Copper-Catalyzed Modular Assembly of Polyheterocycles.

Easy operation, readily accessible starting materials, and short syntheses of the privileged scaffold indeno[1,2-c]isoquinolinone were achieved by an multicomponent reaction (MCR)-based protocol via an ammonia-Ugi-four component reaction (4CR)/copper-catalyzed annulation sequence. The optimization and scope and limitations of this short and general sequence are described. The methodology allows an efficient construction of a wide variety of indenoisoquinolinones in just two steps.

Introduction

The quest for novel synthetic routes for nitrogen (N)-containing heterocycles using atom-economical and efficient pathways is an active field in synthetic chemistry nowadays. This is due to widespread applications of N-containing heterocycles in almost all branches of organic chemistry including active pharmaceutical research,[1] functional materials,[2] catalysis,[3] and coordination chemistry.[4] Among the N-containing heterocycles, the indenoisoquinoline is a highly valuable scaffold, endowed with inhibition activities against topoisomerase I (Topo1)[5] in clinical testing with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs, topotecan and irinotecan.[6] Several indenoisoquinolines, such as indotecan (LMP400, Figure A), have entered phase I clinical trials.[7]

Figure 1

(A) Clinical Topo1 inhibitor LMP-400; (B) Ugi reactions with ammonia, yielding 5-aminothiazole and oxazole derivatives; (C) synthesis of ustiloxin D utilizing an ammonia–Ugi reaction; (D) Pd-mediated C(sp3)–H bond activation in ammonia–Ugi 4-CR adducts; and (E) our work: copper-catalyzed arylation of 1,3-indandione of ammonia–Ugi 4-CR adducts.

The Ugi reaction is one of the most prominent multicomponent reaction (MCR) families.[8] It has attracted much attention due to the possibility of introducing versatile functional groups in the Ugi adducts, which can undergo further condensations or cyclization reactions, leading to an array of structurally diverse scaffolds.[9] Specifically, the Ugi four-component reaction (Ugi-4-CR) utilizing ammonia as the amine component can be an extremely valuable approach because it is inexpensive, is easily available, and permits reduced waste. However, relatively fewer studies have focused on it, most of which report an excessive byproduct formation and low yield (Figure B–D).[10]

Nowadays, introducing cleaner, safer, and easier accessible nitrogen donors to N-containing organic compounds is an extensively studied topic.[11] In 2009, the Chen group reported a simple, one-step assembly of Ugi adducts suitable for elaboration into a variety of 5-aminoazole compounds through postcondensation modifications by employing concentrated aqueous ammonia as a convenient source (Figure B).[10] Hutton et al. synthesized ustiloxin D utilizing an ammonia–Ugi reaction (Figure C).[12] Recently, Polindara-García and his colleagues developed a novel protocol for the fast introduction of the picolinamide directing group in aliphatic ketones using the ammonia–Ugi 4-CR reaction and the subsequent Pd-mediated γ-C(sp3)–H bond activation (Figure D).[13]

Ullmann–Hurtley condensations are powerful tools for the formation of carbon–heteroatom and carbon–carbon bonds in the construction of a wide variety of heterocycles.[14] In 2012, Zhao et al. reported the synthesis of indolo[2,1-b]quinazoline derivatives via copper-catalyzed Ullmann-type intermolecular C–C and intramolecular C–N couplings.[14c] In 2016, a series of isoquinoline derivatives were synthesized, with high chemo- and regioselectivities, via the copper-catalyzed cascade reaction of 2-haloaryloxime acetates with β-diketones, β-keto esters, and β-keto nitriles.[14f] In addition, an Ugi-type MCR/copper-catalyzed annulation sequence has been an important strategy, leading to high structural diversity and molecular complexity.[15] Inspired by the remarkable progress of this key reaction achieved and based on our ongoing interest in MCR chemistry,[9,16] we envisioned that indeno[1,2-c]isoquinolinone derivatives could be alternatively synthesized in a concise manner by an Ugi reaction of o-halobenzoic acids and ammonia, followed by a Cu-catalyzed annulation reaction with 1,3-indandione (Figure E).

Results and Discussion

The Ugi adduct model 5a was readily obtained in 58% yield by reacting equimolar quantities of 2-iodobenzoic acid 1a, paraformaldehyde 3a, and tert-butyl isocyanide 4a with an excess of an aqueous ammonia solution (1.2 equiv) 2 in 2,2,2-trifluoroethanol (TFE) under 60 °C for 12 h in a closed vial. Thereafter, we investigated the copper-catalyzed tandem reaction and optimized the reaction conditions by variation of the Cu source, base, solvent, time, and temperature (Table ). When the reaction was carried out with 1,3-indandione 6a (1 equiv) in the presence of 5 mol % CuCl2 using 2.0 equiv of K2CO3 as the base in MeCN at 90 °C for 3 h, the desired product 7aa was obtained in 61% yield (entry 1). Cs2CO3 (65% yield, entry 2) was superior to K2CO3 and was selected as the base for further studies. To our delight, the desired product 7aa was formed in 70% yield with the addition of 1.5 equiv of 1,3-indandione 6a (entry 3). Increasing the amount of 6a to 2.0 equiv afforded 7aa in 68% yield (entry 4). However, replacing the catalyst with CuI, CuSO4, CuCl, CuBr, CuBr2, Cu(NO3)2, Cu2O, and CuCN resulted in lower yields of 7aa of 49, 32, 44, 23, 25, 36, 64, and 57%, respectively (entries 5–12). The yield of 7aa decreased to 62% at a temperature of 80 °C (entry 13). Also, a higher temperature of 100 °C did not increase the yield (entry 14). Variation of solvents yielded the following: a moderate yield of the product was obtained (42%) when dioxane was chosen as the solvent (entry 15), while no reaction at all occurred when toluene was used (entry 16). Moreover, a trace amount of products was produced in polar aprotic solvents such as dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) (entries 17 and 18). Finally, MeCN was the best solvent for this reaction among the selected solvents (entry 3 vs entries 15–18). Decreasing and increasing the reaction time did not help in improving the outcome of the product (entries 19 and 20). Notably, 35% yield was obtained when the reaction was run in the microwave irritation for 1 h (entry 21). Finally, the optimized reaction conditions were concluded to be the Ugi intermediate 5a (0.3 mmol), 1,3-indandione 6a (0.45 mmol), 5 mol % CuCl2, and 2.0 equiv of Cs2CO3 in MeCN (4 mL) at 90 °C for 3 h (entry 3).

Table 1

Optimization of Reaction Conditionsa,b

Reaction conditions: 5a (0.3 mmol), 6a, catalyst (5 mmol %), base (0.6 mmol), solvent (4 mL).

TFE = 2,2,2-trifluoroethanol.

Isolated yields.

N.D. = not detected.

Microwave.

Green color indicates best condition screened.

With the optimal conditions in hand, a set of Ugi products were synthesized in moderate to good yields and were examined to determine the scope of the tandem reaction to furnish the corresponding products 7a–t (Scheme ). All of the substrates 1–6 led to the expected indeno[1,2-c]isoquinolinone products 7a–t in just two simple steps. We initially replaced 1,3-indanedione with 5,6-dimethoxy-1,3-indanedione, and the reaction proceeded smoothly to afford the corresponding indenoisoquinoline derivatives in good yield (7ab). Paraformaldehyde was utilized in many cases and resulted in moderate to good yields (7a–e, 7n, 7t). Further, various aliphatic aldehydes including acetaldehyde (7f), isobutyraldehyde (7g), butyraldehyde (7h), 3-methylbutanal (7i), cyclopentanecarbaldehyde (7j), 3-phenylpropanal (7k), and 3-(methylthio)propanal (7r) proceeded well in this MCR and tandem reaction. We found that aromatic aldehydes bearing weak electron-withdrawing groups such as 4-Br and 4-Cl led to derivatives 7o and 7s in good yields. Similarly, the use of benzaldehyde and an electron-donating group 4-OMe in the aromatic aldehyde was compatible in this process to deliver the products in good yields (7p, 7m). Heterocyclic pyridine aldehydes demonstrated good behavior in the Cu-mediated reaction and furnished 7q in good yield (65%). In addition, commercially available 5-methoxy-, 4-methoxy-, 5-methyl-, 4-methyl-, and 4-nitro-substituted 2-bromobenzoic acid reacted to give the expected product 7n–t in moderate to good yields.

Scheme 1

Ammonia–Ugi Reaction and the Subsequent Copper-Catalyzed Tandem Reaction,,

The Ugi reaction was carried out using 1 (2.0 mmol), 2 (2.4 mmol), 3 (2.0 mmol), and 4 (2.0 mmol) in CF3CH2OH (1.0 M) for 12 h at 60 °C.

Reaction conditions: 5 (0.3 mmol), 6 (0.45 mmol), Cs2CO3 (0.6 mmol), CuCl2 (0.015 mmol), CH3CN (4 mL), 90 °C, 3 h.

Yield refers to the purified products. First yield refers to the Ugi reaction and second yield to the cyclization.

After successfully demonstrating the cyclization reactions with different aldehydes and 2-halogenbenzoic acids, we then examined indandione with various Ugi adducts by simply changing the isocyanide pool in the MCR and then studying the subsequent annulation. Benzyl isocyanide (7d, 7j, 7n) and substituted benzyl isocyanides with electron-donating and -withdrawing groups like 4-chloro (7e), 2,3-dimethoxy (7i) and 4-cyano (7p) reacted smoothly with 40, 75, 62, 80, 72, and 35% yields, respectively. Isocyanobenzene containing valuable functional groups such as ethyl and anisole was also applied and gave the corresponding products in good yields (7h, 7f). Similarly, (2-isocyanoethyl)benzene (7o) and methyl 2-isocyanoacetate (7l) also furnished the different indeno[1,2-c]isoquinolinone products in 49 and 59% yields, respectively. In addition, aliphatic linear (7b), cyclic (7c) and branched isocyanides like tert-butyl isocyanide (7a, 7g, 7m, 7q–t) and tert-octyl isocyanide (7k) also yielded different tetraheterocycles. Scheme clearly indicates that there are no electronic or steric effects on the outcome of the reaction.

