ChemistryGeneral chemistry

All solvents and reagents were purchased from commercial sources and were of analytical grade. Demineralized water is referred to as H2O, as was used in all cases unless noted otherwise (e.g., brine). All reactions were routinely monitored with thin-layer chromatography (TLC), using aluminum silica gel coated 60 F254 plates from Merck (Darmstadt, Germany) and visualized by UV irradiation at 254 nm or staining with ninhydrin or KMnO4 solution. Purification by flash column chromatography was carried out with the use of silica gel irregular ZEOprep® particles (60–200 µm) from VWR (Amsterdam, The Netherlands) or using an Isolera™ One or Selekt automatic flash chromatography system from Biotage® (Uppsala, Sweden) with pre-packed cartridges (Phenomenex (Torrance, CA, USA) Gemini® Claricep™ (silica) or Biotage® Sfär C18 D Duo 100 Å 30 µm (C18)). Solutions were concentrated using a Heidolph (Schwabach, Germany) Hei-VAP Value rotary evaporator. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker (Billerica, MA, USA) AV-400 liquid spectrometer (1H NMR, 400 MHz and 13C NMR, 101 MHz) at ambient temperature and subsequently analyzed with MestReNova v14.1.0 software (Mestrelab Research S.L., Santiago de Compostela, Spain). Chemical shifts are reported in parts per million (ppm), designated by δ and corrected to the internal standard tetramethylsilane (δ = 0). Multiplicities are indicated by s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; td, triplet of doublets; t, triplet; dt, doublet of triplets; tt, triplet of triplets; q, quartet; p, pentet; m, multiplet; br s, broad singlet; br t, broad triplet. Coupling-constants (J) are reported in Hz. Mass and compound purity analyses were performed with liquid chromatography-mass spectrometry (LC–MS) using a LCMS-2020 system from Shimadzu (Kyoto, Japan) coupled to a Phenomenex Gemini® C18 110 Å column (50 mm × 3 mm × 3 μm). Samples were prepared by dissolving 0.3–0.8 mg of compound in 1 mL of a 1:1:1 mixture of CH3CN/H2O/tBuOH and were eluted using an isocratic system of H2O/CH3CN with 0.1% FA, using gradients from 100:0 to 60:40 and 90:10 to 10:90 in an elution time of 15 min. All tested compounds were determined to be of > 95% purity determined by HPLC.

Synthetic procedures General procedure A:

To a stirred solution of the appropriate commercially available methylaminobenzoic acid (453 mg, 3.00 mmol, 1.0 equiv) in 1,4-dioxane (7.5 mL), was added dropwise Fmoc-Cl (0.72 mL, 3.60 mmol, 1.2 equiv). The mixture stirred for 10 min at 0 °C under N2 atmosphere followed by the addition of a suspension of K2CO3 (1.66 g, 12.0 mmol, 4.0 equiv) in 1,4-dioxane (7.5 mL) and the reaction mixture was allowed to stir at rt for 41 h. Subsequently, the mixture was diluted with H2O and neutralized to pH 7 with 0.5 M aqueous HCl. The aqueous phase was extracted with DCM (2 × 100 mL) and the combined organic phase was dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of 2 to 4% MeOH in DCM as mobile phase provided intermediates 1a and 1b.

General procedure B:

To a stirred solution of commercially available substituted benzoyl chloride (1.2 equiv) in DCM or 1,4-dioxane (0.2 M) at 0 °C under N2 atmosphere was added dropwise the appropriate bromoalcohol (1.0 equiv) and Et3N (2.0 equiv). The reaction mixture stirred for 0.5 h at 0 °C and overnight at rt. Subsequently, the mixture was quenched with H2O, diluted with DCM and the phases were separated. The aqueous phase was extracted with DCM (two times) and the combined organic phase was washed with brine, dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of EtOAc in PE as mobile phase provided intermediates 2a-2b, 2d-2f, 2h, 2k-2l and 2p.

General procedure C:

A stirred mixture of the appropriate substituted benzoic acid (1.2 equiv) and thionyl chloride (0.2 M) was refluxed at 75 °C for 4 h under N2 atmosphere. After cooling down to rt the thionyl chloride was evaporated in vacuo and the crude benzoyl chloride was used as described in general procedure B to provide intermediates 2c, 2g, 2i-2j, 2m and 8a-8e.

General procedure D:

To a stirred solution of the appropriate substituted benzoic acid (1.0 equiv) in DCM (0.2 M) was added DMAP (cat.) and EDC·HCl (2.0 equiv). The mixture stirred for 1.5 h at rt before 3-bromopropan-1-ol (1.2 equiv) was added and the reaction continued at rt overnight under N2 atmosphere. The mixture was diluted with DCM and washed with H2O (two times). The aqueous phase was extracted with DCM and the combined organic phase was dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of EtOAc in PE as mobile phase provided intermediates 2n-2o and 12a-12b.

General procedure E:

To a stirred solution of the appropriate bromopropyl benzoate (1.0 equiv) in anhydrous DMF (0.2 M) were added 1-Boc-piperazine (1.2 equiv) and K2CO3 (2.0 equiv). The reaction mixture was stirred for 72 h at room temperature (rt) under N2 atmosphere followed by addition of H2O and EtOAc. After separation, the organic phase was washed four times with H2O, once with brine, dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of MeOH in DCM as mobile phase provided intermediates 3a-3c. After NMR and LC–MS analyses, the formed intermediate was dissolved in DCM (0.2 M) and allowed to cool down to 0 °C after which TFA (20 equiv) was added dropwise. The mixture was stirred for 4 h, concentrated in vacuo and co-evaporated with toluene to remove excess TFA. The obtained oil was dissolved in EtOAc and subsequently co-evaporated with 4 N HCl in 1,4-dioxane to obtain intermediates 4a-4c as dihydrochloride salts.

General procedure F:

The appropriate bromopropyl benzoate (1.0 equiv), appropriate intermediate 4 (1.2 equiv) and K2CO3 (4.0 equiv) were dissolved in anhydrous DMF (0.2 M). The reaction mixture stirred for 68 h at rt under N2 atmosphere followed by 4 h at 50 °C. EtOAc and H2O were added and after separation the organic phase was washed four times with H2O, once with brine. The organic phase was dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of MeOH in DCM as mobile phase provided final compounds 6a-6k, 6u-6v, 9a, 9c-9f and intermediates 9h-9m, 13a-13b.

General procedure G:

The appropriate bromopropyl benzoate (3.0 equiv), piperazine (1.0 equiv) and K2CO3 (4.0 equiv) were dissolved in anhydrous DMF (0.2 M). The reaction mixture stirred for 68 h at rt under N2 atmosphere followed by 4 h at 50 °C. EtOAc and H2O were added and after separation the organic phase was washed four times with H2O, once with brine. The organic phase was dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of MeOH in DCM as mobile phase provided final compounds 6p-6t.

General procedure H:

To a stirred solution of intermediate 5 (1.0 equiv) in DCM (0.2 M) at 0 °C was added dropwise the commercially available substituted benzoyl chloride (1.1 equiv) and Et3N (3.0 equiv). The reaction mixture stirred for 1 h gradually warming up to rt under N2 atmosphere. Subsequently, the mixture was quenched with H2O, diluted with DCM and the phases were separated. The aqueous phase was extracted with DCM (two times) and the combined organic phase was washed with brine, dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of MeOH in DCM as mobile phase provided final compounds 6l and 6m.

General procedure I:

A stirred mixture of the appropriate substituted benzoic acid (1.2 equiv) and thionyl chloride (0.2 M) was refluxed at 75 °C for 4 h under N2 atmosphere. After cooling down to rt the thionyl chloride was evaporated in vacuo and the crude benzoyl chloride was used as described in general procedure H to provide final compounds 6n, 6o and 9b.

