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[ CAS No. 790184-33-7 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

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Chemical Structure| 790184-33-7

Chemical Structure| 790184-33-7

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Quality Control of [ 790184-33-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 790184-33-7 ]

Product Details of [ 790184-33-7 ]

CAS No. :	790184-33-7	MDL No. :	MFCD11041200
Formula :	C₅H₁₁NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LQMMFVPUIVBYII-RXMQYKEDSA-N
M.W :	101.15	Pubchem ID :	641497
Synonyms :

Calculated chemistry of [ 790184-33-7 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	31.84
TPSA :	21.26 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.02 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	-0.14
Log Po/w (WLOGP) :	-0.39
Log Po/w (MLOGP) :	-0.16
Log Po/w (SILICOS-IT) :	1.1
Consensus Log Po/w :	0.42

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.38
Solubility :	42.3 mg/ml ; 0.418 mol/l
Class :	Very soluble
Log S (Ali) :	0.15
Solubility :	142.0 mg/ml ; 1.4 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.86
Solubility :	13.9 mg/ml ; 0.138 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 790184-33-7 ]

Signal Word:	Danger	Class:	8,3
Precautionary Statements:	P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405	UN#:	2734
Hazard Statements:	H314-H226	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 790184-33-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 790184-33-7 ]

[ 790184-33-7 ] Synthesis Path-Downstream 1~78

1
(2S,5R)-5-Methyl-2-[1-methyl-1-((R)-2-methyl-morpholin-4-yl)-ethyl]-cyclohexanone [ No CAS ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide In tetrahydrofuran; methanol at 20℃; for 4h;

Reference： [1]Pedrosa, Rafael; Andres, Celia; Mendiguchia, Pilar; Nieto, Javier [Journal of Organic Chemistry, 2006, vol. 71, # 23, p. 8854 - 8863]

2
[ 98-59-9 ]
[ 790184-33-7 ]
(2R)-2-methyl-4-tosyl-morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In ethyl acetate for 50h;

Reference： [1]Pedrosa, Rafael; Andres, Celia; Mendiguchia, Pilar; Nieto, Javier [Journal of Organic Chemistry, 2006, vol. 71, # 23, p. 8854 - 8863]

3
[ 914359-99-2 ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 90 percent / LiAlH₄; AlCl₃ / tetrahydrofuran / 0 °C 2: PCC; 3 Angstroem molecular sieves / CH₂Cl₂ / 20 °C 3: aq. KOH / tetrahydrofuran; methanol / 4 h / 20 °C

Reference： [1]Pedrosa, Rafael; Andres, Celia; Mendiguchia, Pilar; Nieto, Javier [Journal of Organic Chemistry, 2006, vol. 71, # 23, p. 8854 - 8863]

4
[ 914360-11-5 ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: PCC; 3 Angstroem molecular sieves / CH₂Cl₂ / 20 °C 2: aq. KOH / tetrahydrofuran; methanol / 4 h / 20 °C

Reference： [1]Pedrosa, Rafael; Andres, Celia; Mendiguchia, Pilar; Nieto, Javier [Journal of Organic Chemistry, 2006, vol. 71, # 23, p. 8854 - 8863]

5
[ 914359-85-6 ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 92 percent / AIBN; Ph₃SnH / toluene / Heating 2: 90 percent / LiAlH₄; AlCl₃ / tetrahydrofuran / 0 °C 3: PCC; 3 Angstroem molecular sieves / CH₂Cl₂ / 20 °C 4: aq. KOH / tetrahydrofuran; methanol / 4 h / 20 °C

Reference： [1]Pedrosa, Rafael; Andres, Celia; Mendiguchia, Pilar; Nieto, Javier [Journal of Organic Chemistry, 2006, vol. 71, # 23, p. 8854 - 8863]

6
[ 454251-71-9 ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: K₂CO₃ / CH₂Cl₂ / 5 h / 0 °C 2: 92 percent / AIBN; Ph₃SnH / toluene / Heating 3: 90 percent / LiAlH₄; AlCl₃ / tetrahydrofuran / 0 °C 4: PCC; 3 Angstroem molecular sieves / CH₂Cl₂ / 20 °C 5: aq. KOH / tetrahydrofuran; methanol / 4 h / 20 °C

Reference： [1]Pedrosa, Rafael; Andres, Celia; Mendiguchia, Pilar; Nieto, Javier [Journal of Organic Chemistry, 2006, vol. 71, # 23, p. 8854 - 8863]

7
[ 1184297-45-7 ]
[ 790184-33-7 ]
[ 1184297-40-2 ]

Yield	Reaction Conditions	Operation in experiment
11%	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide	3.5 3.5) δ-Chloro-thiophene^-carboxylic acid [(S)-2-[2-ethyl-3-(3-oxo-morpholin-4-yl)- benzenesulfonylamino]-3-((R)-2-methyl-morpholin-4-yl)-3-oxo-propyl]-amide:To intermediate 11 (200 mg, 0.39 mmol) in DCM/DMF 2:1 (7ml) was added (R)-2- methyl-morpholine (described in EP 656365), HATU (162 mg, 0.43 mmol) and DIPEA (263 μl, 1.55 mmol). After stirring overnight the mixture was purified by prep. HPLC. Yield after lyophilisation: 26 mg, 11 %, colourless, amorphous solid. MS (ES+): m/e = 599,2 / 601 ,2 , chloro pattern.