We also introduced ortho halo heterocyclic carboxylic acids such as 2-chloroquinoline-3-carboxylic acid and 2-bromothiophene-3-carboxylic acid in the Ugi reaction, which reacted with 25% ammonia solution 2, paraformaldehyde 3a, and tert-butyl isocyanide 4a instead of a benzoic acid component to deliver products 5u and 5v. Following the present protocol, it is interesting that under optimized reaction conditions, the former substrate 5u provided the corresponding pentacyclic multiheterocyclic compound N-(tert-butyl)-2-(6,13-dioxo-6,13-dihydro-5H-benzo[b]indeno[1,2-h][1,6]naphthyridin-5-yl)acetamide (7u) in good yield. However, the latter substrate 5v afforded the tetracyclic compound N-(tert-butyl)-2-(4,10-dioxo-4,10-dihydro-5H-indeno[1,2-b]thieno[2,3-d]pyridin-5-yl)acetamide (7v) in moderate yield (Scheme ).

Scheme 2

Synthesis of Heterocyclic Fused Indenopyridone Derivatives

Furthermore, the scalability of this method was investigated (Scheme A). A four-component reaction of 2-iodobenzoic acid, ammonia, cyclopentanecarbaldehyde, and benzyl isocyanide was conducted on a 5 mmol scale, which further reacted with 1,3-indandione, while the polyheterocyclic product 7j could be obtained in 40% overall yield (0.93 g). To further underscore the usefulness of the herein described indeno[1,2-c]isoquinolinones, we performed several late-stage functionalizations (Scheme ). The bromo group of 7o was coupled with (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid to give the derivate 8 by a Suzuki reaction (Scheme B). In another application, product 7p was reacted with sodium azide to afford tetrazole 9 in good yield (Scheme C). Finally, while reducing the nitro group of product 7t with Pd/C, a mixture of 10 and the major overreductive product 11 (Supporting Information) was obtained. Therefore, we chose SnCl2 for the selective reduction of a nitro group to deliver 10 in excellent yield (96%) and used it for further coupling (Scheme D). The intriguing scaffold urea 12 was successfully achieved by reacting 10 with (isocyanatomethyl)benzene in a cosolvent system.[17] In addition, we also coupled 10 with Boc-l-phenylalanine to afford a starting point for peptide synthesis. This effort was initially hindered by the lack of reactivity of 10 under standard amide coupling conditions (N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1′-carbonyldiimidazole (CDI), etc.). A phosphorous oxychloride-mediated amide-bond-forming protocol was utilized for the formation of the desired product 13 in good yield.[18] Such kind of derivatives could be potentially useful as fluorescent tags to follow a peptide in biological material.

Scheme 3

Gram-Scale Reaction and Synthetic Applications

The crystal structure of compound 7aa is shown in Figure , which unambiguously supports our chemistry (Figure ). The structure features the high planarity of the tetracyclic structure and an intermolecular hydrogen bonding between two adjacent molecules.

Figure 2

Crystal structure of 7aa (CCDC 1991899) featuring a dimer and an intermolecular hydrogen bond between the NH of one molecule and the CO of the neighboring molecule of 2.1 Å length.

A plausible mechanism of this tandem reaction is hypothesized and shown in Scheme . The reaction is presumably initiated with the reaction of Cu(I) active species, which was present in copper salts and 1,3-indandione 6a to produce intermediate A, and the oxidative addition of the Ugi adduct 2-iodo-N-phenylbenzamide 5a to this copper(I) complex results in the formation the Cu(III) intermediate B, which is further converted into intermediate C via reductive elimination. The intramolecular addition of the amide nitrogen to the carbonyl group in intermediate C gives intermediate D, which is then converted into 7aa by dehydration.

Scheme 4

Plausible Reaction Mechanism

Conclusions

Our work features the development of an efficient route for the synthesis of a bioactive indenoisoquinoline library by incorporating a copper-catalyzed tandem reaction with the step-economical, high-yielding ammonia–Ugi MCR. Diversity can be achieved through the aldehyde, isocyanide, and 2-halogen benzoic acid components. This protocol offers a rapid approach to the indenoisoquinolinone scaffold, along with the achievement of remarkable structural diversity and brevity. The process is a simple operation, which uses readily available starting materials and provides good scalability. Furthermore, the current protocol was successfully extended to the synthesis of other benzo-1,4-dioxane-, urea-, and peptide-containing and tetrazolo indenoisoquinolinone cores, thus aiding future structure–activity relationship (SAR) studies for discovering potent and selective Topo1 inhibitors.

Experimental Section

General Information

Nuclear magnetic resonance spectra were recorded on a Bruker Avance 500 spectrometer. Chemical shifts for 1H NMR are reported relative to tetramethylsilane (TMS) (δ 0 ppm) or an internal solvent peak (CDCl3 δ 7.26 ppm, CD3OD δ 3.31 ppm or D2O δ 4.79 ppm), and coupling constants are in hertz (Hz). The following abbreviations were used for spin multiplicity: s = singlet, d = doublet, t = triplet, dt = double triplet, ddd = doublet of double doublet, m = multiplet, and br = broad. Chemical shifts for 13C NMR are reported in parts per million (ppm) relative to the solvent peak (CDCl3 δ 77.23 ppm, DMSO δ 39.52 ppm, CD3OD δ 49.00 ppm). Filtrations were performed on a silica bed (Screening Devices BV, 60–200 μm, 60 Å). Flash chromatography was performed on a Grace Reveleris X2 using Grace Reveleris silica columns (12 g), and a gradient of petroleum ether/ethyl acetate (0–100%) or dichloromethane/methanol (0–20%) was applied. Thin-layer chromatography (TLC) was performed on Fluka precoated silica gel plates (0.20 mm thick, particle size 25 μm). Reagents were available from commercial suppliers and used without any purification unless otherwise noted. All isocyanides were made in house by performing the Ugi procedure. Other reagents were purchased from Sigma-Aldrich, ABCR, Acros, Fluorochem, and AK Scientific and were used without further purification. Mass spectra were recorded on a Waters investigator supercritical fluid chromatograph with a 3100 MS detector (electrospray ionization (ESI)) using a solvent system of methanol and CO2 on a Viridis silica gel column (4.6 × 250 mm2, 5 μm particle size) and are reported as (m/z). High-resolution mass spectra (HRMS) were recorded using an LTQ-Orbitrap-XL (Thermo Fisher Scientific; ESI pos. mode) at a resolution of 60 000@m/z400. Melting points were obtained on a melting point apparatus and were uncorrected. Yields given refer to chromatographically purified compounds unless otherwise stated.

General Experimental Procedure and Characterization

General Procedure A

A calculated volume of a 25% ammonia solution (2.4 mmol) was added to a stirred solution or suspension of the carboxylic acid (2 mmol) in 2,2,2-trifluoroethanol (2 mL). The aldehyde (2 mmol) and isocyanide (2 mmol) were then introduced, and stirring was continued at 60 °C in a close screwed vial in a heating metal block overnight. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography to give the desired product 5.

General Procedure B

Ugi adduct 5 (0.3 mmol), indandione 6 (0.45 mmol), and Cs2CO3 (0.6 mmol) were added to a 10 mL round-bottom flask equipped with a magnetic stir bar, and 4 mL of acetonitrile was added. The mixture was heated to 90 °C in an oil bath for 5 min, and then CuCl2 (0.0015 mmol) was added and reacted for 3 h. The progress of the reaction was monitored by TLC for the disappearance of 5. After the reaction was completed, the solvent was removed by rotary evaporation and the crude was product purified by column chromatography to give the desired product 7.

Gram-Scale Synthesis of 7j

An oven-dried 50 mL flask equipped with a magnetic stirrer bar was charged with a calculated volume of a 25% ammonia solution (5.5 mmol) and 2-iodobenzoic acid (5 mmol) in 2,2,2-trifluoroethanol (5 mL). Then, cyclopentanecarbaldehyde (5 mmol) and benzyl isocyanide (5 mmol) were added to the solution and the reaction mixture was stirred at 60 °C in an oil bath overnight. The Ugi adduct 5j was filtered and was then added to indandione 6a (1.5 equiv) and Cs2CO3 (2 equiv) in acetonitrile (1.3 M) and heated to 90 °C in an oil bath for 5 min. Then, CuCl2 (10 mol %) was added and reacted for 5 h. The progress of the reaction was monitored by TLC for the disappearance of 5j. After the reaction was completed, the solvent was removed by rotary evaporation and the crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 3:2) to afford the product 7j (0.93 g, 40% yield).

Procedure C

Compound 7o (0.1 mmol) and (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (0.15 mmol) were placed in a 25 mL round-bottom flask, and toluene/ethanol (v/v = 5:1) (3 mL) and sat. NaHCO3 (3 mL) were added. The mixture was flushed by N2 for 10 min. Then, Pd(dppf)Cl2 (0.01 mmol) was added and the reaction mixture was allowed to react at 90 °C in an oil bath for 12 h. Then, the reaction mixture was cooled to room temperature and treated with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After the removal of EtOAc, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1:1) to afford the product 8.

Procedure D

Compound 7p (0.1 mmol), NaN3 (0.12 mmol), and NH4Cl (0.12 mmol) in DMF (1 mL) were placed in a closed 4 mL screwcap glass vial and heated in a heating metal block at 100 °C for 18 h. DMF was removed under vacuum, and the residue was purified by column chromatography (silica gel, methanol/dichloromethane = 1:4) to afford the product 9.

