[ CAS No. 2524-67-6 ] {[proInfo.proName]}

Name: 2524-67-6|4-Morpholinoaniline|97%
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Product Details of [ 2524-67-6 ]

CAS No. :	2524-67-6	MDL No. :	MFCD00006169
Formula :	C₁₀H₁₄N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PHNDZBFLOPIMSM-UHFFFAOYSA-N
M.W :	178.23	Pubchem ID :	75655
Synonyms :

Calculated chemistry of [ 2524-67-6 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.4
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	56.57
TPSA :	38.49 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.71
Log Po/w (XLOGP3) :	0.68
Log Po/w (WLOGP) :	0.73
Log Po/w (MLOGP) :	0.83
Log Po/w (SILICOS-IT) :	1.25
Consensus Log Po/w :	1.04

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.65
Solubility :	4.0 mg/ml ; 0.0224 mol/l
Class :	Very soluble
Log S (Ali) :	-1.07
Solubility :	15.3 mg/ml ; 0.0861 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.22
Solubility :	1.07 mg/ml ; 0.006 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	2.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.43

Safety of [ 2524-67-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 2524-67-6 ]

* 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 [ 2524-67-6 ]
Downstream synthetic route of [ 2524-67-6 ]

[ 2524-67-6 ] Synthesis Path-Upstream 1~15

1
[ 10389-51-2 ]
[ 2524-67-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With palladium 10% on activated carbon; hydrogen In methanol at 40℃; for 18 h;	4-(4-nitrophenyl) morpholine (0.600 g, 2.882 mmol) and methanol (60 ml) were added to the hydrogenation reaction vessel. 10percent Palladium on carbon (0.060 g) was added under nitrogen protection. The reaction system was replaced with hydrogen for 3-4 times, and was stirred under hydrogen pressure to react for 18 hours under 40°C. HPLC detected that the reaction has completed, and then the reaction solution was cooled to room temperature, and filtered through Celite. The residue was washed with methanol. The combined filtrate was concentrated under vacumm by rotary evaporator to give the solid desired product (0.500 g, HPLC purity: 97.1percent, yield: 97percent). ¹H NMR(400MHz, DMSO-d₆) δ 6.83-6.80(2H, d), 6.71-6.68(2H, d), 3.88-3.86(4H, t), 3.46(2H, s), 3.06-3.03 ppm(4H, t).
97%	With palladium on activated charcoal; hydrogen In methanol at 20℃;	General procedure: Afterwards, the obtained compound, 2a was hydrogenated. Pd/C (2.78mmol) was added to a stirred solution of 1-methyl-4-(2-methyl-4-nitrophenyl-piperazine (5.53mmol)) in methyl alcohol (15ml) in N₂ atmosphere. Following this it was hydrogenated overnight by maintaining the reaction flask in an atmosphere of H₂ gas (balloon). The resultant was filtered thorough celite plate and concentrated under vacuum. The crude product was purified with silica-gel column chromatography (5percentMeOH/DCM, 1percentNH₃) to yield the desired product, 3a as a brown solid, 87percent yield.
87%	With palladium on activated charcoal; hydrogen In methanol at 20℃;	4-Fluoronitrobenzene (382 mg, 2.7 mmol) was dissolved in DMSO (7 ml), potassium carbonate (561 mg, 4.0 mmol) and morpholine (472 mg, 5.4 mmol) were added, and the mixture was stirred at 90° C. overnight. Then, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with saturated aqueous NaCl. The organic layer was dried over Na₂CO₃, the solvent was evaporated, and the obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate (2:1)) to give compound Y180 (yield; 493 mg, 88percent). Compound Y180 (483 mg, 2.3 mmol) was dissolved in methanol (25 ml), Pd/C (205 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. Then, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate (1:2)) to give compound Y183 (yield; 358 mg, 87percent). Compound Y491 (mentioned later) (134 mg, 0.3 mmol) was dissolved in dichloromethane (4 ml), compound Y183 (158 mg, 0.9 mmol) and triethylamine (123 μl, 0.9 mmol) were added, and the mixture was stirred at room temperature for 45 min. Then, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (22:1)) to give the title compound (yield; 120 mg, 69percent). ¹H NMR (500 MHz, CDCl₃) δ8.43 (s, 1H), 8.00 (d, 1H, J=8.0 Hz), 7.70 (d, 1H, J=8.0 Hz), 7.53 (t, 1H, J=8.0 Hz), 7.43 (bs, 1H), 6.98 (dd, 2H, J=9.0, 3.5 Hz), 6.76 (dd, 2H, J=9.0, 3.5 Hz), 5.55 (dd, 1H, J=6.5, 6.0 Hz), 4.05 (bs, 2H), 3.83-3.81 (m, 4H), 3.10-3.08 (m, 4H), 2.80-2.63 (m, 4H), 1.64-1.54 (m, 3H), 1.42 (s, 9H), 1.86-1.01 (m, 2H) ¹³C NMR (125 MHz, CDCl₃) δ155.0, 150.1, 141.6, 140.8, 131.3, 131.0, 129.8, 127.4, 125.8, 125.6, 116.2, 79.7, 66.9, 58.6, 50.9, 49.2, 48.7, 36.5, 29.6, 28.6, 18.5 HRMS (FAB-) m/z: [M-H]^- calcd for C₂₇H₃₇N₄O₇S₂, 593.2104. found, 593.2197

87.4%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 17 h; Inert atmosphere	4-(4-Nitrophenyl)morpholine (2.20 g, 10.6 mmol) was dissolved in 12 mL of methanol.Replace the nitrogen,Add 30mg of 10percent palladium on carbon,The system replaces hydrogen three times,The reaction was stirred at room temperature for 17 h.Palladium charcoal is filtered off,The filtrate was dried to give a pale yellow oil, 1.65 g.Yield: 87.4percent.
86%	With ammonium chloride; zinc In ethanol; water for 0.5 h; Reflux	Compound 7-b (1.5 g, 7.21 mmol) and ammonium chloride (1.0 g, 18.03 mmol) were dissolved in 50percent ethanol-water (20 mL), Zn-powder (1.2 g, 18.03 mmol) was then added. The mixture was refluxed for 30 minutes. After cooled to room temperature, the mixture was filtrated. The filter cake was washed with ethanol (10 mL), the combined filtrate were concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3), the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give light brown solid 7-a (1.1 g, yield: 86percent), which was used directly for the next step without purification. LC-MS (ESI): m/z=179 [M+H]⁺.
85%	With palladium 10% on activated carbon; hydrogen In ethyl acetate at 80℃; for 12 h;	To a mixture of 5a (2.13g, 10mmol) in dry ethyl acetate was added 10percent Pd/C (0.5g), following the reaction mixture was stirred under hydrogen gas at 80°C for 12h. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (dichloromethane/methanol 15:1 by volume) to give 4-morpholinyl aniline 6a (1.5g, yield 85percent). ¹H NMR (400MHz, CDCl₃) δ 6.81–6.77 (m, 2H), 6.68–6.64 (m, 2H), 3.85–3.83 (m, 4H), 3.03–3.01 (m, 4H).
77%	With water; ammonium chloride; zinc In tetrahydrofuran; methanol at 20℃;	Synthesis of 4-Morpholin-4-yl-phenylamine Ammonium chloride (1.2 g, 23.0 mmol) in water (4.5 mL) then MeOH (9 mL) were added to a stirred solution of 4-(4-nitro-phenyl)-morpholine (480 mg, 2.3 mmol) in THF (9 mL). Zinc powder (1.2 g, 18.4 mmol) was then added portion wise and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered over celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to afford 316 mg (77percent) of 4-morpholin-4-yl-phenylamine. ¹H NMR: (DMSO-d₆): δ 6.7 (m, 2H), 6.5 (m, 2H), 4.6 (s, 2H), 3.7 (t, 4H), 2.8 (t, 4H).
74.1%	With iron(III) chloride hexahydrate; pyrographite; hydrazine hydrate In ethanol at 65 - 78℃; for 5 h;	General procedure: A mixture of compounds 5a–e (0.05 mol) in ethanol was heated to 65 °C, FeCl_3·6H₂O (2.8 g, 0.001 mol) and activated carbon (0.18 g, 0.015 mol) were added, and 80percent hydrazine hydrate (25 g, 0.5 mol) was added drop wise at such a rate to keep the temperature below 70 °C, the reaction was heated at reflux for 5 h and then cooled to room temperature and concentrated. Water (100 mL) was added, the reaction solution was extracted three times with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to obtain the compounds 6a–e.
74.1%	With iron(III) chloride hexahydrate; hydrazine hydrate In ethanol for 5 h;	General procedure: A mixture of compounds 5 or 7a-c (0.05 mol) in ethanolwas heated to 65 °C, FeCl3·6H2O (2.8 g, 1 mmol) and activatedcarbon (0.18 g, 15 mmol) were added, and 80percent hydrazinehydrate (25 g, 0.5 mol) was added dropwise at such arate to keep the temperature below 70 °C, the reaction washeated at reflux for 5 h and then cooled to room temperatureand concentrated. Water (100 mL) was added, the reactionsolution was extracted three times with CH2Cl2 (60 mL). Theorganic extracts were combined, dried over sodium sulfate,filtered, and concentrated to obtain the compounds 8a-d.
73%	With iron; acetic acid In methanol; water	4 g of iron powder, 30 mL of water and 0.5 mL of glacial acetic acid were added to a 100 mL round bottom flask and heated to reflux for 10 min.Then, a solution of 3.12 g (0.015 mol) of 4-(4-nitrophenyl)morpholine dissolved in 20 mL of methanol was added, the reaction was stirred, and the reaction was traced to the end point by TLC.A small amount of anhydrous sodium sulfite was added, and after cooling, the pH was adjusted to 8-9 with a 10percent sodium carbonate solution, and filtered through Celite.The filter cake was washed with hot ethanol, and the filtrate was evaporated to a solvent.Washed with saturated sodium carbonate solution and saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give a yellow solid 1.96g,Melting point: 132-133 ° C, yield 73percent.
73%	With iron; acetic acid In methanol; water	Weigh 4g of iron powder in a 100ml round bottom flask.Add 30 ml of water and 0.5 ml of glacial acetic acid.Activated under reflux for 10 min,Then weighed 3.12 g (0.015 mol) of the previous synthesis4-(4-nitrophenyl)morpholine in 20 ml of methanol,Add to the reaction bottle,TLC tracks the reaction, the reaction is complete,Add a small amount of anhydrous sodium sulfite, cool and then adjust the pH to 8-9 with 10percent sodium carbonate solution, filter with diatomaceous earth, filter cake with hot ethanol, until the filtrate is colorless, the filtrate is steamed a part of solvent After that, it was extracted with ethyl acetate, washed successively with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate.Concentrated to give 1.96 g of a yellow solid.The yield was 73percent.
70%	With ammonia In methanol	REFERENCE EXAMPLE 20 Preparation of 4-Morpholin-4-yl-phenylamine 4-(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;) (Lancaster Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5percent palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70percent yield, mp 132-133° C.). GC/CMS (EI, M+) m/z=178.
70%	With ammonia In methanol	REFERENCE EXAMPLE 20 Preparation of 4Morpholin-4-yl-phenylamine. 4(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;). (Lancaster Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5percent palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70percent yield, mp 132-133° C.). GC/MS (EI, Mt) m/z=178.
70%	With ammonia In methanol	Reference Example 20 Preparation of 4-Morpholin-4-yl-phenylamine 4-(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;) (Lancaster Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5percent palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70percent yield, mp 132-133° C.). GC/MS (EI, M+) m/z=178.
68%	With iron; ammonium chloride In methanol; water at 60℃; for 2 h;	10 (7.13 g, 34.26 mmol) and ammonium chloride (3.66 g, 68.52 mmol) were added to the reaction flask and 30 ml of MeOHAnd water (30 ml) was added with iron powder (7.67 g, 137.04 mmol) under stirring. The reaction was carried out at 60 ° C for 2 hours. The filter was washed with n-butanol and extracted with n-butanol (150 ml x 3) Washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 4.15 g of a dark brown solid (yield: 68percent).
209 mg	With iron; ammonium chloride In methanol; water at 100℃;	General procedure: The compound S1 (261 mg, 1.25 mmol), iron powder (210 mg, 4.76 mmol, 3 equiv.) and ammonium chloride (335 mg, 6.27 mmol, 5 equiv.) were dissolved in methanol : water (2 : 1, 15 mL). The reaction mixture was heated at 100 °C overnight, cooled to RT, filtered through celite and the solvent was reduced under vacuum. The condensed mixture was extracted with DCM, washed with brine, dried with sodium sulfate and all solvent was evaporated to furnish the condensed residue, which was purified by flash chromatography (elution system - EA/Hexane = 1 : 1 ) to obtain the title compound (245 mg, 1.43 mmol).

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[ 70291-67-7 ]
[ 2524-67-6 ]

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3
[ 30483-75-1 ]
[ 2524-67-6 ]

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4
[ 350-46-9 ]
[ 2524-67-6 ]

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[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 13, p. 4377 - 4385
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5
[ 100-00-5 ]
[ 2524-67-6 ]

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6
[ 110-91-8 ]
[ 589-87-7 ]
[ 2524-67-6 ]
[ 106-50-3 ]
[ 106-40-1 ]

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7
[ 110-91-8 ]
[ 106-40-1 ]
[ 2524-67-6 ]

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8
[ 110-91-8 ]
[ 106-47-8 ]
[ 2524-67-6 ]

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9
[ 106-39-8 ]
[ 2524-67-6 ]

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10
[ 92-53-5 ]
[ 2524-67-6 ]

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11
[ 110-91-8 ]
[ 106-40-1 ]
[ 2524-67-6 ]
[ 159724-40-0 ]

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12
[ 586-78-7 ]
[ 2524-67-6 ]

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13
[ 5382-54-7 ]
[ 2524-67-6 ]

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[3] Patent: US2004763, 1932, ,
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14
[ 110-91-8 ]
[ 106-40-1 ]
[ 2524-67-6 ]
[ 159724-40-0 ]

Reference： [1] Organic Letters, 2003, vol. 5, # 19, p. 3515 - 3517

15
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[ 1056634-68-4 ]

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[ 2524-67-6 ] Synthesis Path-Downstream 1~88

1
[ 10389-51-2 ]
[ 2524-67-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 3h;	General procedure: To 17a (1 g, 7.8 mmol) in EtOH (20 mL) was added 10% Pd/C50 mg. The reaction mixture was stirred for 3 h under hydrogen at roomtemperature. The mixture was then filtered with Celite, and the filtratewas concentrated and dried under vacuum to yield 0.74 g (97%) of 18aas a white solid. MS (ESI) m/z 98 [M+H]+.
99%	With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; for 2h;	The compound 4- (4-nitrophenyl) morpholine 92b (1.01 g, 4.86 mmol) was dissolved in tetrahydrofuran (100 mL), 10% palladium on carbon (517 mg) was added, and then stirred under a hydrogen atmosphere for 2 hours.After the reaction was completed, the filtrate was filtered, and the solvent was removed under reduced pressure.The target product 4-morpholinoaniline 92c (860 mg, white solid) was obtained in a yield of 99%.
98%	With palladium 10% on activated carbon; hydrazine hydrate; In ethanol; at 78 - 80℃; for 0.5h;Inert atmosphere;	General procedure: The mixture of 16 (10.0 mmol) and Pd/C (10 wt%, 0.2 g) in EtOH(200 mL) was heated to reflux under argon. Then hydrazine hydrate(85 wt%, 200.0 mmol) was added dropwise to the mixture over 0.5 hmaintaining the temperature at 78-80 C. After the addition wascompleted, the reaction mixture was stirred and refluxed for 2 h. Thehot solution was then filtered by vacuum through celite pad. The solventwas concentrated to provide the target compounds without furtherpurificationas.