General procedure J:

To a stirred solution of the appropriate commercially available chlorosulfonylbenzoic acid (1.0 equiv) in 1,4-dioxane (0.4 M) was added dropwise an aqueous solution of KHF2 (3.0 equiv, 2 M). The mixture was stirred at rt for 1 h followed by dilution with EtOAc. The organic phase was washed with H2O, dried over MgSO4, filtrated and concentrated in vacuo to provide intermediates 7a and 7b.

General procedure K:

To a stirred mixture of the appropriate commercially available amino-substituted benzoic acid (1.0 equiv) in 1,4-dioxane and H2O (1:1 or 2:1) was added Et3N or NaOH (2.0 equiv) followed by slow addition of Boc2O (2.0 equiv). The reaction mixture was stirred for 17 h at rt and subsequently acidified by addition of 1 M aqueous HCl until no further precipitation was observed. The formed suspension was filtrated, the residue rinsed with H2O and subsequently dissolved in EtOH followed by concentration in vacuo to give intermediates 7d-7h.

General procedure L:

A stirred mixture of the appropriate substituted benzoic acid (1.2 equiv) in DCM or toluene (0.2 M) was allowed to cool down to 0 °C. Subsequently, oxalyl chloride (2.0 equiv) and two drops of DMF (cat.) were added and the reaction mixture was stirred for 4 h at 0 °C under N2 atmosphere. The solvent was evaporated in vacuo and the crude benzoyl chloride was used as described in general procedure B to provide intermediates 8f-8k.

General procedure M:

To a stirred solution of 4-hydroxy-3,5-dimethoxybenzoic acid (1.0 equiv) in THF (0.2 M) at 0 °C was added tetrabutylammonium hydroxide (2.0 equiv) and the appropriate bromoalkylamine (1.5 equiv). The reaction mixture was stirred for two days under N2 atmosphere followed by concentration in vacuo. The obtained residue was dissolved in water and 4 M aqueous HCl was added until pH 4 was reached. The aqueous solution was extracted twice with DCM. The combined organic phase was dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of MeOH in DCM as mobile phase provided intermediates 11a and 11b.

General procedure N:

The appropriate Boc-protected intermediate was dissolved in DCM (0.2 M) and allowed to cool down to 0 °C after which TFA (20 equiv) was added dropwise. The mixture was stirred for 4 h, concentrated in vacuo and co-evaporated with toluene to remove the excess TFA. The obtained oil was dissolved in DCM (0.2 M) and the stirred solution was cooled to 0 °C. Acryloyl chloride (1.5 equiv) was added followed by Et3N (3.0 equiv), and the reaction mixture stirred for 2 h at 0 °C under N2 atmosphere. The mixture was diluted with DCM and subsequently washed twice with brine. The organic phase was dried over MgSO4, filtrated and concentrated in vacuo. Flash column chromatography on silica gel using a gradient of MeOH in DCM as mobile phase provided final compounds 10a-10f and 14a-14b.

3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)benzoic acid (1a). Intermediate 1a was obtained from 3-(methylamino)benzoic acid as a white solid (312 mg, 0.83 mmol, 28%) following general procedure A. 1H NMR (400 MHz, CDCl3) δ 10.59 (br s, 1H), 8.04 – 7.93 (m, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.45 – 6.90 (m, 8H), 4.46 (d, J = 6.7 Hz, 2H), 4.12 (s, 1H), 3.31 (s, 3H). LC–MS (ESI +) m/z calcd. for C23H19NO4 [(M + H)]+: 374.14; found: 374.10. HPLC tR: 10.989 min.

4-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)benzoic acid (1b). Intermediate 1b was obtained from 4-(methylamino)benzoic acid as a white solid (428 mg, 1.15 mmol, 38%) following general procedure A. 1H NMR (400 MHz, CDCl3) δ 8.15 – 8.01 (m, 2H), 7.80 – 7.69 (m, 2H), 7.48 – 7.33 (m, 4H), 7.30 – 7.11 (m, 4H), 4.53 (d, J = 6.3 Hz, 2H), 4.18 (t, J = 6.4 Hz, 1H), 3.32 (s, 3H). LC–MS (ESI +) m/z calcd. for C23H19NO4 [(M + H)]+: 374.14; found: 374.10. HPLC tR: 10.922 min.

3-bromopropyl benzoate (2a). Intermediate 2a was obtained from benzoyl chloride following general procedure B. Column chromatography with 3% EtOAc in PE as mobile phase. Transparent oil (520 mg, 2.14 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ 8.04 – 7.99 (m, 2H), 7.55 – 7.48 (m, 1H), 7.43 – 7.36 (m, 2H), 4.41 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 6.6 Hz, 2H), 2.25 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C10H11BrO2 [(M + H)]+: 243.00; found: 242.90. HPLC tR: 10.765 min.

3-bromopropyl 4-methylbenzoate (2b). Intermediate 2b was obtained from 4-methylbenzoyl chloride following general procedure B. Column chromatography with 0 to 4% EtOAc in PE as mobile phase. Transparent oil (556 mg, 2.16 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ 7.96 – 7.90 (m, 2H), 7.26 – 7.21 (m, 2H), 4.45 (t, J = 6.0 Hz, 2H), 3.55 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H), 2.31 (p, J = 6.6, 6.2 Hz, 2H). LC–MS (ESI +) m/z calcd. for C11H13BrO2 [(M + H)]+: 257.02; found: 256.95. HPLC tR: 11.284 min.

3-bromopropyl 3,4-dimethybenzoate (2c). Intermediate 2c was obtained from 3,4-dimethybenzoic acid following general procedure C. Column chromatography with 20 to 50% DCM in PE as mobile phase. Transparent oil (513 mg, 1.89 mmol, 76%). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 7.9, 1.9 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 4.41 (t, J = 6.0 Hz, 2H), 3.53 (t, J = 6.6 Hz, 2H), 2.33 – 2.23 (m, 8H). LC–MS (ESI +) m/z calcd. for C12H15BrO2 [(M + H)]+: 271.03; found: 270.95. HPLC tR: 11.974 min.

3-bromopropyl 3,5-dimethylbenzoate (2d). Intermediate 2d was obtained from 3,5-dimethylbenzoyl chloride following general procedure B. Column chromatography with 0 to 5% EtOAc in PE as mobile phase. Transparent oil (871 mg, 3.21 mmol, quant.). 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.60 (m, 2H), 7.17 – 7.11 (m, 1H), 4.41 (t, J = 6.0 Hz, 2H), 3.52 (t, J = 6.6 Hz, 2H), 2.38 – 2.31 (m, 6H), 2.27 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C12H15BrO7 [(M + H)]+: 271.03; found: 270.95. HPLC tR: 12.128 min.

3-bromopropyl 4-chlorobenzoate (2e). Intermediate 2e was obtained from 4-chlorobenzoyl chloride following general procedure B. Column chromatography with 2 to 5% EtOAc in PE as mobile phase. Transparent oil (765 mg, 2.75 mmol, quant.). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 3.54 (t, J = 6.5 Hz, 2H), 2.31 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C10H10BrClO2 [(M + H)]+: 276.96; found: 276.85. HPLC tR: 11.559 min.

3-bromopropyl 3,4-dichlorobenzoate (2f). Intermediate 2f was obtained from 3,4-dichlorobenzoyl chloride following general procedure B. Column chromatography with 2 to 4% EtOAc in PE as mobile phase. Yellow oil (703 mg, 2.25 mmol, 90%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 4.48 (t, J = 6.1 Hz, 2H), 3.54 (t, J = 6.5 Hz, 2H), 2.33 (p, J = 6.4 Hz, 2H).

3-bromopropyl 3-(dimethylamino)benzoate (2g). Intermediate 2g was obtained from 3-(dimethylamino)benzoic acid following general procedure C. Column chromatography with 20 to 50% DCM in PE as mobile phase. Transparent oil (211 mg, 0.74 mmol, 21%). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.34 (m, 2H), 7.28 (t, J = 7.9 Hz, 1H), 6.91 (ddd, J = 8.3, 2.8, 1.1 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.98 (s, 6H), 2.31 (p, J = 6.4 Hz, 2H). LC–MS (ESI +) m/z calcd. for C12H16BrNO2 [(M + H)]+: 286.04; found: 285.95. HPLC tR: 10.793 min.