Procedure E

To a flask were added 7t (0.2 mmol), HCOONH4 (2 mmol), and 10% Pd/C (10 mg). Anhydrous ethanol (4 mL) was added as a solvent, and the reaction mixture was stirred at room temperature for 8 h. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (v/v, 3:2) as an eluent to give product 10 (26 mg, 35% yield) as a red solid, and 2-(2-amino-5,11-dioxo-5,6a,11,11a-tetrahydro-6H-indeno[1,2-c]isoquinolin-6-yl)-N-(tert-butyl)acetamide 11 (44 mg, 58% yield) was obtained using ethyl acetate/petroleum ether (v/v, 4:1) as an eluent as a white solid.

Procedure F

To a solution of 7t (0.3 mmol) in EtOH (1 mL) was added SnCl2 (1.5 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 10 min and then refluxed in an oil bath for 4 h. After the completion of the reaction, ice-cold water was added to the reaction mixture. The obtained residue was diluted with a 20% NaOH solution, and the aqueous layer was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated to provide the product 10 (108 mg, 96% yield).

Procedure G

Compound 10 (0.1 mmol) was dissolved in a solvent mixture of dry DMF and THF (1:4 v/v) (1 mL) in a 10 mL round-bottom flask. To this solution was added phenyl isocyanate (0.15 mmol), and the mixture stirred under an inert atmosphere at 90 °C in an oil bath for 8 h. The reaction mixture was cooled to room temperature. Solvents was removed under vacuum, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 3:7) to afford the product 12 (32 mg, 64% yield).

Procedure H

Boc-l-phenylalanine (0.1 mmol) and compound 10 (0.1 mmol) were dissolved in dry pyridine (0.3 mL). The solution was cooled to −15 °C, and phosphorus oxychloride (0.11 mmol) was added dropwise with vigorous stirring. The reaction was completed after 30 min (monitored by TLC). The reaction mixture was then quenched with crushed ice/water (10 mL) and extracted with EtOAc (three times, 10 mL). The combined EtOAc layers were washed with saturated NaHCO3 and NaCl (three times, 10 mL each). After being dried on Na2SO4, the EtOAc layer was filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1:1) to afford the product 13 (49 mg, 78% yield).

N-(2-(tert-Butylamino)-2-oxoethyl)-2-iodobenzamide (5a)

It was synthesized according to procedure A on a 2 mmol scale (418 mg, 58%) as a white solid; mp: 178–179 °C; R = 0.58 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.82 (dd, J = 13.1, 7.6 Hz, 1H), 7.42–7.30 (m, 3H), 7.08 (ddd, J = 10.8, 6.6, 2.7 Hz, 1H), 6.89–6.70 (m, 1H), 4.08 (t, J = 4.7 Hz, 2H), 1.33 (d, J = 12.3 Hz, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.8, 167.9, 141.3, 139.9, 131.3, 128.4, 128.1, 92.6, 51.6, 44.6, 28.8. HRMS (ESI) m/z: [M + H]+ calcd for C13H18IN2O2, 361.0408; found, 361.0407.

N-(2-(Butylamino)-2-oxoethyl)-2-iodobenzamide (5b)

It was synthesized according to procedure A on a 2 mmol scale (353 mg, 49%) as a yellow solid; mp: 195–196 °C; R = 0.38 (50% EtOAc/dichloromethane). 1H NMR (500 MHz, chloroform-d) δ 7.88 (d, J = 7.9 Hz, 1H), 7.40 (q, J = 7.9 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H), 6.98 (s, 1H), 6.75 (s, 1H), 4.17 (d, J = 5.2 Hz, 2H), 3.29 (q, J = 6.8 Hz, 2H), 1.56–1.48 (m, 2H), 1.36 (q, J = 7.5 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.8, 168.4, 141.1, 139.9, 137.7, 131.5, 128.7, 128.4, 128.2, 128.0, 127.6, 92.5, 43.9, 43.7. 13C{1H} NMR (126 MHz, chloroform-d) δ 169.7, 168.3, 141.2, 140.0, 131.5, 128.4, 128.2, 92.5, 43.9, 39.5, 31.5, 20.1, 13.8. HRMS (ESI) m/z: [M + H]+ calcd for C13H18IN2O2, 361.0408; found, 361.0407.

N-(2-(Cyclohexylamino)-2-oxoethyl)-2-iodobenzamide (5c)

It was synthesized according to procedure A on a 2 mmol scale (347 mg, 45%) as an off-white solid; mp: 160–161 °C; R = 0.32 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.86 (d, J = 7.9 Hz, 1H), 7.46–7.33 (m, 2H), 7.12 (ddt, J = 9.4, 7.2, 3.6 Hz, 2H), 6.75 (d, J = 8.0 Hz, 1H), 4.13 (d, J = 5.2 Hz, 2H), 3.84–3.54 (m, 1H), 1.96–1.82 (m, 2H), 1.70 (dt, J = 13.5, 3.9 Hz, 2H), 1.60 (dt, J = 12.9, 3.9 Hz, 1H), 1.38–1.25 (m, 3H), 1.24–1.11 (m, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.8, 167.4, 141.3, 139.9, 131.4, 128.4, 128.2, 92.6, 48.6, 44.0, 32.9, 25.5, 24.8. HRMS (ESI) m/z: [M + H]+ calcd for C15H20IN2O2, 387.0564; found, 387.0565.

N-(2-(Benzylamino)-2-oxoethyl)-2-iodobenzamide (5d)

It was synthesized according to procedure A on a 2 mmol scale (284 mg, 36%) as a yellow solid; mp: 143–144 °C; R = 0.34 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 4.8 Hz, 2H), 7.33–7.24 (m, 5H), 7.12 (dt, J = 8.4, 4.3 Hz, 2H), 6.92 (s, 1H), 4.46 (d, J = 4.7 Hz, 2H), 4.28–3.95 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.8, 168.4, 141.1, 139.9, 137.7, 131.5, 128.7, 128.4, 128.2, 128.0, 127.6, 92.5, 43.9, 43.7. HRMS (ESI) m/z: [M + H]+ calcd for C16H16IN2O2, 395.0251; found, 395.0246.

N-(2-((4-Chlorobenzyl)amino)-2-oxoethyl)-2-iodobenzamide (5e)

It was synthesized according to procedure A on a 2 mmol scale (512 mg, 60%) as a yellow solid; mp: 166–167 °C; R = 0.22 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.82 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.33 (p, J = 7.3 Hz, 2H), 7.24–7.15 (m, 5H), 7.10 (t, J = 7.2 Hz, 1H), 4.36 (s, 2H), 4.30–3.93 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.9, 168.6, 140.9, 140.0, 136.4, 133.2, 131.5, 129.2, 128.7, 128.3, 128.2, 92.6, 43.9, 42.9. HRMS (ESI) m/z: [M + H]+ calcd for C16H15ClIN2O2, 428.9861; found, 428.9860.

2-Iodo-N-(1-oxo-1-((4-phenoxyphenyl)amino)propan-2-yl)benzamide (5f)

It was synthesized according to procedure A on a 2 mmol scale (369 mg, 38%) as a yellow solid; mp: 178–179 °C; R = 0.65 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 9.36 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.45–7.37 (m, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.17–7.05 (m, 3H), 6.97 (dd, J = 20.7, 8.3 Hz, 4H), 5.11 (t, J = 7.2 Hz, 1H), 1.64 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 170.0, 169.7, 157.6, 153.4, 141.0, 140.0, 133.5, 131.6, 129.7, 128.3 (d, J = 3.2 Hz), 123.0, 121.7, 119.6, 118.4, 92.5, 50.3, 18.4. HRMS (ESI) m/z: [M + H]+ calcd for C22H20IN2O3, 487.0513; found, 487.0512.

N-(1-(tert-Butylamino)-3-methyl-1-oxobutan-2-yl)-2-iodobenzamide (5g)

It was synthesized according to procedure A on a 2 mmol scale (322 mg, 40%) as a white solid; mp: 234–235 °C; R = 0.51 (20% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.89 (d, J = 8.0 Hz, 1H), 7.48–7.36 (m, 2H), 7.12 (ddd, J = 8.0, 6.3, 2.9 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 5.92 (s, 1H), 4.29 (dd, J = 8.8, 7.1 Hz, 1H), 2.19 (h, J = 6.8 Hz, 1H), 1.39 (s, 9H), 1.06 (dd, J = 10.8, 6.8 Hz, 6H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.7, 169.2, 141.8, 140.0, 131.2, 128.3, 128.1, 92.4, 59.7, 51.8, 31.3, 28.8, 19.3, 18.6. HRMS (ESI) m/z: [M + H]+ calcd for C16H24IN2O2, 403.0877; found, 403.0872.

N-(1-((2-Ethylphenyl)amino)-1-oxopentan-2-yl)-2-iodobenzamide (5h)

It was synthesized according to procedure A on a 2 mmol scale (486 mg, 54%) as a yellow solid; mp: 190–191 °C; R = 0.48 (30% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.10 (s, 1H), 7.93–7.89 (m, 1H), 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.44–7.37 (m, 2H), 7.24 (t, J = 7.7 Hz, 2H), 7.19–7.12 (m, 2H), 6.45 (d, J = 8.0 Hz, 1H), 4.83 (td, J = 7.7, 6.4 Hz, 1H), 2.69 (qd, J = 7.5, 3.3 Hz, 2H), 2.19–2.05 (m, 1H), 1.93–1.80 (m, 1H), 1.61–1.55 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H), 1.05 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.8, 169.4, 141.3, 140.0, 135.3, 134.7, 131.5, 128.7, 128.3, 126.6, 125.7, 123.5, 92.3, 54.4, 33.7, 24.4, 19.1, 14.1, 13.9. HRMS (ESI) m/z: [M + H]+ calcd for C20H24IN2O2, 451.0877; found, 451.0876.

