                        Supplementary Information:
    Identifying opportunities for late-stage C-H alkylation with in silico
         reaction screening and high-throughput experimentation

                David F. Nippa1,2,† , Kenneth Atz1,† , Alex T. Müller1 , Jens Wolfard1 , Clemens Isert3 ,
                     Martin Binder1 , Oliver Scheidegger1 , David B. Konrad2,∗ , Uwe Grether1,∗ ,
                                      Rainer E. Martin1,∗ & Gisbert Schneider3,∗
1
    Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.,
                                      Grenzacherstrasse 124, 4070 Basel, Switzerland.
     2
       Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstrasse 5, 81377 Munich, Germany.
     3
       ETH Zurich, Department of Chemistry and Applied Biosciences, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
                4
                  ETH Singapore SEC Ltd, 1 CREATE Way, #06-01 CREATE Tower, Singapore, Singapore.
                                     † These authors contributed equally to this work.
                                     ∗ To whom correspondence should be addressed.
           E-mail: david.konrad@cup.lmu.de, uwe.grether@roche.com, rainer_e.martin@roche.com, gisbert@ethz.ch




                                                           1
Supplementary Note 1             Training Details

PyTorch Geometric (2.0.2) [1] and PyTorch (1.10.1+cu102) [2] functionalities were used for neural network
training. Training was performed on a graphical processing unit GPU (Nvidia GeForce GTX 1080 Ti) for four
hours, using a batch size of 16 samples. The Adam stochastic gradient descent optimizer was employed [3], with
a learning rate of 10−4 , mean squared error (MSE) loss on the training set, a decay factor of 0.5 applied after
100 epochs, and an exponential smoothing factor of 0.9. The final model was stored after 1000 epochs. All the
models considered in this study were trained on the Euler computing cluster at ETH Zurich, Switzerland.




                                                       2
Supplementary Note 2              Clustering

Figure S1 illustrates the clustered chemical space of 3180 advanced heterocyclic building blocks within principal
component analysis (PCA). Exemplary chemical structures at the corners of the scatter plot are highlighted.




Figure S1: Compound clustering. Principal component analysis (PCA) of the 3180 advanced heterocyclic build-
ing blocks, based on ECFP4 molecular fingerprint descriptors. [4] Colors indicate the eight compound groups
(clusters) obtained in the clustering process. The explainable variance for the investigated data set of the first
two principal components is 22.2% and 9.6%, respectively. A-C: Chemical structures from three selected regions
of the investigated chemical space. A: Amid derivatives (54, 55) populating the bottom left of the PCA plot. B:
Benzimidazole derivatives 56 and 57 populating the upper center of the PCA plot. C: Pyridine oxide derivatives
58 and 59 populating the center right of the PCA plot.



Supplementary Note 3              Steric and electronic graph-features

To validate the influence of electronic features in the input molecular graph on model performance as conducted
in a previous study [5], two different GNNs have been trained for reaction yield and binary reaction outcome
prediction (Table S1 and S2). The QM features were calculated on-the-fly using the DelFTa software package
trained on the QMugs data collection [6–9]. Reaction yields were predicted with an error margin of 18 – 19
% and binary reaction outcome could be learned with an area under the receiver operating characteristic curve
(AUC) of 82-83 % (Table S1). Electronic effects have shown significant improvements for the investigated tasks.


                     Table S1: Neural network performance for reaction yields prediction.
                                                   PCC              MAE / %
                                    GNN3D          0.686 (±0.006)   18.7 (±0.2)
                                    GNN3DQM        0.67 (±0.01)     18.6 (±0.6)




                Table S2: Neural network performance for binary reaction outcome prediction.
                                              Absolute accuracy / %      F -score
                               GNN3D          80.8 (±1.2)                82.7 (±0.6)
                               GNN3DQM        80.5 (±0.7)                82.5 (±0.2)




                                                            3
Supplementary Note 4               Systematic literature analysis

Following the previously reported systematic analysis of chemical transformations (SACT) concept [5], suitable
Minisci-type alkylation reactions were identified. SACT comprises of (1) literature search, (2) literature data
curation and evaluation, (3) methodology extraction, (4) reaction data curation and analysis.


The literature search (1) was conducted using three different, renowned tools, Scopus (Elsevier, Amsterdam,
Netherlands), Web of Science (Clarivate Analytics, Philadelphia, USA) and SciFinder-n (Chemical Abstracts
Service, Columbus, USA) on the 30th of August 2022. On all databases a keyword search for "Minisci reaction"
was carried out and the results download.

These files were subjected to a custom-built Alteryx Designer (Irvine, US) data curation (2) workflow that re-
moved duplicates, added information from other databases, e.g., journal impact factor, and carried out further
filtering as well as calculations before splitting the publications into four quadrants based on journal impact
factor and citations per year. After the removal of duplicates, 114 unique publication records were identified.
With the available data, various different clustering approaches could have been carried out using a selection
of the following dimensions, e.g., journal and affiliation, citations, journal impact factor, technologies, catalysts,
starting materials, and publication year. For this work, clustering by citations per year over journal impact fac-
tor to determine the most relevant Minisci methodology publications (high citations/year, high journal impact
factor and high citations/year, low journal impact factor) was chosen. Removal of review papers delivered 45
remaining records [10–54], which underwent manual analysis to guarantee that the papers are within the scope of
the automated HTE system (e.g., photo- and electrochemistry out of scope). To allow for a broad utilization in
medicinal chemistry, the publications were specially screened for a fast, robust and easily adaptable procedure.
Among those, only Sutherland and co-workers [41] delivered a Minisci methodology that fulfilled those precise
criteria. The metal- and catalyst-free setup as well as the ability to work with multiple non-pre-functionalized
alkyl carboxylic allows for customized screening template design depending on project needs.


Next, using the simple user-friendly reaction format (SURF, see Section SI9 for further details), the reaction
data from [41] was extracted and curated manually (3). This resulted in a high-quality data set comprising 45
borylation reactions serving as an ideal starting point for the development of the screening plate (see Section
SI 6) through data analysis (4). Further, as a SURF file is machine-readable, the data was directly available as
input for the machine learning pipelines.




                                                          4
Supplementary Note 5           LSF informer library




Figure S2: Fragments and drugs of the LSF informer library 1-9. For compounds that have a trading name and
a CAS number, the identifiers are depicted below the molecule.




                                                    5
Figure S3: Selection of decoy substrates 10-25 used to generate unsuccessful reaction data to create a balanced
training set. For compounds that have a trading name and a CAS number, the identifiers are depicted below the
molecule




                                                      6
Figure S4: Relevant fragments from the Roche library 26-34. Part 1. For compounds that have a CAS number,
the identifier is depicted below the molecule.




                                                   7
Figure S5: Relevant fragments from the Roche library 35-43. Part 2. For compounds that have a CAS number,
the identifier is depicted below the molecule.




                                                   8
Figure S6: Selection of substrates from [41], which also underwent screening with the designed plate and showed
similar performance. For compounds that have a CAS number, the identifier is depicted below the molecule.




                                                      9
Supplementary Note 6              Screening plate design and testing

As indicated in the main manuscript (Section 4.2), the screening plate was designed around the literature data
obtained from Sutherland et al. [41], which showed good yields on average (60%) for a variety of carboxylic
acid coupling partners. To assess the reactivity of a substrate with a variety of different alkyl rests (rings and
chains), a screening plate with 24 different alkyl carboxylic acids was assembled. The carboxylic acids scope from
Sutherland et al. [41] was extended by sp3 -rich N -heterocyclic carboxylic acids with relevance to drug discovery
projects (o, p, q, r, Figure 2). The reactions were miniaturized to 0.5 µmol scale, downsizing by a factor of 300
compared to the literature procedure. [41] To achieve this small reaction scale, stock solutions of all components
in the reaction solvent (DMSO) were produced. Using simple substrate 1, different oxidant and carboxylic acid
ratios (3:10, 6:10, 3:20, 6:20) were tested to identify the more favourable screening condition (higher conversion).
Further, the influence of the atmosphere (under air, under nitrogen in a glovebox), and the concentration (2,
16 mmol/L) on the reaction outcome were assessed. The results of this optimization process, which led to the
final plate design (Figure 2) are disclosed below.


Air and inert atmosphere


To understand if the reaction requires an air-free atmosphere to deliver good yields, a selection of acid com-
binations were tested under air and in the glovebox on starting material 1. The experimental results revealed
that carrying out the reaction in the glovebox leads to significantly higher yields compared to the corresponding
reaction under air (Figure S7).




Figure S7: Results from the plate testing with different carboxylic acids (a, b, f, g, h, j, o, p, q, u, s, w) under
air and in the glovebox. The yield difference shown in the columns reflects the yield improvements when carrying
out the reaction in a glovebox. Reaction conditions: Starting material (1, 5 umol), oxidant (NH4 )2 S2 O8 , solvent
DMSO/H2 O (600:1), c = 2 mmol/L, 18 h, 40 °C.


Based on these outcomes, all further screening experiments took place in the glovebox.


Carboxylic acid and oxidant ratio


                                                        10
To identify the influence of the oxidant and carboxylic acid equivalents on the reaction success, four different
combinations (3:10, 3:20, 6:10, 6:20) were experimentally tested. For these experiments, three different carboxylic
acids (e, j, o) were reacted with starting material 1. All other parameters were held constant (c = 2 mmol/L, t
= 18 h, T = 40 °C, glovebox).




Figure S8: Results from plate testing with different oxidant and carboxylic acid equivalents on model substrate
1. The influence on three different carboxylic acids (e, j, o) was tested. Reaction conditions: Starting material
(1, 5 umol), oxidant (NH4 )2 S2 O8 , solvent DMSO/H2 O (600:1), c = 2 mmol/L, 18 h, 40 °C, glovebox.


The results in Figure S8 show that for two of the three alkyl carboxylic acids (e, j), the 6:20 oxidant to carboxylic
acid ratio delivered the best results. Even though for o, the 6:10 ratio showed the best results, the performance
of 6:20 was in a similar range. Thus, the 6:20 ratio was incorporated into the final plate layout.