3-bromopropyl 4-(dimethylamino)benzoate (2h). Intermediate 2h was obtained from 4-(dimethylamino)benzoyl chloride following general procedure B. Column chromatography with 5 to 25% EtOAc in PE as mobile phase. Yellow oil (488 mg, 1.71 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.1 Hz, 2H), 6.62 (d, J = 9.1 Hz, 2H), 4.38 (t, J = 6.0 Hz, 2H), 3.53 (t, J = 6.7 Hz, 2H), 3.01 (s, 6H), 2.27 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C12H16BrNO2 [(M + H)]+: 286.04; found: 285.90. HPLC tR: 11.085 min.

3-bromopropyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)benzoate (2i). Intermediate 2i was obtained from 1a following general procedure C. Column chromatography with 10 to 25% EtOAc in PE as mobile phase. Yellow oil (297 mg, 0.71 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.86 (m, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.48 – 7.04 (m, 8H), 4.53 – 4.34 (m, 4H), 4.12 (s, 1H), 3.50 (t, J = 6.5 Hz, 2H), 3.30 (s, 3H), 2.29 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C26H24BrNO4 [(M + H)]+: 494.10; found: 494.10. HPLC tR: 12.951 min.

3-bromopropyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)benzoate (2j). Intermediate 2j was obtained from 1b following general procedure C. Column chromatography with 0 to 25% EtOAc in PE as mobile phase. Yellow oil (422 mg, 0.85 mmol, 29%). 1H NMR (400 MHz, CDCl3) δ 8.01 – 7.95 (m, 2H), 7.76 – 7.69 (m, 2H), 7.46 – 7.33 (m, 4H), 7.28 – 7.16 (m, 4H), 4.61 – 4.46 (m, 4H), 4.16 (t, J = 6.5 Hz, 1H), 3.57 (t, J = 6.5 Hz, 2H), 3.30 (s, 3H), 2.34 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C26H24BrNO4 [(M + H)]+: 494.10; found: 494.10. HPLC tR: 12.978 min.

3-bromopropyl 2-methoxybenzoate (2k). Intermediate 2k was obtained from 2-methoxybenzoyl chloride following general procedure B. Column chromatography with 5 to 15% EtOAc in PE as mobile phase. Transparent oil (652 mg, 2.39 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 8.0, 1.8 Hz, 1H), 7.45 (ddd, J = 7.9, 7.1, 1.8 Hz, 1H), 7.01 – 6.91 (m, 2H), 4.41 (t, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.55 (t, J = 6.6 Hz, 2H), 2.26 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C11H13BrO3 [(M + H)]+: 273.01; found: 272.90. HPLC tR: 10.530 min.

3-bromopropyl 3-methoxybenzoate (2l). Intermediate 2l was obtained from 3-methoxybenzoyl chloride following general procedure B. Column chromatography with 5 to 15% EtOAc in PE as mobile phase. Transparent oil (1.27 g, 4.66 mmol, 78%). 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.60 (m, 1H), 7.54 (dd, J = 2.8, 1.5 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.09 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 4.44 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.53 (t, J = 6.6 Hz, 2H), 2.30 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C11H13BrO3 [(M + H)]+: 273.01; found: 272.90. HPLC tR: 11.110 min.

3-bromopropyl 4-methoxybenzoate (2m). Intermediate 2m was obtained from 4-methoxybenzoic acid following general procedure C. Column chromatography with 2 to 8% EtOAc in PE as mobile phase. Yellow oil (1.15 g, 4.21 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ 8.02 – 7.96 (m, 2H), 6.95 – 6.89 (m, 2H), 4.44 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 3.55 (t, J = 6.6 Hz, 2H), 2.31 (p, J = 6.2 Hz, 2H). LC–MS (ESI +) m/z calcd. for C11H13BrO3 [(M + H)]+: 273.01; found: 272.95. HPLC tR: 10.938 min.

3-bromopropyl 3,4-dimethoxybenzoate (2n). Intermediate 2n was obtained from 3,4-dimethoxybenzoic acid following general procedure D. Column chromatography with 10 to 20% EtOAc in PE as mobile phase. Transparent oil (513 mg, 1.69 mmol, 28%). 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 3.94 (s, 3H), 3.94 (s, 3H), 3.55 (t, J = 6.5 Hz, 2H), 2.32 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C12H15BrO4 [(M + H)]+: 303.02; found: 302.95. HPLC tR: 10.466 min.

3-bromopropyl 3,5-dimethoxybenzoate (2o) Intermediate 2o was obtained from 3,5-dimethoxybenzoic acid following general procedure D. Column chromatography with 40 to 70% DCM in PE as mobile phase. Transparent oil (1.09 g, 3.60 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 2.4 Hz, 2H), 6.64 (t, J = 2.4 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 3.82 (s, 6H), 3.54 (t, J = 6.5 Hz, 2H), 2.31 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C12H15BrO4 [(M + H)]+: 303.02; found: 302.95. HPLC tR: 11.275 min.

3-bromopropyl 3,4,5-trimethoxybenzoate (2p). Intermediate 2p was obtained from 3,4,5-trimethoxybenzoyl chloride following general procedure B. Column chromatography with 5 to 15% EtOAc in PE as mobile phase. White solid (6.66 g, 18.2 mmol, 91%). 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.92 (s, 9H), 3.54 (t, J = 6.5 Hz, 2H), 2.34 (p, J = 6.3 Hz, 2H). LC–MS (ESI +) m/z calcd. for C13H17BrO5 [(M + H)]+: 333.03; found: 333.00. HPLC tR: 10.538 min.

tert-butyl 4-(3-((2-methoxybenzoyl)oxy)propyl)piperazine-1-carboxylate (3a). Intermediates 3a and 4a were obtained from 2k following general procedure E. Column chromatography with 0 to 1.5% MeOH in DCM as mobile phase. Transparent oil (275 mg, 0.73 mmol, 53%). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.9, 1.8 Hz, 1H), 7.47 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.02 – 6.95 (m, 2H), 4.36 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.44 (t, J = 4.7 Hz, 4H), 2.51 (t, J = 7.5, 7.1 Hz, 2H), 2.41 (t, J = 5.1 Hz, 4H), 1.99 – 1.90 (m, 2H), 1.46 (s, 9H). LC–MS (ESI +) m/z calcd. for C20H30N2O5 [(M + H)]+: 379.22; found: 379.20. HPLC tR: 6.521 min. 3-(piperazin-1-yl)propyl 2-methoxybenzoate dihydrochloride (4a). White solid (quant.) used without further analyses.

tert-butyl 4-(3-((3,5-dimethoxybenzoyl)oxy)propyl)piperazine-1-carboxylate (3b). Intermediates 3b and 4b were obtained from 2o following general procedure E. Column chromatography with 1 to 3% MeOH in DCM as mobile phase. Transparent oil (1.16 g, 2.85 mmol, 80%). 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 2.4 Hz, 2H), 6.65 (t, J = 2.4 Hz, 1H), 4.37 (t, J = 6.5 Hz, 2H), 3.83 (s, 6H), 3.43 (t, J = 5.1 Hz, 4H), 2.50 (t, J = 7.1 Hz, 2H), 2.40 (t, J = 5.0 Hz, 4H), 2.02 – 1.90 (m, 2H), 1.46 (s, 9H). 3-(piperazin-1-yl)propyl 3,5-dimethoxybenzoate dihydrochloride (4b). White solid (954 mg, 2.50 mmol, 88%) used without further analyses.

tert-butyl 4-(3-((3,4,5-trimethoxybenzoyl)oxy)propyl)piperazine-1-carboxylate (3c). Intermediates 3c and 4c were obtained from 2p following general procedure E. Column chromatography with 2% MeOH in DCM as mobile phase. Transparent oil (4.95 g, 11.3 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 2H), 4.39 (t, J = 6.6, 2.1 Hz, 2H), 3.92 (s, 9H), 3.52 – 3.34 (m, 4H), 2.51 (t, J = 7.0 Hz, 2H), 2.47 – 2.33 (m, 4H), 1.98 (p, J = 6.7, 6.3 Hz, 2H), 1.47 (s, 9H). LC–MS (ESI +) m/z calcd. for C22H34N2O7 [(M + H)]+: 439.24; found: 439.15. HPLC tR: 6.746 and 7.023 min. 3-(piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate dihydrochloride (4c). White solid (4.29 g, 10.4 mmol, 91%) used without further analyses.