N-(1-((2,3-Dimethoxybenzyl)amino)-4-methyl-1-oxopentan-2-yl)-2-iodobenzamide (5i)

It was synthesized according to procedure A on a 2 mmol scale (398 mg, 39%) as a yellow solid; mp: 156–157 °C; R = 0.45 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.97–7.68 (m, 1H), 7.38–7.31 (m, 2H), 7.08 (ddd, J = 8.0, 6.5, 2.6 Hz, 1H), 7.03–6.95 (m, 2H), 6.90 (dd, J = 7.7, 1.6 Hz, 1H), 6.86 (dd, J = 8.2, 1.5 Hz, 1H), 6.57 (d, J = 8.6 Hz, 1H), 4.73 (td, J = 8.4, 8.0, 5.0 Hz, 1H), 4.48 (d, J = 5.7 Hz, 2H), 3.87 (d, J = 1.7 Hz, 6H), 1.86–1.71 (m, 2H), 1.72–1.63 (m, 1H), 0.97 (dd, J = 10.4, 6.2 Hz, 6H). 13C{1H} NMR (126 MHz, chloroform-d) δ 171.3, 169.3, 152.6, 147.2, 141.7, 139.8, 131.5, 131.2, 128.2, 128.1, 124.2, 121.4, 112.0, 92.4, 60.8, 55.8, 52.2, 41.1, 38.8, 24.9, 23.0, 22.2. HRMS (ESI) m/z: [M + H]+ calcd for C22H28IN2O4, 511.1088; found, 511.1083.

N-(2-(Benzylamino)-1-cyclopentyl-2-oxoethyl)-2-iodobenzamide (5j)

It was synthesized according to procedure A on a 2 mmol scale (573 mg, 62%) as a yellow solid; mp: 205–206 °C; R = 0.54 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J = 8.4 Hz, 1H), 8.50 (t, J = 6.0 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.38–7.28 (m, 5H), 7.27–7.22 (m, 1H), 7.17 (td, J = 7.6, 1.7 Hz, 1H), 4.38 (d, J = 6.0 Hz, 1H), 4.35–4.29 (m, 2H), 2.28 (q, J = 8.2 Hz, 1H), 1.79 (m, J = 13.8, 4.8 Hz, 1H), 1.70–1.55 (m, 3H), 1.49 (m, J = 7.1, 3.0 Hz, 2H), 1.45–1.37 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 171.5, 169.1, 143.3, 139.9, 139.5 (d, J = 3.9 Hz), 131.2, 128.7, 128.3, 127.7, 127.2, 93.9, 57.8 (d, J = 3.9 Hz), 42.5, 42.0, 29.7, 29.4, 25.4, 25.1. HRMS (ESI) m/z: [M + H]+ calcd for C21H24IN2O2, 463.0877; found, 463.0876.

2-Iodo-N-(1-oxo-4-phenyl-1-((2,4,4-trimethylpentan-2-yl)amino)butan-2-yl)benzamide (5k)

It was synthesized according to procedure A on a 2 mmol scale (572 mg, 55%) as a yellow solid; mp: 157–158 °C; R = 0.46 (20% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.87 (dt, J = 8.0, 1.4 Hz, 1H), 7.41–7.27 (m, 4H), 7.22 (d, J = 7.3 Hz, 3H), 7.11 (ddd, J = 7.6, 5.6, 1.8 Hz, 1H), 6.95 (t, J = 18.8 Hz, 1H), 6.48 (d, J = 36.1 Hz, 1H), 4.98–4.49 (m, 1H), 2.80 (dt, J = 9.4, 6.2 Hz, 2H), 2.37–2.16 (m, 1H), 2.18–2.00 (m, 1H), 1.86 (dd, J = 14.8, 1.2 Hz, 1H), 1.79–1.55 (m, 1H), 1.43 (t, J = 3.3 Hz, 6H), 1.00 (d, J = 2.0 Hz, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.8, 169.1, 141.5, 141.2, 140.0, 131.3, 128.6, 128.5, 128.3, 128.1, 126.1, 92.6 (d, J = 3.2 Hz), 55.6, 54.0, 51.7, 34.3 (d, J = 3.6 Hz), 31.9, 31.7, 31.5, 29.3 (d, J = 2.7 Hz), 28.9. HRMS (ESI) m/z: [M + H]+ calcd for C25H34IN2O2, 521.1665; found, 521.1655.

Methyl (2-(2-Iodobenzamido)-2-phenylacetyl)glycinate (5l)

It was synthesized according to procedure A on a 2 mmol scale (307 mg, 34%) as a yellow solid; mp: 159–160 °C; R = 0.32 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.88 (dd, J = 8.0, 1.1 Hz, 1H), 7.57–7.52 (m, 2H), 7.47–7.35 (m, 5H), 7.18 (d, J = 6.9 Hz, 1H), 7.12 (td, J = 7.6, 1.8 Hz, 1H), 6.49 (t, J = 5.4 Hz, 1H), 5.76 (d, J = 6.7 Hz, 1H), 4.20–3.99 (m, 2H), 3.75 (s, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.9, 169.7, 168.6, 141.0, 140.0, 137.1, 131.4, 129.1, 128.7, 128.6, 128.1, 127.7, 92.4, 57.6, 52.5, 41.5. HRMS (ESI) m/z: [M + H]+ calcd for C18H18IN2O4, 453.0306; found, 453.0304.

N-(2-(tert-Butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-2-iodobenzamide (5m)

It was synthesized according to procedure A on a 2 mmol scale (354 mg, 38%) as a yellow solid; mp: 197–198 °C; R = 0.2 (30% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.85 (dd, J = 7.9, 1.1 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.41–7.30 (m, 3H), 7.15–7.04 (m, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.40 (s, 1H), 5.76 (d, J = 7.2 Hz, 1H), 3.80 (s, 3H), 1.26 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.0, 168.5, 159.4, 141.4, 139.9, 131.2, 130.5, 128.8, 128.4, 128.1, 114.2, 92.5, 57.0, 55.3, 51.7, 28.5. HRMS (ESI) m/z: [M + H]+ calcd for C20H24IN2O3, 467.0826; found, 467.0824.

N-(2-(Benzylamino)-2-oxoethyl)-2-bromo-5-methoxybenzamide (5n)

It was synthesized according to procedure A on a 2 mmol scale (316 mg, 42%) as a yellow solid; mp: 153–154 °C; R = 0.5 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.40 (dd, J = 14.2, 7.9 Hz, 3H), 7.33–7.14 (m, 5H), 6.96 (d, J = 3.1 Hz, 1H), 6.79 (dd, J = 8.8, 3.0 Hz, 1H), 4.38 (d, J = 5.7 Hz, 2H), 4.13 (d, J = 5.3 Hz, 2H), 3.74 (s, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 168.5, 168.0, 158.8, 137.8, 137.6, 134.1, 128.6, 127.7, 127.5, 117.8, 114.6, 109.6, 55.6, 43.7, 43.6. HRMS (ESI) m/z: [M + H]+ calcd for C17H18BrN2O3, 377.0495; found, 377.0496.

2-Bromo-N-(1-(4-bromophenyl)-2-oxo-2-(phenethylamino)ethyl)-5-methoxybenzamide (5o)

It was synthesized according to procedure A on a 2 mmol scale (555 mg, 51%) as a yellow solid; mp: 191–192 °C; R = 0.48 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.71 (d, J = 6.6 Hz, 1H), 7.54–7.43 (m, 3H), 7.37–7.26 (m, 2H), 7.21 (dd, J = 5.2, 1.9 Hz, 3H), 7.07 (d, J = 3.1 Hz, 1H), 7.00–6.93 (m, 2H), 6.86 (dd, J = 8.8, 3.1 Hz, 1H), 6.47 (t, J = 5.9 Hz, 1H), 5.66 (d, J = 6.6 Hz, 1H), 3.80 (s, 3H), 3.59 (dt, J = 13.3, 6.7 Hz, 1H), 3.36 (dtd, J = 12.2, 7.0, 5.2 Hz, 1H), 2.69 (td, J = 6.9, 2.2 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 168.9, 166.6, 158.9, 138.3, 137.1, 136.9, 134.4, 132.1, 129.1, 128.6, 128.6, 126.5, 122.5, 118.0, 115.1, 109.7, 57.2, 55.7, 41.0, 35.3. HRMS (ESI) m/z: [M + H]+ calcd for C24H23Br2N2O3, 545.0070; found, 545.0071.

2-Bromo-N-(2-((4-cyanobenzyl)amino)-2-oxo-1-phenylethyl)-4-methoxybenzamide (5p)

It was synthesized according to procedure A on a 2 mmol scale (610 mg, 64%) as a white solid; mp: 193–194 °C; R = 0.58 (66% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.03 (t, J = 5.9 Hz, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.55 (dd, J = 6.6, 2.9 Hz, 2H), 7.40 (t, J = 8.5 Hz, 3H), 7.37–7.33 (m, 3H), 7.13–7.02 (m, 3H), 6.79 (dd, J = 8.7, 2.5 Hz, 1H), 6.13 (d, J = 7.4 Hz, 1H), 4.41 (dd, J = 15.8, 6.0 Hz, 1H), 4.27 (dd, J = 15.8, 5.6 Hz, 1H), 3.84 (s, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 170.2, 166.8, 161.6, 143.4, 137.8, 132.2, 131.1, 129.0, 128.5, 128.1, 127.8, 127.2, 120.6, 119.0, 118.7, 113.3, 110.8, 57.5, 55.8, 43.0. HRMS (ESI) m/z: [M + H]+ calcd for C24H21BrN3O3, 478.0761; found, 478.0760.

2-Bromo-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-2-yl)ethyl)-4-methoxybenzamide (5q)

It was synthesized according to procedure A on a 2 mmol scale (235 mg, 28%) as a brown solid; mp: 164–165 °C; R = 0.36 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.55 (d, J = 5.0 Hz, 1H), 8.15 (d, J = 5.9 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.25 (t, J = 6.3 Hz, 1H), 7.16 (s, 2H), 6.93–6.85 (m, 1H), 5.65 (d, J = 5.8 Hz, 1H), 3.83 (s, 3H), 1.31 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 167.2, 166.7, 161.4, 156.2, 148.6, 137.4, 131.5, 128.8, 123.0, 121.2, 120.5, 118.9, 113.4, 59.1, 55.7, 51.7, 28.6. HRMS (ESI) m/z: [M + H]+ calcd for C19H23BrN3O3, 420.0917; found, 420.0916.

