Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods

Transcription

1 Electronic Supplementary Material (ESI) for Chemical Science. This journal is The Royal Society of Chemistry Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods Peter S. Kutchukian, a James F. Dropinski, b Kevin D. Dykstra, c Bing Li, c Daniel A. DiRocco, b Eric C. Streckfuss, c Louis-Charles Campeau, b Tim Cernak, c Petr Vachal, c Ian W. Davies, b Shane Krska* c and Spencer D. Dreher* b a Department of Structural Chemistry, Merck Research Laboratories, Merck and Co., Inc., Boston, MA 02, USA b Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co., Inc., Rahway, J 070, USA c Department of Discovery Chemistry, Merck Research Laboratories, Merck and Co., Inc., Rahway, J 070, USA Table of Contents shane_krska@merck.com spencer_dreher@merck.com Electronic Supplementary Information I. General Information Section - General Experimental Procedures S2 II. General Information Section 2- Principal Component Analyses S III. Experimental Section Comparison of Suzuki-Miyaura Cross Coupling Methods using the Aryl Pinacol Boronate Informer Library S IV. Experimental Section 2 Comparison of Aryl Pinacol Boronate Cyanation Methods using the Aryl Pinacol Boronate Informer Library S7 V. Experimental Section Comparison of Aryl Halide C- coupling Methods using the Aryl Halide Informer Library S27 VI. Experimental Section - Comparison of Informer Library Approach with Fragment-based Robustness Test VII. Appendix. H and C MR Spectra VIII. References. S0 S S S

2 I. General Information Section - General Experimental Procedures All reagents were used as purchased from commercial suppliers. Solvents were purchased from Aldrich, anhydrous, sure-seal quality, and used with no further purification. The reagents and catalysts were purchased from commercial sources and stored in the glovebox. All reactions, including parallel synthesis, were performed inside an MBraun glovebox operating with a constant 2 -purge (oxygen typically < ppm) unless otherwise noted. Reaction experimental design was aided by the use of Accelrys Library Studio. Reactions run at μmol scale for the limiting reagent were carried out in ml glass vials (Analytical Sales, Cat. o. 00, x 0 mm, ml, flat bottom) equipped with magnetic tumble stir bars (V&P Scientific, Cat. o. 7D- and 7- for microvials) in 2-well reaction plates (Analytical-Sales, Cat. o. 22). Reactions run at 2. μmol scale for the limiting reagent were carried out in 20 μl microvials (Analytical Sales, Cat. o. 2) in 2-well reaction microplates (Analytical- Sales, Cat. o. 220). Liquid handling was done using single and multi-channel Eppendorf pipettors (, 0, 0, and 00 μl). n completion of solution dosing the plates were covered by a perfluoroalkoxy alkane (PFA) mat (Analytical-Sales, Cat. o. 7 and 22), followed by two silicon rubber mats (Analytical-Sales, Cat. o. and 222), and an aluminum cover which was tightly and evenly sealed by screws. The scale-up reactions described below were typically run prior to identification of optimal conditions, and no attempt was made to optimize the isolated yield of material. The goal in these experiments was to isolate pure material for characterization and to provide a standard for quantitative LC analysis. Quantitative analysis was accomplished by reverse phase UPLC (Waters X-Bridge TM BEH 2. micron, RP C-, 2. x 0 mm column, eluents: MeC-H 2 containing 0.0% TFA) using an internal standard (either,-di-tert-butyl biphenyl, or,,-trimethoxybenzene as noted in the experiment). Extinction coefficients for LC analysis were determined by first measuring the molar ratio of a mixture of desired product with internal standard by H-MR analysis, then determining the UV absorption for this mixture by running the same mixture on the UPLC method used for analysis. H and C MR spectra were recorded on a Bruker 00 (00 MHz) as noted, and are internally referenced to residual protio solvent signals. Data for H MR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration and coupling constant (Hz). Data for C MR are reported in terms of chemical shift. Mass spectra were obtained from an Agilent LC/MSD TF model GA.

3 II. General Information Section 2- Creation of Small-Molecule Drug Principal Component Analysis. Selection of Compounds for Analysis. To obtain a set of drugs, FDA approved drugs were downloaded from DrugBank (accessed September 2 th, ), and filtered for MW < 0, umber of atoms >, umber of aromatic rings >0, umber of hydrogen bond acceptors, and number of hydrogen bond donors, resulting in,00 unique compounds. To obtains sets of literature compounds, the products reported for the Suzuki (, seminal), Suzuki (0-, evolved) 2,,,,,7, cyanation,,,,2,, and aryl amine coupling,,7,,, were obtained either from SciFinder or generated by hand. For the aryl amine coupling products, we required the coupling of an aryl group with a secondary amine. This resulted in sets of (seminal Suzuki), 227 (evolved Suzuki), (cyanation), and 7 (aryl amine coupling) for literature products. To obtain the informer products sets of 2 (Suzuki), 2 (cyanation), and (aryl amine coupling) products were generated based on the product of the informer library substrate with the corresponding reactant. An SD file containing all drugs, literature products, and informer library products is included as supplementary information. PCA Training: Fourteen physical chemical properties that are often used to assess the drug-like nature of small molecules were computed for each compound: molecular weight, molecular polar surface area, number of atoms, number of positive atoms, number of negative atoms, number of rotatable bonds, number of rings, number of aromatic rings, number of ring assemblies, number of stereo atoms, number of hydrogen bond acceptors, number of hydrogen bond donors, fraction sp, and AlogP. The principle components were calculated in Pipeline Pilot, using the above physical properties to describe each compound. Prior to training the PCA, properties were centered (subtract mean) and scaled (divide by variance). The principle components that captured the most variance were then visualized in Spotfire. The cumulative total variance explained by the principle components were as follows: 7% (PC), % (PC2), 7% (PC), and 7% (PC). The first two principle components were visualized in the main text (Fig 2), and the third and fourth components are visualized below (Fig S). The loadings of the physical properties used to generate the PCA were assessed to assist in the interpretation of the PCA (Fig S2).

4 Figure S. Principal component analysis (PCA) comparing small molecule drugs with products described in synthetic literature reports. Figure SA shows a principle component analysis (PC vs PC) used to visualize the physicochemical space occupied by marketed small molecule drugs compounds (grey) and products described in literature reports for several reaction types evaluated in this work: in red are compounds that were prepared in the seminal Suzuki-Miyaura paper, in blue are the products formed in leading literature Suzuki-Miyaura reports, recent methods reported for the conversion of aryl pinacol boronates into aryl nitriles and recent Buchwald-Hartwig C- coupling methods. Representative structures from both the small molecule drugs collection and literature reports are highlighted. Figures SB-E depict how properties with the greatest contribution to PC and PC are mapped by the PCA, with black representing the highest values for each parameter.

5 Figure S2. The loadings for PC-PC were visualized to help interpret the PCA. We see that by inspecting the magnitudes of the loadings size (molecular weight, number of atoms) and number of hydrogen bond donors contribute the greatest to PC, while hydrophobicity (ALogP and number of aromatic rings) contribute the greates to PC2. The greatest contributions for PC are fractions sp and number of positive atoms while the greatest contributions to PC are from the number of stereo atoms and the number of rotatable bonds. III. Experimental Section Comparison of Suzuki-Miyaura Cross Coupling Methods using the Aryl Pinacol Boronate Informer Library Experimental Procedure for Figure D, Entry. In a nitrogen filled glovebox to ml reaction vials containing aryl pinacol boronates ( µmol), along with, -di-tert-butyl biphenyl ( µmol) internal standard and magnetic stir bars, was added. µl of a solution of - bromo-h-indole (0. M in DME, µmol,. equiv.) then µl of tetrakis(triphenylphosphine)palladium (0.0 M in DME, 0.0 µmol, mol%) was added, followed by µl of a 2 C (.0 M aquoeus, µmol, 2 equiv.). The reaction vials were sealed and stirred at C for 2 hrs. The rxn vials were then cooled to r.t. and diluted with 00 μl of DMS and were stirred vigorously for min. A μl aliquot was removed from each vial and diluted with 700 μl of MeC and quantitative UPLC-MS analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entry 2. In a nitrogen filled glovebox to ml reaction vials containing aryl pinacol boronates ( µmol), along with, -di-tert-butyl biphenyl ( µmol) internal standard and magnetic stir bars, was added. µl of a solution of - bromo-h-indole (0. M in DME, µmol,. equiv.) then µl of [, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, (0.0M in DME, 0.0 µmol, mol%), followed by µl of a 2 C (.0

6 M aqueous, µmol, 2 equiv.). The reaction vials were sealed and stirred at C for 2 hrs. The rxn vials were then cooled to r.t. and diluted with 00 μl of DMS and were stirred vigorously for min. A μl aliquot was removed from each vial and diluted with 700 μl of MeC and quantitative UPLC-MS analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entries -. In a nitrogen filled glovebox to ml reaction vials containing aryl pinacol boronates ( µmol), along with, -di-tert-butyl biphenyl ( µmol) internal standard and magnetic stir bars, was added. µl of a solution of - chloro-h-indole (0. M in THF, µmol,. equiv.) then µl of palladium XPhos G2 precatalyst (0.0 M in THF, 0.0 µmol, mol%) was added, followed by µl of K P (.0 M aqueous, µmol, 2 equiv.). The reaction vials were sealed and stirred at the desired temperature (as noted in Table ) for 2 hrs. The rxn vials were then cooled to r.t. and diluted with 00 μl of DMS and were stirred vigorously for min. A μl aliquot was removed from each vial and diluted with 700 μl of MeC and quantitative UPLC-MS analysis was performed to determine the solution yield. General Procedure A for Suzuki-Miyaura Scale-up Reactions. In a nitrogen filled glovebox, aryl pinacol boronates (0. mmol) and -chloro-h-indole (.2 mg, 0. mmol, equiv.) were combined with palladium XPhos G2 precatalyst ( mg, 0.0 mmol, mol %) in anhydrous THF (0. M overall conc.). To these mixtures, 0 µl (0.0 mmol) of aq. K 2 C (2.0 M aqueous solution, 0. mmol, equiv.) was added and the mixtures were stirred at 0 C overnight. The mixtures were cooled to r.t., diluted with ethyl acetate ( ml), washed with aqueous sodium bicarbonate (saturated, x ml). The organic phase was dried (a₂s₄), filtered and the solvent was evaporated under reduced pressure. The crude mixtures were diluted with 0. ml of DMS, then filter through a filter plate (0. micron) and purified by RP HPLC (Waters Sunfire TM micron RP C-, 0x 0 mm column, eluents: MeC-H2 containing 0.0% TFA). o attempt was made to obtain optimal yield on these experiments, rather to obtain high purity samples for quantitative UPLC analysis. General Procedure B for Suzuki-Miyaura Scale-up Reactions. In a nitrogen filled glovebox, aryl pinacol boronates (0. mmol) and -bromo-h-indole (22.7 mg, 0. mmol) were combined with [, - bis(diphenylphosphino)ferrocene]dichloropalladium(ii) complex with dichloromethane (. mg, mmol, mol%) in anhydrous DME (0. M overall conc.). To these mixtures, 0 ul of a 2 C (2.0 M aqueous solution 0. mmol, 2 equiv.) was added and the mixtures were stirred at C overnight. The mixtures were cooled to r.t., diluted with 0. ml of DMS then filter through a filter plate (0. micron) and purified by RP HPLC (Waters X-bridge TM micron RP C-, 0x 0 mm column, eluents: MeC-

