[ CAS No. 27757-85-3 ]

Name: 27757-85-3|2-Thiophenemethylamine|97%
Brand: Ambeed
SKU: A174883
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Quality Control of [ 27757-85-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 27757-85-3 ]

SDS Specification

Alternatived Products of [ 27757-85-3 ]

Product Details of [ 27757-85-3 ]

CAS No. :	27757-85-3	MDL No. :	MFCD00005460
Formula :	C₅H₇NS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FKKJJPMGAWGYPN-UHFFFAOYSA-N
M.W :	113.18	Pubchem ID :	34005
Synonyms :

Calculated chemistry of [ 27757-85-3 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.2
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	31.99
TPSA :	54.26 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.4
Log Po/w (XLOGP3) :	0.61
Log Po/w (WLOGP) :	1.05
Log Po/w (MLOGP) :	0.46
Log Po/w (SILICOS-IT) :	2.18
Consensus Log Po/w :	1.14

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.39
Solubility :	4.63 mg/ml ; 0.0409 mol/l
Class :	Very soluble
Log S (Ali) :	-1.32
Solubility :	5.37 mg/ml ; 0.0475 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.65
Solubility :	2.52 mg/ml ; 0.0222 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.61

Safety of [ 27757-85-3 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P264-P271-P280-P301+P330+P331-P304+P340-P305+P351+P338-P310-P363-P370+P378-P403+P233-P501	UN#:	2735
Hazard Statements:	H227-H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 27757-85-3 ]

* 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.

Upstream synthesis route of [ 27757-85-3 ]
Downstream synthetic route of [ 27757-85-3 ]

[ 27757-85-3 ] Synthesis Path-Upstream 1~6

1
[ 27757-85-3 ]
[ 58255-18-8 ]

Reference： [1] Patent: CN103664930, 2016, B,
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 16, p. 3507 - 3518

2
[ 27757-85-3 ]
[ 67-56-1 ]
[ 58255-18-8 ]
[ 26019-17-0 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 21, p. 6166 - 6170[2] Angew. Chem., 2018, vol. 130, p. 6274 - 6278,5

3
[ 909394-40-7 ]
[ 27757-85-3 ]
[ 45644-21-1 ]

Reference： [1] Monatshefte fur Chemie, 2006, vol. 137, # 3, p. 285 - 299

4
[ 27757-85-3 ]
[ 214759-22-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3471 - 3488
[2] Patent: WO2015/61426, 2015, A1,
[3] Patent: TW2018/28950, 2018, A,

5
[ 27757-85-3 ]
[ 548772-41-4 ]

Reference： [1] Synthesis, 2003, # 3, p. 403 - 407

6
[ 27757-85-3 ]
[ 1001414-56-7 ]

Reference： [1] Patent: WO2008/5457, 2008, A2,

[ 27757-85-3 ] Synthesis Path-Downstream 1~68

1
[ 27757-85-3 ]
[ 98-88-4 ]
[ 4595-96-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With dmap; In dichloromethane; at 20℃; for 0.166667h;Flow reactor;	General procedure: Prior to initiating the run, the position of the needle on the autosampler was manually adjusted (with the power to the stepper motor drivers off) so that it was just above the waste position vial. The system (see Fig.2 for a schematic) was primed with dichloromethane and aqueous phosphoric acid by pumping through for around 30 min. Valves were switched to ensure complete filling of the system. The syringe in Syringe Pump 2 was primed by manually taking in the benzoyl chloride solution. The control script was activated with the 2-Way Valve (aqueous out) in the closed position. Once the system appeared to be operating normally, the reaction sequence was initiated by pressing the appropriate key on the keyboard. When all products had been collected, (approximately 10 h), the products were isolated by removing the solvent under reduced pressure. The main control script and the script running on the Raspberry Pi are provided in the Supporting Information section.

Reference： [1]Tetrahedron,2018,vol. 74,p. 3152 - 3157
[2]Journal of the American Chemical Society,1948,vol. 70,p. 1146,4013

2
[ 27757-85-3 ]
[ 607-68-1 ]
2-chloro-N-(thiophen-2-ylmethyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.3%	With triethylamine; In tetrahydrofuran; at 20℃;	General procedure: Compounds were prepared according to methods describedby us [23] and others [17, 26]. A solution of 2,4-dichloroquinazoline 1.0 equiv in THF, alkylamine 1.0 equivand triethylamine 1.2 equiv were added. The reaction proceeded at room temperature until the reaction was finished as observed by TLC. The mixture was concentrated in vacuo,redissolved in ethyl acetate and washed with saturated Na-HCO3 and extract. The organic layer was collected, dried by anhydrous Na2SO4, filtered, and dried under reduced pressure to give the compound as a solid.
	With triethylamine; In tetrahydrofuran; at 20℃;	General procedure: A solution of 2,4-dichloroquinazoline (1.0 equiv.) in THF, triethylamine (1.2 equiv.) and alkylamine (1.2 equiv.) were added. The reaction stirred at room temperature until cannot see reactant spots on TLC. The solvent was removed by evaporated under reduced pressure, dissolved in ethyl acetate and washed with saturated sodium chloride and extracted. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and dried under vacuum to give the compound as a solid

Reference： [1]Medicinal Chemistry,2019,vol. 15,p. 691 - 702
[2]Journal of Medicinal Chemistry,1995,vol. 38,p. 3547 - 3557
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 8099 - 8110
[4]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 267 - 270

3
[ 27757-85-3 ]
[ 32111-21-0 ]
pyrazin-2-ylthien-2-ylmethylamine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 8742 - 8743

4
[ 27757-85-3 ]
[ 1001413-01-9 ]
1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (thiophen-2-ylmethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Thiophene-2-methanamine (0.562 g, 0.00496 mol; Acros) and l-(3,4-difluoro-benzyl)- 2-oxo-l,2-dihydro-pytauidine-3-carboxylic acid (1.32 g, 0.00496 mol) and N,N,N,N'-tetramethyl- O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (2.08 g, 0.00546 mol; Applied Biosystems) was dissolved in N,N-dimethylformamide (15.0 mL, Acros). To this was added N,N-diisopropylethylamine (4.32 mL, 0.0248 mol; Acros) and the reaction was stirred overnight at room temperature. The reaction was evaporated to dryness, then partitioned between 5% citric acid, ethyl acetate. The organic layer was washed with saturated sodium chloride, dried with sodium sulfate, filtered and concentrated. The residue was purified on preparative HPLC. Appropriate fractions were combined and evaporated to give the product in 1.04 g yield. MS m/z= 361.06 M+H.

Reference： [1]Patent: WO2008/5457,2008,A2 .Location in patent: Page/Page column 113

5
[ 27757-85-3 ]
[ 24424-99-5 ]
[ 401485-19-6 ]

Yield	Reaction Conditions	Operation in experiment
99.1%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 3h;	Thiophene-2-methylamine (1.4g, 12.36mmol) and sodium bicarbonate (1.04g, 12.36mmol) were dissolved in anhydrous THF (20mL) then slowly added Boc2O (2.76g, 13.6mmol). This was reacted at room temperature for 3h. Spin-dry the solvent under reduced pressure then added ethyl acetate. The organic phase was collected product was purified by column chromatography to give 2.61g (99.1%).
99%	With 3a,6a-diphenylglycoluril; In ethanol; at 25 - 30℃; for 0.5h;	General procedure: In a 25 mL of round bottom flask, a solution of di-tert-butyldicarbonate (1 mmol) and Diphenyglycouril (10 mol %) were addedin 10 mL of ethanol. A turbid solutionwas obtained. In that solution1 mmol of Amine (1a-y) was added. Reaction mixture was stirredfor 30 min at room temperature. After total consumption of thestarting material (determination by TLC), the solvent was removedin vacuo, and the residue was isolated by column chromatographyon silica gel to get the pure product 3a-y as solid or oil.
96%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 2h;	To a solution of thiephen-2-ylmethanamine (5 g, 44.18 mmol) in THF (20 ml), was added NaHCO3 (3.712 g, 44.18 mmol) and (Boc)2O (10.12 g, 46.38 mmol) slowly. The resulted mixture was stirred at room temperature for two hours. After TLC showed the starting material was disappeared. The reaction was filtrate through a 3.0 g of silica and concentrated to give 9.03 g of product, yield: 96%.

92%	With triethylamine; In dichloromethane; at 0 - 20℃; for 24h;	Intermediate 20: tert-Butyl thiophen-2-ylmethylcarbamateTo a solution of thiophen-2-ylmethanamine (4.73 g, 41.8 mmol) in dichloromethane (50 mL) was added di-ferf-butyl dicarbonate (9.12 g, 41.8 mmol) and triethylamine (5.54 mL, 39.7 mmol) at 0C. The mixture was stirred at ambient temperature for 24 h, washed with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide the title compound (8.2 g, 92% yield). 1H NMR (400 MHz, CDCI3) delta ppm 7.21 (d, J=6.0 Hz, 1 H), 6.85 - 7.01 (m, 2 H), 4.89 (br. s. , 1 H), 4.48 (d, J=5.5 Hz, 2H), 1.46 (s, 9 H). MS m/z 158.0 (M-100 (M-Boc)), retention time = 1 .41 min.
76%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 3h;	A mixture of 2-(aminomethyl)thiophene (1 mL, 10 mmol), di-tert-butyl dicarbonate (2.5 mL, 1 1 mmol), and NaHC03(840 mg, 10 mmol) in THF (13 mL) was stirred at room temperature for 3 h to give a suspension containing pale yellow solids. The mixture was concentrated under reduced pressure, and the residue was extracted with CH2C12and H20. The organic phase was dried over MgSO4, filtered, and purified by flash chromatography on a silica gel column with elution of EtOAc hexane (1 :20) to give tert-butyl (thien-2-yl)methyl carbamate (CioHi5NO2S, 1.62 g, 76% yield).
76%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 3h;	a mixture of THF containing 2-(aminomethyl)thiophene (1 mL, 10 mmol), di-tert-butyl butyl carbonate (2.5 mL, 11 mmol) and NaHC03 (840 mg, 10 mmol) The mixture was stirred at room temperature for 3 hours to obtain a suspension containing a pale yellow solid. The mixture was concentrated under reduced pressure.The residue was extracted with CH 2 Cl 2 and H 2 O. The organic phase was dried over MgSO4, filtered, and purified by flash chromatography eluting with EtOAc/hexane (1:20) Methylcarbamate (C10H15N02S, 1.62 g, 76% yield).
	In dichloromethane; at 20℃;	To a solution of di-tert-butyl dicarbonate (2.1 g, 9.7 mmol) in dichloromethane (10 ml) was added 2-thiophenemethylamine (1.0 mL, 9.7 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in N,N-dimethylformamide (10 ml). N-Bromosuccinimide (1.8 g, 10 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed twice with water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to give the title compound (2.9 g, 9.7 mmoL, 100%).
	With potassium carbonate; In methanol; water; at 20℃;	The flask was charged with 20 mmol of 3,30 mL of methanol,60 mmol K2CO3, 10 mL water,Mmol Boc2O, and the reaction mixture was stirred overnight at room temperature. TLC detection reaction was complete, ethyl acetate extraction reversedShould be liquid. The organic phase was separated and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, filteredThe residue was purified by column chromatography to give 4 as a white solid.
	at 20℃;	2-Thiophenecarbonitrile (150 mmol, 1.0 eq) was dissolved in THF (800 mL). Lithium aluminum hydride (330 mmol, 2.2 eq) was slowly added at 0 C, and the mixture was warmed to room temperature and reacted for 1 h. After cooling to 0 C, the reaction was quenched with water (20 mL), followed by 15% NaOH (40 mL) and water (60 mL) again. The solids were filtered out, and di-tert-butyl dicarbonate (180 mmol, 1.2 eq) was directly added to the filtrate. The mixture was stirred for 1 h, washed with brine (500 mL 2), dried with anhydrous Na2SO4, and filtered. Removal of the solvent produced a light-yellow oil (2a). The obtained 2a was dissolved in DMF (100 mL). NCS/NBS (180 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to produce 2b/2c.

