Rapid Access to Compound Libraries through Flow Technology: Fully Automated Synthesis of a 3-Aminoindolizine Library via Orthogonal Diversification

Transcription

1 Rapid Access to Compound Libraries through Flow Technology: Fully Automated Synthesis of a 3-Aminoindolizine Library via rthogonal Diversification Paul P. Lange and Keith James* Department of Chemistry, The Scripps Research Institute, orth Torrey Pines Road, La Jolla, California 92037, United States Supporting Information General Procedures & Reactor Data Synthesis of Starting Materials Synthesis of aryl bromide TFA salts Synthesis of alkyne reagent chemset 2{1-5} Additional Screening Experiments Synthesis of Libary Compounds (Table 3 & Figure 1 & 2) General Procedure Synthesis of indolizine chemset 12{1,1-1,5} (Table 3) Synthesis of indolizine chemset 12{2,1-2,5} (Table 3) Synthesis of indolizine chemset 12{3,1-3,5} (Table 3) Synthesis of indolizine chemset 12{4,1-4,5} (Table 3) Synthesis of indolizine chemset 12{5,1-5,5} (Table 3) Synthesis of indolizine chemsets 7{1,1}, 13{1,1} & 14{1,1} (Figure 1) Synthesis of indolizine chemset 15{1,1} (Figure 2) Spectroscopic Data S2-S4 S5-S7 S5-S6 S7 S8 S9-S30 S9 S10-S12 S13-S15 S16-S19 S20-S23 S24-S27 S28-S29 S30 S31-S64 S1

2 General Procedures & Reactor Data General Methods. All reagents and solvents were used as received. tert-butyl 4-(2-bromopyrimidin-4- yl)piperidine-1-carboxylate was a chemical donation by Pfizer Ltd. MR spectra were recorded on Bruker DRX- 600, Bruker DRX-500, or Bruker AMX-400 instruments using residual solvent peak as a reference. Data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. LC/MS analyses were carried out using an Agilent Technologies HPLC (Agilent Technologies 1100 Series diode array detector, Agilent Technologies 1100 Series column heater, Agilent 1100 Series pump, and Agilent 1100 Series degasser) interfaced with an Agilent Technologies 6110 Quadrupole LC/MS. Preparative TLC was performed using 20x20 cm silica gel (60 F 254, 0.25 mm) plates from Merck. Isolation and purification of the desired compounds was achieved by eluting with ethyl acetate/hexanes or dichloromethane/methanol. LC/MS Analysis. HPLC analyses was performed using a water (formic acid 0.1% w/v / ammonium formate 0.05% w/v) and MeC (water 5% v/v, formic acid 0.1% v/v, ammonium formate 0.05% w/v) based gradient from 0-100% MeC over 4 minutes. A Waters XBridge C μm (3.0 x 30 mm) column was used at 80 C with a flow rate of 2.4 ml min -1. Injections were made from diluted reaction mixtures and ionization monitored in positive or negative mode. Hastelloy reactor coil. The Hastelloy tubing used in the Conjure flow reactor comes in the form of a reactor diskette. Hastelloy tubing (0.75 mm inner diameter, 4.5 m length, 2000 μl internal volume) is housed between two metal plates. Figure S1 shows the fully assembled reactor diskette (145 mm x 165 mm x 5 mm). S2

3 Figure S1. Hastelloy reactor coil housed between metal plates. Conjure Flow Reactor 1 Figure S2. Conjure flow reactor setup (UV-detector & fraction collector not shown). 1 S3

4 Figure S3. 40-vial carousel within the fluid prep module (no vials loaded for aspiration). Figure S4. 40-vial carousel within the fluid prep module (4 vials loaded for aspiration). S4

5 Synthesis of aryl bromide TFA salts. General procedure for the synthesis of TFA salts. A solution of mono--boc amine (12 mmol), DIPEA (3.13 ml, 20 mmol) and PyBP (5.20 g, 10 mmol) in CH 2 Cl 2 (20 ml) is cooled to 0 C in an ice-bath. To this mixture the corresponding carboxylic acid (10 mmol) in CH 2 Cl 2 (10 ml) is added dropwise. Upon complete addition the reaction mixture was allowed to warm to room temperature and stirred over night. To the reaction mixture was aqueous citric acid solution (25 ml). The mixture was stirred vigorously then transferred to a separatory funnel. The aqueous phase was extracted with CH 2 Cl 2 (3x 25 ml) and the combined organic extracts were dried over MgS 4, filtered and concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 (100 ml) and trifluoroacetic acid (19.1 ml, 25eq) is added dropwise. The resulting mixture is stirred for one hour at room temperature. The volatiles are removed in a stream of nitrogen and the oily residue is triturated with tert-butylmethyl ether (MTBE) (100 ml) to afford a colorless solid. The ether is decanted off and the solid suspended in MTBE/CH 2 Cl 2 (1:1, 100 ml) to dissolve all byproducts from the previous amide coupling. The suspension is filtered and the solid is washed with MTBE/CH 2 Cl 2 (1:1, 25 ml) and dried to afford the corresponding TFA salts. TFA H Br 4 Compound 4: tert-butyl 4-(2-bromopyrimidin-4-yl)piperidine-1-carboxylate (1.71 g, 5 mmol) is dissolved in DCM (50 ml) and trifluoroacetic acid (9.6 ml, 75 mmol) is added dropwise. The resulting mixture is stirred at room temperature for 15 minutes. The volatiles are removed in a stream of nitrogen and the oily residue is triturated with MTBE (50 ml), the resulting ocre solid filtered, washed with MTBE (25 ml) and dried in vacuo to afford 1.65 g (93%) of 4 as an ocre solid. 1 H MR (400 MHz, CHLRFRM-d) δ ppm (m, 2 H) (m, 2 H) 3.01 (tt, J=11.27, 3.76 Hz, 1 H) 3.11 (q, J=11.58 Hz, 2 H) 3.62 (d, J=12.49 Hz, 2 H) 7.24 (d, J=5.08 Hz, 1 H) 8.55 (d, J=5.08 Hz, 1 H) 8.82 (br. s., 2 H) 9.21 (br. s., 1 H); 13 C MR (101 MHz, CHLRFRM-d) δ ppm 27.1, 40.7, 43.7, 117.3, 153.0, 159.8, S5