3-(4-(3-hydroxypropyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (5). To a stirred solution of intermediate 4c (1.23 g, 3.00 mmol, 1.0 equiv) in anhydrous DMF (15.0 mL) was added 3-bromopropan-1-ol (0.29 mL, 3.30 mmol, 1.1 equiv) and K2CO3 (1.24 g, 9.00 mmol, 3.0 equiv). The reaction mixture was allowed to stir overnight at rt under N2 atmosphere followed by filtration and concentration in vacuo. The acquired oil was dissolved in EtOAc (50 mL) and subsequently washed with H2O (50 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic phases were washed with brine (50 mL), dried over MgSO4, filtrated and concentrated in vacuo. The crude product was purified using flash column chromatography on silica gel with 10% MeOH in DCM as mobile phase to obtain intermediate 5 (773 mg, 1.95 mmol, 65%) as a transparent oil. 1H NMR (400 MHz, MeOD) δ 7.32 (s, 2H), 4.36 (t, J = 6.4 Hz, 2H), 3.88 (s, 6H), 3.82 (s, 3H), 3.61 (t, J = 6.2 Hz, 2H), 2.60 – 2.39 (m, 12H), 2.03 – 1.94 (m, 2H), 1.79 – 1.68 (m, 2H). LC–MS (ESI +) m/z calcd. for C20H32N2O6 [(M + H)]+: 396.23; found: 397.20. HPLC tR: 0.818 min.

3-(4-(3-(benzoyloxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6a). Final compound 6a was obtained from intermediates 2a and 4c following general procedure F. Column chromatography with 2 to 4.5% MeOH in DCM as mobile phase. Yellow oil (884 mg, 1.77 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.2 Hz, 2H), 7.55 (tt, J = 7.4, 1.6 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 7.30 (s, 2H), 4.38 (t, J = 6.5 Hz, 4H), 3.91 (s, 9H), 2.59 – 2.41 (m, 12H), 2.03 – 1.93 (m, 4H). 13C NMR (101 MHz, CDCl3) 166.4, 166.0, 152.8, 142.0, 132.7, 130.2, 129.4, 128.2, 125.2, 106.6, 63.4, 63.3, 60.7, 56.1, 55.0, 53.1, 53.1, 26.2, 26.1. LC–MS (ESI +) m/z calcd. for C27H36N2O7 [(M + H)]+: 501.26; found: 501.15. HPLC tR: 8.096 min.

3-(4-(3-((4-methylbenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6b). Final compound 6b was obtained from intermediates 2b and 4c following general procedure F. Column chromatography with 2 to 4% MeOH in DCM as mobile phase. Yellow oil (272 mg, 0.53 mmol, 66%). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.30 (s, 2H), 7.22 (d, J = 8.0 Hz, 2H), 4.45 – 4.29 (m, 4H), 3.90 (s, 9H), 2.57 – 2.45 (m, 12H), 2.38 (s, 3H), 2.03 – 1.89 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.2, 165.8, 152.6, 143.2, 141.9, 129.3, 128.8, 127.3, 125.1, 106.5, 63.3, 62.9, 60.5, 55.9, 54.8, 52.9, 52.9, 26.0, 21.3. LC–MS (ESI +) m/z calcd. for C28H38N2O7 [(M + H)]+: 515.28; found: 515.35. HPLC tR: 7.544 min.

3-(4-(3-((3,4-dimethylbenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6c). Final compound 6c was obtained from intermediates 2c and 4c following general procedure F. Automatic column chromatography with 1 to 6% MeOH in DCM as mobile phase on Biotage Isolera One. Transparent oil (40.4 mg, 0.08 mmol, 14%). 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.78 (m, 1H), 7.76 (dd, J = 7.8, 1.9 Hz, 1H), 7.29 (s, 2H), 7.19 (d, J = 7.9 Hz, 1H), 4.41 – 4.31 (m, 4H), 3.91 (s, 9H), 2.84 – 2.39 (m, 12H), 2.31 (s, 3H), 2.30 (s, 3H), 2.05 – 1.89 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 167.0, 166.3, 153.0, 142.4, 136.8, 130.7, 129.8, 128.0, 127.2, 125.5, 106.9, 63.7, 63.3, 61.1, 56.4, 55.3, 55.2, 53.3, 53.2, 26.4, 26.4, 20.1, 19.8. LC–MS (ESI +) m/z calcd. for C29H40N2O7 [(M + H)]+: 529.29; found: 529.30. HPLC tR: 7.807 min.

3-(4-(3-((3,5-dimethylbenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6d). Final compound 6d was obtained from intermediates 2d and 4c following general procedure F. Automatic column chromatography with 2 to 6% MeOH in DCM as mobile phase on Biotage Isolera One. Yellow oil (241 mg, 0.46 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.62 (m, 2H), 7.30 (s, 2H), 7.20 – 7.14 (m, 1H), 4.44 – 4.30 (m, 4H), 3.91 (s, 9H), 2.86 – 2.36 (m, 12H), 2.36 (s, 6H), 2.04 – 1.89 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.9, 166.2, 152.9, 142.2, 138.0, 134.5, 130.2, 127.2, 125.4, 106.8, 63.6, 63.3, 60.9, 56.2, 55.1, 55.1, 53.2, 53.2, 26.3, 21.2. LC–MS (ESI +) m/z calcd. for C29H40N2O7 [(M + H)]+: 528.29; found: 529.30. HPLC tR: 7.898 min.

3-(4-(3-((4-chlorobenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6e). Final compound 6e was obtained from intermediates 2e and 4c following general procedure F. Automatic column chromatography with 0 to 6% MeOH in DCM as mobile phase on Biotage Isolera One. Yellow oil (306 mg, 0.57 mmol, 71%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.29 (s, 2H), 4.37 (t, J = 6.5 Hz, 4H), 3.91 (s, 9H), 2.80 – 2.23 (m, 12H), 2.03 – 1.92 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.4, 165.9, 153.1, 139.5, 131.1, 128.8, 125.5, 106.9, 63.8, 63.7, 61.1, 56.4, 55.3, 55.2, 53.3, 26.4, 26.4. LC–MS (ESI +) m/z calcd. for C27H35ClN2O7 [(M + H)]+: 535.22; found: 535.15. HPLC tR: 7.716 min.

3-(4-(3-((3,4-dichlorobenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6f). Final compound 6f was obtained from intermediates 2f and 4c following general procedure F. Automatic column chromatography with 2 to 6% MeOH in DCM as mobile phase on Biotage Isolera One. Orange oil (301 mg, 0.53 mmol, 66%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.29 (s, 2H), 4.42 – 4.34 (m, 4H), 3.91 (s, 9H), 2.80 – 2.31 (m, 12H), 2.03 – 1.92 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.3, 164.9, 153.0, 142.3, 137.7, 133.0, 131.6, 130.7, 130.3, 128.8, 125.5, 106.9, 64.2, 63.7, 61.1, 56.4, 55.2, 55.1, 53.3, 26.4, 26.3. LC–MS (ESI +) m/z calcd. for C27H34Cl2N2O7 [(M + H)]+: 569.18; found: 569.10. HPLC tR: 8.162 min.