Reference： [1]Current Patent Assignee: BEIJING LIANXIN PHARMACEUTICAL - WO2009/103440, 2009, A1 Location in patent: Page/Page column 58

8
[ 1257236-39-7 ]
[ 790184-33-7 ]
[ 1257234-85-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine In dichloromethane; ISOPROPYLAMIDE at 60℃; for 2h;	49 A suspension of 2-chloro-N-(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen- 2-yl)acetamide (C1 , 119 mg, 0.235 mmol) in anhydrous DMA (1044 μl_) and DCM (1 mL) was added to (2R)-2-methylmorpholine hydrobromide (FF3, 86 mg, 0.47 mmol) and triethylamine (131 μl_, 0.94 mmol). The resulting solution was stirred at 600C for 2 hours. The crude product was diluted with methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7MNH3/MeOH and the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-[(2R)-2-methylmorpholin-4-yl]-N-[6-(2-morpholin-4-yl-4-oxochromen-8- yl)dibenzothiophen-2-yl]acetamide (125 mg, 93 %) as a white solid; 1H NMR (400 MHz, CDCI3) δ 1.22 (3H, d), 2.18 (1 H, t), 2.47 - 2.53 (1 H, m), 2.79 - 2.86 (2H, m), 3.07 (4H, t), 3.22 (2H, s), 3.50 (4H, t), 3.74 - 3.82 (2H, m), 3.95 - 3.99 (1 H, m), 5.49 (1 H, s), 7.43 - 7.45 (1 H, m), 7.47 - 7.50 (2H, m), 7.58 (1 H, t), 7.73 - 7.77 (2H1 m), 8.25 (1 H, s), 8.27 - 8.29 (1 H, m), 8.71 (1 H, d), 9.27 (1 H, s); m/z: 570.08 (MH+).

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; ASTRAZENECA PLC - WO2010/136778, 2010, A1 Location in patent: Page/Page column 137

9
[ 1257236-39-7 ]
[ 790184-33-7 ]
[ 1257234-87-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine In dichloromethane; ISOPROPYLAMIDE at 60℃; for 2h;	50 A suspension of 2-chloro-N-(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen- 2-yl)acetamide (C1 , 55 mg, 0.11 mmol) in anhydrous DMA (1.5 ml.) and DCM (1 ml_) was added to (2S)-2-methylmorpholine hydrobromide (EE3, 86 mg, 0.47 mmol) and triethylamine (0.059 ml_, 0.42 mmol). The resulting solution was stirred at 600C for 2 hours. The crude product was diluted with methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-[(2S)-2- methylmorpholin-4-yl]-N-[6-(2-morpholin-4-yl-4-oxochromen-8-yl)dibenzothiophen-2- yrjacetamide (108 mg, 81 %) as a white solid; 1H NMR (400 MHz, CDCI3) δ1.22 (3H, d), 2.18 (1H, t), 2.47 - 2.53 (1 H, m), 2.79 - 2.86 (2H, m), 3.07 (4H, t), 3.22 (2H, s), 3.50 (4H, t), 3.74 - 3.82 (2H, m), 3.95 - 3.99 (1 H, m), 5.49 (1H, s), 7.43 - 7.45 (1H, m), 7.47 - 7.50 (2H, m), 7.58 (1H, t), 7.73 - 7.77 (2H, m), 8.25 (1 H, s), 8.27 - 8.29 (1 H, m), 8.71 (1 H, d), 9.27 (1 H, s); m/z: 570.08 (MH+).

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; ASTRAZENECA PLC - WO2010/136778, 2010, A1 Location in patent: Page/Page column 138

10
[ 1257236-43-3 ]
[ 790184-33-7 ]
[ 1257234-97-1 ]

