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Product Details of [ 24691-30-3 ]

CAS No. :24691-30-3 MDL No. :MFCD09991685
Formula : C6H5Cl2NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :HIXZMJPBUJFSPJ-UHFFFAOYSA-N
M.W : 194.02 Pubchem ID :25137682
Synonyms :

Safety of [ 24691-30-3 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501 UN#:2811
Hazard Statements:H301-H311-H331 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 24691-30-3 ]

* 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.

  • Downstream synthetic route of [ 24691-30-3 ]

[ 24691-30-3 ] Synthesis Path-Downstream   1~100

  • 1
  • [ 1007595-29-0 ]
  • [ 24691-30-3 ]
  • [ 1007595-38-1 ]
YieldReaction ConditionsOperation in experiment
66% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h;
66% Stage #1: methyl 10-amino-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate; 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 4-methyl-morpholine; benzotriazol-1-ol In dichloromethane at 20℃; for 1h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; 14 A solution of 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (0.45g, 2.3mmol, Motekaitis, R. J.; ηeinert, D. η.; Martell, Arthur E. J. Org. Chem. 35(8), 2504 (1970)), methyl 10-amino-l,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate (0.50g, 2.3mmol, Intermediate 1 1), ηOBt (0.31g, 2.3mmol) and NMM (0.99mL, 8.1mmol) in DCM (10OmL) was stirred at room temperature for one hour, after which EDC (0.79g, 4.1 mmol) was added. After stirring at room temperature for 12 hours, the crude reaction mixture was washed with saturated aqueous sodium bicarbonate (x2), IN HCl (x2), water (x2), and brine (xl). The organic portion was then dried with MgSO4 and concentrated to a tan solid. Trituration with ether yielded a white solid (0.59g, 66%). MS (ES) (M+H)+: 392 for Ci5Hi9Cl2N3O5; NMR: 1.53 (dd, J=12.43, 4.14 Hz, 1 H), 1.79 - 1.91 (m, 1 H), 2.15 - 2.20 (m, 3 H), 2.85 (s, 1 H), 2.95 (s, 1 H), 3.57 - 3.61 (m, 3 H), 3.73 - 3.82 (m, 1 H), 3.84 - 3.98 (m, 3 H), 3.99 - 4.08 (m, 1 H), 4.16 (s, 1 H), 4.22 - 4.33 (m, 1 H), 6.91 (d, J=8.85 Hz, 1 H), 12.16 (s, 1 H).
  • 2
  • [ 1007595-69-8 ]
  • [ 24691-30-3 ]
  • tert-butyl (3Z)-4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(methoxyimino)piperidine-1-carboxylate [ No CAS ]
  • [ 1007595-65-4 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; 22 A solution of 2.3 g (8.5 mmol) 3,4-dichloro-5-methyl-l//-pyrrole-2-carboxylic acid (Motekaitis, R. J.; ηeinert, D. η.; Martell, Arthur E. J. Org. Chem. 35(8), 2504 (1970)), 2.3 g (8.5 mmol) tert-butyl (3E)-4-amino-3-(methoxyimino)piperidine-l -carboxy late (Intermediate 23), 1.13 g (8.5 mmol) ηOBt, 3.2 g (16.2 mmol) EDC and 1.85 mL (16.2 mmol) NMM in 20 mL DCM was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with IN HCl, water, aqueous Na2CO3, water and brine. Drying (MgSO4) and removal of solvent gave a solid that was triturated with methanol to give 2.4 g of product as a white solid. MS (ES) (M+Na)+: 441 for C17H24Cl2N4O4; NMR: 1.48 (s, 9 H), 1.64 (m, 1 H), 2.24 (s, 3 H), 2.25 (m, 1 H), 3.22 (m, 1 H), 3.63-3.71 (d of m, 1 H), 3.82 (s and m, 4 H), 4.73 (m, 1 H), 5.04 (d, 1 H), 7.61 (d, 1 H), 12.17 (s, 1 H). The product also contained some (<5%) of the corresponding (Z) isomer.
  • 3
  • [ 1007585-28-5 ]
  • [ 24691-30-3 ]
  • methyl 2-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}azepan-1-yl)-1,3-thiazole-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; 9 Example 9Methyl 2-(4-[(3,4-dichloro-5-metliyl-lH-pyrrol-2-yl)carbonyllamino>azepan-l-yl)-l, 3- thiazole-5 -carboxy late A solution of 53 mg (0.27 mmol) 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid(53 mg, 0.27 mmol)(Motekaitis, R. J.; Heinert, D. H.; Martell, Arthur E. J. of Org. Chem. 35(8), 2504 (1970)), 50 mg (0.27 mmol), methyl 2-(4-aminoazepan-l-yl)-l,3-thiazole-5- carboxylate hydrochloride (Intermediate 1, 50 mg 0.27 mmol), 0.37 gm HOBt (0.27 mmol), 97 mg (0.51 mmol) EDC and 56 μL (0.51 mmol) of NMM in 3 mL CH2Cl2 was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with IN HCl5 water, aqueous Na2CO3, water and brine. Drying (MgSO4) and removal of solvent gave a solid that was chromatographed on silica gel (100% CH2Cl2 with gradient elution to 100% EtOAc) to afford 45 mg of product as a white solid. MS (ES) (MH+): 431 for C17H20Cl2N4O3S; NMR: 1.6 (m, IH)5 1.9 (m, 4H)5 2.0 (m, IH), 2.2 (s, 3H)5 3.6 (m, 2H)5 3.7 (s, 3H)5 4.0 (m, IH), 7.2 (d, IH)5 7.9 (s, IH)5 12.0 (s, IH).
  • 4
  • [ 196613-57-7 ]
  • [ 24691-30-3 ]
  • [ 1007585-33-2 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 12h; Intermediate 7 fert-ButvH-lffS^-dichloro-S-methyl-lH-pyrrol-?-vDcarbonvnaminol azepane-l-carboxylate To a suspension of 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (0.906g, 4.67 mmol, WO2006087543) was added l-N-t-butoxycarbony-hexahydro-lH-azepin-4-amine (purchased from Magical Scientific LLP, 1.00 g, 4.67 mmol), EDC (1.45g, 9.33mmol), NMM (0.944g, 9.33mmol), and HOBt (0.63 Ig, 4.67mmol) and the mixture was allowed to stir for 12 hours at room temperature under a nitrogen atmosphere. LCMS indicated no remaining starting material with good conversion to product. The mixture was diluted with CH2Cl2 (10OmL) and organic phase was extracted with IM HCl (3x50mL) and the aqueous layers collected and combined. The aqueous phase was then made basic (pH~9) with 10% NaOH and extracted with CH2Cl2 (3x5 OmL). The organic layers were collected and combined, dried with anhydrous sodium sulfate, filtered, solvent removed under vacuum, and the white solid dried overnight under vacuum. MS (ES) M+H+: 391 for C17H25Cl2N3O3; NMR (CDCl3): 1.49 (s, 9H), 1.70 (m, 3H), 1.89 (m, IH), 2.00 (m, IH), 2.13 (m, IH), 2.30 (s, 3H), 3.26 (m, IH), 3.51 (m, 3H), 4.17 (m, IH), 6.76 (d, IH), 10.92 (s, IH).
  • 5
  • [ 24691-30-3 ]
  • [ 87120-72-7 ]
  • [ 848498-70-4 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide
1.98 g Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid; 1-(tert-butoxycarbonyl)-4-aminopiperidine With triethylamine In N,N-dimethyl-formamide for 0.0833333h; Inert atmosphere; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 5h; Inert atmosphere;
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 16h;
With triethylamine; HATU In DMF (N,N-dimethyl-formamide) at 20℃; for 5.08333h; 3, 4-DICHLORO-5-METHYL-1H-PYRROLE-2-CARBOXYLIC acid (Intermediate 3, 3. 0 g, 0. 016 mol), tert- BUTYL 4-AMINOPIPERIDINE-1-CARBOXYLATE (3. 1 g, 0. 016 MOL), and Et3N (2. 2 MI, 0. 032 mol) were combined in DMF (20 MOI) and stirred under N2 for 5 minutes. HATU (6. 47 g, 0. 017 MOT) was added in one portion, and the reaction was stirred at room temperature for 5 H. THE reaction mixture was diluted with EtOAc and H2O. The organic phase was washed with 1 N HCI, and the combined aqueous portions were extracted once with EtOAc. The combined organic portions were washed sequentially with saturated NAHC03 and saturated NAZI, dried over MGS04, filtered, and concentrated under reduced pressure to give A brown solid. Most of the crude material was isolated by trituration with EtOAc/hexanes to give an off-white solid. The remaining material was chromatographed on silica, eluting with 3 : 1, 2 : 1, and 1 : 1 EtOAc/hexanes to give A light brown solid that was triturated with EtOAc, collected and combined with the other triturated material to give A total of 1. 978 G of the desired product. MS (ES-) : 374. 33, 376. 34 for C16H23Cl2N3O3 H NMR 8 : 1. 16 (s, 9H) ; 1. 20 (m, 2H) ; 1. 53 (m, 2H) ; 1. 93 (s, 3H) ; 2. 65 (m, 2H) ; 3. 65 (m, 3H) ; 6. 97 (d, 1H) ; 11. 72 (s, 1H)

  • 6
  • 6-(4-aminopiperidin-1-yl)-2-(methylthio)pyrimidin-4-amine hydrochloride [ No CAS ]
  • [ 24691-30-3 ]
  • N-{1-[6-amino-2-(methylsulfanyl)-4-pyrimidinyl]-4-piperidinyl}-3,4-dichloro-5-methyl-1 H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 20℃; for 18.0833h; 118 DIISOPROPYLETHYLAMINE (0.21 ML, 1. 25 mmol) and HATU (0.239 g, 0.63 mmol) were added to a stirred solution OF 3, 4-DICHLORO-5-METHYL-1 H-PYRROLE-2-CARBOXYLIC acid (Intermediate 3) (0.122 g, 0.63 mmol) in DMF (2 ml). The resultant solution was stirred for 5 minutes, 6- (4- amino-piperidin-1-yl)-2-(methylthio) pyrimidin-4-amine hydrochloride (Intermediate 46) (0.2 g, 0.63 mmol) was added and the mixture was stirred at room temperature for 18 h. The crude mixture was filtered and purified by semi-preparative HPLC eluting with CH3CN/H20 (0. 1 % TFA) to give the title product (42 mg). MS (ES): 417 (MH+) for C16H20Cl2N6OS 1H NMR No. : 1.22 (m, 2H); 1.61 (m, 2H); 1.92 (s, 3H); 2.84 (m, 2H); 3.78 (m 4H); 5.25 (s, 1H) ; 5.52 (s, 1H) ; 6.50 (m, 2H); 11.72 (s, 1H)
  • 7
  • 1-[6-chloro-4-(1,2,4-oxadiazol-3-yl)pyridin-2-yl]piperidin-4-amine hydrochloride [ No CAS ]
  • [ 24691-30-3 ]
  • 3,4-dichloro-N-{1-[6-chloro-4-(1,2,4-oxadiazol-3-yl)-2-pyridinyl]-4-piperidinyl}-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 20℃; for 1.08333h; 111 Diisopropylethylamine (0.04 ML, 0.46 mmol), HOAT (0.03 g, 0.23 mmol) and HATU (0.08 g, 0.23 mmol) were added to a stirred solution of 3,4-dichloro-5-methyl-1H-pyrrole-2- carboxylic acid (Intermediate 3,0. 04 g, 0.23 mmol) in DMF (2 ML) at room temperature. The resulting solution was stirred for 5 minutes and 1- [6-chloro-4- (1, 2,4-oxadiazol-3-yl) pyridin-2- YL] PIPERIDIN-4-AMINE hydrochloride (Intermediate 56) (0.074 g, 0.23 mmol) was added. The mixture was stirred at room temperature for I h and was filtered and purified by semi- preparative HPLC eluting with CH3CN/H20 (0. 1 % TFA) mixtures to give the title compound (100 MG). MS (ES) : 457 (MH+) for C18H17Cl3N6O2 H NMR 8 : 1.50 (m, 2H); 1.84 (m, 2H); 2.13 (s, 3H); 3.09 (m, 2H); 4.04 (m, 1H) ; 4.20 (d, 2H); 7.08 (s, 1H) ; 7.20 (d, 1 H) ; 7.28 (s, 1H) ; 9.80 (s, 1H) ; 11.91 (s, 1H)
  • 8
  • [ 24691-21-2 ]
  • [ 24691-30-3 ]
YieldReaction ConditionsOperation in experiment
64% Stage #1: ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate With methanol; lithium hydroxide; water In dichloromethane at 70℃; for 2h; Stage #2: With hydrogenchloride; water In methanol; dichloromethane at 0℃; for 1h; Intermediate 28; 3 ,4-Dichloro-5 -methyl- lH-pyrrole-2-carboxylic acid; Ethyl 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylate (Intermediate 29, 7.765 g, 0.03496 mol) was dissolved in MeOH (80 ml) and DCM (10 ml) and slowly added to a 70 0C solution of 2 N LiOH (105 ml, 0.21 mol). After 2 h, the reaction mixture was cooled to room EPO temperature and then in an ice bath, followed by acidification with 2 N HCl. The mixture was stirred at 0 °C for 1 h, and a purple solid was filtered, washed with water and lyophilized overnight to give 4.314 g (0.0222 mol, 64% yield) of the desired product. NMR: 2.17 (s, 3H); MS (ES"): 192.13, 194.13 (M-H)" for C6H5Cl2NO2. 5
64% Stage #1: ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate With methanol; lithium hydroxide; water In dichloromethane at 70℃; for 2h; Stage #2: With hydrogenchloride; water In methanol at 0℃; for 1h; Intermediate 13.4-Dichloro-5-methyl-liJ-pyrrole-2-carboxylic acidEthyl 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylate (Intermediate 2; 7.765 g,0.03496 mol) was dissolved in MeOH (80 ml) and DCM (10 ml) and slowly added to a 70 °C solution of 2 N LiOH (105 ml, 0.21 mol). After 2 h, the reaction mixture was cooled to room temperature and then in an ice bath, followed by acidification with 2 N HCl. The mixture was stirred at 0 °C for 1 h, and a purple solid was filtered, washed with water and lyophilized overnight to give 4.314 g (0.0222 mol, 64% yield) of the desired product. MS (ES'): 192.13, 194.13 for C6H5Cl2NO2; NMR: 2.17 (s, 3H).