3-(4-(3-((3-(dimethylamino)benzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6g). Final compound 6g was obtained from intermediates 2g and 4c following general procedure F. Column chromatography with 6% MeOH in EtOAc as mobile phase. Yellow oil (227 mg, 0.42 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.34 (m, 2H), 7.29 (s, 2H), 7.30 – 7.28 (m, 1H), 6.90 (ddd, J = 8.2, 2.8, 1.0 Hz, 1H), 4.44 – 4.28 (m, 4H), 3.91 (s, 9H), 2.99 (s, 6H), 2.78 – 2.13 (m, 12H), 2.04 – 1.87 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 167.3, 166.3, 153.0, 150.5, 142.2, 131.0, 129.0, 125.4, 117.5, 116.8, 113.2, 106.8, 63.7, 63.3, 61.0, 56.3, 55.2, 55.2, 53.2, 53.2, 40.6, 26.3. LC–MS (ESI +) m/z calcd. for C29H41N3O7 [(M + H)]+: 544.30; found: 544.25. HPLC tR: 7.108 and 7.398 min.

3-(4-(3-((4-(dimethylamino)benzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6h). Final compound 6h was obtained from intermediates 2h and 4c following general procedure F. Column chromatography with 1 to 3.5% MeOH in DCM as mobile phase. Transparent oil (103 mg, 0.19 mmol, 24%). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 9.1 Hz, 2H), 7.29 (s, 2H), 6.64 (d, J = 9.1 Hz, 2H), 4.37 (t, J = 6.5 Hz, 2H), 4.31 (t, J = 6.4 Hz, 2H), 3.91 (s, 6H), 3.91 (s, 3H), 3.04 (s, 6H), 2.81 – 2.25 (m, 12H), 2.04 – 1.88 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 167.0, 166.3, 153.3, 153.0, 142.2, 131.3, 125.4, 117.1, 110.7, 106.8, 63.7, 62.6, 61.0, 56.3, 55.3, 55.2, 53.3, 53.2, 40.1, 26.5, 26.3. LC–MS (ESI +) m/z calcd. for C29H41N3O7 [(M + H)]+: 544.30; found: 544.20. HPLC tR: 7.617 min.

3-(4-(3-((4-(methylamino)benzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6i). Final compound 6i was obtained from intermediates 2i and 4c following general procedure F. Column chromatography with 2 to 6% MeOH in DCM as mobile phase. Yellow oil (64.0 mg, 0.12 mmol, 48%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.9 Hz, 2H), 7.29 (s, 2H), 6.55 (d, J = 9.0 Hz, 2H), 4.37 (t, J = 6.5 Hz, 2H), 4.30 (t, J = 6.4 Hz, 2H), 4.28 – 4.21 (m, 1H), 3.91 (s, 9H), 2.88 (d, J = 4.9 Hz, 3H), 2.83 – 2.21 (m, 12H), 2.05 – 1.87 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 167.0, 166.3, 153.0, 153.0, 142.2, 131.6, 125.5, 118.4, 111.1, 106.8, 63.7, 62.7, 61.0, 56.3, 55.3, 55.2, 53.3, 53.3, 30.2, 26.5, 26.4. LC–MS (ESI +) m/z calcd. for C28H39N3O7 [(M + H)]+: 530.29; found: 530.25. HPLC tR: 9.641 min.

3-(4-(3-((3-(methylamino)benzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6j). Final compound 6j was obtained from intermediates 2j and 4c following general procedure F. Column chromatography with 2 to 6% MeOH in DCM as mobile phase. Yellow oil (147 mg, 0.28 mmol, 46%). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.34 (m, 1H), 7.30 (s, 2H), 7.26 (dd, J = 2.5, 1.5 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.77 (ddd, J = 8.1, 2.6, 1.0 Hz, 1H), 4.46 – 4.28 (m, 4H), 3.91 (m, 10H), 2.86 (s, 3H), 2.78 – 2.24 (m, 12H), 2.03 – 1.90 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 167.1, 166.2, 152.9, 149.3, 142.1, 131.2, 129.1, 125.4, 118.2, 116.8, 112.8, 106.7, 63.6, 63.3, 60.9, 56.2, 55.1, 55.1, 53.2, 53.2, 30.7, 26.3. LC–MS (ESI +) m/z calcd. for C28H39N3O7 [(M + H)]+: 530.29; found: 530.30. HPLC tR: 6.675 and 6.981 min.

3-(4-(3-((2-methoxybenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6k). Final compound 6k was obtained from intermediates 2k and 4c following general procedure F. Automatic column chromatography with 0 to 5% MeOH in DCM as mobile phase on Biotage Isolera One. Orange oil (230 mg, 0.43 mmol, 54%). 1H NMR (400 MHz, CDCl3) δ 7.78 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.51 – 7.43 (m, 1H), 7.30 (s, 2H), 7.02 – 6.94 (m, 2H), 4.47 – 4.27 (m, 4H), 3.91 (s, 9H), 3.90 (s, 3H), 3.34 – 2.17 (m, 12H), 2.05 – 1.89 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.3, 166.3, 159.2, 153.0, 142.2, 133.5, 131.6, 125.4, 120.3, 120.1, 112.0, 106.8, 63.6, 63.3, 61.0, 56.3, 56.0, 55.2, 55.2, 53.2, 53.2, 26.3, 26.3. LC–MS (ESI +) m/z calcd. for C28H38N2O8 [(M + H)]+: 531.27; found: 531.25. HPLC tR: 7.156 min.

3-(4-(3-((3-methoxybenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6l). Final compound 6l was obtained from intermediate 5 and 3-methoxybenzoyl chloride following general procedure H. Column chromatography with 3 to 6% MeOH in DCM as mobile phase. Transparent oil (36.6 mg, 0.07 mmol, 14%). 1H NMR (400 MHz, CDCl3) δ 7.63 (dt, J = 7.7, 1.2 Hz, 1H), 7.55 (dd, J = 2.8, 1.5 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.29 (s, 2H), 7.10 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 4.37 (t, J = 6.3 Hz, 4H), 3.91 (s, 9H), 3.85 (s, 3H), 2.66 – 2.41 (m, 12H), 2.04 – 1.92 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.6, 166.4, 159.7, 153.1, 142.3, 131.8, 129.5, 125.5, 122.1, 119.4, 114.2, 106.9, 63.7, 63.6, 61.1, 56.4, 55.6, 55.2, 53.3, 26.4, 26.4. LC–MS (ESI +) m/z calcd. for C28H38N2O8 [(M + H)]+: 531.27; found: 531.25. HPLC tR: 7.338 min.

3-(4-(3-((4-methoxybenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6m). Final compound 6m was obtained from intermediate 5 and 4-methoxybenzoyl chloride following general procedure H. Column chromatography with 3 to 6% MeOH in DCM as mobile phase. Transparent oil (285 mg, 0.47 mmol, 94%). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 9.1 Hz, 2H), 7.30 (s, 2H), 6.92 (d, J = 9.1 Hz, 2H), 4.37 (t, J = 6.5 Hz, 2H), 4.34 (t, J = 6.5 Hz, 2H), 3.91 (s, 6H), 3.90 (s, 3H), 3.85 (s, 3H), 2.69 – 2.48 (m, 12H), 2.06 – 1.90 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.2, 166.1, 163.3, 152.9, 142.1, 131.5, 125.3, 122.6, 113.5, 106.7, 63.4, 62.9, 60.8, 56.2, 55.4, 55.02, 54.97, 52.90, 52.90, 26.13, 26.09. LC–MS (ESI +) m/z calcd. for C28H38N2O8 [(M + H)]+: 531.27; found 531.25. HPLC tR: 7.291 min.