Yield	Reaction Conditions	Operation in experiment
33%	With triethylamine In dichloromethane; ISOPROPYLAMIDE at 60℃; for 1.5h;	56 A suspension 2-chloro-N-(6-(2-morpholino-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-9- yl)dibenzo[b,d]thiophen-2-yl)acetamide (D1 , 55 mg, 0.11 mmol) in anhydrous DMA (2 ml_) and DCM (1 ml.) was added to (2R)-2-methylmorpholine (FF3, 40.1 mg, 0.40 mmol) and triethylamine (0.059 ml_, 0.42 mmol). The resulting solution was stirred at 600C for 1.5 hours. The crude product was diluted with methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH3/MeOH in DCM. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2- [(2R)-2-methylmorpholin-4-yl]-N-[6-(2-morpholin-4-yl-4-oxopyrido[1 ,2-a]pyrimidin-9- yl)dibenzothiophen-2-yl]acetamide (37.6 mg, 33%) as a cream solid; 1H NMR (400 MHz, DMSO) δ 1.08 (3H1 d), 1.99 (1 H, t), 2.25 - 2.35 (2H, m), 2.77 (1H, d), 2.84 (1 H, d), 3.29 - 3.34 (6H, m), 3.43 - 3.48 (4H, m), 3.67 - 3.70 (1 H, m), 3.78 (1H, d), 5.67 (1H, s), 7.23 (1H, t), 7.62 - 7.66 (2H, m), 7.74 (1 H, d), 7.90 (1 H, d), 8.06 (1 H, d), 8.24 - 8.30 (1 H1 m), 8.67 (1 H, s), 8.93 (1 H, d), 9.94 (1 H, s); m/z: 570 (MH+).

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; ASTRAZENECA PLC - WO2010/136778, 2010, A1 Location in patent: Page/Page column 144

11
[ 1257236-45-5 ]
[ 790184-33-7 ]
[ 1257234-83-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine In ISOPROPYLAMIDE at 20℃; for 72h; Inert atmosphere;	48 N-methyl-2-[(2R)-2-methylmorpholin-4-yl]-N-[6-(2-morpholin-4-yl-4-oxopyrido[1,2- a]pyrimidin-9-yl)dibenzothiophen-2-yl]acetamide (78) N-ethyl-N-isopropylpropan-2-amine (0.393 ml_, 2.25 mmol) was added to a suspension of 2- chloro-N-methyl-N-[6-(2-morpholin-4-yl-4-oxopyrido[1 ,2-a]pyrimidin-9-yl)dibenzothiophen-2- yl]acetamide (D2, 390 mg, 0.75 mmol) and (2R)-2-methylmorpholine hydrobromide (FF3, 205 mg, 1.13 mmol) in anhydrous DMA (7 ml_). The resulting suspension was stirred under nitrogen at 6O0C for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH3ZMeOH in DCM. Pure fractions were evaporated to dryness to afford N-methyl-2-[(2R)-2-methylmorpholin-4- yl]-N-[6-(2-morpholin-4-yl-4-oxopyrido[1 ,2-a]pyrimidin-9-yl)dibenzothiophen-2-yl]acetamide (419 mg, 96 %) as a pale yellow foam. This was slurried in diethyl ether and the precipitate was collected by filtration, washed with Et2O (10 ml.) and dried under vacuum to afford (R)- N-methyl-2-(2-methylmorpholino)-N-(6-(2-morpholino-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-9- yl)dibenzo[b,d]thiophen-2-yl)acetamide (366 mg, 83 %) as a cream solid, which was used without further purification; 1H NMR (400 MHz, CDCI3) δ1.07 (3H, d), 1.81 (1 H, t), 2.13 (1H, t), 2.65 (1 H, d), 2.75 (1 H, d), 2.91 - 3.00 (2H, m), 3.37 - 3.38 (7H1 m), 3.58 (4H1 1), 3.65 -3.77 (3H, m), 5.64 (1 H, s), 7.03 (1 H1 1), 7.29 - 7.32 (1 H1 m), 7.58 - 7.65 (2H1 m), 7.83 (1 H1 d), 7.86 - 7.89 (1 H1 m), 8.05 (1 H1 d), 8.17 - 8.19 (1 H1 m), 9.05 - 9.07 (1 H, m); m/z: 584.49 (MH+).

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; ASTRAZENECA PLC - WO2010/136778, 2010, A1 Location in patent: Page/Page column 136

12
(2R)-2-methyl-4-tosyl-morpholine [ No CAS ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With hydrogen bromide; phenol In acetic acid at 20℃; for 16h;	FF.c A solution of (2R)-2-methyl-4-(4-methylphenyl)sulfonylmorpholine (FF2, 13.5 g, 52.87 mmol), phenol (9.95 g, 105.74 mmol) and 33% HBr in acetic acid (91 mL, 370.10 mmol) was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness, The crude oil was triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to give (2R)-2-methylmorpholine hydrobromide (8.28 g, 86 %) as a pink solid ; 1H NMR (400 MHz, DMSO) δ 1.17 (3H, d), 2.73 (1 H, t), 3.01 (1 H, td), 3.23 (1 H, d), 3.26 (1 H, d), 3.74 (1 H, td), 3.79 (1 H, dqd), 3.98 (1 H, dd), 8.89 (2H, s).