Reference： [1]Patent: CN105524058,2016,A .Location in patent: Paragraph 0363; 0364; 0365; 0366; 0367
[2]Tetrahedron,2020,vol. 76
[3]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 295 - 299
[4]Patent: WO2008/5457,2008,A2 .Location in patent: Page/Page column 185
[5]Chemistry - A European Journal,2014,vol. 20,p. 3800 - 3805
[6]Patent: WO2013/12723,2013,A1 .Location in patent: Page/Page column 49
[7]Journal of Polymer Science, Part A: Polymer Chemistry,2011,vol. 49,p. 4861 - 4874
[8]Patent: WO2015/61426,2015,A1 .Location in patent: Page/Page column 15; 16
[9]Patent: TW2018/28950,2018,A .Location in patent: Paragraph 0040; 0059
[10]European Journal of Organic Chemistry,2010,p. 4412 - 4425
[11]Chemical Communications,2009,p. 3705 - 3707
[12]Patent: US2014/329796,2014,A1 .Location in patent: Paragraph 0318
[13]Patent: CN103664930,2016,B .Location in patent: Paragraph 0037; 0038
[14]Letters in drug design and discovery,2018,vol. 16,p. 102 - 110

6
[ 27757-85-3 ]
[ 16761-18-5 ]
2-chloro-4-(thien-2-ylmethylaminosulphonyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of N-acyl-2-chloro-4-chlorosulphonylaniline (320 mg, 1.2 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol), pyridine (0.1 ml, 1.2 mmol) and 2-thiophenemethylamine (120 mg, 1.08 mmol) in DCM (8 ml) was stirred at ambient temperature for 18 h. The mixture was washed with 1M aqueous hydrochloric acid and then the organic phase was concentrated. The residue was dissolved in ethanol (7 ml), 2M aqueous sodium hydroxide (2 ml) was added and the mixture was heated at 60 C. for 6 h. The solvent was evaporated and the residue dissolved in EtOAc, washed with water, and the solvent phase was concentrated to yield the title compound which was used, without further purification.

Reference： [1]Patent: US6667342,2003,B1 .Location in patent: Page column 70

7
[ 27757-85-3 ]
[ 877173-84-7 ]
[ 924902-39-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80℃; for 16.0h;	To a solution of 3-bromo-7-chloropyrazolo[1 ,5-a]pyrimidine (9.63 g, 41.5 mmol) and diisopropylethylamine (10.9 ml_, 62.3 mmol) in 2-propanol (42 ml_) was added 2- EPO <DP n="47"/>(aminomethyl)thiophene (5.6 g, 49.8 mmol): After heating for 16 h at 80 0C, the reaction mixture was concentrated and the residue partitioned between dichloromethane and water. After separation, the organic phase was washed with 10% citric acid and brine, dried and concentrated to yield the desired 3-bromo-7-(2- thiophenemethylamino)pyrazolo[1 ,5-a]pyrimidine (11.49 g, 92%) as a brown solid. HPLC 99%; 1H NMR (250 MHz, CDCI3) delta 8.88 (t, J = 6.4 Hz, 1H), 8.25 (s, 1H), 8.18 (d, J = 5.3 Hz, 1 H), 7.38 (dd, J = 1.3, 5.1 Hz, 1H), 7.13 (dd, J = 1.3, 3.4 Hz, 1H), 6.95 (dd, J = 3.4, 5.1 Hz, 1H), 6.29 (d, J = 5.3 Hz, 1H), 4.80 (d, J = 6.4 Hz, 2H); 13C NMR (62.9 MHz, CDCI3) delta 150.5, 146.7, 145.5, 143.1, 140.8, 126.8, 126.2, 125.4, 86.5, 81.0, 40.0; MS (APCI) 311/309 [M+H]+.

Reference： [1]Patent: WO2007/17678,2007,A1 .Location in patent: Page/Page column 45-46

8
[ 27757-85-3 ]
[ 83217-48-5 ]
[ 1018480-91-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.416667h;Microwave irradiation; Sealed tube;	General procedure: General procedure B (fast microwave method) (GP2). The appropriate 4-halo-2-(4-(methylsulfonyl)phenyl)-pyrimidine (1 mmol), and corresponding amine (0.2-1 mmol), Cs2CO3 (30 mmol %), and DMF(1.00 mL) were added to a 10-mL microwave vial (Discover; CEM, NC) containing a stirrer bar.The sealed vial was irradiated (100W) at 160 C for 25 min. The vial contents were extracted with water(10 mL) and EtOAc (10 mL 3), and then washed with aq. NaHCO3 (0.1 M; 10 mL). The combinedorganic layers were dried (silica gel) and the product isolated with flash chromatography (generalmethod A; 20-80% ethyl acetate in hexane). If needed, compounds were further purified to >95% puritywith reversed phase HPLC (general method B) on an XBridge C18 column using a gradient mobilephase composed of aq. ammonium hydroxide (0.25 mM) (C) and acetonitrile (D), starting at 20% Drising linearly to 95% D at 60 min.

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 2183 - 2199
[2]Molecules,2018,vol. 23

9
[ 4795-29-3 ]
[ 7154-73-6 ]
[ 2038-03-1 ]
[ 4572-03-6 ]
[ 27757-85-3 ]
[ 109-12-6 ]
[ 3731-53-1 ]
[ 107-10-8 ]
[ 7663-77-6 ]
[ 6628-04-2 ]
[ 2620-50-0 ]
polystyrene carboxaldehyde resin [ No CAS ]
[ 5071-96-5 ]
[ 617-89-0 ]
[ 28466-26-4 ]
[ 42185-03-5 ]
[ 453-71-4 ]
[ 19293-58-4 ]
[ 75-04-7 ]
[ 62-53-3 ]
[ 1003-03-8 ]
[ 51387-90-7 ]
[ 74-89-5 ]
[ 100-46-9 ]
[ 4152-90-3 ]
[ 68-41-7 ]
C₉H₈FN₂O₃Pol [ No CAS ]
C₁₀H₁₀FN₂O₃Pol [ No CAS ]
C₁₁H₁₂FN₂O₃Pol [ No CAS ]
C₁₄H₁₀FN₂O₃Pol [ No CAS ]
C₁₁H₈FN₄O₃Pol [ No CAS ]
C₁₂H₈FN₄O₃Pol [ No CAS ]
C₁₃H₁₀FN₂O₄Pol [ No CAS ]
C₁₅H₁₂FN₂O₃Pol [ No CAS ]
C₁₄H₁₁FN₃O₃Pol [ No CAS ]
C₁₃H₁₄FN₂O₃Pol [ No CAS ]
C₁₃H₁₀FN₂O₃PolS [ No CAS ]
C₁₃H₁₆FN₂O₄Pol [ No CAS ]
C₁₃H₁₄FN₂O₄Pol [ No CAS ]
C₁₆H₁₄FN₂O₄Pol [ No CAS ]
C₁₁H₉FN₃O₅Pol [ No CAS ]
C₁₅H₁₁ClFN₂O₃Pol [ No CAS ]
C₁₇H₁₇FN₃O₃Pol [ No CAS ]
C₁₄H₁₇FN₃O₃Pol [ No CAS ]
C₁₄H₁₇FN₃O₄Pol [ No CAS ]
C₁₅H₁₉FN₃O₃Pol [ No CAS ]
C₁₆H₁₂FN₂O₅Pol [ No CAS ]
C₁₈H₁₃FN₃O₃Pol [ No CAS ]
C₁₅H₁₇FN₃O₄Pol [ No CAS ]
C₁₆H₂₂FN₄O₃Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A library of compounds in which R4 was various groups having the formula [CONHR »] was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows: [72] Aldehyde resin was mixed with a primary amine (R17-NH2) in [DICHLOROETHANE] (DCE), triethylorthoformate (TEOF), and DMF (containing [1%] acetic acid) in a 1: 1: 1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq. ) dissolved in DMF was added (Abdel-Magid, A. F. , et al., Tetrahedron Lett, 3 1: 5595-5598 (1990) ). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL), [MEOH] [(3 X 5] mL), DMF [(3 X 5] mL), [MEOH] [(3 X 5] mL), and [CH2CL2] [(3 X 5] mL). The resin was washed twice with 5 mL DMF containing [1%] Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq. ) and diisopropylcarbodiimide (DIC, 5 eq. ) in 2: 1 DMF : DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL) and [CH2C12] (3 x 5 mL). [73] The resin was shaken with a primary amine [(R2-NH2)] in DMF for 8 hrs, filtered, and washed with DMF (6 x 5 mL), [MEOH] [(3 X 5] mL), and CH2C12 (3 x 5 mL). The aryl nitro group was reduced by the addition of tin (II) chloride dihydrate (20 eq. , >2 M) and N-methyl morpholine (NMM, 20 eq. ) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3 x 5 mL), [MEOH] (3 x 5 mL), and [CH2CI2 (3 X 5] mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq. ) overnight, filtered, and washed with CH2Cl2 (3 x 5 mL), [MEOH] (3 x 5 mL), and CH2CI2 (3 x 5 mL). To produce a free amine, the resin was shaken for 30 min. in CHCl2 with the addition of sodium methoxide in methanol, filtered, and washed with CH2Cl2 [(4 X 5] mL). [[74]] In the final diversification step, the resin was heated at 500 C in DMF with a mono- substituted epoxide [[RLCH (-CH2O-)].] After shaking for 2 to 4 days the resin was filtered and washed with DMF (5 x 5 mL), [MEOH] [(3 X 5] mL), and CH2Cl2 (3 x 5 mL). T he resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA: [CH2C12] (2: 3) for 1 hour at room temperature.