97%	With palladium 10% on activated carbon; hydrogen; In methanol; at 40℃; for 18h;	4-(4-nitrophenyl) morpholine (0.600 g, 2.882 mmol) and methanol (60 ml) were added to the hydrogenation reaction vessel. 10% Palladium on carbon (0.060 g) was added under nitrogen protection. The reaction system was replaced with hydrogen for 3-4 times, and was stirred under hydrogen pressure to react for 18 hours under 40C. HPLC detected that the reaction has completed, and then the reaction solution was cooled to room temperature, and filtered through Celite. The residue was washed with methanol. The combined filtrate was concentrated under vacumm by rotary evaporator to give the solid desired product (0.500 g, HPLC purity: 97.1%, yield: 97%). 1H NMR(400MHz, DMSO-d6) delta 6.83-6.80(2H, d), 6.71-6.68(2H, d), 3.88-3.86(4H, t), 3.46(2H, s), 3.06-3.03 ppm(4H, t).
97%	With palladium on activated charcoal; hydrogen; In methanol; at 20℃;	General procedure: Afterwards, the obtained compound, 2a was hydrogenated. Pd/C (2.78mmol) was added to a stirred solution of 1-methyl-4-(2-methyl-4-nitrophenyl-piperazine (5.53mmol)) in methyl alcohol (15ml) in N2 atmosphere. Following this it was hydrogenated overnight by maintaining the reaction flask in an atmosphere of H2 gas (balloon). The resultant was filtered thorough celite plate and concentrated under vacuum. The crude product was purified with silica-gel column chromatography (5%MeOH/DCM, 1%NH3) to yield the desired product, 3a as a brown solid, 87% yield.
97.4%		11c (0.6 g, 2.9 mmol) was dissolved in tetrahydrofuran (12.5 ml), and methanol (12.5 ml) was added and stirred for 5 min. Ammonium chloride (1.5 g, 28.8 mmol) in water (6.5 mL) was added and the mixture was continued to stir for 30 min. Zinc powder (942 mg, 14.4 mmol) was added to the system and the reaction was continued to stir at 17 C for 3 hours. The reaction liquid was gradually changed from bright yellow to gray, and the reaction was monitored to have been finished by thin-plate chromatography (methanol / dichloromethane = 1:10). After stood for 15 minutes, the reaction was filtered through celite, the cake was rinsed with ethyl acetate (10.5 ml) and the filtrate was concentrated to dryness under reduced pressure. Water was added (5.5 ml) and extracted with ethyl acetate (10 ml x 3). The combined organic phase was washed with saturated sodium chloride solution (10.2 mL), dried and concentrated under reduced pressure to give a pale yellow solid 11d (500 mg, 99.1% purity, yield 97.4%).
96%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 5h;	26.9 g (129 mmol) of Intermediate B and 1.34 g (5% m/m) of 10% palladium on carbon were added to 500 mL of a 90% ethanol solution, and hydrogen gas was introduced thereto, and reacted at room temperature for 5 hours.After the reaction was completed, suction filtration, washing the filter cake with 100 mL of 90% ethanol.The filtrate was concentrated under reduced pressure to give a purple solid (22.0 g).The yield was 96%.
95%	With palladium 10% on activated carbon; hydrazine hydrate; In ethanol; at 75℃; for 8h;	General procedure: 10% Pd/C(1.43 g, 13.5 mmol), hydrazine (8 mL) and nitrobenzene derivatives2a-2c and 4a-4d (19 mmol) were dissolved in ethanol (60 mL) and useargon to remove the gas three times. The resulted mixture was heated to75 C for 8 h. After that, the reaction solution was filtered throughcelite. Then the crude products were purified by column chromatographyon silica gel to afford desired intermediates 3a-3b, 5a-5e.
94.5%	With hydrogen; In tetrahydrofuran; at 20℃; under 760.051 Torr; for 10h;	4-(4-nitrophenyl)morpholine (8.33 g, 0.04 mol) was added to a 250 mL eggplant-shaped flask, 100 mL of tetrahydrofuran was added, and the mixture was stirred at room temperature, and 6 g of Raney nickel was added.After vacuuming for 3 times, hydrogen gas was passed through a hydrogen balloon (pressure was 1 atm), and the reaction was carried out at room temperature. The reaction was followed by thin layer chromatography (TLC). After 10 hours, TLC showed the reaction was finished, and the reaction mixture was filtered over Celite, and tetrahydrofuran (20 mL) ×2) Washing diatomaceous earth,The tetrahydrofuran was evaporated to dryness to give 7.91 g of the white solid, 4-morpholinylaniline, yield 94.5%
87%	With palladium on activated charcoal; hydrogen; In methanol; at 20℃;	4-Fluoronitrobenzene (382 mg, 2.7 mmol) was dissolved in DMSO (7 ml), potassium carbonate (561 mg, 4.0 mmol) and morpholine (472 mg, 5.4 mmol) were added, and the mixture was stirred at 90 C. overnight. Then, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with saturated aqueous NaCl. The organic layer was dried over Na2CO3, the solvent was evaporated, and the obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate (2:1)) to give compound Y180 (yield; 493 mg, 88%). Compound Y180 (483 mg, 2.3 mmol) was dissolved in methanol (25 ml), Pd/C (205 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. Then, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate (1:2)) to give compound Y183 (yield; 358 mg, 87%). Compound Y491 (mentioned later) (134 mg, 0.3 mmol) was dissolved in dichloromethane (4 ml), compound Y183 (158 mg, 0.9 mmol) and triethylamine (123 mul, 0.9 mmol) were added, and the mixture was stirred at room temperature for 45 min. Then, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (22:1)) to give the title compound (yield; 120 mg, 69%). 1H NMR (500 MHz, CDCl3) delta8.43 (s, 1H), 8.00 (d, 1H, J=8.0 Hz), 7.70 (d, 1H, J=8.0 Hz), 7.53 (t, 1H, J=8.0 Hz), 7.43 (bs, 1H), 6.98 (dd, 2H, J=9.0, 3.5 Hz), 6.76 (dd, 2H, J=9.0, 3.5 Hz), 5.55 (dd, 1H, J=6.5, 6.0 Hz), 4.05 (bs, 2H), 3.83-3.81 (m, 4H), 3.10-3.08 (m, 4H), 2.80-2.63 (m, 4H), 1.64-1.54 (m, 3H), 1.42 (s, 9H), 1.86-1.01 (m, 2H) 13C NMR (125 MHz, CDCl3) delta155.0, 150.1, 141.6, 140.8, 131.3, 131.0, 129.8, 127.4, 125.8, 125.6, 116.2, 79.7, 66.9, 58.6, 50.9, 49.2, 48.7, 36.5, 29.6, 28.6, 18.5 HRMS (FAB-) m/z: [M-H]- calcd for C27H37N4O7S2, 593.2104. found, 593.2197
87.4%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 17h;Inert atmosphere;	4-(4-Nitrophenyl)morpholine (2.20 g, 10.6 mmol) was dissolved in 12 mL of methanol.Replace the nitrogen,Add 30mg of 10% palladium on carbon,The system replaces hydrogen three times,The reaction was stirred at room temperature for 17 h.Palladium charcoal is filtered off,The filtrate was dried to give a pale yellow oil, 1.65 g.Yield: 87.4%.
86%	With ammonium chloride; zinc; In ethanol; water; for 0.5h;Reflux;	Compound 7-b (1.5 g, 7.21 mmol) and ammonium chloride (1.0 g, 18.03 mmol) were dissolved in 50% ethanol-water (20 mL), Zn-powder (1.2 g, 18.03 mmol) was then added. The mixture was refluxed for 30 minutes. After cooled to room temperature, the mixture was filtrated. The filter cake was washed with ethanol (10 mL), the combined filtrate were concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3), the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give light brown solid 7-a (1.1 g, yield: 86%), which was used directly for the next step without purification. LC-MS (ESI): m/z=179 [M+H]+.
85%	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 80℃; under 760.051 Torr; for 12h;	To a mixture of 5a (2.13g, 10mmol) in dry ethyl acetate was added 10% Pd/C (0.5g), following the reaction mixture was stirred under hydrogen gas at 80C for 12h. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (dichloromethane/methanol 15:1 by volume) to give 4-morpholinyl aniline 6a (1.5g, yield 85%). 1H NMR (400MHz, CDCl3) delta 6.81-6.77 (m, 2H), 6.68-6.64 (m, 2H), 3.85-3.83 (m, 4H), 3.03-3.01 (m, 4H).
85%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	4-(4-nitrophenyl)morpholine (1 g, 4.80 mmol) and methanol (30 mL) were placed in a reaction vessel. 10% Pd / C (100 mg) was added to the mixed solution, and the mixture was stirred at room temperature under a balloon pressure filled with hydrogen gas. The reaction solution was filtered through a pad of diatomaceous earth and concentrated. The target compound (728 mg, 85% yield) was used in the next reaction without purification.
77%	With water; ammonium chloride; zinc; In tetrahydrofuran; methanol; at 20℃;	Synthesis of 4-Morpholin-4-yl-phenylamine Ammonium chloride (1.2 g, 23.0 mmol) in water (4.5 mL) then MeOH (9 mL) were added to a stirred solution of 4-(4-nitro-phenyl)-morpholine (480 mg, 2.3 mmol) in THF (9 mL). Zinc powder (1.2 g, 18.4 mmol) was then added portion wise and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered over celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 316 mg (77%) of 4-morpholin-4-yl-phenylamine. 1H NMR: (DMSO-d6): delta 6.7 (m, 2H), 6.5 (m, 2H), 4.6 (s, 2H), 3.7 (t, 4H), 2.8 (t, 4H).
74.1%	With iron(III) chloride hexahydrate; pyrographite; hydrazine hydrate; In ethanol; at 65 - 78℃; for 5h;	General procedure: A mixture of compounds 5a-e (0.05 mol) in ethanol was heated to 65 C, FeCl3·6H2O (2.8 g, 0.001 mol) and activated carbon (0.18 g, 0.015 mol) were added, and 80% hydrazine hydrate (25 g, 0.5 mol) was added drop wise at such a rate to keep the temperature below 70 C, the reaction was heated at reflux for 5 h and then cooled to room temperature and concentrated. Water (100 mL) was added, the reaction solution was extracted three times with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to obtain the compounds 6a-e.
74.1%	With iron(III) chloride hexahydrate; hydrazine hydrate; In ethanol; for 5h;	General procedure: A mixture of compounds 5 or 7a-c (0.05 mol) in ethanolwas heated to 65 C, FeCl3·6H2O (2.8 g, 1 mmol) and activatedcarbon (0.18 g, 15 mmol) were added, and 80% hydrazinehydrate (25 g, 0.5 mol) was added dropwise at such arate to keep the temperature below 70 C, the reaction washeated at reflux for 5 h and then cooled to room temperatureand concentrated. Water (100 mL) was added, the reactionsolution was extracted three times with CH2Cl2 (60 mL). Theorganic extracts were combined, dried over sodium sulfate,filtered, and concentrated to obtain the compounds 8a-d.
74%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 23h;	To a solution of 4-(4-nitrophenyl)morpholine(8.45 g, 0.041 mol) in EtOH (250 mL) was added 10% Pd/C(0.843 g, 10% w/w). The resulting mixture was stirred at roomtemperature under an atmosphere of hydrogen for 23 h. Aftercompletion, the mixture was filtered through Celite and washedwith EtOH. The solvent was removed in vacuo to give the titlecompound 8 (5.25 g, 74%) as a pink solid which was used withoutfurther purification. m.p. 129-130 C (Lit [21]. 129.5-130.5 C). deltaH(400 MHz; CDCl3) 3.02 (4H, t, J 4.7 Hz, H-30), 3.44 (2H, s, NH2),3.85, (4H, t, J 4.7 Hz, H-20), 6.66, (2H, d, J 8.8 Hz, H-3), 6.80 (2H,d, J 8.8 Hz, H-2). deltaC (100 MHz; CDCl3) 51.1 (C-30), 67.0 (C-20), 116.2(C-2), 118.1 (C-3), 140.3 (C-1), 144.4 (C-4); IR numax(ATR)/cm-1: 3393,2855, 1641, 1411, 1259, 1107, 825; m/z (ESI+): 227 (17%), 179 (MH,100%); HRMS (ESI+) found (M+H): 179.1178, C10H15N2O requires179.1179. The 1H NMR data were in agreement with literaturevalues [22].
73%	With iron; acetic acid; In methanol; water;	4 g of iron powder, 30 mL of water and 0.5 mL of glacial acetic acid were added to a 100 mL round bottom flask and heated to reflux for 10 min.Then, a solution of 3.12 g (0.015 mol) of 4-(4-nitrophenyl)morpholine dissolved in 20 mL of methanol was added, the reaction was stirred, and the reaction was traced to the end point by TLC.A small amount of anhydrous sodium sulfite was added, and after cooling, the pH was adjusted to 8-9 with a 10% sodium carbonate solution, and filtered through Celite.The filter cake was washed with hot ethanol, and the filtrate was evaporated to a solvent.Washed with saturated sodium carbonate solution and saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give a yellow solid 1.96g,Melting point: 132-133 C, yield 73%.
73%	With iron; acetic acid; In methanol; water;	Weigh 4g of iron powder in a 100ml round bottom flask.Add 30 ml of water and 0.5 ml of glacial acetic acid.Activated under reflux for 10 min,Then weighed 3.12 g (0.015 mol) of the previous synthesis4-(4-nitrophenyl)morpholine in 20 ml of methanol,Add to the reaction bottle,TLC tracks the reaction, the reaction is complete,Add a small amount of anhydrous sodium sulfite, cool and then adjust the pH to 8-9 with 10% sodium carbonate solution, filter with diatomaceous earth, filter cake with hot ethanol, until the filtrate is colorless, the filtrate is steamed a part of solvent After that, it was extracted with ethyl acetate, washed successively with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate.Concentrated to give 1.96 g of a yellow solid.The yield was 73%.
70%	With ammonia;palladium; In methanol;	REFERENCE EXAMPLE 20 Preparation of 4-Morpholin-4-yl-phenylamine 4-(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;) (Lancaster Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5% palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70% yield, mp 132-133 C.). GC/CMS (EI, M+) m/z=178.
70%	With ammonia;palladium; In methanol;	REFERENCE EXAMPLE 20 Preparation of 4Morpholin-4-yl-phenylamine. 4(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;). (Lancaster Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5% palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70% yield, mp 132-133 C.). GC/MS (EI, Mt) m/z=178.
70%	With ammonia;palladium; In methanol;	Reference Example 20 Preparation of 4-Morpholin-4-yl-phenylamine 4-(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;) (Lancaster Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5% palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70% yield, mp 132-133 C.). GC/MS (EI, M+) m/z=178.
68%	With iron; ammonium chloride; In methanol; water; at 60℃; for 2h;	10 (7.13 g, 34.26 mmol) and ammonium chloride (3.66 g, 68.52 mmol) were added to the reaction flask and 30 ml of MeOHAnd water (30 ml) was added with iron powder (7.67 g, 137.04 mmol) under stirring. The reaction was carried out at 60 C for 2 hours. The filter was washed with n-butanol and extracted with n-butanol (150 ml x 3) Washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 4.15 g of a dark brown solid (yield: 68%).
	With ammonium formate;palladium 10% on activated carbon; In tetrahydrofuran; methanol; at 20℃; for 7h;	N-(4-nitrophenyl)morpholine (18.7g) and (400ml) ammonium formate (23.5g) were suspended in a mixture tetrahydrofuran-methanol: lvol-4vol (400ml) and 10% Pd/C (0.5g) was added to the stirred suspension by portion for 5min. The mixture was <n="13"/>stirred at ambient temperature for 3 hours. Then a mixture tetrahydrofuran-methanol: lvol-4vol (100ml) and ammonium formate (12g) were added to the reaction mixture at once, followed by addition in portions of 10% Pd/C (0.5g) with stirring. The reaction mixture was stirred for additional 4 hours. The solid was filtered, and the solvents from the mother liquor were evaporated under vacuum. The rest was triturated in a mixture ethyl acetate-water (80ml-100ml). The solid was filtered, dried (3O0C, vacuum 10mm, 8 hour) and gave 4-(4-morpholinyl)aniline (11.5g).
	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 2h;	General procedure: Nitro-compound (2a-2e) was dissolved in methanol and stirred at room temperature with palladium/charcoal (5mol%) in a hydrogen gas environment for 2h. The resulting solution was filtered through celite, concentrated, and used in the next step without further purification.
	With hydrazine; In ethanol;Reflux;	General procedure: 4-Nitrobenzyl bromide (46.3mmol) was dissolved in dichloromethane (100mL). The solution was added to the mixture of relative amine (47.0mmol) and triethylamine (70.3mmol) in dichloromethane (20ml). The reaction mixture was stirred at r. t. for 24 h and was extracted with dichloromethane (100ml×3). After removal of the solvent, the residue was crystallized from ethanol, giving yellow powder. Compounds 1 and 2 were used for further reaction without purification. To a suspension of compounds 1-2 (36.2mmol) in 95% ethanol (100ml), 85% NH2NH2·H2O (362mmol), 95% ethanol (100ml) and iron (III) oxide hydroxide (FeO(OH)/C, 2.0g) were added and heated to reflux. When TLC analysis showed complete conversion of the starting material, the reaction mixture was filtrate through Cellit and the filtrate was concentrated in vacuum. The crude product was purified by silica gel colum chromatography (DCM/MeOH) to yield the title compound (3 and 4) as white solid. The mixture of compound 4 (1eq, 18.5mmol), 4-Nitro-1H-pyrazole-3-acid (1.1equiv, 20.4mmol), EDC (1.2equiv, 22.2mmol), HOBT (1.2equiv, 22.2mmol) in DMF (50ml) was stirred for 24h. The ice water (100ml) was added to the reaction mixture. A large amount of yellow solid precipitation (compound 8) was acquired. Compound 8 was used without further purification. Compounds 8 was reduced by the same process as compound 4, and then the resulting compound 12 was purified by column chromatography on silica gel, eluted with the appropriate solvent.
209 mg	With iron; ammonium chloride; In methanol; water; at 100℃;	General procedure: The compound S1 (261 mg, 1.25 mmol), iron powder (210 mg, 4.76 mmol, 3 equiv.) and ammonium chloride (335 mg, 6.27 mmol, 5 equiv.) were dissolved in methanol : water (2 : 1, 15 mL). The reaction mixture was heated at 100 C overnight, cooled to RT, filtered through celite and the solvent was reduced under vacuum. The condensed mixture was extracted with DCM, washed with brine, dried with sodium sulfate and all solvent was evaporated to furnish the condensed residue, which was purified by flash chromatography (elution system - EA/Hexane = 1 : 1 ) to obtain the title compound (245 mg, 1.43 mmol).
	With 5%-palladium/activated carbon; hydrogen; In ethanol; water; at 20℃;	General procedure: The substituted nitro compound 11 (1 equiv in a mixture of EtOH-H2O, 95:5, 20mL) was treated with 10% Pd-carbon (5% w/w). The reaction was subjected to hydrogenation under hydrogen gas at room temperature and the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered through a Celite bed and concentrated in a vacuum to afford product 12.
0.85 g	With palladium on activated charcoal; hydrogen; In ethanol; at 20℃; for 24h;	4-Fluoronitrobenzene (1 g), K2CO3 (1.1 g) and 5 ml DMSO were stirred at room temperature for 30 min.Add morpholine (0.6 g) dropwise, stir at 220 C for 2 h, pour the mixture into 20 mL of alcohol and water mixture (1:1).The yellow precipitate was filtered to give 4-(4-nitrophenyl)morpholine 1.4 g.4-(4-Nitrophenyl)morpholine (1 g), Pd/C (0.1 g) and 20 ml of ethanol were exchanged in a balloon of hydrogen at room temperature for about 24 h.The diatomaceous earth was filtered under reduced pressure, and the filtrate was dried under reduced pressure.The title product was obtained (0.85 g).
2.2 g	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 12h;	PdeC (0.27 g, 10% m/m) wasadded to a solution of 8a (2.7 g, 13.0 mmol) in ethanol (20 ml) andhydrogenated for 12 h at room temperature. The resultant wasfiltered, washed with ethanol and concentrated. 2.2 g of 9a aspurple solid was obtained; yield: 94%; 1H NMR (600 MHz,DMSO-d6) delta 6.68 (d, J 8.5 Hz, 2H), 6.50 (d, J 8.5 Hz, 2H), 4.62 (s,2H), 3.69 (t, J 4.8 Hz,4H), 2.87 (t, J 4.8 Hz,4H). MS (ESI) m/z:179.2 [MH].
	With FeO(OH)/C; hydrazine hydrate; In ethanol; at 0 - 80℃; for 4h;	General procedure: To a solution of 1a (5 g, 22.5 mmol) in 95% ethanol (100 mL) wasadded goethite (FeO(OH))/C (1.0 g) at room temperature. And a solution of 80% hydrazine hydrate (25 mL, 400 mmol) in 95% ethanol (50 mL) was added dropwise to the mixture at 0 C. The reaction mixture was stirred at 80 C for 4 h. The solvent was removed in vacuo to give 2a (3.8 g, yield 74.5%). MS m/z: 278.2 [M+H]+.
0.85 g	With palladium on activated charcoal; hydrogen; at 10 - 35℃; for 24h;	Add 4-fluoronitrobenzene (1g), K2CO3 (1.1g) and 5ml DMSO,The reaction was stirred at room temperature for 30 min, and morpholine (0.6 g) was added dropwise.Heat the reaction at 120 C for 2h and pour the mixture into 20mL of alcohol and water mixed solution (1: 1).The yellow precipitate was filtered to give 1.4 g of 4- (4-nitrophenyl) morpholine.Add 4- (4-nitrophenyl) morpholine (1g), Pd / C (0.1g) and 20ml ethanol,The air was replaced with a hydrogen balloon, and the reaction was performed at room temperature for about 24 hours. Diatomite vacuum filtration,The filtrate was dried under reduced pressure to obtain the title product.(0.85g).
	With sodium tetrahydroborate; In water; for 1h;	General procedure: The catalytic activities of Au/TNT and Au/ANT for the reduction of4NP with NaBH4 were evaluated using 0.015 g of catalyst samples andthe necessary amounts of substrate to obtain a molsubstrate;molAu ratio of500, based on the metal contents determined by AAS. The experimentalprocedure was measured employing a glass reactor (500 mL) equippedwith a mechanical stirrer (Figure S2). All activity performances weredetermined in triplicate. Initially, DI water (17.2 mL), the catalyst(0.015 g), and the 4NP solution (3.8 mL, 0.05 M) were mixed in thereactor at 400 rpm for 15 min. Subsequently, a freshly prepared 1.0Maqueous NaBH4 solution (19 mL) was added, and this was considered asthe zero time. The catalytic reduction of 4NP was then monitored bytaking non-invasive samples (500 ]L) periodically from the reactionmixture at different reaction times, and the reaction progress wasmonitored by UV-vis spectrophotometry between 250 and 550 nm. Toconfirm the obtained results, after each reaction, the samples wereanalyzed using the HPLC-DIONEX liquid chromatography system.