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; ASTRAZENECA PLC - WO2010/136778, 2010, A1 Location in patent: Page/Page column 86

13
C₂₂H₂₉ClN₄O₃Si [ No CAS ]
[ 790184-33-7 ]
C₂₇H₃₉N₅O₄Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 110℃;	K.10 Step 10: A mixture of the chloropyrimidine from step 9 (120 mg, 0.26 mmol), 'Pr2NEt (200 mg, 1.56 mmol) and (R)-2-methylmorpholine (79 mg, 0.78 mmol) in DMSO (3 mL) was stirred at 110 °C overnight. Upon cooling to room temperature, water (30 mL) was added and the resulting layer was extracted with EtOAc (30 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to yield the product which was used in the next step without further purification. MS (ESI) m/z =526.2 [M+H]+.
	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 110℃;	K A mixture of the chloropyrimidine from step 9 (120 mg, 0.26 mmol), 'Pr2NEt (200 mg, 1.56 mmol) and (R)-2-methylmorpholine (79 mg, 0.78 mmol) in DMSO (3 mL) was stirred at 110 °C overnight. Upon cooling to room temperature, water (30 mL) was added and the resulting layer was extracted with EtOAc (30 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to yield the product which was used in the next step without further purification. MS (ESI) m/z =526.2 [M+H]+.

Reference： [1]Current Patent Assignee: TATE & LYLE PUBLIC LIMITED COMPANY - WO2014/137723, 2014, A1 Location in patent: Page/Page column 83-84
[2]Current Patent Assignee: TATE & LYLE PUBLIC LIMITED COMPANY - WO2014/134774, 2014, A1 Location in patent: Page/Page column 80; 82; 83

14
C₂₂H₂₉ClN₄O₃Si [ No CAS ]
[ 790184-33-7 ]
C₂₁H₂₅N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 110 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / Reflux

Reference： [1]Current Patent Assignee: TATE & LYLE PUBLIC LIMITED COMPANY - WO2014/134774, 2014, A1

15
[ 1430063-93-6 ]
[ 790184-33-7 ]
C₂₆H₄₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27.9%	With potassium carbonate In tetrahydrofuran at 20℃; for 15h;	8 Example 8. Synthesis of compound SA-6 To a suspension of K2CO3 (25 mg, 0.18mmol) in THF (5 mL) was added (R)-2-methylmorpholine ( 20mg, 0.20 mmol) and SA( 36 mg, 0.09 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified with by reverse-phase prep-HPLC to afford the title compound SA-6 as a white solid (11 mg, 27.9%).

Reference： [1]Current Patent Assignee: SAGE THERAPEUTICS INC - WO2014/169836, 2014, A1 Location in patent: Page/Page column 91

16
[ 127958-66-1 ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 16h;	General Procedure for synthesis of 5: General procedure: LAH (2 equiv.) in THF (100 mL) was cooled to 0oC inan ice bath under nitrogen. A solution of 4 (1 equiv.) in THF (20 mL) was added dropwise, and the resulting solution was stirred at RT for 16 hrs. The reaction mixture was cooled to 0oC andcarefully quenched with water (2 mL), 2 N NaOH (2 mL) and water (8 mL). The resulting slurrywas stirred at RT for 1 h and filtered through Celite. The filter cake was washed with ethylacetate and discarded. The filtrate was dried (Na2SO4), separated and concentrated to afford 5 asa colorless oil.

Reference： [1]Dugar, Sundeep; Sharma, Amit; Kuila, Bilash; Mahajan, Dinesh; Dwivedi, Sandeep; Tripathi, Vinayak [Synthesis, 2014, vol. 46]

17
C₅H₁₀ClNO₂ [ No CAS ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / dichloromethane; isopropyl alcohol / 1 h / 0 - 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 16 h / 0 - 20 °C

Reference： [1]Dugar, Sundeep; Sharma, Amit; Kuila, Bilash; Mahajan, Dinesh; Dwivedi, Sandeep; Tripathi, Vinayak [Synthesis, 2014, vol. 46]

18
[ 1527475-89-3 ]
[ 790184-33-7 ]
[ 1527474-16-3 ]

Yield	Reaction Conditions	Operation in experiment
37.5%	With N-ethyl-N,N-diisopropylamine In butan-1-ol for 3h; Reflux;

Reference： [1]Henderson, Jaclyn L.; Kormos, Bethany L.; Hayward, Matthew M.; Coffman, Karen J.; Jasti, Jayasankar; Kurumbail, Ravi G.; Wager, Travis T.; Verhoest, Patrick R.; Noell, G. Stephen; Chen, Yi; Needle, Elie; Berger, Zdenek; Steyn, Stefanus J.; Houle, Christopher; Hirst, Warren D.; Galatsis, Paul [Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 419 - 432]