Reference： [1]Patent: WO2003/105779,2003,A2 .Location in patent: Page 26

10
[ 27757-85-3 ]
[ 38521-46-9 ]
[ 1132803-89-4 ]

Yield	Reaction Conditions	Operation in experiment
24%	With phosphorus trichloride; In chlorobenzene; at 145℃; for 3h;	Synthesis of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide (precursor V1); A suspension of 8.0 g (51.5 mmol) of 2-mercaptonicotinic acid, 5.8 g (51.5 mmol) of 2-(aminomethyl)-thiophene and 3.5 g (25.8 mmol) of phosphorus trichloride in chlorobenzene (260 ml) was heated for 3 h under reflux (145 C.). When the reaction solution had cooled to 60 C., filtration with suction was carried out at that temperature. The solid obtained was taken up in a DCM/MeOH mixture (3:1, vv, 300 ml) and washed with water (2×50 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Crystallization of the residue from ethyl acetate yielded 3.1 g (12.4 mmol, 24%) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide.1H NMR (400 MHz, DMSO-d6) d ppm 4.73 (d, J=5.52 Hz, 2H) 6.97 (dd, J=5.02, 3.51 Hz, 1H) 7.01-7.11 (m, 2H) 7.41 (dd, J=5.27, 1.25 Hz, 1H) 7.98 (td, J=6.27, 2.01 Hz, 1H) 8.54 (dd, J=7.53, 2.01 Hz, 1H) 11.28 (t, J=5.52 Hz, 1H) 14.06 (br.s., 1H)

Reference： [1]Patent: US2009/76086,2009,A1 .Location in patent: Page/Page column 9

11
[ 27757-85-3 ]
[ 30529-70-5 ]
[ 1134169-31-5 ]

Yield	Reaction Conditions	Operation in experiment
63%		Synthesis of 2-chloro-6-methyl-N-(thiophen-2-ylmethyl)nicotinamide (precursor V4); 2.67 g (7.0 mmol) of HATU and 4.0 ml (23.2 mmol) of DIPEA were added at 0 C. to a solution of 1.0 g (5.8 mmol) of 2-chloro-6-methyl-nicotinic acid in DMF (20 ml), and the mixture was stirred for 20 min at 0 C. At that temperature, 656 mg (5.8 mmol) of thiophen-2-ylmethylamine were added. Stirring was then carried out for 16 h at RT. The mixture was then diluted with EA and washed in succession with sat. aq. NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 4:1) of the residue yielded 966 mg (3.6 mmol, 63%) of 2-chloro-6-methyl-N-(thiophen-2-ylmethyl)nicotinamide.

Reference： [1]Patent: US2009/76086,2009,A1 .Location in patent: Page/Page column 10

12
[ 27757-85-3 ]
[ 383132-31-8 ]
[ 1121056-60-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20.0℃; for 0.5h;	A mixture of <strong>[383132-31-8]5-bromo-7-chloroindole-2-carboxylic acid</strong> (1.02 g, 3.71 mmol), 2- thiophenemethylamine (418.5 muL, 4.08 mmol), N, N-di-isopropylethylamine (1.94 mL, 11.12 mmol), and PyBroP (1.90 g, 4.08 mmol) was stirred in DMF (15 mL) at room temperature for 30 min. The mixture was diluted with EtOAc (150 mL) and washed successively with 2N HCl (2 x 50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic phase was dried (MgSO4), and filtered through a small pad of silica gel. Concentration of the solvent gave 5-bromo-7-chloro-lH-indole-2-carboxylic acid (thiophen-2-ylmethyl)-amide (1.50 g) as a white solid which was used for the next step without further purification. 1H NMR (d6-DMSO, 300 MHz) delta 4.67 (d, 2H, J - 5.9 Hz), 6.97 (dd, IH, J = 3.5, 5 Hz), 7.06 (dd, IH, J = 1.2, 3.5 Hz), 7.19 (s, IH), 7.41 (dd, IH, J = 1.2, 5 Hz), 7.46 (d, IH, J = 1.5 Hz), 7.86 (d, IH, J = 1.5 Hz), 9.21 (t, IH, J = 5.9 Hz), 1 1.98 (s, IH); MS (ESI) m/z = 368.9, 370.9 (MH+).

Reference： [1]Patent: WO2009/23179,2009,A2 .Location in patent: Page/Page column 183

13
[ 27757-85-3 ]
[ 20028-68-6 ]
C₁₃H₉Cl₂N₃S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7855 - 7865

14
[ 1003-31-2 ]
[ 27757-85-3 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃;	General procedure: 2-Thiophenecarbonitrile (150 mmol, 1.0 eq) was dissolved in THF (800 mL). Lithium aluminum hydride (330 mmol, 2.2 eq) was slowly added at 0 C, and the mixture was warmed to room temperature and reacted for 1 h. After cooling to 0 C, the reaction was quenched with water (20 mL), followed by 15% NaOH (40 mL) and water (60 mL) again. The solids were filtered out, and di-tert-butyl dicarbonate (180 mmol, 1.2 eq) was directly added to the filtrate. The mixture was stirred for 1 h, washed with brine (500 mL 2), dried with anhydrous Na2SO4, and filtered. Removal of the solvent produced a light-yellow oil (2a). The obtained 2a was dissolved in DMF (100 mL). NCS/NBS (180 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to produce 2b/2c.

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 4991 - 5002
[2]Chemical Communications,2009,p. 3705 - 3707
[3]European Journal of Organic Chemistry,2015,vol. 2015,p. 5944 - 5948
[4]Catalysis science and technology,2016,vol. 6,p. 4768 - 4772
[5]ChemCatChem,2016,vol. 8,p. 1329 - 1334
[6]ChemMedChem,2017,vol. 12,p. 319 - 326
[7]Organic Letters,2018,vol. 20,p. 7212 - 7215
[8]Letters in drug design and discovery,2018,vol. 16,p. 102 - 110
[9]Advanced Synthesis and Catalysis,2019,vol. 361,p. 5412 - 5420

15
[ 27757-85-3 ]
[ 38267-96-8 ]
[ 1225440-72-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	[0085] Procedure for the preparation of 6-bromo-N-(thiophen-2-ylmethyl)quinazolin- 4-amine: To a solution of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (0.3 g, 1.23 mmol) in DMF (8 mL)were added thiophen-2-ylmethanamine (0.139 g, 1.23 mmol) and Hunig's base (0.21 mL, 1.23 mmol). The reaction mixture was stirred at room temperature for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (100 mL) and washed with 10% KHS04 (25 mL) and three times with 3N LiCl (3 x 30 mL). The organic layer was extracted, dried on MgS04, filtered, and concentrated in vacuo. The residue was purified directly on silica column. Gradient elution with ethyl acetate (15?75%) in hexanes provided the title compound as a colorless solid: yield (0.39 g, 1.22 mmol, 99 %).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6700 - 6705
[2]Patent: WO2011/41655,2011,A1 .Location in patent: Page/Page column 25
[3]Journal of Agricultural and Food Chemistry,2019,vol. 67,p. 11005 - 11017

16
[ 27757-85-3 ]
[ 73776-25-7 ]
[ 1242554-79-5 ]

Yield	Reaction Conditions	Operation in experiment
48%		Synthesis of Intermediate VVV01: 2-Chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide; A solution of 2.1 g (10.0 mmol) <strong>[73776-25-7]2-chloroquinoline-3-carboxylic acid</strong> in thionyl chloride (60 ml) was heated for 2 h at 85 C. Then excess thionyl chloride was removed under vacuum. The residue was taken up with DCM (60 ml) and the solution was cooled to 0 C. and then mixed with 4.0 ml (30.0 mmol) NEt3 and 1.03 ml (10.0 mmol) thiophene-2-methylamine. After stirring for 90 min at RT it was diluted with EE and washed with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EE. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) with the residue yielded 1.44 g (4.8 mmol, 48%) 2-chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide.

Reference： [1]Patent: US2010/234372,2010,A1 .Location in patent: Page/Page column 17

17
[ 27757-85-3 ]
[ 3930-83-4 ]
[ 26059-85-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 8h;	General procedure: To a 10 mL reaction tube were added MCM-41-L-Proline-CuBr(135 mg, 0.1 mmol), 2-halobenzamide 1 (1.0 mmol), benzylamine derivative 2 (2.0 mmol), K2CO3 (3.0 mmol), and DMSO (3 mL). The reaction mixture was stirred at 110 or 120 C under air for 6-12 h.After being cooled to room temperature, the reaction mixture was diluted with 20 mL of EtOAc, and filtered. The MCM-41-L-Proline-CuBr complex was washed with distilled water (2 5 mL) and ethanol (2 5 mL), and reused in the next run. The filtrate was washed with water (2 10 mL) and dried over MgSO4. After being concentrated in vacuo, the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 3:1 to 2:1)to afford the target product 3.

Reference： [1]Journal of Organometallic Chemistry,2019,vol. 897,p. 161 - 169
[2]Organic Letters,2011,vol. 13,p. 1274 - 1277

18
[ 27757-85-3 ]
[ 131002-03-4 ]
[ 1269219-57-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 10h;	General procedure: To a 10 mL reaction tube were added MCM-41-L-Proline-CuBr(135 mg, 0.1 mmol), 2-halobenzamide 1 (1.0 mmol), benzylamine derivative 2 (2.0 mmol), K2CO3 (3.0 mmol), and DMSO (3 mL). The reaction mixture was stirred at 110 or 120 C under air for 6-12 h.After being cooled to room temperature, the reaction mixture was diluted with 20 mL of EtOAc, and filtered. The MCM-41-L-Proline-CuBr complex was washed with distilled water (2 5 mL) and ethanol (2 5 mL), and reused in the next run. The filtrate was washed with water (2 10 mL) and dried over MgSO4. After being concentrated in vacuo, the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 3:1 to 2:1)to afford the target product 3.