2-Bromo-N-(1-(tert-butylamino)-4-(methylthio)-1-oxobutan-2-yl)-5-methylbenzamide (5r)

It was synthesized according to procedure A on a 2 mmol scale (256 mg, 32%) as a yellow solid; mp: 178–179 °C; R = 0.42 (30% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.43 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.06 (dd, J = 8.2, 2.2 Hz, 1H), 6.69 (s, 1H), 4.78 (dt, J = 8.1, 6.7 Hz, 1H), 2.61 (dddd, J = 41.8, 13.3, 8.7, 6.3 Hz, 2H), 2.30 (s, 3H), 2.21–2.03 (m, 5H), 1.34 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 169.8, 167.7, 137.6, 136.9, 133.1, 132.2, 130.0, 116.0, 53.2, 51.6, 31.9, 30.2, 28.7, 20.8, 15.3. HRMS (ESI) m/z: [M + H]+ calcd for C17H26BrN2O2S, 401.0893; found, 401.0890.

2-Bromo-N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-methylbenzamide (5s)

It was synthesized according to procedure A on a 2 mmol scale (349 mg, 40%) as a yellow solid; mp: 199–200 °C; R = 0.49 (20% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.62 (d, J = 7.0 Hz, 1H), 7.49–7.41 (m, 4H), 7.35–7.30 (m, 2H), 7.18–7.13 (m, 1H), 6.35 (s, 1H), 5.74 (d, J = 7.0 Hz, 1H), 2.37 (s, 3H), 1.27 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 168.3, 166.8, 142.3, 136.9, 134.0, 133.7, 129.7, 129.0, 128.7, 128.2, 119.4, 57.2, 51.9, 28.5, 21.0. HRMS (ESI) m/z: [M + H]+ calcd for C20H23BrClN2O2, 437.0626; found, 437.0625.

2-Bromo-N-(2-(tert-butylamino)-2-oxoethyl)-4-nitrobenzamide (5t)

It was synthesized according to procedure A on a 2 mmol scale (214 mg, 30%) as a white solid; mp: 169–170 °C; R = 0.21 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.49 (d, J = 2.1 Hz, 1H), 8.23 (dd, J = 8.4, 2.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 4.8 Hz, 1H), 6.09 (s, 1H), 4.09 (d, J = 4.7 Hz, 2H), 1.39 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 166.7, 166.1, 148.7, 142.8, 130.1, 128.5, 122.5, 120.3, 52.0, 44.1, 28.7. HRMS (ESI) m/z: [M + H]+ calcd for C13H17BrN3O4, 358.0397; found, 358.0398.

N-(2-(tert-Butylamino)-2-oxoethyl)-2-chloroquinoline-3-carboxamide (5u)

It was synthesized according to procedure A on a 2 mmol scale (255 mg, 40%) as a white solid; mp: 187–188 °C; R = 0.56 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.45 (d, J = 12.3 Hz, 1H), 8.00 (t, J = 7.5 Hz, 1H), 7.89–7.74 (m, 3H), 7.64–7.51 (m, 1H), 6.45 (d, J = 43.1 Hz, 1H), 4.15 (d, J = 5.0 Hz, 2H), 1.39 (d, J = 3.8 Hz, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 167.2, 165.4, 147.9, 146.0, 139.7, 132.1, 128.4 (d, J = 4.1 Hz), 128.2, 127.9, 126.2, 51.8, 44.5, 28.7. HRMS (ESI) m/z: [M + H]+ calcd for C16H19ClN3O2, 320.1160; found, 320.1160.

2-Bromo-N-(2-(tert-butylamino)-2-oxoethyl)thiophene-3-carboxamide (5v)

It was synthesized according to procedure A on a 2 mmol scale (286 mg, 45%) as a white solid; mp: 165–166 °C; R = 0.65 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 7.62 (t, J = 4.3 Hz, 1H), 7.35 (d, J = 5.8 Hz, 1H), 7.25 (d, J = 5.8 Hz, 1H), 6.52 (s, 1H), 4.12 (d, J = 4.6 Hz, 2H), 1.40 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 167.7, 162.4, 135.1, 129.2, 126.2, 113.6, 51.7, 44.2, 28.8. HRMS (ESI) m/z: [M + H]+ calcd for C11H16BrN2O2S, 319.0110; found, 319.0111.

N-(tert-Butyl)-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7aa)

It was synthesized according to procedure B on a 0.3 mmol scale (76 mg, 70%) as a red solid; mp: 256–257 °C; R = 0.48 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.66 (t, J = 7.9 Hz, 1H), 8.31 (t, J = 7.0 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.72 (q, J = 7.0 Hz, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.44 (dt, J = 12.1, 6.9 Hz, 2H), 7.38–7.31 (m, 1H), 6.47 (s, 1H), 5.05 (s, 2H), 1.36 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.6, 166.0, 164.1, 155.8, 137.0, 134.5, 134.3, 133.6, 132.5, 131.0, 128.5, 127.3, 123.6, 123.2, 123.1, 123.0, 109.1, 52.0, 49.5, 28.7. HRMS (ESI) m/z: [M + H]+ calcd for C22H21N2O3, 361.1547; found, 361.1547.

N-(tert-Butyl)-2-(8,9-dimethoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7ab)

It was synthesized according to procedure B on a 0.3 mmol scale (81 mg, 64%) as a red solid; mp: 262–263 °C; R = 0.50 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.58 (dt, J = 8.2, 0.8 Hz, 1H), 8.32–8.17 (m, 1H), 7.77 (s, 1H), 7.70 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.42 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.12 (s, 1H), 6.62 (s, 1H), 4.99 (s, 2H), 4.06 (s, 3H), 3.96 (s, 3H), 1.35 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.4, 166.8, 164.4, 155.6, 152.5, 150.6, 134.3, 132.8, 130.5, 128.5, 127.6, 126.7, 123.1, 122.5, 108.5, 108.3, 107.3, 56.9, 56.3, 51.8, 50.6, 28.6. HRMS (ESI) m/z: [M + H]+ calcd for C24H25N2O5, 421.1758; found, 421.1758.

N-Butyl-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7b)

It was synthesized according to procedure B on a 0.3 mmol scale (73 mg, 68%) as a red solid; mp: 259–260 °C; R = 0.54 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.81–8.53 (m, 1H), 8.40–8.22 (m, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.75 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.59 (dd, J = 7.1, 1.2 Hz, 1H), 7.54–7.41 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 6.69 (s, 1H), 5.14 (s, 2H), 3.30 (q, J = 6.8 Hz, 2H), 1.50 (dd, J = 8.5, 6.2 Hz, 2H), 1.37–1.29 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.6, 167.0, 164.3, 155.6, 136.9, 134.5, 134.4, 133.7, 132.5, 131.2, 128.5, 127.5, 123.7, 123.3, 123.2, 123.1, 109.3, 49.1, 39.6, 31.4, 20.0, 13.7. HRMS (ESI) m/z: [M + H]+ calcd for C22H21N2O3, 361.1547; found, 361.1547.

N-Cyclohexyl-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7c)

It was synthesized according to procedure B on a 0.3 mmol scale (60 mg, 52%) as a red solid; mp: 321–322 °C; R = 0.46 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.64–7.40 (m, 5H), 5.18 (s, 2H), 3.58 (s, 1H), 1.85–1.50 (m, 4H), 1.54 (d, J = 9.3 Hz, 1H), 1.25 (q, J = 10.7 Hz, 5H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.5, 165.5, 162.9, 157.6, 137.4, 134.7, 134.7 (d, J = 24.1 Hz), 134.0, 132.3, 131.8, 128.7, 127.7, 123.3, 123.2, 123.1, 107.3, 48.4, 47.0, 32.7, 25.6, 24.9. HRMS (ESI) m/z: [M + H]+ calcd for C24H23N2O3, 387.1703; found, 387.1704.

N-Benzyl-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7d)

It was synthesized according to procedure B on a 0.3 mmol scale (47 mg, 40%) as a red solid; mp: 289–290 °C; R = 0.55 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.00 (t, J = 6.0 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.91–7.81 (m, 1H), 7.63–7.54 (m, 2H), 7.48 (d, J = 2.5 Hz, 3H), 7.35–7.29 (m, 2H), 7.25 (d, J = 6.3 Hz, 3H), 5.27 (s, 2H), 4.35 (d, J = 5.9 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.5, 166.8, 163.0, 157.5, 139.4, 137.3, 134.8 (d, J = 8.4 Hz), 134.6, 134.1, 132.4, 131.8, 128.8, 128.7, 127.7, 127.4, 123.4, 123.3, 123.1 (d, J = 5.1 Hz), 107.5, 47.4, 42.8. HRMS (ESI) m/z: [M + H]+ calcd for C25H19N2O3, 395.1390; found, 395.1389.

N-(4-Chlorobenzyl)-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7e)

It was synthesized according to procedure B on a 0.3 mmol scale (103 mg, 80%) as a red solid; mp: 291–292 °C; R = 0.42 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.01 (t, J = 6.0 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.58–7.52 (m, 2H), 7.49–7.43 (m, 3H), 7.36 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 5.23 (s, 2H), 4.32 (d, J = 5.9 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.4, 166.9, 162.9, 157.3, 138.5, 137.2, 134.7 (d, J = 6.7 Hz), 134.5, 134.0, 132.3, 132.0, 131.7, 129.6, 128.7, 127.7, 123.3, 123.3, 123.2–122.9 (m), 107.5, 47.3, 42.2. HRMS (ESI) m/z: [M + H]+ calcd for C25H18ClN2O3, 429.1001; found, 429.0999. [M + Na]+ calcd for C25H17ClN2O3Na, 451.0820; found, 451.0819.