19
[ 790184-33-7 ]
[ 507476-70-2 ]
(R)-5-(2-methylmorpholino)quinoline-8-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.7%	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 170℃; for 16h;	General procedure: ER-885211 (4 mg, 0.016 mmol, 24.7% yield) was prepared in a similar manner to ER-886849 starting with Compound 3 (15 mg, 0.064 mmol) and (R)-2-methylmorpholine (22 mg, 0.160 mmol). TEA (0.05 mL, 0.359 mmol) was added to the reaction. A mixture of Compound 3 (201 mg, 0.862 mmol) and (R)-2-hydroxymethyl morpholine hydrochloride (132, 0.856 mmol) in NMP(3 mL) was heated to 170 C. for 16 h. The completed reaction was cooled, filtered, eluted with MeOH (2 mL) then purified directly by HPLC using a C-18 column eluting with a 10-100% acetonitrile in water containing 0.1% TFA. The desired product was collected and concentrated to dry. The resulting product was dissolved in MeOH (2 mL) and passed over a basic silica plug (Biotage, 1 g, SiCO3) eluting with MeOH (5 mL) to provide (R)-5-(2-(hydroxymethyl)morpholino)quinoline-8-carbonitrile or ER-886849 (108 mg, 0.401 mmol, 46.9% yield).

Reference： [1]Patent: US2015/105370,2015,A1 .Location in patent: Paragraph 0334; 0337

20
2-(5-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonate [ No CAS ]
[ 790184-33-7 ]
(R)-2-methyl-4-(2-(5-methyl-4-nitro-1H-pyrazol-1-yl)ethyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In N,N-dimethyl-formamide at 90℃;	D119 (R)-2-methyl-4-(2-(5-methyl-4-nitro-1 H-pyrazol-l -yl)ethyl)morpholine (Dl 19) To a solution of D15 (200 mg, 0.80 mmol) in DMF (10 mL) was added (R)-2-methylmorpholine (97 mg, 0.963 mmol) and K2C03 (333 mg, 2.407 mmol). The mixture was stirred overnight at 90 °C. The reaction mixture was quenched with water and extracted with DCM (20 mLx3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuum. The crude was purified by column chromatography on silica gel (PE:EA1:1)to give the title compound D119 (180 mg, 0.708 mmol, 88 % yield).LCMS: 255 [M+H]. tR 1.19 mins. (LCMS condition 2)

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2015/113452, 2015, A1 Location in patent: Page/Page column 99

21
1-(4-fluorophenyl)-6-formyl-4-oxo-1,4-dihydroquinoline-3-carboxamide [ No CAS ]
[ 790184-33-7 ]
(R)-1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane for 17h;

Reference： [1]Felts, Andrew S.; Rodriguez, Alice L.; Smith, Katrina A.; Engers, Julie L.; Morrison, Ryan D.; Byers, Frank W.; Blobaum, Anna L.; Locuson, Charles W.; Chang, Sichen; Venable, Daryl F.; Niswender, Colleen M.; Daniels, J. Scott; Conn, P. Jeffrey; Lindsley, Craig W.; Emmitte, Kyle A. [Journal of Medicinal Chemistry, 2015, vol. 58, # 22, p. 9027 - 9040]

22
4-chloro-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxamide [ No CAS ]
[ 790184-33-7 ]
(R)-4-(2-methylmorpholin-4-yl)-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; XPhos In 1,4-dioxane	5-2 The following examples in Table 5-1 were prepared in an analogous manner to that described in general scheme 5 using intermediate 5-1 and commercial amines or amines described in the intermediates section. Compounds that were resolved into individual enantiomers were separated after step 1 or step 2 using the SFC conditions noted (column size: 250 mm × 30 mm I. D. 5μm) .

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2016/29454, 2016, A1 Location in patent: Page/Page column 97

23
4,6-diiodo-2-methoxypyrimidine [ No CAS ]
[ 790184-33-7 ]
(R)-4-(6-iodo-2-methoxypyrimidin-4-yl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.6%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	D374 Description 0374(R)-4-(6-iodo-2-methoxypyrimidin-4-yl)-2-methylmorpholine (D374) To a solution of 4,6-diiodo-2-methoxypyrimidine (600 mg, 1.66 mmol) in DMF (10 mL) was added (R)-2-methylmorpholine (201 mg, 1.99 mmcl) and DIPEA (429 mg, 3.32 mmcl). The mixture was stirred at room temperature overnight. The reaction mixture was poured intowater (100 mL), extracted with EtOAc (50 mL x 3). The combined organic layers werewashed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated to dryness. Theresidue was purified by silica gel chromatography eluted with (EtOAc: petroleum ether =1:1 0-i :5) to give the product (R)-4-(6-iodo-2-methoxypyrimidin-4-yl)-2-methylmorpholine(520 mg, 93.6% yield) as a yellow oil.LC-MS: (mobile phase: from 90% water (0.1% FA) and 10% CH3CN (0.1% FA) to 5% water (0.1% FA) and 95% CH3CN (0.1% FA) in 2.5 mm), Rt 1.55 mm; MS Calcd.: 335; MS Found:336 [M+H].