6 10: Compound 10 was synthesized according to the general procedure from 6-bromonicotinic acid (1.10 g, 5.0 mmol) and mono--boc-piperazine (1.12 g, 6.0 mmol) to afford 1.54 g (80%) of 10 as a white solid. 1 H MR (500 MHz, Acetone) δ ppm (m, 3 H) 4.04 (br. s., 4 H) 4.41 (br. s., 1 H) (m, 1 H) (m, 1 H) (m, 1 H); 13 C MR (126 MHz, Acetone) δ ppm 45.0, 129.0, 131.5, 139.0, 143.9, 149.7, The TFA salt precursor for chemset 13{1,1}was synthesized according to the general procedure from 6- bromonicotinic acid (500 mg, 2.5 mmol) and mono--boc-, -dimethyl-1,3-diaminopropane (559 mg, 3.0 mmol) to afford 810 mg (81%) of a white solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm (m, 2 H) 2.72 (s, 3 H) 3.04 (s, 5 H) (m, 2 H) 7.58 (d, J=8.07 Hz, 1 H) 7.71 (d, J=7.70 Hz, 1 H) 8.46 (br. s., 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 23.7, 33.5, 37.6, 44.8, 47.0, 128.1, 130.3, 134.6, 137.5, 148.4, The TFA salt precursor for chemset 14{1,1} was synthesized according to the general procedure from 6- bromoisonicotinic acid (500 mg, 2.5 mmol) and mono--boc-piperazine (607 mg, 3.0 mmol) to afford 624 mg (65%) of a white solid. 1 H MR (500 MHz, DMS-d 6 ) δ ppm 3.06 (br. s., 2 H) 3.14 (br. s., 2 H) 3.45 (br. s., 3 H) 3.79 (br. s., 2 H) 7.50 (d, J=4.40 Hz, 1 H) 7.75 (s, 1 H) 8.50 (d, J=4.77 Hz, 1 H); 13 C MR (126 MHz, DMS-d 6 ) δ ppm 38.6, 42.6, 120.9, 125.3, 141.6, 145.9, 151.0, S6

7 Synthesis of alkyne reagent chemset. -methyl--propargylbenzylamine 2{1} is commercially available from Sigma-Aldrich and was used as received.,-diphenylpropargylamine 2{2}, 2 -propargylpiperidine 2{3}, 3 -propargylmorpholine 2{4}, 4 -Boc- -methylpropargylamine 2{5}, 5 and -propargyl- -Boc-piperazine 6 were synthesized according to the procedures reported in the literature. Precursor for chemset 15{1,1}: -propargyl- -Boc-piperazine (564 mg, 2.5 mmol) is dissolved in DCM (25 ml) and trifluoroacetic acid (4.80 ml, 62.5 mmol) is added dropwise. The resulting mixture is stirred for one hour at room temperature. The volatiles are removed in a stream of nitrogen and the oily residue is triturated with MTBE (50 ml), the resulting white solid filtered, washed with MTBE (25 ml) and dried in vacuo to afford 784 mg (89%) of a white solid. 1 H MR (400 MHz, Acetone) δ ppm 3.07 (t, J=2.49 Hz, 1 H) (m, 4 H) (m, 4 H) 3.83 (d, J=2.63 Hz, 2 H); 13 C MR (126 MHz, Acetone) δ ppm 43.3, 46.6, 48.6, 75.9, Yang, Y.; Cheng, K.; Zhang, Y. rg. Lett. 2009, 11, Tsou, H.-R.; et al. J. Med. Chem. 2001, 44, Verron, J.; Malherbe, P.; Prinssen, E.; Thomas, A. W.; ock,.; Masciadri, R. Tet. Lett. 2007, 48, Bradbury, B. J.; Baumgold, J.; Jacobson, K. A. J. Med. Chem. 1990, 33, Zheng, H.; et al. M. Bioorg. Med. Chem. 2005, 13, S7

8 ptimization of the first acylation conditions Table 1. Screening of conditions for the first step acylation. a entry solvent time acyl. reagent setup 11{1} (%) observation 1 MeC 10 min AcCl batch 100 precipitation 2 DMF 10 min AcCl batch 100 precipitation 3 MeC 10 min Ac 2 batch 100 clear soln. 4 DMF 10 min Ac 2 batch 100 clear soln. 5 MeC 10 min Ac 2 flow b 100 clear soln. 6 DMF 10 min Ac 2 flow b 100 clear soln. a 8.8 mg (0.025 mmol) of TFA salt 10 dissolved in 75 μl MeC. 3eq of Et 3 added, followed by a solution of acylating reagent in MeC (25 μl, 1.2 M, 0.03 mmol) and stirred at RT for 10 min. Analysis by LC-MS. Precipitation observed directly upon addition of base. b Reaction conditions: Accendo Conjure Flow Reactor, 200 μl segment: 0.05 mmol 10, PFA tubing (0.75 mm i.d., 0.7 ml internal vol.). Reaction quenched with MeH (200 μl) upon re-aspiration from the incubation chamber. ptimization of first step acylation conditions for more reactive aryl bromide TFA salts For the use of aryl bromide TFA salts bearing both a strong nucleophilic moiety as well as a good electrophilic group (like salt 4) an alternative base than triethylamine had to be employed to avoid selfoligomerization via nucleophilic substitution in the stock solution (Table 2). Table 2. Base screening for the first step acylation of TFA salt 4. a entry base TFA salt amine-i amine-ii amine-iii (%) (%) (%) (%) observation 1 Et clear soln. 2 DIPEA clear soln. 3 DBU complex mix. 4 pyridine b clear soln. 5 2,6-lutidine precipitation 6 DMAP clear soln. 7 MM precipitation 8 DABC complex mix. 9 PhMe precipitation a 9.5 mg (0.025 mmol) of TFA salt 4 dissolved in 75 μl MeC. 3eq of base added and stirred at RT for 1 h. Analysis by LC-MS. Precipitation observed directly upon addition of base. b 5eq of pyridine required to allow full dissolution of salt 4. DIPEA: Hünig s base. DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene. DMAP: 4-,- Dimethylaminopyridine. MM: -Methylmorpholine. DABC: 1,4-Diazabicyclo[2.2.2]octane. S8