3-(4-(3-((3,4-dimethoxybenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6n). Final compound 6n was obtained from intermediate 5 and 3,4-dimethoxybenzoic acid following general procedure I. Column chromatography with 3 to 6% MeOH in DCM as mobile phase. Transparent oil (36.9 mg, 0.07 mmol, 33%). 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.29 (s, 2H), 6.89 (d, J = 8.5 Hz, 1H), 4.36 – 4.33 (m, 4H), 3.94 (s, 3H), 3.93 (s, 3H), 3.91 (s, 6H), 3.91 (s, 3H), 2.75 – 2.37 (m, 12H), 2.05 – 1.93 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.5, 166.3, 153.1, 153.0, 148.7, 142.3, 125.4, 123.6, 122.9, 112.0, 110.3, 106.9, 63.7, 63.3, 61.0, 56.4, 56.1, 56.1, 55.23, 55.19, 53.2, 26.4, 26.3. LC–MS (ESI +) m/z calcd. for C29H40N2O9 [(M + H)]+: 561.28; found: 561.25. HPLC tR: 7.093 min.

3-(4-(3-((3,5-dimethoxybenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (6o). Final compound 6o was obtained from intermediate 5 and 3,5-dimethoxybenzoic acid following general procedure I. Column chromatography with 3 to 6% MeOH in DCM as mobile phase. Transparent oil (82.0 mg, 0.15 mmol, 73%). 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 2H), 7.18 (d, J = 2.4 Hz, 2H), 6.65 (t, J = 2.4 Hz, 1H), 4.37 (t, J = 6.3 Hz, 2H), 4.37 (t, J = 6.3 Hz, 2H), 3.91 (s, 6H), 3.91 (s, 3H), 3.83 (s, 6H), 2.70 – 2.39 (m, 12H), 2.05 – 1.92 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 166.4, 166.3, 160.7, 153.0, 142.2, 132.3, 125.4, 107.2, 106.8, 105.5, 63.6, 61.0, 56.3, 55.6, 55.2, 55.1, 53.2, 53.2, 26.3, 26.3. LC–MS (ESI +) m/z calcd. for C29H40N2O9 [(M + H)]+: 561.28; found: 561.25. HPLC tR: 7.540 min.

piperazine-1,4-diylbis(propane-3,1-diyl) bis(2-methoxybenzoate) (6p). Final compound 6p was obtained from intermediate 2k following general procedure G. Column chromatography with 3 to 5% MeOH in DCM as mobile phase. Transparent oil (492 mg, 1.05 mmol, 47%). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.9, 1.8 Hz, 2H), 7.49 – 7.41 (m, 2H), 6.99 – 6.92 (m, 4H), 4.34 (t, J = 6.4 Hz, 4H), 3.87 (s, 6H), 2.70–2.40 (m, 12H), 1.94 (p, J = 6.8 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ 165.9, 158.8, 133.2, 131.2, 119.9, 119.8, 111.7, 62.9, 55.6, 54.8, 52.8, 25.9. LC–MS (ESI +) m/z calcd. for C26H34N2O6 [(M + H)]+: 471.25; found: 471.15. HPLC tR: 6.734 min.

piperazine-1,4-diylbis(propane-3,1-diyl) bis(3-methoxybenzoate) (6q). Final compound 6q was obtained from intermediate 2l following general procedure G. Column chromatography with 3 to 5% MeOH in DCM as mobile phase. Transparent oil (450 mg, 0.96 mmol, 45%). 1H NMR (400 MHz, CDCl3) δ 7.63 (dt, J = 7.6, 1.2 Hz, 2H), 7.55 (dd, J = 2.7, 1.5 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 7.08 (ddd, J = 8.2, 2.7, 1.0 Hz, 2H), 4.36 (t, J = 6.5 Hz, 4H), 3.83 (s, 6H), 2.60 – 2.41 (m, 12H), 1.96 (p, J = 7.1 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ 166.2, 159.4, 131.5, 129.2, 121.7, 119.1, 114.0, 63.4, 55.2, 54.9, 53.0, 26.1. LC–MS (ESI +) m/z calcd. for C26H34N2O6 [(M + H)]+: 471.25; found: 471.25. HPLC tR: 7.020 and 7.365 min.

piperazine-1,4-diylbis(propane-3,1-diyl) bis(4-methoxybenzoate) (6r). Final compound 6r was obtained from intermediate 2m following general procedure G. Automatic column chromatography with 3 to 5% MeOH in DCM as mobile phase on Biotage Isolera One. Transparent oil (365 mg, 0.78 mmol, 55%). 1H NMR (400 MHz, CDCl3) 8.02 – 7.95 (m, 4H), 6.96 – 6.88 (m, 4H), 4.34 (t, J = 6.5 Hz, 4H), 3.85 (s, 6H), 2.64 – 2.31 (m, 12H), 2.02 – 1.85 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.4, 163.4, 131.6, 122.8, 113.6, 63.2, 55.5, 55.2, 53.2, 26.4. LC–MS (ESI +) m/z calcd. for C26H34N2O6 [(M + H)]+: 471.25; found: 471.15. HPLC tR: 7.050 and 7.294 min.

piperazine-1,4-diylbis(propane-3,1-diyl) bis(3,4-dimethoxybenzoate) (6s). Final compound 6s was obtained from intermediate 2n following general procedure G. Column chromatography with 0.5 to 4% MeOH in DCM as mobile phase. Transparent oil (59.7 mg, 0.77 mmol, 15%). 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 8.4, 2.0 Hz, 2H), 7.54 (d, J = 2.0 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.36 (t, J = 6.5 Hz, 4H), 3.94 (s, 6H), 3.94 (s, 6H), 2.66 – 2.37 (m, 12H), 2.03 – 1.91 (m, 4H).13C NMR (101 MHz, CDCl3) δ 166. 5, 153.0, 148.7, 123.6, 122.9, 112.0, 110.3, 63.3, 56.1, 56.1, 55.2, 53.2, 26.4. LC–MS (ESI+) m/z calcd. for C28H38N2O8 [(M + H)]+: 531.27; found: 531.25. HPLC tR: 6.736 and 6.928 min.

piperazine-1,4-diylbis(propane-3,1-diyl) bis(3,5-dimethoxybenzoate) (6t). Final compound 6t was obtained from intermediate 2o following general procedure G. Column chromatography with 0.5 to 4% MeOH in DCM as mobile phase. Transparent oil (501 mg, 0.94 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 2.4 Hz, 4H), 6.62 (t, J = 2.4 Hz, 2H), 4.36 (t, J = 6.5 Hz, 4H), 3.81 (s, 12H), 2.66 – 2.36 (m, 12H), 1.95 1.96 (p, J = 7.6, 6.5 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ 166.0, 160.4, 132.0, 106.9, 105.2, 63.4, 55.3, 54.9, 53.0, 26.0. LC–MS (ESI +) m/z calcd. for C28H38N2O8 [(M + H)]+: 531.27; found: 531.25. HPLC tR: 7.833 min.

3-(4-(3-((2-methoxybenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4-dimethoxybenzoate (6u). Final compound 6j was obtained from intermediates 2n and 4a following general procedure F. Column chromatography with 3 to 5% MeOH in DCM as mobile phase. Transparent oil (120 mg, 0.24 mmol, 43%). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.9, 1.8 Hz, 1H), 7.68 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.47 (ddd, J = 8.5, 7.4, 1.8 Hz, 1H), 7.04 – 6.94 (m, 2H), 6.89 (d, J = 8.5 Hz, 1H), 4.41 – 4.31 (m, 4H), 3.94 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 2.61 – 2.40 (m, 12H), 2.01 – 1.90 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.4, 166.3, 159.1, 152.9, 148.6, 133.5, 131.6, 123.5, 122.9, 120.3, 120.1, 112.0, 112.0, 110.2, 63.3, 63.3, 56.0, 56.0, 55.9, 55.2, 53.2, 26.4, 26.2. LC–MS (ESI +) m/z calcd. for C27H36N2O7 [(M + H)]+: 501.26; found: 501.20. HPLC tR: 2.491 min.