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2017/12576, 2017, A1 Location in patent: Page/Page column 255

24
[ 790184-33-7 ]
[ 66298-49-5 ]
(R)-4-(6-iodo-2-methylpyrimidin-4-yl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In isopropyl alcohol at 65℃; for 2h;	D407 Description D407(R)-4-(6-lodo-2-methyl pyrim idi n-4-yI)-2-methyl morpholi ne (D407) To a suspension of 4,6-diiodo-2-methylpyrimidine (150 mg, 0.434 mmol) in i-PrOH (2 mL)was added (R)-2-methylmorpholine (53 mg, 0.52 mmcl) and TEA (131 mg, 1.30 mmol) at it.The resulting mixture was stirred at 65 °C for 2 hrs. The resulting mixture was poured into water (60 mL) and extracted with EtOAc (60 mL). The organic solution was washed with brine, dried over Na2SO4 and then concentrated. The crude was purified by column chromatography(PE: EtOAc = 7: 1)to give the title compound (110mg, yield 80%) ascolorless oil.D407 1H NMR (300 MHz, CDCI3): ö 6.77 (s, 1H), 4.24-3.96 (m, 3H), 3.67-3.54 (m, 2H), 3.07- 2.95 (m, 1H), 2.71-2.60 (m, 1H), 2.46 (s, 3H), 1.25 (d, J 6.0 Hz, 3H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2017/12576, 2017, A1 Location in patent: Page/Page column 272

25
[ 10111-08-7 ]
[ 790184-33-7 ]
(R)-4-((1H-imidazol-2-yl)methyl)-2-methylmorpholine [ No CAS ]

Reference： [1]Patent: WO2016/202253,2016,A1 .Location in patent: Page/Page column 123; 124

26
3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole [ No CAS ]
[ 790184-33-7 ]
C₂₆H₃₇N₅O₃Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 100℃;

Reference： [1]Scott, Jack D.; DeMong, Duane E.; Greshock, Thomas J.; Basu, Kallol; Dai, Xing; Harris, Joel; Hruza, Alan; Li, Sarah W.; Lin, Sue-Ing; Liu, Hong; Macala, Megan K.; Hu, Zhiyong; Mei, Hong; Zhang, Honglu; Walsh, Paul; Poirier, Marc; Shi, Zhi-Cai; Xiao, Li; Agnihotri, Gautam; Baptista, Marco A. S.; Columbus, John; Fell, Matthew J.; Hyde, Lynn A.; Kuvelkar, Reshma; Lin, Yinghui; Mirescu, Christian; Morrow, John A.; Yin, Zhizhang; Zhang, Xiaoping; Zhou, Xiaoping; Chang, Ronald K.; Embrey, Mark W.; Sanders, John M.; Tiscia, Heather E.; Drolet, Robert E.; Kern, Jonathan T.; Sur, Sylvie M.; Renger, John J.; Bilodeau, Mark T.; Kennedy, Matthew E.; Parker, Eric M.; Stamford, Andrew W.; Nargund, Ravi; McCauley, John A.; Miller, Michael W. [Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2983 - 2992]

27
3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole [ No CAS ]
[ 790184-33-7 ]
(R)-2-methyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dimethyl sulfoxide / 100 °C 2: hydrogenchloride / methanol; 1,4-dioxane / 1 h / 65 °C

Reference： [1]Scott, Jack D.; DeMong, Duane E.; Greshock, Thomas J.; Basu, Kallol; Dai, Xing; Harris, Joel; Hruza, Alan; Li, Sarah W.; Lin, Sue-Ing; Liu, Hong; Macala, Megan K.; Hu, Zhiyong; Mei, Hong; Zhang, Honglu; Walsh, Paul; Poirier, Marc; Shi, Zhi-Cai; Xiao, Li; Agnihotri, Gautam; Baptista, Marco A. S.; Columbus, John; Fell, Matthew J.; Hyde, Lynn A.; Kuvelkar, Reshma; Lin, Yinghui; Mirescu, Christian; Morrow, John A.; Yin, Zhizhang; Zhang, Xiaoping; Zhou, Xiaoping; Chang, Ronald K.; Embrey, Mark W.; Sanders, John M.; Tiscia, Heather E.; Drolet, Robert E.; Kern, Jonathan T.; Sur, Sylvie M.; Renger, John J.; Bilodeau, Mark T.; Kennedy, Matthew E.; Parker, Eric M.; Stamford, Andrew W.; Nargund, Ravi; McCauley, John A.; Miller, Michael W. [Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2983 - 2992]

28
3,6-di-bromo-isothiazolo[4,3-b]pyridine [ No CAS ]
[ 790184-33-7 ]
(R)-4-(6-bromoisothiazolo[4,3-b]pyridin-3-yl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	In ethanol Reflux;

Reference： [1]Pu, Szu-Yuan; Wouters, Randy; Schor, Stanford; Rozenski, Jef; Barouch-Bentov, Rina; Prugar, Laura I.; O'Brien, Cecilia M.; Brannan, Jennifer M.; Dye, John M.; Herdewijn, Piet; De Jonghe, Steven; Einav, Shirit [Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6178 - 6192]