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[43]Patent: WO2007/64818,2007,A1 .Location in patent: Page/Page column 11-12
[44]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2012,vol. 51,p. 731 - 738
[45]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4377 - 4385
[46]Journal of Medicinal Chemistry,2012,vol. 55,p. 10685 - 10699
[47]European Journal of Medicinal Chemistry,2017,vol. 125,p. 1036 - 1050
[48]European Journal of Medicinal Chemistry,2018,vol. 155,p. 303 - 315
[49]European Journal of Medicinal Chemistry,2018,vol. 158,p. 593 - 619
[50]European Journal of Medicinal Chemistry,2019,vol. 162,p. 161 - 175
[51]European Journal of Medicinal Chemistry,2019,vol. 163,p. 690 - 709
[52]Patent: CN109678803,2019,A .Location in patent: Paragraph 0223-0227
[53]New Journal of Chemistry,2019,vol. 43,p. 10190 - 10202
[54]European Journal of Medicinal Chemistry,2019,vol. 181
[55]Bioorganic Chemistry,2020,vol. 94
[56]Patent: CN110330484,2019,A .Location in patent: Paragraph 0107-0109
[57]International Journal of Molecular Sciences,2019,vol. 20
[58]Journal of Medicinal Chemistry,2020,vol. 63,p. 3327 - 3347
[59]Journal of Medicinal Chemistry,2020
[60]Catalysis Today,2020
[61]Patent: CN111217815,2020,A .Location in patent: Paragraph 0090; 0105; 0106

2
[ 110-91-8 ]
[ 106-40-1 ]
[ 2524-67-6 ]
[ 159724-40-0 ]

Reference： [1]Organic Letters,2003,vol. 5,p. 3515 - 3517

3
[ 2524-67-6 ]
[ 555-57-7 ]
[ 33375-06-3 ]
C₃₆H₂₉IN₂O₆ [ No CAS ]
C₆₃H₅₈N₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Pargyline; C₃₆H₂₉IN₂O₆ With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 20℃; for 72h; Stage #2: 4-morpholino-4-yl-phenylamine With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; Stage #3: (1R)-1-phenylethyl isocyanate With dmap; triethylamine In tetrahydrofuran at 20℃; for 48h;

Reference： [1]Lo, Michael M.-C.; Neumann, Christopher S.; Nagayama, Satoshi; Perlstein, Ethan O.; Schreiber, Stuart L. [Journal of the American Chemical Society, 2004, vol. 126, # 49, p. 16077 - 16086]

4
[ 2524-67-6 ]
[ 483324-01-2 ]
N-(4-morpholin-4-ylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Organic Letters,2005,vol. 7,p. 4113 - 4116

5
[ 2524-67-6 ]
[ 15790-94-0 ]
EP₇-229 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With TEA; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dichloromethane at 20℃; for 2h;

Reference： [1]Urbani, Paolo; Cavallo, Paolo; Cascio, Maria Grazia; Buonerba, Mariafrancesca; De Martino, Giovanni; Di Marzo, Vincenzo; Saturnino, Carmela [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 1, p. 138 - 141]

6
[ 2524-67-6 ]
[ 4640-67-9 ]
(E)-3-Amino-1-(4-fluoro-phenyl)-3-(4-morpholin-4-yl-phenylamino)-propenone [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 9463 - 9469

7
[ 2524-67-6 ]
[ 501-53-1 ]
[ 348626-43-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In dichloromethane; at 20℃;	In a 250 ml reaction flask was taken 1.78 g 4-morpholinyl aniline in 100 ml of methylene chloride was added 2.8 ml of triethylamine, cooled in an ice bath; dropwise benzyl chloroformate 2.1 ml, warmed to room temperature then stirred until TLC monitoring (thin layer chromatography) completion of the reaction; and finally 30 ml of water was added, liquid separation, the organic layer 3 times with 20 ml of water, dried over magnesium sulfate, concentrated and the crude product was by column chromatography to give the desired formula (III) structure of the compound. Analysis of the product: the product obtained weighed and yield was calculated, the result is: the desired structure of formula () weight compound 2.89 g, 92% yield.
	With sodium hydrogencarbonate; In water; acetone; at 20℃; for 5h;	A solution of benzylchloroformate (9.2ml, 65mmol, Aldrich) in 10ml of acetone was added dropwise to a stirred suspension of 4-(4-morpholmy,l)-N- benzyloxycarbonylaniline (11.5g, 65mmol) and sodium bicarbonate (Hg, 130mmol) in a mixture acetone water (300ml-150ml) at 0-50C for a half hour. Then the mixture was stirred at ambient temperature for 5 hours. The solid was filtered, and the solvents from the mother liquor were evaporated under vacuum. The rest was dissolved in dichloromethane- water (30OmI-IOOmI). After phase separation dichloromethane was evaporated under vacuum and gave 4-(4-mophiholinyl)-N-benzyloxycarbonylaniline (17g)

Reference： [1]Patent: CN108997247,2018,A .Location in patent: Paragraph 0067-0070
[2]Organic and Biomolecular Chemistry,2008,vol. 6,p. 4634 - 4642
[3]Journal of Medicinal Chemistry,2005,vol. 48,p. 5900 - 5908
[4]Patent: WO2007/64818,2007,A1 .Location in patent: Page/Page column 12

8
[ 4752-10-7 ]
[ 2524-67-6 ]
4-chloro-N-(4-morpholinophenyl)phthalazin-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	In ethanol for 3h; Reflux;	Synthesis of 4-chloro-N-(4-morpholinophenyl)phthalazin-1-amine (7) 1,4-dichlorophthalazine (6) (1.99g, 10mmol) was dissolved in ethanol (15 mL) and 4- morpholinoaniline(1.6g, 9mmol) was added and refluxed for 3 hours. After 3 hours, ethanol was concentrated and reaction was purified by Flash chromatography on silica gel. Yellow solid; Yield: 83%; Rf = 0.288 (50% EtOAc/Hexane on silica); 1H NMR (400 MHz, CDCl3) δ 8.21 - 8.17 (m, 1H, Ar-H), 8.03 (dd, J = 7.0, 1.9 Hz, 1H), 7.88 (ddt, J = 11.6, 7.2, 5.6 Hz, 2H), 7.54 (d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.85 - 3.81 (m, 4H), 3.07 (brs, 4H); 13C NMR (101 MHz, CDCl3) δ 151.96, 147.97, 132.57, 132.52, 126.63, 125.97, 122.77, 121.73, 116.40, 66.86, 49.68; LCMS (ESI): Calculated for [M+1]+ C18H17ClN4O 341.11, found 341.45.

Reference： [1]Kharbanda, Anupreet; Zhang, Lingtian; Saha, Debasmita; Tran, Phuc; Xu, Ke; Li, Ming O.; Leung, Yuet-Kin; Frett, Brendan; Li, Hong-yu [European Journal of Medicinal Chemistry, 2021, vol. 223]
[2]Duncton, Matthew A. J.; Piatnitski, Evgueni L.; Katoch-Rouse, Reeti; Smith II, Leon M.; Kiselyov, Alexander S.; Milligan, Daniel L.; Balagtas, Chris; Wong, Wai C.; Kawakami, Joel; Doody, Jacqueline F. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 6, p. 1579 - 1581]

9
[ 2524-67-6 ]
[ 85888-81-9 ]
[ 879213-64-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1726 - 1730

10
[ 2524-67-6 ]
[ 959755-46-5 ]
[ 959755-48-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol for 4.5h; Heating / reflux;	4 A mixture of 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (123 mg, 443 μmol), 4-(4- morpholino)aniline (118 mg. 0.664mmol) and N-ethyldiisopropylamine (116 mL, 0.664mmol) is heated at reflux in 2-propanol (3 mL) for 4.5 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and citric acid (10 %). The organic phase is washed once with water and brine, dried over MgSOzi, filtered and evaporated to furnish the title compound (156 mg, 94 %) as a yellow solid. 1H-NMR (400MHz, Cl6-DMSO) δ(ppm) 3.11 (m, 4H), 3.78 (m, 4H), 6.97 (d, 2H), 7.82 (d, 2H), 7.87 (s, IH), 8.71 (s, IH), 9.93 (br s, IH). LCMS, Rt 3.32 min (96.8 %) m/z (APCI) 375 (M+H)+.

Reference： [1]Current Patent Assignee: GALAPAGOS - WO2007/138072, 2007, A2 Location in patent: Page/Page column 44

11
[ 2524-67-6 ]
[ 882672-05-1 ]
[ 1008505-74-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	In acetonitrile; at 125℃; for 0.5h;microwave vial;	6-Bromo-2-chloroquinazoline (prepared in analogy to WO92/15569) (100 mg, 0.412 mmol, 1.0 equiv), (4-morpholin-4-ylphenyl)amine (110 mg, 0.617 mmol, 1.5 equiv), and acetonitrile (5.0 ml) were added to a microwave vial which was heated in a microwave at 125 C for 30 minutes. The reaction was then concentrated to afford a crude solid which was purified by an ISCO system (100% hexanes to 100% EtOAc) to obtain a yellow solid (117 mg, 74% yield). NMR: 9.78 (s, IH), 9.21 (s, IH), 8.13 (s, IH), 7.77 (m, 3H), 7.52 (d, IH), 6.94 (d, 2H), 3.72 (m, 4H), 3.03 (m, 4H); m/z 386.

Reference： [1]Patent: WO2008/20203,2008,A1 .Location in patent: Page/Page column 76

12
[ 92-53-5 ]
[ 2524-67-6 ]

Reference： [1]Journal of the American Chemical Society,1939,vol. 61,p. 2552

13
[ 2524-67-6 ]
[ 463-71-8 ]
[ 51317-66-9 ]

Yield	Reaction Conditions	Operation in experiment
97.56%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.5h;Inert atmosphere;	4-(4-lsothiocyanato-phenyl)-morpholineTo a stirring solution of <strong>[2524-67-6]4-morpholino-4-yl-phenylamine</strong> (2 g, 11.22 mmol) and diisopropylethylamine (2.89 g, 22.42 mmol) in dry dichloromethane (100 ml) at 0 C under N2, thiophosgene (1.54 g, 13.46 mmol) in dichloromethane is added dropwise and stirred for 30 minutes. The reaction mixture is quenched with water (100 ml) and the layers are separated, the organic layer is washed with water (50 ml X2) and dried over anhydrous MgS04 to get the product as brown crystalline solid (2.4 g, 97.56%); TLC: pet ether/ethyl acetate (6/4) R - 0.5;1H-NMR (400 MHz, DMSO-d6): delta [ppm] 7.29 (d, J = 6.92 Hz, 2H), 6.95 (d, J = 6.96 Hz, 2H), 3.71 (t, J = 4.96 Hz, 4H), 3.14 (t, J = 4.84 Hz, 4H).
97.56%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.5h;Inert atmosphere;	To a stirring solution of <strong>[2524-67-6]4-morpholino-4-yl-phenylamine</strong> (2 g, 11.22 mmol) and diisopropylethylamine (2.89 g, 22.42 mmol) in dry dichloromethane (100 ml) at 0 C under N2> thiophosgene (1.54 g, 13.46 mmol) in dichloromethane is added dropwise and stirred for 30 minutes. The reaction mixture is quenched with water (100 ml) and the layers are separated, the organic layer is washed with water (50 ml X2) and dried over anhydrous MgSO4to get the product as brown crystalline solid (2.4 g, 97.56%); TLC: pet ether/ethyl acetate (6/4) Rf- 0.5; 1H-NMR (400 MHz, DMSO-d6): delta [ppm] 7.29 (d, J = 6.92 Hz, 2H), 6.95 (d, J = 6.96 Hz, 2H), 3.71 (t, J = 4.96 Hz, 4H), 3.14 (t, J = 4.84 Hz, 4H).
64%	With sodium hydroxide; In chloroform; water; at 0℃; for 24h;	General procedure: To a solution of 4-substituted aniline (5.61 mmol) in chloroform(50 mL) was gradually added thiophosgene (6.17 mmol) by syringe and thena solution of NaOH (16.83 mmol) in distilled water was added to this mixture.The reaction mixture was stirred for 24 h at 0C and washed with distilled water (2x25 mL). The organic phase was separated and dried on anhydrous Na2SO4.The solvent and excess of thiophosgene was evaporated in vacuo and then thecrude product was recrystallized from ethanol.

With sodium carbonate; In tetrahydrofuran; water; at 23℃;

General procedure: A solution of the arylamine derivative in THF was added to saturated NaHCO3 aqueous solution. Then a solution of CSCl2 in THF was added dropwise and the resulting mixture was stirred at 23 C for 2 h, TLC showed that there was no starting material left. To the above solution, the amine derivative was added dropwise at 0-10 C. When TLC indicated that the reaction was complete, the solution was extracted with MTBE three times and the organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness to produce a crude product. After re-crystallizationin MTBE, a pure product was obtained.