3-(4-(3-((3,5-dimethoxybenzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4-dimethoxybenzoate (6v). Final compound 6j was obtained from intermediates 2n and 4b following general procedure F. Automatic column chromatography with 0 to 5% MeOH in DCM as mobile phase on Biotage Isolera One. Transparent oil (676 mg, 1.27 mmol, 87%). 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 2.4 Hz, 2H), 6.87 (d, J = 8.5 Hz, 1H), 6.62 (t, J = 2.4 Hz, 1H), 4.42 – 4.30 (m, 4H), 3.92 (s, 3H), 3.90 (s, 3H), 3.80 (s, 6H), 2.62 – 2.38 (m, 12H), 2.00 – 1.90 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 165.8, 165.7, 160.2, 152.5, 148.2, 131.8, 123.0, 122.4, 111.5, 109.8, 106.7, 63.2, 62.8, 55.5, 55.5, 55.03, 54.7, 54.6, 52.8, 25.9, 25.8. LC–MS (ESI +) m/z calcd. for C28H38N2O8 [(M + H)]+: 531.27; found: 531.25. HPLC tR: 7.045 and 7.432 min.

3-(fluorosulfonyl)benzoic acid (7a). Intermediate 7a was obtained from 3-(chlorosulfonyl)benzoic acid following general procedure J. White solid (602 mg, 2.94 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ 13.87 (br s, 1H), 8.50 – 8.43 (m, 2H), 8.42 – 8.38 (m, 1H), 7.95 (t, J = 7.8 Hz, 1H). LC–MS (ESI-) m/z calcd. for C7H5FO4S [(M-H)]−: 202.98; found: 202.95. HPLC tR: 8.100 min.

4-(fluorosulfonyl)benzoic acid (7b). Intermediate 7b was obtained from 4-(chlorosulfonyl)benzoic acid following general procedure J. White solid (961 mg, 4.71 mmol, 94%). 1H NMR (400 MHz, CDCl3) δ 8.38 – 8.32 (m, 2H), 8.18 – 8.12 (m, 2H). LC–MS (ESI-) m/z calcd. for C7H5FO4S [(M-H)]−: 202.98; found: 203.00. HPLC tR: 8.464 min.

4-isothiocyanatobenzoic acid (7c). A stirred solution of thiophosgene (0.15 mL, 2.00 mmol, 1.0 equiv) in acetone (2.00 mL) was allowed to cool down to 0 °C followed by addition of a solution of 4-aminobenzoic acid (274 mg, 2.00 mmol, 1.0 equiv) in acetone (2.00 mL). The mixture was allowed to stir at 0 °C for 3 h and at rt for 16 h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (20 mL) and washed with sat. NaHCO3 solution (20 mL). The aqueous phase was acidified to pH 3 by dropwise addition of 3 M aqueous HCl and extracted three times with EtOAc (20 mL). The combined organic phase was dried over MgSO4, filtrated and concentrated in vacuo to provide intermediate 7c as a yellow solid. (136 mg, 0.76, 38%). 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H). LC–MS (ESI-) m/z calcd. for C8H5NO2S [(M-H)]−: 178.00; found: 177.90. HPLC tR: 9.494 min.

3-((tert-butoxycarbonyl)amino)benzoic acid (7d). Intermediate 7d was obtained from 3-aminobenzoic acid following general procedure K with Et3N. White solid (quant.). 1H NMR (400 MHz, CDCl3) δ 8.00 (t, J = 2.0 Hz, 1H), 7.79 – 7.70 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 6.65 (br s, 1H), 1.54 (s, 9H). LC–MS (ESI-) m/z calcd. for C12H15NO4 [(M-H)]−: 236.09; found: 236.05. HPLC tR: 9.131 min.

4-((tert-butoxycarbonyl)amino)benzoic acid (7e). Intermediate 7e was obtained from 4-aminobenzoic acid following general procedure K with Et3N. White solid (quant.). 1H NMR (400 MHz, CDCl3) δ 8.16 – 7.93 (m, 2H), 7.64 – 7.34 (m, 2H), 6.83 (br s, 1H), 1.54 (s, 9H). LC–MS (ESI-) m/z calcd. for C12H15NO4 [(M-H)]−: 236.09; found: 236.05. HPLC tR: 9.117 min.

4-((tert-butoxycarbonyl)amino)-3-methoxybenzoic acid (7f). Intermediate 7f was obtained from 4-amino-3-methoxybenzoic acid following general procedure K with NaOH. Brown solid (1.86 g, 6.95 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 1H), 7.97 (br s, 1H), 7.63 (dd, J = 8.4, 1.9 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 3.93 (s, 3H), 1.53 (s, 9H). LC–MS (ESI-) m/z calcd. for C13H17NO5 [(M-H)]−: 266.10; found: 266.00. HPLC tR: 9.926 min.

4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid (7g). Intermediate 7g was obtained from 4-(aminomethyl)benzoic acid following general procedure K with NaOH. White solid (1.77 g, 7.06 mmol, 88%). 1H NMR (400 MHz, MeOD) δ 7.98 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.29 (s, 2H), 1.46 (s, 9H). LC–MS (ESI-) m/z calcd. for C13H17NO4 [(M-H)]−: 250.11; found: 250.10. HPLC tR: 8.717 min.

4-(2-((tert-butoxycarbonyl)amino)ethyl)benzoic acid (7h). Intermediate 7h was obtained from 4-(2-aminoethyl)benzoic acid hydrochloride following general procedure K with NaOH. White solid (945 mg, 3.56 mmol, 89%). 1H NMR (400 MHz, MeOD) δ 7.97 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 3.30 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H), 1.43 (s, 9H). LC–MS (ESI-) m/z calcd. for C14H19NO4 [(M-H)]−: 264.12; found: 264.10. HPLC tR: 9.064 min.

2-bromoethyl 3-(fluorosulfonyl)benzoate (8a). Intermediate 8a was obtained from 7a and 2-bromoethan-1-ol following general procedure C. Column chromatography with 30% EtOAc in PE as mobile phase. Transparent oil (259 mg, 0.83 mmol, 82%). 1H NMR (400 MHz, CDCl3) δ 8.69 (t, J = 1.8 Hz, 1H), 8.48 (dt, J = 7.9, 1.5 Hz, 1H), 8.23 (ddd, J = 7.9, 2.0, 1.2 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 4.71 (t, J = 6.0 Hz, 2H), 3.69 (t, J = 6.0 Hz, 2H).

4-bromobutyl 3-(fluorosulfonyl)benzoate (8b). Intermediate 8b was obtained from 7a and 4-bromobutan-1-ol following general procedure C. Column chromatography with 20% EtOAc in PE as mobile phase. Transparent oil (294 mg, 0.87 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 8.65 (t, J = 1.8 Hz, 1H), 8.46 (dt, J = 7.9, 1.4 Hz, 1H), 8.21 (ddd, J = 7.9, 2.0, 1.2 Hz, 1H), 7.79 (t, J = 8.0, 0.7 Hz, 1H), 4.45 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 6.2 Hz, 2H), 2.14 – 1.94 (m, 4H).

2-bromoethyl 4-(fluorosulfonyl)benzoate (8c). Intermediate 8c was obtained from 7b and 2-bromoethan-1-ol following general procedure C. Column chromatography with 10% to 20% EtOAc in PE as mobile phase. Transparent oil (503 mg, 1.62 mmol, 50%). 1H NMR (400 MHz, CDCl3) δ 8.37 – 8.30 (m, 2H), 8.16 – 8.08 (m, 2H), 4.72 (t, J = 6.1 Hz, 2H), 3.71 (t, J = 6.0 Hz, 2H).

3-bromopropyl 4-(fluorosulfonyl)benzoate (8d). Intermediate 8d was obtained from 7h and 3-bromopropan-1-ol following general procedure C. Column chromatography with 20% EtOAc in PE as mobile phase. Transparent oil (756 mg, 2.33 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ 8.33 – 8.25 (m, 2H), 8.11 (d, J = 8.5 Hz, 2H), 4.56 (t, J = 6.1 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H), 2.37 (p, J = 6.3 Hz, 2H).

