file of SYLVIA
sylvia_<version>_<OS>.tar.gz
and copy it into a temporary sub directory (e.g., /home/myName/sylviaTemp).
Please do not forget to save a copy of the distribution file for backup purposes.
2) Uncompress and de-archive the distribution file by using the following commands:
gunzip sylvia_<version>_<OS>.tar.gz
tar xvf sylvia_Code_<version>_<OS>.tar
3) A sub directory sylvia-<version>-installer will be created automatically. Change to
this directory and run the installation shell script install.sh. Follow the instructions
printed to the screen and specify a proper installation directory (installDir) for
SYLVIA.
4) After the installation is finished, a desktop link to the GUI version of SYLVIA should
have been created. Open the link. A dialog box for the installation of the license key
file (licenses.xml) will be opened. Click on the button "Install license file…" and
open your license key file which will then be installed on your system.
5) If no desktop link was created, open a new shell and start the GUI version with the
command
installDir/bin/Sylvia
Program Installation
38
and follow the instructions as described in (4).
For XT version (GUI and batch version)
1) The batch mode version of SYLVIA can be started with the command
installDir/bin/sylvia –help
that prints the command line options on your screen (all command line options are
also described in the online help of the GUI version).
For the batch version, it is also recommended to copy the license key file
(licenses.xml) into the sub-directory "etc" of the installation directory of SYLVIA
(e.g.,"installDir/etc").
2) You may add the SYLVIA installation directory to the environment variable "PATH"
in the ".login" or ".cshrc" file (".profile" or ".bashrc") or create a symbolic link in
the standard installation directory for binary executable files (local or system wide,
e.g., "/usr/local/bin").
3) The command line tools to generate customized starting material databases
("extractSM") and reaction center substructure databases ("extractRCSS") are
also located in the directory "installDir/bin". Both tools can be started with the
commands
installDir/bin/extractSM --help
installDir/bin/extractRCSS –help
that print the command line options on your screen (all command line options are
also described in the online help of the GUI version).
7.2.2 Microsoft Windows Platforms (win32, 7/8/10)
Please note. Administrator rights are required to install SYLVIA.
1) Download the Microsoft setup program of SYLVIA
sylvia_<version>_Win32_Setup.exe
and copy it into a temporary directory. Please do not forget to save a copy of the
setup program for backup purposes.
2) Double-click the setup program to start the installation of the program and follow
the instructions on the screen.
3) After the installation is finished, a desktop icon with a link to the GUI version of
SYLVIA should have been created. Double-click the icon. A dialog box for the
installation of the license key file (licenses.xml) will be opened. Click on the button
"Install license file…" and open your license key file which will then be installed on
your system.
For XT version only (GUI and batch version)
1) Double-click the desktop link for the batch mode version of SYLVIA. A console with
Program Installation
39
a command line prompt will be opened. To access SYLVIA from any directory on
your computer, it is recommended to add the installation directory of SYLVIA
(absolute path) to the system variable Path of your Windows system.
2) The batch mode version of SYLVIA can be started in the console (Windows DOS
prompt or Powershell) with the command
sylvia.exe --help
that prints the command line options on your screen (all command line options are
also described in the online help of the GUI version).
3) The command line tools to generate customized starting material databases
(extractSM) and reaction center substructure databases (extractRCSS) are also
located in the directory installDir/bin. Both tools can be started with the commands
installDir/bin/extractSM --help
installDir/bin/extractRCSS --help
that print the command line options on your screen (all command line options are
also described in the online help of the GUI version).
4) In order to execute SYLVIA and the associated tools from any directory on a
Windows machine, add the sub-directory "bin" of the installation directory of
SYLVIA (e.g., "C:\Program Files (x86)\sylvia\bin") to the environment variable
"Path" of the system settings as following.
a) Open the "Start" menu of the Windows system, then select "Control Panel" →
"System and Security" → "System" and click on the link "Advanced System
Settings" in the upper left part of the control panel. The "Systems Properties"
dialog appears (see Figure 10).
b) Select the tab "Advanced" in the "Systems Properties" dialog and press the
button "Environment Variables…" (see Figure 10).