Reference： [1]Journal of Organometallic Chemistry,2019,vol. 897,p. 161 - 169
[2]Organic Letters,2011,vol. 13,p. 1274 - 1277

19
[ 27757-85-3 ]
[ 131002-02-3 ]
[ 167994-99-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 10h;	General procedure: To a 10 mL reaction tube were added MCM-41-L-Proline-CuBr(135 mg, 0.1 mmol), 2-halobenzamide 1 (1.0 mmol), benzylamine derivative 2 (2.0 mmol), K2CO3 (3.0 mmol), and DMSO (3 mL). The reaction mixture was stirred at 110 or 120 C under air for 6-12 h.After being cooled to room temperature, the reaction mixture was diluted with 20 mL of EtOAc, and filtered. The MCM-41-L-Proline-CuBr complex was washed with distilled water (2 5 mL) and ethanol (2 5 mL), and reused in the next run. The filtrate was washed with water (2 10 mL) and dried over MgSO4. After being concentrated in vacuo, the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 3:1 to 2:1)to afford the target product 3.

Reference： [1]Journal of Organometallic Chemistry,2019,vol. 897,p. 161 - 169
[2]Organic Letters,2011,vol. 13,p. 1274 - 1277

20
[ 27757-85-3 ]
[ 99848-43-8 ]
[ 219773-58-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 12h;	General procedure: To a 10 mL reaction tube were added MCM-41-L-Proline-CuBr(135 mg, 0.1 mmol), 2-halobenzamide 1 (1.0 mmol), benzylamine derivative 2 (2.0 mmol), K2CO3 (3.0 mmol), and DMSO (3 mL). The reaction mixture was stirred at 110 or 120 C under air for 6-12 h.After being cooled to room temperature, the reaction mixture was diluted with 20 mL of EtOAc, and filtered. The MCM-41-L-Proline-CuBr complex was washed with distilled water (2 5 mL) and ethanol (2 5 mL), and reused in the next run. The filtrate was washed with water (2 10 mL) and dried over MgSO4. After being concentrated in vacuo, the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 3:1 to 2:1)to afford the target product 3.

Reference： [1]Journal of Organometallic Chemistry,2019,vol. 897,p. 161 - 169
[2]Organic Letters,2011,vol. 13,p. 1274 - 1277

21
[ 1003-31-2 ]
[ 98-03-3 ]
[ 27757-85-3 ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: Solutions of nitrile dissolved in Toluene (5 mL) and DIBAL (1 M) in Toluene were pumped at the appropriate flow rate and mixed in a 0.85 mL Microreactor Explorer Kit chip reactor. For longer residence times extra 20 ml tubing was added at the end of the reactor. The solution at the microreactor outlet was poured into a 1% Sodium Tartrate solution at 0 C. The crude solution was extracted with EtOAc. The extracts were dried over MgSO4, filtered and evaporated to yield the desired product. All products obtained and discussed in this work have been previously reported and characterized.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6058 - 6060

22
[ 27757-85-3 ]
[ 22884-10-2 ]
[ 931-53-3 ]
[ 529-20-4 ]
[ 1355324-07-0 ]

Yield	Reaction Conditions	Operation in experiment
64%		Step A: Compound 204. A mixture of 2-methyl-benzaldehyde (193 mg, 1.61 mmol) and thiophen-2-yl-methylamine (182 mg, 1.61 mmol) in MeOH (4 ml) was stirred at RT for 30 minutes. Imidazol-l-yl-acetic acid (202 mg, 1.61 mmol) was added and the reaction mixture stirred for 10 minutes. Cyclohexyl isocyanide (176 mg, 1.61 mmol) was then added and the reaction mixture was stirred at RT overnight. The precipitate was filtered and washed with MeOH to afford the desired product (463 mg, 64% yield). 1H NMR (300 MHz, DMSO-d6): delta 8.15-8.01 (m, 1H), 7.62-7.52 (m, 1H), 7.31-6.69 (m, 9H), 6.24 (s, 1H), 5.65-4.66 (m, 4H), 2.60 (m, 1H), 2.20-2.05 (m, 3H), 1.76-1.51 (m, 5H), 1.29-0.83 (m, 5H); MS: 451.2 (M+l)+.

Reference： [1]Patent: WO2012/9678,2012,A1 .Location in patent: Page/Page column 91

23
[ 27757-85-3 ]
[ 22884-10-2 ]
[ 931-53-3 ]
[ 529-20-4 ]
C₂₅H₃₀N₄O₂S*(x)ClH [ No CAS ]

Reference： [1]Patent: WO2012/9678,2012,A1

24
[ 27757-85-3 ]
[ 5813-89-8 ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 7150 - 7158
[2]Chemistry Letters,2012,vol. 41,p. 633 - 635
[3]Synlett,2012,vol. 23,p. 801 - 804
[4]Chemistry - A European Journal,2018,vol. 24,p. 1067 - 1071
[5]Green Chemistry,2019,vol. 21,p. 962 - 967
[6]Journal of Organic Chemistry,2017,vol. 82,p. 13632 - 13642
[7]Chemical Communications,2012,vol. 48,p. 2642 - 2644
[8]ChemCatChem,2019,vol. 11,p. 401 - 406

25
[ 27757-85-3 ]
[ 103-82-2 ]
[ 99329-49-4 ]

Reference： [1]Synlett,2012,vol. 23,p. 2201 - 2204
[2]Applied Organometallic Chemistry,2019,vol. 33
[3]Chemistry - A European Journal,2012,vol. 18,p. 3822 - 3826
[4]ACS Catalysis,2015,vol. 5,p. 3271 - 3277
[5]Applied Organometallic Chemistry,2020,vol. 34

26
[ 27757-85-3 ]
[ 70593-57-6 ]
[ 1227486-75-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 18h;	A solution of <strong>[70593-57-6]4,6-dichloronicotinamide</strong> (123 mg, 0.643 mmol), thiophen-2-ylmethanamine (0.065 mL, 0.634 mmol) and DIPEA (0.230 mL, 1.32 mmol) in NMP (4 mL) was stirred at 90 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo to give 6-chloro-4-(thiophen-2-ylmethylamino)nicotinamide as a solid (168 mg).

Reference： [1]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 78

27
[ 27757-85-3 ]
[ 1386399-17-2 ]
[ 1386399-31-0 ]

Yield	Reaction Conditions	Operation in experiment
64.2%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	Example 54; (2-Morpholin-4-yl-ethyl)-(3 - { 3 - [(thiophen-2-ylmethyl)-amino] -phenyl } - 1 H-pyrazolo [3 ,4- d]pyrimidin-6-yl)-amine; Step A; (2-Morpholin-4-yl-ethyl)-[3-{ 3-[(thiophen-2-ylmethyl)-amino]-phenyltrimethylsilanyl-ethoxymethyl)- lH-pyrazolo[3,4-d]pyrimidin-6-yl]-amine; To a stirred solution of [3-(3-bromo-phenyl)- l-(2-trimethylsilanyl-ethoxymethyl)-lH- pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 40 supra) (250 mg, 0.468 mmol), thiophen-2-yl-methylamine (80 mg, 0.70 mmol), DavePhos (30 mg, 0.076 mmol) and i-BuONa (70 mg, 0.73 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (42 mg, 0.073 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100 C for 4 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200- 300 mesh, dichloromethane : MeOH, 100: 1, v/v) to give (2-morpholin-4-yl-ethyl)-[3-{ 3- [(thiophen-2-ylmethyl)-amino]-phenyl}- l-(2-trimethylsilanyl-ethoxymethyl)-lH-pyrazolo[3,4- d]pyrimidin-6-yl] -amine. (Yield 170 mg, 64.2%).LC-MS: [M+H]+ 566.3.
64.2%	With sodium t-butanolate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	Step A (2-Morpholin-4-yl-ethyl)-[3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine To a stirred solution of [3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 40 supra) (250 mg, 0.468 mmol), thiophen-2-yl-methylamine (80 mg, 0.70 mmol), DavePhos (30 mg, 0.076 mmol) and t-BuONa (70 mg, 0.73 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (42 mg, 0.073 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100 C. for 4 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 100:1, v/v) to give (2-morpholin-4-yl-ethyl)-[3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine. (Yield 170 mg, 64.2%). LC-MS: [M+H]+ 566.3.

Reference： [1]Patent: WO2012/98068,2012,A1 .Location in patent: Page/Page column 73
[2]Patent: US2012/184508,2012,A1 .Location in patent: Page/Page column 32

28
[ 27757-85-3 ]
[ 1386399-16-1 ]
[ 1386399-30-9 ]

Yield	Reaction Conditions	Operation in experiment
92.9%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	Example 53; N-(3- { 3- [(Thiophen-2-ylmethyl)-amino] -phenyl } - lH-pyrazolo[3 ,4-d]pyrimidin-6-yl)- cyclohexane- 1 ,4-diamine; Step A; { 4- [3- { 3- [(Thiophen-2-ylmethyl)-amino] -phenyl } - 1 -(2-trimethylsilanyl-ethoxymethyl)- lH-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester; To a stirred solution of {4-[3-(3-bromo-phenyl)- l-(2-trimethylsilanyl-ethoxymethyl)-lH- pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 39 supra) (300 mg, 0.48 mmol), thiophen-2-yl-methylamine (120 mg, 1.06 mmol), DavePhos (20 mg, 0.048 mmol) and i-BuONa (56 mg, 0.58 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (28 mg, 0.48 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100 C for 4 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane : MeOH, 100: 1, v/v) to give {4-[3-{ 3-[(thiophen-2-ylmethyl)- amino] -phenyl } - 1 -(2-trimethylsilanyl-ethoxymethyl)- 1 H-pyrazolo [3 ,4-d]pyrimidin-6-ylamino] - cyclohexylj-carbamic acid tert-butyl ester. (Yield 290 mg, 92.9%).LC-MS: [M+H]+ 650.3.

Reference： [1]Patent: WO2012/98068,2012,A1 .Location in patent: Page/Page column 71-72

29
[ 27757-85-3 ]
{4-[3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester [ No CAS ]
{4-[3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.9%	With sodium t-butanolate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	Step A {4-[3-{3-[(Thiophen-2-ylmethyl)-amino]-phenyl}-142-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester To a stirred solution of {4-[3-(3-bromo-phenyl)-142-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 39 supra) (300 mg, 0.48 mmol), thiophen-2-yl-methylamine (120 mg, 1.06 mmol), DavePhos (20 mg, 0.048 mmol) and t-BuONa (56 mg, 0.58 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (28 mg, 0.48 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100 C. for 4 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 100:1, v/v) to give {4-[3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-142-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 290 mg, 92.9%). LC-MS: [M+H]+ 650.3.