Reaction concentration
To avoid requiring additional solvent addition, i.e., only dosing the stock solutions and using their solvent volume,
a final comparison test was carried out comparing the influence of the solvent concentration. In the initial
experiments, a reaction concentration of 0.002 mol/L was used. This baseline was compared to an increased
concentration (0.016 mol/L, factor 8).
Experimental results (Figure S9) revealed that an increased reaction condition yields a higher amount of alkylated
products. This experiment concluded the plate testing as all reactions nearly reached full starting material con-
version. The final plate layout used for the screening experiments is depicted in Figure 2C of the main manuscript.


Application of reaction conditions to literature substrates
To verify that we did not optimize our conditions for a specific substrate, i.e., compound 1, five other starting ma-
terials (44-48, Section SI5, Figure S6) from Sutherland et al. [41] were screened with the optimized conditions on
the whole plate (Figure 2). Similar performance as described in the paper was observed for the coupling with car-
boxylic acid e, confirming that the miniaturized plate can be used for a broader range of substrates and carboxylic
acids. The detailed screening data is attached as a SURF file as one of the supplementary files of this manuscript.




                                                         11
Figure S9: Results from plate testing with two different reaction concentrations on model substrate 1. The influ-
ence of using a slightly higher reaction concentration (0.016 compared to 0.002 mol/L) with different carboxylic
acids (a, b, f, g, h, j, o, p, q, u, s, w) was tested The yield difference shown in the columns reflects the yield
improvements when carrying out the reaction with higher concentration. Reaction conditions: Starting material
(1, 5 umol), oxidant (NH4 )2 S2 O8 , solvent DMSO/H2 O (600:1), c = varied, 18 h, 40 °C, glovebox.




                                                       12
Supplementary Note 7              HTE screening protocol

All generated screening data used the plate design depicted in the paper (Figure 2) and the procedure below, only
the starting materials (1-9 and 26-43) were varied. In a nitrogen-filled glovebox from mbraun (Garching, DE) that
does not contain any liquids, all solid reaction components were dosed into 4 mL glass vials from Analytical Sales
(Flanders, US) using a CHRONECT Quantos from Axel Semrau GmbH & Co. KG (Spockhövel, DE) coupled
with an XPE206 balance from Mettler Toledo (Greifensee, CH). The vials were sealed and discharged from the
glovebox before being transferred to another glovebox from LC Technologies (Salisbury, US), where solvents were
added to the vials to generate the stock solutions. The remaining stock solutions with liquid components were
prepared in a similar manner. Then according to the plate design, the stock solutions were transferred into 1
mL glass vials from Analytical Sales (Flanders, US) on a 24- or 96-well plate from Analytical Sales (Flanders,
US) using multichannel pipettes from Eppendorf (Hamburg, DE). The plate was heated within the glovebox (LC
Technologies) on a Junior benchtop solution from Unchained Labs (Pleasanton, US) and VP 721F-1 Parylene
Encapsulated Stainless Steel Stir Discs from V&P Scientific Inc. (San Diego, US) were used to stir the reaction
mixture. Only one internal process control (IPC) was taken after the overnight reaction by diluting the reaction
mixture using a Freedom EVO 100 liquid handler from Tecan (Männedorf, CH) with MeCN/H2 O (4:1) to a
defined concentration (1 mmol/L). After shaking on a Teleshake 95 from Inheco (Martinsried, DE), the samples
were transferred onto a 96-deep-well plate (1 mL) from Eppendorf (Hamburg, DE). The plates were analyzed
on a Waters (Milford, US) UPLC-MS system equipped with a Waters Acquity sample manager with a flow-
through needle, a Waters Acquity sample organizer and a Waters QDa single quadrupole mass spectrometer.
The separation was achieved on a ZORBAX RRHT Eclipse Plus C18, 95 Å, 2.1 x 30 mm, 1.8 µm column (P/N
959731-902, LOT: USUXY02479) from Agilent (Santa Clara, USA) at 50 °C. A 2-minute gradient was used and
the injection volume accounted for 2 µL. 2 min gradient: A: 0.1% HCOOH in H2 O; B: 0.07% HCOOH in MeCN
at flow 1 mL/min. Gradient: 0 min, 3% B; 0.2 min, 3% B; 1.5 min, 97% B; 0.3 min, 97% B; 0.1 min 3% B. The
raw data were processed with MassLynx V4.2 and the obtained .rpt file underwent parsing with a customized
script, before being subjected to the automated reaction data analysis pipeline (Section SI8).




                                                       13
Supplementary Note 8              Automated reaction data analysis pipeline

In general, the same automated reaction data analysis pipeline as described in the SI (Section SI6) in a previous
manuscript [5] was used. In this case, the framework was applied to rapidly identify if drugs or fragments were
alkylated or not. Therefore, the MS searched for the sum formulas of the desired products (mono-, di- and tri-
alkylated products), which were generated hands-free using a customized script based on the substrate chemical
formula.


In addition to the reaction mixtures, all starting materials and, if available, reference products using the same
solvent mixture (MeCN:H2 O, 4:1) are measured on the LCMS to obtain the retention time (LC) and mass pat-
tern (MS). This data is stored in a database and needed for the initial two steps of the matching process. More
relevant for LSF though, are the desired/potential products of the reaction. Those masses and chemical formulas
are calculated based on the starting material information and the transformation. This Alteryx workflow allows
hands-free generation of the potential products including molecular weight, mono-isotopic mass and chemical
formula (Hill notation). In addition to being used for the reaction data analysis, this data is also the foundation
for generating the LCMS input file.


Once the reaction data has passed through the cleaning process, it is compared to the LCMS information from
the above-mentioned data sets, starting off with the identification of the starting material. If a trace from the
reaction mixture matches the retention time (± 0.02 min) and the mass pattern (chemical formula detected,
mass channel match with database reference), it receives the starting material tag. The remaining data is then
compared to the products that could potentially be formed and are desired (mono-, di- or trialkylated species).
Since the exact position of the new functional groups is not known, no reference compounds are available. There-
fore, only the five most abundant masses per peak are used for tagging and compared to information from the
potential product database. Based on the abundance of the mass and if the chemical formula was found by the
LCMS, the tag is complemented by an MS reliability score. The score is higher if the chemical formula was found
and the correct mass of the desired product (± 0.5 Da) appears in a more abundant channel. For this study,
only high MS reliability scores were subjected to the machine learning platform. Last, the unmatched data is
classified as unidentified products, and the mass differences between the peak and parent material are calculated
to avoid manual calculating of mass differences.


After the tagging is completed, the data streams are recombined and subjected to calculations in order to quan-
tify the reaction components from starting material through reagents to products. To do so, the sum of all LC
peaks (integral) is calculated and each peak is then divided by this value. This gives a quantitative measure
of the product distribution within the sample, an LCMS conversion. While there are numerous approaches to
using internal standards or assays, due to the nature of LSF they have not been applied. LSF reactions tap into
new, unexplored chemical space and generally, multiple different components are formed. Therefore, selecting an
internal standard that does not overlap with one of these unknown components, is highly difficult.

Upon completion of the calculations, using the identifiers mentioned earlier, reaction information, such as condi-
tions and components, are added to the components that have been identified and quantified. This follows the
FAIR data principle and generates a curated, high-quality LSF screening data set that can be stored and shared
in the SURF convention (Section SI9). This allows rapid subjecting of the data to machine learning algorithms as
done in this research. It also enables direct visualization of the data in known interfaces, such as TIBCO Spotfire
(Somerville, USA) or Tableau (Seattle, USA). Using this workflow, the data curation of one plate usually takes
less than one minute.




                                                        14
Supplementary Note 9              SURF convention

The simple user-friendly reaction format (SURF) aims at standardizing reaction data reporting through a simple,
yet comprehensive and structured format that is usable with a basic understanding of a spreadsheet. SURF does
not require any coding experience, advanced IT skills or a web interface. It enables every chemist within or outside
the lab to document chemical synthesis in a machine-readable and shareable format. SURF allowed extraction
and documentation of the alkylation reactions from literature faster. The generated reaction screening data
were also transformed into SURF before being directly subjected to the machine learning pipelines. Reaction
documentation following SURF can be implemented in every spreadsheet as the only requirement is the existence
of rows and columns.

Each row of the spreadsheet represents the information and data for one single reaction. The SURF convention
contains constant (CC) and flexible (FC) categories. CCs never change and are always present, independent of the
number of reaction components. They capture the origin and ids of the reaction as well as basic characteristics
(reaction type, named reaction, reaction technology) and conditions (temperature, time, atmosphere, scale,
concentration, stirring/shaking). Add-ons, such as the procedure or comments, belong to the CCs, too. The FCs
describe the more variable part of a reaction, the starting material(s), solvent(s), reagent(s) and product(s). Two
identifier options (CAS and SMILES) are available for each component. While the SMILES string is available
for every compound and serves as structural input for machine learning models, the CAS number, even though
not always available, can be handy for chemists in the lab to order, itemize and find chemicals. For the starting
material(s) and reagent(s), e.g., catalyst, ligand, additive, the number and type of columns remain the same
(CAS, Smiles, equivalents). If multiple starting materials or reagents are used, additional columns are required.
In that case, the three information columns are duplicated and the X is replaced by a number, starting from 1
for the first component, 2 for the second, etc. The same accounts for multiple solvents or products, however, due
to their role, they possess more and partly different columns. While the CAS number and/or the SMILES string
remain as an identifier, the solvent fraction (in decimals) instead of equivalents is recorded. This allows exact
determination of the ratio between solvents. The product category withholds the largest amount of headers as
SURF records the yield (in percent), but also the yield type (e.g., isolated, lcms, gcms) as well as the detected
mass by MS and the 1 H NMR sequence in addition to the common identifiers CAS and Smiles. This not
only allows rapid comparison when experiments are reproduced but can also deliver important increments for
machine learning models by differentiating between yield types. As most electronic lab journals already record
the above-mentioned parameters, by enforcing of documentation compliance combined with simple automated
data extraction and cleaning pipelines, numerous reaction data could be accessible in the SURF convention, and
readily available for machine learning applications. We spent thoughts on how to further reduce complexity
by introducing specific SURFs without FCs for chemical transformations where the reaction components are
generally the same. An excellent example would be Suzuki-Miyaura couplings that utilize a set of six to seven
components (organoboron species, halide, catalyst, ligand, base, solvents). [55, 56] However, generating different
tailored templates would ultimately end up in various different formats and mismatching headers falling short of
the main SURF goal to standardize reaction documentation.

