101537-64-8|3-(N-Boc-amino)thiophene-2-carboxylic acid| Ambeed

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Quality Control of [ 101537-64-8 ] Purity: 98% SDS Specification

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Product Details of [ 101537-64-8 ]

CAS No. :	101537-64-8
Formula :	C₁₀H₁₃NO₄S
M.W :	243.28
SMILES Code :	O=C(C1=C(NC(OC(C)(C)C)=O)C=CS1)O
MDL No. :	MFCD02682396
InChI Key :	QAXIGPOUDYLWDU-UHFFFAOYSA-N
Pubchem ID :	2756772

Safety of [ 101537-64-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of [ 101537-64-8 ]

* 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 [ 101537-64-8 ]

[ 101537-64-8 ] Synthesis Path-Downstream 1~35

1
[ 101537-64-8 ]
t-Butyl 2-Azidocarbonylthiophene-3-carbamate [ No CAS ]

References: [1]Journal of Heterocyclic Chemistry,1986,vol. 23,p. 1103 - 1108.

2
[ 149587-72-4 ]
[ 101537-64-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With water monomer; sodium hydroxide; In tetrahydrofuran; at 70℃; for 12h;	Compound 2 (2158 mg, 8.40 mmol) was dissolved in THF (10 mL), NaOH solution (8.2 mL, 4 M, 33.60 mmol) was added with stirring, and the temperature was raised to 70 C. to react for 12 h. After TLC monitoring reaction, add HCl (4M) to adjust pH to 2, distill under reduced pressure until a large amount of solid is precipitated, and dry after suction filtration to obtain corresponding product 3 (1.98g), white solid, melting point: 152C, yield 97%.
13.8 g (97%)	With sodium hydroxide; In tetrahydrofuran;	Method B 3-t-Butoxycarbonylaminothiophene-2-carboxylic acid Methyl 3-t-butoxycarbonylaminothiophene-2-carboxylate (15.0 g, 58.3 mmol) was warmed in a mixture of 1 N sodium hydroxide (116.6 ml) and tetrahydrofuran (60 ml) at 50 C. for 16 hours. The mixture was evaporated to a volume of approximately 60 ml, and acidified (pH=2) with hydrochloric acid under cooling in an ice bath. The precipitate was filtered off, washed with water, and dried to afford 13.8 g (97%) of 3-t-butoxycarbonylaminothiophene-2-carboxylic acid. M.p. 168-169 C. Litt. m.p. 168-169 C. (i. Chem. Res. (S), 296, 1985). 1 H-NMR (DMSO-D6, δ): 1.49 (s, 9H), 7.76 (d, 1H), 7.85 (d, 1H), 9.45 (s, 1H), 13.45 (s, 1H).
		A mixture of methyl 3-amino-2-thiophene-carboxylate (2.53 g, 15.9 mmol), Boc2O (7.64 g, 35 mmol), and DMAP (2.04 g, 16.7 mmol) was dissolved in acetone (15 mL) and TEA (5 mL). The reaction mixture was stirred vigorously for 4 h and diluted to a volume of 75 mL with dichloromethane. The resulting solution was washed with cold 1 N HCl (3×50 mL), 1 N NaOH (3×50 mL), and brine (50 mL). The dichloromethane solution was then dried over MgSO4, filtered, and concentrated in vacuo to yield a yellow oil. The crude product was loaded onto a short plug of silica and eluted with 9:1 hexanes/ethyl acetate to yield a pale yellow solid (1.2 g) that was used without further purification. The solid was dissolved in methanol (76 mL) and 50% NaOH (4 mL) and the mixture was stirred for 4 h. The reaction was diluted to a volume of 160 mL with water and concentrated briefly in vacuo. The remaining aqueous solution was washed with diethyl ether (2×80 mL), cooled in an ice bath, and cautiously acidified to pH 2 with sulfuric acid. The suspension was washed with ethyl acetate (3×50 mL) and the combined organic washes were dried over MgSO4, filtered, and concentrated in vacuo to yield (11) as a white solid (0.79 g) in 69% yield over two steps. 1H NMR (DMSO-d6) δ 9.43 (s, 1H), 7.80 (d, J=5.4 Hz, 1H), 7.72 (d, J=5.4 Hz. 1H), 1.46 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ165.8, 151.8, 144.9, 133.1, 121.2, 109.9, 81.5, 28.6; EI-MS mae 243.0563 (M+calculated 243.0565 for C10H13NO4S).