Reference： [1]Patent: EP1215208,2002,A2 .Location in patent: Example C(54)
[2]Patent: WO2012/25186,2012,A1 .Location in patent: Page/Page column 76
[3]Patent: WO2013/124026,2013,A1 .Location in patent: Page/Page column 77; 78
[4]Phosphorus, Sulfur and Silicon and the Related Elements,2014,vol. 189,p. 661 - 673
[5]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1948 - 1952
[6]Letters in drug design and discovery,2013,vol. 10,p. 640 - 650

14
[ 2524-67-6 ]
[ 30529-70-5 ]
[ 681161-09-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With pyridine; In chloroform; at 60℃; for 120h;	5 g of <strong>[30529-70-5]2-chloro-6-methylnicotinic acid</strong>, 5.45 g [OF 4- (4-MORFORINO)] aniline, and 7.2 mL of pyridine were added to 100 mL of chloroform, and heated at [60C] for five days. When the reaction was completed, the reaction mixture was cooled to room temperature and a little amount of solid extracted from the reaction was filtered and washed with 10 mL of chloroform to remove any impurities therein. The solvent chloroform was concentrated with 60 mL of methanol under reduced pressure and stirred for 1 hour. Then, the organic layer was filtered and washed twice with 10 mL of methanol to give a solid product. The product was dried in vacuo at [35-45C] to give 7.31 g of the desired compound (89% yield). m. p.: 220-221C [LH-NMR] (DMSO-d6), [PPM] : 8 2.39 (s, 3H), 3.04 (t, 4H), 3.73 (t, 4H), 6.61 (dd, 1H), 6.89 (d, 2H), 7.57 (dd, 2H), 8.05 (dd, [1H),] 10.21 (s, [1H)]

Reference： [1]Patent: WO2004/33450,2004,A1 .Location in patent: Page 10

15
[ 2524-67-6 ]
[ 133831-28-4 ]
[ 866000-98-8 ]

Yield	Reaction Conditions	Operation in experiment
98%		To a solution of 3-formyl-lH-indole-6-carboxylic acid methyl ester (500 mg, 2.46 mmol), 4-morpholinoaniline (482.3 mg, 2.71 mmol) and dibutyltin dichloride (76 mg, 0.25 mmol) in THF was added phenylsilane (334 ul, 2.71 mmol). The mixture was stirred at room temperature overnight under nitrogen, THF was evaporated off the mixture and the residue was purified by flash chromatography (hexane/EtOAc, 20/80) to afford the title compound 123 (881 mg, 98%). H-NMR (DMSO) 8 : 8.00 (d, J= 1.0 Hz, 1H), 7.70 (d, J= 8.2 Hz, 1H) ; 7.58 (dd, J= 8.4, 1.6 Hz, 1H); 7.52 (d, J=2.0 Hz, 1H); 6.70 (d, J= 9.0 Hz, 2H); 6.59 (d, J= 9.0 Hz, 2H) ; 5.48 (t, J= 5.8 Hz, 1H); 4.31 (d, J=5.7 Hz, 2H); 3.83 (s, 3H) ; 3.68 (t, J=4.7 Hz, 4H) ; 2.86 (t, J=4.7 Hz, 4H).

Reference： [1]Patent: WO2005/92899,2005,A1 .Location in patent: Page/Page column 104

16
[ 5781-53-3 ]
[ 2524-67-6 ]
[ 892491-25-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	Methyl chlorooxaacetate (4.64 mL, 50 mmol) was added dropwise to an ice cooled solution of 4-morpholinoaniline (8.91 g, 50 mmol) and ethyldiisopropylamine (9.4 mL, 55 mmol) in DCM (125 mL).The reaction was stirred for 2 h at room temperature then quenched with water (100 mL).The organic layer was removed, dried (MgSO4), filtered and evaporated to EPO <DP n="313"/>give the title compound (11.7 g, 89%): 1H NMR deltaltheta.63 (IH, s), 7.61 (2H , d), 6.92 (2H , d), 3.88 (3H, s), 3.78-3.68 (4H, m), 3.15-3.04 (4H, m); MS m/e MH+ 265.
89%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 18 - 25℃; for 2h;	Intermediate 1: Methyl [(4-morpholin-4-yl phenyl)aminol(oxo)acetateMethyl chloro(oxo)acetate; (4.64 mL, 50 mmol) was added dropwise to an ice cooled solution of 4-morpholinoaniline (8.91 g, 50 mmol) and ethyldiisopropylamine (9.4 mL, 55 mmol) in DCM (125 mL). The reaction was stirred for 2 hours at room temperature then quenched with H2O (100 mL). The organic layer was removed, dried, filtered and concentrated in vacuo to give the title compound (11.7 g, 89%): 1H NMR: 10.63 (IH, s), 7.61 (2H, d), 6.92 (2H, d), 3.88 (3H, s), 3.78-3.68 (4H, m), 3.15-3.04 (4H, m); MS MH+ 265.

Reference： [1]Patent: WO2006/64189,2006,A1 .Location in patent: Page/Page column 311
[2]Patent: WO2006/134317,2006,A1 .Location in patent: Page/Page column 59
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3873 - 3878

17
[ 464213-93-2 ]
[ 2524-67-6 ]
[ 37091-73-9 ]
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-morpholinoaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane;	Example 110 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-morpholinoaniline 4-Morpholinoaniline (0.286 g, 1.60 mmol), triethylamine (0.162 g, 1.60 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.271 g, 1.60 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexane: ethyl acetate = 1:2) and then recrystallized from ether to obtain the titled compound (0.077 g, 0.144 mmol, 27percent).

Reference： [1]Patent: EP1314712,2003,A1

18
[ 2524-67-6 ]
[ 7693-46-1 ]
(4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester, hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	In tetrahydrofuran; at 20℃; for 0.00277778h;	EXAMPLE 14; 1-(4-Morpholin-4-yl-phenyl)-3-(1-thieno [3,2-d]pyrimidin-4-yl-pyrrolidin-3-yl)-urea a. (4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester; hydrochloride A solution of 4-nitrophenyl chloroformate (798 mg, 3.96 mmol) in THF (2.0 mL) was added rapidly by syringe over 10 s at rt under air to a stirred solution of 4-morpholin-4-yl-phenylamine (675 mg, 3.79 mmol) in THF (8.8 mL), with a heavy grey precipitate forming ?instantly?. The reaction was immediately capped and stirred ?rt? for 30 min (vial spontaneously warmed), and was then filtered. The grey filter cake was washed with dry THF (2×10 mL), and dried under high vacuum at 80 C. to afford the title compound as a grey powder (1.361 g, 95%). A portion was partitioned with CDCl3 and aqueous 0.5 M trisodium citrate to generate the CDCl3-soluble free base: 1H-NMR (300 MHz, CDCl3) delta 8.28 (m, 2H), 7.42-7.31 (m, 4H), 6.95-6.88 (m, 3H), 3.87 (m, 4H), 3.14 (m, 4H).
95%	In tetrahydrofuran; at 20℃; for 0.502778h;	A solution of 4-nitrophenyl chloroformate (798 mg, 3.96 mmol) in THF (2.0 mL) was added rapidly by syringe over 10 s at rt under air to a stirred solution of 4-morpholin-4-yl-phenylamine (675 mg, 3.79 mmol) in THF (8.8 mL), with a heavy grey precipitate forming "instantly". The reaction was immediately capped and stirred "rt" for ~30 min (vial spontaneously warmed), and was then filtered. The grey filter cake was washed with dry THF (2*10 mL), and dried under high vacuum at 80 C. to afford the title compound as a grey powder (1.361 g, 95%).
95%	In tetrahydrofuran; at 20℃; for 0.502778h;	A solution of 4-nitrophenyl chloroformate (798 mg, 3.96 mmol) in THF (2.0 mL) was added rapidly by syringe over 10 s at rt under air to a stirred solution of 4-morpholin-4-yl-phenylamine (675 mg, 3.79 mmol) in THF (8.8 mL), with a heavy grey precipitate forming ?instantly?. The reaction was immediately capped and stirred ?rt? for 30 min (vial spontaneously warmed), and was then filtered. The grey filter cake was washed with dry THF (2×10 mL), and dried under high vacuum at 80 C. to afford the title compound as a grey powder (1.361 g, 95%). A portion was partitioned with CDCl3 and aqueous 0.5 M trisodium citrate to generate the CDCl3-soluble free base: 1H-NMR (300 MHz, CDCl3) delta 8.28 (m, 2H), 7.42-7.31 (m, 4H), 6.95-6.88 (m, 3H), 3.87 (m, 4H), 3.14 (m, 4H).

95%	In tetrahydrofuran; at 20℃; for 0.502778h;	EXAMPLE 66; 4-[7-(3-Methanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; a. (4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester; hydrochloride; A solution of 4-nitrophenyl chloroformate (798 mg, 3.96 mmol) in THF (2.0 mL) was added rapidly by syringe over 10 s at rt under air to a stirred solution of 4-morpholin-4-yl-phenylamine (675 mg, 3.79 mmol) in THF (8.8 mL), with a heavy grey precipitate forming ?instantly?. The reaction was immediately capped and stirred ?rt? for 30 min (vial spontaneously warmed), and was then filtered. The grey filter cake was washed with dry THF (2×10 mL), and dried under high vacuum at 80 C. to afford the title compound as a grey powder (1.361 g, 95%). A portion was partitioned with CDCl3 and aqueous 0.5 M trisodium citrate to generate the CDCl3-soluble free base: 1H-NMR (300 MHz, CDCl3) delta 8.28 (m, 2H), 7.42-7.31 (m, 4H), 6.95-6.88 (m, 3H), 3.87 (m, 4H), 3.14 (m, 4H).
95%	In tetrahydrofuran; at 20℃; for 0.501333h;	EXAMPLE NO. 43; 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-morpholin-4-yl-phenyl)-urea (Compound No. 43); a. (4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester; hydrochloride; A solution of 4-nitrophenyl chloroformate (798 mg, 3.96 mmol) in THF (2.0 mL) was added rapidly by syringe over 10 s at rt under air to a stirred solution of 4-morpholin-4-yl-phenylamine (675 mg, 3.79 mmol) in THF (8.8 mL), with a heavy grey precipitate forming ?instantly?. The reaction was immediately capped and stirred ?rt? for 30 min (vial spontaneously warmed), and was then filtered. The grey filter cake was washed with dry THF (2×10 mL), and dried under high vacuum at 80 C. to afford the title compound as a grey powder (1.361 g, 95%). A portion was partitioned with CDCl3 and aqueous 0.5 M trisodium citrate to generate the CDCl3-soluble free base: 1H-NMR (300 MHz, CDCl3) delta 8.28 (m, 2H), 7.42-7.31 (m, 4H), 6.95-6.88 (m, 3H), 3.87 (m, 4H), 3.14 (m, 4H).

Reference： [1]Patent: US2006/281768,2006,A1 .Location in patent: Page/Page column 25
[2]Patent: US2006/281769,2006,A1 .Location in patent: Page/Page column 40
[3]Patent: US2006/281771,2006,A1 .Location in patent: Page/Page column 64
[4]Patent: US2006/281772,2006,A1 .Location in patent: Page/Page column 81
[5]Patent: US2007/4763,2007,A1 .Location in patent: Page/Page column 52

19
[ 2524-67-6 ]
[ 99-58-1 ]
[ 875748-92-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 18h;	3-Bromo-4-methoxy-N-(4-morpholin-4-yl-plienyl)-benzamide; A mixture of <strong>[99-58-1]3-bromo-4-methoxy-benzoic acid</strong> (500mg), N-(4- aminophenyl)morpholine (385mg), EDAC (828mg), HOBT (583mg) and N- methylmorpholine (714mul) in DMF (5ml) was stirred at room temperature for 18h. The mixture was then diluted with water (30ml) and the resulting solid collected by filtration and dried (818mg)

Reference： [1]Patent: WO2007/31791,2007,A1 .Location in patent: Page/Page column 140

20
[ 2524-67-6 ]
[ 10130-89-9 ]
4-[N-[4-(4-morpholino)phenyl]sulfamoyl]benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With pyridine; In dichloromethane; at 0 - 30℃; for 5h;	4 g of 4-(4-morpholino)aniline and 5.45 ml of pyridine were added to 100 ml ofdichloromethane, stirred to dissolve and cooled to 0C. Then, 4.95g of4-(chlorosulfonyl)benzoic acid was added and the mixture was stirred at 0~5C for 2hours, followed by stirring at 20~30C for 3 hours more. After the reaction wascompleted, the reaction mixture was concentrated under reduced pressure and theresidue was crystallized by 80 ml of methanol. Then, 120 ml of water was added,stirred at room temperature for 3 hours, filtered, and washed with mixed solvent of 5ml of methanol and 25 ml of water, to give a solid product. To purify the solid product,mixed solvent of 30 ml of methanol and 150 ml of water and 6.6 ml of 3N-NaOHsolution were added in sequence and stirred for 2 hours. The insoluble solid productwas filtered, washed with 30 ml of water for removing impurities and crystallized byadding 6.6 ml of 3N-HC1 slowly. The mixture was stirred at room temperature for 4hours, filtered and washed with 40 ml of water, to give a crystalline product. Theproduct was dried in vacua at 40~50C to give 6.51 g of the desired compound (80%yield).m.p.:256~258C(dec.)XH-NMR (DMSO-d ), ppm: 5 3.00 (t, 4H), 3.68 (t, 4H), 6.78 (d, 2H), 6.85 (d, 2H),7.77 (d, 2H), 8.04 (d, 2H), 9.98 (s, 1H)

Reference： [1]Patent: WO2006/11719,2006,A1 .Location in patent: Page/Page column 6; 8-9; 17

21
[ 2524-67-6 ]
[ 42518-42-3 ]
2-chloro-5,6-dimethyl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With aniline In ethanol Heating / reflux;	1 To 240 mg (1.02 mmol of 2, 4-dichloro-5, β-dimethyl- thieno [2 , 3-d] pyrimidine in 50 ml of ethyl alcohol were added 220.20 mg (1.23mmol) of 4- (4-morpholino) aniline and 130.90 mg (1.23 mmol) of aniline, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 430 mg (quantitative) of 2-chloro-5, 6-dimethyl- thieno [2 , 3-d] pyrimidin-4-yl-4-morpholin-4-yl-phenylamine . 220 mg (0.53 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 223 μi (1.59 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120 "C . After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 30 mg (15% yield) of 5, β-dimethyl-2-piperazin-l- yl-thieno[2,3-d] pyrimidin-4-yl-4-morpholin-4-yl- phenylamine. To 9 mg (0.02 mmol) of the obtained compound and 5, 6-dimethyl-2-piperazin-l-yl-thieno [2, 3-d] pyrimidin- 4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl EPO chloride were added 3.5 μJt (0.02 irunol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure, and the residue was crystallized from dimethyl chloride, thus obtaining 6 mg (30% yield) of the title product.1H NMR (CDCl3) ppm : 8.85-8.95 (d, IH), 8.27-8.35 (m, IH), 7.79-8.01 (m, IH), 7.60-7.79 (m, IH), 7.25-7.30(m, 2H), 6.87-6.95 (m, 2H), 3.92-3.70 (m, 10H), 3.40 (br,2H), 3.18-3.13 (t, J=3.4Hz, 4H), 2.50 (s, 3H), 2.37 (s,3H) .
100%	With aniline In ethanol Heating / reflux;	1 EXAMPLE 1Preparation of 4-[5,6-dimethyl-4-(4-morpholin-4-yl-phenylamino)-thieno[2,3-d]pyrimidin-2-yl]-piperazin-1-yl-pyridin-2-yl-methanoneTo 240 mg (1.02 mmol of 2,4-dichloro-5,6-dimethyl-thieno[2,3-d]pyrimidine in 50 ml of ethyl alcohol were added 220.20 mg (1.23 mmol) of 4-(4-morpholino)aniline and 130.90 mg (1.23 mmol) of aniline, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 430 mg (quantitative) of 2-chloro-5,6-dimethyl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. 220 mg (0.53 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 223 μl (1.59 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120° C. After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 30 mg (15% yield) of 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. To 9 mg (0.02 mmol) of the obtained compound and 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl chloride were added 3.5 μl (0.02 mmol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure, and the residue was crystallized from dimethyl chloride, thus obtaining 6 mg (30% yield) of the title product.1H NMR (CDCl3) ppm: 8.85-8.95 (d, 1H), 8.27-8.35 (m, 1H), 7.79-8.01 (m, 1H), 7.60-7.79 (m, 1H), 7.25-7.30 (m, 2H), 6.87-6.95 (m, 2H), 3.92-3.70 (m, 10H), 3.40 (br, 2H), 3.18-3.13 (t, J=3.4 Hz, 4H), 2.50 (s, 3H), 2.37 (s, 3H).

Reference： [1]Current Patent Assignee: CREAPLANET CO. LTD. - WO2007/35010, 2007, A2 Location in patent: Page/Page column 11-12
[2]Current Patent Assignee: CREAPLANET CO. LTD. - US2008/234482, 2008, A1 Location in patent: Page/Page column 3; 4

22
[ 85373-96-2 ]
[ 2524-67-6 ]
[ 929891-53-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 1.0h;	3-Bromo-N-(4-morpholin-4-ylphenyl)-4-trifluoromethoxy-benzamide; A solution of <strong>[85373-96-2]3-bromo-4-trifluoromethoxybenzoic acid</strong> (515mg), N-(4- aminophenyl)morpholine (323mg), EDAC (763mg), HOBT (538mg) and N- methylmorpholine (597mul) in DMF (5ml) was stirred at room temperature. After Ih, water (10ml) was added and the resulting suspension filtered. The residue was dried in vacuo and then purified by flash column chromatography, eluting with 2 : 1 petroleum ether : ethyl acetate. The title compound was isolated as an off-white solid (532mg). 1H NMR (DMSO, delta) 3.07 (t, 4H)5 3.80 (t, 4H)5 6.84 (d, 2H), 7.31 (dd, IH), 7.42 (d, 2H)5 7.68 (s, IH)5 7.76 (dd, IH)5 8.07 (s, IH). LCMS- ES+ = 446.