64% Stage #1: ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate With methanol; lithium hydroxide; water In dichloromethane at 70℃; for 2h; Stage #2: With hydrogenchloride In dichloromethane at 0℃; for 1h; Ethyl 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylate (Intermediate 10; 7.765 g,0.03496 mol) was dissolved in MeOH (80 ml) and DCM (10 ml) and slowly added to a 70 °C solution of 2 N LiOH (105 ml, 0.21 mol). After 2 h, the reaction mixture was cooled to room temperature and then in an ice bath, followed by acidification with 2 N HCl. The mixture was stirred at 0 °C for 1 h, and a purple solid was filtered, washed with water and lyophilized EPO overnight to give 4.314 g (0.0222 mol, 64% yield) of the desired product. M/z (ES'): 192.13, 194.13 for C6H5Cl2NO2. NMR: 2.17 (s, 3H).
64% Stage #1: ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate With methanol; lithium hydroxide; water In dichloromethane at 70℃; for 2h; Stage #2: With hydrogenchloride In dichloromethane at 0℃; for 1h; Ethyl 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylate (Intermediate 43; 7.765 g,0.03496 mol) was dissolved in MeOH (80 ml) and DCM (10 ml) and slowly added to a 70 °C solution of 2 N LiOH (105 ml, 0.21 mol). After 2 h, the reaction mixture was cooled to room temperature and then in an ice bath, followed by acidification with 2 N HCl. The mixture was stirred at 0 0C for 1 h, and a purple solid was filtered, washed with water and lyophilized overnight to give 4.314 g (0.0222 mol, 64% yield) of the desired product. M/z (ES"): 192.13,194.13 for C6H5Cl2NO2; NMR: 2.17 (s, 3H).
64% Stage #1: ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate With lithium hydroxide; water In methanol; dichloromethane at 70℃; for 2h; Stage #2: With hydrogenchloride In methanol; dichloromethane; water at 0℃; for 1h; Ethyl 3, 4-DICHLORO-5-METHYL-1H-PYRROLE-2-CARBOXYLATE (Intermediate 4, 7. 765 g, 0. 03496 mol) was dissolved in MeOH (80 ML) and DCM (10 ML) and slowly added to A 70 °C solution of 2 N LiOH (105 MOL, 0. 21 mol). After 2 h, the reaction mixture was cooled to room temperature and then in an ice bath, followed by acidification with 2 N HCI. The mixture was stirred at 0 °C for I h, and A purple solid was filtered, washed with water and LYOPHILIZED overnight to give 4. 314 g (0. 0222 mol, 64% yield) of the desired product. MS (ES-) : 192. 13, 194.13 for C6H5Cl2NO2 1H NMR No. : 2. 17 (s, 3H)
With water; sodium hydroxide In methanol
With water; sodium hydroxide In methanol at 50℃; for 24h;

  • 9
  • trans-ethyl 3-(4-aminocyclohexyl)benzoate [ No CAS ]
  • [ 24691-30-3 ]
  • trans-ethyl 3-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}cyclohexyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 18 - 25℃; 1 Example 1; trans-Ethyl 3-C4- ( IY3.4-dichloro- 5 -methyl- lH-vrrol-2- vl)carbonyllamino}cvclohexvl)benzoate; To a stirred solution of trans-ethyl 3-(4-aminocyclohexyl)benzoate (Intermediate 12;280 mg, 0.911 mmol), 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (Intermediate 28; 172 mg, 0.911), ΗOBt (123 mg, 0.911 mmol) and JV-methylmorpholine (0.5 ml, 4.56 mmol) in methlyene chloride (5 ml) was added EDC (314 mg, 1.64 mmol). The reaction mixture was stirred overnight and then partitioned between DCM and water. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate, and saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (1.5:1 hexanes/ethyl acetate) to provide the title compound (117 mg, 30%). NMR: 1.32 (t, 3Η), 1.51 (m, 4H), 1.83 (br d, 2H), 1.99 (br d, 2H), 2.13-2.30 (m, 4H), 2.63 (m, 2H), 3.84 (m, IH), 4.31 (q, 2H), 7.14 (d, IH), 7.46 (dd, IH), 7.58 (d, IH), 7.70-7.94 (m, 2H), 11.99 (br s, IH); MS m/z 423, 425.
  • 10
  • (1,2-cis)-4-bromo-2-methoxycyclohex-3-en-1-amine [ No CAS ]
  • [ 24691-30-3 ]
  • N-[(1,2)-cis-4-bromo-2-methoxycyclohex-3-en-1-yl]-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; cis-ethyl 3-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}cyclohexyl)benzoate; benzotriazol-1-ol In dichloromethane at 0℃; for 0.166667h; Intermediate 26; iV-[(l,2)-cis-4-Bromo-2-methoxycvclohex-3-en-l-yl1-3,4-dichloro-5-methyl-lH-pyrrole-2- carboxamide; (l,2-cis)-4-Bromo-2-methoxycyclohex-3 -en- 1 -amine (Intermediate 24; 125 mg, 0.61 mmol), 5-methyl-3,4-dichloropyrolyl carboxylic acid (141 mg, 0.73 mmol), ΗOBt (262 mg, 1.94 mmol) and N-methyl-morpholine (216 mg, 2.14 mmol) were mixed in dry DCM (10 ml) and cooled down to O0C. l-(3-Dimethylaminopropyl)-3-ethylcarbodiirnide hydrochloride (175 mg, 0.92 mmol) was added, the mixture was stirred for 10 minutes. 3,4-dichloro-5-methyl- lH-pyrrole-2-carboxylic acid (Intermediate 28; 125 mg, 0.61 mmol) was added, the mixture was stirred for over night, diluted with 50 ml of DCM and washed with 5% HCl and brine. The organic phase was dried and concentrated under vacuum. The residue was dissolved in DCM (6 ml), heated, and hexane was added and the resulting precipitate was filtered and collected as the desired product (220 mg). NMR (CDCl3): 1.87 (m, 1Η), 2.04 (m, 1Η), 2.26 (s, 3Η), 2.59 (m, 2H), 3.45 (s, 3H), 3.73 (m, IH), 4.28 (m, IH), 6.31 (m, IH), 7.27 (m, IH), 9.83 (br, IH). MS (ESN): 381.16 (M-I) for C14Hi5Cl2N2O2Br.
  • 11
  • [ 24691-30-3 ]
  • [ 848500-48-1 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride for 0.5h; Heating / reflux; A solution of 3,4-dichloro-5-methyl-lif-pyrrole-2-carboxylic acid (Intermediate 42) inSOCl2 (50 ml) was heated at reflux for 30 min. Solvent was removed and the residue was dried in vacuo. NMR (CDCl3): 9.0 (s, IH); 2.4 (s, 3H).
With thionyl chloride for 0.5h; Reflux;
With oxalyl dichloride In dichloromethane at 20℃; for 15h;
With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; 1 4.8.6. General procedure F. Synthesis of Compounds 7a-i, 15a-d and 22a-b (with 7a as an Example) General procedure: To a solution of 4,5-dibromo-1H-pyrrole-2-carboxylic acid (157 mg, 0.584 mmol) in anhydrous dichloromethane (4 mL) oxalyl chloride (2M solution in dichloromethane, 1.46 mL, 2.92 mmol) was added dropwise and the solution stirred at rt for 15 h under argon atmosphere. The solvent was evaporated under reduced pressure, fresh anhydrous dichloromethane (4 mL), 6a (150 mg,0.487 mmol) and pyridine (2 mL) were added and the reaction mixture stirred under argon atmosphere at rt for 15 h. Solvent was removed under reduced pressure, the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL), saturated aqueous NaHCO3 solution (3*20 mL) and brine (2*20 mL). The organic phase was dried over Na2SO4, filtered and the solvent removed under reduced pressure.