	With sodium hydroxide; In ethanol; water monomer; at 20℃; for 1h;	To a mixture of methyl 3-amino-2-thiophenecarboxylate (8 g, 51 mmol) and BOC2O (11 g, 50 mmol) in CH2Cl2 (400 ml) was added 4-(dimethylamino)pyridine (1 g, 8.1 mmol). The reaction was stirred at RT overnight and washed with 1N HCl (100 ml), followed by water and brine.The organic layer was dried over Na2SO4 and evaporated under reduced pressure and used for the next step without further purification.To the residue (2 g, ~7 mmol) in EtOH (50 ml) was added 1N NaOH (25 ml), the reaction was stirred at RT for 1 h and the solvent was evaporated under reduced pressure.water (5 ml) was added and the solution was acidified with HOAc. The precipitate was filtered and used in the next step without further purification. MS (ES-): 242 (M-H)-.
		Methyl 3-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate (32 g, 124.4 mmol) (step 1) was dissolved with methanol (140 mL) and sodium hydroxide was added (IN, 190 mL). The mixture was stirred at 50 0C for 16 h. Some starting material was remaining by TLC and so additional sodium hydroxide was added (1.7N, 275 mL) and the mixture was stirred at 50 0C for 2 h. The mixture was cooled to rt and acidified to pH 5 with HCl (IN). Solids were filtered out and combined with the solid remaining after extraction with EtOAc, drying with Na2SO4, and evaporation. The product was used without further purification.

References: [1]Patent: CN114213400,2022,A .Location in patent: Paragraph 0053-0057.
[2]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 4333 - 4340.
[3]Patent: US5284847,1994,A .
[4]Patent: US2009/155202,2009,A1 .Location in patent: Page/Page column 15-16.
[5]Patent: US2003/225106,2003,A1 .Location in patent: Page 99.
[6]Patent: WO2006/23707,2006,A2 .Location in patent: Page/Page column 34.
[7]ChemMedChem,2010,vol. 5,p. 118 - 129.

3
[ 22288-78-4 ]
[ 101537-64-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 4333 - 4340.
[2]Patent: CN114213400,2022,A .

4
[ 24424-99-5 ]
[ 101537-64-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 4333 - 4340.

5
[ 101537-64-8 ]
[ 106-47-8 ]
[ 453560-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Step B-Preparation of {3-[(tert-butoxy)carbonylamino](2-thienyl)}-N-(4-chlorophenyl)carboxamide To a mixture of the thienyl carboxylic acid from Step A (300 mg, 1.23 mmol) and 4-chloroaniline (160 mg, 1.25 mmol) and DIEA (300 μl, 1.6 mmol) was added EDC (300 mg, 1.6 mmol) and HOBt (170 mg, 1.25 mmol) in CH2Cl2, the reaction was stirred at RT overnight.The solution was washed with 1N HCl and saturated NaHCO3, followed by H2O and brine.The organic layer was dried over Na2SO4 and evaporated under reduced pressure and purified with preparative TLC to give the amide. MS (ES+): 353 (M+H)+; (ES-): 351 (M-H)-.

References: [1]Patent: US2003/225106,2003,A1 .Location in patent: Page 99.