Reference： [1]Patent: WO2007/31791,2007,A1 .Location in patent: Page/Page column 138

23
[ 2524-67-6 ]
[ 936092-53-4 ]
N-tert-butyl-3-[5-methyl-2-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With caesium carbonate In 1,4-dioxane; N,N-dimethyl-formamide at 160℃; for 0.333333h; Microwave irradiation;	165 [0336] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-morpholin-4-yl-phenylarnine (60 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 °C for 20 min. After cooling to room temperature, the cap was remoyed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a grey solid (45 mg, 32%).[0337] 1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 2.12 (s, 3H), 3.00 (t, J= 4.8 Hz5 4H)5 3.73 (t, J= 4.8 Hz5 4H)5 6.82 (d, J= 9.1 Hz5 2H), 7.45-7.52 (m, 4H), 7.56 (s, IH), 7.89 (s, IH), 8.10-8.17 (m, 2H), 8.52 (s, IH)5 8.73 (s, IH). MS (ES+): m/z 497 (M+H)+.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2007/53452, 2007, A1 Location in patent: Page/Page column 169

24
[ 2524-67-6 ]
[ 1147550-11-5 ]
[ 94641-22-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	Stage #1: 4-morpholino-4-yl-phenylamine; ammonium thiocyanate In acetic acid for 0.5h; Stage #2: With bromine In acetic acid at 90℃; for 0.5h;	2.A A. Preparation of the intermediate 6-morpholin-4-yl-benzothiazol-2-amine: To a solution of 4-N-morpholinoaniline (1.78 g, 10 mmol) in acetic acid (20 mL) was added NH4SCN (2.28 g, 30 mmol) in small amounts several times. After stirring the mixture for 30 minutes, a solution of bromine in acetic acid (1.6 g in 5 mL) was added to the mixture and stirred overnight at room temperature. The mixture was then heated at 90° C. for 30 minutes, and then was cooled and neutralized with saturated NaHCO3, and then extracted three times with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated to dryness. To the residue was added 30 mL of 10% HCl and neutralized with saturated NaHCO3, to give a brown solid (1.541 g, 66%).
57.3%	With bromine; acetic acid at 10 - 20℃;	5.4 General procedure for preparation of compounds 7a-e General procedure: A mixture of compounds 6a-e (0.05 mol) and NH4SCN (19.03 g, 0.25 mol) in 100 mL glacial acetic acid was cooled to 10 °C in an ice bath and stirred for 10-20 min, and then bromine (2.82 mL, 0.055 mol) in glacial acetic acid was added drop wise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 4-6 h and then poured into hot water, and basified to pH 11.0 with ammonia solution (NH4OH). The resulting precipitate was filtered, washed with water and dried to get a light yellow to brown solid. The crude product was purified by chromatography on silica gel using MeOH/CH2Cl2 to afford the compounds 7a-e.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2007/232604, 2007, A1 Location in patent: Page/Page column 39
[2]Ma, Junjie; Chen, Dong; Lu, Kuan; Wang, Lihui; Han, Xiaoqi; Zhao, Yanfang; Gong, Ping [European Journal of Medicinal Chemistry, 2014, vol. 86, p. 257 - 269]

25
[ 2524-67-6 ]
[ 1030626-87-9 ]
[ 1030626-88-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 90℃; for 16.0h;Product distribution / selectivity;	A.5 (5-Chloro-[l, 2, 4]triazolo[l, 5-a]pyridin-8-yl)-(4-morpholin-4-yl-phenyl)-amine[0332] A suspension of 8-bromo-5-chloro-[l,2,4]triazolo[l,5-a]pyridine (160 mg, 0.69 mmol),4-morpholin-4-yl-phenylamine (135 mg, 0.76 mmol), sodium-tert-butoxide (93 mg, 0.96 mmol), tris(dibenzylideneacetone)dipalladium (0) (13 mg, 13.76 mumol) and Xantphos (16 mg, 27.52 mumol) in dry toluene is heated at 90 0C in a sealed tube under a nitrogen atmosphere for 16 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and 10 % aqueous citric acid. The organic phase is further washed with water (Ix) and brine (Ix), dried over magnesium sulfate, filtered and evaporated. The solid residue (207 mg) is purified by flash chromatography (silica gel, dichloromethane/methanol 97:3) affording the title compound (70 mg) as a solid.

Reference： [1]Patent: WO2008/65198,2008,A1 .Location in patent: Page/Page column 70

26
[ 2524-67-6 ]
[ 1042917-75-8 ]
[ 1042917-78-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20 - 100℃;	b) 6-{6-[4-(terf-Butoxycarbonyl)aminopiperidin-1 -yl]pyridin-3-yl}-2-[4-(4- morpholino)phenyl]amino-9-(tetrahydropyran-2-yl)-9H-purineTo a solution of the compound obtained in the previous section (70 mg, 0.136 mmol) in toluene (1.75 mL) under Ar-atmosphere, sodium te/t-butoxide (18 mg, 0.190 mmol), BINAP (7 mg, 0.010 mmol), Pd2(dba)3 (16 mg, 0.005 mmol) and [4- (4-morpholino)phenyl]amine (36 mg, 0.200 mmol) were added at room temperature. The reaction mixture was heated at 100 C overnight. It was diluted with EtOAc and washed thrice with H2O. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 63 mg of the desired compound (71 % yield). LC-MS (method 1 ): tR = 9.52 min; m/z = 656 (MH+)

Reference： [1]Patent: WO2008/90181,2008,A1 .Location in patent: Page/Page column 71

27
[ 2524-67-6 ]
[ 499195-60-7 ]
[ 1056634-62-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With toluene-4-sulfonic acid; In 1,4-dioxane;Heating / reflux;	A mixture of <strong>[499195-60-7]ethyl 4-(2-chloropyrimidin-4-yl)benzoate</strong> (26.15 g, 99.7 mmol) and 4-morpholinoaniline (23.10 g, 129.6 mmol) was suspended in 1,4-dioxane (250 mL). p- Toluenesulfonic acid monohydrate (17.07 g, 89.73 mmol) was added. The mixture was heated at reflux for 40 h., cooled to ambient temperature, concentrated then the residue was partitioned between ethyl acetate and 1 : 1 saturated sodium bicarbonate/water (IL total). The organic phase was washed with water (2 x 100 mL) and concentrated. The aqueous phase was extracted with dichloromethane (3 x 200 mL). The material which precipitated during this workup was collected by filtration and set aside. The liquid organics were combined, concentrated, triturated with methanol (200 mL) and filtered to yield additional yellow solid. The solids were combined, suspended in methanol (500 mL), allowed to stand overnight then sonicated and filtered. The solids were washed with methanol (2x 50 mL) to give, after drying, ethyl 4-(2-(4- morphonlinophenylamino)pyrimidin-4-yl)benzoate (35.39 g , 88%). 1H NMR (300 MHz, J6-DMSO) delta 9.49 (IH, s); 8.54 (IH, d, J= 5.0 Hz); 8.27 (2H, d, J= 8.7 Hz); 8.10 (2H, d, J= 8.7 Hz), 7.66 (2H, d, J= 9.1 Hz); 7.38 (IH, d, J= 5.0Hz); 6.93 (2H, d, J= 8.7 Hz); 4.35 (2H, q, J= 6.9 Hz), 3.73 (4H, m); 3.04 (4H, m); 1.34 (3H, t, J= 6.9 Hz); LC-ESI- MS (method B): rt 7.5 min.; m/z 404.1 [M+H]+.

Reference： [1]Patent: WO2008/109943,2008,A1 .Location in patent: Page/Page column 57

28
[ 216959-94-3 ]
[ 2524-67-6 ]
[ 1092949-85-3 ]

Yield	Reaction Conditions	Operation in experiment
		100 mg (0.45 mmol) of 4-(2-Amino-thiazol-4-yl)-benzoic acid was combined with 171 mg (0.45 mmol) of HATU. This mixture was dissolved in 3 mL of DMF. To this mixture was added DIEA (O.lmL). Reaction mixture was stirred at room temperature for 40 minutes, at which point 80.2 mg (0.45 mmol) of 4-morpholin-4-yl-phenylamine was added. Reaction mixture was heated at 60 0C overnight. The crude product was purified using reverse phase HPLC.

Reference： [1]Patent: WO2008/154601,2008,A1 .Location in patent: Page/Page column 39

29
[ 2524-67-6 ]
[ 1119280-68-0 ]
[ 1152473-50-1 ]

Yield	Reaction Conditions	Operation in experiment
10%		To a solution of <strong>[1119280-68-0]2-chlorothieno[3,2-d]pyrimidine</strong> (150mg, 0.87mmol) and 4- morpholinoaniline (188mg, 1.05mmol) in NMP (5mL) was added diisopropylethylamine (337muL, 1.93mmol). The reaction was heated at 25O 0C in a microwave reactor for 20min, then diluted with EtOAc and 5%aq. citric acid. The aqueous layer was extracted twice further with EtOAc and the combined organic fractions washed with sat. aq. NaHCO3, dried (Na2SO4) filtered and concentrated to afford the crude product. Purification by silica gel chromatography using 30-70% EtOAc/DCM as eluent then afforded the product as an orange gum. Trituration with EtOAc three times and collection of the fine solid afforded compound 7 as a dark yellow solid (26mg, 10%).

Reference： [1]Patent: WO2009/62258,2009,A1 .Location in patent: Page/Page column 96

30
[ 2524-67-6 ]
[ 1119280-66-8 ]
[ 1152473-54-5 ]

Yield	Reaction Conditions	Operation in experiment
5%		A solution of <strong>[1119280-66-8]2-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (100 mg, 0.65 mmol), p- morpholino-aniline and p-TsOH.H2O (150 mg, 0.78 mmol) in dioxane was heated under reflux for 3 days. The dioxane was removed in vacuo and ethyl acetate added. The solution was washed with saturated sodium bicarbonate then with 2% aqueous citric acid. The resultant solid was purified by flash chromatography (4:1 ethyl acetate/petroleum spirit) to afford compound 9 (10 mg, 5%).

Reference： [1]Patent: WO2009/62258,2009,A1 .Location in patent: Page/Page column 103

31
[ 2524-67-6 ]
[ 420-04-2 ]
[ 247234-41-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrogenchloride; In ethanol; water; at 0℃; for 10h;Reflux;	Concentrated hydrochloric acid (4 mL) was added to a solution of 4-morpholinoaniline (1.78 g, 10 mmol) in EtOH (10 mL) at 0 C. Then cyanamide (2 mL of 50% solution in water, 25.7 mmol) was added and the mixture was heated to reflux for 10 h. After cooling to room temperature, the solvent was removed under reduced pressure. Then saturated sodium carbonate aqueous solution (10 mL) was added to the residue. The solid was filtered off, washed with acetone and dried under reduced pressure to afford compound 7 as: Off white solid; yield 2.3 g (82%);16 m.p. 224-226 C; IR: 3084, 1693, 1631, 1518, 1450, 1406, 1267 cm-1. Anal. calcd for C11H16N4O: C, 59.98; H, 7.32; N, 25.44; found: C, 59.87; H, 7.49; N, 25.59%. ESI-MS: 221.2 [M + H]+, 219.1 [M - H]-; 1H NMR (300 MHz, DMSO-d6): delta 7.16 (brs, 2H), 6.86-6.89 (m, 4H), 6.59 (brs, 1H), 4.25 (brs, 1H), 3.71-3.74 (m, 4H), 3.02-3.05 (m, 4H); 13C NMR (75 MHz, DMSO-d6): delta 160.0, 154.9, 147.7, 124.7, 116.1, 66.1, 48.9.
82%	With hydrogenchloride; In ethanol; water; at 80 - 90℃; for 10h;	1.78g (10mmol) 4-morpholinoaniline and 1.7 ml (20mmol) 50% aqueous solution of cyanamide were dissolved in 50 ml anhydrous ethanol. Add dropwise 1.5 ml concentrated hydrochloric acid . At 80-90 C, heat at reflux for 2h. Then add supplementary 1.5 ml concentrated hydrochloric acid. Continue the reaction for 8h. Concentrated to remove ethanol, by adding an aqueous solution of sodium carbonate, precipitated solid, filtering, after washing the filter cake is washed with acetone, the white solid obtained 2.3g, yield 82%.
78%	With hydrogenchloride; In ethanol; water; at 90℃; for 12h;	Add the compound 4-morpholinylaniline (8.9 g, 0.05 mol) to a 250 mL eggplant-shaped flask, add 100 mL of ethanol, stir at room temperature, add hydrochloric acid (10.5 mL, 0.126 mol), heat to 90 C, then add NH2CN (6.3g, 0.15mol)a solution prepared with 10 mL of H2O, The reaction was followed by thin layer chromatography (TLC). After 12 h, TLC showed the end of the reaction. Ethanol was evaporated from the reaction mixture. After evaporation, 35 mL of H2O was added and stirred for 20 min. The insoluble impurities were removed by filtration, and the filtrate was diluted with 20 wt% NaOH. The aqueous solution was adjusted to alkaline (pH>12), and a large amount of solid appeared after stirring in an ice water bath., drying to obtain 1-(4-morpholinylphenyl)guanidine 6.92 g, yield 78%

40%	With hydrogenchloride; In water; isopropyl alcohol; at 80℃;Inert atmosphere;	General procedure: A mixture of compounds 5a-5i (10.0 mmol), concentrated hydrochloricacid (12.2 mmol) and melamine (20.0 mmol) in isopropylalcohol (10.0 mL) was refluxed for 8 h. Progress of reaction wasmonitored by tlc and after complete conversion of starting materialreaction mixture was cooled to rt. The reaction mixture wasquenched in saturated sodium carbonate solution (20.0 mL) andfiltered. The solid was washed with water (50.0 mL). The crudeproduct thus obtainedwas dried at 50 C under reduced pressure toget compounds 6a-6i.
	With nitric acid; In ethanol; water; at 75℃; for 18h;	A solution of 4-morpholinoaniline (1 g) in ethanol (6 mL) was treated with HNO3 (0.35 mL) and 50% aqueous cyanamide (0.75 mL). The mixture was heated at 75 0C for 18 hours. The mixture was cooled to room temperature, and concentrated in vacuo. The resulting solid was filtered, and washed with diethyl ether to afford the product, which was used without further purification.

Reference： [1]Journal of Chemical Research,2016,vol. 40,p. 511 - 513
[2]Patent: ,2016, .Location in patent: Paragraph 0031; 0032; 0033; 0034; 0035; 0036
[3]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 2902 - 2905
[4]Patent: CN108707119,2018,A .Location in patent: Paragraph 0066; 0091; 0092; 0112; 0113
[5]European Journal of Medicinal Chemistry,2018,vol. 157,p. 935 - 945
[6]Patent: WO2009/70516,2009,A1 .Location in patent: Page/Page column 79

32
[ 2524-67-6 ]
[ 153034-94-7 ]
[ 1184931-48-3 ]

Yield	Reaction Conditions	Operation in experiment
47%		A vessel was charged with <strong>[153034-94-7]2-fluoro-4-iodo-5-methylpyridine</strong> (1.0 g, 4.22 mmol), 4- morpholinoaniline (0.752 g, 4.22 mmol), 1.6 M hydrochloric acid (2.64 mL, 4.22 mmol), dioxane (5 mL), and water (5 mL), then sealed and heated at 120 C for 16 h. The reaction mixture was then partitioned between saturated NaHCO3 and ethyl acetate, and the organic phase was isolated, washed with brine and dried over MgSO4. The final crude oil was <n="19"/>triturated with ethyl acetate to afford the title compound as a solid (850 mg, 47% yield). MS: M(Ci6Hi8IN3O) = 395.24, (M+H)+ = 396.

Reference： [1]Patent: WO2009/105498,2009,A1 .Location in patent: Page/Page column 17-18

33
[ 659731-48-3 ]
[ 2524-67-6 ]
[ 1184931-50-7 ]

Yield	Reaction Conditions	Operation in experiment
16%		A vessel was charged with <strong>[659731-48-3]5-chloro-2-fluoro-4-iodopyridine</strong> (794 mg, 3.09 mmol), A- morpholinoaniline (0.5 g, 2.81 mmol), 4.0 M hydrochloric acid (1.4 mL, 5.61 mmol), dioxane (2.5 mL), and water (2.5 mL), and sealed and heated in 125 C overnight. The reaction mixture was then partitioned between saturated NaHCO3 and ethyl acetate and the organic phase was isolated, washed with brine and dried over MgSO4. The final product <n="20"/>was purified by flash chromatography on silica gel column eluting with ethyl acetate and hexane to give the title compound as a solid (200 mg, 16% yield). MS: M(Ci5Hi5ClIN3O) =415.66, (M+H)+ = 417.

Reference： [1]Patent: WO2009/105498,2009,A1 .Location in patent: Page/Page column 18-19

34
[ 2524-67-6 ]
[ 1036756-07-6 ]
[ 1036743-20-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	In isopropyl alcohol at 90℃; for 1h; Sealed tube;	23.6 Step 6: 6-Bromo-5-fluoro-N-(4-morpholinophenyl)quinazolin-2-amine; To a solution of 6-bromo-2-chloro-5-fluoroquinazoline, 23-3 (1 eq) in isopropanol was added 4-morpholinoaniline (1 eq) and the mixture was heated to 90° C. for 1 h in a sealed tube. The SNAR went to completion by LC/MS and purification on prep HPLC yielded 6-bromo-5-fluoro-N-(4-morpholinophenyl)quinazolin-2-amine in quantitative yield. ES/MS m/z 403(MH+).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); GLAXOSMITHKLINE PLC; NOVARTIS AG - US2010/216767, 2010, A1 Location in patent: Page/Page column 88

35
[ 2524-67-6 ]
[ 63744-22-9 ]
[ 445263-72-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 8h;	General procedure: <strong>[63744-22-9]6,8-dibromoimidazo[1,2-a]pyrazine</strong> (6, 1.86 g, 6.72 mmol) was added to asolution of 3a-3c, 5a-5e (5.6 mmol), DIPEA (1.4 mL, 8.4 mmol) inisopropanol (60 mL), stirred at 85 C for 8 h, and then the solvent wasevaporated to dryness. The crude product was purified by columnchromatography to obtain the desired intermediates 7a, 11a-11 g.
72.6%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 16h;Inert atmosphere;	11d (0.5 g, 2.8 mmol), 1a (0.8 g, 2.8 mmol), isopropanol (5.1 ml), and diisopropylethylamine (0.7 g, 5.6 mmol) were added to a 25 ml three-necked flask. The system was replaced with nitrogen for three times under stirring. The system was refluxed for 16 hours in 100 C oil bath. The system was cooled to 17 C, and concentrated to dryness under reduced pressure, purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/10 to 1: 3) to give light yellow solid Compound 11e (0.7 g, 99.5% purity, yield 72.6%). MS m/z 374.0 [M+H]+.