With oxalyl dichloride In dichloromethane at 120℃; for 5h; Inert atmosphere; 4.6.9. General procedure E. Synthesis of compounds 7a-d, 15, 23,43a-b, 46a-b, 50, 56 and 60 (with 7a as an example) General procedure: To a solution of 4,5-dibromo-1H-pyrrole-2-carboxylic acid(200 mg, 0.743 mmol) in anhydrous dichloromethane (5 mL), oxalylchloride (0.317 mL, 3.70 mmol) was added dropwise and the solutionstirred at rt for 15 h under argon atmosphere. The solvent wasevaporated under reduced pressure, fresh anhydrous dichloromethane(2 mL), 6a (0.251 g, 0.616 mmol) and pyridine (2 mL) wereadded and the reaction mixture stirred under argon atmosphere atrt for 15 h. Solvent was removed under reduced pressure, the residuedissolved in ethyl acetate (15 mL) and washed with HCl 1Msolution (15 mL) and brine (2 15 mL). The organic phasewas driedover Na2SO4, filtered and the solvent removed under reducedpressure. The solid was then washed with diethyl ether (2 5 mL)to afford 7a (0.153 g) as light brown solid.
With oxalyl dichloride In dichloromethane at 20℃; for 8h;
With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; General procedure B. Synthesis of compounds 2c, 2d, 5a, 5b, 16a-c, 24, 27b, 30a-i, 37, 43, and 47 (with 2c as an example) General procedure: To a suspension of 4-bromo-3-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (101mg, 0.42mmol) in anhydrous dichloromethane (10mL) oxalyl chloride (0.181mL, 2.11mmol) was added dropwise and the solution stirred at room temperature under an argon atmosphere overnight. The solvent was evaporated under reduced pressure, ethyl 2-aminobenzo [d]thiazole-6-carboxylate (1b, 94mg, 0.42mmol) and toluene (20mL) were added, and the suspension was stirred at 130°C overnight. The precipitate in the reaction mixture was filtered off, resuspended in 1M HCl (100mL), sonicated and filtered off. The crude product was dispersed in methanol (100mL), heated, filtered off and dried, to obtain 2c (121mg) as a gray solid.

Reference: [1]Current Patent Assignee: ASTRAZENECA PLC - WO2006/92599, 2006, A2 Location in patent: Page/Page column 67
[2]Basarab, Gregory S.; Hill, Pamela J.; Garner, C. Edwin; Hull, Ken; Green, Oluyinka; Sherer, Brian A.; Dangel, P. Brian; Manchester, John I.; Bist, Shanta; Hauck, Sheila; Zhou, Fei; Uria-Nickelsen, Maria; Illingworth, Ruth; Alm, Richard; Rooney, Mike; Eakin, Ann E. [Journal of Medicinal Chemistry, 2014, vol. 57, # 14, p. 6060 - 6082]
[3]Durcik, Martina; Tammela, Päivi; Barančoková, Michaela; Tomašič, Tihomir; Ilaš, Janez; Kikelj, Danijel; Zidar, Nace [ChemMedChem, 2018, vol. 13, # 2, p. 186 - 198]
[4]Durcik, Martina; Lovison, Denise; Skok, Žiga; Durante Cruz, Cristina; Tammela, Päivi; Tomašič, Tihomir; Benedetto Tiz, Davide; Draskovits, Gábor; Nyerges, Ákos; Pál, Csaba; Ilaš, Janez; Peterlin Mašič, Lucija; Kikelj, Danijel; Zidar, Nace [European Journal of Medicinal Chemistry, 2018, vol. 154, p. 117 - 132]
[5]Tiz, Davide Benedetto; Skok, Žiga; Durcik, Martina; Tomašič, Tihomir; Mašič, Lucija Peterlin; Ilaš, Janez; Zega, Anamarija; Draskovits, Gábor; Révész, Tamás; Nyerges, Ákos; Pál, Csaba; Cruz, Cristina D.; Tammela, Päivi; Žigon, Dušan; Kikelj, Danijel; Zidar, Nace [European Journal of Medicinal Chemistry, 2019, vol. 167, p. 269 - 290]
[6]Skok, Žiga; Barančoková, Michaela; Benek, Ondřej; Cruz, Cristina Durante; Tammela, Päivi; Tomašič, Tihomir; Zidar, Nace; Mašič, Lucija Peterlin; Zega, Anamarija; Stevenson, Clare E. M.; Mundy, Julia E. A.; Lawson, David M.; Maxwell, Anthony; Kikelj, Danijel; Ilaš, Janez [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 12, p. 2433 - 2440]
[7]Durcik, Martina; Nyerges, Ákos; Skok, Žiga; Skledar, Darja Gramec; Trontelj, Jurij; Zidar, Nace; Ilaš, Janez; Zega, Anamarija; Cruz, Cristina D.; Tammela, Päivi; Welin, Martin; Kimbung, Yengo R.; Focht, Dorota; Benek, Ondřej; Révész, Tamás; Draskovits, Gábor; Szili, Petra Éva; Daruka, Lejla; Pál, Csaba; Kikelj, Danijel; Mašič, Lucija Peterlin; Tomašič, Tihomir [European Journal of Medicinal Chemistry, 2021, vol. 213]
  • 12
  • [ 848499-19-4 ]
  • [ 24691-30-3 ]
  • 2-chloro-6-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 0.5h; Stage #2: 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride In DMF (N,N-dimethyl-formamide) 20 Diisopropylethylamine (0.063 ML, 0.37 mmol), EDC (0.095 g, 0.31 mmol) and HOAT (0.042 g, 0. 31 mmol) were added to a stirred solution OF 3, 4-DICHLORO-5-METHYL-LH-PYRROLE-2- carboxylic acid (Intermediate 3,0. 060 g, 0. 31 mmol) in DMF (1.0 ML) at room temperature. The resultant solution was stirred for 30 mins and a solution of 2- (4-aminopiperidin-1-yl)-6- chloroisonicotinamide hydrochloride (Intermediate 70,0. 096 g, 0.37 mmol) in 1 ml of DMF was added. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x2) and the combined organic extracts were washed with) N HCI, water and brine, dried over MgS04 and concentrated under vacuum. The residue was purified by reverse phase chromatography to give the desired product as a white solid (40 mg). MS (ES): 431 (M+1) for C17H18Cl3N5O2 IH NMR 5 : 1. 56 (m, 2H) ; 1. 88 (m, 2H); 2. 17 (s, 3H); 3. 11 (t, 2H); 4.10 (m, 1H) ; 4.25 (m, 2H); 6.97 (S, IH) ; 7. 18 (s, 1H) ; 7.23 (d, 1H) ; 7.69 (s, 1H) ; 8. 14 (s, 1H); 11. 95 (s, 1H)
  • 13
  • 2-(4-aminopiperidin-1-yl)-1,3-thiazole-5-carboxamide hydrochloride [ No CAS ]
  • [ 24691-30-3 ]
  • 2-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 0.5h; Stage #2: 2-(4-aminopiperidin-1-yl)-1,3-thiazole-5-carboxamide hydrochloride at 20℃; 29 DIISOPROPYLETHYLAMINE (0.19 ML, 1.12 mmol), EDC (0.098 g, 0.51 mmol) and HOAT (0.070 g, 0.51 mmol) were added to a stirred solution of 3,4-dichloro-5-methyl-1H-pyrrole-2- carboxylic acid (Intermediate 3, 0. 1 g, 0.51 mmol) in DMF (1.5 ML) at room temperature. The resultant solution was stirred for 30 mins and 2- (4-aminopiperidin-1-yl)-1, 3-thiazole-5- carboxamide hydrochloride (Intermediate 81; 0.163 g, 0.62 mmol) was added. The reaction was stirred at room temperature overnight under nitrogen. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with 1 N HCI, water and brine, dried over MgS04 and concentrated under vacuum. The residue was purified by reverse phase chromatography (water/acetonitrile gradient, 20-95%) to give the desired product as a white solid (50 mg). MS (ES): 402 (M+L) for C15H17Cl2N5O2S H NMR â : 1. 58 (m, 2H); 1.82 (m, 2H); 2.11 (s, 3H); 3.17 (t, 2H); 3.81 (m, 2H); 3.97 (m, IH) ; 7.07 (BRS, 1H) ; 7.20 (d, IH) ; 7.61 (brs, IH) ; 7.71 (s, IH) ; 11.90 (s, 1H)
  • 14
  • ethyl 2-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-methyl-1,3-thiazole-5-carboxylate trifluoroacetate [ No CAS ]
  • [ 24691-30-3 ]
  • [ 1206908-48-6 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; for 20h; 1.IV Step IV: Synthesis of ethyl 2-rrii?.5^.6^-6-(r(3.4-dichloro-5-methyl-lH-pyrrol-2- yl)carbonyl]amino}-3-azabicvclor3.1.01hex-3-yn-4-methyl-l,3-thiazole-5-carboxylate:To a solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (0.15 g, 0.76 mmol) in anhydrous dimethylformamide, N-hydroxybenzotriazole (0.124 g, 0.912 mmol), l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (0.174 g, 0.912 mmol), and N-methyl morpholine (0.32 ml, 2.28 mol) was added. To this reaction mixture, ethyl 2-[(lR,5S,6s)-6- amino-3-azabicyclo[3.1.0]hex-3-yl]-4-methyl-l,3-thiazole-5-carboxylate (0.29 g, 0.76 mmol) was added and was stirred at ~ 25 0C for about 20 hours. The reaction was quenched with ice- cooled water and extracted with ethyl acetate. The combined organic layers were washed with 5% aq. sodium bicarbonate solution, water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue. The obtained residue was purified using column chromatography to obtain the title compound (120 mg).1II ΝMR (400 MHz, CDCl3 + CD3OD): δ 1.33-1.38 (q, 3H, J = 7.12 Hz), 2.1-2.15 (m, 2H), 2.24 (s, 3H), 2.58-2.61 (m, 4H), 3.79-3.85 (m, 2H), 3.89-3.95 (m, 2H), 4.29-4.37 (q, 2H, J = 7.12 Hz).EIMS m/z 443.23 (M+)
120 mg With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide 1.IV Step IV: Synthesis of ethyl 2-[(1R,5S,6s)-6-[(3,4-dichloro-5-methyl-1H-pyrrol-2-1)carbonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl]-4-methyl-1,3-thiazole-5-carboxylate [0468] To a solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (0.15 g, 0.76 mmol) in anhydrous dimethylformamide, N-hydroxybenzotriazole (0.124 g, 0.912 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.174 g, 0.912 mmol), and N-methyl morpholine (0.32 ml, 2.28 mol) was added. To this reaction mixture, ethyl 2-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-methyl-1,3-thiazole-5-carboxylate (0.29 g, 0.76 mmol) was added and was stirred at ˜25° C. for about 20 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layers were washed with 5% aq. sodium bicarbonate solution, water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue. The obtained residue was purified using column chromatography to obtain the title compound (120 mg). [0469] 1H NMR (400 MHz, CDCl3+CD3OD): δ 1.33-1.38 (q, 3H, J=7.12 Hz), 2.1-2.15 (m, 2H), 2.24 (s, 3H), 2.58-2.61 (m, 4H), 3.79-3.85 (m, 2H), 3.89-3.95 (m, 2H), 4.29-4.37 (q, 2H, J=7.12 Hz). [0470] EIMS m/z 443.23 (M+)
  • 15
  • 6-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]pyridine-3-carbonitrile trifluoroacetate [ No CAS ]
  • [ 24691-30-3 ]
  • [ 1206908-55-5 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 16h; 2.III Step III: Synthesis of 3.4-dichloro-N4(li?.5£6s)-3-(5-cvanopyridin-2-vn-3- azabicyclor3.1.01hex-6-yll-5-methyl-lH-pyrrole-2-carboxamide To a solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (124 mg, 0.64 mmol) in anhydrous N,N-dimethylformamide (3 ml), N-hydroxybenzotriazole (0.10 g, 0.76 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g, 0.76 mmol) and N.N- diisopropyl ethylamine (0.16 g, 1.28 mmol) was added. To this reaction mixture, a N,N- dimethylformamide (2 ml), 6-[(li?,55',6>s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]pyridine-3- carbonitrile trifluoroacetate salt (0.2 g, 0.64 mmol) previously treated with N,N-diisopropyl ethylamine (0.083 g, 0.64 mmol) was added and the reaction mixture was stirred at ~ 25 0C for about 16 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layers were washed with 5% aq. sodium bicarbonate solution; water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue that after triturating with ether afforded the title compound (100 mg). 1U ΝMR (400 MHz, CD3OD): δ 2.06-2.1 (m, 2H), 2.27 (s, 3H), 2.50-2.55 (m, IH), 3.55- 3.62 (m, 2H), 3.85-3.92 (m, 2H), 6.56 (d, IH, J = 9 Hz), 7.72 (d, IH, J = 8.72 Hz), 8.36 (s, IH). EIMS m/z 376.06 (M+)