The results of this paper would have not been achieved without FAIR data handling using SURF. The manually
extracted reaction data (45 reactions from one publication), which were used in this manuscript for data analysis
and selectivity prediction, reported in SURF are attached to the SI as a tab-delimited text file. Further, the
reaction data of the scale-up experiments in SURF is also added to the SI of this manuscript and significantly
increased the efficiency when compiling the experimental part (Section SI12). Moreover, two empty SURF
templates are attached as tab-delimited text files: The first file contains the general SURF template, which
can be adjusted by introducing additional columns depending on the reaction specifics. The second file is a
customized SURF template that should accommodate the vast of chemical transformations: It contains columns
for two starting materials, two reagents, one catalyst, one ligand, one additive, two solvents and two products.



                                                        15
Supplementary Note 10               Screening results of acids and fragments

For the investigated carboxylic acids (Figure S10) as well as for the N -hetero arenes (Figure S11) different average
reaction yields were observed. Figure S10 illustrates the observed reaction yields for 22 carboxylic acids (a-w).
Carboxylic acids substituted with cyclic ethers (e.g., u, s, a) and alkanes (e.g., b, e, g) were observed with high
reaction yields, whereas cyclic boc-protected amines (e.g., o, p, q, r) and amides (d) resulted in low yields of the
respective desired reaction products. Figure S11 illustrates the observed reaction yields for 27 N -hetero arenes
(1-9 and 26-43). Substituted pyridines (e.g., 30, 31, 36, 39; see Section SI5) were observed with lower yields
compared to compounds lacking meta-substituents (e.g., 26, 32, 38, 41).




                               Figure S10: Analysis of screening results for acids.




                                                         16
Figure S11: Analysis of screening results for substrates.




                           17
Supplementary Note 11                 Machine learning outliers

The observed outliers (17/1148) for reaction yield prediction with a mean absolute error (MAE) ≥ 70% are
illustrated in Table S3.

                           Table S3: Machine learning outliers for reaction yield prediction.
                                   Reaction ID             MAE (%)   Ground truth (%)
                                   eln044720-053-1-1-b1    82.1      0.0
                                   eln044720-053-1-1-b2    100.0     0.0
                                   eln036496-183-15-1-b6   81.9      3.9
                                   eln036496-188-2-1-d3    73.0      75.9
                                   eln046486-037-1-1-a2    70.8      0.0
                                   eln044720-053-1-1-a2    82.3      0.0
                                   eln036496-183-15-1-b3   71.2      99.0
                                   eln044720-053-1-1-a5    70.3      0.0
                                   eln044720-045-1-1-d2    71.9      87.0
                                   eln036496-191-1-1-d2    73.7      75.0
                                   eln046486-035-1-1-a1    70.5      12.9
                                   eln046486-037-1-1-a1    80.5      88.9
                                   eln044720-053-1-1-c2    75.5      95.9
                                   eln046486-035-1-1-a2    78.1      0.0
                                   eln044720-041-1-1-d2    91.7      0.0
                                   eln044720-053-1-1-a1    72.7      97.0
                                   eln044720-041-1-1-c2    97.6      0.0



The outlier data does not indicate any clear trends, where the model did not perform well. However, selected
outliers are discussed below. The two most occurring acids (3x) are A1 (a) and D2 (s). For s, the oxygen
in proximity to the reactive site could have led to increased difficulties when predicting the outcome of the
transformation as the results for this acid vary broadly across the data set, which is already visible based on the
three data points in the table. While the coupling of s worked well with 1 and 5, it was not reactive at all with 38.
For a, a conversion could always be observed experimentally, however, the values for the three substrates (35, 45,
46) differ largely as well. Discrepancies of 45 and 46 might originate due to the new chemical classes (quinones),
which are not broadly represented in the data set. 35 generated difficulties for the model (six appearances in
the table) as it showed varying experimental behaviour depending on the paired acid. The complexity of the
structure including various functional groups with different demanding electronic and steric effects around the
pyridine might have led to the observed high MAEs.




                                                            18
Supplementary Note 12               Scale-up reactions

Supplementary Note 12.1                 Reagent and purification information
Reactions were set up and conducted in nitrogen-filled gloveboxes from mbraun (Garching, DE) and LC Tech-
nologies (Salisbury, US). All chemicals were purchased from Sigma Aldrich (St. Louis, US), AstaTech (Bristol,
US), Combi-Blocks (San Diego, US), TRC (Toronto, CA), Thermo Scientific (Waltham, US) or obtained from
the Roche compound library and used as received. All solids were dosed using a CHRONECT Quantos from Axel
Semrau GmbH & Co. KG (Spockhövel, DE) coupled with an XPE206 balance from Mettler Toledo (Greifensee,
CH). Anhydrous solvents were purchased from Sigma Aldrich, stored in the glovebox and added to the reaction
vials using pipettes from Eppendorf (Hamburg, DE). The vials were heated on a Junior benchtop solution from
Unchained Labs (Pleasanton, US) and the reaction mixture was stirred by VP 721F-1 Parylene Encapsulated
Stainless Steel Stir Discs from V&P Scientific Inc. (San Diego, US). Purification by flash column chromatogra-
phy was performed using SiliaSep Premium Flash Cartridges from Silicycle (Quebec, CA) on a Combi Flash Rf
from Teledyne ISCO (Nebraska, US) or by reversed-phase high-pressure liquid chromatography (RP-HPLC) on a
Gilson (Middleton, USA) GX-281 liquid handler equipped with a Shimadzu (Kyoto, JP) LC-20AP dual pump, a
Thermo Fisher Scientific (Waltham, US) UV/VIS-Thermo Ultimate 300 Detector, a VWR (Radnor, US) ELSD90
ELSD detector and a Thermo Fisher Scientific (Waltham, US) Thermo MSQ Plus MS Single Quadrupole using
a Phenomenex (Torrance, US) Gemini NX C18 column (12 nm, 5 um silica, 30 mm diameter, 100 mm length,
flow rate of 40 mL/min) or YMC (Kyoto, JP) Triart C18 (12 nm, 5 um, 100x30 mm) column. The used eluent
solvents, gradients and cartridge sizes for flash chromatography and RP-HPLC are described individually for
each experiment.


Supplementary Note 12.2                 Analytical information
All compounds were characterized by nuclear magnetic resonance (NMR) spectroscopy and (flow injection analysis
(FIA)) high-resolution mass spectrometry (HRMS) or gas-chromatography mass spectrometry (GCMS). NMR
spectra were recorded on a Bruker Avance III, 600 MHz spectrometer equipped with a 5 mm TCI, Z-gradient
CryoProbe, a Bruker Avance Neo, 400 MHz spectrometer equipped with a 5 mm Z-gradient iProbe or a Bruker
Avance III HD, 300 MHz spectrometer equipped with a 5 mm BBI-Probe. NMR data are reported as follows:
chemical shift in reference to the residual solvent peak (δ ppm), multiplicity (s = singlet, d = doublet, dd =
doublet of doublet, t = triplet, dt = doublet of triplet, td = triplet of doublet, q = quintet, m = multiplet),
coupling constant (Hz), and integration. 1 H NMR residual solvent peaks in respective deuterated solvents for
CHCl3 at 7.26 ppm and DMSO at 2.50 ppm. 13 C NMR residual solvent peaks in respective deuterated solvents
for CHCl3 at 77.16 ppm and DMSO at 39.52 ppm.

LC-MS high-resolution spectra were recorded with an Agilent LC system consisting of Agilent 1290 high-pressure
gradient system, and an Agilent 6545 QTOF. The separation was achieved on a Zorbax Eclipse Plus C18 1.7
µm 2.1 x 50 mm column (P/N 959731-902) at 55 °C; A: 0.01% HCOOH in H2 O; B: MeCN at flow 0.8 mL/min.
Gradient: 0 min 5% B, 0.3 min 5% B, 4.5 min 99% B, 5 min 99% B. The injection volume was 2 µL. Ionization
was performed in an Agilent Multimode source. The mass spectrometer was run in “2 GHz extended dynamic
range” mode, resulting in a resolution of about 20 000 at m/z = 922. Mass accuracy was ensured by internal drift
correction. GC-MS spectra were recorded on an Agilent 5975B single quadrupole mass spectrometer. Separation
was achieved on an Agilent 7890A using a HP-1ms column (15 m ID: 250 µm and 0.25 µm film) with He as carrier
gas. Sample introduction was done via a Split injector at 270°C. After 0.5 min at a constant temperature, the
temperature was ramped from 100 °C or 45 °C to 320 °C with 35 °C/min. The mass spectrometer was operated in
EI (electron ionization) mode at 70 eV. FIA-HRMS spectra were recorded with an Agilent LC system consisting
of an Agilent 1290 high-pressure gradient system, and an Agilent 6540 QTOF. No separation was intended and
the injected sample was flushed directly into the Agilent Jetstream source. The mass spectrometer was run in “2
GHz extended dynamic range” mode, resulting in a resolution of about 20 000 at m/z 922. Mass accuracy was
ensured by internal drift correction.


                                                      19
Supplementary Note 12.3                          Experimental procedures and analytical data
4-(13-chloro-5-cyclobutyl-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene)piperi-
dine-1-carboxylic acid ethyl ester (7b1),
4-(13-chloro-7-cyclobutyl-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene)piperi-
dine-1-carboxylic acid ethyl ester (7b2),
4-[13-chloro-5,7-di(cyclobutyl)-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene]-
piperidine-1-carboxylic acid ethyl ester (7b3):



                                     O
      Cl                                             Cl
                                         OH                                  Cl                    Cl
                         N            (10 eq.)                          N
                                                                                               N                    N
                             (NH4)2S2O8 (3.0 eq.)
                 N                                              N
                             DMSO/H2O (1/0.05)
                                                                                       N                    N
             O       O            (0.05 M)                  O       O
                                                                                   O       O            O       O
                                 40 °C, 18 h



             7                                                  7b1                7b2                      7b3
                                                            (9%)                   (4%)                 (4%)


                                             Figure S12: Alkylation of Loratadine (7).