Reference： [1]Bioorganic Chemistry,2020,vol. 95
[2]Patent: EP3553065,2019,A1 .Location in patent: Paragraph 0124; 0127
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5988 - 5993

36
[ 2524-67-6 ]
[ 3588-57-6 ]
[ 1253047-07-2 ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 836 - 843

37
[ 3034-52-4 ]
[ 2524-67-6 ]
[ 1290104-72-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With toluene-4-sulfonic acid; In isopropyl alcohol; at 80℃; for 504h;	General procedure: 1.0 equiv of the halothiazole, 1.5 equiv of the amino-substrate and 0.5 equiv of p-toluenesulfonic acid were dissolved in i-propanol and the reaction mixture was stirred at 80 C until the reaction was complete (TLC). The reaction mixture was then diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine followed by general work-up. Purification was carried out by Kugelrohr distillation.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2149 - 2154

38
[ 2524-67-6 ]
[ 1292317-55-5 ]
[ 1292310-49-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	In 1,4-dioxane; ethanol at 80℃; for 72h; Inert atmosphere;	5.4 To 5-(2-chloropyrimidin-4-yl)-2-tetrahydropyran-4-yloxy-benzonitrile (9 g, 28.5 mmol) in EtOH (42 mL) and /?-dioxane (42 mL) was added 4-morpholinoaniline (5.6 g, 31.3 mmol). The reaction was heated to 80 °C and stirred under N2 (g) for three days. The solvent was removed under vacuum. The product was dissolved in warm (55 °C) MeOH (25 mL). The solution was cooled to room temperature. The product precipitated to provide 13 g (100%) material. 1H NMR (DMSO) δ 9.90 (br s, 1H), 8.58-8.54 (m, 2H), 8.45 (d, 2H), 7.84-7.80 (m, 2H), 7.58-7.50 (m, 3H), 5.00-4.90 (m, 1H), 4.05-3.95 (m, 4H), 3.91-3.84 (m, 2H), 3.60-3.52 (m, 2H), 3.48-3.36 (m, 4H), 2.10-2.00 (m, 2H), 1.75-1.65 (m, 2H). LCMS [M+H]+ 458.2251.

Reference： [1]Current Patent Assignee: MYREXIS, INC.; ALZHEIMER'S INSTITUTE OF AMERICA, INC. - WO2011/46970, 2011, A1 Location in patent: Page/Page column 139; 140; 141

39
[ 24415-66-5 ]
[ 2524-67-6 ]
[ 878426-13-2 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3935 - 3949

40
[ 16096-32-5 ]
[ 79-37-8 ]
[ 2524-67-6 ]
[ 1257652-40-6 ]

Yield	Reaction Conditions	Operation in experiment
37%	Stage #1: 4-methyl-1H-indole; oxalyl dichloride In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; Stage #2: 4-morpholino-4-yl-phenylamine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 45℃; for 18h; Inert atmosphere;	5.2.2. Indole-3-glyoxylamides 3-32, 34-42; general procedure General procedure: A dry 50 mL capacity carousel reaction tube was charged with the relevant substituted indole (1.5 mmol), and this starting material dissolved in dry THF (12 mL). Oxalyl chloride (144 μL, 209 mg, 1.65 mmol) was added and the mixture stirred at room temp. After 24 h, either N,N-diisopropylethylamine (590 μL, 438 mg, 3.4 mmol) or 2,6-lutidine(396 μL, 364 mg, 3.4 mmol) was introduced to the reaction, followed by the relevant amine (1.8 mmol). The temperature was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, then the residue resuspended in a mixture of ethyl acetate (20 mL) and brine (10 mL) and stirred vigorously for 30 min. After passing through a liquid-liquid extraction column, ensuring washing through of the column with additional ethyl acetate, a second extraction was carried out with sat. NH4Cl (10 mL) in the same manner. Product solutions were then evaporated to dryness giving the crude indole-3-glyoxylamide derivatives, which were purified as necessary (see Supplementary Information for individual compound details). Typically, two sequential recrystallizations, from ethyl acetate-hexane followed by 2-propanol-water, afforded final products of good purity. For products derived from poorly nucleophilic anilines (p-1H-pyrazol-1-ylaniline,p-pyrrol-1-ylaniline and p-morpholinoaniline), a further modification was used. Immediately following introduction of the arylamine to the reaction mixture, DMAP (18 mg, 0.15 mmol, 10 mol%) was added to assist the final step, as its use was found to enhance the extent of conversion in the final step in such cases.

Reference： [1]Location in patent: experimental part Thompson, Mark J.; Louth, Jennifer C.; Ferrara, Steven; Jackson, Matthew P.; Sorrell, Fiona J.; Cochrane, Edward J.; Gever, Joel; Baxendale, Sarah; Silber, B. Michael; Roehl, Henry H.; Chen, Beining [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4125 - 4132]

41
[ 53924-05-3 ]
[ 79-37-8 ]
[ 2524-67-6 ]
[ 1257652-38-2 ]

Yield	Reaction Conditions	Operation in experiment
6%	Stage #1: 7-chloro-1H-indole; oxalyl dichloride In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; Stage #2: 4-morpholino-4-yl-phenylamine With 2,6-dimethylpyridine In tetrahydrofuran at 45℃; for 18h; Inert atmosphere;	5.2.2. Indole-3-glyoxylamides 3-32, 34-42; general procedure General procedure: A dry 50 mL capacity carousel reaction tube was charged with the relevant substituted indole (1.5 mmol), and this starting material dissolved in dry THF (12 mL). Oxalyl chloride (144 μL, 209 mg, 1.65 mmol) was added and the mixture stirred at room temp. After 24 h, either N,N-diisopropylethylamine (590 μL, 438 mg, 3.4 mmol) or 2,6-lutidine(396 μL, 364 mg, 3.4 mmol) was introduced to the reaction, followed by the relevant amine (1.8 mmol). The temperature was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, then the residue resuspended in a mixture of ethyl acetate (20 mL) and brine (10 mL) and stirred vigorously for 30 min. After passing through a liquid-liquid extraction column, ensuring washing through of the column with additional ethyl acetate, a second extraction was carried out with sat. NH4Cl (10 mL) in the same manner. Product solutions were then evaporated to dryness giving the crude indole-3-glyoxylamide derivatives, which were purified as necessary (see Supplementary Information for individual compound details). Typically, two sequential recrystallizations, from ethyl acetate-hexane followed by 2-propanol-water, afforded final products of good purity. For products derived from poorly nucleophilic anilines (p-1H-pyrazol-1-ylaniline,p-pyrrol-1-ylaniline and p-morpholinoaniline), a further modification was used. Immediately following introduction of the arylamine to the reaction mixture, DMAP (18 mg, 0.15 mmol, 10 mol%) was added to assist the final step, as its use was found to enhance the extent of conversion in the final step in such cases.

42
[ 2524-67-6 ]
[ 16013-85-7 ]
[ 868077-97-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine; In methanol; at 20 - 30℃; for 5h;	Preparation of 2-(4-morpholinophenylamino)-6-chloro-3-nitropyridine To 50 ml of methanol were added 2 g (10.4 mmol) of 2,6-dichloronitropyridine and 1.73 ml (12.4 mmol) of triethylamine and 1.94 g (10.4 mmol) of 4-morpholinoaniline was then added thereto, followed by reaction at room temperature (20 to 30) for about 5 hours. After the reaction was complete, the reactant was filtered, washed with 20 ml of methanol and then dried under vacuum at about 40 to afford 3.17 g (yield: 91%) of the desired compound. Mass (M+): 335.0 1H-NMR (DMSO-d6): 3.13(m, H), 3.74(brm, 4H), 6.93(d, 1H), 6.97(d, 2H), 7.42(d, 1H), 8.50(d, 1H), 10.05(s, 1H).
91%	With triethylamine; In methanol; at 20 - 30℃; for 5h;	Example 1-13 Preparation of 2-(4-morpholinophenylamino)-6-chloro-3-nitropyridine To 50ml of methanol were added 2g (10.4mmol) of 2,6-dichloronitropyridine and 1.73ml (12.4mmol) of triethylamine and 1.94g (10.4mmol) of 4-morpholinoaniline was then added thereto, followed by reaction at room temperature (20 to 30C) for about 5 hours. After the reaction was complete, the reactant was filtered, washed with 20ml of methanol and then dried under vacuum at about 40C to afford 3.17g (yield: 91%) of the desired compound. Mass (M+): 335.0 1H-NMR (DMSO-d6): 3.13(m, H), 3.74(brm, 4H), 6.93(d, 1H), 6.97(d, 2H), 7.42(d, 1H), 8.50(d, 1H), 10.05(s, 1H).

Reference： [1]Patent: US2011/306606,2011,A1 .Location in patent: Page/Page column 12
[2]Patent: EP2394993,2011,A2 .Location in patent: Page/Page column 17

43
[ 2524-67-6 ]
[ 87486-34-8 ]
[ 1346673-06-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	In isopropyl alcohol; at 90℃; for 16h;Inert atmosphere; microwave irradiation;	A microwave vial equipped with a magnetic stirrer was charged with 3,5-dibromo-l- methylpyrazin-2(lH)-one (1.97 g, 7.4 mmol), 4-morpholinobenzenamine (1.97 g, 11.1 mmol), and isopropanol (25 mL). The system was evacuated and then refilled with N2. It was heated at 90°C for 16 h. Then, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 5: 1 petroleum ether/ethyl acetate to afford 122a (2.3 g, 85percent). LCMS: [M+H]+ 365.

Reference： [1]Patent: WO2011/140488,2011,A1 .Location in patent: Page/Page column 172

44
[ 2524-67-6 ]
[ 957344-74-0 ]
[ 957346-50-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2266 - 2270

45
[ 166526-03-0 ]
[ 2524-67-6 ]
[ 1374210-52-2 ]

Reference： [1]Patent: US2012/108566,2012,A1

46
[ 166526-03-0 ]
[ 2524-67-6 ]
[ 1374215-07-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 72h;	To 10 ml of NMP was added 15.1 (375 mg), 16.1 (413 mg), and Cs2CO3 (780 mg). The reaction was stirred at 120 C. for 72 hours. The reaction mixture was cooled and a H2O/TFA mixture was added. A preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 5% to 60% B mixture over 10 minutes was run. Compound 16.2 was isolated and was converted to title compound utilizing similar chemistry as described in Example 15. UV: 264 nm. M+H found for C26H30N6O3: 475.5. NMR (CD3OD): 8.15 (1H, s), 7.18-7.00 (8H, m), 6.02 (1H, s), 3.84 (8H, dt, J=0.8 Hz, 8.4 Hz), 3.21-3.15 (8H, m) ppm.

Reference： [1]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 49-50

47
[ 890094-38-9 ]
[ 2524-67-6 ]
[ 1350545-50-4 ]

Yield	Reaction Conditions	Operation in experiment
74.7%	In butan-1-ol; at 90℃; for 4.0h;	4-morpholinophenylamine(3.6g) was added to a solution of Compound 2-3(4.3g) in n-butanol(150ml). The mixture was reacted at 90C for 4 hours, cooled to room temperature, filtered, washed and dried to obtain a red solid(5.3g) in a yield of 74.7%. MS m/z(ESI): 359[M+H]+.

Reference： [1]Patent: EP2578584,2013,A1 .Location in patent: Paragraph 0129; 0130

48
[ 2524-67-6 ]
[ 58142-97-5 ]
N-(4-morpholinophenyl)-5-nitroisoquinolin-1-amine [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2013,vol. 61,p. 747 - 756

49
[ 70291-67-7 ]
[ 2524-67-6 ]

Yield	Reaction Conditions	Operation in experiment
83%	With ammonium hydroxide; potassium phosphate; copper(l) iodide; N¹,N²-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide In water; dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere;
80%	With dicyclohexyl(2',4',6'-triisopropyl-5-methoxy-3,4,6-trimethyl-[1,1'-biphenyl]-2-yl)phosphine; C₅₀H₇₀NO₄PPdS; C₅₀H₇₀NO₄PPdS; dicyclohexyl(2',4',6'-triisopropyl-4-methoxy-3,5,6-trimethyl-[1,1'-biphenyl]-2-yl)phosphine; ammonia; sodium t-butanolate In 1,4-dioxane at 60℃; for 24h; Inert atmosphere;

Reference： [1]Fan, Mengyang; Zhou, Wei; Jiang, Yongwen; Ma, Dawei [Organic Letters, 2015, vol. 17, # 23, p. 5934 - 5937]
[2]Cheung, Chi Wai; Surry, David S.; Buchwald, Stephen L. [Organic Letters, 2013, vol. 15, # 14, p. 3734 - 3737]

50
[ 16681-56-4 ]
[ 2524-67-6 ]
[ 1537903-08-4 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 832 - 835

51
[ 2524-67-6 ]
[ 87350-77-4 ]

Yield	Reaction Conditions	Operation in experiment
80%		General procedure: An aromaticamine (1 mmol), nanomagnetic-supported sulfonic acid (c-Fe2O3-SO3H)(0.65 g), NaNO2 (2 mmol, 0.138 g), and 0.2 mL of H2O were homogenized bygrinding in a mortar with a pestle for a few minutes. Formation of a reddishbrowngas was observed as soon as H2O was added. The diazotization reactionlasted for approximately 5-30 min. Next, KI (2.5 mmol, 0.415 g) was added tothe diazonium salt and grinding was continued for 10-20 min. After completionof the reaction, the mixture was triturated with EtOAc (5 mL). The c-Fe2O3-SO3K was separated from the solution using a magnetic bar. The organic layerwas treated with aq 10% Na2SO3 (15 mL), then dried over anhydrous Na2SO4.After evaporation of the solvent, the crude product was afforded. Purifiedproducts were obtained by recrystallization from ethanol or by flashchromatography (n-hexane-EtOAc, 95:5).
70%		General procedure: To a stirring mixture of glacial acetic acid (0.12 mL, 2.1 mmol) and TBN (0.30 mL, ~2.3mmol)inethanol(10mL), Sac -H (0.37g, 2.0 mmol) was slowly added at low temperature (an ice bath). After 5 min, aniline derivative 1(a-l) (2.0 mmol) was added dropwise over 5 minutes into the mixture. The solvent, t -BuOH, and residue TBN were removed under reduced pressure after consuming of aniline derivatives (monitored by a color test of azo coupling with 2-naphthol). Then, 5 mL of 0.4 M TEAI solution was added into stirring as-obtained intermediate 2(a-l) in one portion at low temperature. After confirmation of substrate consumption by a negative test of azo coupling with 2-naphthol, the boiling water was added to the reaction mixture (15 mL) and the aqueous layer was separated. The organic layer was was hed with aq. 10% sodium sulphite (3 ×5 mL), then dried over Na2 SO4 , filtered, and dried under reduced pressure in a rotary evaporator. The purification was conducted by flash chromatography with n-hexane-EtOAc (9:1,v/v) as eluent.
45%	With diiodomethane; 2-Methyl-2-nitropropane; In acetonitrile; at 20 - 60℃; for 3.66667h;Inert atmosphere;	25 g (140 mmol, 1 eq.) of 4-(4-aminophenyl)morpholine were dissolved in 300 ml of dry acetonitrilee in a 500 ml three-necked round-bottomed flask. A thermometer, drip top and reflux condenser were placed on the flask, and a silicone oil scrubber was placed on the cooler. To the solution diiodomethane (34 mL, 112.7 g, 420 mmol, 3 eq) was added. Argon was slowly passed through the apparatus and 28 ml (26.19 g, 210 mmol, 1.5 eq.) of 90% tert-butyl-nitrite was added under stirring at room temperature. After stirring for 1 hour at room temperature, the mixture was stirred at 60 C for 2 hours and 40 minutes. At this point, the thin layer chromatography no longer shows the starting material. The reflux condenser is then replaced by a 20 cm Vigreux column and distillation column and the volatiles are distilled off under vacuum. The residue was dissolved in 200 ml of dichloromethane and extracted with 20 ml of saturated NaHC03 and 20 ml of 10% Na2S203. The organic layer was separated, evaporated to 100 mL and filtered through silica gel with (150 g) dichloromethane. Wash with dichloromethane until the product is detected in the filtrate by TLC. After evaporation, 24.12 g of crude product was obtained, which is recrystallized from 280 g of acetone. Yield: 18.28 g (63 mmol, 45%) of pale yellow crystals. Rf=0.53 ethyl-acetate:cyclohexane 2:1.NMR (DMSO-d6, 500 MHz): d 3.08 (t , / = 5.0 Hz, 4H), 3.71 (t , / = 5.0 Hz, 4H), 6.77 (d , / = (0260) 9.0 Hz, 2H), 7.50 (d ,/ = 9.0 Hz, 2H). 13C DEPTq NMR (DMSO-d6, 500 MHz): d 47.8, 65.9, 80.9, 117.4, 137.2, 150.6.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 3648 - 3651
[2]Turkish Journal of Chemistry,2020,vol. 44,p. 535 - 542
[3]Patent: WO2019/202346,2019,A2 .Location in patent: Page/Page column 38-39

52
[ 2524-67-6 ]
[ 835-45-0 ]
[ 1266346-03-5 ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 115 - 130

53
[ 2524-67-6 ]
[ 35578-47-3 ]
C₁₅H₁₉N₂O₆Pol [ No CAS ]
C₃₉H₃₈Br₂N₅O₆Pol [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 9271 - 9274,4
Angew. Chem.,2014,vol. 126,p. 9425 - 9428,4
Angewandte Chemie,2014,vol. 126,p. 9425 - 9428,4

54
[ 933-20-0 ]
[ 2524-67-6 ]
6-chloro-N<SUP>2</SUP>-(4-morpholinophenyl)-1,3,5-triazine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
124 mg	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 17h;Cooling with ice;	To a solution of 2-amino-4,6-dichloro-1,3,5-triazine (124 mg, 0.75 mmol) in THF (1.2 mL), cooled with ice bath, DIEA (0.18 mL, 1.33 mmol) and 4-morpholinoaniline (89 mg, 0.50 mmol) in THF solution (0.8 mL) were added slowly then stirred with ice bath for 1 h and then at ambient temperature for further 16 h. The precipitate was collected by filtration, washed with ethyl acetate then dried to afford 2-amino-4-chloro-6-[(4-morpholinophenyl)amino]-1,3,5-triazine (124 mg). 1H NMR (400 MHz, DMSO-d6) delta 9.85 - 9.45 (m, 1H), 7.65 - 7.20 (m, 4H), 6.88 (d, J = 9.0 Hz, 2H), 3.77 - 3.69 (m, 4H), 3.08 - 3.01 (m, 4H).; LCMS (m/z): 307.1 [M+H]+.