9 Synthesis of library compounds General procedure for the synthesis of chemsets 7, 12, 13, 14 & 15 using a Conjure flow reactor. 7 The corresponding TFA salt and base (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 or 0.25 mmol for pyridine) and electrophilic reagent (1.20 M in MeC, 50 μl, 0.06 mmol) were aspirated from their respective source vials located in position C (TFA salt/base) and position D (electrophilic reagent), mixed through a PFA mixing tube (0.2 mm i. d.), and loaded into a sample loop in the incubation chamber to remain for 10 min at room temperature. The alkyne (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (1.5 μmol PdCl 2 (PPh 3 ) 2, 5 μmol CuI, 0.25 mmol DBU in MeC, 150 μl) were aspirated from their respective source vials located in position A (alkyne) and position B (catalyst), mixed with the segment containing the -modified material in MeC through a PFA mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment (400 μl) was injected into the flow reactor (Hastelloy coil, 0.75 mm i. d., 2.0 ml internal vol.) set at 180 C and passed through the reactor at a flow-rate of 286 μl min -1 (7 min residence time). A total of 2 reaction segments prepared in this manner were collected. Upon complete collection, the volatile reaction components were removed from the reaction solution in a stream of nitrogen. The crude oily residue was purified by preparative TLC (silica gel, hexanes/ethyl acetate or dichloromethane/methanol) to afford the desired library compounds. Catalyst stock solution component amount in solvent 150 μl corresponds to PdCl 2 (PPh 3 ) mg mmol, 3 mol% CuI 12.6 mg 1.5 ml MeC mmol, 10 mol% DBU 500 μl mmol, 500 mol% 7 S9

10 Indolizine chemset 12{1,1-1,5} (Table 3) Compound 12{1,1}. Compound 12{1,1} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), acetic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -methyl-propargylbenzylamine 2{1} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, dichloromethane/methanol 19:1) to afford 23.1 mg (59%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.14 (s, 3 H) 2.69 (s, 3 H) 3.51 (br. s., 2 H) 3.63 (d, J=8.44 Hz, 4 H) 3.69 (br. s., 2 H) 4.08 (s, 2 H) 6.42 (d, J=4.04 Hz, 1 H) 6.52 (d, J=4.03 Hz, 1 H) 6.58 (d, J=9.17 Hz, 1 H) (m, 1 H) 7.31 (d, J=4.40 Hz, 5 H) 8.21 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.3, 41.4, 41.5, 46.1, 60.6, 98.4, 104.8, 114.0, 117.4, 118.9, 122.3, 127.3, 128.3, 128.5, 131.9, 135.8, 137.7, 169.1, 169.4; HRMS (ESI-TF): C 23 H : [M+H] + : calculated , found Compound 12{1,2}. Compound 12{1,2} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), acetic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol),,diphenylpropargylamine 2{2} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, dichloromethane/methanol 19:1) to afford S10

11 34.3 mg (78%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.10 (s, 3 H) 3.32 (br. s., 2 H) 3.39 (br. s., 2 H) 3.44 (br. s., 2 H) (m, 2 H) 6.56 (d, J=4.03 Hz, 1 H) 6.71 (dd, J=3.85, 1.65 Hz, 1 H) 6.78 (dd, J=9.17, 1.47 Hz, 1 H) 6.97 (dd, J=8.80, 1.10 Hz, 4 H) 7.01 (td, J=7.34, 1.10 Hz, 2 H) (m, 4 H) 7.45 (d, J=9.17 Hz, 1 H) 7.75 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.2, 41.2, 45.9, 99.6, 112.3, 115.9, 117.8, 119.6, 120.5, 121.4, 122.6, 127.0, 129.2, 129.3, 145.7, 168.6, 169.0; HRMS (ESI-TF): C 27 H : [M+H] + : calculated , found Compound 12{1,3}. Compound 12{1,3} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), acetic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), - propargylpiperidine 2{3} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, dichloromethane/methanol 19:1) to afford 21.5 mg (61%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 1.62 (d, J=5.14 Hz, 2 H) 1.75 (dt, J=10.82, 5.59 Hz, 4 H) 2.14 (s, 3 H) (m, 4 H) 3.54 (br. s., 2 H) 3.66 (d, J=5.50 Hz, 4 H) 3.71 (br. s., 2 H) 6.39 (d, J=3.67 Hz, 1 H) 6.45 (d, J=4.03 Hz, 1 H) 6.54 (dd, J=9.17, 1.47 Hz, 1 H) 7.30 (d, J=9.17 Hz, 1 H) 8.12 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.3, 24.1, 26.3, 41.5, 46.2, 53.3, 98.2, 103.3, 113.8, 117.3, 118.9, 122.5, 127.6, 137.0, 169.1, 169.5; HRMS (ESI-TF): C 20 H : [M+H] + : calculated , found Compound 12{1,4}. Compound 12{1,4} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the S11