6
[ 22288-78-4 ]
[ 24424-99-5 ]
[ 101537-64-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With dmap; sodium hydroxide; triethanolamine; In methanol; acetone;	A. Preparation of 3-[(tert-Butoxy)carbonylamino]-2-thiophenecarboxylic Acid (11) A mixture of methyl 3-amino-2-thiophene-carboxylate (2.53 g, 15.9 mmol), Boc2O (7.64 g, 35 mmol), and DMAP (2.04 g, 16.7 mmol) was dissolved in acetone (15 mL) and TEA (5 mL). The reaction mixture was stirred vigorously for 4 h and diluted to a volume of 75 mL with dichloromethane. The resulting solution was washed with cold 1 N HCl (350 mL), 1 N NaOH (350 mL), and brine (50 mL). The dichloromethane solution was then dried over MgSO4, filtered, and concentrated in vacuo to yield a yellow oil. The crude product was loaded onto a short plug of silica and eluted with 9:1 hexanes/ethyl acetate to yield a pale yellow solid (1.2 g) that was used without further purification. The solid was dissolved in methanol (76 mL) and 50% NaOH (4 mL) and the mixture was stirred for 4 h. The reaction was diluted to a volume of 160 mL with water and concentrated briefly in vacuo. The remaining aqueous solution was washed with diethyl ether (280 mL), cooled in an ice bath, and cautiously acidified to pH 2 with sulfuric acid. The suspension was washed with ethyl acetate (350 mL) and the combined organic washes were dried over MgSO4, filtered, and concentrated in vacuo to yield (11) as a white solid (0.79 g) in 69% yield over two steps. 1H NMR (DMSO-d6) δ 9.43 (s, 1H), 7.80 (d, J=5.4 Hz, 1H), 7.72 (d, J=5.4 Hz, 1H), 1.46 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ165.8, 151.8, 144.9, 133.1, 121.2, 109.9, 81.5, 28.6; EI-MS m/e 243.0563 (M+ calculated 243.0565 for C10H13NO4S).
	With dmap; In sodium hydroxide; ethanol; dichloromethane; water;	EXAMPLE 1 Step A-Preparation of 3-[(tert-butoxy)carbonylamino]thiophene-2-carboxylic acid To a mixture of methyl 3-amino-2-thiophenecarboxylate (8 g, 51 mmol) and BOC2O (11 g, 50 mmol) in CH2Cl2 (400 ml) was added 4-(dimethylamino)pyridine (1 g, 8.1 mmol). The reaction was stirred at RT overnight and washed with 1N HCl (100 ml), followed by water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure and used for the next step without further purification. To the residue (2 g, ~7 mmol) in EtOH (50 ml) was added IN NaOH (25 ml), the reaction was stirred at RT for 1 h and the solvent was evaporated under reduced pressure. Water (5 ml) was added and the solution was acidified with HOAc. The precipitate was filtered and used in the next step without further purification. MS (ES-): 242 (M-H)-.
	With dmap; sodium hydroxide; In ethanol; dichloromethane; water;	Step A-Preparation of 3-[(tert-butoxy)carbonylamino]thiophene-2-carboxylic acid To a mixture of methyl 3-amino-2-thiophenecarboxylate (8 g, 51 mmol) and BOC2O (11 g, 50 mmol) in CH2Cl2 (400 ml) was added 4-(dimethylamino)pyridine (1 g, 8.1 mmol). The reaction was stirred at RT overnight and washed with 1N HCl (100 ml), followed by water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure and used for the next step without further purification. To the residue (2 g, ~7 mmol) in EtOH (50 ml) was added 1N NaOH (25 ml), the reaction was stirred at RT for 1 h and the solvent was evaporated under reduced pressure. Water (5 ml) was added and the solution was acidified with HOAc. The precipitate was filtered and used in the next step without further purification. MS (ES-): 242 (M-H)-.

References: [1]Patent: US7452730,2008,B2 .
[2]Patent: US2003/125339,2003,A1 .
[3]Patent: US6878714,2005,B2 .

