Structure of 100523-84-0
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| CAS No. : | 100523-84-0 |
| Formula : | C5H3BrO2S |
| M.W : | 207.05 |
| SMILES Code : | BrC1=CC(=CS1)C(=O)O |
| English Name : | 5-Bromothiophene-3-carboxylic acid |
| MDL No. : | MFCD08695074 |
| InChI Key : | YCNXGPMGMAKDPM-UHFFFAOYSA-N |
| Pubchem ID : | 12039978 |
| Num. heavy atoms | 9 |
| Num. arom. heavy atoms | 5 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 1 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 38.98 |
| TPSA ? Topological Polar Surface Area: Calculated from |
65.54 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.4 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.15 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.21 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.35 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.62 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.95 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.82 |
| Solubility | 0.311 mg/ml ; 0.0015 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-3.16 |
| Solubility | 0.144 mg/ml ; 0.000694 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.9 |
| Solubility | 2.61 mg/ml ; 0.0126 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.04 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.41 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With bromine; acetic acid at 20℃; | a Step a Mix compound 1a (25g, 0.195mol) with 100mL of acetic acid, and slowly drop a mixture of bromine (11mL, 0.215mol) and glacial acetic acid (75mL) at room temperature.After the addition is complete, stir at room temperature overnight. After TLC detects that the reaction is complete, the reaction solution is added to ice water to precipitate solids. The crude product is filtered and washed three times with ice water to obtain 1b39g of white solids, with a yield of 98% |
| 82% | With pyridinium tribromide; hydrogen bromide; acetic acid at 20℃; for 24h; | To a 3 L flask was charged compound 1 (150.0 g, 1.17 mol), AcOH (1 L), Pyridinium tribromide (375.0 g, 1.17 mol) and 48% HBr (100 mL) was dropwised. After the addition, the reaction was stirred for 24 h at room temperature and poured onto water (3 L). The solids were filtered, washed with water and dried to obtain compound 2 (198.7 g, 82%). 5-Bromothiophene-3-carboxylic acid (2):1H NMR (400 MHz, DMSO-d6) δ: 12.96 (s, 1H), 8.26 (d, J1.6 Hz, 1H), 7.47 (d, J1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 162.84, 135.81, 135.19, 130.75, 112.93; HRMS calcd for C5H4BrO2S[M+H] : 206.9110, found 206.9109. |
| 82% | With pyridinium tribromide; hydrogen bromide; acetic acid at 20℃; for 24h; | To a 3 L flask was charged compound 1 (150.0 g, 1.17 mol), AcOH (1 L), Pyridinium tribromide (375.0 g, 1.17 mol) and 48% HBr (100 mL) was dropwised. After the addition, the reaction was stirred for 24 h at room temperature and poured onto water (3 L). The solids were filtered, washed with water and dried to obtain compound 2 (198.7 g, 82%). 5-Bromothiophene-3-carboxylic acid (2):1H NMR (400 MHz, DMSO-d6) δ: 12.96 (s, 1H), 8.26 (d, J1.6 Hz, 1H), 7.47 (d, J1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 162.84, 135.81, 135.19, 130.75, 112.93; HRMS calcd for C5H4BrO2S[M+H] : 206.9110, found 206.9109. |
| 74% | With bromine In acetic acid | |
| 70% | With bromine In acetic acid | 1.d (d) (d) 5-bromo-3-thiophenecarboxylic acid A solution containing 16 g of Br2 (0.1 mol) in glacial acetic acid (200 ml) is added slowly to a solution of 3-thiophenecarboxylic acid (12.8 g; 0.1 mol) in 100 ml of glacial acetic acid. The mixture is stirred for 20' and then poured into water and ice. The white precipitate is filtered, washed and crystallized from water. Yield, 70%. |
| 54.7% | With bromine In acetic acid at 20℃; | |
| 52% | With bromine; acetic acid | |
| 51% | With bromine; acetic acid at 20℃; for 2h; | |
| 50% | With bromine In acetic acid at 20℃; for 0.25h; | 7.A A. To a stirred solution of 3-thiophenecarboxylic acid (1.00 g, 7.80 mmol) in glacial acetic acid (9 mL) at ambient temperature under nitrogen atmosphere was slowly added bromine (0.39 mL, 7.53 mmol) in glacial acetic acid (6 mL). The reaction mixture was stirred for 15 minutes, then quenched with cold water (50 mL). The precipitate was filtered, washed with water and dried in vacuum oven at 50° C. to afford 5-bromo-3-thiophenecarboxylic acid as a colorless solid (0.78 g, 50%): mp 133-135° C.; 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.5 Hi, 1H), 7.51 (d, J=1.5 Hz, 1H). |
| 48% | With bromine; acetic acid at 20℃; for 0.25h; | |
| 47.1% | With bromine In acetic acid for 0.25h; Ambient temperature; | |