To a solution of 4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene)piperidine-
1-carboxylic acid ethyl ester (7, 57.4 mg, 0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O,
cyclobutanecarboxylic acid (b, 150.2 mg, 1.50 mmol, 10.0 eq.) and ammonium persulfate (102.7 mg, 450 umol,
3.00 eq.) was added. The reaction mixture was degassed while bubbling nitrogen through it. The reaction
mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with NaHCO3 solution and extracted
with DCM. The combined organic layers were washed with water, and brine, dried over Na2 SO4 , filtered and
concentrated to dryness. The crude material was purified by reversed-phase HPLC (Gemini NX, 12 nm, 5 um,
100 x 30 mm) using a MeCN gradient (20-40-55%) in H2 O + 0.1% HCOOH. The solvent was removed from prod-
uct containing fractions. Evaporation of solvents gave the title compounds 4-(13-chloro-5-cyclobutyl-4-azatricy-
clo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene)piperidine-1-carboxylic acid ethyl ester (7b1, 6.3 mg,
9%) as an off-white powder, 4-(13-chloro-7-cyclobutyl-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-
2-ylidene)piperidine-1-carboxylic acid ethyl ester (7b2, 2.7 mg, 4%) as an off-white powder and 4-[13-chloro-5,7-di-
(cyclobutyl)-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene]piperidine-1-carboxylic acid ethyl
ester (7b3, 3.8 mg, 4%) as an off-white powder.

7b1:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 7.34 (d, J = 7.9 Hz, 1H), 7.12 - 7.18 (m, 3H), 7.01 (d, J = 7.9 Hz,
1H), 4.15 (q, J = 7.1 Hz, 2H), 3.76 - 3.81 (m, 1H), 3.60 - 3.66 (m, 1H), 3.35 - 3.40 (m, 1H), 3.26 - 3.31 (m, 1H),
3.19 - 3.24 (m, 2H), 2.75 - 2.85 (m, 2H), 2.53 - 2.56 (m, 1H), 2.30 - 2.38 (m, 6H), 2.20 - 2.30 (m, 2H), 2.00 - 2.06
(m, 1H), 1.85 - 1.89 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3 ) δ (ppm) 161.96, 155.75,
140.18, 138.04, 137.48, 134.69, 132.91, 130.76, 130.28, 128.92, 126.19, 119.22, 61.51, 45.17, 42.16, 31.97, 31.68,
31.15, 30.87, 29.04, 28.73, 18.48, 14.92, 14.89. HRMS C26 H29 ClN2 O2 ; calc. for (M+H+ ): 437.1918, found:
437.2.

7b2:
1
 H NMR (600 MHz, CDCl3 ) δ (ppm) 8.36 (d, J = 5.1 Hz, 1H), 7.12 (s, 3H), 7.08 (d, J = 4.9 Hz, 1H), 4.15
(q, J = 7.2 Hz, 2H), 3.75 - 3.85 (m, 2H), 3.61 - 3.68 (m, 1H), 3.34 - 3.40 (m, 1H), 3.11 - 3.19 (m, 3H), 2.77 - 2.87
(m, 2H), 2.35 - 2.44 (m, 5H), 2.21 - 2.24 (m, 2H), 2.07 - 2.11 (m, 2H), 1.85 - 1.90 (m, 1H), 1.26 (t, J = 7.1 Hz,
3H). 13 C NMR (151 MHz, CDCl3 δ (ppm) 158.25, 155.71, 152.61, 146.89, 139.42, 136.99, 136.81, 134.78,


                                                                      20
133.01, 131.34, 131.15, 129.53, 126.19, 120.12, 61.52, 44.99, 44.88, 37.91, 31.91, 30.80, 30.80, 29.45, 28.30, 26.95,
18.57, 14.89. HRMS C26 H29 ClN2 O2 ; calc. for (M+H+ ): 437.1918, found: 437.2.

7b3:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 7.17 (d, J = 8.1 Hz, 1H), 7.10 - 7.12 (m, 2H), 6.98 (s, 1H), 4.15 (q,
J = 7.2 Hz, 2H), 3.75 - 3.86 (m, 2H), 3.58 - 3.66 (m, 2H), 3.33 - 3.38 (m, 1H), 3.08 - 3.21 (m, 3H), 2.74 - 2.82
(m, 2H), 2.32 - 2.38 (m, 6H), 2.24 - 2.26 (m, 3H), 1.99 - 2.12 (m, 3H), 1.85 - 1.89 (m, 2H), 1.26 (t, J = 7.1 Hz,
3H). HRMS C30 H35 ClN2 O2 ; calc. for (M+H+ ): 491.2387, found: 491.2.




                                                         21
4-[5-(benzoxymethyl)-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene]-
piperidine-1-carboxylic acid ethyl ester (7t1),
4-[7-(benzoxymethyl)-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene]-
piperidine-1-carboxylic acid ethyl ester (7t2)


                                                                                                                    Ph
                                             O                                                                  O
       Cl                                               Cl
                                Ph      O
                                                   OH                                      Cl
                           N          (10 eq.)                                N
                               (NH4)2S2O8 (3.0 eq.)                               O                         N
                                                                                      Ph
                   N           DMSO/H2O (1/0.05)                      N

               O       O                                          O       O                         N
                                      (0.05 M)
                                     40 °C, 18 h                                                O       O



              7                                                        7t1                          7t2
                                                                      (10%)                         (9%)


                                       Figure S13: Alkylation of Loratadine (7).

To a solution of 4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene)piperidine-
1-carboxylic acid ethyl ester (7, 57.4 mg, 0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O,
2-benzoxyacetic acid (t, 249.3 mg, 1.50 mmol, 10.0 eq.) and ammonium persulfate (102.7 mg, 450 umol, 3.00 eq.)
was added. The reaction mixture was degassed while bubbling nitrogen through it. The reaction mixture
was stirred at 40 °C for 18 hr. The reaction mixture was quenched with NaHCO3 solution and extracted
with DCM. The combined organic layers were washed with water, and brine, dried over Na2 SO4 , filtered and
concentrated to dryness. The crude material was purified by reversed-phase HPLC (Gemini NX, 12 nm, 5 um,
100 x 30 mm) using a MeCN gradient (55-75-90-100%) in H2 O + 0.1% HCOOH. The solvent was removed from
product containing fractions. Evaporation of solvents gave the title compounds 4-[5-(benzoxymethyl)-13-chloro-4-
azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene]piperidine-1-carboxylic acid ethyl ester (7t1,
8.1 mg, 10%) as an off-white powder and 4-[7-(benzoxymethyl)-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(15)-
,3,5,7,11,13-hexaen-2-ylidene]piperidine-1-carboxylic acid ethyl ester (7t2, 6.6 mg, 9%) as an off-white powder.



7t1:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 7.47 (d, J = 8.0 Hz, 1H), 7.35 - 7.38 (m, 4H), 7.33 - 7.34 (m, 1H),
7.29 - 7.31 (m, 1H), 7.16 - 7.17 (m, 1H), 7.14 - 7.15 (m, 2H), 4.66 (d, J = 2.4 Hz, 2H), 4.63 (s, 2H), 4.15 (q,
J = 7.1 Hz, 2H), 3.84 - 3.86 (m, 2H), 3.37 - 3.41 (m, 1H), 3.31 - 3.36 (m, 1H), 3.03 - 3.10 (m, 2H), 2.78 - 2.87
(m, 2H), 2.42 - 2.47 (m, 1H), 2.31 - 2.36 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H). HRMS C30 H31 ClN2 O3 ; calc. for
(M+H+ ): 503.2023, found: 503.2.

7t2:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.42 (d, J = 5.0 Hz, 1H), 7.38 - 7.40 (m, 1H), 7.35 - 7.38 (m, 3H), 7.32
- 7.35 (m, 1H), 7.30 (d, J = 5.0 Hz, 1H), 7.11 - 7.15 (m, 3H), 4.62 (s, 2H), 4.52 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H),
3.81 - 3.82 (m, 2H), 3.36 - 3.31 (m, 1H), 3.12 - 3.19 (m, 3H), 2.78 - 2.86 (m, 2H), 2.44 - 2.46 (m, 1H), 2.33 - 2.41
(m, 2H), 2.26 - 2.29 (m, 1H), 1.26 (t, J = 7.1 Hz, 3 H). HRMS C30 H31 ClN2 O3 ; calc. for (M+H+ ): 503.2023,
found: 503.2.




                                                             22
4-(13-chloro-7-cyclohexyl-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene)piperi-
dine-1-carboxylic acid ethyl ester (7e1),
4-(13-chloro-5-cyclohexyl-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene)piperi-
dine-1-carboxylic acid ethyl ester (7e2)



                                        O
      Cl                                               Cl
                                            OH
                           N                                                N           Cl
                                         (10 eq.)
                                                                                                              N
                               (NH4)2S2O8 (3.0 eq.)
                   N                                                N
                               DMSO/H2O (1/0.05)
               O       O                                        O       O                             N
                                    (0.05 M)
                                   40 °C, 18 h                                                    O       O



               7                                                    7e1                           7e2
                                                                    (11%)                         (5%)


                                    Figure S14: Alkylation of Loratadine (7).

To a solution of 4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene)piperidine-
1-carboxylic acid ethyl ester (7, 57.4 mg, 0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O, cyclohex-
anecarboxylic acid (e, 192.3 mg, 186.7 uL, 1.50 mmol, 10.0 eq.) and ammonium persulfate (102.7 mg, 450 umol,
3.00 eq.) was added. The reaction mixture was degassed while bubbling nitrogen through it. The reaction
mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with NaHCO3 solution and extracted
with DCM. The combined organic layers were washed with water, and brine, dried over Na2 SO4 , filtered and con-
centrated to dryness. The crude material was purified by reversed-phase HPLC (YMC-Triart C18, 12 nm, 5 um,
100 x 30 mm) using a MeCN gradient (20-98%) in H2 O + 0.1% HCOOH. The solvent was removed from prod-
uct containing fractions. Evaporation of solvents gave the title compounds 4-(13-chloro-7-cyclohexyl-4-azatricy-
clo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene)piperidine-1-carboxylic acid ethyl ester (7e1, 8.1 mg,
11%) as an off-white powder and 4-(13-chloro-5-cyclohexyl-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-
hexaen-2-ylidene)piperidine-1-carboxylic acid ethyl ester (7t2, 5.4 mg, 5%) as an off-white powder.