4-bromobutyl 4-(fluorosulfonyl)benzoate (8e). Intermediate 8e was obtained from 7b and 4-bromobutan-1-ol following general procedure C. Column chromatography with 10% EtOAc in PE as mobile phase. Transparent oil (227 mg, 0.67 mmol, 41%). 1H NMR (400 MHz, CDCl3) δ 8.32 – 8.26 (m, 2H), 8.13 – 8.07 (m, 2H), 4.44 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 6.3 Hz, 2H), 2.11 – 1.94 (m, 4H).

3-bromopropyl 3-((tert-butoxycarbonyl)amino)benzoate (8f). Intermediate 8f was obtained from 7d and 3-bromopropan-1-ol following general procedure L. Column chromatography with 5 to 15% EtOAc in PE as mobile phase. Yellow oil (157 mg, 0.44 mmol, 15%). 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.89 (m, 1H), 7.78 – 7.70 (m, 1H), 7.70 (dt, J = 7.7, 1.3 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 6.79 (s, 1H), 4.46 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.37 – 2.19 (m, 2H), 1.53 (s, 9H).

3-bromopropyl 4-((tert-butoxycarbonyl)amino)benzoate (8g). Intermediate 8g was obtained from 7e and 3-bromopropan-1-ol following general procedure L. Column chromatography with 5 to 15% EtOAc in PE as mobile phase. Yellow oil (231 mg, 0.65 mmol, 22%). 1H NMR (400 MHz, CDCl3) δ 8.00 – 7.92 (m, 2H), 7.49 – 7.42 (m, 2H), 6.89 (s, 1H), 4.44 (t, J = 6.1 Hz, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.31 (p, J = 6.3 Hz, 2H), 1.52 (s, 9H).

4-bromobutyl 4-((tert-butoxycarbonyl)amino)benzoate (8h). Intermediate 8h was obtained from 7e and 4-bromobutan-1-ol following general procedure L. Column chromatography with 5 to 10% EtOAc in PE as mobile phase. White solid (332 mg, 0.89 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 8.01 – 7.92 (m, 2H), 7.54 – 7.45 (m, 2H), 7.28 (br s, 1H), 4.33 (t, J = 6.2 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 2.05 – 1.97 (m, 2H), 1.97 – 1.88 (m, 2H), 1.51 (s, 9H).

3-bromopropyl 4-((tert-butoxycarbonyl)amino)-3-methoxybenzoate (8i). Intermediate 8i was obtained from 7f and 3-bromopropan-1-ol following general procedure L. Column chromatography with 5 to 15% EtOAc in PE as mobile phase. Yellow oil (321 mg, 0.83 mmol, 28%). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.5, 1.8 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.30 (br s, 1H), 4.44 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 3.54 (t, J = 6.6 Hz, 2H), 2.32 (p, J = 6.3 Hz, 2H), 1.53 (s, 9H).

3-bromopropyl 4-(((tert-butoxycarbonyl)amino)methyl)benzoate (8j). Intermediate 8j was obtained from 7g and 3-bromopropan-1-ol following general procedure L in the presence of pyridine (6.0 equiv). Column chromatography with 5 to 10% EtOAc in PE as mobile phase. White solid (743 mg, 2.00 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 5.16 (br s, 1H), 4.45 (t, J = 6.0 Hz, 2H), 4.34 (d, J = 6.6 Hz, 2H), 3.54 (t, J = 6.5 Hz, 2H), 2.31 (p, J = 6.3 Hz, 2H), 1.46 (s, 9H).

3-bromopropyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)benzoate (8k). Intermediate 8k was obtained from 7h and 3-bromopropan-1-ol following general procedure L in the presence of pyridine (6.0 equiv). Column chromatography with 5 to 10% EtOAc in PE as mobile phase. White solid (192 mg, 0.50 mmol, 17%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 4.72 (br t, J = 6.2 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 3.55 (t, J = 6.6 Hz, 2H), 3.39 (q, J = 6.8 Hz, 2H), 2.87 (t, J = 7.0 Hz, 2H), 2.32 (p, J = 6.3 Hz, 2H), 1.43 (s, 9H).

3-(4-(2-((3-(fluorosulfonyl)benzoyl)oxy)ethyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (9a). Final compound 9a was obtained from intermediates 8a and 4c following general procedure F. Column chromatography with 6 to 10% MeOH in EtOAc as mobile phase. Transparent oil (13.2 mg, 0.02 mmol, 4%). 1H NMR (400 MHz, CDCl3) δ 8.66 (t, J = 1.8 Hz, 1H), 8.43 (dt, J = 7.9, 1.4 Hz, 1H), 8.20 (ddd, J = 7.9, 2.0, 1.2 Hz, 1H), 7.76 (t, J = 8.4 Hz, 1H), 7.29 (s, 2H), 4.52 (t, J = 5.9 Hz, 2H), 4.37 (t, J = 6.6 Hz, 2H), 3.91 (s, 9H), 2.81 (t, J = 6.0 Hz, 2H), 2.72–2.40 (m, 10H), 2.00 (p, J = 6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 166.4, 164.2, 153.0, 136.5, 132.3, 130.2, 129.7, 125.4, 106.9, 63.6, 63.4, 61.1, 56.6, 56.4, 55.2, 53.4, 53.2, 26.3. LC–MS (ESI +) m/z calcd. for C26H33FN2O9S [(M + H)]+: 569.20; found: 569.15. HPLC tR: 7.638 min.

3-(4-(3-((3-(fluorosulfonyl)benzoyl)oxy)propyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (9b). Final compound 9b was obtained from intermediate 5 and 7a following general procedure I. Column chromatography with 3% MeOH in DCM as mobile phase. Transparent oil (30.3 mg, 0.05 mmol, 5%).1H NMR (400 MHz, CDCl3) δ 8.65 (t, J = 1.6 Hz, 1H), 8.43 (dt, J = 8.0, 1.6 Hz, 1H), 8.20 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.29 (s, 2H), 4.45 (t, J = 6.6 Hz, 2H), 4.37 (t, J = 6.6 Hz, 2H), 3.91 (s, 6H), 3.91 (s, 3H), 2.85 – 2.24 (m, 12H), 2.09 – 1.87 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.3, 164.2, 153.0, 136.4, 132.4, 132.3, 130.2, 129.6, 125.5, 106.9, 64.7, 63.7, 61.1, 56.4, 55.2, 55.0, 53.3, 26.4, 26.2. LC–MS (ESI +) m/z calcd. for C27H35FN2O9S [(M + H)]+: 583.21; found: 583.25. HPLC tR: 7.585 min.

3-(4-(4-((3-(fluorosulfonyl)benzoyl)oxy)butyl)piperazin-1-yl)propyl 3,4,5-trimethoxybenzoate (9c). Final compound 9c was obtained from intermediates 8b and 4c following general procedure F. Column chromatography with 4 to 8% MeOH in DCM as mobile phase. Transparent oil (40.1 mg, 0.06 mmol, 13%). 1H NMR (400 MHz, CDCl3) δ 8.65 (t, J = 1.8 Hz, 1H), 8.44 (dt, J = 7.9, 1.5 Hz, 1H), 8.20 (ddd, J = 7.9, 2.0, 1.2 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.29 (s, 2H), 4.41 (t, J = 6.6 Hz, 2H), 4.37 (t, J = 6.6 Hz, 2H), 3.91 (s, 9H), 2.63 – 2.33 (m, 12H), 2.01 – 1.93 (m, 2H), 1.84 (p, J = 8.0, 7.0, 6.5 Hz, 2H), 1.70 – 1.60 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 166.3, 164.2, 153.0, 136.4, 133.9, 132.4, 132.2, 130.1, 129.6, 125.5, 106.9, 66.1, 63.7, 61.0, 58.1, 56.4, 55.2, 53.3, 26.8, 26.4, 23.5. LC–MS (ESI +) m/z calcd. for C28H37FN2