| 46% | With bromine In acetic acid at 0 - 20℃; | 59; 60 A solution of bromine (2 mL, 39.06 mmol) in glacial acetic acid (64 mL) was added slowly to a stirred solution of Int-1 (5 g, 39.06 mmol) in glacial acetic acid (37 mL) at 0° C. and stirred at room temperature for 20 minutes. The reaction mixture was then poured into ice water while stirring vigorously. The white precipitated solid was filtered, washed with water and recrystallised from hot water to afford pure Int-2 as white solid (3.68 g, 46%). 1H NMR (200 MHz, dmso-d6): δ 7.55 (s, 1H), 8.17 (s, 1H). To a stirred solution of Int-2 (3.4 g, 16.42 mmol) in methanol (40 mL) was added H2SO4 (321 mg, 3.28 mmol) and stirred under reflux for 12 hours. Volatiles from the reaction mixture were distilled off under reduced pressure and the resulting residue was extracted with DCM (75 mL). The organic extract was washed with water (40 mL), saturated aqueous NaHCO3 solution (40 mL), brine (40 mL) and dried over Na2SO4, filtered and concentrated under vacuum to afford pure Int-3 as colorless viscous oil (3.3 g, 91%). 1H NMR (200 MHz, dmso-d6): δ 7.98 (s, 1H), 7.44 (s, 1H), 3.87 (s, 3H). To a stirred solution of Int-3 (0.5 g, 2.26 mmol) in dioxane (25 mL) was added Int-4 (0.51 g, 2.26 mmol) followed by Pd (OAc) 2 (105 mg, 0.45 mmol), xanthpos (265 mg, 0.497 mmol) and CS2CO3 (1.18 g, 3.62 mmol). The reaction mixture was degassed under vacuum, bubbled with N2 for 10 minutes and stirred under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure and was purified by column chromatography to isolate product and a very close spot together eluting with EtOAc. This mixture (140 mg) was further purified with preparative HPLC to obtain pure Int-5 as a yellow solid (80 mg, 10%). Mass (m/z): 366.0 [M++1]. 1H NMR (200 MHz, dmso-d6): 9.50 (d, J=7 Hz, 1H), 8.51 (d, J=7 Hz, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.74 (brs, 1H), 7.66 (d, J=11.8 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J=5.6 Hz, 1H), 6.87 (t, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.73 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.91 mmol) in THF: MeOH: H2O (2:1:2) (50 ml) was added LiOH (0.24 g, 5.74 mmol) at room temperature and stirred while heating at 50° C. for 16 hours. Volatiles from the reaction mixture were distilled off under reduced pressure, the reaction mixture was acidified to about pH 5-6 with 2N HCl. The precipitated solid was filtered and dried under vacuum to afford pure Int-6 (0.51 g, 76%). Mass (m/z): 352.0 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 12.45 (brs, 1H), 10.87 (s, 1H), 9.70 ((brs, 1H), 8.60 (d, J=4.68 Hz, 1H), 7.67-7.59 (m, 2H), 7.45 (t, J=8.4 Hz, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.04 (s, 2H), 2.65 (s, 3H). |
| 44% | With bromine; acetic acid at 20℃; for 0.5h; | |
| 38% | With bromine; acetic acid for 0.25h; | |
| 26% | With bromine In acetic acid for 0.5h; | To a solution of thiophene-3-carboxylic acid (5.00 g, 39.0 mmol) in acetic acid(140 mL), was added dropwise, a solution of bromine (6.60 g, 40.0 mmol) in acetic acid (40 mL). The reaction mixture was stirred for 30 minutes and then poured into water. The resultant solid was collected by filtration to afford the title compound as a grey solid (2.07g, 26%). LCMS (Method B): RT = 2.9 min, M+H+ = 208. |
| With bromine; acetic acid | ||
| In acetic acid | d (d) (d) 5-bromo-3-thiophenecarboxylic acid. A solution containing 16 g of Br2(0.1 mol) in glacial acetic acid (200 ml) is added slowly to a solution of 3-thiophenecarboxylic acid (12.8 g; 0.1 mol) in 100 ml of glacial acetic acid. The mixture is stirred for 20' and then poured into water and ice. The white precipitate is filtered, washed and crystallized from water. Yield, 70%. | |
| With bromine; acetic acid at 20℃; for 0.5h; | 1.1 Step; 5-Bromo-thiophene-3-carboxylic acid; To a solution of thiophene-3-carboxylic acid (25 g, 195 mmol) in AcOH (700 ml) was added bromine (10.6 ml) in AcOH (200 ml) dropwise. After the addition, the reaction was stirred for 30 minutes at room temperature and poured onto water. A white precipitate was formed, which was filtered and dried to obtain 5-bromo-thiophene-3-carboxylic acid (14.5 g) as a white solid after crystallization (water). | |
| With bromine In acetic acid | 268.a 5-Bromo-N-ethyl-2-(trimethylsilyl)-3-thiophenecarboxamide a) To a solution of 3-thiophenecarboxylic acid (7.7 g, 60 mmol) in 70 mL acetic acid was added a solution of 9.6 g bromine in 50 mL acetic acid at RT and stirring was continued at RT for 0.5 h. After that, the reaction mixture was poured into 600 mL ice-water. The precipitate was filtered, washed with water and air-dried to give 7.9 g of 5-bromo-3-thiophenecarboxylic acid. | |