100 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.25℃; for 0.16h; 2.III Step III: Synthesis of 3,4-dichloro-N-[(1R,5S,6s)-3-(5-cyanopyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-methyl-1H-pyrrole-2-carboxamide [0483] To a solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (124 mg, 0.64 mmol) in anhydrous N,N-dimethylformamide (3 ml), N-hydroxybenzotriazole (0.10 g, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g, 0.76 mmol) and N,N-diisopropyl ethylamine (0.16 g, 1.28 mmol) was added. To this reaction mixture, a N,N-dimethylformamide (2 ml), 6-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]pyridine-3-carbonitrile trifluoroacetate salt (0.2 g, 0.64 mmol) previously treated with N,N-diisopropyl ethylamine (0.083 g, 0.64 mmol) was added and the reaction mixture was stirred at ˜25° C. for about 16 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layers were washed with 5% aq. sodium bicarbonate solution; water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue that after triturating with ether afforded the title compound (100 mg). [0484] 1H NMR (400 MHz, CD3OD): δ 2.06-2.1 (m, 2H), 2.27 (s, 3H), 2.50-2.55 (m, 1H), 3.55-3.62 (m, 2H), 3.85-3.92 (m, 2H), 6.56 (d, 1H, J=9 Hz), 7.72 (d, 1H, J=8.72 Hz), 8.36 (s, 1H). [0485] EIMS m/z 376.06 (M+)
  • 16
  • ethyl 3-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]benzoate trifluoroacetate [ No CAS ]
  • [ 24691-30-3 ]
  • [ 1206908-58-8 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 16h; 3.IV Step IV: Synthesis of Ethyl 3-Ff lJg.S5'.65V6-{rf3.4-dchloro-5-methyl-lH-ρyrrol-2- yl)carbonvnamino}-3-azabicyclor3.1.01hex-3-yl1benzoateTo a solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (75 mg, 0.38 mmol) in anhydrous dimethylformamide, N-hydroxybenzotriazole (0.06 g, 0.46 mmol), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (0.09 g, .46 mmol) and N,N-Diisopropyl ethylamine (0.15 g 1.15 mmol) was added. To this reaction mixture, ethyl 3-[(lR,5S,6s)-6- amino-3-azabicyclo[3.1.0]hex-3-yl]benzoate trifluoroacetate salt (0.14 g, 0.38 mmol) was added and the reaction mixture was stirred at ~ 25 0C for about 16 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layers were washed with 5% aq. sodium bicarbonate solution, water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue. The obtained residue was purified using column chromatography to obtain the title compound (60 mg). EIMS m/z 422.3 [M+H]+ 1H NMR (CD3OD, 400 MHz) δl.35-1.39(t, 3H, 7.08Hz), 1.96-2.0 l(m, 2H), 2.23(s, 3h), 2.58-2.63( m, IH), 3.75-3.78(m, 2H), 4.31-4.36(q, 2H, 7.08Hz), 6.81-6.83(m, IH), 7.21- 7.32(m, 3H).
60 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.25℃; for 0.16h; 3.IV Step IV: Synthesis of Ethyl 3-[(1R,5S,6s)-6-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl]benzoate [0497] To a solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (75 mg, 0.38 mmol) in anhydrous dimethylformamide, N-hydroxybenzotriazole (0.06 g, 0.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.09 g, 0.46 mmol) and N,N-Diisopropyl ethylamine (0.15 g 1.15 mmol) was added. To this reaction mixture, ethyl 3-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]benzoate trifluoroacetate salt (0.14 g, 0.38 mmol) was added and the reaction mixture was stirred at ˜25° C. for about 16 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layers were washed with 5% aq. sodium bicarbonate solution, water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue. The obtained residue was purified using column chromatography to obtain the title compound (60 mg). [0498] EIMS m/z 422.3 [M+H]+ [0499] 1H NMR (CD3OD, 400 MHz) δ 1.35-1.39 (t, 3H, 7.08 Hz), 1.96-2.01 (m, 2H), 2.23 (s, 3h), 2.58-2.63 (m, 1H), 3.75-3.78 (m, 2H), 4.31-4.36 (q, 2H, 7.08 Hz), 6.81-6.83 (m, 1H), 7.21-7.32 (m, 3H
  • 17
  • [ 1206908-66-8 ]
  • [ 24691-30-3 ]
  • [ 1206908-67-9 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 16h; 4.II Step II: Synthesis of 3Λ-dichloro-5-methyl-N-r(l&5£6s)-3-(trifIuoroacetyl)-3- azabicyclo[3.1.0]hex-6-yl1- lH-pyrrole-2-carboxamideTo a solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (4g, 2.04 mmol) in anhydrous dimethylformamide (20 ml), N-hydroxybenzotriazole (3.36g, 24.9 mmol), l-ethyl-3- (3-dimethylamino- propyl) carbodiimide hydrochloride (4.76g, .24.9 mmol) and N, N- diisopropyl ethylamine (5.36 g, 41.6 mmol) was added. To this reaction mixture, dimethylformamide (5 ml), l-[(l^,5S,6s)-6-amino-3-azabicyclo[3.1.01hex-3-yl]-2,2,2- trifluoroethanone trifluoroacetate salt (0.14 g, 0.38 mmol) previously treated with N,N- diisopropyl ethylamine (2.68 g, 20.8 mmol) was added and the reaction mixture was stirred at ~ 25 0C for about 16 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layers were washed with 5% aq. sodium bicarbonate solution; water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue that after triturating with ether afforded the title compound (2.7g). EIMS m/z 370.61 [M+H]+
2.7 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.25℃; for 0.16h; 4.II Step II: Synthesis of 3,4-dichloro-5-methyl-N-[(1R,5S,6s)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-pyrrole-2-carboxamide [0502] To a solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (4 g, 2.04 mmol) in anhydrous dimethylformamide (20 ml), N-hydroxybenzotriazole (3.36 g, 24.9 mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (4.76 g, 0.24.9 mmol) and N,N-diisopropyl ethylamine (5.36 g, 41.6 mmol) was added. To this reaction mixture, dimethylformamide (5 ml), 1-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-2,2,2-trifluoroethanone trifluoroacetate salt (0.14 g, 0.38 mmol) previously treated with N,N-diisopropyl ethylamine (2.68 g, 20.8 mmol) was added and the reaction mixture was stirred at ˜25° C. for about 16 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layers were washed with 5% aq. sodium bicarbonate solution; water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue that after triturating with ether afforded the title compound (2.7 g). [0503] EIMS m/z 370.61 [M+H]+
  • 18
  • ethyl 2-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-[(3'-chlorobiphenyl-3-yl)methyl]-1,3-thiazole-5-carboxylate trifluoroacetate [ No CAS ]
  • [ 24691-30-3 ]
  • [ 1206910-03-3 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 16h; 11.III Step III: Synthesis of ethyl 44f3'-chlorobiphenyl-3-yl)methyl1-2-r(li?.5,S'.6,y)-6-{IY3,4- dichloro-5-methyl-lH-pyrrol-2-yl)carbonyllamino|-3-azabicvclor3.1.01hex-3-yl1-l ,3- thiazole-5-carboxylateTo a solution of 3,4-di-chloro-5-methyl-pyrrole-2-carboxylic acid (0.4 g, 0.7 mmol) in anhydrous dimethylformamide (5 ml) l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.16 g, 0.84 mmol) N-hydroxybenzotriazole (0.11 g, 0.84 mmol), N, N- Diisopropyl ethylamine (0.28 g, 2.1 mmol) was added followed by addition of ethyl 2- [(li?,55',6Λ')-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-[(3'-chlorobiphenyl-3-yl)methyl]-l,3- thiazole-5-carboxylate (0.14 g, 0-.7 mmol). The reaction mixture was stirred at ~ 25 0C for about 16 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue that was purified by column choromatography (SiO2 100-200 mesh) using 1% methanol/dichloromethane as eluent(150 mg).EIMS m/z 629.24 [M+Η]+
150 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.25℃; for 0.16h; 11.III Step III: Synthesis of ethyl 4-[(3′-chlorobiphenyl-3-yl)methyl]-2-[(1R,5S,6s)-6-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl]-1,3-thiazole-5-carboxylate [0771] To a solution of 3,4-di-chloro-5-methyl-pyrrole-2-carboxylic acid (0.4 g, 0.7 mmol) in anhydrous dimethylformamide (5 ml) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.16 g, 0.84 mmol) N-hydroxybenzotriazole (0.11 g, 0.84 mmol), N,N-Diisopropyl ethylamine (0.28 g, 2.1 mmol) was added followed by addition of ethyl 2-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-[(3′-chlorobiphenyl-3-yl)methyl]-1,3-thiazole-5-carboxylate (0.14 g, 0-0.7 mmol). The reaction mixture was stirred at ˜25° C. for about 16 hours. The reaction was quenched with ice-cooled water and extracted with ethyl acetate. The combined organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated to obtain a solid residue that was purified by column choromatography (SiO2 100-200 mesh) using 1% methanol/dichloromethane as eluent (150 mg). [0772] EIMS m/z 629.24 [M+H]+
  • 19
  • [ 1229426-77-0 ]
  • [ 24691-30-3 ]
  • [ 1229573-50-5 ]
YieldReaction ConditionsOperation in experiment
49% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 18 - 26℃; 25 Intermediate 25; Ethyl (3S,4R)-4-{ r(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyllamino)-3- ethoxypiperidine- 1 -carboxylate; To a solution of 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (WO200687543, 1.18 g, 6.15 mmol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-l-carboxylate (Intermediate 24, 1.33 g, 6.15 mmol) in dichloromethane (170 mL) were added HOBT (941 mg, 6.15 mmol) and N-methyl morpholine (2.02 mL, 18.45 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (2.11 g, 11.07 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight. The reaction was quenched with the addition of 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by flash column chromatography (silica, 35% ethylacetate in pet ether) afforded ethyl (3S,4R)-4-{ [(3,4-dichloro-5-methyl-lH-pyrrol-2- yl)carbonyl] amino }-3-ethoxypiperidine-l -carboxylate 1.9 g (49%) as solid. 1U NMR (400 MHz, DMSO-dfi): δ 1.15 (t, 3H), 1.17 (t, 3H), 1.59 (m, 2H), 2.15 (s, 3H), 2.94 (m, 2H), 3.37 (t, IH), 3.46 (m, IH), 3.97 (m, IH), 6.64 (m, IH), 4.03 (q, 2H), 4.10 (q, 2H), 7.07 (d, IH), 12.10 (s, IH). LC-MS: m/z 391 (M+H).