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8917 - 8933
[2]Patent: EP2824099,2015,A1 .Location in patent: Paragraph 0155; 0156

55
[ 2524-67-6 ]
[ 956100-63-3 ]
8-bromo-N-(4-morpholinophenyl)quinazolin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51.5%	With potassium carbonate; In acetonitrile; at 120.0℃; for 12.0h;	To a solution of 4-morpholinoaniline (154 mg, 0.86 mmol, 1 eq.) and 8-bromo-2- chloroquinazoline (210 mg, 0.86 mmol, 1 eq.) in MeCN (10 mL) was added K2CO3(138 mg, 1 mmol, 2 eq.), and the mixture was stirred at 120 C for 12 h. The mixture was cooled to r.t. and filtered. The filtrate was concentrated. The resulting residue was purified via column chromatography (PE/EA=1 : 1, v/v) to afford 8-bromo-N-(4-morpholinophenyl)quinazolin-2- amine as a brown solid (170 mg, 51.5% yield).

Reference： [1]Patent: WO2015/27222,2015,A2 .Location in patent: Paragraph 0220

56
[ 2524-67-6 ]
[ 1056634-68-4 ]

Reference： [1]Patent: EP2949647,2015,A1
[2]Journal of Chemical Research,2016,vol. 40,p. 511 - 513
[3]Patent: ,2016,
[4]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 2902 - 2905
[5]Patent: CN108707119,2018,A

57
[ 2524-67-6 ]
[ 510-30-5 ]
C₄₀H₆₀N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: echinocystic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 4-morpholino-4-yl-phenylamine In tetrahydrofuran at 20℃;	General procedure B for the synthesis of EA derivatives (9-12) General procedure: To the solution of EA (47 mg, 0.1 mmol) in 4 mL dry THF was added EDC (29 mg, 0.15 mmol). The reaction mixture was stirred at rt for 30 min and then corresponding amine was added. After completion (TLC) the solvent was removed under reduced pressure. The mixture was resolved in AcOEt and washed with water and brine twice. The organic layer was dried over Na2SO4, then filtered and concentrated. The crude product was purified by column chromatography.

Reference： [1]Yu, Fei; Wang, Qi; Wang, Han; Si, Long-Long; Liu, Jia-Xin; Han, Xu; Xiao, Su-Long; Zhang, Li-He; Zhou, De-Min [Chinese Chemical Letters, 2016, vol. 27, # 5, p. 711 - 713]

58
[ 2524-67-6 ]
[ 955369-56-9 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-morpholinophenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ACS Chemical Biology,2016,vol. 11,p. 921 - 930

59
[ 10132-07-7 ]
[ 2524-67-6 ]
6-chloro-N₂-(4-morpholinophenyl)pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
218 mg	In 1,2-dimethoxyethane; at 120℃; for 12h;Microwave irradiation;	A solution of 4-amino-2,6-dichioropyrimidine (736mg, 4.49 mmol) and 4-morpholinoaniline (400 mg, 2.24 mmol) in dimethoxyethane (18 mE) was heated with the microwave synthesizer at 120 C. for 12 h. The reaction mixture was cooled to ambient temperature, filtered to remove insoluble material, water was added to the filtrate and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by chromatography on silica gel, eluted with hexane/ethyl acetate to afford 6-chloro-N2-(4-morpholinophenyl)pyrimi- dine-2,4-diamine (218 mg).10124] ?H NMR (400 MHz, DMSO-d5) oe 9.06 (s, 1H),7.61-7.50 (m, 2H), 6.89-6.79 (m, 4H), 5.84 (s, 1H), 3.76-3.69(m, 4H), 3.05-2.97 (m, 4H); ECMS (mlz): 306.1 [M+H].

Reference： [1]Patent: US2016/207906,2016,A1 .Location in patent: Page/Page column 10
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 145 - 151

60
[ 52127-83-0 ]
[ 2524-67-6 ]
4-chloro-6-morpholino-N-(4-morpholinophenyl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.54%	With toluene-4-sulfonic acid; In butan-1-ol; at 100℃; for 24h;	Example 1 Step 7 Synthesis of 4- (2,6-dichloro-pyrimidin-4-yl) morpholine (0.50g, 2.15mmol) was dissolved in n-butanol (20 mL) was added 4- do morpholino aniline (0.38g, 2.15mmol), p-toluenesulfonic acid monohydrate (0.26g, 1.72mmol), the reaction was heated to 100 24h.The solvent was distilled off under reduced pressure, ethyl acetate (50 mL) was dissolved the residue, saturated NaHCO3Wash solution, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.The solvent was evaporated, and purified by chromatography (eluent: EA / PE = 1/1, DCM / CH3OH = 10/1, gradient elution) to give the product 0.43g, Yield: 53.54%.

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 7268 - 7274
[2]Patent: CN103483345,2016,B .Location in patent: Paragraph 0225-0228

61
[ 28539-02-8 ]
[ 2524-67-6 ]
N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-4-morpholinoaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In methanol; at 20℃; for 3h;	Weigh benzotriazole (5mmol, 596mg), 40% formic acid (5mmol, 375mg) placed in 100mL round bottomBottles , 60mL of methanol was added , stirred for 2 hours at room temperature , there are a lot of white solid precipitated , suction filtered , the filter cake washed with cold methanol , and dried ,To give 1-hydroxymethyl benzene and triazole , quality 671mg ( 90% yield ) . Weigh 1-hydroxymethyl benzo triazole (lmmol,149mg), 4_ (4_ morpholinyl ) aniline (lmmol, 178mg) a 50mL round bottom flask was added 20mL of methanol , stirred at room temperatureMixed 3h, has a large amount of solid precipitated , suction filtered , the filter cake washed with cold methanol , and dried to give the title compound . An off-white solid , mass :278mg ( 90% yield ) .

Reference： [1]Patent: CN102688233,2016,B .Location in patent: Paragraph 0093-0095

62
ammonium thiocyanate [ No CAS ]
[ 2524-67-6 ]
[ 94641-22-2 ]

Yield	Reaction Conditions	Operation in experiment
57.3%	Stage #1: ammonium thiocyanate; 4-morpholino-4-yl-phenylamine With acetic acid at 10℃; Stage #2: With bromine at 20℃;	5.4. General Procedure for Preparation of Compounds 9a-d General procedure: A mixture of compounds 8a-d (0.05 mol) and NH4SCN(19.03 g, 0.25 mol) in glacial acetic acid (100 mL) wascooled to 10 °C in an ice bath and stirred for 10-20 min, andthen bromine (2.82 mL, 0.055 mol) in glacial acetic acid wasadded dropwise at such a rate to keep the temperature below10 °C throughout the addition. The reaction mixture wasstirred at room temperature for 4-6 h and then poured intohot water, and basified to pH 11.0 with ammonia solution(NH4OH). The resulting precipitate was filtered, washedwith water and dried to get a light yellow to brown solid.The crude product was purified by chromatography on silicagel using MeOH/CH2Cl2 to afford the compounds 9a-d.

Reference： [1]Bao, Guanglong; Du, Baoquan; Ma, Yuxiu; Zhao, Meng; Gong, Ping; Zhai, Xin [Medicinal Chemistry, 2016, vol. 12, # 5, p. 489 - 498]

63
[ 2524-67-6 ]
[ 41360-32-1 ]
C₁₈H₂₀N₂O₅S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 9094 - 9106

64
[ 2524-67-6 ]
[ 6388-47-2 ]
8-chloro-3-(4-morpholinophenyl)quinazolin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With trimethyl orthoformate; In tetrahydrofuran; at 110℃; for 18h;Sealed tube;	General procedure: 3-Chloroanthranilic acid was taken in a sealed tube together with trimethyl orthoformate (1.2 equiv), aromatic amine (1.2 equiv), and THF, and the resulting reaction mixture was heated at 110C for 18h. It was cooled down to room temperature, saturated sodium bicarbonate solution was added, and the crude product was extracted with ethyl acetate. The combined organic layer was dried with magnesium sulfate, filtered, concentrated under reduced pressure, and purified through flash column chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 1036 - 1050

65
[ 2524-67-6 ]
[ 160893-07-2 ]
5-methoxy-N-(4-morpholinophenyl)quinolin-2-amine [ No CAS ]

Reference： [1]Chemical Biology and Drug Design,2017,vol. 89,p. 98 - 113

66
[ 2524-67-6 ]
[ 1395886-42-6 ]
2-[(2-[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)amino]benzamide [ No CAS ]
2-N,4-N-bis[4-(morpholin-4-yl)phenyl]pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 11% 2: 20%	With trifluoroacetic acid In isopropyl alcohol at 80℃;	4.8 General procedure for the synthesis of compounds 5h-5r General procedure: A chloro-intermediate (4g-i) (0.32mmol) and amino-intermediate (3a-c) (0.32mmol) were combined in a round bottom flask with 5ml of isopropanol and catalytic amounts of TFA. The reaction mixture was stirred at 80°C overnight. The reaction was then cooled down to room temperature, neutralized with 1M NaOH, and evaporated under vacuum to give a crude product. The crude product was purified by silica-gel column chromatography to yield a desired product.

Reference： [1]Phuangsawai, Oraphan; Beswick, Paul; Ratanabunyong, Siriluk; Tabtimmai, Lueacha; Suphakun, Praphasri; Obounchoey, Phongphat; Srisook, Pimonwan; Horata, Natharinee; Chuckowree, Irina; Hannongbua, Supa; Ward, Simon E.; Choowongkomon, Kiattawee; Gleeson, M. Paul [European Journal of Medicinal Chemistry, 2016, vol. 124, p. 896 - 905]

67
[ 2524-67-6 ]
1-benzyl-4-(3-chloro-6-methyl)pyrimidinyl-furo[3,2-c] piperidine [ No CAS ]
4-(5-benzyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)-5-methyl-N-(4-morpholinophenyl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃; for 6h;Inert atmosphere;	General procedure: A solution of compound 10 (500 mg, 1.47 mmol), aniline (150 mg, 1.62 mmol), Pd(OAc)2 (16 mg, 0.074 mmol), rac-BINAP (46 mg, 0.074 mmol) and Cs2CO3 (958 mg, 2.94 mmol) in dioxane (10 mL) was stirred under N2 atmosphere at 90 C for 6 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by flash chromatography to give compound 5a as an off-white solid (420 mg, 72%). MS m/z 397.2 [M+H]+.
	With hydrogenchloride; potassium iodide; In 1,4-dioxane; 2,2,2-trifluoroethanol; at 150℃; for 2h;Microwave irradiation;	To a 10 mL microwave vessel charged with a solution of 14a (0.500 g, 1.53 mmol), 4-morpholinoaniline (0.300 g, 1.68 mmol)in 2,2,2-trifluoroethanol (5 mL) was added KI (0.101 g, 0.61 mmol)and dioxane (saturated with HCl gas, 6.6 M, 0.67 mL). The mixture was stirred at 150C for 2 h at automatic CEM microwave reactor.The reaction mixture was cooled to room temperature, diluted with water (20 mL), neutralized with saturated aq. NaHCO3,extracted with CH2Cl2 (20 mL 3), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography to give compound15a as a yellow solid (0.415 g, 58%).
3.4 g	With hydrogenchloride; potassium iodide; In 1,4-dioxane; 2,2,2-trifluoroethanol; at 165℃; for 2h;Microwave irradiation;	1-Benzyl-4- (3-chloro-6-methyl) pyrimidinyl-furo [3,2-c] -piperidine was added to a microwave vial(2.85 g, 1 eq), 4-morpholinoaniline (1.5 g, 1 eq),Dioxane in hydrochloric acid (6.6 M)(2.8 mL, 2.2 eq), potassium iodide (0.5 g, 0.04 eq)And trifluoroethanol (10 mL), and the mixture was reacted at 165 C under microwave for 2 hours. Water (20 mL) was added,Washed with saturated aqueous NaHCO3, extracted with dichloromethane (10 mL * 5), the organic phases were combined, dried over anhydrous sodium sulfate,Filtration, concentration,Crude silica gel column chromatography gave 1-benzyl-4- (3- (4-morpholinylanilino) -6-methyl) pyrimidinyl-furo [3,2-Piperidine (3.4 g).

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2592 - 2597
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 75 - 83
[3]Patent: CN103102359,2016,B .Location in patent: Paragraph 0102-0105

68
[ 854382-06-2 ]
[ 2524-67-6 ]
[ 761394-93-8 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 2930 - 2943

69
[ 30483-75-1 ]
[ 2524-67-6 ]

Reference： [1]Organic Letters,2017,vol. 19,p. 2809 - 2812

70
[ 2524-67-6 ]
[ 5334-40-7 ]
C₁₄H₁₅N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1,2-dichloro-ethane; In N,N-dimethyl-formamide; for 24h;	General procedure: 4-Nitrobenzyl bromide (46.3mmol) was dissolved in dichloromethane (100mL). The solution was added to the mixture of relative amine (47.0mmol) and triethylamine (70.3mmol) in dichloromethane (20ml). The reaction mixture was stirred at r. t. for 24 h and was extracted with dichloromethane (100ml×3). After removal of the solvent, the residue was crystallized from ethanol, giving yellow powder. Compounds 1 and 2 were used for further reaction without purification. To a suspension of compounds 1?2 (36.2mmol) in 95percent ethanol (100ml), 85percent NH2NH2·H2O (362mmol), 95percent ethanol (100ml) and iron (III) oxide hydroxide (FeO(OH)/C, 2.0g) were added and heated to reflux. When TLC analysis showed complete conversion of the starting material, the reaction mixture was filtrate through Cellit and the filtrate was concentrated in vacuum. The crude product was purified by silica gel colum chromatography (DCM/MeOH) to yield the title compound (3 and 4) as white solid. The mixture of compound 4 (1eq, 18.5mmol), 4-Nitro-1H-pyrazole-3-acid (1.1equiv, 20.4mmol), EDC (1.2equiv, 22.2mmol), HOBT (1.2equiv, 22.2mmol) in DMF (50ml) was stirred for 24h. The ice water (100ml) was added to the reaction mixture. A large amount of yellow solid precipitation (compound 8) was acquired. Compound 8 was used without further purification. Compounds 8 was reduced by the same process as compound 4, and then the resulting compound 12 was purified by column chromatography on silica gel, eluted with the appropriate solvent.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 155,p. 303 - 315

71
[ 2524-67-6 ]
[ 82113-65-3 ]
[ 87350-77-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: bis(trifluoromethanesulfonyl)amide With tert.-butylnitrite; acetic acid In ethanol Cooling with ice; Stage #2: 4-morpholino-4-yl-phenylamine With tetraethylammonium iodide In water at 20℃;

Reference： [1]Khaligh, Nader Ghaffari [Heteroatom Chemistry, 2018, vol. 29, # 2]

72
[ 659731-48-3 ]
[ 2524-67-6 ]
[ 1184931-35-8 ]

Reference： [1]Patent: WO2009/105498,2009,A1

73
[ 2524-67-6 ]
[ 153034-94-7 ]
N-methyl-2-[(5-methyl-2-[4-(4-morpholinyl)phenyl]amino}-4-pyridinyl)amino]benzamide trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2009/105498,2009,A1

74
[ 2524-67-6 ]
[ 530-62-1 ]
[ 161596-47-0 ]
C₂₂H₂₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		In a 2000 ml three-necked flask equipped with a reflux condenser, 63.0 g of 4-morpholinylaniline (Structure II) was added.80.0 g of <strong>[161596-47-0](S)-N-glycidylphthalimide</strong> (Structure III),1300 ml of isopropanol, reacted at reflux temperature;The thin layer was followed by the completion of the reaction (ethyl acetate: petroleum ether = 1:1), then cooled to room temperature and filtered to give 142 g of crude solid.Dissolved in 1000 ml of anhydrous tetrahydrofuran;Further, 65 g of diimidazole carbonate was added thereto, and the mixture was stirred overnight, and tetrahydrofuran was distilled off.Re-dissolved in 1500 ml of ethyl acetate and washed 3 times in 20 ml of water.Drying, concentration, column chromatography gave the compound of formula I.Product analysis: The obtained product was weighed and the yield was calculated. The result was:The compound of formula I weighs 78.3 g and the yield is 65%;

Reference： [1]Patent: CN108892663,2018,A .Location in patent: Paragraph 0052; 0053; 0054

75
[ 126728-20-9 ]
[ 2524-67-6 ]
2-chloro-N-(4-morpholinophenyl)pyrido[2,3-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃; for 6h;	<strong>[126728-20-9]2,4-dichloropyrido[2,3-d]pyrimidine</strong> (200 mg, 0.99 mmol) To a solution of the compound in ethanol (2 mL) 4-morpholinoaniline (196 mg, 1.09 mmol) and Diisopropylethylamine (0.44 mL, 2.49 mmol) was added to a solution of And the mixture was stirred at room temperature for 6 hours.The resulting solid was filtered and washed with ethanol to give the desired compound (305 mg, 78%, 0.89 mmol) as a pale green solid.