| With pyridinium hydrobromide perbromide; acetic acid In ethyl acetate | R.124 5-Bromo-3-thiophenecarboxylic Acid Reference Example 124 5-Bromo-3-thiophenecarboxylic Acid A mixture of 3-thiophenecarboxylic acid (12.81 g), pyridinium bromide perbromide (35.54 g) and acetic acid (50 ml) was stirred at 45° C. for 48 hours. The mixture was poured into ice-water and precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-3-thiophenecarboxylic acid (19.78 g) as crystals. mp 137°-138° C. | |
| With pyridinium tribromide; hydrogen bromide In acetic acid at 20℃; | 1.1 To a solution of thiophene-3-carboxylic acid (12.6 g, 0.1 mol) in AcOH (96 ml), being stirred at room temperature, HBr solution (8 ml) was added, and the stirring continued until the color of mixture turned to yellow. Pyridinium bromide perbromide (27 g) was then sequentially added. The mixture was poured into ice-water, stirred for about 30 minutes. A white precipitate was formed, which was filtered and dried to obtain 5-bromo-thiophene-3-carboxylic acid (10.8 g) as a white solid after crystallization in hot water. HPLC: 92%. | |
| With 2-(4-bromo-3-oxobutyl)isoindoline-1,3-dione In acetic acid at 20℃; for 0.25h; | 26.1.A PREPARATION 26-1; C5-PHENYLTHIOPHEN-3-YL) METHYLAMINE A. 5-BROMOTHIOPHENE-3-CARBOXYLIC acid Prepare a solution of thiophene carboxylic acid (500 mg, 3.90 mmol) in HOAC (5 mL). Add Br2 (0.17 mL, 0. 85 MMOL), in HOAc (3 mL), dropwise. Then stir the mixture for 15 minutes at room temperature under nitrogen. Quench the reaction with ice cold water and stir for an additional 10 minutes. Cool the SOLUTION-10°C when the product will precipitate out. Filter the solution, rinse the filter cake with ice cold water, and dry the product to afford 473 mg of 5-BROMOTHIOPHENE-3-CARBOXYLIC acid as a white solids NMR (dimethylsulfoxide-d6) S 12.90 (br s, 1H), 8.18 (d, J = 1. 5 Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H). | |
| With bromine; acetic acid for 1h; | 26 5-Bromo-thiophene-3-carboxylic acid Thiophene-3-carboxylic acid (25 g, 195 mmol) was dissolved in acetic acid (200 mL). Bromine (10.4 mL, 200 mmol) was added slowly over the course of 0.5 hour. The mixture was stirred for a further 0.5 hour and then poured onto ice. After 0.5 hours the white precipitate that formed was collected by filtration. Recrystallisation from water gave the title compound as a white solid (13.7 g). 1H NMR (400 MHz, d6-DMSO): δ 8.25 (s, 1 H), 7.45 (s, 1 H). | |
| With N-Bromosuccinimide | ||
| With bromine In acetic acid | A (A) (A) 5-Bromothiophene-3-carboxylic Acid Bromine (46.5 g) in acetic acid (200 mL) was added dropwise to a solution of thiophene-3-carboxylic acid (38 g) in acetic acid (300 mL). After the addition was complete, stirring was continued at room temperature for 30 min. The reaction mixture was poured into 2000 mL of ice/water and the precipitated solid was collected and recrystallized from water to give a colourless solid; MS (ES-) 205, 207 (MH+). | |
| With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; | 118.a PREPARATION EXAMPLE 118; 5-Bromo-thiophene-3-carboxylic acid [2-(4-fluorophenyl)-ethyl]-amide; a) 5-Bromo-thiophene-3-carboxylic acid; To a solution of thiophene-3-carboxylic acid (18.2 g) in N,N-dimethylformamide (250 mL) was added N-bromosuccinimide (27.8 g) in small amounts on an ice bath. After stirring at room temperature overnight, the reaction solution was poured into water (1.5 L), and the resulting solid was collected by filtration and washed with water. After dissolving in ethyl acetate, and dried with anhydrous magnesium sulfate, the drying agent was removed by filtration, and evaporation in vacuo was carried out. The solid that was generated by dissolving the residue in ethyl acetate, and adding hexane were collected by filtration, and the crude product (16 g) of 5-bromo-thiophene-3-carboxylic acid was obtained as a colorless solid. | |
| Stage #1: 3-Thiophene carboxylic acid With hydrogen bromide In acetic acid at 20℃; Stage #2: With pyridinium hydrobromide perbromide In acetic acid at 20℃; | 1.1 Step 1: Synthesis of 5-bromo-thiophene-3-formic acid Thiophene-3-formic acid (12.6g) and AcOH (96ml) are added to a reaction flask (250ml), to dissolved after stirred at room temperature, HBr solution (8ml) is then added to the reaction flask, and the reaction is rapidly changed to a light yellow. Pyridinium bromide perbromide (27g) is then added to the flask in batches at room temperature. After addition, the reaction is stirred at room temperature, and the reaction is tracked by HPLC. The above mixture is poured into ice-water after reaction, stirred for about 30 minutes, filtered to form a white powder solid, the white powder solid is crystallized with hot water, filtered and dried to obtain a crystal of 5-bromo-thiophene-3- formic acid (10.8g), content of 92% meastured by HPLC. | |