7
[ 101537-64-8 ]
[ 101537-66-0 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenylphosphoranyl azide; triethylamine; In dichloromethane; tert-butyl alcohol;	Method C Di-t-butyl thiophene-2,3-dicarbamate A mixture of 3-t-butoxycarbonylaminothiophene-2-carboxylic acid (10.0 g, 41.1 mmol), diphenylphosphoryl azide (14.14 g, 51.37 mmol) and triethylamine (5.85 ml, 42.2 mmol) in t-butyl alcohol (1000 ml) was stirred under reflux for 10 hours. The mixture was evaporated and the residue was dissolved in methylene chloride (300 ml). The solution was washed successively with 5% aqueous citric acid, water, saturated aqueous NAHCO3, followed by evaporation to give 5.9 g of a substance which was purified by recrystallization from heptane-methylene chloride to afford di-t-butyl thiophene-2,3-dicarbamate. M.p. 168-170 C. Litt. m.p.: 165-167 C. (J. Chem. Res. (S), 296, 1985).

References: [1]Patent: US5284847,1994,A .

8
[ 1544-85-0 ]
[ 101537-64-8 ]
[ 877997-59-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 60℃; for 16h;	3-[(Tert-butoxycarbonyl)amino]thiophene-2-carboxylic acid (7.3 g, 30.3 mmol) (step 2) was dissolved in DCM (155 niL), triethyl amine (12 mL), DMF (31 mL) and 2,2-difluoro- l,3-benzodioxol-5-amine (5 g, 29 mmol) was added. PyBOP (16.5 g, 32 mmol) was added and the mixture was stirred at 600C for 16 h. The reaction mixture was cooled and diluted with water and EtOAc. The organic layer was washed with water, dried with Na2SO4, and evaporated. The crude residue was purified using silica gel chromatography to yield the desired product (7.7 g, 67 %). 1H NMR (DMSO-J6) 69.95 (bs, IH), 7.95 (d, IH), 7.65, (s, IH), 7.45 (m, 2H), 7.10 (s, 2H), 1.50 (s, 9H); LCMS: 398.9 [M+H]+, RT 4.12 min.

References: [1]Patent: WO2006/23707,2006,A2 .Location in patent: Page/Page column 35.

9
[ 101537-64-8 ]
[ 108-44-1 ]
[ 1029280-44-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 1.5h;	Example 9; Preparation of 3-(3-Methylphenyl)-2-[l-(9H-purin-6-ylamino)propyl]thieno[3,2- dl pyr imidin-4(3H) -one; 9a. Synthesis of tert-Butyl {2-[(3-methylphenyl)carbamoyl]-3-thienyl}carbamate; [00176] Following the procedure in Example Ia and using 3-[(tert- butoxycarbonyl)amino]thiophene-2-carboxylic acid (2.500 g, 10.28 mmol), the product was obtained as a white solid (3.21g, 94%).

References: [1]Patent: WO2008/64018,2008,A1 .Location in patent: Page/Page column 72.

10
[ 101537-64-8 ]
[ 95-53-4 ]
[ 1029280-37-2 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	Example 8; Preparation of 3-(2-Methylphenyl)-2-ri-(9H-purin-6-ylamino)propyllthienor3,2- dl pyr imidin-4(3H) -one; 8a. Synthesis of tert-Butyl {2-[(2-methylphenyl)carbamoyl]-3-thienyl}carbamate.; [00169] Following the procedure in Example Ia starting with 3-[(tert- butoxycarbonyl)amino]thiophene-2-carboxylic acid (2.500 g, 10.28 mmol) and 2- methylaniline (1.64 mL, 15.4 mmol) the product was obtained as a gum (2.658g, 77%) which crystallized on standing.

References: [1]Patent: WO2008/64018,2008,A1 .Location in patent: Page/Page column 70.