7 H2 containing 0.% H H). o attempt was made to obtain optimal yield on these experiments, rather to obtain high purity samples for quantitative UPLC analysis. -(H-indol--yl)-[,2,]triazolo[,-a]pyridine H Scale-up Method A: obtained. mg white solid (2% yield). H MR (00 MHz, DMS-d ) δ.2 (s, H),.2 (d, J =.7 Hz, H),.2 (d, J =. Hz, H),.0 (dd, J =.,. Hz, H), 7.2 (d, J =. Hz, H), 7.77 (d, J =. Hz, H), 7.7 (d, J =. Hz, H), (m, 2H),.. (m, H). C MR (2 MHz, DMS-d ) δ.,.,., 2.0, 2., 2.7, 27.22, 2.0, 2.2,.7,.,.0,., 0.7. MS ESI [M+H] + calculated for C H 2.0, found (H-indol--yl)--(phenylsulfonyl)-H-pyrrolo[2,-b]pyridine H S Scale-up Method A: obtained 27 mg white solid (72% yield). H MR (00 MHz, DMS-d ) δ. (s, H),. (dd, J =.,. Hz, H),. (dd, J = 7.,.7 Hz, H),. (dd, J = 7.,. Hz, 2H),.2 (s, H), (m, 2H), (m, H), 7. (s, H), (m, 2H),. (t, J = 2. Hz, H). C MR (2 MHz, DMS-d ) δ 7.,.,.0,.7,., 0.0, 2., 2.07, 27., 2.7, 2.0, 22.7, 2., 2., 2.2,.,.2,.7,.2,.. MS ESI [M+H] + calculated for C 2 H 2 S 7.0, found 7..

8 -methyl-h,'h-,'-biindole H Scale-up Method A: obtained.2 mg white solid (% yield). H MR (00 MHz, DMS-d ) δ.02 (s, H), 7. (d, J =.0 Hz, H), 7.7 (d, J =.2 Hz, H), (m, 2H), 7.0 (d, J =.2 Hz, H), (m, 2H), (m, H), 7. (ddd, J =.2,.,. Hz, H),. (s, H),. (s, 2H). C MR (2 MHz, DMS-d ) δ 7.70, 7., 2., 27.0, 2.27, 2., 2., 2.,.7,.,.7,.,.7,.7,.,., 2.. MS ESI [M+H] + calculated for C 7 H 2 2.2, found (2-(-methyl-H-pyrazol--yl)pyrimidin--yl)-H-indole H Scale-up Method A: obtained. mg of a white solid (.7 % yield). H MR (00 MHz, DMS-d ) δ. (s, H),.7 (s, 7H),. (t, J =.2 Hz, H), (m, H), 7.7 (d, J =.7 Hz, H), (m, H),. (d, J =.2 Hz, 2H),. (s, H),. (d, J =.0 Hz, H),.0 (s, H),.2 (s, H), 2.7 (dp, J =.0,. Hz, H), 2. (d, J = 0. Hz, H),.2 (s, H). C MR (2 MHz, DMS-d ) δ.,.7, 2., 27., 27., 2.0, 2.,.,.2,.0,., 0.,.7. MS ESI [M+H] + calculated for C H 27.2 found (H-indol--yl)--(tetrahydro-2H-pyran--yl)-H-benzo[d]imidazole

9 H Scale-up Method A: obtained 2. mg of a white solid as a TFA salt (% yield). H MR (00 MHz, DMS-d ) δ.2 (s, H),. (s, H),. (s, H), (m, 2H), 7.77 (d, J =. Hz, H), 7. (d, J =. Hz, H), (m, 2H),.0 (t, J = 2. Hz, H),..0 (m, H),.0 (dd, J =.,. Hz, 2H),. (s, H),.7. (m, 2H), (m, H). C MR (2 MHz, DMS-d ) δ 0.7,.,., 2., 27.07,.7,.,.,.,.,.0,.2,.7, 2.7. MS ESI [M+H] + calculated for C H 7., found.. -(H-indol--yl)quinolone H Scale-up Method A: obtained. mg of a off white solid as a TFA salt (% yield). H MR (00 MHz, DMS-d ) δ. (s, H),.2 (d, J = 2. Hz, H),. (d, J = 2. Hz, H),.7 (dd, J =.,. Hz, H),.2 (d, J =. Hz, H), 7. (d, J =. Hz, H), 7. (ddd, J =.,.,. Hz, H), 7.7 (t, J = 7.7 Hz, 2H), 7. (dd, J =.2,.7 Hz, H), (m, H),. (t, J = 2.2 Hz, H). C MR (2 MHz, DMS-d ) δ.0,.,.0, 2.00, 2., 2.2, 2., 27.2, 2.,.,.70,.. MS ESI [M+H] + calculated for C 7 H , found (H-indol--yl)--phenylbenzo[d]thiazol-2-amine

10 H S H Scale-up Method A: obtained. mg of a white solid as a TFA salt (2% yield). H MR (00 MHz, DMS-d ) δ. (s, 2H),. (s, H), (m, H), (m, 7H), (m, H), 7. (td, J = 7.,. Hz, H),. (t, J = 2. Hz, H), 2. (p, J =. Hz, H). C MR (2 MHz, DMS-d ) δ 7.,.0, 7.02,.22,., 2.22, 27., 2., 2.,.0,.,.,.,., 7.,.,., 0.7,.,.2. MS ESI [M+H] + calculated for C 2 H S. found, 2.. -(H-indol--yl)--methyl-H-carbazole H Scale-up Method A: obtained. mg of a white solid as a TFA salt ( % yield). H MR (00 MHz, DMS-d ) δ.2 (s, H),. (d, J =. Hz, H),.2 (d, J = 7. Hz, H), 7. (dd, J =.,. Hz, H), 7.7 (d, J =. Hz, H), (m, H), (m, 2H), (m, H), 7.2 (t, J = 7. Hz, H),.. (m, H),.2 (s, H). C MR (2 MHz, DMS-d ) δ., 0.2, 7.,.,., 2.7, 2.2, 2., 2., 2., 22.7,.,.7,.,.,.,.,.,., 2.. MS ESI [M+H] + calculated for C 2 H 2 2., found 2.. -(H-indol--yl)phenyl)--methyl-,2,-oxadiazole H Scale-up Method B: obtained. mg of a white solid (.7 % yield).

11 H MR (00 MHz, DMS-d ) δ.2 (s, H),.27 (s, 2H),.27 (d, J =. Hz, H), 7. (ddt, J =., 7.,. Hz, H), (m, H), (m, 7H), 7. (t, J = 2.7 Hz, H), 7. (dd, J =.2,.7 Hz, H),. (s, 2H),. (d, J =. Hz, H), 2.7 (s, 7H). C MR (2 MHz, DMS-d ) δ 77.,.7, 2.,., 2., 0., 0., 2.02, 27., 27.0, 2., 2., 2.,.,.0,., 0.7, 2.. MS ESI [M+H] + calculated for C 7 H 27., found (-fluoro--(h-indol--yl)pyridin--yl)morpholine H F Scale-up Method A: obtained 2 mg of a white solid as a TFA salt (72% yield). H MR (00 MHz, DMS-d ) δ.2 (s, H),.0 (d, J =. Hz, H), (m, 2H), 7.7 (t, J = 2. Hz, H), 7.2 (dt, J =.2,. Hz, H), 7.0 (t, J =. Hz, H),.. (m, H),..7 (m, H),..7 (m, H). C MR (2 MHz, DMS-d ) δ 2.,.2, 2., 27., 2.0,.,.22,.0, 2., 2.,.,.,.0,., 0.7,.. F MR (70 MHz, DMS-d ) δ -7. MS ESI [M+H] + calculated for C 7 H F 27. found (-(-((-chlorophenyl)sulfonyl)piperazin--yl)pyridin--yl)-h-indole H Cl S Scale-up Method B: obtained 2 mg of a white solid (2% yield). H MR (00 MHz, DMS-d ) δ. (s, H),. (d, J = 2. Hz, H), (m, H), (m, 2H), (m, H), 7.2 (dd, J =.2,.7 Hz, H),.2 (d, J =. Hz, H),. (s, H),..2 (m, H),.0 (t, J =. Hz, H). C MR (2 MHz, DMS-d ) δ 7.7,.70,., 7.0,.2,.2, 0., 2.7, 27.2, 2.7,.,.0,.,.00,.0,.00,.72, 0.7. MS ESI [M+H] + calculated for C 2 H 2 Cl 2 S 2., found..

12 -(-(H-tetrazol--yl)phenyl)-H-indole H H Scale-up Method A: obtained 2 mg of a white solid (.% yield). H MR (00 MHz, DMS-d ) δ.2 (s, H),. (d, J =. Hz, H),. (s, 2H), 7. (dt, J = 7.,. Hz, H), 7.0 (dt, J = 7.,. Hz, H), 7.7 (d, J =. Hz, H), 7.7 (d, J =. Hz, H), 7.2 (t, J = 7.7 Hz, H), (m, H),. (d, J = 2. Hz, 2H). C MR (2 MHz, DMS-d ) δ 7., 2.,.,.0, 0., 2.7, 27., 27.7, 2., 2.2, 2., 2.0,.,.7,., 0.,.. MS ESI [M+H] + calculated for C H 2., found ([2,'-bipyridin]--yl)-H-indole H Scale-up Method A: obtained mg of a white solid as a TFA salt (2% yield). H MR (00 MHz, DMS-d ) δ.0 (s, H),. (d, J = 2.2 Hz, H),. (d, J = 2. Hz, H),.0.7 (m, 2H),.2 (dd, J =., 2. Hz, H),.22 (d, J =. Hz, H), (m, 2H), 7.7 (d, J =. Hz, H), (m, 2H),.. (m, H). C MR (2 MHz, DMS-d ) δ.7,.2, 7.,.,.72,.7, 2., 2., 27.0, 2., 2., 2.0,.,.2,.0. MS ESI [M+H] + calculated for C H 27., found (-cyclopropyl--(h-indol--yl)phenyl)thiazole

13 H S Scale-up Method A: obtained. mg of a white solid as a TFA salt (2% yield). H MR (00 MHz, DMS-d ) δ.0 (s, H),. (d, J = 2.2 Hz, H),. (d, J = 2. Hz, H),.0.7 (m, 2H),.2 (dd, J =., 2. Hz, H),.22 (d, J =. Hz, H), (m, 2H), 7.7 (d, J =. Hz, H), (m, 2H),.. (m, H). C MR (2 MHz, DMS-d ) δ.7,.2, 7.,.,.72,.7, 2., 2., 27.0, 2., 2., 2.0,.,.2,.0. MS ESI [M+H] + calcd for C H 2 S., found 7.. -(H-indol--yl)-,-naphthyridine H Scale-up Method A: obtained 7. mg of a white solid as a TFA salt (72% yield). H MR (00 MHz, DMS-d ) δ. (s, H),. (d, J = 2. Hz, H),.07 (dd, J =.2,. Hz, H),. (d, J = 2. Hz, H),.0 (dd, J =.,. Hz, H), 7. (d, J =. Hz, H), 7. (dd, J =.,.2 Hz, H), 7.7 (d, J =. Hz, H), 7. (dd, J =.,. Hz, H), 7. (t, J = 2. Hz, H),.. (m, H). C MR (2 MHz, DMS-d ) δ 2.0,.2,., 2.2,.2, 7.2,., 2.7, 2., 2., 27.7, 2.7, 2.,.0,.0,.,.. MS ESI [M+H] + calculated for C H 2., found (-(,-dimethyl-h-pyrazol--yl)phenyl)-h-indole