Reference： [1]Patent: US2012/184508,2012,A1 .Location in patent: Page/Page column 31

30
[ 98-03-3 ]
[ 27757-85-3 ]

Yield	Reaction Conditions	Operation in experiment
61.8%		With a warm meter,Blender, dropping funnel,A reflux condenser was charged with 44.0 g (0.392 mol) of 2-thiophenecarboxaldehyde, 400 ml of ethanol,31.3 g (0.451 mol, 15% excess) of hydroxylamine hydrochloride and 30 ml of water were added and the mixture was stirred for 60 minutes to dissolve completely. Under the water bath,176.4 g (about 1.764 mol, 4.5 times the amount) of 36.5% hydrochloric acid was added dropwise,70.6 g (1.08 mol, 2.75 times the amount of) zinc powder was gradually put into the flask,The reaction temperature is controlled at 30-40 ,Feeding completed, continue stirring for 60 minutes, add 153.8 ml (about 2.16 moles, 2.0 times the amount of zinc powder) 25-28% aqueous ammonia solution,At a controlled temperature below 40 C, a solution of 70.56 grams (1.764 moles, 1.0 times the acid amount)Sodium hydroxide and 141 ml of water formulated solution,Continue stirring for 60 minutes, filtered with suction, the filter cake was washed with about 200 ml of ethanol and drained,Filtrate and ethanol wash liquidAnd then extracted with 80 ml * 4 methylene chloride, the extract was combined, into the distillation kettle,First atmospheric distillation,Recycled water vacuum pump vacuum distillation to T kettle: 120 degrees Celsius / -0.08Mpa only, the kettle residual liquid standby.Distillate with about 20% hydrochloric acid to adjust PH: 1-2, atmospheric distillation,When the distillation temperature is greater than 98 when only,Cooled to room temperature, neutralized with 20% sodium hydroxide to pH: 13-14,Extract with 15 mL * 3 dichloromethane,The resulting extract was combined with the residue in the previous kettle, vacuum-distilled,A total of 27.4 grams of 79-81 [deg.] C / 2.2 Kpa fraction was collected (GC content greater than 99.5%;Yield: 61.8%),The resulting gas chromatogram shown in Figure 3.

Reference： [1]Patent: CN106674190,2017,A .Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041
[2]Patent: EP2511283,2012,A1
[3]Patent: US2013/45942,2013,A1
[4]Organic Letters,2014,vol. 16,p. 484 - 487
[5]Green Chemistry,2017,vol. 19,p. 789 - 794
[6]Journal of the American Chemical Society,2017,vol. 139,p. 11493 - 11499
[7]Science,2017,vol. 358,p. 326 - 332
[8]Journal of Molecular Structure,2017,vol. 1146,p. 337 - 346
[9]Patent: JP2015/172077,2015,A
[10]Chemical Science,2020,vol. 11,p. 4332 - 4339

31
[ 27757-85-3 ]
[ 2004-06-0 ]
[ 34198-97-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With bis(isopropyl)ethylamine; In propan-1-ol; at 80℃; for 7h;	A mixture of 2-(aminomethyl)thiophene (0.25 mL, 2.5 mmol), 6-chloropurine ribofuranoside (143 mg, 0.5 mmol), and diisopropylethylamine (2 mL, 12 mmol) in 1-propanol (25 mL) was heated at 80 C for 7 h. The mixture was concentrated by rotary evaporation, and recrystallized from MeOH to yield the desired product JMF3462 (154 mg, 85% yield). The purity of product was 99% as shown by HPLC on an HC-C18 column (Agilent, 4.6 250 mm, 5 mupiiota) with elution of gradients of 50% aqueous MeOH. C15H17N5O4S; white powder; mp 149.2-149.7 C; [a]25D= -68.2 (DMSO, c = 1.0); TLC (2-propanol/hexane, (2:3)) Rf= 0.35; NMR (DMSO- ;, 400 MHz) 6 8.51 (1 H, br s), 8.39 (1 H, s), 8.27 (1 H, br s), 7.32 (1 H, d, J = 5.2 Hz), 7.28 (1 H, d, J= 3.2 Hz), 6.93 (1 H, dd, J= 1.8, 2.6 Hz), 5.89 (1 H, d, J = 6.0 Hz), 5.46-5.45 (1 H, m), 5.36 (1 H, q, J= 4.6 Hz), 5.20-5.18 (1 H, m), 4.64 (2 H, s), 4.16-4.13 (1 H, m), 3.97-3.95 (1 H, m), 3.70-3.65 (1 H, m), 3.58-3.52 (1 H, m), 3.57- 3.52 (1 H, m),13C NMR (DMSO-c/e, 100 MHz) delta 154.1, 152.2, 148.5, 142.9, 140.0, 126.5, 125.3, 124.7, 120.0, 87.9, 85.9, 73.5, 70.6, 61.6, 42.9; ESI-MS calcd for C15H18N5O4S: 364.1080, found: m/z 364.1081 [M + H]+.
85%	With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 80℃; for 7h;	2-(aminomethyl)thiophene (0.25 mL '2.5 mmol), 6-chloropurine nucleofuranoside (143 mg, 0.5 mmol) ' and diisopropylethylamine (2 mL, 12 mmol) of a 1-propanol mixture (25 mL) was heated at 80 C for 7 h. The mixture was concentrated by rotary evaporation and recrystallised from MeOH to give the desired product JMF 3462 ( 154 mg, 85% yield). The product purity was 99% as indicated by HPLC on an HC-C18 column (Agilent, 4.6 chi 250 mm, 5 mueta) with a gradient of 50% MeOH in water.
	With triethylamine; In propan-1-ol; at 70℃; for 8h;	First step, hydroxyamine hydrochloride (3.27 g) and NaOAc (4.39 g) were added to a solution of 2-thiophenecarbaldehyde (3.0 g) in EtOH (80 ml). The reaction mixture was stirred at room temperature for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 2-thiophenecarbaldehyde oxime (2.75 g) as a pale yellowish solid. Second step, 2-thiophenecarbaldehyde oxime (2.75 g) and zinc dust (8.63 g) in HOAc (25 ml) was stirred at room temperature for 6 h. The reaction solution was filtered to remove the excess zinc dust and ZnOAc residue, and the filtrate was concentrated to yield 2-thiopheneylmethanamine (1.25 g) as a yellowish oil. Third step, a mixture of 2-thiopheneylmethanamine (592 mg), 6-chloropurine riboside (500 mg) and triethylamine (7.3 ml) in PrOH (60ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-(2-thiopheneylmethyl)-adenosine(490 mg) as a white solid: positive ESIMS m/z 364[M + H]+, 386[M + Na]+ and 402[M + K]+; negative ESIMS m/z 399[M + Cl]-; 1H NMR (300MHz, DMSO-d6): the adenosine moiety delta 8.50 (1H, brs, -NH), 8.38 (1H, s, H-2), 8.26 (1H, s, H-8), 5.88 (1H, d, 6.3Hz, H-1), 5.43 (1H, brs, -OH), 5.19 (1H, brs, -OH), 4.61 (1H, m, H-2'), 4.14 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, dd, 12.0Hz, 3.6Hz, H-5a'), 3.54 (1H, dd, 12.0Hz, 3.6Hz, H-5b'); the 2-thiopheneylmethyl delta 7.32 (1H, m, H-5"), 7.02 (1H, m, H-3"), 6.92 (1H, m, H-4"), 4.85 (2H, brs, H-7"); 13C NMR (75MHz, DMSO-d6): the adenosine moiety delta 154.1 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 140.2 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1), 86.1 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-6'); the 2-thiopheneylmethyl moiety delta 143.0 (s, C-2"), 126.7 (d, C-4"), 125.6 (d, C-3"), 124.9 (d, C-5"), 38.3 (t, C-6)o

490 mg	With triethylamine; In propan-1-ol; at 70℃; for 8h;	Third step, a mixture of 2-thiopheneylmethanamine (592 mg), 6-chloropurine riboside (500 mg) and triethylamine (7.3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-(2-thiopheneylmethyl)-adenosine (490 mg) as a white solid: positive ESIMS m/z 364[M+H]+, 386[M+Na]+ and 402[M+K]+; negative ESIMS m/z 399[M+Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.50 (1H, brs, -NH), 8.38 (1H, s, H-2), 8.26 (1H, s, H-8), 5.88 (1H, d, 6.3 Hz, H-1'), 5.43 (1H, brs, -OH), 5.19 (1H, brs, -OH), 4.61 (1H, m, H-2'), 4.14 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, dd, 12.0 Hz, 3.6 Hz, H-5a'), 3.54 (1H, dd, 12.0 Hz, 3.6 Hz, H-5b'); the 2-thiopheneylmethyl delta 7.32 (1H, m, H-5"), 7.02 (1H, m, H-3"), 6.92 (1H, m, H-4"), 4.85 (2H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.1 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 140.2 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.1 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-6'); the 2-thiopheneylmethyl moiety delta 143.0 (s, C-2"), 126.7 (d, C-4"), 125.6 (d, C-3"), 124.9 (d, C-5"), 38.3 (t, C-6").
490 mg	With triethylamine; In propan-1-ol; at 70℃; for 8h;	592 mg of 2-thiophene methylamine was taken and dissolved in propanol (60 mL). To a solution of 6-chloropurine nucleoside (500 mg) and triethylamine (7.3 mL)The mixture was heated to 70 C., reacted for 8 hours, and the solvent was recovered with a reaction solution. Chloroform-methanol (20: 1) separated by silica gel column chromatography,To obtain 490 mg of N6-(2-thiophene methyl)-adenosine as a white solid

Reference： [1]Patent: WO2015/61426,2015,A1 .Location in patent: Page/Page column 14
[2]Patent: TW2018/28950,2018,A .Location in patent: Paragraph 0040; 0052
[3]Patent: EP2511283,2012,A1 .Location in patent: Page/Page column 47
[4]Patent: US2013/45942,2013,A1 .Location in patent: Paragraph 0144; 0147
[5]Patent: JP2015/172077,2015,A .Location in patent: Paragraph 0111

32
[ 27757-85-3 ]
[ 892-48-8 ]
[ 1394955-71-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8066 - 8074,9

33
[ 27757-85-3 ]
[ 4942-47-6 ]
[ 676244-04-5 ]

Yield	Reaction Conditions	Operation in experiment
62%		General procedure: To a solution of the corresponding carboxylic acid (0.5 mmol) in DCM (8 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCI, 0.6 mmol), 4-(dimethylamino) pyridine (DMAP, 10 mg) and triethylamine (0.1 mL) at room temperature. After stirring for 0.5 h, the corresponding amine (0.5 mmol) was added to the reaction mixture. After 12 h the mixture was partitioned between DCM and brine and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified with flash chromatography (Ethyl acetate-DCM gradient elution) to give the target acetamide or carboxamide.