| With bromine; acetic acid | ||
| With bromine; acetic acid at 20℃; | 2 Bromine (9 mL, 0.2 mol) in glacial acetic acid (190 mL) was added dropwise to a solution of thiophene-3-carboxylic acid (24.00 g, 0.1873 mol) in glacial acetic acid (190 mL). After stirring at room temperature for 90 min, the crude was poured into ice-water (1 L), a white precipitate was filtered, triturated with hot water (200 mL), filtered, rinsed with water (3×100 mL) and dried under reduced pressure. Crystallization from hot ethanol afforded the corresponding product as a white crystalline solid (15.45 g, 40%). | |
| With bromine In ethyl acetate at 20℃; for 0.25h; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; | a Step a Dissolve compound 1b (1035 mg, 5 mmol) in dry dichloromethane (30 mL), add oxalyl chloride (846 μL, 10 mmol),Add another drop of N,N-dimethylformamide (about 0.2 mL), stir at room temperature for 4 hours, spin the solvent to dryness, and obtain a crude product.Dissolve the crude product in dry dichloromethane (30mmol), add methanol (1mL) and stir at room temperature. TLC detects that the reaction is complete.Add 20 mL of saturated brine, extract twice with dichloromethane (30 mL), combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain the target product 1027 mg 3a. The total yield of the two steps is 93% |
| With thionyl chloride for 0.25h; Heating; | ||
| With thionyl chloride for 6h; Heating; |
| With thionyl chloride for 2h; Heating / reflux; | 1.2 Step 2; 5-Bromo-thiophene-3-carboxylic acid ethyl ester; A solution of 5-bromo-thiophene-3-carboxylic acid (14.5 g, 70 mmol) was dissolved in SOC12 and the mixture was refluxed for 2 hours. The mixture was concentrated under reduced pressure to give a yellow oil. The oil was was dissolved in EtOH and the mixture was refluxed for 1 hour, then concentrated under reduced pressure to give 5-bromo-thiophene-3-carboxylic acid ethyl ester as an oil (16.46 g, quantitative). | |
| With thionyl chloride for 6h; Reflux; Inert atmosphere; | ||
| With thionyl chloride; N,N-dimethyl-formamide In toluene at 110℃; for 4h; | 5.2.1 General procedure for amide formation (method A) General procedure: A solution of bromo heteroaryl carboxylic acid (2mmol), thionyl chloride (4mmol) and DMF (5 drops) in toluene (10mL) was refluxed at 110°C for 4h. The reaction mixture was cooled to room temperature and the solvent and the excess of thionyl chloride removed under reduced pressure. To the residue was added at 0°C the corresponding N-methyl amine (2mmol) and Et3N (2mmol) in CH2Cl2 (10mL) under N2 atmosphere. After 30min at 0°C, the ice bath was removed and the solution was warmed up and stirred at room temperature overnight. The reaction mixture was extracted twice with CH2Cl2 (2×15mL) and the organic layer dried over MgSO4, filtered and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes and EtOAc as eluant or by trituration in a mixture of diethyl ether/petroleum ether to afford the desired compound. | |
| With thionyl chloride | ||
| With thionyl chloride; N,N-dimethyl-formamide Heating; | ||
| With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 4.5h; Reflux; | 1 To a solution of 1.00 g (4.83 mmol) of 5-bromothiophene-3-carboxylic acid in 20 mL of CH2Cl2 were added one drop of N,N-dimethylformamide and 1.0 mL (11 mmol) of oxalyl dichloride. The solution was heated under reflux for 3 h and 1.0 mL (11 mmol) of oxalyl dichloride was again added thereto and the mixture heated under reflux for a further 1.5 h. The solvent was then removed under reduced pressure. | |
| With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
| With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
| With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 1.5h; | 118.b b) Title Compound; To a solution of 5-bromo-thiophene-3-carboxylic acid (5 g) and [2-(4-fluorophenyl)-ethyl]methyl-amine (the compound of Preparation Example 14) (3.7 g) in dichloromethane (150 mL) was added 1-Ethyl-3-(3-dimethylamino propyl)-carbodiimide.hydrochloride (5.1 g) was added. After stirring for 1.5 hours, the residue resulting from evaporation of the reaction solution in vacuo was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (6 g) was obtained as a colorless oily matter. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 62% | With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine at 85℃; for 12h; Inert atmosphere; | 1 Step 1. Tert-butyl N-(5-bromothiophen-3-yl)carbamate To a solution of 5-bromothiophene-3-carboxylic acid (3.0 g, 14.5 mmol) in tert-butanol (30 ml) was add DPPA (3.14 ml, 14.5 mmol) and DIPEA (3.79 ml, 21.7 mmol). The RM was stirred at 85° C under N2 for 12 h, then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (9- 17 % EtOAc in petrol) to give the title compound as a white solid. Y = 62 %. |