14 H Scale-up Method A: obtained.7 mg of a white solid as a TFA salt (% yield). H MR (00 MHz, DMS-d ) δ.2 (s, 2H), (m, H), (m, H), (m, H), (m, H),.7 (s, 2H),. (s, 2H), 2. (s, H), 2. (d, J =. Hz, H), 2.2 (s, 7H). C MR (2 MHz, DMS-d ) δ.27,.0,.,., 2.2, 27., 2., 2.0,.,.,., 7.,., 0.7,., 2.7. MS ESI [M+H] + calculated for C H 7 27., found (-(2-(-(H-indol--yl)phenoxy)ethyl)-H-,2,-triazol--yl)propan-2-ol H H Scale-up Method A: obtained 2.2 mg of a white solid as a TFA salt (% yield). H MR (00 MHz, DMS-d ) δ. (s, H), 7. (s, H), (m, H), (m, H), 7.2 (dd, J =.0,. Hz, H), (m, 2H),. (t, J = 2. Hz, H),. (s, H),.7 (t, J =.2 Hz, 2H),. (t, J =.2 Hz, 2H),.2 (d, J = 7. Hz, H),.7 (s, H). C MR (2 MHz, DMS-d ) δ 7.,.0, 7.02,.22,., 2.22, 27., 2., 2.,.0,.,.,.,., 7.,.,., 0.7,.,.2. MS ESI [M+H] + calculated for C 2 H , found.2. -(H-indol--yl)--methyl-H-imidazo[,-b]pyridine

15 H Scale-up Method A: obtained mg of a white solid as a TFA salt (% yield). H MR (00 MHz, DMS-d ) δ.2 (s, H),..7 (m, 2H),. (d, J = 2. Hz, H), (m, 2H), (m, 2H),. (t, J = 2. Hz, H),. (s, H). C MR (2 MHz, DMS-d ) δ.27,., 7.00,.7,., 27.7, 2., 2., 2.,.0,.,.,., 0.. MS ESI [M+H] + calculated for C H 2 2., found (-(pyrazin-2-yl)phenyl)-h-indole H Scale-up Method A: obtained. mg of a white solid (.% yield). H MR (00 MHz, DMS-d ) δ.2 (s, 0H),.2 (d, J =. Hz, H),..7 (m, 0H),.7. (m, 0H),.2.22 (m, H), (m, H), 7.7 (s, 0H), 7. (d, J =.2 Hz, 0H), (m, H),.2. (m, 0H),..0 (m, 2H). C MR (2 MHz, DMS-d ) δ.7,.0,.,., 2.7,.,., 2.0, 2.0, 27., 27., 27.0, 2.02,.7,.,.,.. MS ESI [M+H] + calculated for CH 27., found (-cyclobutyl--(trifluoromethyl)pyridin--yl)-h-indole H F F F Scale-up Method A: obtained 22. mg of a white solid as a TFA salt (70.% yield).

16 H MR (00 MHz, DMS-d ) δ.2 (s, H),. (d, J = 2.2 Hz, H),.2 (d, J = 2. Hz, H), (m, H), 7. (d, J =. Hz, H), (m, 2H),.0 (s, H),.7 (p, J =. Hz, H),. (d, J =. Hz, 0H), (m, 2H), 2.2 (qt, J =., 2. Hz, 2H), (m, H),.. (m, H). C MR (2 MHz, DMS-d ) δ.7, 0.0,.7,.,., 2., 2., 27.7, 2.2,.,.,., 0.7,.7, 2.2, 7.. F MR (70 MHz, DMS-d ) δ -. MS ESI [M+H] + calculated for C H F 2.2, found 7.. -(H-indol--yl)--(tetrahydrofuran--yl)benzamide H H Scale-up Method A: obtained. mg of a white solid (27. % yield). H MR (00 MHz, DMS-d ) δ.2 (s, H),. (d, J =. Hz, H), (m, 2H), (m, 2H), 7.7 (d, J =. Hz, H), 7. (d, J =. Hz, H), (m, 2H),.7 (s, H),.. (m, H),. (td, J =.,. Hz, 2H),.7 (td, J =.,. Hz, H),. (dd, J =.,. Hz, H), 2. (dtd, J = 2.7, 7.,.7 Hz, H), 2.0. (m, H). C MR (2 MHz, DMS-d ) δ.,.7,., 2., 2., 2.07, 27.0, 2.7,.,.7,.,., 72., 7.0, 0.7, 0.7, 2.. MS ESI [M+H] + calculated for CH22 0., found (-(H-indol--yl)pyridin-2-yl)acetonitrile H Scale-up Method A: obtained. mg of a white solid as a TFA salt (2.% yield). H MR (00 MHz, DMS-d ) δ.2 (s, H),.0 (d, J = 2.2 Hz, H),. (dd, J =.2, 2. Hz, H), (m, 2H), 7.0 (d, J =.2 Hz, H), (m, H), 7. (dd, J =.,. Hz, H),.. (m, H),.2 (s, 2H).

17 C MR (2 MHz, DMS-d ) δ.2, 7.,.,.,.72, 2.7, 2., 27., 2.2, 2.2,.7,.,., 0., MS ESI [M+H] + calculated for C H 2., found 2.2. benzyl (-(-(H-indol--yl)phenyl)cyclopropyl)carbamate H H Scale-up Method A: obtained. mg of a white solid (.% yield). H MR (00 MHz, DMS-d ) δ. (s, H),.22 (s, H), 7.2 (d, J =. Hz, 2H), (m, 2H), (m, 7H), 7. (dt, J = 7.,.2 Hz, H),.0 (s, 2H),.2. (m, H). C MR (2 MHz, DMS-d ) δ., 2.02, 7.,.7,., 2.0, 2.2, 2.22, 2.2, 27., 2.2, 2.7, 2.02, 2.,.,.2,.,.,.2,.2,.. MS ESI [M+H] + calculated for C 2 H , found.. benzyl 2-(H,'H-[,'-biindole]--carbonyl)pyrrolidine--carboxylate H H Scale-up Method A: obtained. mg of a white solid (. % yield). H MR (00 MHz, DMS-d ) δ. (d, J =. Hz, H),.. (m, H),. (d, J = 7. Hz, H), (m, H), 7. (d, J =.0 Hz, H), (m, H), (m, 7H), 7.0 (q, J = 7., 7.0 Hz, H),. (d, J = 2. Hz, H),.2 (ddd, J = 2.0,.,. Hz, H),.. (m, H),

18 . (d, J =.2 Hz, 2H),.0. (m, H), (m, H), 2.0. (m, 2H),. (qd, J =., 7.7,.0 Hz, H). C MR (2 MHz, DMS-d) δ.22,.,.2, 7., 7., 7.,.0,.77, 2., 2., 2.22, 27., 27.72, 27., 27., 2., 2., 2.2, 22.,.7,.,.7,.07,.2, 2.,.,.,.2,., 2., 2.0, 7.7, 7.0, 2.,.2, 2., 2.7. MS ESI [M+H] + calculated for C 2 H 2., found.7. Experimental Section 2 Comparison of Aryl Pinacol Boronate Cyanation Methods using the Aryl Pinacol Boronate Informer Library Experimental Procedure f o r Figure D, Entry. In a fume-hood under air, to ml reaction vials containing aryl pinacol boronates ( µmol) equipped with magnetic stir bars and containing potassium carbonate (.2 mg, 0.0 µmol, equiv.) was added 0 ul of a solution of CuC (0. M in DMF,.0 µmol, equiv.). The mixture was stirred at 0 C for 2 hours, then was cooled to room temperature and quenched with 00 ml quench solution :: of DMF/MeH/DCE.,'-di-tert-butyl-,'-biphenyl internal standard (0. M in DCE,.0 µmol, equiv.) was then added to each well, and this was stirred at RT for 2 two hours. µl from each reaction was diluted in 00 µl in AC and quantitative UPLC- MS analysis was performed to determine the solution yield. Experimental Procedure f o r Figure D, Entry 7. In a fume-hood under air, to ml reaction vials containing aryl pinacol boronates ( µmol) equipped with magnetic stir bars was added a solution of CuI (0.M in DMA,.0 µmol,. equiv.). The mixture was stirred at 0 C for hours, then was cooled to room temperature and quenched with 00 ml quench solution :: of DMF/MeH/DCE.,'- di-tert-butyl-,'-biphenyl internal standard (0. M in DCE,.0 µmol, equiv.) was then added to each well, and this was stirred at RT for 2 two hours. µl from each reaction was diluted in 00 µl in AC and quantitative UPLC-MS analysis was performed to determine the solution yield. Experimental Procedure f o r Figure D, Entry. In a fume-hood under air, to ml reaction vials containing aryl pinacol boronates ( µmol) equipped with magnetic stir bars was added a mixture of Cu( ) 2 (0.2 M,.0 µmol, 2 equiv.), CsF (0. M,.0 µmol, equiv.) and Zn(C) 2 (0. M, 0.0 µmol, equiv) in MeH/ water (7: ratio). The mixture was stirred at 0 C for hours, then was cooled to room temperature and quenched with 00 ml quench solution :: of DMF/MeH/DCE.,'- di-tert-butyl-,'-biphenyl internal standard (0. M in DCE,.0 µmol, equiv.) was then added to each