12 TFA salt, 0.15 mmol for Et 3 ), acetic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), - propargylmorpholine 2{4} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, dichloromethane/methanol 19:1) to afford 21.9 mg (62%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.14 (s, 3 H) (m, 4 H) 3.54 (br. s., 2 H) 3.65 (d, J=8.07 Hz, 4 H) 3.71 (br. s., 2 H) (m, 4 H) 6.42 (d, J=4.03 Hz, 1 H) 6.52 (d, J=4.03 Hz, 1 H) 6.56 (dd, J=9.17, 1.47 Hz, 1 H) (m, 1 H) 8.21 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.3, 41.4, 46.1, 52.4, 67.2, 98.5, 104.0, 114.1, 117.8, 118.9, 122.4, 127.9, 135.3, 169.2, 169.3; HRMS (ESI-TF): C 19 H : [M+H] + : calculated , found Compound 12{1,5}. Compound 12{1,5} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), acetic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -Boc-methylpropargylamine 2{5} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, dichloromethane/methanol 19:1) to afford 25.9 mg (65%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 1.35 (br. s., 9 H) 2.14 (s, 3 H) 3.27 (s, 3 H) 3.53 (br. s., 2 H) 3.65 (br. s., 4 H) 3.72 (br. s., 2 H) 6.47 (d, J=4.03 Hz, 1 H) (m, 2 H) 7.37 (d, J=9.17 Hz, 1 H) 7.89 (br. s., 1 H); 13 C MR (151 MHz, CHLRFRM-d) δ ppm 21.3, 28.1, 37.4, 41.4, 46.1, 81.1, 99.0, 110.0, 114.9, 118.1, 118.9, 122.7, 125.0, 129.2, 154.8, 169.0, 169.1; HRMS (ESI-TF): C 21 H : [M+H] + : calculated , found S12

13 Indolizine chemset 12{2,1-2,5} (Table 3) Compound 12{2,1}. Compound 12{2,1} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzoic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -methyl-propargylbenzylamine 2{1} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 24.3 mg (54%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.69 (s, 3 H) 3.50 (br. s., 2 H) (m, 6 H) 4.09 (s, 2 H) 6.41 (d, J=3.67 Hz, 1 H) 6.52 (d, J=4.03 Hz, 1 H) (m, 1 H) (m, 1 H) 7.31 (d, J=4.40 Hz, 5 H) (m, 5 H) 8.22 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 41.6, 55.1, 58.4, 60.6, 98.4, 104.8, 114.1, 117.5, 119.0, 122.4, 127.0, 127.3, 127.7, 128.3, 128.6, 128.6, 130.1, 135.1, 135.9, 137.7, 169.4, 170.6; HRMS (ESI-TF): C 28 H : [M+H] + : calculated , found Compound 12{2,2}. Compound 12{2,2} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzoic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol),,diphenylpropargylamine 2{2} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford S13

14 29.6 mg (59%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm (m, 8 H) 6.55 (d, J=4.03 Hz, 1 H) 6.71 (d, J=4.03 Hz, 1 H) (m, 1 H) 6.96 (d, J=8.07 Hz, 6 H) 7.21 (t, J=7.70 Hz, 4 H) (m, 2 H) (m, 4 H) 7.74 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 42.2, 47.4, 99.6, 112.3, 116.0, 117.7, 119.6, 120.5, 121.4, 122.6, 127.0, 128.5, 129.2, 129.3, 130.0, 135.1, 145.7, 168.6, 170.5; HRMS (ESI-TF): C 32 H : [M+H] + : calculated , found Compound 12{2,3}. Compound 12{2,3} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzoic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), - propargylpiperidine 2{3} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 21.6 mg (52%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 1.62 (d, J=3.67 Hz, 2 H) 1.75 (dt, J=11.10, 5.64 Hz, 4 H) (m, 4 H) 3.54 (br. s., 2 H) 3.71 (br. s., 6 H) 6.39 (d, J=4.03 Hz, 1 H) 6.45 (d, J=4.03 Hz, 1 H) (m, 1 H) 7.29 (d, J=9.17 Hz, 1 H) (m, 5 H) 8.13 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 24.1, 26.3, 40.6, 43.6, 53.3, 98.2, 103.3, 113.7, 117.3, 118.9, 122.5, 127.0, 127.6, 128.6, 130.0, 135.1, 137.0, 169.6, 170.6; HRMS (ESI-TF): C 25 H : [M+H] + : calculated , found Compound 12{2,4}. Compound 12{2,4} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzoic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), - S14

15 propargylmorpholine 2{4} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 31.9 mg (76%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm (m, 4 H) (m, 8 H) (m, 4 H) 6.42 (d, J=4.03 Hz, 1 H) 6.52 (d, J=4.04 Hz, 1 H) 6.56 (d, J=9.17 Hz, 1 H) 7.31 (d, J=9.17 Hz, 1 H) (m, 5 H) 8.21 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 41.3, 48.7, 52.4, 67.2, 98.5, 104.0, 114.1, 117.8, 118.9, 122.4, 127.0, 127.9, 128.6, 130.1, 135.0, 135.3, 169.2, 170.6; HRMS (ESI-TF): C 24 H : [M+H] + : calculated , found Compound 12{2,5}. Compound 12{2,5} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzoic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -Boc-methylpropargylamine 2{5} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 26.1 mg (56%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 1.34 (br. s., 9 H) 3.26 (s, 3 H) 3.54 (br. s., 2 H) 3.70 (br. s., 6 H) 6.46 (d, J=4.03 Hz, 1 H) 6.66 (d, J=9.90 Hz, 2 H) 7.35 (d, J=9.17 Hz, 1 H) (m, 5 H) 7.89 (br. s., 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 28.1, 40.0, 44.3, 99.0, 110.1, 115.0, 118.1, 118.9, 119.9, 122.6, 125.0, 127.0, 128.4, 128.6, 130.1, 134.2, 135.0, 154.8, 168.9, 170.6; HRMS (ESI-TF): C 26 H : [M+H] + : calculated , found Indolizine chemset 12{3,1-3,5} (Table 3) S15