2-(5,11-Dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-N-(4-phenoxyphenyl)propanamide (7f)

It was synthesized according to procedure B on a 0.3 mmol scale (96 mg, 66%) as a red solid; mp: 255–256 °C; R = 0.66 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.67–7.47 (m, 6H), 7.36 (t, J = 7.8 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.1 Hz, 4H), 5.58 (s, 1H), 1.78 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.7, 167.1, 162.6, 157.8, 152.3, 137.4, 135.4, 134.8, 134.5 (d, J = 28.0 Hz), 132.4, 131.7, 130.4, 128.4, 127.7, 124.2 (d, J = 10.1 Hz), 123.8, 123.5, 123.2 (d, J = 20.1 Hz), 122.1, 119.7, 118.4, 108.5, 57.5, 15.4. HRMS (ESI) m/z: [M + Na]+ calcd for C31H22N2O4Na, 509.1472; found, 509.1470.

N-(tert-Butyl)-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-3-methylbutanamide (7g)

It was synthesized according to procedure B on a 0.3 mmol scale (74 mg, 61%) as a red solid; mp: 249–250 °C; R = 0.44 (10% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.77 (d, J = 8.1 Hz, 1H), 8.68 (s, 1H), 8.52 (d, J = 7.6 Hz, 1H), 8.36 (dd, J = 8.2, 1.3 Hz, 1H), 7.82–7.77 (m, 1H), 7.65 (dd, J = 7.1, 1.3 Hz, 1H), 7.58–7.49 (m, 2H), 7.41 (t, J = 7.4 Hz, 1H), 4.67 (d, J = 10.8 Hz, 1H), 3.32–3.21 (m, 1H), 1.42 (s, 9H), 1.18 (d, J = 6.6 Hz, 3H), 0.68 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.9, 168.7, 165.7, 157.3, 137.5, 134.5, 134.4, 134.1, 132.3, 130.8, 128.2, 127.5, 124.7, 124.1, 123.6, 123.2, 110.4, 75.3, 51.2, 29.7, 28.6, 19.8. HRMS (ESI) m/z: [M + H]+ calcd for C25H27N2O3, 403.2016; found, 403.2015.

2-(5,11-Dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-N-(2-ethylphenyl)pentanamide (7h)

It was synthesized according to procedure B on a 0.3 mmol scale (93 mg, 69%) as a red solid; mp: 285–286 °C; R = 0.64 (30% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 10.24 (s, 1H), 8.77 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.55 (m, J = 7.7, 2.9 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 7.8 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 5.47 (dd, J = 9.2, 6.3 Hz, 1H), 2.82–2.76 (m, 1H), 2.74 (d, J = 7.6 Hz, 2H), 2.55–2.44 (m, 1H), 1.36–1.31 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H), 0.93 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.8, 168.9, 165.8, 156.7, 137.3, 135.1, 135.0, 134.7, 134.3, 134.1, 133.6, 132.3, 131.1, 128.9, 128.2, 127.8, 126.6, 125.4, 124.1, 123.7, 123.5, 122.9, 110.7, 67.7, 31.5, 24.8, 19.8, 14.3, 13.4. HRMS (ESI) m/z: [M + Na]+ calcd for C29H26N2O3Na, 473.1836; found, 473.1834.

N-(2,3-Dimethoxybenzyl)-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-4-methylpentanamide (7i)

It was synthesized according to procedure B on a 0.3 mmol scale (110 mg, 72%) as a red solid; mp: 301–302 °C; R = 0.58 (50% EtOAc/petroleum ether). Mixture of rotamers (ratio, 3:2); 1H NMR (500 MHz, chloroform-d) δ 8.71 (dd, J = 20.7, 6.9 Hz, 1H), 8.33 (dd, J = 20.5, 7.7 Hz, 1.6H), 8.14 (d, J = 7.2 Hz, 0.6H), 7.75 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 7.0 Hz, 0.6H), 7.58–7.43 (m, 2H), 7.39 (t, J = 7.3 Hz, 0.6H), 7.33 (d, J = 7.5 Hz, 0.4H), 7.26 (t, J = 7.3 Hz, 0.4H), 7.19 (t, J = 7.6 Hz, 0.4H), 7.03 (t, J = 7.9 Hz, 0.6H), 6.94 (d, J = 7.6 Hz, 0.6H), 6.86 (t, J = 7.3 Hz, 1H), 6.73 (t, J = 8.0 Hz, 0.8H), 6.63–6.54 (m, 0.8H), 5.43 (dd, J = 10.0, 5.1 Hz, 0.6H), 4.66 (dd, J = 15.4, 6.0 Hz, 0.6H), 4.56–4.43 (m, 1H), 4.39 (dd, J = 14.6, 5.3 Hz, 0.4H), 3.87 (d, J = 11.7 Hz, 3.6H), 3.75 (s, 1.2H), 3.62 (s, 1.2H), 2.71 (ddd, J = 14.3, 9.6, 5.0 Hz, 0.6H), 2.62–2.49 (m, 0.4H), 2.09 (td, J = 10.9, 8.2, 4.2 Hz, 0.6H), 1.94 (ddd, J = 14.3, 9.8, 4.5 Hz, 0.4H), 1.72 (s, 0.4H), 1.53 (d, J = 9.0 Hz, 0.6H), 1.39–1.31 (m, 1H), 1.02 (d, J = 6.4 Hz, 1.2H), 0.87 (d, J = 6.6 Hz, 1.8H), 0.83 (d, J = 6.6 Hz, 1.2H), 0.78 (d, J = 6.5 Hz, 1.8H). 13C{1H} NMR (126 MHz, chloroform-d, major rotamer) δ 190.7, 170.1, 165.2, 156.9, 152.6, 147.2, 137.3, 134.4, 134.0, 133.2, 132.2, 131.5, 131.0, 130.4, 128.2, 127.5, 124.1, 123.7, 123.4, 122.6, 120.9, 111.9, 110.3, 64.4, 60.8, 55.8, 38.9, 37.6, 25.2, 22.9, 21.4. HRMS (ESI) m/z: [M + H]+ calcd for C31H31N2O5, 511.2228; found, 511.2225.

N-Benzyl-2-cyclopentyl-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7j)

It was synthesized according to procedure B on a 0.3 mmol scale (104 mg, 75%) as a red solid; mp: 262–263 °C; R = 0.81 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.87 (t, J = 6.0 Hz, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.31 (dd, J = 8.3, 1.3 Hz, 1H), 7.78 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 7.65 (dd, J = 7.1, 1.3 Hz, 1H), 7.53 (dtd, J = 12.0, 7.4, 1.3 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.36 (s, 1H), 7.32–7.27 (m, 2H), 5.00 (d, J = 10.9 Hz, 1H), 4.72 (dd, J = 15.1, 6.6 Hz, 1H), 4.39 (dd, J = 15.1, 5.2 Hz, 1H), 1.95 (ddd, J = 12.6, 7.6, 5.0 Hz, 1H), 1.78–1.35 (m, 8H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.8, 170.0, 165.7, 156.9, 138.2, 137.4, 134.5, 134.5, 134.1, 132.3, 131.0, 128.7, 128.1, 127.6, 127.5, 127.4, 124.2, 124.0, 123.6, 123.3, 110.3, 71.9, 43.5, 39.1, 30.6, 25.4, 24.6. HRMS (ESI) m/z: [M + H]+ calcd for C30H27N2O3, 463.2016; found, 463.2017.

2-(5,11-Dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-4-phenyl-N-(2,4,4-trimethylpentan-2-yl)butanamide (7k)

It was synthesized according to procedure B on a 0.3 mmol scale (101 mg, 65%) as a red solid; mp: 274–275 °C; R = 0.65 (20% EtOAc/petroleum ether). Mixture of rotamers (ratio, 3:1); 1H NMR (500 MHz, chloroform-d) δ 8.75 (d, J = 8.1 Hz, 1H), 8.36 (dd, J = 8.1, 1.3 Hz, 1H), 7.98 (s, 0.75H), 7.85 (d, J = 6.8 Hz, 0.75H), 7.80 (td, J = 7.0, 1.7 Hz, 1H), 7.69 (d, J = 7.5 Hz, 0.25H), 7.60 (ddd, J = 14.2, 6.6, 1.7 Hz, 1H), 7.56–7.50 (m, 1H), 7.46–7.31 (m, 2H), 7.13–6.88 (m, 5H), 6.39 (dd, J = 10.0, 3.3 Hz, 0.25H), 5.79 (s, 0.25H), 5.05 (dd, J = 9.9, 4.3 Hz, 0.75H), 3.06 (dq, J = 11.7, 6.8, 4.0 Hz, 1H), 2.80 (dt, J = 14.5, 7.4 Hz, 0.25H), 2.69 (dq, J = 9.4, 5.9, 3.1 Hz, 1.5H), 2.56 (dt, J = 14.7, 7.6 Hz, 0.25H), 2.42 (dq, J = 19.3, 7.8, 6.4 Hz, 1H), 1.95–1.71 (m, 1.5H), 1.68 (d, J = 10.3 Hz, 0.5H), 1.45 (d, J = 4.7 Hz, 4.5H), 1.38 (s, 1H), 1.27 (d, J = 5.5 Hz, 1.5H), 0.95 (s, 6.75H), 0.81 (s, 2.25H). 13C{1H} NMR (126 MHz, chloroform-d, major rotamer) δ 190.8, 168.7, 165.3, 157.1, 138.9, 137.2, 134.5, 134.2, 133.8, 132.3, 130.7, 128.4, 128.4, 128.2, 127.5, 126.3, 124.0, 123.7, 123.6, 123.1, 110.2, 66.3, 55.4, 51.5, 32.4, 31.4, 30.0, 29.2, 29.0. HRMS (ESI) m/z: [M + H]+ calcd for C34H37N2O3, 521.2799; found, 521.2795.