  • 20
  • [ 1093115-40-2 ]
  • [ 24691-30-3 ]
  • [ 1093115-41-3 ]
YieldReaction ConditionsOperation in experiment
89.1% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 18 - 26℃; 77 Intermediate 77; Ethyl (3S,4R)-4-{ r(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyllamino)-3- propoxypiperidine- 1 -carboxylate; To a solution of 3,4-dichloro-5-meΛyl-lH-pyirole-2-caΛoxylic acid (WO2006087543, 1.77 g, 9.13 mmol) and ethyl (3S,4R)-4-amino-3-propoxypiperidine-l-carboxylate (see Intermediate 73, 2.1 g, 9.13 mmol) in dichloromethane (150 mL) was added N- Hydroxybenzotriazole (1.67 g, 10.95 mmol) and N-methylmorpholine (2.76 g, 27.39 mmol). The reaction mixture was stirred for 1 h at room temperature and l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (3.023 g, 16.43 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (30 mL) and the layers were separated. The organic layer was washed with sodium bicarbonate (40 mL), water (60 mL) and finally with brine successively, and dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to afford ethyl (3S,4R)-4-{ [(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyl]amino}- 3 -propoxypiperidine- 1 -carboxylate 3.3 g (89.1.%) as solid. 1U NMR (400 MHz, CDClO: δ 0.95 (t, 3H), 1.30 (t, 3H), 1.60 (m, 2H), 1.80 (m, 2H), 2.22 (s, 3H), 3.90 (m, 2H), 3.25 (m, IH), 3.42 (m, IH), 3.65 (m, IH), 4.22 (m, 4H), 4.41 (m, 1H).7.21 (d, IH), 9.91 (m, IH). LCMS: m/z 407.3 (M+H).
  • 21
  • [ 1229573-44-7 ]
  • [ 24691-30-3 ]
  • [ 1229573-45-8 ]
YieldReaction ConditionsOperation in experiment
73.6% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 18 - 26℃; 19 Intermediate 19; Ethyl (3S,4R)-4-{ r(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyllamino)-3-(prop-2-en-l- yloxy)piperidine- 1 -carboxylate; To a solution of 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (WO200687543, 2.27 g, 11.8 mmol) and Ethyl (3S,4R)-4-amino-3-(prop-2-en-l-yloxy)piperidine-l-carboxylate (Intermediate 18, 2.7 g, 11.8 mmol) in dichloromethane (180 mL) was added HOBt (1.85 g, 11.8 mM) and N-methylmorpholine (3.8 mL, 35.43 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (4.07 g, 21.3 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight, treated by the addition of 2 N HCl (120 mL) and the resulting layers were evaporated. The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica gel, 35% ethylacetate in pet ether) to afforded 3.5 g (73.6%) as brown solid. NMR (400 MHz, DMSOd6): δ 1.24 (t, 3H), 1.62 (m, 2H), 2.16 (s, 3H), 2.97 (m, 2H), 3.53 (m, 2H), 3.97 (m, 4H), 4.15 (q, 2H), 4.21 (m, IH), 5.13 (d, IH), 5.23 (d, IH), 5.87 (m, IH), 7.10 (d, IH), 12.10 (s, IH).
  • 22
  • [ 1229573-57-2 ]
  • [ 24691-30-3 ]
  • [ 1229573-60-7 ]
YieldReaction ConditionsOperation in experiment
67% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 18 - 26℃; 40 Intermediate 40; Methyl (3S,4R)-4-{ r(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyllamino)-3- methylpiperidine- 1 -carboxvlate; To a solution of S^-dichloro-S-methyl-lH-pyrrole^-carboxylic acid (WO2006087543. 2.8 g, 14.53 mmol) and methyl (3S,4R)-4-amino-3-methylpiperidine-l-carboxylate (Intermediate 37, 2.5 g, 14.53 mmol) in dichloromethane (200 mL) was added ΗOBT (2.22 g, 14.53 mmol) and N-methyl morpholine (4.82 mL, 43.60 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (5.12 g, 26.16 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica, 35% ethylacetate in pet ether) afforded methyl (3S,4R)-4-{ [(3,4-dichloro-5-methyl-lΗ-pyrrol-2-yl)carbonyl]amino}-3- methylpiperidine-1-carboxylate 3.4 g (67%) as brown solid. MASS (APCI): m/z 348.0 (M+H). 1U NMR (400 MHz, DMSO-d): δ 0.85 (d, 3H), 2.01 (m, 2H), 2.18 (s, 3H), 3.39 (m, 4H), 3.52 (s, 3H), 4.16 (m, IH), 7.05 (d, IH), 12.01 (s, IH).
  • 23
  • [ 14235-81-5 ]
  • [ 24691-30-3 ]
  • [ 908580-27-8 ]
YieldReaction ConditionsOperation in experiment
46% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 4-Ethynylaniline In N,N-dimethyl-formamide at 20℃; for 72h; 3,4-Dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (Intermediate 42; 2 g, 10.3 mmol) and HATU (4.3 g, 11.3 mmol, 1.1 eq.) were dissolved in dry DMF (100 ml) and DIEA (3.98 g, 30.9 mmol, 3 eq.). The reaction mixture was stirred at 0°C for 30 minutes. The solution was warmed to room temperature and (4-ethynylphenyl)amine (1.2 g, 10.3 mmol, 1 eq.) was added in a single portion. The reaction was stirred for 3 days while monitoring by LC/MS. The reaction mixture was concentrated to 1A the volume via rotary evaporation, diluted with EtOAc and washed with H2O (3 x 50 ml) and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude reaction mixture was purified by flash column chromatography (20% EtOAc / hexanes). Isolation gave 1.4 g of the title compound in a 46% yield. M/z 293, 295; NMR: 2.23 (s, 3H), 4.11 (s, IH), 7.45 (d, 2H), 7.67 (d, 2H), 9.6 (s, IH), 12.2 (s, IH).
  • 24
  • [ 24691-30-3 ]
  • [ 147081-49-0 ]
  • [ 1006885-48-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester In N,N-dimethyl-formamide 1 Intermediate 1 fert-Butyi ϖ-RVS-ll'fSλ-dichloro-S-methyl-lij-pyrrol-l-vϖcarbonyllaminolpyrrolidine-l- carboxylateTo a stirred solution of 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (0.312 g, 1.61 mmol) (Motekaitis, R. J.; Heinert, D. H.; Martell, Arthur E. J. of Org. Chem. 35(8), 2504 (1970)) in DMF (3 niL) was added triethylamine (0.436 mL, 3.22 mmol) followed by the addition of HATU (0.612 g, 1.61 mmol) at room temperature. The resultant solution was stirred for 30 mins and tert-butyl (3i?)-3-aminopyrrolidine-l-carboxylate (0.300 g, 1.61 mmol) was added to it at once. The reaction was allowed to stir overnight. It was concentrated and the residue was partitioned between water and ethyl acetate. The layers separated and the aqueous was extracted with ethyl acetate two more times. The extracts were combined and washed with IN HCl, saturated NaHCO3 solution followed by water and brine. It was dried over magnesium sulfate, concentrated under reduced pressure to give the product as a light brown solid. MS (ES): 362 (M+l) for C15H21Cl2N3O31H NMR (300 MHz): 1.39 (s, 9H); 1.95 (m, IH); 2.07 (m, IH); 2.17(s, 3H); 3.16 (m, IH); 3.37 (m, 2H); 3.50 (m, IH); 4.35 (m, IH); 7.47 (m, IH); 11.94 (s, IH).
  • 26
  • [ 907544-20-1 ]
  • [ 24691-30-3 ]
  • [ 907544-08-5 ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: (3S,4R)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate; 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 4-methyl-morpholine; benzotriazol-1-ol In dichloromethane for 0.25h; Inert atmosphere; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide
  • 28
  • [ 24691-30-3 ]
  • [ 848499-34-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane
Multi-step reaction with 3 steps 1: triethylamine; HATU / DMF (N,N-dimethyl-formamide) / 5.08 h / 20 °C 2: dichloromethane / 0.5 h / 20 °C 3: sodium carbonate / chloroform; water; isopropyl alcohol
  • 29
  • [ 24691-30-3 ]
  • 2-chloro-6-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: 80 °C
  • 30
  • [ 24691-30-3 ]
  • [ 848501-73-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C 4: water; sodium hydroxide / methanol
  • 31
  • [ 24691-30-3 ]
  • [ 848502-97-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C 4: water; sodium hydroxide / methanol
Multi-step reaction with 4 steps 1.1: triethylamine / N,N-dimethyl-formamide / 0.08 h / Inert atmosphere 1.2: 5 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride / water / 1.5 h / 20 °C 3.1: triethylamine / 1-methyl-pyrrolidin-2-one / 0.33 h / Microwave irradiation 4.1: lithium hydroxide / water; tetrahydrofuran / 1 h / Reflux
  • 32
  • [ 24691-30-3 ]
  • [ 848502-99-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C 4: water; sodium hydroxide / methanol
  • 33
  • [ 24691-30-3 ]
  • methyl 2-chloro-6-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C
  • 34
  • [ 24691-30-3 ]
  • [ 848502-98-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C
Multi-step reaction with 3 steps 1.1: triethylamine / N,N-dimethyl-formamide / 0.08 h / Inert atmosphere 1.2: 5 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride / water / 1.5 h / 20 °C 3.1: triethylamine / 1-methyl-pyrrolidin-2-one / 0.33 h / Microwave irradiation
  • 35
  • [ 24691-30-3 ]
  • [ 1360573-51-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C
  • 36
  • [ 24691-30-3 ]
  • 1-tert-butyl 2-methyl(2S)-4-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrrolidine-1,2-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: sodium cyanoborohydride
Multi-step reaction with 3 steps 1: triethylamine; HATU / DMF (N,N-dimethyl-formamide) / 5.08 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C 3: sodium tris(acetoxy)borohydride / acetic acid; 1,2-dichloro-ethane / 20 °C
  • 37
  • [ 24691-30-3 ]
  • methyl 4-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-L-prolinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: sodium cyanoborohydride 4: hydrogenchloride / 1,4-dioxane
Multi-step reaction with 4 steps 1: triethylamine; HATU / DMF (N,N-dimethyl-formamide) / 5.08 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C 3: sodium tris(acetoxy)borohydride / acetic acid; 1,2-dichloro-ethane / 20 °C 4: hydrogenchloride / 1,4-dioxane / 0.33 h / 20 °C
  • 38
  • [ 24691-30-3 ]
  • 4-(4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-L-proline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: sodium cyanoborohydride 4: hydrogenchloride / 1,4-dioxane 5: water; sodium hydroxide / methanol
Multi-step reaction with 5 steps 1: triethylamine; HATU / DMF (N,N-dimethyl-formamide) / 5.08 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C 3: sodium tris(acetoxy)borohydride / acetic acid; 1,2-dichloro-ethane / 20 °C 4: hydrogenchloride / 1,4-dioxane / 0.33 h / 20 °C 5: lithium hydroxide; water / acetonitrile / 0.5 h / 20 - 70 °C