| With diphenyl phosphoryl azide; triethylamine Heating / reflux; | 37.b b) 2-Bromo-4- (N T-BUTYLOXYCARBONVL) AMINOTHIOPHENE 2-Bromothiophene-4-carboxylic acid (3 g) was dissolved in dry warm t-butanol (24 ml). Triethylamine (2.02 ml) was added followed by diphenylphosphoryl azide (3.12 ml). The solution was heated slowly to reflux and heating continued at reflux overnight. The reaction mixture was then allowed to cool, poured into water (150 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts were dried, filtered and evaporated. The crude product was purified by column chromatography, eluting with 5% ethyl acetate in hexane, to give a white solid (1.69 g). MS (ES) 276 (M-H)-. 'H NMR (DMSO-D6) 1.44 (s, 9H), 7.03 (s, 1H), 7.51 (s, 1H), 9.65 (s, 1H). | |
| With diphenyl phosphoryl azide; triethylamine Heating / reflux; | 13.b b) 2-BROMO-4-(N-TERT-BUTYLOXYCARBONYL) AMINOTHIOPHENE 2-Bromothiophene-4-carboxylic acid (3 g) was dissolved in dry warm t-butanol (24 ml). Triethylamine (2.02 ml) was added followed by diphenylphosphoryl azide (3.12 ml). The solution was heated slowly to reflux and heating continued at reflux overnight. The reaction mixture was then allowed to cool, poured into water (150 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts were dried, filtered and evaporated. The crude product was purified by column chromatography, eluting with 5% ethyl acetate in hexane, to give a white solid (1.69 g). MS (ES) 276 (M-H)-. 'H NMR (DMSO-D6) 1.44 (s, 9H), 7.03 (s, 1H), 7.51 (s, 1H), 9.65 (s, 1H). |
| Stage #1: 2-bromothiophene-4-carboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; for 2h; Stage #2: <i>tert</i>-butyl alcohol In toluene at 100℃; for 2h; | 112.2 (Step 2) (Step 2) [0352] Triethylamine (15 mL) and diphenylphosphoryl azide (16.5 mL) were added to a solution of the mixture of 2-bromothiophene-4-carboxylic acid obtained in the above-described Step (14.48 g) in toluene (250 mL) at room temperature. The reaction solution was stirred for 2 hours. 2-Methyl-2-propanol (40 mL) was added to the reaction solution, and then the reaction solution was stirred at 100°C for 2 hours. The reaction solution was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent: hexane/ethyl acetate) to obtain tert-butyl(5-bromothiophen-3-yl)carbamate as a white solid. | |
| 22.3 % | With diphenyl phosphoryl azide; triethylamine In toluene at 100℃; | 4.1 Step 1: Dissolve 4A (2g, 9.66mmol, 1eq) in toluene (40mL), add triethylamine (2.44g, 24.15mmol, 2.5eq), after adding DPPA (3.19g, 11.59mmol, 1.2eq) and tert-butanol (7.16g, 96.6mmol, 10eq), the mixture was raised to 100°C and stirred overnight. Pour the reaction solution into 50mL of water, extract with EA (50mL×3), and dry the organic phase over sodium sulfate. Concentrate under reduced pressure, mix with silica gel, and perform column chromatography (PE:EA=5:1) to obtain off-white solid 4B (0.6g, yield 22.3%). |
| With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine In toluene at 85℃; for 3h; | 254 Example 254 - Synthesis of Tert-butyl N-(5-bromo-3-thienyl)carbamate (Intermediate 55) To a solution of 5-bromothiophene-3-carboxylic acid (2.00 g, 9.66 mmol) in toluene (25 mL) was added DIPEA (2.0 mL, 11.5 mmol) 2-methylpropan-2-ol (11.7 mL, 123.28 mmol) and DPPA (2.5 mL, 11.7 mmol). The mixture was heated to 85 °C for 3 h. The mixture was cooled to r.t. and water (20 mL) was added and the aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were washed with 1 M NaOH (20 mL) and brine (30 mL), passed through phase separator paper, and concentrated under reduced pressure. The residue was purified by FCC (25 g SiO2 cartridge, 0-20% EtOAc in heptane) to afford the title compound as a pale-yellow solid (1.97 g, 90% purity, 66% Yield). 1H NMR (500 MHz, DMSO) δ 9.70 (s, 1H), 7.15 (s, 1H), 7.04 (d, J = 1.7 Hz, 1H), 1.46 (s, 9H). LCMS: m/z = 221.8/223.8 [M-tButyl+H]+, (ESI-), RT = 1.06, Method D |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 60% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 49h; | 2.d (d) 5-BROMOTHIOPHENE-N-METHYL-3-CARBOXYLAMIDE 4.7 g (35 mmol) of 1-hydroxybenzotriazole, 2.2 g (32 mmol) of methylamine hydrochloride and 4.5 ml (32 mmol) of triethylamine are successively added to a solution of 6.7 g (32 mmol) of 5-bromothiophene-3- carboxylic acid in 120 ml of dichloromethane. The reaction medium is cooled to 0oC and a solution of 6.7 g (35 mmol) of 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride is added dropwise. After 1 hour at 0oC, the reaction medium is stirred at room temperature for 2 days. The dichloromethane phase is washed with water, dried over sodium sulfate, filtered and evaporated under vacuum. The residue obtained is triturated from a HEPTANE/ETHYL acetate mixture, filtered and evaporated. 5.6 g (60%) of 5-bromothiophene-N-methyl-3-carboxylamide are obtained. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | Stage #1: 5-bromo-3-thiophenecarboxylic acid ethyl ester With methanol; sodium hydroxide; lithium hydroxide monohydrate In tetrahydrofuran at 20℃; for 18h; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate | |
| With ethanol; lithium hydroxide monohydrate; sodium hydroxide | 179 EXAMPLE 179: Compound 436B: N-[3-(4-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1- (2,2,2-trifluoroethyl)-1H-indol-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-(morpholin-4-yl)thiophene-3- carboxamide The ethyl ester was saponified under standard conditions to provide the carboxylic acid. To a mixture of morpholine (12.1 mmol, 1.06 mL, 5 eq) and 5-bromothiophene-3-carboxylic acid (500 mg, 2.41 mmol, 1 eq) in toluene (6 mL) were added di-tert-butyl-(2-phenylphenyl)phosphane (JohnPhos) (144.1 mg, 483 μmol, 0.2 eq), diacetoxypalladium (54.2 mg, 241.49 μmol, 0.1 eq), sodium t-butoxide (2 M, 3.6 mL, 3 eq) at 20 °C under nitrogen. The reaction was then heated to 100 °C and stirred for 16 h. The reaction was poured into EDTA (sat., 30 mL) and stirred for 2 h. The aqueous phase was extracted with EA (3x20 mL). The combined organic phase was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by pre- HPLC, column: Phenomenex Luna C18200x40mmx10um; mobile phase: [water(0.2%FA)-ACN];B%: 10%-50%, 8min to give the desired intermediate (100 mg, 19.4% yield) as yellow solid. LC-MS (ES+, m/z): 214.1 [(M+H)+]. | |
| With ethanol; lithium hydroxide monohydrate; sodium hydroxide | 179 EXAMPLE 179: Compound 436B: N-[3-(4-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1- (2,2,2-trifluoroethyl)-1H-indol-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-(morpholin-4-yl)thiophene-3- carboxamide The ethyl ester was saponified under standard conditions to provide the carboxylic acid. To a mixture of morpholine (12.1 mmol, 1.06 mL, 5 eq) and 5-bromothiophene-3-carboxylic acid (500 mg, 2.41 mmol, 1 eq) in toluene (6 mL) were added di-tert-butyl-(2-phenylphenyl)phosphane (JohnPhos) (144.1 mg, 483 μmol, 0.2 eq), diacetoxypalladium (54.2 mg, 241.49 μmol, 0.1 eq), sodium t-butoxide (2 M, 3.6 mL, 3 eq) at 20 °C under nitrogen. The reaction was then heated to 100 °C and stirred for 16 h. The reaction was poured into EDTA (sat., 30 mL) and stirred for 2 h. The aqueous phase was extracted with EA (3x20 mL). The combined organic phase was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by pre- HPLC, column: Phenomenex Luna C18200x40mmx10um; mobile phase: [water(0.2%FA)-ACN];B%: 10%-50%, 8min to give the desired intermediate (100 mg, 19.4% yield) as yellow solid. LC-MS (ES+, m/z): 214.1 [(M+H)+]. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | Stage #1: methanol; 2-bromothiophene-4-carboxylic acid With sulfuric acid for 12h; Reflux; Stage #2: With sodium hydrogencarbonate In water | 59; 60 A solution of bromine (2 mL, 39.06 mmol) in glacial acetic acid (64 mL) was added slowly to a stirred solution of Int-1 (5 g, 39.06 mmol) in glacial acetic acid (37 mL) at 0° C. and stirred at room temperature for 20 minutes. The reaction mixture was then poured into ice water while stirring vigorously. The white precipitated solid was filtered, washed with water and recrystallised from hot water to afford pure Int-2 as white solid (3.68 g, 46%). 1H NMR (200 MHz, dmso-d6): δ 7.55 (s, 1H), 8.17 (s, 1H). To a stirred solution of Int-2 (3.4 g, 16.42 mmol) in methanol (40 mL) was added H2SO4 (321 mg, 3.28 mmol) and stirred under reflux for 12 hours. Volatiles from the reaction mixture were distilled off under reduced pressure and the resulting residue was extracted with DCM (75 mL). The organic extract was washed with water (40 mL), saturated aqueous NaHCO3 solution (40 mL), brine (40 mL) and dried over Na2SO4, filtered and concentrated under vacuum to afford pure Int-3 as colorless viscous oil (3.3 g, 91%). 1H NMR (200 MHz, dmso-d6): δ 7.98 (s, 1H), 7.44 (s, 1H), 3.87 (s, 3H). To a stirred solution of Int-3 (0.5 g, 2.26 mmol) in dioxane (25 mL) was added Int-4 (0.51 g, 2.26 mmol) followed by Pd (OAc) 2 (105 mg, 0.45 mmol), xanthpos (265 mg, 0.497 mmol) and CS2CO3 (1.18 g, 3.62 mmol). The reaction mixture was degassed under vacuum, bubbled with N2 for 10 minutes and stirred under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure and was purified by column chromatography to isolate product and a very close spot together eluting with EtOAc. This mixture (140 mg) was further purified with preparative HPLC to obtain pure Int-5 as a yellow solid (80 mg, 10%). Mass (m/z): 366.0 [M++1]. 