16 Compound 12{3,1}. Compound 12{3,1} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), butyric anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -methyl-propargylbenzylamine 2{1} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 23.5 mg (56%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 1.00 (t, J=7.34 Hz, 3 H) 1.70 (dq, J=14.86, 7.40 Hz, 2 H) 2.34 (t, J=7.52 Hz, 2 H) 2.69 (s, 3 H) 3.52 (br. s., 2 H) 3.66 (s, 3 H) 3.62 (s, 3 H) 4.09 (s, 2 H) 6.42 (d, J=3.67 Hz, 1 H) 6.52 (d, J=4.03 Hz, 1 H) 6.58 (dd, J=9.17, 1.47 Hz, 1 H) 7.26 (s, 1 H) (m, 5 H) 8.22 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 13.9, 18.6, 35.2, 41.6, 45.4, 46.7, 58.0, 60.6, 98.4, 104.8, 114.1, 117.5, 118.9, 122.3, 127.3, 127.7, 128.3, 128.6, 132.1, 137.7, 169.4, 171.7; HRMS (ESI-TF): C 25 H : [M+H] + : calculated , found Compound 12{3,2}. Compound 12{3,2} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), butyric anhydride (1.20 M in MeC, 50 μl, 0.06 mmol),,diphenylpropargylamine 2{2} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 28.1 mg (60%) of a yellow solid. 1 H MR (400 MHz, CHLRFRM-d) δ ppm 0.99 (t, J=7.46 Hz, 3 H) S16

17 1.67 (sxt, J=7.43 Hz, 2 H) 2.29 (t, J=7.61 Hz, 2 H) 3.33 (br. s., 3 H) (m, 5 H) 6.56 (d, J=4.10 Hz, 1 H) 6.72 (d, J=4.10 Hz, 1 H) 6.78 (dd, J=9.07, 1.46 Hz, 1 H) (m, 4 H) 7.01 (t, J=7.32 Hz, 2 H) (m, 4 H) (m, 1 H) 7.75 (s, 1 H); 13 C MR (101 MHz, CHLRFRM-d) δ ppm 13.9, 18.6, 35.1, 41.4, 45.2, 99.5, 112.3, 116.0, 117.8, 119.6, 120.5, 121.4, 122.6, 127.0, 129.2, 129.3, 145.7, 168.6, 171.6; HRMS (ESI-TF): C 29 H : [M+H] + : calculated , found Compound 12{3,3}. Compound 12{3,3} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), butyric anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), - propargylpiperidine 2{3} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 19.3 mg (51%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 0.99 (t, J=7.52 Hz, 3 H) (m, 2 H) (m, 2 H) 1.75 (quin, J=5.59 Hz, 4 H) 2.35 (t, J=7.52 Hz, 2 H) (m, 4 H) 3.55 (br. s., 2 H) 3.65 (br. s., 2 H) 3.67 (br. s., 4 H) 6.39 (d, J=3.67 Hz, 1 H) 6.45 (d, J=4.03 Hz, 1 H) 6.54 (dd, J=9.17, 1.47 Hz, 1 H) (m, 1 H) 8.12 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 13.9, 18.6, 24.1, 26.3, 35.2, 41.6, 45.4, 53.3, 98.2, 103.3, 113.8, 118.9, 122.5, 127.6, 128.5, 137.0, 169.4, 171.7; HRMS (ESI-TF): C 22 H : [M+H] + : calculated , found Compound 12{3,4}. Compound 12{3,4} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), butyric anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), - S17

18 propargylmorpholine 2{4} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 23.8 mg (62%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm (m, 3 H) (m, 2 H) 2.34 (t, J=7.70 Hz, 2 H) (m, 4 H) 3.55 (br. s., 2 H) (m, 6 H) (m, 4 H) 6.42 (d, J=4.03 Hz, 1 H) 6.52 (d, J=4.03 Hz, 1 H) 6.56 (dd, J=9.17, 1.47 Hz, 1 H) 7.31 (dd, J=9.17, 0.73 Hz, 1 H) 8.20 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 13.9, 18.6, 35.1, 41.5, 45.4, 52.4, 67.2, 98.5, 104.0, 114.1, 117.8, 118.9, 122.4, 127.9, 135.2, 169.2, 171.7; HRMS (ESI-TF): C 21 H : [M+H] + : calculated , found Compound 12{3,5}. Compound 12{3,5} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), butyric anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -Boc-methylpropargylamine 2{5} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 28.0 mg (65%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 0.98 (t, J=7.34 Hz, 3 H) 1.34 (br. s., 9 H) (m, 2 H) 2.33 (t, J=7.52 Hz, 2 H) 3.26 (s, 3 H) 3.53 (br. s., 2 H) 3.65 (br. s., 4 H) 3.70 (br. s., 2 H) 6.46 (d, J=4.04 Hz, 1 H) (m, 2 H) 7.35 (d, J=8.80 Hz, 1 H) 7.88 (br. s., 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 13.9, 18.6, 28.1, 35.1, 37.1, 41.5, 49.5, 86.3, 98.9, 110.0, 118.9, 122.6, 125.0, 128.4, 132.0, 132.1, 154.8, 168.9, 171.7; HRMS (ESI-TF): C 23 H : [M+H] + : calculated , found S18