19 well, and this was stirred at RT for 2 two hours. µl from each reaction was diluted in 00 µl in AC and quantitative UPLC-MS analysis was performed to determine the solution yield. Experimental Procedure f o r Figure D, Entry. In a fume-hood under air, to ml reaction vials containing aryl pinacol boronates ( µmol) equipped with magnetic stir bars was added a mixture of Cu( ) 2 (0.2 M,.0 µmol, 2 equiv.), CsF (0. M,.0 µmol, equiv.) and Zn(C) 2 (0. M, 0.0 µmol, equiv) in MeH/ water (7: ratio). The mixture was stirred at 70 C for hours, then was cooled to room temperature and quenched with 00 ml quench solution :: of DMF/MeH/DCE.,'- di-tert-butyl-,'-biphenyl internal standard (0. M in DCE,.0 µmol, equiv.) was then added to each well, and this was stirred at RT for 2 two hours. µl from each reaction was diluted in 00 µl in AC and quantitative UPLC-MS analysis was performed to determine the solution yield. Experimental Procedure f o r Figure D, Entry. In a fume-hood under air, to ml reaction vials containing aryl pinacol boronates ( µmol) equipped with magnetic stir bars was added a mixture of Cu( ) 2 (0.2 M,.0 µmol, 2 equiv.), CsF (0. M,.0 µmol, equiv.) and Zn(C) 2 (0. M, 0.0 µmol, equiv) in MeH/ water (7: ratio). The mixture was stirred at 0 C for hours, then was cooled to room temperature and quenched with 00 ml quench solution :: of DMF/MeH/DCE.,'- di-tert-butyl-,'-biphenyl internal standard (0. M in DCE,.0 µmol, equiv.) was then added to each well, and this was stirred at RT for 2 two hours. µl from each reaction was diluted in 00 µl in AC and quantitative UPLC-MS analysis was performed to determine the solution yield. Experimental Procedure f o r Figure D, Entry. In a fume-hood under air, to ml reaction vials containing aryl pinacol boronates ( µmol) equipped with magnetic stir bars was added a mixture of Cu( ) 2 (0.2 M,.0 µmol, 2 equiv.), CsF (0. M,.0 µmol, equiv.) and Zn(C) 2 (0. M, 0.0 µmol, equiv) in DMF/ MeH/ water (:: ratio). The mixture was stirred at 70 C for hours, then was cooled to room temperature and quenched with 00 ml quench solution :: of DMF/MeH/DCE.,'-di-tert-butyl-,'-biphenyl internal standard (0. M in DCE,.0 µmol, equiv.) was then added to each well, and this was stirred at RT for 2 two hours. µl from each reaction was diluted in 00 µl in AC and quantitative UPLC-MS analysis was performed to determine the solution yield. Experimental Procedure f o r Figure D, Entry 2. In a fume-hood under air, to ml reaction vials containing aryl pinacol boronates ( µmol) equipped with magnetic stir bars was added a mixture of Cu( ) 2 (0.2 M,.0 µmol, 2 equiv.), CsF (0. M,.0 µmol, equiv.) and Zn(C) 2 (0. M, 0.0 µmol, equiv) in in DMF/ MeH/ water (:: ratio). The mixture was stirred at 0 C for hours, then was cooled to room temperature and quenched with 00 ml quench solution :: of DMF/MeH/DCE.,'-di-tert-butyl-,'-biphenyl internal standard (0. M in DCE,.0 µmol, equiv.)

20 was then added to each well, and this was stirred at RT for 2 two hours. µl from each reaction was diluted in 00 µl in AC and quantitative UPLC-MS analysis was performed to determine the solution yield. General Procedure for B o ronate Cyanation Scale-up Reactions. Aryl pinacol boronate (0.0 g, 0. mmol) was added to a stirred, cooled room temperature mixture of CsF (0.0 g, 0.0 mmol), Zn(C) 2 (0.0 g, 0.00 mmol) and Cu( ) 2 (0.0 g, 0.0 mmol) in DMF (.0 ml), water (0.0 ml) and methanol (0. ml) and then the mixture was stirred at 70 C for overnight. The mixture was cooled, diluted with ethyl acetate (2 ml), washed with water ( x 2 ml), and the solvent was evaporated under reduced pressure. The reactions were then diluted with 0. ml DMS, filtered through filter plate (0. micron) and submit to High Througput Purifcation group (HTP) for mass triggered reverse phase HPLC purification. -(phenylsulfonyl)-h-pyrrolo[2,-b]pyridine--carbonitrile: S C Scale-up Isolated yield:.% H MR (00 MHz, DMS-d ) δ.0 (s, H),. (dd, J =.,. Hz, H),.0. (m, H), 7.0 (t, J = 7. Hz, H), 7. (t, J = 7. Hz, 2H), 7.0 (dd, J =.,. Hz, H). C MR (2 MHz, DMS-d ) δ 7.2,.,.0,.2,.07, 0., 2.77, 2.2, 2.,.,.70, 0.. [M+H] + calculated for 2.07; found 2.0 -methyl-h-indole--carbonitrile: C Scale-up Isolated yield: 2.%

21 H MR (00 MHz, DMS-d ) δ.2 (s, H), (m, 2H), (m, H), (m, H),. (s, H). C MR (2 MHz, DMS-d ) δ 2.0, 2.2,.,.,.2,.,.7,.0. [M+H]+ calculated for.07; found.07 -(tetrahydro-2h-pyran--yl)-h-benzo[d]imidazole--carbonitrile: C Scale-up Isolated yield: 2.% H MR (00 MHz, DMS-d ) δ.7 (s, H),.7 (s, H), 7. (s, H), 7. (d, J =.7 Hz, H),.7 (tt, J =.7,. Hz, H),.0 (dd, J =.,. Hz, 2H),. (td, J =., 2. Hz, 2H), (m, H). C MR (2 MHz, DMS-d ) δ 2.0, 2.2,.,.,.2,.,.7, 2.2,.0. [M+H]+ calculated for 227.2; found Quinoline--carbonitrile: C Scale-up Isolated yield: 2.% H MR (00 MHz, DMS-d ) δ. (d, J = 2. Hz, H),. (d, J = 2. Hz, H),.2.0 (m, 2H),.00 (ddd, J =.,.,. Hz, H), 7.0 (t, J = 7. Hz, H). C MR (2 MHz, DMS-d ) δ 0.,., 2.,., 2., 2., 2., 2., 7.2,.0. [M+H]+ calculated for.002; found.0. -(benzo[d]thiazol-2-ylamino)benzonitrile:

22 H S C Scale-up Isolated yield: 2.% H MR (00 MHz, DMS-d ) δ.02 (s, H), (m, 2H), 7. (dd, J = 7.7,.2 Hz, H), (m, 2H), 7.70 (d, J = 7. Hz, H), 7. (td, J = 7.,. Hz, H), (m, H). C MR (2 MHz, DMS-d ) δ., 2.0,.2,., 0., 2.0, 2.2, 2.7,.,.,.,.7. [M+H]+ calculated for 2.07; found methyl-h-carbazole--carbonitrile: C Scale-up Isolated yield:.% H MR (00 MHz, DMS-d ) δ.7 (d, J =. Hz, H),..7 (m, H), (m, 2H), 7.70 (d, J =. Hz, H), (m, H), (m, H),. (s, H). C MR (2 MHz, DMS-d ) δ 2.0,.7, 2.2, 27., 2., 22., 2.,.,.2,.,., 0.0. [M+H]+ calculated for.0; found.0. -(-methyl-,2,-oxadiazol--yl)benzonitrile: C Scale-up Isolated yield:.% H MR (00 MHz, DMS-d ) δ.2.2 (m, 2H),.0 (dd, J = 7.7,. Hz, H), 7.0 (t, J =.0 Hz, H), 2.7 (s, H). C MR (2 MHz, DMS-d ) δ 7.0,.7,.0,.,., 0.7, 2.02,.,.0, 2..

23 [M+H]+ calculated for.0; found.0. -fluoro-2-morpholinoisonicotinonitrile: C F Scale-up Isolated yield: 2.% H MR (00 MHz, DMS-d ) δ. (d, J =. Hz, H), 7.2 (dd, J =.0,. Hz, H),.. (m, H),.7. (m, H). C MR (2 MHz, DMS-d ) δ.,.,.0,.2,.7,.77,., 7.7. [M+H]+ calculated for ; found (-((-chlorophenyl)sulfonyl)piperazin--yl)nicotinonitrile: C S Cl Scale-up Isolated yield:.7% H MR (00 MHz, DMS-d ) δ.7 (d, J = 2. Hz, H), 7. (dd, J =., 2. Hz, H), (m, 2H), (m, 2H),.2 (d, J =. Hz, H),..7 (m, H),.02 (t, J =. Hz, H). C MR (2 MHz, DMS-d ) δ., 2., 0.,.7,.27, 0., 2.,., 7.2,.,.7,.7. [M+H]+ calculated for 2.002; found 2.0. [2,'-bipyridine]--carbonitrile: C Scale-up Isolated yield:.% H MR (00 MHz, DMS-d ) δ.7 (d, J = 2. Hz, H),.7 (d, J = 2.0 Hz, H),.7 (dd, J =.,. Hz, H),. (dt, J =.0, 2. Hz, H),. (dd, J =., 2.0 Hz, H),. (d, J =. Hz, H), 7. (dd, J =.0,. Hz, H).

24 C MR (2 MHz, DMS-d ) δ 7.,.22,.,.,.7,.,., 2., 2.2, 7.,.70. [M+H]+ calculated for.07; found.0. -cyclopropyl--(thiazol--yl)benzonitrile: C S Scale-up Isolated yield: 2.% H MR (00 MHz, DMS-d ) δ. (s, H),. (s, H), 7.7 (t, J =. Hz, H), 7.7 (t, J =.7 Hz, H), 7.2 (t, J =. Hz, H), 2.0 (tt, J =.,. Hz, H),.0 0. (m, 2H), (m, 2H). C MR (2 MHz, DMS-d ) δ.,.7, 7.0, 2., 2.2, 27.2,., 2.,.2,.0. [M+H]+ calculated for 22.0; found 22.0.,-naphthyridine--carbonitrile C Scale-up Isolated yield:.% H MR (00 MHz, DMS-d ) δ. (d, J = 2.0 Hz, H),.2. (m, 2H),.7. (m, H), 7. (dd, J =.,.2 Hz, H). C MR (2 MHz, DMS-d ) δ.,.0,.2,.0,.0, 7.7, 27., 7.,.72. [M+H]+ calculated for.072; found.0. -(,-dimethyl-h-pyrazol--yl)benzonitrile: C

25 Scale-up Isolated yield: 2.% H MR (00 MHz, DMS-d ) δ.0 7. (m, 2H), (m, 2H),. (s, H), 2.0 (s, H), 2. (s, H). C MR (2 MHz, DMS-d ) δ.,., 0.,.0, 2.0,.7,.0,.2,.7,.0. [M+H]+ calculated for 7.027; found 7.. -(2-(-(2-hydroxypropan-2-yl)-H-,2,-triazol--yl)ethoxy)benzonitrile: C H Scale-up Isolated yield: 2.% H MR (00 MHz, DMS-d ) δ 7. (s, H), (m, 2H), (m, 2H),.0 (s, H),.7 (t, J =. Hz, 2H),.2 (t, J =. Hz, 2H),. (s, H). C MR (2 MHz, DMS-d ) δ.0,.2,.7, 2.,.7,.,., 7.0, 7.2,.07,.. [M+H]+ calculated for ; found methyl-h-imidazo[,-b]pyridine--carbonitrile: C Scale-up Isolated yield:.% H MR (00 MHz, DMS-d ) δ.2 (d, J =. Hz, H),.72. (m, 2H),. (s, H). C MR (2 MHz, DMS-d ) δ.7,., 7.,.2,.,., 2.77, 0.2. [M+H]+ calculated for.022; found.0. -(pyrazin-2-yl)benzonitrile: C

26 Scale-up Isolated yield: 7.0% H MR (00 MHz, DMS-d ) δ. (d, J =. Hz, H),.0 (dd, J = 2.,. Hz, H),.72 (d, J = 2. Hz, H),.. (m, 2H),.0 (d, J =. Hz, 2H). C MR (2 MHz, DMS-d ) δ 0.0,.,.0,.2, 0.,., 27.,.0, 2.2. [M+H]+ calculated for.07; found.0. -cyano--(tetrahydrofuran--yl)benzamide: H C Scale-up Isolated yield:.% H MR (00 MHz, DMS-d ) δ.7 (d, J =. Hz, H),.0 7. (m, 2H), (m, 2H),.7 (dtt, J =.2,.,. Hz, H),..7 (m, 2H),.7 (td, J =.2,. Hz, H),. (dd, J =.0,.2 Hz, H), (m, H),.. (m, H). C MR (2 MHz, DMS-d ) δ.,.7, 2.0, 2.72,.2,.0, 72.,.7, 0.7, [M+H]+ calculated for 2.077; found 2.0. Benzyl (-(-cyanophenyl)cyclopropyl)carbamate: H C Scale-up Isolated yield:.2% H MR (00 MHz, DMS-d ) δ.2 (s, H), (m, H), (m, H), 7.7 (hept, J = 7.,. Hz, H),.0 (s, 2H),.0. (m, H). C MR (2 MHz, DMS-d ) δ.,., 7., 0.07, 2.7, 2., 2., 2., 2.2, 2.,.0,.,.,.,.. [M+H]+ calculated for ; found Benzyl (R)-2-(-cyano-H-indole--carbonyl)pyrrolidine--carboxylate:

27 C H Scale-up Isolated yield:.% H MR (00 MHz, DMS-d ) δ 2. (s, 2H),. (s, H),. (s, H),.7.2 (m, 2H), 7. (dd, J =.,.0 Hz, 2H), 7. (ddd, J =.,.,. Hz, 2H), 7. (s, 2H), (m, H), 7..7 (m, H),.2 (ddd, J =.,.,. Hz, 2H),..0 (m, 2H),. (d, J =. Hz, H),. (d, J =. Hz, H),. (dddd, J = 7.7,.,.,. Hz, H), (m, 2H),.0 (dh, J = 7.,. Hz, 7H). C MR (2 MHz, DMS-d ) δ.,., 7.2,.,.0, 2., 2.27, 2.2, 27.0, 27.7, 27.2, 2., 2.,.7,.0,.22,.,.0,., 2., 2., 7.7, 7.07, 2.07,.02, 2., 2.. [M+H] + calculated for: 7.2; found 7.. V. Experimental Section Comparison of Aryl Halide C- coupling Methods using the Aryl Halide Informer Library Experimental Procedure for Figure D, Entry. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides 2,22,2,2,2,2,27,2,2,0,,2,,,,,7, (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, µl of (o-tol) P) 2 PdCl 2 (0.02M in toluene, 0.2 µmol, mol%) was added. Then a µl mixture of piperidine (0.2M,.7 µmol,. equiv.) and atbu (0.M, 7. µmol, equiv.) in toluene was added to the reaction vials. The reaction vials were sealed and stirred at 0 C for hrs. The reaction vials were then cooled to r.t. and diluted with 0 μl of % AcH in DMS containing,,-trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entry 2. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, µl of J-00 ligand (0.02M in DME, 0.2 µmol, mol%) and µl Pd(Ac) 2 (0.02M in DME, 0.2 µmol, mol%) was added. Then a µl mixture of of piperidine (0.2M,.7 µmol,. equiv.) and atbu (0.M, 7. µmol, equiv.) in DME was added to the reaction vials. The reaction vials were sealed and stirred at 0 C for hrs. The reaction vials were then cooled to r.t. and diluted

28 with 0 μl of % AcH in DMS containing,,-trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entry. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, µl of [,-Bis(2,-di-isopropylphenyl)-,-dihydroimidazol-2-ylidene]chloro][-phenylallyl] palladium(ii) (0.02M in DME, 0.2 µmol, mol%) was added. Then a µl mixture of piperidine (0.2M,.7 µmol,. equiv.) and KtBu (0.M, 7. µmol, equiv.) in DME was added to the reaction vials. The reaction vials were sealed and stirred at room temperature for hrs. The reaction vials were then diluted with 0 μl of % AcH in DMS containing,,-trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entry. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, 2. µl of RuPHS G2 biaryl Pd precatalyst (0.02M in dioxane, 0.2 µmol, mol%) was added. Then a solution of 2. µl of piperidine (0.M,.7 µmol,. equiv.) and LiHMDS (0.M, 7. µmol, equiv.) in dioxane was added to the reaction vials. The reaction vials were sealed and stirred at 0 C for hrs. The reaction vials were then diluted with 0 μl of % AcH in DMS containing,,- trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entry. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, 2. µl of RuPHS G2 biaryl Pd precatalyst (0.02M in tbuh, 0.2 µmol, mol%) was added. Then a mixture of 2. µl of piperidine (0.M,.7 µmol,. equiv.) and K 2 C (0.M, 7. µmol, equiv.) in tbuh was added to the reaction vials. The reaction vials were sealed and stirred at 0 C for hrs. The reaction vials were then diluted with 0 μl of % AcH in DMS containing,,- trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entry. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir

29 bars, 2. µl of RuPHS G2 biaryl Pd precatalyst (0.02M in dioxane, 0.2 µmol, mol%) was added. Then a mixture of 2. µl of piperidine (0.M,.7 µmol,. equiv.) and Cs 2 C (0.M, 7. µmol, equiv.) in dioxane was added to the reaction vials. The reaction vials were sealed and stirred at 0 C for hrs. The reaction vials were then diluted with 0 μl of % AcH in DMS containing,,- trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entries 7 and. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, µl of a DMS solution of tbuxphs G biaryl Pd precatalyst (0.02M, 0.2 µmol, mol%) was added. Then a mixture of µl of piperidine (0.2M,.7 µmol,. equiv.) and P2Et phosphazene (0.M, µmol, 2 equiv.) in dioxane was added to the reaction vials. The reaction vials were sealed and stirred room temperature or 0 C as described in Table for hrs. The reaction vials were then diluted with 0 μl of % AcH in DMS containing,,-trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entry. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, µl of CuI (0.2M in DMF, 2. µmol, 0 mol%) was added. Then a mixture of µl of piperidine (0.2M,.7 µmol,. equiv.) and Cs 2 C (0.M, 7. µmol, equiv.) in DMF was added to the reaction vials. The reaction vials were sealed and stirred at 0 C for hrs. The reaction vials were then diluted with 0 μl of % AcH in DMS containing,,-trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entry. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, 2 µl of a mixture containing CuI (0.0M, 0.2 µmol, mol%), 2-Isobutyrylcyclohexanone (0.0M, µmol, 0 mol%), piperidine (0.M,.7 µmol,. equiv.) and Cs 2 C (0.M, 7. µmol, equiv.) in DMF was added. The reaction vials were sealed and stirred at 0 C for hrs. The reaction vials were then diluted with 0 μl of % AcH in DMS containing,,-trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield.

30 Experimental Procedure for Figure D, Entries -. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, 2. µl of a mixture of K P (0.M, 7. µmol, equiv.), CuI (0.02M, 0.2 µmol, mol%) and piperidine (0. M,.7 µmol,. equiv.) in DMS was added. Then a solution of 2. µl of the appropriate oxamate ligand (0.0M, 0. µmol, mol%) in DMS was added to the reaciton vials. The reaction vials were sealed and stirred at 0 C for hrs. The reaction vials were then cooled to r.t. and diluted with 0 μl of % AcH in DMS, containing,,-trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. Experimental Procedure for Figure D, Entries -. In a nitrogen filled glovebox, to the collection of high-complexity aryl halides (2. µmol/ reaction) in 20 ul microvials equipped with magnetic stir bars, 2. µl of a mixture of K P (0.M, 7. µmol, equiv.), CuI (0.0M, 0.2 µmol, 2 mol%) and piperidine (0. M,.7 µmol,. equiv.) in DMS was added. Then a solution of 2. µl of the appropriate oxamate ligand L2- L (0.M,.2 µmol, 0 mol%) in DMS was added to the reaciton vials. The reaction vials were sealed and stirred at 0 or C as noted in Table for hrs. The reaction vials were then cooled to r.t. and diluted with 0 μl of % AcH in DMS, containing,,-trimethoxybenzene (M) and were shaken vigorously. A 2 μl aliquot was removed from each vial, and diluted with 700 μl of MeC and quantitative UPLC analysis was performed to determine the solution yield. General Procedure A Scale-up Reactions f o r C - Coupling of X with piperidine. In a nitrogen filled glovebox, 0 mg of aryl halide was charged to a -ml vial with stirbar. Then CuI ( mol%), K P ( equiv.), DMS ( ml), piperidine (2 equiv.) and finally oxamate ligand L (0 mol%) were added, in that order. The reactions were then capped and heated at 0 C for h. The reactions were then cooled to room temperature, filtered and submitted directly for MS-directed purification. o attempt was made to obtain optimal yield on these experiments, rather to obtain high purity samples for quantitative UPLC analysis. Isolated yields for the compound using this method is noted below. General Procedure B Scale-up Reactions f o r C- Couplings of X2, X, X, X, X, X, X2, X and X with piperidine. In a nitrogen filled glovebox, 0 mg of aryl halide was charged to a -ml vial with stirbar. Then CuI ( mol%), K P ( equiv.), DMS ( ml), piperidine (2 equiv.) and finally oxamate ligand L (0 mol%) were added, in that order. The reactions were then capped and heated at 0 C for h. The reactions were then cooled to room temperature, filtered and submitted directly for MSdirected purification. o attempt was made to obtain highest yield on these experiments, rather to obtain

31 high purity samples for quantitative UPLC analysis. Isolated yields for compounds using this method are noted below. General Procedure C Scale-up Reactions f o r C- Couplings of X, X and X with piperidine. In a nitrogen filled glovebox, 0 mg of aryl halide was charged to a -ml vial with stirbar. Then tbuxphs G pre-catalyst ( mol%), DMS (0.2M concentration relative to aryl halide), piperidine (2 equiv.) and finally P2Et phosphazene (2 equiv.) were added, in that order. The reactions were then capped and heated at 0 C for h. The reactions were then cooled to room temperature, and 2MeTHF solvent was added ( ml) followed by H Cl ( ml). The aqueous layer was cut, the organic layer was stripped and the resulting residue was dissolved in DMS ( ml) and purified by MS-directed durification. o attempt was made to obtain highest yield on these experiments, rather to obtain high purity samples for quantitative UPLC analysis. Isolated yields for compounds using this method are noted below. General Procedure D Scale-up Reactions f o r C- Coupling of X with piperidine In a nitrogen filled glovebox, 0 mg of aryl halide was charged to a -ml vial with stirbar. Then [,-Bis(2,-diisopropylphenyl)-,-dihydroimidazol-2-ylidene]chloro][-phenylallyl]palladium(II) ( mol%), DME (0.2M concentration relative to aryl halide), piperidine (2 equiv.) and finally KtBu (2 equiv.) were added, in that order. The reaction was then capped and stirred at room temperature for h. The reaction was then cooled to room temperature, and 2MeTHF solvent was added ( ml) followed by H Cl ( ml). The aqueous layer was cut, the organic layer was stripped and the resulting residue was dissolved in DMS ( ml) and purified by MS-directed durification. o attempt was made to obtain highest yield on these experiments, rather to obtain high purity samples for quantitative UPLC analysis. Isolated yields for the compound using this method is noted below. General Procedure E Scale-up Reactions for C-Coupling of X with piperidine. In a nitrogen filled glovebox, 0 mg of aryl halide was charged to a -ml vial with stirbar. Then RuPhos G2 biaryl precatalyst ( mol%), LiHMDS (2 equiv.), dioxane (0.2M concentration relative to aryl halide), and finally piperidine (2 equiv.) were added, in that order. The reaction was then capped and stirred at 0 C for h. The reaction was then cooled to room temperature, and 2MeTHF solvent was added ( ml) followed by H Cl ( ml). The aqueous layer was cut, the organic layer was stripped and the resulting residue was dissolved in DMS ( ml) and purified by MS-directed durification. o attempt was made to obtain highest yield on these experiments, rather to obtain high purity samples for quantitative UPLC analysis. Isolated yields for the compound using this method is noted below.