1H NMR (200 MHz, dmso-d6): 9.50 (d, J=7 Hz, 1H), 8.51 (d, J=7 Hz, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.74 (brs, 1H), 7.66 (d, J=11.8 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J=5.6 Hz, 1H), 6.87 (t, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.73 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.91 mmol) in THF: MeOH: H2O (2:1:2) (50 ml) was added LiOH (0.24 g, 5.74 mmol) at room temperature and stirred while heating at 50° C. for 16 hours. Volatiles from the reaction mixture were distilled off under reduced pressure, the reaction mixture was acidified to about pH 5-6 with 2N HCl. The precipitated solid was filtered and dried under vacuum to afford pure Int-6 (0.51 g, 76%). Mass (m/z): 352.0 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 12.45 (brs, 1H), 10.87 (s, 1H), 9.70 ((brs, 1H), 8.60 (d, J=4.68 Hz, 1H), 7.67-7.59 (m, 2H), 7.45 (t, J=8.4 Hz, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.04 (s, 2H), 2.65 (s, 3H). |
| 76% | With thionyl chloride Reflux; | |
| 73.9% | Stage #1: 2-bromothiophene-4-carboxylic acid With thionyl chloride for 0.5h; Reflux; Stage #2: methanol for 1h; Reflux; |
| With hydrogenchloride In water for 3h; Heating / reflux; | 26.1.B B. 5-BROMOTHIOPHENE-3-CARBOXYLIC acid methyl ester Prepare a solution of 5-bromothiophene-3-carboxylic acid (500 mg, 2.41 mmol) in methanol (5 mL). Add concentrated hydrochloric acid (0.1 mL). Reflux the mixture for 3 hours, cool to room temperature, pour into water, and extract with diethyl ether (3 X 10 mL). Wash the combined organic phases with water (10 mL), then saturated aqueous sodium hydrogencarbonate (10 mL). Dry (magnesium sulfate), filter and concentrate. Perform flash chromatography on silica gel eluting with 5: 1 HEXANE/ETHYL acetate to afford 409 mg of 5-bromothiophene-3-carboxylic acid methyl ester as a white SOLID. 1H NMR (CDC13) 6 8.10 (d, J= 1.5 Hz, 1H), 7.17 (d, J= 1.5 Hz, 1H), 3.86 (s, 3H). | |
| With sulfuric acid for 14h; Reflux; | 27 5-Bromo-thiophene-3-carboxylic acid (13 g, 64 mmol) was dissolved in methanol (140 mL). Concentrated sulphuric acid (6.5 mL) was added and the mixture heated at reflux for 14 hours. The reaction was quenched by adding a solution of saturated aqueous sodium bicarbonate and most of the solvent was removed by evaporation under vacuum. The mixture was then diluted with a solution of saturated aqueous sodium bicarbonate and the product extracted with DCM. The organic solution was dried over sodium sulphate, filtered and the solvent removed by evaporation to give a white crystalline solid (13.2g). H NMR (400 MHz, CDCI3): δ 8.0 (s, 1 H), 7.5 (s, 1 H), 3.85 (s, 3H). | |
| With hydrogenchloride for 16h; Reflux; | ||
| With hydrogenchloride Reflux; | ||
| 4.3 g | With acetic acid for 0.5h; Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; for 72h; | N-(3-Methoxybenzyl)-5-bromothiophene-3-carboxamide:; 5-Bromothiophene-3-carboxylic acid (70%) (200 mg, 0.6 mmol of mono bromide) was dissolved in DMF with 3-methoxybenzyl amine (0.3 g, 2.2 mmol), EDCI (0.42 g, 2.2 mmol), and HOBt hydrate (0.06g, 0.4 mmol). The reaction mixture was stirred at room temperature for 3 days, diluted with EtOAc and the organic layer washed with 10% citric acid, saturated sodium bicarbonate, and brine. The organic layer was then dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography on silica (10 to 30 5 EtOAc/hexanes) to give the product as a colorless oil, 195 mg, 0.6 mmol, 100%. ¹H NMR 500 MHz (CDC13) 7.81 (1H, s), 7.35 (1H, s), 7.28 (lH, m), 6.93 (lH, m), 6.87 (2H, m), 6.23 (lH, br s), 4.57 (2H, d), 3.84 (3H, s). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With bromine; acetic acid for 0.666667h; | Preparation of N-(3-methoxybenzyl)-5-{IH-pyrrolo[2,3-b]pyridin-3- yl)thiophene-3-carboxamide; [00263] 5-Bromothiophene-3-carboxylic acid:; Thiophene-3-carboxylic acid (0.51 g, 4 mmol) was dissolved in HOAc (5 mL) and Br2 (0.21 mL, 4 mmol) was added in 1 mL HOAc. The reaction mixture was stirred for 40 minutes, poured into water and a white precipitate formed, which was filtered and dried to 0.70 g grams of product that contains about 30 % 2,5-dibromothiophane- 3-carboxylic acid. | |