19 Indolizine chemset 12{4,1-4,5} (Table 3) Compound 12{4,1}. Compound 12{4,1}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzyl bromide (1.20 M in MeC, 50 μl, 0.06 mmol), -methyl-propargylbenzylamine 2{1} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 10.3 mg (24%) of a yellow solid. Compound 12{4,1}was also synthesized according to the general flow procedure using a catalyst stock solution containing 7eq of DBU base (1.5 μmol PdCl 2 (PPh 3 ) 2, 5 μmol CuI, 0.35 mmol DBU in MeC, 150 μl) and otherwise identical reaction components to afford 14.4 mg (33%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.45 (br. s., 4 H) 2.65 (s, 3 H) 3.52 (s, 2 H) 3.64 (br. s., 4 H) 4.05 (s, 2 H) 6.36 (d, J=4.03 Hz, 1 H) 6.47 (d, J=3.67 Hz, 1 H) 6.57 (dd, J=9.17, 1.47 Hz, 1 H) (m, 3 H) 7.29 (d, J=3.67 Hz, 2 H) 7.30 (d, J=2.57 Hz, 4 H) (m, 2 H) 8.17 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 41.5, 45.4, 53.0, 60.6, 62.9, 98.0, 104.5, 107.1, 114.5, 114.7, 114.9, 118.2, 118.7, 121.9, 127.2, 127.7, 128.3, 128.6, 129.0, 135.7, 137.6, 168.9; HRMS (ESI-TF): C 28 H 30 4 : [M+H] + : calculated , found Compound 12{4,2}. Compound 12{4,2}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzyl bromide (1.20 M in MeC, 50 μl, 0.06 mmol),,diphenylpropargylamine 2{2} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, S19

20 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 23.0 mg (47%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.28 (br. s., 4 H) 3.35 (br. s., 3 H) 3.49 (s, 2 H) 3.56 (br. s., 1 H) 6.53 (d, J=4.03 Hz, 1 H) 6.70 (d, J=4.03 Hz, 1 H) 6.78 (dd, J=9.17, 1.47 Hz, 1 H) (m, 6 H) (m, 4 H) (m, 3 H) (m, 2 H) 7.43 (d, J=9.17 Hz, 1 H) 7.75 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 47.2, 52.8, 62.8, 99.2, 112.1, 116.3, 118.5, 119.3, 120.5, 121.1, 122.5, 126.8, 127.2, 128.3, 129.0, 129.3, 137.5, 145.8, 168.2; HRMS (ESI-TF): C 32 H 30 4 : [M+H] + : calculated , found Compound 12{4,3}. Compound 12{4,3}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzyl bromide (1.20 M in MeC, 50 μl, 0.06 mmol), - propargylpiperidine 2{3} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 11.3 mg (28%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm (m, 2 H) 1.76 (quin, J=5.59 Hz, 4 H) 2.51 (br. s., 4 H) (m, 4 H) 3.58 (s, 2 H) 3.69 (br. s., 4 H) 6.38 (d, J=3.67 Hz, 1 H) 6.44 (d, J=4.03 Hz, 1 H) 6.57 (dd, J=9.17, 1.47 Hz, 1 H) (m, 2 H) (m, 4 H) 8.11 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 24.2, 26.3, 45.9, 53.0, 53.3, 62.9, 97.8, 102.9, 114.3, 118.0, 118.6, 122.2, 127.2, 127.7, 128.3, 129.1, 136.8, 137.5, 167.1; HRMS (ESI-TF): C 25 H 30 4 : [M+H] + : calculated , found S20

21 Compound 12{4,4}. Compound 12{4,4}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzyl bromide (1.20 M in MeC, 50 μl, 0.06 mmol), - propargylmorpholine 2{4} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 16.7 mg (41%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 1.80 (br. s., 2 H) 2.50 (br. s., 4 H) (m, 4 H) 3.56 (s, 2 H) 3.68 (br. s., 4 H) (m, 4 H) 6.39 (d, J=4.03 Hz, 1 H) 6.50 (d, J=4.03 Hz, 1 H) 6.58 (dd, J=9.17, 1.47 Hz, 1 H) (m, 2 H) (m, 4 H) 8.18 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 41.7, 52.4, 53.0, 62.9, 67.2, 98.1, 103.6, 114.6, 118.7, 122.0, 127.2, 128.0, 128.3, 129.0, 132.1, 135.1, 137.5, 168.8; HRMS (ESI-TF): C 24 H : [M+H] + : calculated , found Compound 12{4,5}. Compound 12{4,5}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), benzyl bromide (1.20 M in MeC, 50 μl, 0.06 mmol), -Boc-methylpropargylamine 2{5} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford S21

22 16.6 mg (37%) of a yellow solid. 1H MR (600 MHz, CHLRFRM-d) δ ppm 1.31 (br. s., 6 H) 1.52 (t, J=15.35 Hz, 3 H) 2.49 (br. s., 4 H) 3.26 (s, 3 H) 3.55 (s, 2 H) 3.67 (br. s., 4 H) 6.44 (d, J=3.95 Hz, 1 H) 6.62 (br. s., 1 H) 6.67 (dd, J=9.21, 1.32 Hz, 1 H) 7.28 (dd, J=6.14, 2.63 Hz, 1 H) (m, 5 H) 7.86 (br. s., 1 H); 13 C MR (151 MHz, CHLRFRM-d) δ ppm 28.0, 37.3, 53.0, 62.8, 81.0, 98.6, 109.7, 115.4, 118.6, 122.1, 124.7, 127.2, 128.3, 129.0, 137.4, 154.9, 168.5; HRMS (ESI-TF): C 26 H : [M+H] + : calculated , found S22