11
[ 101537-64-8 ]
[ 62-53-3 ]
[ 1029280-25-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1.5 - 3h;Product distribution / selectivity;	Example 3; Preparation of IC491791: 2-ri-(4-Amino-benzoimidazol-l-yl)-ethyll-3-phenyl-3H- thienor3,2-dlpyrimidin-4-one; E1 E2[00149] E2: (2-Phenylcarbamoyl-thiophen-3-yl)-carbamic acid tert-butyl ester.; To a solution of 3-tert-butoxycarbonylamino-thiophene-2-carboxylic acid (1.5 g, 6.17 mmol) in DMF (15 mL) was added diisopropylethylamine (DIEA) (2.14 mL, 12.3 mmol), aniline (0.844 mL, 9.26 mmol), and O-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (2.68 g., 7.04 mmol) was stirred at room temperature for 3 h. The reaction mixture was then treated with H2O (30 mL). Added ethyl acetate (75 mL), followed by a solution of saturated aqueous sodium carbonate, and washed the organic layer. The organic layer was then washed again sequentially with H2O (60 mL), a solution of saturated aqueous sodium carbonate (1 x 60 mL), H2O (60 mL), IN HCl (1 x 60 mL), and H2O (60 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated to afford the product as a golden oil. LC/MS (AP-ESI, CH3CO2H 0.05%) m/z 319 (MH+). Example 7; Preparation of 3-Phenyl-2-ri-(9H-purin-6-ylamino)propyllthieno-r3,2-rflpyrimidin-4(3H)-onea.; Synthesis of tert-Butyl [2-(anilinocarbonyl)-3-thienyl]carbamate.; [00162] N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (7.648 g, 20.12 mmol) was added portion wise to a stirred solution of [A] 3-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylic acid (4.078 g, 16.76 mmol), aniline (2.29 mL, 25.1 mmol) and N,N-diisopropylethylamine (5.84 mL, 33.5 mmol) in dry N,N-dimethylformamide (40.0 mL) under nitrogen. After 90 min ethyl acetate (500ml) was added then washed with water (250ml), sat.NaηCO3 (200ml), water (300ml), 0.1N.HC1 (400ml) and brine (150ml). The organic layer was dried over MgSO4, filtered and evaporated to give a tan oil. This was chromatographed over 12Og SiO2 eluting with 1500ml 10%ethyl acetate-hexane. The product was obtained as a white solid (4.95g, 92%).

References: [1]Patent: WO2008/64018,2008,A1 .Location in patent: Page/Page column 60; 67.

12
[ 536-90-3 ]
[ 101537-64-8 ]
[ 1029280-61-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 1.5h;	Example 12; Preparation of 3-(3-Methoxyphenyl)-2-ri-(9H-purin-6-ylamino)propyllthienor3,2- dl pvr imidin-4(3H) -one; 12a. Synthesis of tert-Butyl {2-[(3-methoxyphenyl)carbamoyl]-3-thienyl}carbamate.; [00197] Following the procedure from Example Ia and using 3-[(tert- butoxycarbonyl)amino]thiophene-2-carboxylic acid (2.000 g, 8.221 mmol) and 3- methoxyaniline (1.38 mL, 12.3 mmol) the product was obtained as a white solid (2.636g, 92%).

References: [1]Patent: WO2008/64018,2008,A1 .Location in patent: Page/Page column 78.

13
[ 101537-64-8 ]
[ 106-49-0 ]
[ 1029280-50-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 1.5h;	Example 10; Preparation of 3-(4-methylphenyl)-2-[l-(9H-purin-6-ylamino)propyl1thieno[3,2- dl pyr imidin-4(3H) -one; 10a. Synthesis of tert-Butyl {2-[(4-methylphenyl)carbamoyl]-3-thienyl}carbamate.; [00183] Following the procedure from Example Ia and using 3-[(tert- butoxycarbonyl)amino]thiophene-2-carboxylic acid (2.000 g, 8.221 mmol) and p- toluidine (1.32 g, 12.3 mmol) the product was obtained as a white solid (2.61g, 95%).

References: [1]Patent: WO2008/64018,2008,A1 .Location in patent: Page/Page column 74.