29
4-[(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclohexanone [ No CAS ]
[ 790184-33-7 ]
5-methyl-4-({cis-4-[(2R)-2-methyl-4-morpholinyl]cyclohexyl}oxy)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
5-methyl-4-({trans-4-[(2R)-2-methyl-4-morpholinyl]cyclohexyl}oxy)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-[(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclohexanone; (2R)-2-methyl-morpholine With acetic acid In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 20h;

Reference： [1]Degorce, Sébastien L.; Bodnarchuk, Michael S.; Cumming, Iain A.; Scott, James S. [Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8934 - 8943]

30
C₁₂H₁₈ClNO [ No CAS ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / tetrahydrofuran; ethanol / 35 °C / Cooling with ice; Green chemistry 2: 2-Chloroethyl chloroformate / dichloromethane / 2.5 h / Cooling with ice; Reflux; Green chemistry

Reference： [1]Current Patent Assignee: SHANGHAI BALMXY PHARMACEUTIC - CN108570014, 2018, A

31
[ 120800-90-0 ]
[ 790184-33-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 2-Chloroethyl chloroformate In dichloromethane for 2.5h; Cooling with ice; Reflux; Green chemistry;	4.4 (4) The pale yellow viscous material (300 g, 1.57 mol) obtained in the third step was dissolved in 1.5 L of dichloromethane, andchloroethyl 1-chloroformate (247g, 1.73 mol)was slowly added dropwiseunder ice bath. The system was naturally warmed to room temperature, and after heating for half an hour, the mixture was heated to reflux for 2hours. The dichloromethane was concentrated and evaporated, and the residue was dissolved in 1.6 L of methanol and refluxed for 1 hour. Then, methanol was distilled off, and2 L of isopropyl etherwas added to the residue.Filtration, filter cake washed twice with isopropyl ether, collected, dried, dissolved in 1.5L water, 2Msodium hydroxide solutionwas added dropwise in an ice bath, the pH was adjusted to more than 12, then extracted with dichloromethane 3 times, combined The organic phase was subjected to atmospheric distillation to give133 g of (S)-2-methylmorpholineas a colorless oil, yield 84%.

Reference： [1]Current Patent Assignee: SHANGHAI BALMXY PHARMACEUTIC - CN108570014, 2018, A Location in patent: Paragraph 0086; 0088; 0093

32
[ 790184-33-7 ]
(R)-(2-chloro-4-methoxypyrimidin-5-yl)(2-methylmorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere 2: tetrahydrofuran / 3 h / -40 - -10 °C / Inert atmosphere

Reference： [1]Thomas, Michael G.; De Rycker, Manu; Ajakane, Myriam; Albrecht, Sébastian; Álvarez-Pedraglio, Ana Isabel; Boesche, Markus; Brand, Stephen; Campbell, Lorna; Cantizani-Perez, Juan; Cleghorn, Laura A.T.; Copley, Royston C.B.; Crouch, Sabrinia D.; Daugan, Alain; Drewes, Gerard; Ferrer, Santiago; Ghidelli-Disse, Sonja; Gonzalez, Silvia; Gresham, Stephanie L.; Hill, Alan P.; Hindley, Sean J.; Lowe, Rhiannon M.; Mackenzie, Claire J.; Maclean, Lorna; Manthri, Sujatha; Martin, Franck; Miguel-Siles, Juan; Nguyen, Van Loc; Norval, Suzanne; Osuna-Cabello, Maria; Woodland, Andrew; Patterson, Stephen; Pena, Imanol; Quesada-Campos, Maria Teresa; Reid, Iain H.; Revill, Charlotte; Riley, Jennifer; Ruiz-Gomez, Jose Ramon; Shishikura, Yoko; Simeons, Frederick R.C.; Smith, Alasdair; Smith, Victoria C.; Spinks, Daniel; Stojanovski, Laste; Thomas, John; Thompson, Stephen; Underwood, Tim; Gray, David W.; Fiandor, Jose M.; Gilbert, Ian H.; Wyatt, Paul G.; Read, Kevin D.; Miles, Timothy J. [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1180 - 1202]

33
[ 790184-33-7 ]
3,3,3-trifluoro-N-(trans-4-((4-methoxy-5-((R)-2-methylmorpholine-4-carbonyl)pyrimidin-2-yl)amino)cyclohexyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere 2: tetrahydrofuran / 3 h / -40 - -10 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 16 h / 120 °C