32 General Procedure F Scale-up Reactions for C-Coupling of X with piperidine. In a nitrogen filled glovebox, 0 mg of aryl halide was charged to a -ml vial with stirbar. Then RuPhos G2 biaryl precatalyst ( mol%), Cs 2 C (2 equiv.), dioxane (0.2M concentration relative to aryl halide), and finally piperidine (2 equiv.) were added, in that order. The reaction was then capped and stirred at 0 C for h. The reaction was then cooled to room temperature, and 2MeTHF solvent was added ( ml) followed by H Cl ( ml). The aqueous layer was cut, the organic layer was stripped and the resulting residue was dissolved in DMS ( ml) and purified by MS-directed durification. o attempt was made to obtain highest yield on these experiments, rather to obtain high purity samples for quantitative UPLC analysis. Isolated yields for compounds using this method are noted below. Product of X + piperidine C 2 Me H Scale-up Method A: 2 mg (2% yield). Methyl yl)acetate H MR (00 MHz, DMS-d ) δ. (d, J = 2. Hz, H),. (d, J = 2. Hz, H),..0 (m, H),.2 (s, H),.07 (t, J =. Hz, H), 2. (m, H), (m, H), (om, 2H), 2.0 (m, H),. (tt, J =.,. Hz, H),.0 (m, H),. (m, 2H). C MR (2 MHz, DMS-d ) δ 7.2,.,.,.2, 2.7, 2.,., 2., 0.7, 2., 0.2, 7.,.7, 2.0, 2.2, 2., 2.0. LRMS-ESI m/z calcd. for C H 2 : 7.7, found. [M+H] + Product of X2 + piperidine 2-(2,-dioxo--(piperidin--yl)-2,,,7-tetrahydro-H,H-pyrido[,2,-de]quinoxalin-- Scale-up Method B:.7 mg (% yield). Ethyl -methyl--oxo--(piperidin--yl)-,-dihydro-h-benzo[f]imidazo[,-a][,]diazepine-- carboxylate

33 H MR (00 MHz, Acetic Acid-d ) δ. (bs, H), 7.7 (d, J = 2. Hz, H), 7. (d, J =. Hz, H), 7.7 (dd, J =., 2. Hz, H),. (bm, 2H),.0. (m, H),.2 (s, H),.2 (m, H),.70 (m, 2H),. (t, J = 7. Hz, H). C MR (2 MHz, Acetic-d) δ 7.7, 2.2, 0.02,.,.2, 2., 2.70, 2.7, 2.0, 2.0,.0, 0.7, 0., 2.,., 2.7, 2.,.2. LRMS-ESI m/z calcd. for C H 2 :., found. [M+H] + Product of X + piperidine S Scale-up Method B: mg (% yield).,-dimethyl--(-(methylsulfonyl)phenyl)--((-(piperidin--yl)pyridin-2-yl)oxy)furan-2(h)-one H MR (00 MHz, DMS-d ) δ.0 (d, J =. Hz, H), 7. (d, J =. Hz, H), 7.7 (dd, J =., 0.7 Hz, H), 7.0 (dd, J =.0,. Hz, H), 7.00 (dd, J =.0, 0. Hz, H),.2 (s, H),. 2. (m, H),.70 (s, H),. (m, H),. (m, 2H). C MR (2 MHz, DMS) δ.,.0,.,.,.2, 7.2,.,.2, 2., 27.,.7,.7, 0.2,.7, 2., 2., LRMS-ESI m/z calcd. for C 2 H 2 2 S : 2., found.2 [M+H] + Product of X + piperidine F

34 Scale-up Method B:. mg (% yield). -(tert-butyl) 2-methyl (2S,R)--((-fluoro-7-(piperidin--yl)isoindoline-2-carbonyl)oxy) pyrrolidine-,2-dicarboxylate H MR (00 MHz, DMS-d ) δ 7. (m, 2H),.27.0 (m, H),. (m, H),. (m, H),. (s, H),..7 (m, H),.0 2. (m, H), (m, H), 2. (m, H),. (m, H),.0. (m, 2H),.7 (m, H). C MR (2 MHz, DMS-d ) δ 7.27, 72.,.,.,.,., 2.,.0, 2., 2.,.0,.,.2,., 0.0,, 7.2, 7., 7.2,.00, 7.,.2,.7, 2.72, 2., 2.7,.,.2,.7,.0,.0,., 2.2, 2.2, 2.0, 2.7, 2.2. The sample is a mixture of diastereomers LRMS-ESI m/z calcd. for C 2 H F :.2, found 2. [M+H] + Product of X + piperidine H Scale-up Method C:. mg (% yield). Benzyl (R)-2-(-(piperidin--yl)-H-indole--carbonyl)pyrrolidine--carboxylate H MR (00 MHz, DMS-d ) δ 2.0 (d, J =. Hz, H),. (d, J =. Hz, H),. (bs, H), 7.70 (d, J =. Hz, H), 7.7 (dd, J = 7.7, 7.0 Hz, H), 7. (om, 2H), 7..2 (om, H),.0. (m, H),.0 (s, H),.. (m, H),. (om, H), (m, H),. (m, H),.0.77 (om, H),. (bs, 2H). C MR (2 MHz, DMS-d ) δ.2,.,.,., 7., 7., 7.,.,.,.0,.0, 2., 2., 2.2, 27., 27.0, 27., 2., 2.07,.2,.,.,.2,.0,.27, 2., 2.0, 7., 7.0, 7.7, 7.2, 2.,., 2., 2., 2.,.. Resonances are doubled; likely due to rotamers Product of X + piperidine

35 Cl Scale-up Method B:.0 mg (7% yield). Ethyl -(-chloro--(piperidin--yl)-,-dihydro-h-benzo[,]cyclohepta[,2-b]pyridin-- ylidene)piperidine--carboxylate H MR (00 MHz, DMS-d ) δ.0 (d, J = 2.7 Hz, H), 7.0 (d, J = 2.2 Hz, H), 7. (dd, J =., 2. Hz, H), (om, 2H),.0 (q, J = 7. Hz, 2H),.0 (dt, J = 2.,.2 Hz, 2H),..0 (om, H), (m, 2H), 2. (m, H), (m, 2H), 2. (m, H),.2. (m, H),. (m, 2H),.7 (t, J = 7. Hz, H). C MR (2 MHz, DMS-d ) δ.0,.,.2, 0.,.0,.02,.,.2,.2,.72, 0., 2., 2.0, 2.0,.,.,.0,.7,.70,.27, 0., 0., 2.2, 2.,.0. LRMS-ESI m/z calcd. for C 27 H 2 Cl 2 :.22, found. [M+H] + Product of X + piperidine CH Scale-up Method B: 2. mg (.% yield).. -benzyl 2-methyl (2S,R)--((-(piperidin--yl)isoindoline-2-carbonyl)oxy)pyrrolidine-,2- dicarboxylate H MR (00 MHz, DMS-d ) δ (om, H), 7. (m, H), 7.0 (m, H),.2. (m, H),..7 (om, 2H),.7 (bs, H),.. (m, H),.2.72 (m, H),. (om, H),. (d, J = 2.2 Hz, H),.2. (m, 2H),.0 (m, 2H), (m, H), 2.2 (td, J =.,.2 Hz, H),.7 (om, H),.. (m, 2H).

36 C MR (2 MHz, DMS-d ) δ 72., 72., 72., 72.,.,.,.,.,.,., 7., 7.0, 0., 2.7, 2.2, 2.0, 2., 2.77, 2.7, 2., 2., 2.2, 2.0, 2.0, 27.72, 27.,.0,.,.,.0,.,.0, 7., 7.2, 7.0, 7.2, 7.0,.7,.,.2,.7, 7.0,.2,.7,.,.27,., 2.2, 2., 2.,.0,., 0.7,.,.7, 2., 2., 2.7, 2., 22.. The sample is a mixture of diastereomers; some resonances are doubled due to rotamers LRMS-ESI m/z calcd. for C 2 H : 07.2, found 0.2 [M+H] + Product of X + piperidine F H H Scale-up Method D:. mg (0% yield) -(-fluorobenzyl)--hydroxy--(piperidin--yl)-,-naphthyridine-7-carboxamide H MR (00 MHz, DMS-d ) δ.0 (bs, H),.2 (t, J =. Hz, H),.0 (dd, J =.,. Hz, H),. (dd, J =.,.7 Hz, H), 7.7 (dd, J =.,.2 Hz, H), (m, 2H), (m, 2H),. (d, J =. Hz, 2H),. (t, J =.2 Hz, H),.7 (m, H),.0 (m, 2H). C MR (2 MHz, DMS-d ) δ 70.,.70 (d, J = 22. Hz),.72,., 0.,.77,.7 (d, J =.0 Hz),., 2. (d, J =. Hz), 2.2, 22.2,.7,. (d, J = 2.2 Hz), 2.2,., 2.00, 2. LRMS-ESI m/z calcd. for C 2 H 2 F 2 : 0., found. [M+H] + Product of X2 + piperidine H H H Scale-up Method B: 7. mg (.% yield).

37 -Ethyl--(((R,2R)-2-hydroxycyclopentyl)amino)--(2-hydroxyethyl)-7-(-methoxy--(piperidin-- yl)benzyl)-,7-dihydro-h-purine-2,-dione H MR (00 MHz, DMS-d ) δ 7.02 (m, H),.7 (m, H),.0 (m, H),.2 (m, H),. (s, H),. (bs, 2H),.0. (m, H),..2 (m, H),.72 (s, H),.7.7 (m, 2H), 2. (m, H), 2.0 (m, H),. (m, H),.7. (m, H),. (m, H),.0 (t, J = 7.0, H). C MR (2 MHz, DMS) δ.2,.0,.0, 0.,.7, 2., 2., 2., 2.,.7, 2.,.7,., 7.72, 70.7,.,.2,.,.2,.2,.0,.2, 2., 0.0, 2.2, 2.7, 2.07,.7. LRMS-ESI m/z calcd. for C 27 H : 2.2, found 27. [M+H] + Product of X + piperidine H S Scale-up Method C: 7. mg ( % yield) tert-butyl (S,Z)-(,-dimethyl--oxo--(-(piperidin--yl)thiophen-2-yl)tetrahydropyrimidin-2(H)- ylidene)carbamate H MR (00 MHz, DMS-d ) δ.7 (s, H),. (d, J =. Hz, H),. (d, J =. Hz, H),. (dd, J =.,. Hz, H),.0 (d, J =. Hz, H),.0 (s, H), (m, H),. (s, H),.. (m, H),.. (m, 2H),. (s, H). C MR (2 MHz, DMS-d ) δ.,., 7.,.02, 7.7,.2,.0, 7.,.0, 0.,., 2., 2., 2., 2., 2.0. LRMS-ESI m/z calcd. for C H 0 S : 0., found 07. [M+H] + Product of X+ piperidine F Scale-up Method B: 0.0 mg (7.% yield).