Figure 10 The "System Properties" dialog.
c) The "Environment Variables" dialog appears. Select "Path" in the list of
"System variables" and click on the button "Edit" (see Figure 11 left).
d) Add the full path of the sub-directory corina (e.g.," C:\Program Files
Program Installation
40
(x86)\sylvia\bin" at the end of the field "Variable value" (see Figure 11 right).
Note. The newly added path variable has to be separated by the character ";" (semi
colon) from the existing path variables.
Figure 11 Specifying the "Environment Variable" for SYLVIA.
e) Confirm all changes by clicking the button "Ok" and close the "Control Panel".
7.3 Program Updates
For program updates, it is recommended to completely uninstall the current installation
before installing the update version.
Problems and Help!
41
8 Problems and Help!
If you have any difficulties with the installation of SYLVIA or if you encounter any
problems when running SYLVIA, please send all your inquiries to the following
address:
Molecular Networks GmbH Computerchemie Neumeyerstr. 28 90411 Nuremberg Germany
or contact us by email [email protected],
or by Fax +49 911 597 424 09.
Please include the input file, the output file, and any error message and send them to
us by email. These files will help us to analyze your problem; if your system displays
any error messages, please add them to your report. Thank you!
You can also use the report form in section 11 on page 44 of this manual.
Acknowledgements
42
9 Acknowledgements
SYLVIA is developed at Molecular Networks GmbH, Erlangen, Germany.
Some of the methods incorporated have been developed at the research group of Prof.
Dr. Johann Gasteiger at the University of Erlangen-Nuremberg, Erlangen, Germany.
The authors would like to thank all people involved in this software project.
The graphical user interface of SYLVIA has been developed using QT Designer,
Version 3.3.3 (Copyright 2002-2003, Trolltech AS, Norway. All rights reserved.
http://www.trolltech.com/).
Furthermore, the following components and/or component libraries are used and
acknowledged:
Xerces-C library (http://xml.apache.org/xerces-c/), copyright 1999-2005, The
Apache Software Foundation, MD, USA (http://www.apache.org/).
MinGW collection (http://www.mingw.org), copyright 2004.
References
43
10 References
[1] MOSES is a C++ software library for Chemoinformatics applications that is owned,
developed and maintained by Molecular Networks GmbH, Nuremberg, Germany.
[2] a) Dalby, A.; Nourse, J. G.; Hounshell, W. D.; Gushurst, A. K. I.; Grier, D. L.; Leland, B.
A.; Laufer, J. Description of Several Chemical Structure File Formats Used by
Computer Programs Developed at Molecular Design Limited. J. Chem. Inf. Comput.
Sci. 1992, 32, 244-255. b) A detailed description of the file formats Mol, SD, and RD is
available on the Internet for download as a PDF document at
http://accelrys.com/products/informatics/cheminformatics/ctfile-formats/no-fee.php.
[3] a) Weininger, D. SMILES, a Chemical Language and Information System. 1.
Introduction to Methodology and Encoding Rules. J. Chem. Inf. Comput. Sci. 1988, 28,
31-36. b) Daylight Software Manual. Daylight Chemical Information Systems: Santa Fe,
NM, USA, 1993, http://www.daylight.com.
[4] Boda, K.; Seidel, T.; Gasteiger, J. Structure and reaction based evaluation of synthetic
accessibility. J. Comput.-Aided Mol. Des. 2007, 21, 311-325 (DOI 10.1007/s10822-
006-9099-2).
[5] Gasteiger, J.; Ihlenfeldt, W.-D.; Fick, R.; Rose, J. R. Similarity Concepts for the
Planning of Organic Reactions and Syntheses. J. Chem. Inf. Comput. Sci. 1992, 32,
700-712 (DOI 10.1021/ci00010a018).
Report Form
44
11 Report Form
In the case of problems occurring during installation or running SYLVIA, please
complete the following form and send it or fax it to
Molecular Networks GmbH Computerchemie Neumeyerstr. 28 90411 Nuremberg, Germany FAX: +49 911 597 424 09
____________________________________________________________________
User:
____________________________________________________________________
SYLVIA program and version number:
Command line to run SYLVIA:
Error and warning messages by SYLVIA:
____________________________________________________________________
System messages:
____________________________________________________________________
Short description:
Please include the input file, output file and any log files generated by SYLVIA and
forward it by email to [email protected]. These files will help us to analyze your
problems. All data will be treated confidentially.
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