  • 39
  • [ 24691-30-3 ]
  • [ 848503-01-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: hydrogenchloride / 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C 4: water; sodium hydroxide / methanol 5: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide
  • 40
  • [ 1601751-76-1 ]
  • [ 24691-30-3 ]
  • [ 1624309-49-4 ]
YieldReaction ConditionsOperation in experiment
66.6% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; ethyl acetate at 0 - 20℃; for 6h;
  • 41
  • [ 503167-63-3 ]
  • [ 24691-30-3 ]
  • O1-tert-butyl O3-methyl (3SR,4RS)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]piperidine-1,3-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 4-aminopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester In N,N-dimethyl-formamide at 20℃; for 18h;
  • 42
  • tert-butyl (3SR,4RS)-4-amino-3-chloro-piperidine-1-carboxylate [ No CAS ]
  • [ 24691-30-3 ]
  • tert-butyl (3SR,4RS)-3-chloro-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% Stage #1: tert-butyl (3SR,4RS)-4-amino-3-chloro-piperidine-1-carboxylate; 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 4-methyl-morpholine; benzotriazol-1-ol In dichloromethane at 20℃; for 1h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
  • 43
  • [ 1007595-32-5 ]
  • [ 24691-30-3 ]
  • [ 1007595-41-6 ]
YieldReaction ConditionsOperation in experiment
76% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h;
  • 44
  • [ 24691-30-3 ]
  • tert-butyl (3SR,4RS)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methylsulfanyl-piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: thionyl chloride / 0.5 h / Reflux 2: triethylamine / dichloromethane / 2 h / 20 °C
  • 45
  • [ 24691-30-3 ]
  • C12H17Cl2N3OS [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: thionyl chloride / 0.5 h / Reflux 2: triethylamine / dichloromethane / 2 h / 20 °C 3: hydrogenchloride / water; 1,4-dioxane / 0.75 h / 20 °C
  • 46
  • [ 24691-30-3 ]
  • 2-[(3SR,4RS)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methoxy-1-piperidyl]thiazole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: thionyl chloride / 0.5 h / Reflux 2: pyridine / 20 °C 3: trimethylsilyl iodide / acetonitrile / 1.5 h / Reflux 4: N-ethyl-N,N-diisopropylamine / 7 h / 120 °C 5: lithium hydroxide / water / 1 h / Reflux
  • 47
  • [ 24691-30-3 ]
  • 2-[(3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)-amino]-3-methoxy-1-piperidyl]thiazole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: benzotriazol-1-ol; 4-methyl-morpholine / dichloromethane / 1 h 2: trimethylsilyl iodide / acetonitrile / 1.5 h / Inert atmosphere; Reflux 3: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 0.33 h / 150 °C 4: lithium hydroxide / water; tetrahydrofuran / 1 h / Reflux
  • 48
  • [ 24691-30-3 ]
  • 3,4-dichloro-5-methyl-N-(4-piperidyl)-1H-pyrrole-2-carboxamide hydrochloride salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: triethylamine / N,N-dimethyl-formamide / 0.08 h / Inert atmosphere 1.2: 5 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride / water / 1.5 h / 20 °C
Multi-step reaction with 2 steps 1: triethylamine; HATU / DMF (N,N-dimethyl-formamide) / 5.08 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C
  • 49
  • [ 882737-71-5 ]
  • [ 24691-30-3 ]
  • ethyl (3R,4S)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methoxy-piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% Stage #1: ethyl (3S,4R)-4-amino-3-methoxypiperidine-1-carboxylate; 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 4-methyl-morpholine; benzotriazol-1-ol In dichloromethane for 1h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
  • 50
  • [ 24691-30-3 ]
  • [ 907572-18-3 ]
  • ethyl (3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methoxy-piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid; ethyl (-)-cis-4-amino-3-methoxy-1-piperidinecarboxylate With 4-methyl-morpholine; benzotriazol-1-ol In dichloromethane for 1h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
  • 51
  • methyl 2-[(3R,4R)-4-amino-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate hydrochloride salt [ No CAS ]
  • [ 24691-30-3 ]
  • methyl 2-[(3R,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methoxy-1-piperidyl]thiazole-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: methyl 2-[(3R,4R)-4-amino-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate hydrochloride salt; 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 4-methyl-morpholine; benzotriazol-1-ol In dichloromethane at 20℃; for 1h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
  • 52
  • ethyl (3RS,4SR)-4-amino-3-methoxypiperidine-1-carboxylic acid hydrochloride salt [ No CAS ]
  • [ 24691-30-3 ]
  • ethyl (3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methoxy-piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With acetic acid; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: ethyl (3RS,4SR)-4-amino-3-methoxypiperidine-1-carboxylic acid hydrochloride salt In N,N-dimethyl-formamide at 20℃; for 18h;
  • 53
  • C10H20N2O2*ClH [ No CAS ]
  • [ 24691-30-3 ]
  • C16H23Cl2N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With acetic acid; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: C10H20N2O2*ClH In N,N-dimethyl-formamide at 20℃; for 18h;
  • 54
  • methyl 2-[(3S,4S)-4-amino-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate hydrochloride salt [ No CAS ]
  • [ 24691-30-3 ]
  • methyl 2-[(3S,4S)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methoxy-1-piperidyl]thiazole-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45 mg Stage #1: methyl 2-[(3S,4S)-4-amino-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate hydrochloride salt; 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 4-methyl-morpholine; benzotriazol-1-ol In dichloromethane at 20℃; for 1h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
  • 55
  • [ 1007595-35-8 ]
  • [ 24691-30-3 ]
  • [ 1007595-46-1 ]
YieldReaction ConditionsOperation in experiment
52% Stage #1: methyl 4-amino-3,3-dimethoxypiperidine-1-carboxylate; 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With 4-methyl-morpholine; benzotriazol-1-ol In dichloromethane at 20℃; for 1h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;
  • 56
  • ethyl (3SR,4RS)-4-amino-3-allyloxy-piperidine-1-carboxylate [ No CAS ]
  • [ 24691-30-3 ]
  • ethyl (3SR,4RS)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-allyloxy-piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: ethyl (3SR,4RS)-4-amino-3-allyloxy-piperidine-1-carboxylate In N,N-dimethyl-formamide
  • 57
  • C11H18N2O3 [ No CAS ]
  • [ 24691-30-3 ]
  • ethyl (3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-prop-2-ynoxy-piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
480 mg With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;
  • 58
  • ethyl 5-((4-aminophenyl)amino)-1,2,4-oxadiazole-3-carboxylate [ No CAS ]
  • [ 24691-30-3 ]
  • C17H15Cl2N5O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.75h; Stage #2: ethyl 5-((4-aminophenyl)amino)-1,2,4-oxadiazole-3-carboxylate In dichloromethane at 0℃; for 48h; Reflux; To a stirred solution of 3,4-dichloro-5-methyl-pyrrole-2-carboxylic acid (1.0 eq) in dry dichloromethane (10 mL), diisopropylethylamine (3.0 eq) and TBTU (1.1 eq) were added. After stirring for 45 min the amine 33 was added at 0 °C, and the mixture allowed to warm to room temperature; stirring then continued for 48 h. On completion, the reaction mixture was diluted with dichloromethane (30 mL) then washed with 1 M HCl (2 x 20 mL), water (20 mL), saturated NaHCO3 solution (2 x 20 mL), water (20 mL) and dried over anhydrous Na2SO4. The solvent was concentrated in vacuo and the residue of crude ester immediately used in the next step. The crude ester (1.0 eq) was dissolved in THF, then 1 M NaOH (1.1 eq) was added and the reaction mixture stirred at room temperature for 2 h. THF was evaporated under vacuum and the resulting aqueous solution neutralized with 1 M HCl until the product 35 precipitated. It was then dried overnight. Brown solid; m.p. 176-180 °C. 1H NMR (DMSO-d6, 400 MHz): δ = 2.22 (s, 3H,Ar-CH3), 7.40 (d, 2H, J = 8.8 Hz, Ar-H), 7.57 (d, 2H, J = 8.8 Hz,Ar-H), 9.35 (s, 1H, Ar-NH), 9.36 (s, 1H, CONH), 12.14 (s, 1H, NH) ppm. 13C NMR (DMSO-d6, 100 MHz): δ = 10.75, 108.28, 110.89, 119.63, 119.67, 120.48, 127.81, 133.80, 134.31, 151.96, 157.00, 180.65 ppm. MS (ESI): m/z (%) 350.0 (M-H-CO2)-. IR (KBr): ν = 3394, 3321, 1651, 1598, 1515, 1449, 1409, 1373, 1317, 1249, 1190, 1130, 1045, 960, 800, 738, 627 cm-1. HRMS Calcd for C14H10Cl2N5O2 m/z: 350.0212 (M + H)+, found 350.0217. HPLC: tr = 12.44 min (97.2% at 254 nm).
  • 59
  • methyl (4-amino-1H-pyrrole-2-carbonyl)glycinate [ No CAS ]
  • [ 24691-30-3 ]
  • methyl (4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carbonyl)glycinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
32 mg Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl (4-amino-1H-pyrrole-2-carbonyl)glycinate In N,N-dimethyl-formamide at 0 - 45℃; General procedure for acylation with HATU General procedure: To the solution of 1 equivalent carboxylic acid in dimethyl formamide (DMF), 1.2 equivalent of N-ethyldiisopropylamine (DIPEA) and 1.1 equivalent of HATU were added and stirred for 30 minutes at room temperature. Than the solution of 1.2 equivalent of amine in DMF was added and the reaction was stirred overnight. After the reaction was completed, DMF was removed and the residue was purified by flash column chromatography.