38 (R)--((H-,2,-triazol--yl)methyl)--(-fluoro--(piperidin--yl)phenyl)oxazolidin-2-one H MR (00 MHz, DMS-d ) δ. (d, J =.0 Hz, H), 7.77 (d, J =.0 Hz, H), 7. (dd, J =., 2. Hz, H), 7.0 (ddd, J =., 2., 0.7 Hz, H), 7.0 (dd, J =.7,. Hz, H),.2 (m, H),. (s, H),.2 (d, J =. Hz, H),. (t, J =.2 Hz, H),. (dd, J =.,.7 Hz, H), (m, H),. (m, H),. (m, 2H). C MR (2 MHz, DMS) δ.0 (d, J = 2.7 Hz),.7, 7. (d, J =. Hz),., 2. (d, J =. Hz), 2.2,.0 (d, J =. Hz),.7 (d, J =. Hz), 7.2 (d, J = 2. Hz), 7.2, 2., 2. (d, J = 2. Hz), 7., 2.2, 2.. LRMS-ESI m/z calcd. for C 7 H F 2 :., found.2 [M+H] + Product of X + piperidine S H Scale-up Method B: 2.2 mg (.7% yield). -(tert-butyl)-'-((-oxo--(piperidin--yl)-2-propylquinazolin-(h)-yl)methyl)-[,'-biphenyl]-2- sulfonamide H MR (00 MHz, Acetic Acid-d ) δ. (dd, J =.0,. Hz, H),.0 (d, J = 2. Hz, H), (om, 2H), 7. (td, J = 7.,. Hz, H), 7. (td, J =.,. Hz, H), 7.2 (d, J =.2 Hz, 2H), (om, H),.0 (s, 2H),. (t, J =. Hz, H),. (m, H),.2 (q, J = 7. Hz, 2H),.7 (m, 2H),.0 (t, J = 7. Hz, H),.0 (s, H). C MR (2 MHz, Acetic Acid-d ) δ 2.0,., 7.,.77,.7,.0,.2,.77, 2.,., 0., 2., 27.7, 2., 2.2, 2.,.2,.2,., 2.7,., 2., 2., 22.0, 2.00, 2.. LRMS-ESI m/z calcd. for C H 0 S : 72.2, found 7. [M+H] + Product of X + piperidine

39 H C H C H C H CH CH H C CH Scale-up Method E: 0.0 mg (.2% yield). tert-butyl (R)--(2-acetamidopropan-2-yl)--methyl--(piperidin--yl)-2,-dihydrospiro[indene-,'- piperidine]-'-carboxylate H MR (00 MHz, DMS-d ) δ 7. (s, H), 7. (s, H),.72 (s, H),.0 (om, H), 2. (bs, 2H), 2.7 (bs, H), (om, H),. (bs, H),. (m, H),. (bs, 2H),.0 (s, H),.2 (om, H),.07 (s, H). LRMS-ESI m/z calcd. for C 2 H :., found. [M+H] + Product of X7 + piperidine F F F H Scale-up Method C: mg (% yield) (S)--(cyclopropylethynyl)--(piperidin--yl)--(trifluoromethyl)-,-dihydro-2Hbenzo[d][,]oxazin-2-one H MR (00 MHz, DMS-d ) δ 7.0 (dd, J =., 2.7 Hz, H),.7 (d, J = 2. Hz, H),. (d, J =. Hz, H),.0 (s, H),..00 (m, H),. (m, H),. (m, H),. (m, 2H), (m, 2H), 0.7 (m, 2H). C MR (2 MHz, DMS-d ) δ., 7., 27.7, 2.7, 2.0 (q, J = 27.2 Hz), 2.,.72,.,.0,.,.0, 7., 0., 2., 2.0,.00,., -0.. LRMS-ESI m/z calcd. for C H F 2 2 :., found. [M+H] + Product of X + piperidine

40 S Scale-up Method F:.0 mg (2.% yield). Methyl -(-(tert-butylthio)--(-(piperidin--yl)benzyl)--(quinolin-2-ylmethoxy)-h-indol-2-yl)- 2,2-dimethylpropanoate H MR (00 MHz, Acetic Acid-d ) δ. (d, J =. Hz, H),. (d, J =. Hz, H),.0 (dd, J =.2,. Hz, H), (om, 2H), 7.72 (ddd, J =.,.,. Hz, H), 7. (d, J =.7 Hz, 2H), 7. (d, J = 2. Hz, H), 7. (d, J =. Hz, H), 7.02 (d, J =. Hz, 2H),. (dd, J =., 2. Hz, H),. (s, 2H),.2 (s, 2H),. (s, H),. (m, H),. (bs, 2H), 2.0 (m, H),.7 (m, 2H),.2 (s, H),. (s, H). C MR (2 MHz, Acetic) δ 7.7,.2,.0,.,.7, 2., 0.,.2, 2., 2.2,., 2.07, 27., 27., 27., 2., 2.0,., 2.7,.2,.0,.,.,., 7.,.,.0,., 0.7, 2.7, 2.7, 2.0. LRMS-ESI m/z calcd. for C 0 H 7 S :., found 0. [M+H] + VI. Experimental Section - Comparison of Informer Library Approach with Fragment-based Robustness Test Experimental Procedure Figure umol Microscale F ragment Additive Reactions for Suzuki Miyaura Couplings. In a nitrogen filled glovebox, into x ml v i als containing stirbars, THF solutions of ul of phenylpinacolboronate (0.7 M,.0 umol, equiv), ul of chlorobenzene (0.7M,.0 umol, equiv), and XPhos G biaryl precatalyst (0.07M, 0.7 umol, mol%) were combined. Then in the appropriate vials were added the following: Vial : 0 ul THF Vial 2: 0 ul indole F (0.7 M in THF,.0 umol, equiv) Vial : 0 ul oxadiazole F2 (0.7 M in THF,.0 umol, equiv) Vial : 0 ul chlorosulfonamide F (0.7 M in THF,.0 umol, equiv)

41 Vial : 0 ul tetrazole F (0.7 M in THF,.0 umol, equiv) Finally, 0 ul of aqueous K P ( M, 0 umol, 2 equiv) was added to each reaction. The reactions were then sealed and heated at 0 C for h, then cooled to room temperature. The reacitons were diluted with 00 ul of acetonitrile, mixed thoroughly, then ul of these reactions were added to 700 ul of AC. UPLC analysis of the reactions revealed the area counts of product and fragment remaining for each reaction. The performance of vials 2- was compared to the performance of vial. The amount of fragment remaining was determined by comparison of reactions 2- with UPLC analysis of solutions of unreacted fragments F-F of the same overall concentration. Results from this test are presented graphically in the bar graph below, with the LC area counts of product and the fragments remaining depicted. Figure S Experimental Procedure Figure umol Microscale F ragment Additive Reactions for Cu C- Couplings. In a nitrogen filled glovebox, i nto x ml v i als containing stirbars, was added ul of a DMS solution of bromobenzene (0. M, umol), followed by 0 ul of a DMS mixture containing copper idodie (0.0 M, 2

42 mol%), K P (.0 M, 0 umol, equiv.) and piperidine (0. M, umol,. equiv.). Then in the appropriate vials were added the following: Vial : 0 ul DMS Vial 2: ul -n-butylchlorobenzene F (.0 M in DMS,.0 umol, equiv) + ul DMS Vial : ul -benzylindole F (.0 M in DMS,.0 umol, equiv) + ul DMS Vial : ul -phenylbutanoic acid F7 (.0 M in DMS,.0 umol, equiv) + ul DMS Vial : ul -n-butylchlorobenzene F (.0 M in DMS,.0 umol, equiv), ul -benzylindole F (.0 M in DMS,.0 umol, equiv.), ul -phenylbutanoic acid F7 (.0 M in DMS,.0 umol, equiv) Finally, a DMS solution of oxamate ligand L (0.2 M, 0 mol%) was added to each vial. The reactions were then sealed and heated at 0 C for h, then cooled to room temperature. The reacitons were diluted with 00 ul of acetonitrile, mixed thoroughly, then ul of these reactions were added to 700 ul of AC. UPLC analysis of the reactions revealed the area counts of product and fragment remaining for each reaction. The performance of vials 2- was compared to the performance of vial. The amount of fragment remaining was determined by comparison of reactions 2- with UPLC analysis of solutions of unreacted fragments F-F7 of the same overall concentration. Results from this test are presented graphically in the bar graph below, with the LC area counts of product and the fragments remaining depicted.

43 Figure S Experimental Procedure Figure umol Microscale F ragment Additive Reactions for Cu C- Couplings. In a nitrogen filled glovebox, i nto x ml v i als containing stirbars, was added ul of a DMS solution of bromobenzene (0. M, umol), followed by 0 ul of a DMS mixture containing copper idodie (0.0 M, 2 mol%), K P (.0 M, 0 umol, equiv.) and piperidine (0. M, umol,. equiv.). Then in the appropriate vials were added the following: Vial : 0 ul DMS Vial 2: ul -n-butylchlorobenzene F (.0 M in DMS,.0 umol, equiv) + ul DMS Vial : ul -phenylbutanoic acid F7 (.0 M in DMS,.0 umol, equiv) + ul DMS Vial : ul -n-butylchlorobenzene F (.0 M in DMS,.0 umol, equiv), ul -phenylbutanoic acid F7 (.0 M in DMS,.0 umol, equiv) + ul DMS

44 Finally, a DMS solution of oxamate ligand L (0.2 M, 0 mol%) was added to each vial. The reactions were then sealed and heated at 0 C for h, then cooled to room temperature. The reacitons were diluted with 00 ul of acetonitrile, mixed thoroughly, then ul of these reactions were added to 700 ul of AC. UPLC analysis of the reactions revealed the area counts of product and fragment remaining for each reaction. The performance of vials 2- was compared to the performance of vial. The amount of fragment remaining was determined by comparison of reactions 2- with UPLC analysis of solutions of unreacted fragments F and F7 of the same overall concentration. Results from this test are presented graphically in the bar graph below, with the LC area counts of product and the fragments remaining depicted. Figure S

45 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E DMS 2.0 DMS 2.0 DMS 2.0 DMS 2. DMS H 7 2 7

46 E E+00.0E+07.0E+0.E+0 2.0E+0 2.E+0.0E+0.E+0.0E+0.E+0.0E+0.E H 7

47 E+07 E+00.00E E+07.00E+07.00E+07.00E+07.00E E+07.00E+07.00E+07.00E+0.E+0.E+0.0E DMS 2.0 DMS 2. DMS 2. DMS 2.2 DMS HD H 7 2 S

48 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS..2 DMS.0E+0.E E+0 H S E+0.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E E

49 E+07 E+00.00E E+07.00E+07.00E+07.00E+07.00E E+07.00E+07.00E+07.00E+0.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 7 CH

50 7 CH H DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS 2..70E+0.0E+0.0E+0.0E+0.0E+0.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

51 E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2. DMS 2. DMS 2. DMS HD H 2 7 CH 2

52 E+00.0E+0 2.0E+0.0E+0.0E+0.0E+0.0E+0 7.0E+0.0E+0.0E H 2 7 CH 2

53 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD. HD..... HD H

54 DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS 2.7.E+0.0E H.E+0.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E E

55 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E+07 7.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 7

56 DMS 0.2 DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS.E+0.0E+0 H E+0.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E

57 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E+07 7.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 S 7 H