23 Indolizine chemset 12{5,1-5,5} (Table 3) Compound 12{5,1}. Compound 12{5,1}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), tosyl chloride (1.20 M in MeC, 50 μl, 0.06 mmol), -methyl-propargylbenzylamine 2{1} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 1:1) to afford 21.0 mg (42%) of a yellow solid. Compound 12{5,1}was also synthesized according to the general flow procedure using a catalyst stock solution containing 7eq of DBU base (1.5 μmol PdCl 2 (PPh 3 ) 2, 5 μmol CuI, 0.35 mmol DBU in MeC, 150 μl) and otherwise identical reaction components to afford 24.7 mg (49%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.48 (s, 3 H) 2.68 (s, 3 H) 3.06 (br. s., 4 H) 3.76 (br. s., 4 H) 4.08 (s, 2 H) 6.41 (d, J=4.03 Hz, 1 H) 6.49 (dd, J=8.99, 1.28 Hz, 1 H) 6.52 (d, J=3.67 Hz, 1 H) 7.26 (br. s., 1 H) (m, 5 H) 7.37 (m, J=8.44 Hz, 2 H) 7.66 (m, J=8.07 Hz, 2 H) 8.17 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.5, 41.6, 46.0, 60.7, 98.4, 104.9, 114.0, 118.8, 122.6, 127.3, 127.6, 127.7, 128.3, 128.6, 129.8, 132.3, 135.9, 137.6, 144.1, 169.1; HRMS (ESI-TF): C 28 H S: [M+H] + : calculated , found Compound 12{5,2}. Compound 12{5,2}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), tosyl chloride (1.20 M in MeC, 50 μl, 0.06 mmol),,diphenylpropargylamine 2{2} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the S23

24 volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 1:1) to afford 28.9 mg (53%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.46 (s, 3 H) 2.85 (br. s., 4 H) 3.52 (br. s., 4 H) 6.54 (d, J=4.03 Hz, 1 H) (m, 2 H) 6.93 (d, J=8.07 Hz, 4 H) 7.02 (t, J=7.34 Hz, 2 H) 7.23 (t, J=7.70 Hz, 4 H) 7.35 (m, J=8.07 Hz, 2 H) 7.41 (d, J=9.17 Hz, 1 H) 7.61 (m, J=8.07 Hz, 2 H) 7.64 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.5, 41.4, 45.8, 99.6, 112.4, 116.0, 117.5, 119.6, 120.5, 121.4, 122.7, 126.9, 127.7, 129.3, 129.8, 132.3, 144.1, 145.7, 168.5; HRMS (ESI-TF): C 32 H S: [M+H] + : calculated , found Compound 12{5,3}. Compound 12{5,3}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), tosyl chloride (1.20 M in MeC, 50 μl, 0.06 mmol), - propargylpiperidine 2{3} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 1:1) to afford 16.8 mg (31%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 1.64 (d, J=5.14 Hz, 2 H) 1.74 (quin, J=5.50 Hz, 4 H) 2.49 (s, 3 H) (m, 4 H) 3.08 (br. s., 4 H) 3.79 (br. s., 4 H) 6.40 (d, J=4.03 Hz, 1 H) (m, 2 H) (m, 1 H) 7.39 (m, J=8.07 Hz, 2 H) 7.68 (m, J=8.07 Hz, 2 H) 8.06 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.5, 24.1, 26.3, 40.7, 46.1, 53.3, 98.3, 103.3, 113.7, 117.0, 118.8, 122.6, 127.6, 127.7, 129.8, 132.3, 136.9, 144.1, 163.7; HRMS (ESI-TF): C 25 H S: [M+H] + : calculated , found S24

25 Compound 12{5,4}. Compound 12{5,4}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), tosyl chloride (1.20 M in MeC, 50 μl, 0.06 mmol), - propargylmorpholine 2{4} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 1:1) to afford 25.5 mg (54%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.46 (s, 3 H) (m, 4 H) 3.04 (br. s., 4 H) 3.74 (br. s., 4 H) (m, 4 H) 6.39 (d, J=4.03 Hz, 1 H) 6.46 (dd, J=9.17, 1.47 Hz, 1 H) 6.50 (d, J=4.03 Hz, 1 H) (m, 1 H) 7.36 (m, J=8.44 Hz, 2 H) 7.64 (m, J=8.07 Hz, 2 H) 8.11 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.5, 34.6, 46.0, 52.4, 67.2, 98.6, 104.0, 114.1, 117.5, 118.9, 122.5, 127.7, 127.9, 129.9, 132.3, 144.2, 150.5, 166.1; HRMS (ESI-TF): C 24 H S: [M+H] + : calculated , found Compound 12{5,5}. Compound 12{5,5}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 10 and Et 3 (0.33 M in MeC/H 2 (9:1), 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), tosyl chloride (1.20 M in MeC, 50 μl, 0.06 mmol), -Boc-methylpropargylamine 2{5} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 1:1) to afford 20.5 mg (40%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 1.26 (br. s., 9 H) 2.46 (s, 3 H) 3.03 (br. s., 4 H) 3.23 (s, 3 H) 3.76 (br. s., 4 H) 6.44 (d, J=4.03 Hz, 1 H) 6.57 (d, J=9.17 Hz, 1 H) 6.63 (br. s., 1 H) 7.31 (d, J=9.17 Hz, 1 H) 7.35 (m, J=8.07 Hz, 2 H) 7.63 (m, J=8.44 Hz, 2 H) 7.81 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.5, 28.0, 39.2, 46.0, 94.6, 99.0, 106.3, 109.9, 111.1, 111.8, S25

26 114.7, 118.8, 122.8, 125.0, 127.7, 129.8, 132.2, 144.1, 154.7, 168.7; HRMS (ESI-TF): C 26 H S: [M+H] + : calculated , found S26

27 Indolizine chemsets 7{1,1}, 13{1,1} & 14{1,1} (Figure 1) Compound 7{1,1}. Compound 7{1,1}was synthesized according to the general flow procedure using 2 segments (400 μl each) containing TFA salt 4 and pyridine (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.25 mmol for pyridine), acetic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -methyl-propargylbenzylamine 2{1} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 18.5 mg (51%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm (m, 2 H) (m, 2 H) 2.13 (s, 3 H) (m, 4 H) (m, 1 H) 3.19 (td, J=12.84, 2.57 Hz, 1 H) 3.95 (d, J=13.57 Hz, 1 H) 4.05 (s, 2 H) 4.75 (d, J=13.20 Hz, 1 H) 6.37 (d, J=7.34 Hz, 1 H) 6.43 (d, J=4.03 Hz, 1 H) 6.57 (d, J=4.03 Hz, 1 H) (m, 1 H) (m, 4 H) 8.13 (d, J=7.34 Hz, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.4, 30.8, 31.2, 41.5, 41.7, 44.2, 46.6, 60.7, 95.5, 104.2, 105.1, 127.3, 128.1, 128.3, 128.5, 135.4, 137.7, 155.4, 168.8; HRMS (ESI-TF): C 22 H 26 4 : [M+H] + : calculated , found Compound 13{1,1}. Compound 13{1,1} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing the precursor TFA salt and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), acetic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -methyl-propargylbenzylamine 2{1} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of S27