14
[ 372-39-4 ]
[ 101537-64-8 ]
[ 1029280-55-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 1.5h;	Example 11; Preparation of 3-(3,5-Difluorophenyl)-2-[l-(9H-purin-6-ylamino)propyl]thieno[3,2- d] pyrimidin-4(3H)-one; 11a. Synthesis of tert-Butyl {2-[(3,5-difluorophenyl)carbamoyl]-3- thienyl}carbamate.; [00190] Following the procedure from Example Ia and using 3-[(tert- butoxycarbonyl)amino]thiophene-2-carboxylic acid (2.000 g, 8.221 mmol) and [B] 3,5-difluoroaniline (2.65g, 20.5 mmol ) for 6 days the product was obtained as a yellow solid (1.447g 49%).

References: [1]Patent: WO2008/64018,2008,A1 .Location in patent: Page/Page column 76.

Yield	Reaction Conditions	Operation in experiment
		Example 1 Synthesis of Representative Thiophene-Containing Monomers Methyl 3-aminothiophene-2-carboxylate was Boc-protected and the resulting ester was saponified to yield 3-[(tert-butoxy)carbonylamino]-2-thiophene-carboxylic acid (11). Methyl 3-hydroxythiophene-2-carboxylate (12) was prepared by cyclization of methylthioglycolate and methyl-2-chloroacrylate in methanolic sodium methoxide (Huddleston et al., Synth. Commun. 1979, 9, 731).

16
C₅₈H₆₅N₁₈O₁₁Pol [ No CAS ]
[ 101537-64-8 ]
C₆₈H₇₆N₁₉O₁₄PolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Resin (R1) was treated with 80% TFA in dichloromethane and washed thoroughly. Iv solution of (11) (36 mg, 0.148 mmol) and HBTU (28 mg, 0.079 mmol) in DMF (0.45 mL) and DIEA (0.5 mL) was mixed at 40 C. for 25 min and poured onto the deprotected resin. The resin slurry was shaken for 4 h at room temperature and filtered. After washing with DMF and dichloromethane, the resin was treated with 80% TFA in dichloromethane. The resin was filtered and washed before cleavage with Dp (1 mL) at 40 C. for 4 h. The crude product was purified by reversed-phase HPLC to afford (3) as a slightly yellow solid upon lyophilization (3.4 mg, 9.4% recovery). MALDI-TOF-MS m/z-1239.46 (1239.54 calcd for M+H).Resin (R1) was treated with 80% TFA in dichloromethane and washed thoroughly. A solution of (11) (36 mg. 0.148 mmol) and HBTU (28 mg, 0.079 mmol) in DMF (0.45 mL) and DIFA (0.5 mL) was mixed at 40 C. for 25 min and poured onto the deprotected resin. The resin slurry was shaken for 4 h at room temperature and filtered. After washing with DMF and dichloromethane, the resin was treated with 80% TFA in dichloromethane. The resin was filtered, neutralized and shaken in a solution of acetic anhydride (0.2 mL), DIEA (0.2 mL) and DMF (1.6 mL) for 30 min. The resin was then filtered and washed with DMF before cleavage with Dp (1 mL) at 40 C. for 4 h. The crude product was purified by reversed-phase HPLC to afford (4) as a pale yellow solid upon lyophilization (4.2 mg, 11.2% recovery). MALDI-TOF-MS m/z 1281.62 (1281.55 calcd for M+H).

References: [1]Patent: US2009/155202,2009,A1 .Location in patent: Page/Page column 17.

17
[ 98-16-8 ]
[ 101537-64-8 ]
[ 1208328-34-0 ]

References: [1]ChemMedChem,2010,vol. 5,p. 118 - 129.