7e1:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 7.34 - 7.35 (m, 1H), 7.17 - 7.18 (m, 2H), 7.14 - 7.15 (m, 1H), 6.97 (d,
J = 7.8 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.82 - 3.87 (m, 2H), 3.35 - 3.40 (m, 1H), 3.27 - 3.31 (m, 1H), 3.09 -
3.13 (m, 1H), 2.68 - 2.84 (m, 1H), 2.33 - 2.36 (m, 3H), 1-94 - 1.97 (m, 1H), 1.88 - 1.90 (m, 1H), 1.73 - 1.76 (m,
1H), 1.38 - 1.49 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H). HRMS C28 H33 ClN2 O2 ; calc. for (M+H+ ): 465.2231, found:
465.2.

7e2:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.32 (d, J = 5.2 Hz, 1H), 7.11 - 7.13 (m, 3H), 7.07 (d, J = 5.3 Hz,
1H), 4.15 (q, J = 7.1 Hz, 2H), 3.38 - 3.42 (m, 1H), 3.18 - 3.28 (m, 2H), 3.12 - 3.15 (m, 1H), 3.01 - 3.05 (m, 1H),
2.81 - 2.87 (m, 1H), 2.75 - 2.79 (m, 1H), 2.38 - 2.42 (m, 3H), 2.19 - 2.21 (m, 1H), 1.87 - 1-91 (m, 1H), 1.80 - 1.85
(m, 3H), 1.72 - 1.73 (m, 1H), 1.40 - 1.46 (m, 6H), 1.26 (t, J = 7.1 Hz, 3H). HRMS C28 H33 ClN2 O2 ; calc. for
(M+H+ ): 465.2231, found: 465.2.




                                                        23
4-[13-chloro-5-(4,4-difluorocyclohexyl)-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-
2-ylidene]piperidine-1-carboxylic acid ethyl ester (7j1),
4-[13-chloro-7-(4,4-difluorocyclohexyl)-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-
2-ylidene]piperidine-1-carboxylic acid ethyl ester (7j2)


                                                                                                                  F F
                                               O
       Cl                                          OH    Cl

                          N    F                                                 N
                                   F         (10 eq.)                                        Cl

                              (NH4)2S2O8 (3.0 eq.)                                       F                    N
                  N                                                    N             F
                              DMSO/H2O (1/0.05)
              O       O                                            O       O                          N
                                        (0.05 M)
                                       40 °C, 18 h                                                O       O



              7                                                            7j1                    7j2
                                                                       (8%)                       (6%)


                                        Figure S15: Alkylation of Loratadine (7).

To a solution of 4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene)piperidine-
1-carboxylic acid ethyl ester (7, 57.4 mg, 0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O,
4,4-difluorocyclohexanecarboxylic acid (j, 246.2 mg, 1.50 mmol, 10.0 eq.) and ammonium persulfate (102.7 mg,
450 umol, 3.00 eq.) was added. The reaction mixture was degassed while bubbling nitrogen through it. The
reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with NaHCO3 solution and
extracted with DCM. The combined organic layers were washed with water, and brine, dried over Na2 SO4 , filtered
and concentrated to dryness. The crude material was purified by reversed-phase HPLC (YMC-Triart C18, 12 nm,
5 um, 100 x 30 mm) using a MeCN gradient (20-98%) in H2 O + 0.1% HCOOH. The solvent was removed from
product containing fractions. Evaporation of solvents gave the title compounds 4-[13-chloro-5-(4,4-difluorocyclo-
hexyl)-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene]piperidine-1-carboxylic acid ethyl es-
ter (7j1, 7.8 mg, 8%) as an off-white powder and 4-[13-chloro-7-(4,4-difluorocyclohexyl)-4-azatricyclo[9.4.0.03,8]-
pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene]piperidine-1-carboxylic acid ethyl ester (7j2, 6.0 mg, 6%) as an
off-white powder.

7j1:
1
  H NMR (600 MHz, CDCl3 ) δ (ppm) 7.37 - 7.39 (m, 1H), 7.17 - 7.18 (m, 1H), 7.14 - 7.15 (m, 2H), 6.98 (d,
J = 7.9 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.36 - 3.41 (m, 1H), 3.28 - 3.32 (m, 1H), 3.11 - 3.16 (m, 2H), 2.77
- 2.86 (m, 4H), 2.46 - 2.50 (m, 1H), 2.29 - 2.35 (m, 4H), 2.18 - 2.23 (m, 2H), 2.02 - 2.04 (m, 1H), 1.96 - 1.98
(m, 1H), 1.82 - 1.90 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H). HRMS C28 H31 ClF2 N2 O2 ; calc. for (M+H+ ): 501.2042,
found: 501.2.

7j2:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.37 (d, J = 5.3 Hz, 1H), 7.12 - 7.14 (m, 3H), 7.09 (d, J = 5.3 Hz,
1H), 4.15 (q, J = 7.1 Hz, 2H), 3.41 - 3.45 (m, 1H), 3.28 - 3.33 (m, 1H), 3.14 - 3.25 (m, 2H), 2.98 - 3.02 (m, 1H),
2.80 - 2.90 (m, 3H), 2.38 - 2.44 (m, 3H), 2.24 - 2.31 (m, 2H), 2.16 - 2.19 (m, 1H), 1.78 - 1.93 (m, 6H), 1.26 (t,
J = 7.1 Hz, 3H). HRMS C28 H31 ClF2 N2 O2 ; calc. for (M+H+ ): 501.2042, found: 501.2.




                                                              24
4-(13-chloro-5-tetrahydropyran-2-yl-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-yli-
dene)piperidine-1-carboxylic acid ethyl ester (7s)


                                                            O
                  Cl                                  O                    Cl
                                                                OH
                                      N                      (10 eq.)                             N

                                                   (NH4)2S2O8 (3.0 eq.)                               O

                              N                                                           N
                                                   DMSO/H2O (1/0.05)
                          O       O                       (0.05 M)                    O       O

                                                       40 °C, 18 h


                          7                                                                7s
                                                                                          (10%)


                                          Figure S16: Alkylation of Loratadine (7).

To a solution of 4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene)piperidine-
1-carboxylic acid ethyl ester (7, 57.4 mg, 0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O,
tetrahydropyran-2-carboxylic acid (s, 195.2 mg, 1.50 mmol, 10.0 eq.) and ammonium persulfate (102.7 mg,
450 umol, 3.00 eq.) was added. The reaction mixture was degassed while bubbling nitrogen through it. The
reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with NaHCO3 solution and
extracted with DCM. The combined organic layers were washed with water, and brine, dried over Na2 SO4 , filtered
and concentrated to dryness. The crude material was purified by reversed-phase HPLC (Gemini NX, 12 nm,
5 um, 100 x 30 mm) using a MeCN gradient (30-65-90%) in H2 O + 0.1% HCOOH. The solvent was removed from
product containing fractions. Evaporation of solvents gave the title compound 4-(13-chloro-5-tetrahydropyran-
2-yl-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene)piperidine-1-carboxylic acid ethyl ester
(7s, 7.1 mg, 10%) as an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 7.45 (dd, J = 11.9, 7.9 Hz, 1H), 7.28 - 7.31 (m, 1H), 7.13 - 7.18 (m,
3H), 4.44 (dt, J = 11.2, 2.4 Hz, 1H), 4.12 - 4.17 (m, 3H), 3.59 - 3.66 (m, 1H), 3.29 - 3.39 (m, 2H), 2.98 - 3.12
(m, 2H), 2.78 - 2.87 (m, 2H), 2.31 - 2.46 (m, 4H), 1.88 - 1.95 (m, 1H), 1.65 - 1.73 (m, 3H), 1.57 - 1.60 (m, 1H),
1.40 - 1.47 (m, 1H), 1.26 (td, J = 7.1, 3.3 Hz, 4H). HRMS C27 H31 ClN2 O3 ; calc. for (M+H+ ): 467.2023, found:
467.2.




                                                                25
2-cyclopropyl-7-methyl-14-tetrahydropyran-2-yl-2,4,9,15-tetrazatricyclo[9.4.0.03,8]pentadeca-1(15)-
,3(8),4,6,11,13-hexaen-10-one (8s)


                                                           O
                                                     O
                                  O                            OH                            O
                         HN                                 (10 eq.)                HN

                                                  (NH4)2S2O8 (3.0 eq.)
                              N                                                 N        N       N
                     N                N
                                                  DMSO/H2O (1/0.05)
                                                                                                     O
                                                         (0.05 M)
                                                      40 °C, 18 h

                          8                                                                  8s
                                                                                         (20%)

                                          Figure S17: Alkylation of Nevirapine (8).

To a solution of 2-cyclopropyl-7-methyl-2,4,9,15-tetrazatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-10-
one (8, 40.0 mg, 0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O, tetrahydropyran-2-carboxylic acid
(s, 195.2 mg, 1.50 mmol, 10.0 eq.) and ammonium persulfate (102.7 mg, 450 umol, 3.00 eq.) was added. The
reaction mixture was degassed while bubbling nitrogen through it. The reaction mixture was stirred at 40 °C
for 18 hr. The reaction mixture was quenched with NaHCO3 solution and extracted with DCM. The combined
organic layers were washed with water, and brine, dried over Na2 SO4 , filtered and concentrated to dryness. The
crude material was purified by reversed-phase HPLC (Gemini NX, 12 nm, 5 um, 100 x 30 mm) using a MeCN
gradient (20-45-65%) in H2 O + 0.1% HCOOH. The solvent was removed from product containing fractions.
Evaporation of solvents gave the title compound 2-cyclopropyl-7-methyl-14-tetrahydropyran-2-yl-2,4,9,15-tetraza-
tricyclo[9.4.0.03,8]pentadeca-1(15),3(8),4,6,11,13-hexaen-10-one (8s, 10.6 mg, 20%) as an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.16 (d, J = 4.9 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.38 (s, 1H), 7.25
(m, 1H), 6.91 (dd, J = 4.9, 0.7 Hz, 1H), 4.39 - 4.46 (m, 1H), 4.14 - 4.16 (m, 1H), 3.71 - 3.74 (m, 1H), 3.61 - 3.66
(m, 1H), 2.35 (s, 3H), 2.16 - 2.23 (m, 1H), 1.93 - 1.96 (m, 1H), 1.58 - 1.73 (m, 4H), 1.43 - 1.50 (m, 1H), 0.90 -
0.96 (m, 2H), 0.41 - 0.48 (m, 2H). HRMS C20 H22 N4 O2 ; calc. for (M+H+ ): 351.1743, found: 351.18.