Reference： [1]Bioorganic and medicinal chemistry,2012,vol. 20,p. 6394 - 6402,9

34
[ 27757-85-3 ]
[ 10111-08-7 ]
C₉H₉N₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 20℃; for 3h;	2-(2-Aminomethyl)thiophene (5 mmol) dissolved in 5 mL of methanol was added dropwise to methanolic solution of 2-imidazole carbaldehyde (5 mmol). The mixture was allowed to stir at room temperature for 3 h, followed by dropwise addition of sodium borohydride (10 mmol) in 10 mL of sodium hydroxide solution. The resulting solution was stirred for 3 h and concentrated under reduced pressure; the residue was then extracted with three 10 mL portions of chloroform. The combined extract was dried over anhydrous MgSO4 and filtered, and the solvent was removed under reduced pressure to yield an oily product (L1). Yield: 0.466 g (62%)

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 70,p. 280 - 293

35
[ 27757-85-3 ]
[ 3314-30-5 ]
C₁₃H₁₁N₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 20℃; for 3h;	General procedure: 2-(2-Aminomethyl)thiophene (5 mmol) dissolved in 5 mL of methanol was added dropwise to methanolic solution of 2-imidazole carbaldehyde (5 mmol). The mixture was allowed to stir at room temperature for 3 h, followed by dropwise addition of sodium borohydride (10 mmol) in 10 mL of sodium hydroxide solution. The resulting solution was stirred for 3 h and concentrated under reduced pressure; the residue was then extracted with three 10 mL portions of chloroform. The combined extract was dried over anhydrous MgSO4 and filtered, and the solvent was removed under reduced pressure to yield an oily product (L1). Yield: 0.466 g (62percent)

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 70,p. 280 - 293

36
[ 27757-85-3 ]
[ 1003-31-2 ]

Yield	Reaction Conditions	Operation in experiment
67.9%	With 5% active carbon-supported ruthenium; oxygen; In toluene; at 150℃; under 3750.38 Torr; for 4h;Autoclave;	General procedure: In a typical process, into a 25 ml autoclave equipped with a magnetic stirrer were added 5%Ru/AC (0.03 mmol, 3 mol%), benzylamine (1 mmol), 5 mL toluene at room temperature successively. After which the resulting reaction mixture was heated at 150 C for 4 h under 0.5 MPa of oxygen atmosphere. The final reaction conversion and selectivity towards the corresponding nitriles were determined by Gas Chromatograph. After reaction, the product was purified by column chromatography of the reaction mixture on neutral alumina using hexanes/dichloromethane (80:20) or hexanes/EtOAc (30:1) as eluent.

Reference： [1]Advanced Synthesis and Catalysis,2014,vol. 356,p. 189 - 198
[2]Organic Letters,2014,vol. 16,p. 6484 - 6487
[3]Chemistry - A European Journal,2016,vol. 22,p. 5156 - 5159
[4]Chemistry Letters,2017,vol. 46,p. 330 - 333
[5]ChemSusChem,2015,vol. 8,p. 92 - 96
[6]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3356 - 3359
[7]Angewandte Chemie - International Edition,2016,vol. 55,p. 15802 - 15806
Angew. Chem.,2016,vol. 128,p. 16034 - 16038,5
[8]Organic and Biomolecular Chemistry,2017,vol. 15,p. 328 - 332

37
[ 1003-31-2 ]
[ 27757-85-3 ]
C₅H₅NS [ No CAS ]
[ 94488-33-2 ]

Reference： [1]ACS Catalysis,2014,vol. 4,p. 2191 - 2194

38
[ 27757-85-3 ]
[ 38266-87-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	With indium(III) chloride; Acetaldehyde oxime; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; In toluene; at 100℃; for 6h;	General procedure: A mixture of 2 mmol primary amine, acetaldoxime (6.2 mmol),InCl3 (0.1 mmol), TEMPO (0.2 mmol), and Toluene (10 ml) was placed in a 20 ml three-necked flasks. O2 was bubbled into the flask at a flow rate of 20 ml/min. The reaction mixture was stirred at 100 C for several hours and the reaction progress was monitored by TLC. After cooling to room temperature, the solution was directly evaporated to dryness and the residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1:8)to give the corresponding oximes.

Reference： [1]Advanced Synthesis and Catalysis,2015,vol. 357,p. 1175 - 1180
[2]Tetrahedron Letters,2014,vol. 55,p. 5751 - 5755

39
[ 27757-85-3 ]
[ 137-07-5 ]
[ 34243-38-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 2,8-dibromo-10-(4-bromophenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-dipyrrolo[1,2-c:2?,1?-f ][1,3,2]diazaborinin-4-ium-5-uide; In acetonitrile; at 50℃; under 1500.15 Torr; for 5h;Irradiation; Green chemistry;	General procedure: Amine (1 mmol), 2-aminothiophenol (2 mmol), BODIPY photosensitizer (0.01 mmol, 1.0 mol%), and acetonitrile (5 mL) were added to a dry 10-mL flask. The flask was pressurized with air (2 bar) and then heated to 50 C. The solution was then irradiated using a 35-W xenon lamp through a cutoff filter (0.72M NaNO2 aqueous solution, which is transparent for light >385nm, because lamps could emit a small amount of ultraviolet light). After the reaction was completed, the solvent was evaporated under reduced pressure. The crude product was further purified using column chromatography.

Reference： [1]Synthetic Communications,2014,vol. 44,p. 3189 - 3198
[2]RSC Advances,2015,vol. 5,p. 5015 - 5023

40
[ 27757-85-3 ]
[ 616-24-0 ]
C₁₀H₁₅NS [ No CAS ]

Reference： [1]Chemistry - A European Journal,2017,vol. 23,p. 6763 - 6767
[2]Green Chemistry,2020,vol. 22,p. 1894 - 1905
[3]Chemistry - A European Journal,2015,vol. 21,p. 3815 - 3820

41
[ 27757-85-3 ]
[ 214759-22-5 ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 3471 - 3488
[2]Patent: WO2015/61426,2015,A1
[3]Patent: TW2018/28950,2018,A
[4]Letters in drug design and discovery,2018,vol. 16,p. 102 - 110

42
[ 27757-85-3 ]
[ 56844-12-3 ]
6-bromo-N-(thiophen-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	In isopropyl alcohol; at 80℃; for 1h;Inert atmosphere;	General procedure: Compound 1 (1.00 g, 4.01 mmol) was mixed with the benzylamine (2-3 eq.) and i-PrOH (2-10 mL) and agitated at 80 C for 1-50 h, under nitrogen atmosphere. Then the mixture was cooled to rt, concentrated in vacuo, diluted with water (50 mL) and diethyl ether (100 mL) or EtOAc (100 mL). After phase separation, the water phase was extracted with more diethyl ether (2×50 mL) or EtOAc (2×50 mL). The combined organic phases were washed with saturated aq NaCl solution (25-50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude oil was purified by drying under reduced pressure to constant weight, by silica-gel column chromatography or crystallized as specified for each individual compound.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 94,p. 175 - 194

43
[ 27757-85-3 ]
[ 120-72-9 ]
[ 102241-69-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With iron(II) triflate; oxygen; In chlorobenzene; at 110℃; for 6h;Schlenk technique;	General procedure: To a Schlenk tube were added benzylamine 1 (1.3 mmol), indole 2(2.0 mmol), Fe(OTf)2 (10 mol%), and anhydrous chlorobenzene (2 mL).The tube was equipped with an O2 balloon, and the mixture wasstirred at 110 C until complete consumption of indole (TLC monitoring).When the reaction was complete, the mixture cooled to r.t., dilutedwith CH2Cl2 (10 mL), and washed with H2O (2 × 10 mL). The organicextract was dried (anhyd Na2SO4) and concentrated under reducedpressure, and the resulting residue was purified by columnchromatography (silica gel, hexane-EtOAc) to afford the correspondingbis(indolyl)methane products 3 and 4.

Reference： [1]Synthesis,2015,vol. 47,p. 1766 - 1774
[2]RSC Advances,2020,vol. 10,p. 23254 - 23262
[3]Chemistry - An Asian Journal,2019,vol. 14,p. 4154 - 4159

44
[ 27757-85-3 ]
[ 75-15-0 ]
[ 36810-92-1 ]

Yield	Reaction Conditions	Operation in experiment
92%		General procedure: The solution of 3-(2-aminoethyl)indole (80.1 mg, 0.5 mmol) in EtOH (1 mL, 0.5 M) was treated with carbon disulfide (114.2 mg, 1.5 mmol) followed by triethylamine (50.6 mg, 0.5 mmol). After stirring at room temperature for 1 hour, Boc2O (109.1 mg, 0.5 mmol) and DMAP (1.8 mg, 0.015 mmol) was added to the reaction mixture at 0 C. The reaction was stirred at room temperature for 2 hours and leave it additionally 2 hour to remove SCO gas. After the reaction completes, the crude product was extracted with ethyl acetate (50 mL) and purified by silica gel chromatography to afford 3-(2-isothiocyanatoethyl)-1H-indole (89.9 mg, 89%).
		General procedure: CS2 (2.3mL, 30mmol) was added dropwise to the mixture of 2-thiophenemethylamine (30mmol) and triethylamine (12mL) in THF (25mL) at 0C within 30min. After stirring at room temperature for 1h, the mixture was cooled down to 0C and then add the toluene sulfonyl chloride (6g, 31.5mmol). After stirring at room temperature for 1h, the mixture was dispersed in 5% HCl (100mL) and petroleum ether, washed sequentially with water, saturated NaHCO3 solution and brine, dried with anhydrous Na2SO4 and evaporated in vacuo to give compound 1. HCl (10.5mL) was added to the mixture of benzene or benzene derivatives (6.65mmol) and paraformaldehyde (11.97mmol). After stirring at 60C for 10h, the mixture was cooled down to room temperature and then the mixture was dispersed in water and ethyl acetate, washed sequentially with water, 5% HCl, saturated NaHCO3 solution and brine, dried with anhydrous Na2SO4. Removal of the solvent gave a residue to afford compound 2. A solution of methyl anthranilate or methyl anthranilate derivatives (0.01mol) and 2-(isothiocyanatomethyl)thiophene (1.55g, 0.01mol) in the mixture of triethylamine and ethanol was heated at reflux temperature for 4h. The reaction mixture was cooled down to room temperature and then filtered to give intermediate 3, which was then reacted with compound 2 (0.01mmol) mentioned above in the presence of K2CO3 and 1,4-dioxane. After reflux for 10h, the mixture was cooled down to room temperature and dissolved in ethyl acetate, washed sequentially with water, 5% HCl, saturated NaHCO3 solution and brine, dried with anhydrous Na2SO4. Removal of the solvent gave a residue which was recrystallized from ethanol to obtain target compound 4, respectively.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 62 - 66
[2]European Journal of Medicinal Chemistry,2019,vol. 176,p. 41 - 49
[3]European Journal of Medicinal Chemistry,2020,vol. 205