Methyl (2-(5,11-Dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-2-phenylacetyl)glycinate (7l)

It was synthesized according to procedure B on a 0.3 mmol scale (80 mg, 59%) as a red solid; mp: 255–256 °C; R = 0.50 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.76 (d, J = 8.1 Hz, 1H), 8.33 (d, J = 8.1, 1.3 Hz, 1H), 7.85–7.70 (m, 1H), 7.67–7.59 (m, 1H), 7.50 (m, J = 19.0, 7.4 Hz, 6H), 7.42 (t, J = 7.2 Hz, 1H), 7.35–7.31 (m, 2H), 7.05 (d, J = 5.5 Hz, 1H), 6.55 (s, 1H), 4.35 (dd, J = 18.3, 6.2 Hz, 1H), 4.01 (dd, J = 18.3, 4.1 Hz, 1H), 3.77 (s, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.6, 170.0, 168.1, 164.3, 156.4, 137.1, 134.6, 134.5, 133.4, 133.2, 132.4, 131.0, 129.5, 129.1, 128.7, 127.6, 127.5, 124.1, 123.7, 123.5, 122.8, 110.2, 66.2, 52.5, 41.8. HRMS (ESI) m/z: [M + H]+ calcd for C27H21N2O5, 453.1445; found, 453.1446. [M + Na]+ calcd for C27H20N2O5Na, 475.1264; found, 475.1263.

N-(tert-Butyl)-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-2-(4-methoxyphenyl)acetamide (7m)

It was synthesized according to procedure B on a 0.3 mmol scale (78 mg, 56%) as a red solid; mp: 259–260 °C; R = 0.38 (30% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.76 (d, J = 8.1 Hz, 1H), 8.33 (dd, J = 8.0, 1.3 Hz, 1H), 7.78 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.66–7.60 (m, 1H), 7.57–7.52 (m, 1H), 7.50 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.40–7.31 (m, 4H), 6.95 (d, J = 8.8 Hz, 2H), 6.48 (s, 1H), 3.83 (s, 3H), 1.39 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.7, 167.3, 164.4, 159.6, 156.9, 137.3, 134.6, 134.3, 133.4, 132.4, 130.9, 128.7, 128.6, 127.4, 125.9, 124.3, 123.7, 123.3, 123.1, 114.6, 109.9, 55.3, 52.0, 29.7, 28.6. HRMS (ESI) m/z: [M + H]+ calcd for C29H27N2O4, 467.1965; found, 467.1959.

N-Benzyl-2-(3-methoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7n)

It was synthesized according to procedure B on a 0.3 mmol scale (79 mg, 62%) as a red solid; mp: 299–300 °C; R = 0.72 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 8.98 (t, J = 6.0 Hz, 1H), 8.45 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.50 (dd, J = 5.5, 2.8 Hz, 1H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 7.42–7.37 (m, 3H), 7.31 (t, J = 7.4 Hz, 2H), 7.25 (d, J = 8.1 Hz, 3H), 5.21 (s, 2H), 4.34 (d, J = 5.8 Hz, 2H), 3.87 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.6, 166.8, 162.6, 158.8, 155.1, 139.5, 137.6, 134.4, 134.0, 131.3, 128.8, 127.7, 127.4, 126.2, 124.9, 124.8, 124.3, 123.0, 122.9, 109.3, 107.8, 55.9, 47.4, 42.8. HRMS (ESI) m/z: [M + H]+ calcd for C26H21N2O4, 425.1496; found, 425.1496.

2-(4-Bromophenyl)-2-(3-methoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-N-phenethylacetamide (7o)

It was synthesized according to procedure B on a 0.3 mmol scale (87 mg, 49%) as a red solid; mp: 274–275 °C; R = 0.51 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.67 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.61–7.55 (m, 1H), 7.47 (d, J = 7.7 Hz, 3H), 7.40 (dd, J = 8.9, 2.7 Hz, 1H), 7.29 (s, 1H), 7.25–7.10 (m, 8H), 6.74 (s, 1H), 6.35 (s, 1H), 3.93 (s, 3H), 3.66 (s, 2H), 2.87 (s, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.7, 167.5, 164.0, 159.3, 153.7, 138.3, 137.3, 134.2, 133.5, 132.8, 132.3, 130.6, 128.9, 128.7, 128.6, 126.6, 126.4, 125.4, 125.1, 123.5, 122.7, 122.5(d, J = 12.1 Hz), 110.6, 108.5, 55.7, 41.0, 35.2, 29.7. HRMS (ESI) m/z: [M + H]+ calcd for C33H26BrN2O4, 593.1071; found, 593.1070.

N-(4-Cyanobenzyl)-2-(2-methoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-2-phenylacetamide (7p)

It was synthesized according to procedure B on a 0.3 mmol scale (55 mg, 35%) as a red solid; mp: 283–284 °C; R = 0.54 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 8.09 (s, 1H), 7.68 (d, J = 7.4 Hz, 2H), 7.50 (dd, J = 27.1, 7.3 Hz, 4H), 7.37 (m, J = 7.7 Hz, 5H), 7.31 (m, J = 7.3 Hz, 2H), 7.18 (dd, J = 8.8, 2.5 Hz, 1H), 4.49 (dd, J = 15.8, 6.2 Hz, 1H), 4.24 (dd, J = 16.0, 5.5 Hz, 1H), 3.94 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.7, 167.5, 164.4, 162.8, 158.2, 145.7, 136.8, 134.6, 134.5, 134.4, 133.8, 132.5, 132.4, 131.65 (d, J = 4.5 Hz), 131.1, 128.6, 128.1, 124.4, 123.0, 119.4, 117.8, 117.0, 109.8, 108.7, 104.5, 56.2, 56.1, 43.1. HRMS (ESI) m/z: [M + H]+ calcd for C33H24N3O4, 526.1761; found, 526.1755. [M + Na]+ calcd for C33H23N3O4Na, 548.1581; found, 548.1574.

N-(tert-Butyl)-2-(2-methoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-2-(pyridin-2-yl)acetamide (7q)

It was synthesized according to procedure B on a 0.3 mmol scale (91 mg, 65%) as a red solid; mp: 252–253 °C; R = 0.54 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 9.95 (s, 1H), 8.72 (s, 1H), 8.40–8.17 (m, 2H), 7.78 (s, 1H), 7.67–7.48 (m, 2H), 7.30 (d, J = 4.0 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.04 (dd, J = 25.8, 7.9 Hz, 3H), 6.55 (d, J = 7.4 Hz, 1H), 4.03 (s, 3H), 1.43 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 191.3, 164.6, 164.4, 163.3, 157.6, 155.9, 148.4, 138.2, 137.8, 134.9, 134.5, 132.0, 131.2, 130.2, 123.4, 122.7, 122.5, 120.3, 117.5, 116.8, 109.1, 104.0, 59.1, 55.8, 51.8, 28.8. HRMS (ESI) m/z: [M + H]+ calcd for C28H26N3O4, 468.1918; found, 468.1913.

N-(tert-Butyl)-2-(3-methyl-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-4-(methylthio)butanamide (7r)

It was synthesized according to procedure B on a 0.3 mmol scale (85 mg, 63%) as a red solid; mp: 283–284 °C; R = 0.56 (30% EtOAc/petroleum ether). Mixture of rotamers (ratio, 1:1); 1H NMR (500 MHz, DMSO-d6) δ 8.51 (dd, J = 20.7, 8.2 Hz, 1H), 8.06 (s, 0.5H), 7.97 (s, 0.5H), 7.86 (d, J = 7.7 Hz, 0.5H), 7.68 (dd, J = 18.6, 11.5 Hz, 1.5H), 7.59–7.27 (m, 4H), 6.37 (d, J = 10.0 Hz, 0.5H), 5.31 (s, 0.5H), 2.92 (s, 0.5H), 2.65 (s, 0.5H), 2.45 (d, J = 5.6 Hz, 5.5H), 2.16 (s, 0.5H), 1.96 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 16.5 Hz, 9H). 13C{1H} NMR (126 MHz, DMSO-d6, major rotamer) δ 190.7, 167.1, 162.8, 157.8, 138.1, 137.5, 135.8, 134.2, 133.4, 131.1, 129.9, 127.8, 124.9, 123.8, 123.0, 122.6, 108.6, 61.1, 56.1, 51.3, 31.9, 29.0, 21.6, 15.0. HRMS (ESI) m/z: [M + H]+ calcd for C26H29N2O3S, 449.1893; found, 449.1893.

N-(tert-Butyl)-2-(4-chlorophenyl)-2-(2-methyl-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7s)

It was synthesized according to procedure B on a 0.3 mmol scale (86 mg, 59%) as a red solid; mp: 261–262 °C; R = 0.58 (20% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.58 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.64 (dd, J = 6.4, 1.9 Hz, 2H), 7.37 (d, J = 8.2 Hz, 4H), 7.32 (dd, J = 13.0, 8.6 Hz, 4H), 6.43 (s, 1H), 2.56 (s, 3H), 1.39 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.8, 166.8, 164.3, 156.6, 145.8, 137.2, 134.4, 134.4, 133.6, 132.9, 132.4, 131.0, 129.4, 129.3, 129.2, 128.7, 128.6, 128.4, 123.4, 123.4, 110.1, 52.1, 29.7, 28.5, 22.2. HRMS (ESI) m/z: [M + H]+ calcd for C29H26ClN2O3, 485.1627; found, 485.1623.

N-(tert-Butyl)-2-(2-nitro-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (7t)

It was synthesized according to procedure B on a 0.3 mmol scale (98 mg, 81%) as a red solid; mp: 239–240 °C; R = 0.40 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 9.45 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H), 8.18 (dd, J = 8.8, 2.3 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.63 (dd, J = 6.9, 1.3 Hz, 1H), 7.49 (td, J = 7.6, 1.4 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 6.28 (s, 1H), 5.11 (s, 2H), 1.40 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 189.6, 165.0, 162.9, 157.5, 151.4, 136.5, 134.4, 133.8, 133.1, 131.9, 130.6, 126.3, 123.7, 123.4, 120.7, 119.1, 108.2, 52.3, 49.2, 28.7. HRMS (ESI) m/z: [M + H]+ calcd for C22H20N3O5, 406.1398; found, 406.1397.