58 E+00.0E+07.0E+0.E+0 2.0E+0 2.E+0.0E+0.E+0.0E+0.E H 2 S 7 H

59 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E+07 7.E+07.0E+07.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H CH 2

60 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS 2..E+0.0E+0 7.E+0 H CH E+0.E+0.0E+0.E+0.0E+0.E+0.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E E

61 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E+07 7.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 7 CH 2

62 DMS 0. DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.0 DMS. DMS. DMS. DMS. DMS E+0.0E+0.0E+0.70E+0 H CH 2.0E+0.0E+0.0E+0.0E+0.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

63 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H F 22

64 DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS..2 DMS.0E+0.E+0 H F E+0.E+0.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E E

65 E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E F F F H 2 H F 22

66 E+0 0.0E E+0.0E+0.0E+0.0E+0.0E+07.2E+07.E+07.E+07.E E E+07 2.E+07 2.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2. DMS HD H S Cl

67 DMS 0. DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.0 DMS. DMS. DMS. DMS. DMS.00E+0 H E+0.00E S Cl 7.00E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E

68 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 H 7

69 DMS 0. DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.0 DMS. DMS. DMS. DMS.. DMS.0E+0.0E+0.70E+0 H H 7.0E+0.0E+0.0E+0.0E+0.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

70 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E+07 7.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 7 2

71 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS.0E+0.E+0 H 2 7.0E E+0 7.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E E

72 DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2.2 DMS 2. DMS 2. DMS HD H S 22 2

73 DMS 0. DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.0 DMS. DMS. DMS. DMS. DMS..0.E+0.0E+0 H S 22 2.E+0.0E+0 7.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E E

74 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E+07 7.E+07.0E+07.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 7

75 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS..2 DMS 7.0E+0.E+0.0E+0 H E+0.0E+0.E+0.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E E

76 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E+07 7.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2. DMS 2. DMS HD H 2 7 CH 2 C H 22

77 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS. 2.7.E+0 H H 22 C 7 CH 2.0E+0.E+0.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E

78 E+07 E+00.00E E+07.00E+07.00E+07.00E+07.00E E+07.00E+07.00E+07.00E+0.E+0.E+0.0E+0.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H CH 2 CH 2 H 27

79 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS..2 DMS E+0 2.2E+0 H CH 2 CH 2 H E+0.E+0.E+0.E+0.2E+0.0E+0.0E+0.0E+0.0E+0 2.0E+0 0.0E E

80 E+0 0.0E E+0.0E+0.0E+0.0E+0.0E+07.2E+07.E+07.E+07.E E E+07 2.E+07 2.E+07 2.E+07.0E+07.2E+07.E+07.E+07.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 7 CH

81 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS..2 DMS 0..E E+0 H 2 7 CH.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E

82 E+00.0E+0.0E+07.E E+07 2.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2. DMS 2. DMS HD H 2 7 2

83 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS..2 DMS.0E+0.E+0 H 2 7.0E E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E

84 E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2.2 DMS 2. DMS HD H 2 7 F 2 F 22 F 2

85 E E+00.0E+07.0E+0.E+0 2.0E+0 2.E+0.0E+0.E+0.0E+0.E+0.0E+0.E+0.0E H 2 7 F 2 F 22 F 2

86 H 2 7 F 2 F 22 F 2-2 F F F 7

87 E E+07 E+00.00E E+07.00E+07.00E+07.00E+07.00E E+07.00E+07.00E+07.00E+0.E+0.E+0.0E+0.0E+0.0E+0.0E+0.70E+0.0E+0.0E E+0 2.E+0 2.E+0 2.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2 H

88 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS E+0 H E+0.00E+0 2 H E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E+0

89 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E+07 7.E+07.0E+07.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2.. HD H 2 7

90 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS 2.72.E+0.0E+0 H 2 7.E E+0 2.E+0 2.0E+0.E+0.0E+0.0E+0 0.0E

91 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2. DMS 2. DMS HD H 2 H

92 DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS.2 DMS.2..70E+0.0E+0 H H E+0.0E+0.0E+0.E E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

93 E+0-2.0E+0 0.0E E+0.0E+0.0E+0.0E+0.0E+07.2E+07.E+07.E+07.E E E+07 2.E+07 2.E+07 2.E+07.0E+07.2E+07.E+07.E+07.E+07.0E+07.2E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD.. HD.7 HD H 2 H

94 E E+00.0E+07.0E+0.E+0 2.0E+0 2.E+0.0E+0.E+0.0E+0.E+0.0E+0.E DMS. DMS. DMS 0.02 DMS 0. DMS 0. DMS 0.2 DMS H 2 H

95 E+0 0.0E E+0.0E+0.0E+0.0E+0.0E+07.2E+07.E+07.E+07.E E E+07 2.E+07 2.E+07 2.E+07.0E+07.2E HD S 2 7

96 -(phenylsulfonyl)-h-pyrrolo[2,-b]pyridine--carbonitrile DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS..2 DMS.0E+0.70E+0.0E+0 2 S E+0.0E+0.0E+0.E+0.E+0 A2.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

97 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD CH 7 2

98 DMS 0.2 DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS..0E+0.0E+0 7.E+0 2.E+0 2 CH.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

99 DMS 2. DMS 2. DMS 2. DMS 2.2 DMS 2..2 HD

100 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS.0.0E E+0 7.0E+0.E+0.0E+0.E+0.0E+0.E+0.0E+0.E+0.0E+0 2.E+0 2.0E+0.E+0.0E+0.0E E E

101 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD

102 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS.2 DMS.70E+0.0E E+0.0E+0.0E+0.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

103 HD DMS 2. DMS 2. DMS 2. DMS 2.0 DMS E+07 2.E+07 7 H S E+07.E+07.0E+07.0E+0 0.0E

104 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS.7. DMS.2 DMS 2.E E+0 H S 7.0E+0.0E E+0.0E+0.0E+0.0E+0.0E+0.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E E+0

105 E+07 E+00.00E E+07.00E+07.00E+07.00E+07.00E E+07.00E+07.00E+07.00E+0.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD CH

106 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS 2.7.0E+0.70E+0.0E+0.0E+0 2.0E E+0.E+0 CH.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

107 HD DMS 2. DMS 2. DMS 2. DMS 2.0 DMS E+07 CH.0E+07.E E+07 2.E+07.0E+07 2.E E+07.E+07.0E+07.0E+0 0.0E E

108 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS 2..0E+0.0E+0 CH.0E+0.E E+0.00E E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

109 HD DMS 2.2 DMS 2. DMS 2. DMS 2.0 DMS F

110 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0.07 DMS. DMS.7 DMS.7 DMS. DMS.E+0.00E F.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

111 F 7 2

112 HD DMS 2. DMS 2. DMS 2. DMS 2.0 DMS E+07.0E E S 7 Cl 22 2.E+07 2.E E E+07.E+07.E+07.E+07.2E+07.0E+07.0E+0.0E+0.0E+0 2.0E+0 0.0E E

113 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS 2.E+0 2.E S Cl E+0 2.0E+0.E+0.E+0.E+0.2E+0.0E+0.0E+0.0E+0.0E+0 2.0E+0 0.0E E

114 E+0 0.0E E+0.0E+0.0E+0.0E+0.0E+07.2E+07.E+07.E+07.E E E+07 2.E+07 2.E+07 2.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS

115 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS.E+0 2.E+0.00E E E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

116 E+0 0.0E E+0.0E+0.0E+0.0E+0.0E+07.2E+07.E+07.E+07.E E E+07 2.E+07 2.E+07 2.E+07.0E+07.2E+07.E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD S 2 7 2

117 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS.2.0.0E+0.0E+0 7.0E+0 2.E+0.E+0 S 2.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

118 HD DMS 2. DMS 2. DMS 2. DMS 2.0 DMS

119 DMS 0.2 DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS.0E+0.70E+0 2.0E+0.0E E+0.0E+0.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

120 HD DMS 2. DMS 2. DMS 2. DMS 2.0 DMS E+07.E+07 H C 2 7.0E+07 CH 2.E+07.0E+07 2.E E+07.E+07.0E+07.0E+0 0.0E

121 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS.7.0.E+0 H C 2 7.E+0.00E+0 CH 2.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

122 HD DMS 2. DMS 2. DMS 2. DMS 2.0 DMS E+07 7.E E+07 7 H 2 CH CH 7.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07 2.E E+07.E+07.0E+07.0E+0 0.0E E

123 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS...0E+0.0E+0 2.0E+0 7 H 2 CH CH 7.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E

124 HD 2.2 DMS 2. DMS 2. DMS 2. DMS 2.0 DMS E+07 7.E CH 7.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E+07 2.E E+07.E+07.0E+07.0E+0 0.0E E

125 -methyl-h-imidazo[,-b]pyridine--carbonitrile DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS E CH.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E

126 HD DMS 2. DMS 2. DMS 2. DMS 2.0 DMS E+0.00E+07.00E E+07.00E+07.00E+07.00E+07.00E E+07.00E+07 E

127 DMS 0. DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.0 DMS. DMS. DMS.7 DMS. DMS 2.E+0 2.E E E+0.0E+0.70E+0.0E+0.0E+0.0E+0.0E+0.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E E+0

128 DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H 2

129 DMS 0.2 DMS 0. DMS 0. DMS 0.27 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.. DMS E E+0.0E+0 2 H 7.0E+0.70E+0 2.0E+0.0E+0.0E+0.0E+0.E+0.E+0.00E+0.00E+0.00E E+0.00E+0.00E+0.00E+0.00E E+0.00E+0 E E E+0

130 E+0 0.0E+00.0E+0.0E+07.E E+07 2.E+07.0E+07.E+07.0E+07.E+07.0E+07.E+07.0E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS HD H

131 DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.02 DMS. DMS. DMS. DMS.2 DMS.. 2.E+0 2.E H E+0 2.0E+0.E+0.E+0.E+0.2E+0.0E+0.0E+0.0E+0.0E+0 2.0E+0 0.0E E

132 E+0 0.0E E+0.0E+0.0E+0.0E+0.0E+07.2E+07.E+07.E+07.E E E+07 2.E+07 2.E+07 2.E+07.0E+07.2E DMS 2. DMS 2. DMS 2. DMS 2.2 DMS.2 HD H

133 E E+00.0E+07.0E+0.E+0 2.0E+0 2.E+0.0E+0.E+0.0E+0.E+0.0E+0.E+0.0E+0.E+0 7.0E+0 7.E+0.0E+0.E+0.0E DMS. DMS. DMS. DMS 0.02 DMS 0. DMS 0. DMS 0.2 DMS 0. DMS 0. DMS 0.2 DMS H

134 H MR of Product of X + piperidine

135 C MR of Product of X + piperidine

136 H MR of Product of X2 + piperidine

137 C MR of Product of X2 + piperidine

138 H MR of Product of X + piperidine S

139 C MR of Product of X + piperidine S

140 H MR of Product of X + piperidine F

141 C MR of Product of X + piperidine F

142 H MR of Product of X + piperidine H

143 C MR of Product of X + piperidine H

144 H MR of Product of X + piperidine Cl

145 C MR of Product of X + piperidine Cl

146 H MR of Product of X + piperidine Me 2 C

147 C MR of Product of X + piperidine Me 2 C

148 H MR of Product of X + piperidine

149 C MR of Product of X + piperidine