45
[ 27757-85-3 ]
[ 98-98-6 ]
[ 34999-03-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With pyridine; triphenyl phosphite; at 80℃; for 6h;	The ligands L1 and L2 have been prepared followinga common synthetic procedure. To a pyridinesolution of pyridine-2-carboxylic acid (10 mmol,1.231 g), furfurylamine (0.9712 g, 10 mmol) for L1 or 2-thiophenemethyl amine (1.1312 g, 10 mmol) for L2 wasadded at stirring condition. Then tri-phenylphosphite(3.101 g, 10 mmol) was added to this mixture andallowed to heat in oil bath at 80C for about 6 h(scheme 1). The resulting orange coloured solution waskept to evaporate for a few days to collect a whitecrystalline solid, after washing by methanol and waterthoroughly. The crystalline material was dried in vacuoover silica gel was used for characterization by usingphysico-chemical and spectroscopic tools. Single crystalsof L1 and L2 suitable for X-ray diffraction studywere obtained by slow evaporation from an ethanolic solution.
	With pyridine; phosphorous acid trimethyl ester; at 80℃; for 6h;	General procedure: A common synthetic procedure has been followed to obtain L1 and L2. To a pyridine solutionof pyridine-2-carboxylic acid (1.231 g, 10 mmol), furfurylamine (0.9712 g, 10 mmol)for L1 or 2-thiophenemethyl amine (1.1312 g, 10 mmol) for L2 was added with stirring.Then, tri-phenylphosphite (3.101 g, 10 mmol) was added to this mixture and heated in anoil bath at 80 C for 6 h (scheme 1). The resulting orange solution was allowed to evaporatefor a few days to collect a white crystalline solid after washing with methanol and waterthoroughly. The crystalline material dried in vacuo over silica gel was used for characterizationusing physicochemical and spectroscopic tools.

Reference： [1]Journal of Organic Chemistry,2019,vol. 84,p. 13112 - 13123
[2]Journal of Chemical Sciences,2015,vol. 127,p. 1747 - 1755
[3]Organic Letters,2019,vol. 21,p. 4495 - 4499
[4]Journal of Coordination Chemistry,2015,vol. 68,p. 4038 - 4054
[5]Journal of Organic Chemistry,2019,vol. 84,p. 2850 - 2861

46
[ 27757-85-3 ]
[ 354824-10-5 ]
N-{1,4-dioxo-3-[(thiophen-2-ylmethyl)amino]-1,4-dihydronaphthalen-2-yl}-N-(2-methoxyethyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.5%	With triethylamine; In toluene; at 45℃; for 3h;	General procedure: To a suspension of (16) (0.461g, 1.5mmol) in 5ml of toluene was added benzylamine(0.193g, 1.80mmol) and triethylamine (0.227g, 2.25mmol) and stirred at 45C for3h. The toluene was removed in vacuo, distilledwater was added and extracted with EtOAc. The organic layer was washed withbrine and dried over anhydrous Na2SO4. Purification bycolumn (1:2 EtOAc/Hexanes) afforded (28)as orange solids, 85.0%.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 104,p. 42 - 56
[2]ChemMedChem,2016,p. 1944 - 1955

47
[ 27757-85-3 ]
2-(4-(benzothiazol-2-yl)phenyl)butanoic acid [ No CAS ]
2-(4-(benzothiazol-2-yl)phenyl)-N-(thiophen-2-ylmethyl)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;	2-(4-(benzothiazol-2-yl)phenyl)butanoic acid (762 mg, 2.56 mmol), HATU(1.02 g, 2.69 mmol) and Et3N (0.7 mL, 5.12 mmol) were dissolved inDCM (12 mL) and 2-thiophenemethylamine (305 mg, 2.69 mmol) was added to thesolution. The mixture was stirred at rt overnight, washed by 1 M of HCl,saturated Na2CO3 and brine. After extracting by DCM,collected organic layers were dried over Na2SO4 andconcentrated to get the crude, which was triturated by 10% ether in PE to givethe product as white solid. (910 mg, 91%)LC-MS (ESI): [M+1]+ = 393.45, tR = 4.30 min.1H NMR (400 MHz, CDCl3)delta 8.04 (t, J = 8.5 Hz, 3H), 7.90 (d, J = 7.9 Hz, 1H), 7.49 (t, J= 7.6 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.6 Hz,1H), 7.18 (d, J = 4.9 Hz, 1H), 6.89 (dd, J = 9.1, 4.2 Hz, 2H),5.94 (s, 1H), 4.58 (qd, J = 15.3, 5.7 Hz, 2H), 3.30 (t, J = 7.5Hz, 1H), 2.31-2.15 (m, 1H), 1.94-1.79 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, CDCl3) delta 172.51,167.66, 154.14, 142.91, 140.96, 135.04, 132.67, 128.70, 127.95, 126.83, 126.37,125.80, 125.23, 125.19, 123.19, 121.64, 55.07, 38.51, 26.59, 12.30.
91%	With triethylamine; HATU; In dichloromethane; at 22℃;	2-(4-(benzothiazol-2-yl)phenyl)butanoic acid (762 mg, 2.56 mmol), HATU (1.02 g, 2.69 mmol) and Et3N (0.7 mL, 5.12 mmol) were dissolved in DCM (12 mL) and 2-thiophenemethylamine (305 mg, 2.69 mmol) was added to the solution. The mixture was stirred at rt overnight, washed by 1 M of HCl, saturated Na2CO3 and brine. After extracting by DCM, collected organic layers were dried over Na2SO4 and concentrated to get the crude, which was triturated by 10% ether in PE to give the product as white solid. (910 mg, 91%) LC-MS (ESI): [M+1]+=393.45, tR=4.30 min. 1H NMR (400 MHz, CDCl3) delta 8.04 (t, J=8.5 Hz, 3H), 7.90 (d, J=7.9 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.38 (t, J=7.6 Hz, 1H), 7.18 (d, J=4.9 Hz, 1H), 6.89 (dd, J=9.1, 4.2 Hz, 2H), 5.94 (s, 1H), 4.58 (qd, J=15.3, 5.7 Hz, 2H), 3.30 (t, J=7.5 Hz, 1H), 2.31-2.15 (m, 1H), 1.94-1.79 (m, 1H), 0.92 (t, J=7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) delta 172.51, 167.66, 154.14, 142.91, 140.96, 135.04, 132.67, 128.70, 127.95, 126.83, 126.37, 125.80, 125.23, 125.19, 123.19, 121.64, 55.07, 38.51, 26.59, 12.30.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 7661 - 7670
[2]Patent: US10221168,2019,B1 .Location in patent: Page/Page column 68; 69

48
[ 27757-85-3 ]
[ 394-28-5 ]
2-bromo-5-fluoro-N-(thiophen-2-ylmethyl)benzamide [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2016,vol. 2016,p. 389 - 393

49
[ 27757-85-3 ]
[ 132715-69-6 ]
2-bromo-3-fluoro-N-(thiophen-2-ylmethyl)benzamide [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2016,vol. 2016,p. 389 - 393

50
[ 27757-85-3 ]
[ 6967-82-4 ]
5-(thiophen-2-ylmethyl)phenanthridin-6(5H)-one [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2016,vol. 2016,p. 389 - 393

51
[ 27757-85-3 ]
[ 6967-82-4 ]
2-bromo-N-(thiophen-2-ylmethyl)benzamide [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2016,vol. 2016,p. 389 - 393

52
[ 27757-85-3 ]
[ 1180-71-8 ]
2-((1S,3aS,4aR,4bR,9aR,11aS)-1-(furan-3-yl)-9a-(hydroxymethyl)-4b,7,7,11a-tetramethyl-3,5-dioxotetradecahydroisobenzofuro[5,4-f]oxireno[2,3-d]isochromen-9-yl)-N-(thiophen-2-ylmethyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With montmorillonite K-10; In dichloromethane; for 10h;Sonication;	General procedure: To a round-bottom flask was added montmorilloniteK-10 (0.3 g mmol-1), and 1 (2.0 mmol) in CH2Cl2 wasdispersed on K-10. Then the appropriate amine (3.6 mmol)was added dropwise and the mixture was sonicatedin an ultrasonic bath; the progress of the reaction wasmonitored by TLC and after completion of the reaction(10-12 h), the products were extracted by washing theK-10 with CH2Cl2. The organic phase was dried withNa2SO4, filtered and the solvent was removed in vacuo toyield the crude products. The crude products were purifiedby column chromatography over silica gel using 2-5%EtOH-CH2Cl2 as eluent to give analytically pure products3a-o. The products were characterized by correspondingspectroscopic data (1H and 13C NMR, and HRMS).

Reference： [1]Journal of the Brazilian Chemical Society,2016,vol. 27,p. 161 - 178

53
[ 27757-85-3 ]
[ 4653-11-6 ]
4-(thiophen-2-yl)-N-(thiophen-2-ylmethyl)butanamide [ No CAS ]

Reference： [1]ACS Chemical Neuroscience,2016,vol. 7,p. 737 - 748

54
[ 129820-44-6 ]
[ 27757-85-3 ]

Yield	Reaction Conditions	Operation in experiment
53%	With hydrogen; palladium; In tetrahydrofuran; N,N-dimethyl-formamide; at 50℃; under 6080.41 Torr; for 24h;Inert atmosphere;	General procedure: The hydrogenation of 3-phenylpropylazide (Table 2, entry 1) is given as an example. 3-Phenylpropylazide (3a) (207.2 mg, 1.29 mmol) was charged into an Ar-filled 100 mL glass autoclave equipped with a Teflon-coated magnetic stirring bar. THF (1.2 mL) degassed by three freeze-thaw cycles was introduced via a Teflon cannula, followed by the addition of a solution of the Pd NPs catalyst in DMF (5.0 mM, 20 muL, 0.10 mumol, S/Pd = 12,900:1). Hydrogen was introduced into the reaction vessel until the pressure gauge indicated 8 atm, and then the pressure was carefully released to 1 atm by opening the stop valve. This procedure was repeated five times,and finally hydrogen was pressurized to 8 atm. The vessel was placed in a water bath controlled at 50 C, and the reaction mixture was vigorously stirred for 16 h. After careful venting of the hydrogen, the reaction mixture was concentrated under reduced pressure. 1,1,2,2-Tetrachloroethane (124.0 mg, 0.739 mmol) was added as an internal standard for the NMR analysis, and the produced 3-phenylpropylamine (4a) was quantified (99.5%). The reaction mixture was carefully concentrated under reduced pressure to remove THF. To this crude mixture were added dichloromethane (5 mL) and triethylamine (0.45 mL, 3.2 mmol), and the mixture was cooled to 0 C. Boc2O (726.7 mg, 3.3 mmol) was added at 0 C, and the solution was stirred at room temperature over night. The reaction mixture was diluted by addition of dichloromethane (10 mL). The solution was washed 3 times successively with water, then once with brine, and dried over magnesium sulfate. After removal of the drying agent by filtration, the solution was concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography (hexane : ethyl acetate = 20:1), giving pure carbamate Boc-4a as a colorless oil (248.3 mg, 87%).