                                                               26
4-[13-chloro-5-(4,4-difluorocyclohexyl)-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-
2-ylidene]piperidine-1-carboxylic acid ethyl ester (7q1),
4-[5-(1-tert-butoxycarbonylpyrrolidin-3-yl)-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-
hexaen-2-ylidene]piperidine-1-carboxylic acid ethyl ester (7q2)


                                                                                    Boc
                                            O                                   N
      Cl                                                                                  Cl
                                                OH
                                     N                Cl
                          N                                                                                N
                               Boc       (10 eq.)
                                                                            N
                               (NH4)2S2O8 (3.0 eq.)                                                            N
                  N                                                                                N           Boc
                               DMSO/H2O (1/0.05)
              O       O                                             N                          O       O
                                     (0.05 M)
                                   40 °C, 18 h                  O       O


              7                                                     7q1                            7q2
                                                                    (4%)                           (4%)


                                     Figure S18: Alkylation of Loratadine (7).

To a solution of 4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene)piperidine-
1-carboxylic acid ethyl ester (7, 57.4 mg, 0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O,
1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (q, 322.9 mg, 1.50 mmol, 10.0 eq.) and ammonium persul-
fate (102.7 mg, 450 umol, 3.00 eq.) were added. The reaction mixture was degassed while bubbling nitrogen
through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with
NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water, and brine,
dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by reversed-phase
HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm) using a MeCN gradient (50-70-85-100%) in H2 O + 0.1%
TEA. The solvent was removed from product containing fractions. Evaporation of solvents gave the title com-
pounds 4-[5-(1-tert-butoxycarbonylpyrrolidin-3-yl)-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-
hexaen-2-ylidene]piperidine-1-carboxylic acid ethyl ester (7j1, 3.73 mg, 4%) as an off-white powder and 4-[5-(1-
tert-butoxycarbonylpyrrolidin-3-yl)-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene]-
piperidine-1-carboxylic acid ethyl ester (7q2, 3.69 mg, 4%) as an off-white powder.

7q1:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.37 - 8.38 (m, 1H), 7.13 - 7.14 (m, 3H), 7.05 - 7.06 (m, 1H), 4.15 (d,
J = 7.1 Hz, 2H), 3.77 - 3.81 (m, 2H), 3.56 - 3.63 (m, 2H), 3.41 - 3.46 (m, 2H), 3.25 - 3.34 (m, 2H), 3.14 - 3.20
(m, 2H), 3.00 - 3.05 (m, 1H), 2.82 - 2.86 (m, 1H), 2.41 - 2.43 (m, 3H), 2.18 - 2.26 (m, 2H), 1.50 (s, 9H), 1.26 (t,
J = 7.1 Hz, 3H). HRMS C28 H31 ClF2 N2 O2 ; calc. for (M+H+ ): 501.2042, found: 501.2.

7q2:
1
 H NMR (600 MHz, CDCl3 ) δ (ppm) 7.33 - 7.35 (m, 1H), 7.17 - 7.18 (m, 1H), 7.12 - 7.15 (m, 2H), 6.97 -
6.99 (m, 1H), 4.15 (d, J = 7.1 Hz, 2H), 3.73 - 3.81 (m, 3H), 3.55 - 3.64 (m, 1H), 3.43 - 3.49 (m, 2H), 3.36 - 3.41
(m, 2H), 3.28 - 3.32 (m, 1H), 3.14 - 3.26 (m, 2H), 2.76 - 2.86 (m, 2H), 2.49 - 2.53 (m, 1H), 2.34 - 2.38 (m, 1H),
2.28 - 2.30 (m, 2H), 2.19 - 2.23 (m, 1H), 2.05 - 2.15 (m, 1H), 1.49 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H). HRMS
C28 H31 ClF2 N2 O2 ; calc. for (M+H+ ): 501.2042, found: 501.2.




                                                           27
N-[(6-tert-butyl-3-pyridyl)methyl]-N-methyl-1-naphthamide (28h)


                                                  O
                                N                                                      N
                                                     OH
                                                    (20 eq.)

                      O    N               (NH4)2S2O8 (6.0 eq.)
                                                                          O    N
                                           DMSO/H2O (1/0.05)
                                                 (0.05 M)
                                               40 °C, 18 h


                          28                                                    28h
                                                                               (28%)

                                    Figure S19: Alkylation of Fragment 28.

To a solution of N-methyl-N-(3-pyridylmethyl)-1-naphthamide (28, 41.5 mg, 0.15 mmol, 1.00 eq.) in 3 mL
degassed DMSO and 5 uL H2 O, pivalic acid (h, 306.4 mg, 348.2 uL, 3.0 mmol, 20.0 eq.) and ammonium
persulfate (205.4 mg, 0.9 mmol, 6.0 eq.) were added. The reaction mixture was degassed while bubbling nitrogen
through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with
NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water, and brine,
dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by reversed-phase
HPLC (Gemini NX, 12 nm, 5 um, 100 x 30 mm) using a MeCN gradient (30-50-65-100%) in H2 O + 0.1% TEA.
The solvent was removed from product containing fractions. Evaporation of solvents gave the title compound
N-[(6-tert-butyl-3-pyridyl)methyl]-N-methyl-1-naphthamide (28h, 14.2 mg, 28%) as an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.62 - 8.63 (m, 1H), 7.88 - 7.90 (m, 4H), 7.86 - 7.91 (m, 2H), 7.42 -
7.47 (m, 3H), 3.17 (s, 2H), 2.75 (s, 3H), 1.41 (s, 10H). HRMS C22 H24 N2 O; calc. for (M+H+ ): 333.1889, found:
333.19.




                                                      28
3-[4-(4-bromo-3-methyl-phenyl)-5-(cyclohexylthio)-1,2,4-triazol-3-yl]-2-phenoxy-pyridine (38e)


                                                     O
                                     Br                                                           Br
                      S
                                                         OH                     S
                   HN       N                                                           N
                                                    (20 eq.)                   HN
                        N
                                           (NH4)2S2O8 (6.0 eq.)                     N

                            O                                                           O
                                 N          DMSO/H2O (1/0.05)                                 N
                                                 (0.05 M)
                                               40 °C, 18 h


                                38                                                      38e
                                                                                    (36%)

                                      Figure S20: Alkylation of Fragment 38.

To a solution of 4-(4-bromo-3-methyl-phenyl)-3-(2-phenoxy-3-pyridyl)-1H-1,2,4-triazole-5-thione (38, 41.5 mg,
0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O, cyclohexanecarboxylic acid (e, 384.5 mg, 373.31 uL,
3.0 mmol, 20.0 eq.) and ammonium persulfate (205.4 mg, 0.9 mmol, 6.0 eq.) were added. The reaction mixture
was degassed while bubbling nitrogen through it. The reaction mixture was stirred at 40 °C for 18 hr. The
reaction mixture was quenched with NaHCO3 solution and extracted with DCM. The combined organic layers
were washed with water, and brine, dried over Na2 SO4 , filtered and concentrated to dryness. The crude material
was purified by reversed-phase HPLC (YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm) using a MeCN gradient
(20-98%) in H2 O + 0.1% HCOOH. The solvent was removed from product containing fractions. Evaporation of
solvents gave the title compound 3-[4-(4-bromo-3-methyl-phenyl)-5-(cyclohexylthio)-1,2,4-triazol-3-yl]-2-phenoxy-
pyridine (38e, 28.5 mg, 36%) as an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.18 (dd, J = 4.9, 2.0 Hz, 1H), 8.11 - 8.15 (m, 1H), 7.48 (d, J = 8.4 Hz,
1H), 7.28 - 7.29 (m, 1H), 7.26 - 7.27 (m, 1H), 7.14 - 7.16 (m, 1H), 7.11 - 7.13 (m, 1H), 7.02 (d, J = 2.6 Hz,
1H), 6.77 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 7.7 Hz, 2H), 3.86 - 3.91 (m, 1H), 2.19 (s, 3H), 2.16 - 2.18 (m, 1H),
1.73 - 1.77 (m, 2H), 1.61 - 1.64 (m, 2H), 1.49 - 1.52 (m, 2H), 1.4.1 - 1.49 (m, 3H), 1.25 - 1. 30 (s, 1H). HRMS
C22 H24 N2 O; calc. for (M+H+ ): 523.1089, found: 523.09.




                                                         29
4-(6-tert-butyl-3-pyridyl)-3-(2,3-dichlorophenyl)-1,2,4-oxadiazol-5-one (40h)


                                                      O                           Cl
                    Cl
                                                          OH                             Cl
                           Cl
                                                          (20 eq.)
                                                                                              N
                                N                                                                 O
                                               (NH4)2S2O8 (6.0 eq.)
                                    O                                                    N
                           N
                                               DMSO/H2O (1/0.05)                                  O
                                    O
                                                     (0.05 M)                       N
                      N
                                                   40 °C, 18 h


                          40                                                       40h
                                                                                  (52%)

                                        Figure S21: Alkylation of Fragment 40.

To a solution of 3-(2,3-dichlorophenyl)-4-(3-pyridyl)-1,2,4-oxadiazol-5-one (40, 46.2 mg, 0.15 mmol, 1.00 eq.) in
3 mL degassed DMSO and 5 uL H2 O, pivalic acid (h, (306.4 mg, 348.2 uL, 3.0 mmol, 20.0 eq.) and ammonium
persulfate (205.4 mg, 0.9 mmol, 6.0 eq.) were added. The reaction mixture was degassed while bubbling nitrogen
through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with
NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water, and brine,
dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by reversed-phase
HPLC (YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm) using a MeCN gradient (20-98%) in H2 O + 0.1% HCOOH.
The solvent was removed from product containing fractions. Evaporation of solvents gave the title compound 4-
(6-tert-butyl-3-pyridyl)-3-(2,3-dichlorophenyl)-1,2,4-oxadiazol-5-one (40h, 28.6 mg, 52%) as an off-white powder.


1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.24 (dd, J = 2.6, 0.7 Hz, 1H), 7.60 (dd, J = 8.7, 2.6 Hz, 1H), 7.49
(d, J = 1.6 Hz, 1H), 7.38 - 7.42 (m, 2H), 1.33 (s, 9H). HRMS C17 H15 Cl2 N3 O2 ; calc. for (M+H+ ): 364.0541,
found: 364.06.