  • 60
  • [ 24691-30-3 ]
  • (R)-methyl 2-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)-3-isopropoxybenzamido)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane / 15 h / 20 °C / Inert atmosphere 2: pyridine / dichloromethane / 15 h / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane / 5 h / 120 °C / Inert atmosphere 2: pyridine / dichloromethane / 15 h / 20 °C / Inert atmosphere
  • 61
  • [ 24691-30-3 ]
  • 2-[(3E)-4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(methoxyimino)piperidin-1-yl]-4-[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylic acid [ No CAS ]
  • 2-[(3Z)-4-[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(methoxyimino)piperidin-1-yl]-4-[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2: 1,2-dichloro-ethane / 0.33 h / 20 °C 3: sodium hydrogencarbonate / N,N-dimethyl-formamide / 1 h / 80 °C 4: water; diethylamine / palladium diacetate; trisodium tris(3-sulfophenyl)phosphine / methanol / 1 h / 20 °C
  • 62
  • C30H47NO6Si [ No CAS ]
  • [ 24691-30-3 ]
  • N-((2S,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-3-hydroxy-5-((4-methoxybenzyl)oxy)-3-((Z)-2-((4-methoxybenzyl)oxy)vinyl)hexan-2-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
54.5 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 2h;
  • 63
  • C30H47NO6Si [ No CAS ]
  • [ 24691-30-3 ]
  • N-((2S,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-3-hydroxy-5-((4-methoxybenzyl)oxy)-3-((Z)-2-((4-methoxybenzyl)oxy)vinyl)hexan-2-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
54.5 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 2h;
  • 64
  • methyl 2-amino-4-(2-morpholinoethoxy)benzo[d]thiazole-6-carboxylate [ No CAS ]
  • [ 24691-30-3 ]
  • 4-(2-((2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)-6-(methoxycarbonyl)benzo[d]thiazol-4-yl)oxy)ethyl)morpholin-4-ium chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
77.2% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; Inert atmosphere; Stage #2: methyl 2-amino-4-(2-morpholinoethoxy)benzo[d]thiazole-6-carboxylate In toluene at 130℃; 10.4 Step 4: Synthesis of 4-(2-((2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)-6- (methoxycarbonyl)benzo[d]thiazol-4-yl)oxy)ethyl)morpholin-4-ium chloride The same operation as in Example 1 (Step 1) was performed using methyl 2-amino-4-(2- morpholinoethoxy)benzo[d]thiazole-6-carboxylate (261 mg, 0.773 mmol) obtained in Step 3 above. Yield: 70 mg (16.5%); beige solid. (0518) 1H NMR (400 MHz, DMSO-d6) d 2.28 (s, 3H), 3.20-3.30 (m, 2H), 3.65 (s, 4H), 3.79 (t, 2H), 3.90 (s, 3H), 4.04 (d, J = 12.5 Hz, 2H), 4.69 (s, 2H), 7.60 (d, J = 1.4 Hz, 1H), 8.36 (s, 1H), 10.68 (s, 1H), 12.12 (s, 1H), 12.68 (s, 1H).To a suspension of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (244 mg, 1.26 mmol) in anhydrous dichloromethane (15 mL) oxalyl chloride (0.539 mL, 6.29 mmol) was added dropwise and the solution stirred at room temperature under argon atmosphere overnight. The solvent was evaporated under reduced pressure, methyl 2-aminobenzo[d]thiazole-6-carboxylate (262 mg, 1.26 mmol) and toluene (20 mL) were added and the suspension was stirred at 130 °C overnight. The precipitate in the reaction mixture was filtered off, suspended in 1 M HCl (100 mL), sonicated and filtered off. The crude product was dispersed in methanol (100 mL), heated, filtered off and dried. Yield: 373 mg (77.2%); grey solid. (0391) 1H NMR (400 MHz, DMSO-d6) d 2.29 (s, 3H), 3.89 (s, 3H), 7.83 (s, 1H), 8.04 (dd, J = 8.5, 1.8 Hz, 1H), 8.67 (s, 1H), 11.98 (s, 1H), 12.35 (s, 1H).
  • 65
  • [ 24691-30-3 ]
  • 4-(2-((6-carboxy-2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-4-yl)oxy)ethyl)morpholin-4-ium chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane / 20 °C / Inert atmosphere 1.2: 130 °C 2.1: sodium hydroxide / 1,4-dioxane / 80 °C
Multi-step reaction with 3 steps 1: oxalyl dichloride / dichloromethane / 15 h / 20 °C / Inert atmosphere 2: toluene / 15 h / 130 °C 3: sodium hydroxide / 1,4-dioxane; water / 15 h / 80 °C
  • 66
  • [ 24691-30-3 ]
  • 2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane / 20 °C / Inert atmosphere 1.2: 130 °C 2.1: potassium hydroxide; 1-methyl-pyrrolidin-2-one / 100 - 115 °C
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane / 15 h / 20 °C / Inert atmosphere 1.2: 15 h / 130 °C / Inert atmosphere 2.1: potassium hydroxide / 1-methyl-pyrrolidin-2-one / 48 h / 100 - 115 °C
  • 67
  • [ 24691-30-3 ]
  • 4-(2-((6-((cyanomethyl)carbamoyl)-2-(3,4-dichloro-5-methyl-1H-pyrrole-2- carboxamido)benzo[d]thiazol-4-yl)oxy)ethyl)morpholin-4-ium chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / dichloromethane / 20 °C / Inert atmosphere 1.2: 130 °C 2.1: sodium hydroxide / 1,4-dioxane / 80 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / N,N-dimethyl-formamide / 0.33 h / 0 °C 3.2: 20 °C
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / dichloromethane / 15 h / 20 °C / Inert atmosphere 2.1: toluene / 15 h / 130 °C 3.1: sodium hydroxide / 1,4-dioxane; water / 15 h / 80 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 0.33 h / 0 °C / pH 8 4.2: 15 h / 20 °C
  • 68
  • [ 66947-92-0 ]
  • [ 24691-30-3 ]
  • methyl 2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazole-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77.2% To a suspension of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (244 mg, 1.26 mmol) in anhydrous dichloromethane (15 mL) oxalyl chloride (0.539 mL, 6.29 mmol) was added dropwise and the solution stirred at room temperature under argon atmosphere overnight. The solvent was evaporated under reduced pressure, <strong>[66947-92-0]methyl 2-aminobenzo[d]thiazole-6-carboxylate</strong> (262 mg, 1.26 mmol) and toluene (20 mL) were added and the suspension was stirred at 130 C overnight. The precipitate in the reaction mixture was filtered off, suspended in 1 M HCl (100 mL), sonicated and filtered off. The crude product was dispersed in methanol (100 mL), heated, filtered off and dried. Yield: 373 mg (77.2%); grey solid. (0391) 1H NMR (400 MHz, DMSO-d6) d 2.29 (s, 3H), 3.89 (s, 3H), 7.83 (s, 1H), 8.04 (dd, J = 8.5, 1.8 Hz, 1H), 8.67 (s, 1H), 11.98 (s, 1H), 12.35 (s, 1H).
  • 69
  • [ 29026-74-2 ]
  • [ 24691-30-3 ]
  • 3,4-dichloro-N-(2-isopropoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 2-isopropoxy-phenylamine With pyridine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.2.3. General procedure C General procedure: To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(1.5 eq.) in anhydrous dichloromethane (10 mL/mmol), oxalyl chloride(7.5 eq.) was added dropwise and the mixture was stirred at roomtemperature for 15 h under argon atmosphere. The solvent was evaporatedunder reduced pressure, anhydrous dichloromethane (10 mL/mmol), amine (1 eq.) and pyridine (1 mL/mmol) were added and thereaction mixture was stirred under argon atmosphere at room temperaturefor 15 h. If precipitated, the product was filtered off from thereaction mixture.
  • 70
  • 4-amino-3-isopropoxybenzamide [ No CAS ]
  • [ 24691-30-3 ]
  • N-(4-carbamoyl-2-isopropoxyphenyl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 4-amino-3-isopropoxybenzamide With pyridine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.2.3. General procedure C General procedure: To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(1.5 eq.) in anhydrous dichloromethane (10 mL/mmol), oxalyl chloride(7.5 eq.) was added dropwise and the mixture was stirred at roomtemperature for 15 h under argon atmosphere. The solvent was evaporatedunder reduced pressure, anhydrous dichloromethane (10 mL/mmol), amine (1 eq.) and pyridine (1 mL/mmol) were added and thereaction mixture was stirred under argon atmosphere at room temperaturefor 15 h. If precipitated, the product was filtered off from thereaction mixture.
  • 71
  • [ 146224-62-6 ]
  • [ 24691-30-3 ]
  • N-(4-carbamoyl-2-hydroxyphenyl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 4-amino-3-hydroxybenzamide With pyridine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.2.3. General procedure C General procedure: To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(1.5 eq.) in anhydrous dichloromethane (10 mL/mmol), oxalyl chloride(7.5 eq.) was added dropwise and the mixture was stirred at roomtemperature for 15 h under argon atmosphere. The solvent was evaporatedunder reduced pressure, anhydrous dichloromethane (10 mL/mmol), amine (1 eq.) and pyridine (1 mL/mmol) were added and thereaction mixture was stirred under argon atmosphere at room temperaturefor 15 h. If precipitated, the product was filtered off from thereaction mixture.
  • 72
  • [ 2835-68-9 ]
  • [ 24691-30-3 ]
  • N-(4-carbamoylphenyl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 4-aminobenzamide With pyridine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.2.3. General procedure C General procedure: To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(1.5 eq.) in anhydrous dichloromethane (10 mL/mmol), oxalyl chloride(7.5 eq.) was added dropwise and the mixture was stirred at roomtemperature for 15 h under argon atmosphere. The solvent was evaporatedunder reduced pressure, anhydrous dichloromethane (10 mL/mmol), amine (1 eq.) and pyridine (1 mL/mmol) were added and thereaction mixture was stirred under argon atmosphere at room temperaturefor 15 h. If precipitated, the product was filtered off from thereaction mixture.
  • 73
  • 4-acetamido-2-isopropoxybenzenaminium chloride [ No CAS ]
  • [ 24691-30-3 ]
  • N-(4-acetamido-2-isopropoxyphenyl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 4-acetamido-2-isopropoxybenzenaminium chloride With pyridine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.2.7.2. N-(4-Acetamido-2-isopropoxyphenyl)-3,4-dichloro-5-methyl-1Hpyrrole-2-carboxamide (68). Synthesized according to Generalprocedure C from 67 (71 mg, 0.29 mmol). The product was purifiedby precipitation in 1 M HCl (10 mL) and a few drops of THF and wasfiltered off as a brown solid. Yield 35% (39 mg). 1H NMR (400 MHz,DMSO) δ = 1.35 (d, 6H, J = 6.0 Hz, CH(CH3)2), 2.03 (s, 3H, pyrrole-CH3 or NHCOCH3), 2.22 (s, 3H, pyrrole-CH3 or NHCOCH3), 4.52-4.69(m, 1H, CH(CH3)2), 7.07 (dd, 1H, J = 8.8, 2.1 Hz, Ar-H-5), 7.51 (d, 1H,J = 2.0 Hz, Ar-H-3), 8.27 (d, 1H, J = 8.8 Hz, Ar-H-6), 9.01 (s, 1H, Ar-NH), 9.94 (s, 1H, Ar-NH), 12.35 (s, 1H, pyrrole-NH) ppm. 13C NMR(100 MHz, DMSO-d6) δ = 11.2, 22.3, 24.5, 71.5, 104.9, 108.8, 109.6,111.3, 119.4, 119.6, 124.0, 129.6, 136.0, 146.2, 156.3, 168.6 ppm.HRMS for C17H18Cl2N3O3 ([M-H]-): calculated 382.0731, found482.0733. HRMS for C17H18Cl2N3O3 ([M-H]-): calculated382.0731, found 382.0733. HPLC purity 95.4%.
  • 74
  • 1-(3-amino-4-isopropoxyphenyl)-3-ethylurea [ No CAS ]
  • [ 24691-30-3 ]
  • 3,4-dichloro-N-(5-(3-ethylureido)-2-isopropoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 1-(3-amino-4-isopropoxyphenyl)-3-ethylurea With pyridine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.2.3. General procedure C General procedure: To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(1.5 eq.) in anhydrous dichloromethane (10 mL/mmol), oxalyl chloride(7.5 eq.) was added dropwise and the mixture was stirred at roomtemperature for 15 h under argon atmosphere. The solvent was evaporatedunder reduced pressure, anhydrous dichloromethane (10 mL/mmol), amine (1 eq.) and pyridine (1 mL/mmol) were added and thereaction mixture was stirred under argon atmosphere at room temperaturefor 15 h. If precipitated, the product was filtered off from thereaction mixture.