| With bromine In acetic acid at 20℃; for 7.5h; | 112.1 (Step 1) (Step 1) A solution of bromine (4.4 mL) in acetic acid (30 mL) was added to a solution of thiophene-3-carboxylic acid (9.8 g) in acetic acid (40 mL) at room temperature for as long as 30 minutes. The reaction solution was stirred at room temperature for 7 hours, and water (200 mL) was added. The deposited precipitate was filtrated to obtain a mixture of 2-bromothiophene-4-carboxylic acid and 2.5-dibromothiophene-3-carboxylic acid (approximately 5:1). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | In water | 268.b 5-Bromo-N-ethyl-2-(trimethylsilyl)-3-thiophenecarboxamide 5-Bromo-N-ethyl-3-thiophenecarboxamide was prepared from 5-bromo-3-thiophenecarboxylic acid (2.1 g, 10 mmol) and 70% ethylamine in water according to the methods of steps a and b of Example 248 in 70% yield. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In tetrahydrofuran; hexane; N,N-dimethyl-formamide | R.142 5-Difluoromethyl-3-thiophenecarboxylic Acid Reference Example 142 5-Difluoromethyl-3-thiophenecarboxylic Acid 5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With potassium carbonate In 1,4-dioxane; water at 80℃; for 12 - 17h; | 4.a; 5.a; 8a To a solution of δ-bromo-S-thiophenecarboxylic acid (875 mg, 4.23 mmol) in dioxane/H2O (5:1 , 21 mL) was added K2CO3 (205 mg, 14.8 mmol), tetrakistriphenylphosphine Pd(O) (297 mg, 0.26 mmol) and 1-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (988 mg, 4.75 mmol). The reaction mixture was heated to 80° C in a sealed tube. After 5h, additional tetrakistriphenylphosphine Pd(O) (108 mg, 0.1 mmol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1 -methyl-1 H-pyrazole (989 mg, 4.75 mmol) were added. After 12h, the reaction solution was then partitioned between H2O- CHCI3, and the aqueous phase was washed several times with CHCI3. The aqueous phase was then adjusted to pH 3 with 2.5M HCI and the aqueous phase extracted with CHCI3. The combined organics were dried (Na2SO4), concentrated under vacuum and dried under high vacuum overnight and used without further purification: LC-MS (ES) m/z = 209 (M+H)+.; To a solution of δ-bromo-S-thiophenecarboxylic acid (414 mg, 2 mmol) in dioxane/H2O (5:1 , 6 mL) was added K2CO3 (828 mg, 6 mmol), tetrakistriphenylphosphine Pd(O) (1 16 mg, 0.1 mmol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1-methyl-1 H-pyrazole (428 mg, 2.2 mmol). The reaction mixture was heated to 80° C in a sealed tube for 12h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ~3 with 3M HCI and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (-100 mg, quant.): LC-MS (ES) m/z = 209 (M+H)+.; To a solution of 2-bromo-4-thiophenecarboxylic acid (104 mg, 0.5 mmol) in dioxane/H2O (4:1 , 10 mL) was added K2CO3 (271 mg, 1.99 mmol), tetrakistriphenylphosphine Pd(O) (28.7 mg, 0.025 mmol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1-methyl-1 H-pyrazole (97 mg, 0.5 mmol). The reaction mixture was heated to 80° C in a sealed tube for 12h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ~3 with 3M HCI and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (104 mg, quant.): LC-MS (ES) m/z = 209 (M+H)+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 68% | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In dichloromethane at 20℃; for 16h; | 1.a; 2.a To a solution of δ-bromo-S-thiophenecarboxylic acid (1 g, 4.85 mmol)[prepared according to J. Org. Chem. 1976, 41 , 2350.], 1 ,1-dimethylethyl (2- amino-2-phenylethyl)carbamate (1.1 g, 4.85 mmol)[from Preparation 1] and diisopropylethyl amine (2.5 ml_, 14.60 mmol) in DCM (50 ml.) at 25 0C was added PyBrOP (2.5 g, 5.30 mmol) in one portion. After 16h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1 % MeOH in DCM) affording the title compound (1.4 g, 68%) as a white solid: LC-MS (ES) m/z = 426 (M+H)+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | Stage #1: 2-bromothiophene-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.0833333h; Stage #2: benzylamine In N,N-dimethyl-formamide at 20℃; for 16h; | 7.B Preparation of N-Benzyl-5-bromothiophene-3-carboxamide B. To a stirred solution of 5-bromo-3-thiophenecarboxylic acid (0.50 g, 2.42 mmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (1.30 mL, 7.46 mmol), 1-hydroxybenzotriazole (0.49 g, 3.61 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g, 3.62 mmol). Benzylamine (0.26 mL, 2.41 mmol) was added 5 minutes later. The reaction mixture was stirred at ambient temperature for 16 h, then diluted with ethyl acetate (75 mL). The organic layer was washed with 10% aqueous hydrochloric acid (25 mL), saturated aqueous sodium bicarbonate (2*25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the title compound as a colorless solid (0.57 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=1.6 Hz, 1H), 7.37-7.31 (m, 6H), 6.14 (br 3, 1H), 4.59 (d, J=5.7 Hz, 2H). |

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