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 4183 - 4186

55
[ 27757-85-3 ]
[ 58255-18-8 ]

Reference： [1]Patent: CN103664930,2016,B
[2]Organic and Biomolecular Chemistry,2017,vol. 15,p. 3507 - 3518

56
[ 27757-85-3 ]
[ 1003-31-2 ]
[ 94488-33-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; N,N-dimethylethylenediamine; copper(l) chloride; In toluene; at 80℃; for 24h;Sealed tube; Schlenk technique;	General procedure: A mixture of benzylamine 1a (107.0 mg, 1.0 mmol), CuCl (5.0 mg, 0.05 mmol, 5 mol%), 2,2,6,6-tetramethyl-1-piperidyloxy (TEMPO, 7.8 mg, 0.05 mmol, 5 mol%), and N,N-dimethylethane-1,2-diamine (DMEDA, 4.4 mg, 0.05 mmol, 5 mol%) in toluene (0.5 mL) sealed in a Schlenk tube (100 mL) with an air balloon was stirred at 80 C for 24 h. The reaction was then monitored by TLC and/or GC-MS. After completion of the reaction, solvent was evaporated under vacuum. The residue was purified by scosh column chromatography on silica gel using petroleum ether and ethyl acetate (0-100/1) as the eluent, giving product 2a in 80% isolated yield

Reference： [1]Chinese Chemical Letters,2017,vol. 28,p. 1336 - 1339

57
[ 27757-85-3 ]
[ 5096-73-1 ]
6-chloro-N-(thiophen-2-ylmethyl)pyridazine-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4279 - 4292

58
[ 27757-85-3 ]
[ 4722-94-5 ]
4-((thiophen-2-ylmethyl)amino)pyridine-2,6-dicarboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7267 - 7283

59
[ 27757-85-3 ]
[ 105170-27-2 ]
3-[N-(2-methylthiophen)]-6-methoxypyridinamine [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 8009 - 8012

60
[ 27757-85-3 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 19432-68-9 ]

Reference： [1]ACS Catalysis,2018,vol. 8,p. 738 - 741

61
[ 27757-85-3 ]
[ 67-56-1 ]
[ 58255-18-8 ]
[ 26019-17-0 ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 6166 - 6170
Angew. Chem.,2018,vol. 130,p. 6274 - 6278,5

62
[ 27757-85-3 ]
[ 1001414-56-7 ]

Reference： [1]Patent: WO2008/5457,2008,A2

63
[ 27757-85-3 ]
[ 728034-12-6 ]
[ 165806-95-1 ]
4-(4-(4-fluorophenyl)-1-(thiophen-2-ylmethyl)-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%		General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were used

Reference： [1]Patent: WO2019/185631,2019,A1 .Location in patent: Page/Page column 14; 65

64
[ 27757-85-3 ]
[ 1003-31-2 ]
[ 5813-89-8 ]

Reference： [1]Chemical Communications,2019,vol. 55,p. 12251 - 12254

65
[ 27757-85-3 ]
[ 118-45-6 ]
5-chloro-2-(thiophen-2-ylmethyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With acetic acid; at 110℃; for 4h;	General procedure: The starting materials 1 and 2 were commercially available (Energy Chemical, Shanghai, China).Compound 2 (3.72 mmol) was added to a stirred solution of compound 1 (3.38 mmol) in glacial aceticacid (10 mL). The reaction mixture was then stirred at 110 C for 4 h. After completion of the reaction,the solvent was evaporated, and the residue was purified on a silica gel column chromatography andeluted with ethyl acetate/petroleum ether (bp 60-90 C) (1:3, v/v) to give compounds 3.

Reference： [1]Molecules,2019,vol. 24

66
[ 4318-37-0 ]
[ 27757-85-3 ]
2,4,6-trichloropyrido[3,4-d]pyrimidine [ No CAS ]
6-chloro-2-(4-methyl-1,4-diazepan-1-yl)-N-(thiophen-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		General procedure: An oven dried pW reactor was charged with 2,4,6-Trichloropyrido[3,4-c/]pyrimidine (Intermediate F) (234 mg, 1 mmol, 1 equiv.) sealed with a septum and purged with Ar atmosphere (3 cycles Ar/vacuum). Then, EtOAc (7 mL. 0.14 M) and N,N- diisopropylethylamine (0.51 mL, 2.9 mmol, 2.9 equiv.) were added and the mixture was homogenized by stirring for 5 min. The corresponding amine or alcohol (RXH) (1.05 mmol, 1.05 equiv.) was added. The resulting mixture was stirred at 22C until complete conversion of the Intermediate F was achieved (2-20 h). The corresponding amine (R3R2NH) (1.5-10.3 mmol, 1.5-10.3 equiv.) was added. The mixture was homogenized by stirring and submitted to reaction under microwave irradiation at 120C for 15-30 min (Energy Power: 60 W). The progress of the reaction was confirmed by TLC (EtOAc:MeOH). The crude mixture was transferred to a round bottom flask by addition of EtOAc and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (70 ml.) and transferred to a separating funnel. The organic phase was washed with water (3 x 30 ml.) and saturated NaCI solution (1 x 30 ml_). The organic phase was dried over anhyd. Na2S04 and filtered through a pad of Na2S04 with a filter plate. The solvent was removed under reduced pressure giving the crude mixture, which was purified by automated flash chromatography (EtOAc:MeOH) yielding the corresponding products (Examples 1-38 and 68-99).

Reference： [1]Patent: WO2020/20939,2020,A1 .Location in patent: Page/Page column 39; 40; 57

67
[ 27757-85-3 ]
2,4,6-trichloropyrido[3,4-d]pyrimidine [ No CAS ]
[ 51387-90-7 ]
6-chloro-N₂-(2-(1-methylpyrrolidin-2-yl)ethyl)-N₄-(thiophen-2-ylmethyl)pyrido[3,4-d]pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		General procedure: An oven dried pW reactor was charged with 2,4,6-Trichloropyrido[3,4-c/]pyrimidine (Intermediate F) (234 mg, 1 mmol, 1 equiv.) sealed with a septum and purged with Ar atmosphere (3 cycles Ar/vacuum). Then, EtOAc (7 mL. 0.14 M) and N,N- diisopropylethylamine (0.51 mL, 2.9 mmol, 2.9 equiv.) were added and the mixture was homogenized by stirring for 5 min. The corresponding amine or alcohol (RXH) (1.05 mmol, 1.05 equiv.) was added. The resulting mixture was stirred at 22C until complete conversion of the Intermediate F was achieved (2-20 h). The corresponding amine (R3R2NH) (1.5-10.3 mmol, 1.5-10.3 equiv.) was added. The mixture was homogenized by stirring and submitted to reaction under microwave irradiation at 120C for 15-30 min (Energy Power: 60 W). The progress of the reaction was confirmed by TLC (EtOAc:MeOH). The crude mixture was transferred to a round bottom flask by addition of EtOAc and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (70 ml.) and transferred to a separating funnel. The organic phase was washed with water (3 x 30 ml.) and saturated NaCI solution (1 x 30 ml_). The organic phase was dried over anhyd. Na2S04 and filtered through a pad of Na2S04 with a filter plate. The solvent was removed under reduced pressure giving the crude mixture, which was purified by automated flash chromatography (EtOAc:MeOH) yielding the corresponding products (Examples 1-38 and 68-99).

Reference： [1]Patent: WO2020/20939,2020,A1 .Location in patent: Page/Page column 39; 40; 57; 58

68
[ 27757-85-3 ]
[ 13035-19-3 ]
2,4,6-trichloropyrido[3,4-d]pyrimidine [ No CAS ]
2-(4-aminopiperidin-1-yl)-6-chloro-N-(thiophen-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		General procedure: An oven dried pW reactor was charged with 2,4,6-Trichloropyrido[3,4-c/]pyrimidine (Intermediate F) (234 mg, 1 mmol, 1 equiv.) sealed with a septum and purged with Ar atmosphere (3 cycles Ar/vacuum). Then, EtOAc (7 mL. 0.14 M) and N,N- diisopropylethylamine (0.51 mL, 2.9 mmol, 2.9 equiv.) were added and the mixture was homogenized by stirring for 5 min. The corresponding amine or alcohol (RXH) (1.05 mmol, 1.05 equiv.) was added. The resulting mixture was stirred at 22C until complete conversion of the Intermediate F was achieved (2-20 h). The corresponding amine (R3R2NH) (1.5-10.3 mmol, 1.5-10.3 equiv.) was added. The mixture was homogenized by stirring and submitted to reaction under microwave irradiation at 120C for 15-30 min (Energy Power: 60 W). The progress of the reaction was confirmed by TLC (EtOAc:MeOH). The crude mixture was transferred to a round bottom flask by addition of EtOAc and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (70 ml.) and transferred to a separating funnel. The organic phase was washed with water (3 x 30 ml.) and saturated NaCI solution (1 x 30 ml_). The organic phase was dried over anhyd. Na2S04 and filtered through a pad of Na2S04 with a filter plate. The solvent was removed under reduced pressure giving the crude mixture, which was purified by automated flash chromatography (EtOAc:MeOH) yielding the corresponding products (Examples 1-38 and 68-99).

Reference： [1]Patent: WO2020/20939,2020,A1 .Location in patent: Page/Page column 39; 40; 58; 59

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P234	Keep only in original container.
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Code	Phrase
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P321
P322
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P378
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P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
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Storage
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P401
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P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 27757-85-3 ]

Quality Control of [ 27757-85-3 ]

Related Doc. of [ 27757-85-3 ]

Product Details of [ 27757-85-3 ]

Calculated chemistry of [ 27757-85-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 27757-85-3 ]

Application In Synthesis of [ 27757-85-3 ]

[ 27757-85-3 ] Synthesis Path-Upstream 1~6

[ 27757-85-3 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 27757-85-3 ]

Amines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 27757-85-3 ]