18
[ 207923-07-7 ]
[ 101537-64-8 ]
3-tert-butyloxycarbonylamino-N-(4-ethyl-3-hydroxyphenyl)thiophen-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine; HATU; In N,N-dimethyl-formamide; for 18h;	The mixture of 5-amino-2-ethylphenol (500 mg, 3.65 mmol), N- i-butyloxycarbonyl 3-aminothiophene-2- carboxylic acid (931 mg, 3.83 mmol), (l-[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate) (1.8 g, 4.75 mmol), Et3N (2.0 mL) in dimethylformamide (20 mL) was stirred for 18 hours. The mixture was poured into water (250 mL), extracted by ethyl acetate (3x50 mL). The combined extracts were washed with brine (50 mL), dried and concentrated. The residue was purified by flash column (40g) to give i-butyloxycarbonyl protected intermediate (773 mg, 60%). LC/MS: RT = 5.78 minutes, purity > 95%, (M-100+H)+ = 262.96.

References: [1]Patent: WO2018/118791,2018,A2 .Location in patent: Paragraph 0221.

19
[ 462-08-8 ]
[ 101537-64-8 ]
3-tert-butyloxycarbonylamino-N-(pyridin-3-yl)thiophene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 18h;	A mixture of 3-i-butyloxycarbonyl amino thiophene-2-carboxylic acid (486 mg, 2.0 mmol), 3-aminopyridine(244 mg, 2.6 mmol), (1- [bis(dimethylarmno)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (1.0 g, 2.6 mmol) and diisopropylethyl amine (1.0 mL, 5.48 mmol) in dimethylformamide (10 mL) was stirred for 18 hours. The mixture was diluted with ethyl acetate (60 mL), washed by water, brine, dried and concentrated. The residue was purified by flash column (30-50% ethyl acetate /hexanes) to give the t- butyloxycarbonyl protected intermediate (500 mg, 78% yield). The product was deprotected by reacting with 4N HCl in dioxane overnight. The solvents were removed under vacuum and the residue partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, dried (magnesium sulfate), filtered and the solvent removed under vacuum to afford the amine product (264 mg, 77% yield).

References: [1]Patent: WO2018/118791,2018,A2 .Location in patent: Paragraph 0202.

20
[ 101537-64-8 ]
3-amino-N-(pyridin-3-yl)thiophene-2-carboxamide [ No CAS ]

References: [1]Patent: WO2018/118791,2018,A2 .

21
[ 101537-64-8 ]
2,3-di(pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

References: [1]Patent: WO2018/118791,2018,A2 .

22
[ 101537-64-8 ]
[ 107-14-2 ]
C₁₂H₁₄N₂O₄S [ No CAS ]

References: [1]Journal of the American Chemical Society,2020,vol. 142,p. 16518 - 16522.

23
[ 101537-64-8 ]
3-aminothiophene-2-carboxylic acid cyanomethyl ester [ No CAS ]

References: [1]Journal of the American Chemical Society,2020,vol. 142,p. 16518 - 16522.

24
[ 593-51-1 ]
[ 101537-64-8 ]
(2-methylcarbamoylthiophen-3-yl)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	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 16.1667h;	A mixture of compound 3 (1970 mg, 8.11 mmol) and methylamine hydrochloride (2737 mg, 40.55 mmol) was stirred in DMF (5 mL) at room temperature, then HATU (4625 mg, 12.17 mmol) was added, and DIEA (5231 mg) was added dropwise after stirring for 10 min. , 40.55mmol), adding a drying tube rt reaction for 16h. After completion of the reaction monitored by TLC, H2O (30 mL) was added and the reaction mixture was extracted with EtOAc (3 x 30 mL). The organic phase was dried with MgSO4, filtered and concentrated under reduced pressure, dissolved in DMSO and then recrystallized by adding water. After suction filtration and drying, the corresponding product 4 (2.162g) was obtained as a white solid, melting point: 108C, yield 96%.

References: [1]Patent: CN114213400,2022,A .Location in patent: Paragraph 0058-0062.

25
[ 101537-64-8 ]
C₁₀H₈Cl₂N₄OS [ No CAS ]