                                                           30
N-[(6-tert-butyl-3-pyridyl)methyl]-4-chloro-N-(4-chlorobenzyl)benzenesulfonamide (33h)


                                                        O
                                           N                OH
                  Cl                                        (20 eq.)                          N
                                    N                                   Cl
                            O
                                S                (NH4)2S2O8 (6.0 eq.)                     N
                                    O                                             O
                                                                                      S
                                                  DMSO/H2O (1/0.05)                       O

                                                       (0.05 M)
                       Cl
                                                     40 °C, 18 h             Cl



                            33                                                    33h
                                                                                  (44%)


                                        Figure S22: Alkylation of Fragment 33.

To a solution of 4-chloro-N-(4-chlorobenzyl)-N-(3-pyridylmethyl)benzenesulfonamide (33, 61.1 mg, 0.15 mmol,
1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O, pivalic acid (h, (306.4 mg, 348.2 uL, 3.0 mmol, 20.0 eq.)
and ammonium persulfate (205.4 mg, 0.9 mmol, 6.0 eq.) were added. The reaction mixture was degassed while
bubbling nitrogen through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was
quenched with NaHCO3 solution and extracted with DCM. The combined organic layers were washed with
water, and brine, dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by
reversed-phase HPLC (Gemini NX, 12 nm, 5 um, 100 x 30 mm) using a MeCN gradient (20-98-100%) in H2 O
+ 0.1% HCOOH. The solvent was removed from product containing fractions. Evaporation of solvents gave
the title compound N-[(6-tert-butyl-3-pyridyl)methyl]-4-chloro-N-(4-chlorobenzyl)benzenesulfonamide (40h, 30.8
mg, 44%) as an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.17 - 8.19 (m, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.1 Hz,
2H), 7.36 - 7.38 (m, 1H), 7.16 (d, J = 8.4 Hz, 3H), 7.02 (d, J = 7.9 Hz, 2H), 4.29 (s, 2H), 4.28 (s, 2H), 1.32 (s,
9H). HRMS C23 H24 Cl2 N2 O2 S; calc. for (M+H+ ): 463.0936, found: 463.10.




                                                            31
N-(4-chlorophenyl)-2-cyclobutyl-6-(phenylthio)-4-(trifluoromethyl)nicotinamide (37b1),
N-(4-chlorophenyl)-5-cyclobutyl-6-(phenylthio)-4-(trifluoromethyl)nicotinamide (37b2)


                                Cl           O                                         Cl                        Cl

                                                OH
                                              (20 eq.)                                             O
                   O                                                    O
                       NH            (NH4)2S2O8 (6.0 eq.)                     NH                        NH
                        F                                                      F                         F
              N             F        DMSO/H2O (1/0.05)            N                F         N               F
                        F                                                      F                         F
                                          (0.05 M)                                           S
              S                                                   S
                                         40 °C, 18 h


                  37                                                  37b1                       37b2
                                                                      (10%)                      (7%)


                                        Figure S23: Alkylation of fragment 37.

To a solution of N-(4-chlorophenyl)-6-(phenylthio)-4-(trifluoromethyl)nicotinamide (37, 61.3 mg, 0.15 mmol,
1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O, cyclobutanecarboxylic acid (b, 300.4 mg, 3.0 mmol, 10.0 eq.)
and ammonium persulfate (205.4 mg, 900 umol, 3.00 eq.) were added. The reaction mixture was degassed
while bubbling nitrogen through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture
was quenched with NaHCO3 solution and extracted with DCM. The combined organic layers were washed with
water, and brine, dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by
reversed-phase HPLC (YMC-Triart C18, 12 nm, 5 µm, 100 x 30 mm) using a MeCN gradient (50-20-98%) in
H2 O + 0.1% TEA. The solvent was removed from product containing fractions. Evaporation of solvents gave the
title compounds N-(4-chlorophenyl)-2-cyclobutyl-6-(phenylthio)-4-(trifluoromethyl)nicotinamide (37b1, 11.5 mg,
10%) and N-(4-chlorophenyl)-5-cyclobutyl-6-(phenylthio)-4-(trifluoromethyl)nicotinamide (37b2, 11.5 mg, 7%)
as a mixture (60:40) in an off-white powder.

37b1 & 37b2:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.31 - 8.35 (m, 1H), 8.11 - 8.13 (m, 1H), 7.64 - 7.67 (m, 2H), 7.51 -
7.54 (m, 2H), 7.50 - 7.55 (m, 2H), 7.50 - 7.52 (m, 3H), 7.45 (d, J = 3.8 Hz, 1H), 7.35 - 7.39 (m, 3H), 7.33 (s,
1H), 7.21 - 7.26 (m, 1H), 7.01 (s, 1H), 4.03 - 4.17 (m, 1H), 3.74 - 3.86 (m, 1H), 2.77 - 2.87 (m, 1H), 2.54 - 2.65
(m, 1H), 2.31 - 2.46 (m, 3H), 2.14 - 2.25 (m, 2H), 2.08 - 2.16 (m, 1H), 1.98 - 2.04 (m, 1H), 1.92 - 1.97 (m, 1H),
1.74 - 1.84 (m, 1H). HRMS C23 H18 ClF3 N2 OS; calc. for (M+H+ ): 463.0780, found: 463.08.




                                                            32
N-(4-chlorophenyl)-6-cyclobutyl-2-phenoxy-4-(trifluoromethyl)nicotinamide (29b)


                                     Cl              O                                             Cl
                       F                                                          F
                   F       F                            OH                    F       F
                            HN                        (20 eq.)                            NH

                                 O           (NH4)2S2O8 (6.0 eq.)                              O

                       N    O                                                     N       O
                                             DMSO/H2O (1/0.05)
                                                  (0.05 M)
                                                 40 °C, 18 h


                             29                                                       29b
                                                                                      (22%)

                                     Figure S24: Alkylation of Fragment 29.

To a solution of N-(4-chlorophenyl)-2-phenoxy-4-(trifluoromethyl)nicotinamide (29, 58.9 mg, 0.15 mmol, 1.00 eq.)
in 3 mL degassed DMSO and 5 uL H2 O, cyclobutanecarboxylic acid (b, (300.4 mg, 3.0 mmol, 20.0 eq.) and
ammonium persulfate (205.4 mg, 0.9 mmol, 6.0 eq.) were added. The reaction mixture was degassed while
bubbling nitrogen through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was
quenched with NaHCO3 solution and extracted with DCM. The combined organic layers were washed with
water, and brine, dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by
reversed-phase HPLC (YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm) using a MeCN gradient (20-98%) in H2 O
+ 0.1% HCOOH. The solvent was removed from product containing fractions. Evaporation of solvents gave the
title compound N-(4-chlorophenyl)-6-cyclobutyl-2-phenoxy-4-(trifluoromethyl)nicotinamide (29b, 15.0 mg, 22%)
as an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 7.55 - 7.58 (m, 2H), 7.33 - 7.36 (m, 2H), 7.18 - 7.24 (m, 3H), 7.13 (s,
1H), 3.56 (t, J = 8.4 Hz, 1H), 2.22 - 2.28 (m, 2H), 2.11 - 2.16 (m, 2H), 1.92 - 2.00 (m, 1H), 1.77 - 1.82 (m, 1H).
HRMS C23 H18 ClF3 N2 O2 ; calc. for (M+H+ ): 447.1009, found: 447.10.




                                                         33
6-cyclobutyl-N-[keto-methyl-(p-tolyl)persulfuranylidene]-2-phenoxy-nicotinamide (34b1),
4-cyclobutyl-N-[keto-methyl-(p-tolyl)persulfuranylidene]-2-phenoxy-nicotinamide (34b2)


                                           O

                                              OH
                                            (20 eq.)                                           O     O
              O    O                                               O      O                                       O
                               O                                                       O                      S
                           S       (NH4)2S2O8 (6.0 eq.)                            S       N              N
          N            N                                       N               N
                                   DMSO/H2O (1/0.05)
                                        (0.05 M)
                                       40 °C, 18 h


                  34                                                   34b1                        34b2
                                                                       (15%)                       (4%)


                                      Figure S25: Alkylation of fragment 34.

To a solution of N-[keto-methyl-(p-tolyl)persulfuranylidene]-2-phenoxy-nicotinamide (34, 55.0 mg, 0.15 mmol,
1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O, cyclobutanecarboxylic acid (b, 300.4 mg, 3.0 mmol, 10.0 eq.)
and ammonium persulfate (205.4 mg, 900 umol, 3.00 eq.) were added. The reaction mixture was degassed while
bubbling nitrogen through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was
quenched with NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water,
and brine, dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by reversed-
phase HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm) using a MeCN gradient (20-98-100%) in H2 O + 0.1%
HCOOH. The solvent was removed from product containing fractions. Evaporation of solvents gave the title com-
pounds 6-cyclobutyl-N-[keto-methyl-(p-tolyl)persulfuranylidene]-2-phenoxy-nicotinamide (34b1, 9.7 mg, 15%) as
an off-white powder and 4-cyclobutyl-N-[keto-methyl-(p-tolyl)persulfuranylidene]-2-phenoxy-nicotinamide (34b2,
2.7 mg, 4%) as an off-white powder.

34b1:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.25 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.32 - 7.37 (m,
4H), 7.13 - 7.15 (m, 3H), 6.93 (d, J = 7.7 Hz, 1H), 3.49 - 3.55 (m, 1H), 3.36 (s, 3H), 2.44 (s, 3H), 2.16 - 2.23
(m, 4H), 1.89 - 1.97 (m, 1H), 1.76 - 1.81 (m, 1H). HRMS C24 H24 N2 O3 S; calc. for (M+H+ ): 421.1508, found:
421.15.

34b2:
1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.09 (d, J = 5.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.40 - 7.44 (m, 2H),
7.28 - 7.29 (m, 2H), 7.17 - 7.21 (m, 3H), 7.02 (dd, J = 5.3, 0.7 Hz, 1H), 3.86 - 3.92 (m, 1H), 3.35 (s, 3H), 2.42
(s, 3H), 2.21 - 2.24 (m, 2H), 2.02 - 2.07 (m, 1H), 1.83 - 1.87 (m, 1H). HRMS C24 H24 N2 O3 S; calc. for (M+H+ ):
421.1508, found: 421.15.