Reference： [1]Patent: KR2018/137057,2018,A .Location in patent: Paragraph 0702-0706; 0712-0716

76
[ 126728-20-9 ]
[ 2524-67-6 ]
N-(3-((4-((4-morpholinophenyl)amino)pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acrylamide [ No CAS ]

Reference： [1]Patent: KR2018/137057,2018,A

77
[ 2524-67-6 ]
[ 1037479-62-1 ]
6-chloro-N-(4-morpholinophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine In ethanol at 20℃; for 0.5h;	30.1 Step 1: 6-chloro-N-(4-morpholinophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(500 mg, 1.83 mmol) To a solution of the compound in ethanol (20 mL)4-morpholinoaniline (195 mg, 1.09 mmol) and Et3N (0.20 mL, 1.46 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The resulting solid was filtered and washed with ethanol to give the desired compound (269 mg, 89%, 0.64 mmol) as a pale yellow solid.
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;

Reference： [1]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - KR2018/137057, 2018, A Location in patent: Paragraph 0640-0643
[2]Yeom, Hyesu; Achary, Raghavendra; Choi, Yunha; Park, Chi Hoon; Lee, Joo-Youn; Lee, Heung Kyoung; Kim, Pilho; Cho, Sung Yun [Bulletin of the Korean Chemical Society, 2022, vol. 43, # 4, p. 577 - 584]

78
[ 2524-67-6 ]
[ 1313613-18-1 ]

Reference： [1]Patent: CN108997247,2018,A

79
[ 2524-67-6 ]
[ 4891-38-7 ]
[ 536-74-3 ]
6-morpholin-4-yl-2,4-diphenyl-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: 4-morpholino-4-yl-phenylamine; phenylpropynoic acid methyl ester at 20℃; for 0.166667h; Stage #2: phenylacetylene With trifluorormethanesulfonic acid; silver trifluoromethanesulfonate In methanol at 120℃; for 24h;	General catalytic procedure for the synthesis of quinolines General procedure: A reaction kettle (30 mL) was charged with aniline (1.0 mmol), and alkyne ester (1.0 mmol). The mixture was stirred at room temperature for 10 minutes, then added terminal alkyne (1.2 mmol, 1.2 eq), AgOTf (5 mol%, 12.9 mg), HOTf (10 mol%, 15 mg), MeOH (2 mL) in the mixture. The mixture was stirred at 120 oC for 24 hours, the mixture was quenched by sat. aq. NaHCO3, and diluted with 20 mL of dichloromethane and washed with 10 mL of H2O. The aqueous layer was extracted twice with dichloromethane (10 mL) and the combined organic phase was dried over Na2SO4. After evaporation of the solvents, the residue was purified by silica gel chromatography (hexane/AcOEt = 5:1) to afford quinoline derivatives. All other compounds are synthesized in a similar manner, with the yields listed in the main text calculated from the isolated, pure products.

Reference： [1]Li, Yunlan; Zhang, Qiurui; Xu, Xuefeng; Zhang, Xu; Yang, Yurong; Yi, Wei [Tetrahedron Letters, 2019, vol. 60, # 14, p. 965 - 970]

80
[ 26452-80-2 ]
[ 2524-67-6 ]
4-chloro-N-[4-(morpholin-4-yl)phenyl]pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere; Sealed tube; regioselective reaction;	4-chloro-N-phenyl-pyridin-2-amine (3a) General procedure: Aniline (62μl, 0.68 mmol), 2,4-dichloropyridine (100 mg, 0.68 mmol), cesium carbonate (442 mg, 1.36 mmol), xantphos (47 mg, 0.08 mmol) and Pd(OAc)2 (12 mg, 0.05 mmol) were combined in a microwave tube, sealed and purged with nitrogen. Dioxane (3 mL) was then added and the reaction solution degassed with nitrogen prior to heating at 100°C for 30 minutes. The reaction mixture was then filtered and the filtrate was purified by reverse phase chromatography, utilizing a 20-65% gradient over 9 mins, with 0.5% ammonia as modifier to afford 4-chloro-N-phenyl-pyridin-2-amine

Reference： [1]Burton, Rebecca J.; Crowther, Mandy L.; Fazakerley, Neal M.; Fillery, Shaun M.; Hayter, Barry M.; Kettle, Jason G.; McMillan, Caroline A.; Perkins, Paula; Robins, Peter; Smith, Peter M.; Williams, Emma J.; Wrigley, Gail L. [Tetrahedron Letters, 2013, vol. 54, # 50, p. 6900 - 6904]

81
[ 2524-67-6 ]
[ 53554-29-3 ]
C₁₇H₂₀N₄O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29

82
[ 59-67-6 ]
[ 2524-67-6 ]
N-(4-morpholinophenyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: nicotinic acid With O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate In acetonitrile at 0 - 20℃; for 1h; Stage #2: 4-morpholino-4-yl-phenylamine With triethylamine In acetonitrile at 20℃; for 3h;	2.1 Experimental procedure for the synthesis of PMHAs The quinaldic acid (1.00g, 5.780mmol) was dissolved in acetonitrile (10mL) and cooled to 0°C. Then O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (2.22g, 6.936mmol) was added to the solution and the resulting mixture was stirred at room temperature for an hour. To that solution, 4-morpholinoaniline (1.02g, 5.780mmol) and triethylamine (1.20mL, 8.670mmol) were added. The reaction mixture was stirred for 3h at ambient temperature. Then the reaction mixture was diluted with ethylacetate (100mL) washed with water (100mL) and brine solution (100mL). The organic layer was separated and dried over anhydrous sodium sulfate. The obtained solid was washed with isopropyl ether yielded PMQA. The same procedure was followed for the synthesis of PMPA and PMTA. 2.1.1 N-(4-morpholinophenyl)quinoline-2-carboxamide (PMQA)Yield 91%, dirty white solid, 1H NMR (300MHz CDCl3): δ 3.15 (t, 4H, J=4.8Hz), 3.87 (t, 4H, J=4.8Hz), 6.97 (d, 2H, J=9.0Hz), 7.65 (d, 1H, J=8.1Hz), 7.76-7.83 (m, 3H), 7.90 (d, 1H, J=7.8Hz), 8.17 (d,1H, J=8.4Hz), 8.34-8.42 (m, 2H), 10.13 (s, 1H). 13C NMR (75MHz CDCl3): δ ppm: 49.78, 66.98, 116.37, 118.78, 121.02, 127.86, 128.07, 129.37, 129.66, 130.29, 130.75, 132.08, 137.81, 148.24, 149.94, 161.83. IR (KBr Disc) cm-1: 3314.96, 2856.67, 2969.22, 2810.41, 1666.96, 1518.80, 1117.85. ESI-MS calculated m/z. 333.14 found 371.85 [M+K]+.

Reference： [1]Nithyabalaji, Rajendran; Krishnan, Hariharasubramanian; Subha, Jeyachandran; Sribalan, Rajendran [Journal of Molecular Structure, 2020, vol. 1204]

83
[ 527-72-0 ]
[ 2524-67-6 ]
N-(4-morpholinophenyl)thiophene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 2-thiophenylcarboxylic acid With O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate In acetonitrile at 0 - 20℃; for 1h; Stage #2: 4-morpholino-4-yl-phenylamine With triethylamine In acetonitrile at 20℃; for 3h;	2.1 Experimental procedure for the synthesis of PMHAs The quinaldic acid (1.00g, 5.780mmol) was dissolved in acetonitrile (10mL) and cooled to 0°C. Then O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (2.22g, 6.936mmol) was added to the solution and the resulting mixture was stirred at room temperature for an hour. To that solution, 4-morpholinoaniline (1.02g, 5.780mmol) and triethylamine (1.20mL, 8.670mmol) were added. The reaction mixture was stirred for 3h at ambient temperature. Then the reaction mixture was diluted with ethylacetate (100mL) washed with water (100mL) and brine solution (100mL). The organic layer was separated and dried over anhydrous sodium sulfate. The obtained solid was washed with isopropyl ether yielded PMQA. The same procedure was followed for the synthesis of PMPA and PMTA. 2.1.1 N-(4-morpholinophenyl)quinoline-2-carboxamide (PMQA)Yield 91%, dirty white solid, 1H NMR (300MHz CDCl3): δ 3.15 (t, 4H, J=4.8Hz), 3.87 (t, 4H, J=4.8Hz), 6.97 (d, 2H, J=9.0Hz), 7.65 (d, 1H, J=8.1Hz), 7.76-7.83 (m, 3H), 7.90 (d, 1H, J=7.8Hz), 8.17 (d,1H, J=8.4Hz), 8.34-8.42 (m, 2H), 10.13 (s, 1H). 13C NMR (75MHz CDCl3): δ ppm: 49.78, 66.98, 116.37, 118.78, 121.02, 127.86, 128.07, 129.37, 129.66, 130.29, 130.75, 132.08, 137.81, 148.24, 149.94, 161.83. IR (KBr Disc) cm-1: 3314.96, 2856.67, 2969.22, 2810.41, 1666.96, 1518.80, 1117.85. ESI-MS calculated m/z. 333.14 found 371.85 [M+K]+.

Reference： [1]Nithyabalaji, Rajendran; Krishnan, Hariharasubramanian; Subha, Jeyachandran; Sribalan, Rajendran [Journal of Molecular Structure, 2020, vol. 1204]

84
[ 372118-01-9 ]
[ 2524-67-6 ]
methyl 6-chloro-4-((4-morpholinophenyl)amino)pyridazine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 18h;	Compound <strong>[372118-01-9]4,6-dichloropyridazine-3-carboxylic acid methyl ester</strong> 1a (581 mg, 2.81 mmol),4-morpholinoaniline 92c (500mg, 2.81mmol),Diisopropylethylamine (3.63 g, 28 mmol) and acetonitrile (10 mL) were mixed, heated to 90 C and stirred for 18 hours.After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/0 to 1/4),The target product 6-chloro-4-((4-morpholinophenyl) amino) pyridazine-3-carboxylic acid methyl ester 92d (768 mg, brown solid) was obtained in a yield of 78%.

Reference： [1]Patent: CN110818641,2020,A .Location in patent: Paragraph 1019-1021; 1030-1033

85
[ 2524-67-6 ]
[ 76661-24-0 ]
5-chloro-N-(4-morpholinophenyl)-4-(3-nitrophenoxy)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.4%	With trifluoroacetic acid; In iso-butanol; at 100℃;	General procedure: To a solution of 3a-r (1.50 mmol, 1 eq) and 6a-b (1.50 mmol, 1eq) in 2-BuOH (8 mL) were added TFA (2 mL). The slurrywas heatedto 100 C for 2e3 h. The reaction mixture was allowed to cool toroom temperature and was neutralized with a saturated aqueoussodium bicarbonate solution. The mixture was then extracted withethyl acetate (50 mL) three times. The crude was purified by flashchromatography with 25:1 (v/v) dichloromethane - methanol.

Reference： [1]European Journal of Medicinal Chemistry,2021,vol. 210

86
[ 2524-67-6 ]
[ 70049-77-3 ]
4-chloro-N-(4-morpholinophenyl)-3-sulfamoylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23.6%	Stage #1: 3-(aminosulfonyl)-4-chlorobenzoyl chloride With N-ethyl-N,N-diisopropylamine In dichloromethane for 0.25h; Cooling with ice; Stage #2: 4-morpholino-4-yl-phenylamine In dichloromethane for 12h; Cooling with ice;	4.1.2. Synthetic routes of compound a series, B series and X series General procedure: a. 3-sulfonamidobenzoic acid or 4-chloro-3-sulfonamidobenzoicacid (3 mmol) and 30 mL of freshly steamed SOCl2, wererefluxed at 105 °C for 3-5 h. Cooling and standing, then evaporatingthe thionyl chloride under reduced pressure to obtain 3-sulfonyl benzoyl chloride or 4-chloro-3-sulfonyl benzoylchloride;b. The corresponding substituted aromatic amine (0.5 mmol) wasweighed and dissolved in 10 mL of dichloromethane, and 65 mLof base DIPEA (0.5 mmol) was added, and the mixture wasstirred for 15 min in an ice bath. Then, 0.75 mmol of the aboveobtained3-sulfonamidobenzoyl chloride or 4-chloro-3-sulfonamidobenzoyl chloride was added, and the mixture was stirred for 12 h under ice-cooling, and the reaction was monitoredby TLC. After the reaction is terminated, the product isisolated and purified to obtain three series of compounds: A, Band X.

Reference： [1]Wang, Xuebao; Wu, Kaiqi; Fang, Longcheng; Yang, Xiaojiao; Zheng, Nan; Du, Zongxuan; Lu, Ying; Xie, Zixin; Liu, Zhiguo; Zuo, Zhigui; Ye, Faqing [European Journal of Medicinal Chemistry, 2021, vol. 218]

87
[ 2524-67-6 ]
[ 32315-10-9 ]
[ 129453-61-8 ]
(7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl (4-morpholinophenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: bis(trichloromethyl) carbonate; fulvestrant With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.333333h; Stage #2: 4-morpholino-4-yl-phenylamine In dichloromethane at 0 - 20℃; for 16h;	18 Example-18: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5- pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-3-yl (4-morpholinophenyl)carbamate To a solution of Fulvestrant (0.5 g) in DCM (8 mL) were added DIPEA (0.21 mL) and triphosgene (0.122 g) at 0°C and stirred the reaction mixture for 10 min at the same temperature. After 10 min, 4-morpholinoaniline (0.220 g) was added in the reaction mixture at 0°C and the reaction mixture was stirred at room temperature for 16h. After completion of reaction on TLC, the reaction mixture was diluted with water (5 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.7 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5- pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-3-yl (4-morpholinophenyl)carbamate as a light yellow gum. LCMS purity: 66%

Reference： [1]Current Patent Assignee: KASHIV BIOSCIENCES LLC - WO2021/100029, 2021, A2 Location in patent: Page/Page column 58

88
[ 2524-67-6 ]
[ 153493-48-2 ]
C₁₄H₁₃ClN₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane at 20℃; for 1h;	General Procedure for the “One-Pot” Synthesisof Compounds 6 (Scheme 3, Route A) General procedure: Step A: To a cooled solution (0 °C) of 5,6-dichloro-[1,2,5]oxadiazolo[3,4-b]pyrazine 4 (1 eq.) (commercially available; for preparation see ref. 2) in dry dichloromethane (1.1 ml/mmol of 4), the corresponding aniline or phenol (1 eq.) in dry dichloromethane (1.1 ml/mmol of 4) was added dropwise, and the resulting mixture was stirred at room temperature for approximately 1 h (TLC control, 1:1 hexane/ethyl acetate). Then the solvent was evaporated and crude intermediate product 5 was used in the next step without purification. Step B: crude product 5 from the previous step was dissolved in dry dichloromethane (1.1 ml/mmol) and the corresponding piperidine or piperazine (1 eq.) in dry dichloromethane (1.1 ml/mmol of starting material) was added and the resulting mixture was stirred at 40 °C until the reaction was completed (usually 2 h, HPLC control). Then the reaction mixture was washed twice with water and the combined organic layers were dried with magnesium sulfate. After the evaporation of the solvent, crude product 6 was purified by reversephase chromatography (C18 column, ACN/H2O).
	In dichloromethane at 20℃; for 1h;	General Procedure for the “One-Pot” Synthesisof Compounds 6 (Scheme 3, Route A) General procedure: Step A: To a cooled solution (0 °C) of 5,6-dichloro-[1,2,5]oxadiazolo[3,4-b]pyrazine 4 (1 eq.) (commercially available; for preparation see ref. 2) in dry dichloromethane (1.1 ml/mmol of 4), the corresponding aniline or phenol (1 eq.) in dry dichloromethane (1.1 ml/mmol of 4) was added dropwise, and the resulting mixture was stirred at room temperature for approximately 1 h (TLC control, 1:1 hexane/ethyl acetate). Then the solvent was evaporated and crude intermediate product 5 was used in the next step without purification. Step B: crude product 5 from the previous step was dissolved in dry dichloromethane (1.1 ml/mmol) and the corresponding piperidine or piperazine (1 eq.) in dry dichloromethane (1.1 ml/mmol of starting material) was added and the resulting mixture was stirred at 40 °C until the reaction was completed (usually 2 h, HPLC control). Then the reaction mixture was washed twice with water and the combined organic layers were dried with magnesium sulfate. After the evaporation of the solvent, crude product 6 was purified by reversephase chromatography (C18 column, ACN/H2O).

Reference： [1]Campos, Pedro M.; Carrasco, Esther; Gomez-Gutierrez, Patricia; Messeguer, Angel; Perez, Juan Jesus.; Vega, Miguel [Current Medicinal Chemistry, 2022, vol. 29, # 9, p. 1640 - 1653]
[2]Campos, Pedro M.; Carrasco, Esther; Gomez-Gutierrez, Patricia; Messeguer, Angel; Perez, Juan Jesus.; Vega, Miguel [Current Medicinal Chemistry, 2022, vol. 29, # 9, p. 1640 - 1653]

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Code	Phrase
H400	Very toxic to aquatic life
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H412	Harmful to aquatic life with long-lasting effects
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[ CAS No. 2524-67-6 ] {[proInfo.proName]}

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[ 2524-67-6 ] Synthesis Path-Upstream 1~15

[ 2524-67-6 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 2524-67-6 ]

Aryls

Amines

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Aliphatic Heterocycles

Morpholines

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[ 2524-67-6 ]

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[ 2524-67-6 ]