  • 75
  • tert-butyl 4-(2-amino-4-(3-ethylureido)phenoxy)piperidine-1-carboxylate [ No CAS ]
  • [ 24691-30-3 ]
  • tert-butyl 4-(2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)-4-(3-ethylureido)phenoxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: tert-butyl 4-(2-amino-4-(3-ethylureido)phenoxy)piperidine-1-carboxylate With pyridine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.2.3. General procedure C General procedure: To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(1.5 eq.) in anhydrous dichloromethane (10 mL/mmol), oxalyl chloride(7.5 eq.) was added dropwise and the mixture was stirred at roomtemperature for 15 h under argon atmosphere. The solvent was evaporatedunder reduced pressure, anhydrous dichloromethane (10 mL/mmol), amine (1 eq.) and pyridine (1 mL/mmol) were added and thereaction mixture was stirred under argon atmosphere at room temperaturefor 15 h. If precipitated, the product was filtered off from thereaction mixture.
  • 76
  • [ 1319746-16-1 ]
  • [ 24691-30-3 ]
  • N-(4-carbamoyl-3-isopropoxyphenyl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 4-amino-2-isopropoxybenzamide With pyridine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.2.3. General procedure C General procedure: To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(1.5 eq.) in anhydrous dichloromethane (10 mL/mmol), oxalyl chloride(7.5 eq.) was added dropwise and the mixture was stirred at roomtemperature for 15 h under argon atmosphere. The solvent was evaporatedunder reduced pressure, anhydrous dichloromethane (10 mL/mmol), amine (1 eq.) and pyridine (1 mL/mmol) were added and thereaction mixture was stirred under argon atmosphere at room temperaturefor 15 h. If precipitated, the product was filtered off from thereaction mixture.
  • 77
  • [ 24691-30-3 ]
  • ethyl 2-((6-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-2-yl)amino)-2-oxoacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: pyridine / dichloromethane / 12 h / 20 °C
  • 78
  • [ 24691-30-3 ]
  • methyl 3-((6-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-2-yl)amino)-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: pyridine / dichloromethane / 12 h / 20 °C
  • 79
  • [ 24691-30-3 ]
  • N-(2-acetamidobenzo[d]thiazol-6-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: pyridine / dichloromethane / 12 h / 20 °C
  • 80
  • [ 24691-30-3 ]
  • 2-((6-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-2-yl)amino)-2-oxoacetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: pyridine / dichloromethane / 12 h / 20 °C 3: sodium hydroxide / 1,4-dioxane / 24 h
  • 81
  • [ 24691-30-3 ]
  • 3,4-dichloro-5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: toluene / Reflux
  • 82
  • [ 24691-30-3 ]
  • N-(6-aminobenzo[d]thiazol-2-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: toluene / Reflux 3: tin(II) chloride dihdyrate / ethanol / Reflux
  • 83
  • [ 24691-30-3 ]
  • ethyl 2-((2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl)amino)-2-oxoacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: toluene / Reflux 3: tin(II) chloride dihdyrate / ethanol / Reflux 4: triethylamine / 1,4-dioxane / 0 - 20 °C
  • 84
  • [ 24691-30-3 ]
  • 2-((2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl)amino)-2-oxoacetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: toluene / Reflux 3: tin(II) chloride dihdyrate / ethanol / Reflux 4: triethylamine / 1,4-dioxane / 0 - 20 °C 5: sodium hydroxide / 1,4-dioxane / 20 °C
  • 85
  • [ 24691-30-3 ]
  • N-(6-acetamidobenzo[d]thiazol-2-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: toluene / Reflux 3: tin(II) chloride dihdyrate / ethanol / Reflux 4: triethylamine / dichloromethane / 20 °C / Inert atmosphere
  • 86
  • [ 24691-30-3 ]
  • 3,4-dichloro-5-methyl-N-(6-ureidobenzo[d]thiazol-2-yl)-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2.1: toluene / Reflux 3.1: tin(II) chloride dihdyrate / ethanol / Reflux 4.1: N,N-dimethyl-formamide / 3 h / 20 °C / Inert atmosphere 4.2: 16 h / Sealed tube
  • 87
  • [ 24691-30-3 ]
  • N-(2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl)isonicotinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2.1: toluene / Reflux 3.1: tin(II) chloride dihdyrate / ethanol / Reflux 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 0.25 h / 0 °C 4.2: 12 h / 20 °C
  • 88
  • [ 24691-30-3 ]
  • tert-butyl (3-((2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl)amino)-3-oxopropyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2.1: toluene / Reflux 3.1: tin(II) chloride dihdyrate / ethanol / Reflux 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 0.25 h / 0 °C 4.2: 12 h / 20 °C
  • 89
  • [ 24691-30-3 ]
  • tert-butyl (2-((2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl)amino)-2-oxoethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2.1: toluene / Reflux 3.1: tin(II) chloride dihdyrate / ethanol / Reflux 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 0.25 h / 0 °C 4.2: 12 h / 20 °C
  • 90
  • [ 24691-30-3 ]
  • N-(6-(3-aminopropanamido)benzo[d]thiazol-2-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2.1: toluene / Reflux 3.1: tin(II) chloride dihdyrate / ethanol / Reflux 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 0.25 h / 0 °C 4.2: 12 h / 20 °C 5.1: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C
  • 91
  • [ 24691-30-3 ]
  • N-(6-(2-aminoacetamido)benzo[d]thiazol-2-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / dichloromethane / 8 h / 20 °C 2.1: toluene / Reflux 3.1: tin(II) chloride dihdyrate / ethanol / Reflux 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 0.25 h / 0 °C 4.2: 12 h / 20 °C 5.1: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C
  • 92
  • methyl 2-amino-4-((tert-butyldimethylsilyl)oxy)benzo[d]thiazole-6-carboxylate [ No CAS ]
  • [ 24691-30-3 ]
  • methyl 4-((tert-butyldimethylsilyl)oxy)-2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazole-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52.9% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: methyl 2-amino-4-((tert-butyldimethylsilyl)oxy)benzo[d]thiazole-6-carboxylate In toluene at 130℃; for 15h; Inert atmosphere; General procedure B. Synthesis of compounds 2c, 2d, 5a, 5b, 16a-c, 24, 27b, 30a-i, 37, 43, and 47 (with 2c as an example) General procedure: To a suspension of 4-bromo-3-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (101mg, 0.42mmol) in anhydrous dichloromethane (10mL) oxalyl chloride (0.181mL, 2.11mmol) was added dropwise and the solution stirred at room temperature under an argon atmosphere overnight. The solvent was evaporated under reduced pressure, ethyl 2-aminobenzo [d]thiazole-6-carboxylate (1b, 94mg, 0.42mmol) and toluene (20mL) were added, and the suspension was stirred at 130°C overnight. The precipitate in the reaction mixture was filtered off, resuspended in 1M HCl (100mL), sonicated and filtered off. The crude product was dispersed in methanol (100mL), heated, filtered off and dried, to obtain 2c (121mg) as a gray solid.
  • 93
  • [ 209459-07-4 ]
  • [ 24691-30-3 ]
  • methyl 2-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)benzo[d]thiazole-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.5% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: methyl 2-aminobenzo[d]thiazole-5-carboxylate In toluene at 130℃; for 15h; Inert atmosphere; General procedure B. Synthesis of compounds 2c, 2d, 5a, 5b, 16a-c, 24, 27b, 30a-i, 37, 43, and 47 (with 2c as an example) General procedure: To a suspension of 4-bromo-3-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (101mg, 0.42mmol) in anhydrous dichloromethane (10mL) oxalyl chloride (0.181mL, 2.11mmol) was added dropwise and the solution stirred at room temperature under an argon atmosphere overnight. The solvent was evaporated under reduced pressure, ethyl 2-aminobenzo [d]thiazole-6-carboxylate (1b, 94mg, 0.42mmol) and toluene (20mL) were added, and the suspension was stirred at 130°C overnight. The precipitate in the reaction mixture was filtered off, resuspended in 1M HCl (100mL), sonicated and filtered off. The crude product was dispersed in methanol (100mL), heated, filtered off and dried, to obtain 2c (121mg) as a gray solid.
  • 94
  • [ 1747-60-0 ]
  • [ 24691-30-3 ]
  • 3,4-dichloro-N-(6-methoxybenzo[d]thiazol-2-yl)-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 6-methoxybenzothiazol-2-ylamine In toluene at 130℃; for 15h; Inert atmosphere; General procedure B. Synthesis of compounds 2c, 2d, 5a, 5b, 16a-c, 24, 27b, 30a-i, 37, 43, and 47 (with 2c as an example) General procedure: To a suspension of 4-bromo-3-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (101mg, 0.42mmol) in anhydrous dichloromethane (10mL) oxalyl chloride (0.181mL, 2.11mmol) was added dropwise and the solution stirred at room temperature under an argon atmosphere overnight. The solvent was evaporated under reduced pressure, ethyl 2-aminobenzo [d]thiazole-6-carboxylate (1b, 94mg, 0.42mmol) and toluene (20mL) were added, and the suspension was stirred at 130°C overnight. The precipitate in the reaction mixture was filtered off, resuspended in 1M HCl (100mL), sonicated and filtered off. The crude product was dispersed in methanol (100mL), heated, filtered off and dried, to obtain 2c (121mg) as a gray solid.
  • 95
  • [ 19759-66-1 ]
  • [ 24691-30-3 ]
  • 3,4-dichloro-N-(6-cyanobenzo[d]thiazol-2-yl)-5-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 15h; Inert atmosphere; Stage #2: 2-amino-6-cyanobenzthiazole In toluene at 130℃; for 15h; Inert atmosphere; General procedure B. Synthesis of compounds 2c, 2d, 5a, 5b, 16a-c, 24, 27b, 30a-i, 37, 43, and 47 (with 2c as an example) General procedure: To a suspension of 4-bromo-3-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (101mg, 0.42mmol) in anhydrous dichloromethane (10mL) oxalyl chloride (0.181mL, 2.11mmol) was added dropwise and the solution stirred at room temperature under an argon atmosphere overnight. The solvent was evaporated under reduced pressure, ethyl 2-aminobenzo [d]thiazole-6-carboxylate (1b, 94mg, 0.42mmol) and toluene (20mL) were added, and the suspension was stirred at 130°C overnight. The precipitate in the reaction mixture was filtered off, resuspended in 1M HCl (100mL), sonicated and filtered off. The crude product was dispersed in methanol (100mL), heated, filtered off and dried, to obtain 2c (121mg) as a gray solid.
  • 96
  • [ 24691-30-3 ]
  • 3,4-dichloro-5-methyl-N-((S)-1-((2R,3R,4R)-3,4,6-trihydroxy-2-methyltetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; toluene / 0 - 20 °C 2: hydrogenchloride / water; tetrahydrofuran / 3 h / 20 °C
  • 97
  • [ 24691-30-3 ]
  • [ 1267883-01-1 ]
  • [ 1267883-00-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; toluene / 0 - 20 °C 2: hydrogenchloride / water / 1 h / 50 °C
  • 98
  • [ 24691-30-3 ]
  • C27H32Cl2N2O6 [ No CAS ]
  • C27H32Cl2N2O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; toluene / 0 - 20 °C 2: hydrogenchloride / water; tetrahydrofuran / 3 h / 20 °C 3: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 3 h / 0 - 20 °C
  • 99
  • [ 24691-30-3 ]
  • C14H31NO4Si [ No CAS ]
  • C20H34Cl2N2O5Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
395 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; toluene at 0 - 20℃;
  • 100
  • [ 24691-30-3 ]
  • C30H47NO6Si [ No CAS ]
  • C36H50Cl2N2O7Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 2h;
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