                                                          34
2-[(5-methyl-2-pyridyl)methylthio]-4-tetrahydropyran-4-yl-3H-benzo[f]benzimidazole (39u)


                                                              O
                                      N                                                        N
                                                                   OH        O
                          H                           O        (20 eq.)            H
                          N       S                                                N       S
                                                     (NH4)2S2O8 (6.0 eq.)
                              N                                                        N
                                                     DMSO/H2O (1/0.05)
                                                           (0.05 M)
                                                          40 °C, 18 h

                           39                                                          39u
                                                                                       (3%)


                                          Figure S26: Alkylation of Fragment 39.

To a solution of 2-[(5-methyl-2-pyridyl)methylthio]-1H-benzo[f]benzimidazole (39, 45.8 mg, 0.15 mmol, 1.00 eq.)
in 3 mL degassed DMSO and 5 uL H2 O, tetrahydropyran-4-carboxylic acid (u, (390.4 mg, 3.0 mmol, 20.0 eq.)
and ammonium persulfate (205.4 mg, 0.9 mmol, 6.0 eq.) were added. The reaction mixture was degassed while
bubbling nitrogen through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was
quenched with NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water,
and brine, dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by reversed-
phase HPLC (Gemini NX, 12 nm, 5 um, 100 x 30 mm) using a MeCN gradient (20-50-55-100%) in H2 O + 0.1%
HCOOH. The solvent was removed from product containing fractions. Evaporation of solvents gave the title com-
pound 2-[(5-methyl-2-pyridyl)methylthio]-4-tetrahydropyran-4-yl-3H-benzo[f]benzimidazole (39u, 2.0 mg, 3%) as
an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.83 (s, 1H), 8.30 - 8.31 (m, 1H), 7.99 - 8.03 (m, 2H), 7.61 - 7.63 (m,
1H), 7.46 - 7.48 (m, 1H), 7.39 - 7.41 (m, 1H), 7.30 - 7.31 (m, 1H), 4.40 (s, 2H), 4.32 - 4.31 (m, 2H), 4.04 - 4.08
(m, 1H), 3.81 - 3.85 (m, 2H), 2.68 - 2.74 (m, 2H), 2.41 - 2.43 (m, 3H), 1.89 - 1.91 (m, 2H). 13 C NMR (151
MHz, CDCl3 ) δ (ppm) 138.8, 130.9, 129.5, 127.4, 124.1, 123.1, 123.0, 114.1, 60.0, 37.4, 31.0, 18.5. HRMS
C23 H23 N3 OS; calc. for (M+H+ ): 390.1562, found: 390.16.




                                                              35
2-[6-(4-chlorophenoxy)-2-(tetrahydrofuryl)-4-(trifluoromethyl)-3-pyridyl]-5-(4-chlorophenyl)oxazole
(35m)


                    Cl                                                             Cl

                                                                O
                                                          O
                                                                    OH                              O
                    O        N                                   (20 eq.)          O        N

                                          N             (NH4)2S2O8 (6.0 eq.)                            N

                                      O                 DMSO/H2O (1/0.05)                           O
                         F        F                                                     F       F
                             F                                (0.05 M)                      F
                                                            40 °C, 18 h

                                               Cl                                                           Cl

                             35                                                                 35m
                                                                                                (3%)


                                              Figure S27: Alkylation of Fragment 35.

To a solution of 2-[6-(4-chlorophenoxy)-4-(trifluoromethyl)-3-pyridyl]-5-(4-chlorophenyl)oxazole (35, 67.7 mg,
0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and 5 uL H2 O, tetrahydrofuran-2-carboxylic acid (m, (348.5 mg,
3.0 mmol, 20.0 eq.) and ammonium persulfate (205.4 mg, 0.9 mmol, 6.0 eq.) were added. The reaction mixture
was degassed while bubbling nitrogen through it. The reaction mixture was stirred at 40 °C for 18 hr. The
reaction mixture was quenched with NaHCO3 solution and extracted with DCM. The combined organic layers
were washed with water, and brine, dried over Na2 SO4 , filtered and concentrated to dryness. The crude material
was purified by reversed-phase HPLC (Gemini NX, 12 nm, 5 um, 100 x 30 mm) using a MeCN gradient (60-80-
95-100%) in H2 O + 0.1% HCOOH. The solvent was removed from product containing fractions. Evaporation
of solvents gave the title compound 2-[6-(4-chlorophenoxy)-2-(tetrahydrofuryl)-4-(trifluoromethyl)-3-pyridyl]-5--
(4-chlorophenyl)oxazole (35m, 2.0 mg, 3%) as an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 7.60 (d, J = 8.1 Hz, 2H), 7.50 (s, 1H), 7.40 - 7.43 (m, 4H), 7.24 (s,
1H), 7.16 (d, J = 8.4 Hz, 2H), 4.99 (dd, J = 7.6, 5.5 Hz, 1H), 3.76 (td, J = 7.6, 5.7 Hz, 1H), 3.68 (q, J = 7.3 Hz,
1H), 2.02 - 2.08 (m, 1H), 2.01 - 2.18 (m, 1H), 1.79 - 1.87 (m, 2H). 13 C NMR (151 MHz, CDCl3 ) δ (ppm)
163.9, 163.8, 155.3, 151.6, 151.4, 134.7, 130.7, 129.6, 129.3, 126.1, 125.6, 123.3, 123.0, 114.1, 107.6, 78.0, 69.7,
34.3, 32.3, 30.3, 29.7, 26.0 . HRMS C25 H17 Cl2 F3 N2 O3 ; calc. for (M+H+ ): 521.0568, found: 521.06.




                                                                 36
Benzoic acid (4-cyclohexyl-8-quinolyl) ester (41e)


                                                       O
                                                                                   O
                                                           OH
                         O                                                             O
                                                            (20 eq.)                       N
                             O
                                               (NH4)2S2O8 (6.0 eq.)
                                 N
                                               DMSO/H2O (1/0.05)
                                                    (0.05 M)
                                                   40 °C, 18 h

                          41                                                        41e
                                                                                   (3%)

                                     Figure S28: Alkylation of Fragment 41.

To a solution of Benzoic acid 8-quinolyl ester (41, 67.7 mg, 0.15 mmol, 1.00 eq.) in 3 mL degassed DMSO and
5 uL H2 O, cyclohexanecarboxylic acid (e, (384.5 mg, 3.0 mmol, 20.0 eq.) and ammonium persulfate (205.4 mg,
0.9 mmol, 6.0 eq.) were added. The reaction mixture was degassed while bubbling nitrogen through it. The
reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with NaHCO3 solution
and extracted with DCM. The combined organic layers were washed with water, and brine, dried over Na2 SO4 ,
filtered and concentrated to dryness. The crude material was purified by reversed-phase HPLC (Gemini NX,
12 nm, 5 um, 100 x 30 mm) using a MeCN gradient (60-80-95-100%) in H2 O + 0.1% HCOOH. The solvent
was removed from product containing fractions. Evaporation of solvents gave the title compound Benzoic acid
(4-cyclohexyl-8-quinolyl) ester (41e, 1.5 mg, 3%) as an off-white powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.81 (d, J = 4.5 Hz, 1H), 8.36 (dd, J = 8.4, 1.3 Hz, 2H), 8.04 - 8.06
(m, 1H), 7.65 - 7.68 (m, 1H), 7.58 - 7.61 (m, 1H), 7.54 - 7.56 (m, 1H), 7.53 - 7.57 (m, 2H), 7.30 - 7.31 (m, 1H),
3.31 - 3.39 (m, 1H), 2.02 - 2.07 (m, 2H), 1.93 - 1.99 (m, 2H), 1.84 - 1.90 (m, 1H), 1.54 - 1.59 (m, 6H). 13 C NMR
(151 MHz, CDCl3 ) δ (ppm) 165.6, 153.4, 150.6, 148.4, 141.6, 133.5, 130.6, 129.7, 128.5, 125.6, 121.4, 120.9,
118.1, 39.2, 33.7, 27.0, 26.4. HRMS C22 H21 NO2 ; calc. for (M+H+ ): 332.1572, found: 332.16.




                                                       37
7-chloro-4-(4-chloro-3-methyl-phenoxy)-2-cyclohexyl-quinoline (26e)


                                                        O

                                                            OH                                 Cl
                                       Cl
                                                             (20 eq.)
                                                (NH4)2S2O8 (6.0 eq.)                 O
                            O

                                                DMSO/H2O (1/0.05)
                                                     (0.05 M)             Cl         N
                   Cl       N
                                                    40 °C, 18 h


                            26                                                     26e
                                                                                  (22%)


                                    Figure S29: Alkylation of Fragment 26.

To a solution of 7-chloro-4-(4-chloro-3-methyl-phenoxy)quinoline (26, 45.6 mg, 0.15 mmol, 1.00 eq.) in 3 mL
degassed DMSO and 5 uL H2 O, cyclohexanecarboxylic acid (e, 384.5 mg, 3.0 mmol, 20.0 eq.) and ammonium
persulfate (205.4 mg, 0.9 mmol, 6.0 eq.) were added. The reaction mixture was degassed while bubbling nitrogen
through it. The reaction mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched with
NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water, and brine,
dried over Na2 SO4 , filtered and concentrated to dryness. The crude material was purified by reversed-phase
HPLC (Gemini NX, 12 nm, 5 um, 100 x 30 mm) using a MeCN gradient (60-80-95-100%) in H2 O + 0.1%
HCOOH. The solvent was removed from product containing fractions. Evaporation of solvents gave the title
compound 7-chloro-4-(4-chloro-3-methyl-phenoxy)-2-cyclohexyl-quinoline (26e, 12.9 mg, 22%) as an off-white
powder.

1
    H NMR (600 MHz, CDCl3 ) δ (ppm) 8.18 (d, J = 8.9 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.45 (dd, J = 8.9,
2.1 Hz, 1 H), 7.44 (d, J = 8.6 Hz, 1 H), 7.07 - 7.08 (m, 1 H), 6.94 - 6.96 (m, 1 H), 6.46 (s, 1 H), 2.72 - 2.76 (m,
1 H), 2.43 (s, 3 H), 1.86 - 1.92 (m, 2 H), 1.83 - 1.85 (m, 2 H), 1.73 - 1.75 (m, 1 H), 1.46 - 1.50 (m, 2 H), 1.38 -
1.41 (m, 2 H), 1.25 - 1.31 (m, 1 H). HRMS C22 H21 Cl2 NO; calc. for (M+H+ ): 386.1000, found: 386.10.




                                                        38
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                                                         41