N-(tert-Butyl)-2-(6,13-dioxo-6,13-dihydro-5H-benzo[b]indeno[1,2-h][1,6]naphthyridin-5-yl)acetamide (7u)

It was synthesized according to procedure B on a 0.3 mmol scale (69 mg, 56%) as a red solid; mp: 297–298 °C; R = 0.62 (75% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J = 8.6 Hz, 1H), 8.02–7.94 (m, 1H), 7.68 (dd, J = 13.5, 7.0 Hz, 2H), 7.63 (d, J = 4.1 Hz, 2H), 7.58 (dd, J = 7.3, 3.9 Hz, 1H), 5.25 (s, 2H), 1.30 (s, 9H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 188.0, 165.6, 163.7, 161.8, 151.5, 147.6, 139.8, 136.8, 134.5, 133.9, 132.5, 130.5, 129.1, 127.1, 126.3, 124.0, 123.1, 118.3, 108.2, 79.7, 55.4, 51.4, 28.9. HRMS (ESI) m/z: [M + H]+ calcd for C25H22N3O3, 412.1656; found, 412.1653.

N-(tert-Butyl)-2-(4,10-dioxo-4,10-dihydro-5H-indeno[1,2-b]thieno[2,3-d]pyridin-5-yl)acetamide (7v)

It was synthesized according to procedure B on a 0.3 mmol scale (41 mg, 37%) as a red solid; mp: 268–269 °C; R = 0.55 (60% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.03 (d, J = 7.6 Hz, 1H), 7.71–7.60 (m, 2H), 7.50 (td, J = 7.7, 1.3 Hz, 1H), 7.46–7.37 (m, 2H), 6.54 (s, 1H), 5.08 (d, J = 5.3 Hz, 2H), 1.37 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 188.3, 165.9, 160.3, 154.4, 141.8, 137.6, 134.4, 134.1, 131.2, 128.2, 127.1, 124.7, 123.9, 123.5, 110.4, 52.0, 49.4, 28.6. HRMS (ESI) m/z: [M + H]+ calcd for C20H19N2O3S, 367.1111; found, 367.1111.

2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-2-(3-methoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-N-phenethylacetamide (8)

It was synthesized according to procedure C on a 0.1 mmol scale (62 mg, 95%) as a red solid; mp: 305–306 °C; R = 0.42 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, chloroform-d) δ 8.70 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 2.7 Hz, 1H), 7.62–7.57 (m, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.47 (s, 1H), 7.41 (dd, J = 8.9, 2.7 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 9.0 Hz, 3H), 7.24–7.13 (m, 5H), 7.11 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.4, 2.2 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.58 (s, 1H), 4.33 (s, 4H), 3.94 (s, 3H), 3.67 (q, J = 6.5 Hz, 2H), 2.88 (t, J = 6.9 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 190.8, 167.9, 164.0, 159.2, 154.1, 143.8, 143.6, 140.9, 138.6, 137.6, 134.4, 133.5, 133.4, 132.0, 130.4, 128.7, 128.6, 127.8, 127.4, 126.5 (d, J = 3.1 Hz), 125.7, 125.4, 125.0, 123.3, 122.5, 120.1, 117.7, 115.8, 110.5, 108.6, 64.5 (d, J = 5.1 Hz), 55.6, 41.1, 35.3. HRMS (ESI) m/z: [M + H]+ calcd for C41H33N2O6, 649.2333; found, 649.2332. [M + Na]+ calcd for C41H32N2O6Na, 671.2153; found, 671.2152.

N-(4-(1H-Tetrazol-5-yl)benzyl)-2-(2-methoxy-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-2-phenylacetamide (9)

It was synthesized according to procedure D on a 0.1 mmol scale (47 mg, 82%) as a red solid; mp: 264–265 °C; R = 0.46 (15% MeOH/dichloromethane). 1H NMR (500 MHz, methanol-d4) δ 8.21 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.98–7.91 (m, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.39 (dd, J = 7.6, 3.4 Hz, 3H), 7.36–7.33 (m, 1H), 7.31 (s, 1H), 7.22 (dd, J = 5.7, 2.6 Hz, 2H), 7.06 (dd, J = 9.0, 2.6 Hz, 1H), 6.87 (s, 1H), 4.66 (d, J = 15.0 Hz, 1H), 4.37 (d, J = 15.0 Hz, 1H), 3.87 (s, 3H). 13C{1H} NMR (126 MHz, methanol-d4) δ 190.8, 168.6, 164.6, 163.4, 161.2, 157.5, 138.9, 136.5, 134.5, 134.3, 133.6, 132.9, 130.8, 130.2, 128.6, 128.5, 128.1, 128.0, 127.7, 126.4, 123.4, 122.5, 117.4, 116.9, 109.1, 103.8, 54.8, 43.2, 35.2. HRMS (ESI) m/z: [M + H]+ calcd for C33H25N6O4, 569.1932; found, 569.1926. [M + Na]+ calcd for C33H24N6O4Na, 591.1751; found, 591.1744.

2-(2-Amino-5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)-N-(tert-butyl)acetamide (10)

It was synthesized according to procedure F on a 0.3 mmol scale (108 mg, 96%) as a red solid; mp: 188–189 °C; R = 0.33 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.55–7.47 (m, 2H), 7.42 (dt, J = 7.3, 3.4 Hz, 2H), 6.73 (dd, J = 8.7, 2.3 Hz, 1H), 6.33 (s, 2H), 5.11 (s, 2H), 1.28 (s, 9H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.5, 166.1, 162.1, 157.9, 154.5, 137.6, 134.9, 134.3, 133.5, 131.4, 130.5, 123.0, 122.6, 115.7 (d, J = 4.9 Hz), 112.3, 106.7, 103.2 (d, J = 7.4 Hz), 51.2, 46.3, 28.9 (d, J = 5.2 Hz). HRMS (ESI) m/z: [M + H]+ calcd for C22H22N3O3, 376.1656; found, 376.1654.

2-(2-Amino-5,11-dioxo-5,6a,11,11a-tetrahydro-6H-indeno[1,2-c]isoquinolin-6-yl)-N-(tert-butyl)acetamide (11)

It was synthesized according to procedure E on a 0.2 mmol scale (44 mg, 58%) as a white solid; mp: 155–156 °C; R = 0.22 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, methanol-d4) δ 8.04 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.71–7.65 (m, 1H), 7.63–7.56 (m, 1H), 7.42–7.31 (m, 2H), 7.15 (d, J = 2.3 Hz, 1H), 6.82 (dd, J = 8.8, 2.3 Hz, 1H), 5.50 (s, 1H), 5.19 (s, 2H), 1.39 (s, 9H). 13C{1H} NMR (126 MHz, methanol-d4) δ 167.7, 163.8, 153.0, 147.8, 140.7, 136.5, 135.8, 129.7, 128.2, 127.5, 124.5, 120.7, 120.3, 115.4, 113.9, 104.3, 71.7, 51.0, 46.2, 29.4, 27.6. HRMS (ESI) m/z: [M + H]+ calcd for C22H24N3O3, 378.1812; found, 378.1811.

N-(tert-Butyl)-2-(5,11-dioxo-2-(3-phenylureido)-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide (12)

It was synthesized according to procedure G on a 0.1 mmol scale (32 mg, 64%) as a red solid; mp: 277–278 °C; R = 0.36 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.77 (s, 1H), 8.57 (d, J = 2.6 Hz, 1H), 8.17 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.74 (dd, J = 8.9, 2.2 Hz, 1H), 7.53 (dd, J = 21.7, 7.5 Hz, 4H), 7.46 (d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H), 5.15 (s, 2H), 1.29 (s, 9H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.3, 165.8, 162.2, 158.1, 152.6, 145.6, 139.7, 137.4, 134.7, 133.8, 133.4, 131.7, 130.1 (d, J = 11.0 Hz), 129.3, 123.3, 122.8, 118.9, 118.2, 118.0, 117.2, 109.4 (d, J = 10.7 Hz), 106.9, 51.3, 46.7, 28.9. HRMS (ESI) m/z: [M + H]+ calcd for C29H27N4O4, 495.2027; found, 495.2026.

tert-Butyl (S)-(1-((6-(2-(tert-Butylamino)-2-oxoethyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (13)

It was synthesized according to procedure H on a 0.1 mmol scale (49 mg, 78%) as a red solid; mp: 298–299 °C; R = 0.28 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.77 (s, 1H), 8.17 (d, J = 10.9 Hz, 2H), 7.88 (d, J = 9.1 Hz, 1H), 7.55 (dd, J = 19.9, 6.6 Hz, 2H), 7.47 (d, J = 6.8 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.34–7.19 (m, 4H), 5.16 (s, 2H), 4.43 (s, 1H), 3.07 (d, J = 14.1 Hz, 1H), 3.00–2.72 (m, 1H), 1.34 (s, 9H), 1.29 (s, 9H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.3, 172.2, 165.7, 162.2, 158.2, 156.0, 144.6, 138.4, 137.4, 134.7, 133.9, 133.2, 131.8, 130.0, 129.8, 128.6, 126.8, 123.4, 123.0 (d, J = 24.2 Hz), 119.3 (d, J = 25.5 Hz), 118.4, 111.4, 106.9, 78.7, 57.2, 51.3, 46.7, 37.7, 28.9 (d, J = 14.0 Hz), 28.7 (d, J = 16.4 Hz). HRMS (ESI) m/z: [M + H]+ calcd for C36H39N4O6, 623.2864; found, 623.2863.