28 nitrogen. The oily residue purified by preparative TLC (silica gel, dichloromethane/methanol 19:1) to afford 18.2 mg (45%) of a yellow solid. 1 H MR (600 MHz, CHLRFRM-d) δ ppm 1.63 (br. s., 3 H) 1.89 (br. s., 1 H) 1.94 (br. s., 1 H) (m, 2 H) (m, 3 H) (m, 2 H) (m, 3 H) 3.34 (br. s., 1 H) 3.47 (br. s., 1 H) 3.52 (br. s., 1 H) 4.09 (s, 2 H) (m, 1 H) (m, 1 H) 6.60 (t, J=9.87 Hz, 1 H) (m, 1 H) (m, 5 H) 8.18 (s, 1 H); 13 C MR (151 MHz, CHLRFRM-d) δ ppm 22.1, 22.7, 30.5, 34.0, 36.9, 42.4, 45.8, 61.4, 98.8, 105.3, 119.6, 119.8, 128.1, 128.1, 129.1, 129.2, 129.4, 129.5, 136.5, 138.6, 171.0, 171.4; HRMS (ESI-TF): C 24 H : [M+H] + : calculated , found Compound 14{1,1}. Compound 14{1,1} was synthesized according to the general flow procedure using 2 segments (400 μl each) containing the precursor TFA salt and Et 3 (0.33 M in MeC, 150 μl, 0.05 mmol for the TFA salt, 0.15 mmol for Et 3 ), acetic anhydride (1.20 M in MeC, 50 μl, 0.06 mmol), -methyl-propargylbenzylamine 2{1} (2.00 M in MeC, 50.0 μl, 0.10 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, dichloromethane/methanol 19:1) to afford 20.9 mg (53%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.15 (s, 3 H) 2.71 (s, 3 H) (m, 2 H) 3.66 (s, 4 H) 3.73 (br. s., 2 H) 4.10 (s, 2 H) 6.53 (q, J=4.04 Hz, 2 H) 6.58 (dd, J=7.34, 1.47 Hz, 1 H) (m, 1 H) 7.33 (d, J=4.04 Hz, 4 H) 7.49 (s, 1 H) 7.95 (d, J=7.34 Hz, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.3, 41.0, 41.5, 46.2, 60.1, 100.9, 104.7, 108.8, 120.0, 120.6, 120.8, 126.7, 127.3, 128.3, 128.4, 136.1, 137.7, 169.1, 170.3; HRMS (ESI-TF): C 23 H : [M+H] + : calculated , found S28

29 Indolizine chemset 15{1,1} (Figure 2) Compound 15{1,1}. Compound 15{1,1}was synthesized according to the general flow procedure using 2 segments (450 μl each) containing the -propargylpiperazine TFA salt and Et 3 (0.67 M in MeC, 150 μl, 0.10 mmol for the TFA salt, 0.40 mmol for Et 3 ), acetic anhydride (2.40 M in MeC, 50 μl, 0.12 mmol), methyl 6-bromonicotinate (0.50 M in MeC, 100 μl, 0.05 mmol) and catalyst stock solution (in MeC, 150 μl) and a flow-rate of 286 μl min -1 (7 min residence time). Upon completion of the reaction, the volatile reaction components (mainly MeC, Et 3, and fluorous spacer) were removed in a stream of nitrogen. The oily residue purified by preparative TLC (silica gel, ethyl acetate/hexanes 4:1) to afford 16.4 mg (54%) of a yellow solid. 1 H MR (500 MHz, CHLRFRM-d) δ ppm 2.17 (s, 3 H) 2.97 (t, J=4.95 Hz, 2 H) (m, 2 H) (m, 2 H) 3.85 (br. s., 2 H) 3.93 (s, 3 H) 6.39 (d, J=4.03 Hz, 1 H) 6.52 (d, J=4.03 Hz, 1 H) 7.12 (dd, J=9.35, 1.28 Hz, 1 H) 7.31 (d, J=9.17 Hz, 1 H) 8.72 (s, 1 H); 13 C MR (126 MHz, CHLRFRM-d) δ ppm 21.3, 41.7, 46.6, 52.0, 52.1, 52.4, 98.4, 104.9, 113.8, 115.1, 118.6, 125.9, 128.9, 134.7, 166.6, 169.0; HRMS (ESI-TF): C 16 H : [M+H] + : calculated , found S29

30 1 H MR (400 MHz, CHLRFRM-d) δ ppm (m, 2 H) (m, 2 H) 3.01 (tt, J=11.27, 3.76 Hz, 1 H) 3.11 (q, J=11.58 Hz, 2 H) 3.62 (d, J=12.49 Hz, 2 H) 7.24 (d, J=5.08 Hz, 1 H) 8.55 (d, J=5.08 Hz, 1 H) 8.82 (br. s., 2 H) 9.21 (br. s., 1 H) ppl177tfa_01 M08(br. s.) M09(br. s.) M07(d) 8.55 M06(d) M05(d) M04(q) M03(tt) M01(m) M02(m) TFA H 4 Br C MR (101 MHz, CHLRFRM-d) δ ppm (s, 1 C) (s, 1 C) (s, 1 C) (s, 1 C) (s, 1 C) (s, 1 C) (s, 1 C) ppl177tfa_02 TFA H Br 4 M07(s) S30