Reference： [1]Thomas, Michael G.; De Rycker, Manu; Ajakane, Myriam; Albrecht, Sébastian; Álvarez-Pedraglio, Ana Isabel; Boesche, Markus; Brand, Stephen; Campbell, Lorna; Cantizani-Perez, Juan; Cleghorn, Laura A.T.; Copley, Royston C.B.; Crouch, Sabrinia D.; Daugan, Alain; Drewes, Gerard; Ferrer, Santiago; Ghidelli-Disse, Sonja; Gonzalez, Silvia; Gresham, Stephanie L.; Hill, Alan P.; Hindley, Sean J.; Lowe, Rhiannon M.; Mackenzie, Claire J.; Maclean, Lorna; Manthri, Sujatha; Martin, Franck; Miguel-Siles, Juan; Nguyen, Van Loc; Norval, Suzanne; Osuna-Cabello, Maria; Woodland, Andrew; Patterson, Stephen; Pena, Imanol; Quesada-Campos, Maria Teresa; Reid, Iain H.; Revill, Charlotte; Riley, Jennifer; Ruiz-Gomez, Jose Ramon; Shishikura, Yoko; Simeons, Frederick R.C.; Smith, Alasdair; Smith, Victoria C.; Spinks, Daniel; Stojanovski, Laste; Thomas, John; Thompson, Stephen; Underwood, Tim; Gray, David W.; Fiandor, Jose M.; Gilbert, Ian H.; Wyatt, Paul G.; Read, Kevin D.; Miles, Timothy J. [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1180 - 1202]

34
[ 790184-33-7 ]
3,3,3-trifluoro-N-(trans-4-((4-methoxy-5-((R)-2-methylmorpholine-4-carbonothioyl)pyrimidin-2-yl)amino)cyclohexyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere 2: tetrahydrofuran / 3 h / -40 - -10 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 16 h / 120 °C 4: Lawessons reagent / tetrahydrofuran / 2 h / 45 °C

Reference： [1]Thomas, Michael G.; De Rycker, Manu; Ajakane, Myriam; Albrecht, Sébastian; Álvarez-Pedraglio, Ana Isabel; Boesche, Markus; Brand, Stephen; Campbell, Lorna; Cantizani-Perez, Juan; Cleghorn, Laura A.T.; Copley, Royston C.B.; Crouch, Sabrinia D.; Daugan, Alain; Drewes, Gerard; Ferrer, Santiago; Ghidelli-Disse, Sonja; Gonzalez, Silvia; Gresham, Stephanie L.; Hill, Alan P.; Hindley, Sean J.; Lowe, Rhiannon M.; Mackenzie, Claire J.; Maclean, Lorna; Manthri, Sujatha; Martin, Franck; Miguel-Siles, Juan; Nguyen, Van Loc; Norval, Suzanne; Osuna-Cabello, Maria; Woodland, Andrew; Patterson, Stephen; Pena, Imanol; Quesada-Campos, Maria Teresa; Reid, Iain H.; Revill, Charlotte; Riley, Jennifer; Ruiz-Gomez, Jose Ramon; Shishikura, Yoko; Simeons, Frederick R.C.; Smith, Alasdair; Smith, Victoria C.; Spinks, Daniel; Stojanovski, Laste; Thomas, John; Thompson, Stephen; Underwood, Tim; Gray, David W.; Fiandor, Jose M.; Gilbert, Ian H.; Wyatt, Paul G.; Read, Kevin D.; Miles, Timothy J. [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1180 - 1202]

35
[ 790184-33-7 ]
3,3,3-trifluoro-N-((1,4-trans)-4-((3-((R)-2-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere 2: tetrahydrofuran / 3 h / -40 - -10 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 16 h / 120 °C 4: Lawessons reagent / tetrahydrofuran / 2 h / 45 °C 5: hydrazine hydrate / 1,4-dioxane / 18 h / 90 °C

Reference： [1]Thomas, Michael G.; De Rycker, Manu; Ajakane, Myriam; Albrecht, Sébastian; Álvarez-Pedraglio, Ana Isabel; Boesche, Markus; Brand, Stephen; Campbell, Lorna; Cantizani-Perez, Juan; Cleghorn, Laura A.T.; Copley, Royston C.B.; Crouch, Sabrinia D.; Daugan, Alain; Drewes, Gerard; Ferrer, Santiago; Ghidelli-Disse, Sonja; Gonzalez, Silvia; Gresham, Stephanie L.; Hill, Alan P.; Hindley, Sean J.; Lowe, Rhiannon M.; Mackenzie, Claire J.; Maclean, Lorna; Manthri, Sujatha; Martin, Franck; Miguel-Siles, Juan; Nguyen, Van Loc; Norval, Suzanne; Osuna-Cabello, Maria; Woodland, Andrew; Patterson, Stephen; Pena, Imanol; Quesada-Campos, Maria Teresa; Reid, Iain H.; Revill, Charlotte; Riley, Jennifer; Ruiz-Gomez, Jose Ramon; Shishikura, Yoko; Simeons, Frederick R.C.; Smith, Alasdair; Smith, Victoria C.; Spinks, Daniel; Stojanovski, Laste; Thomas, John; Thompson, Stephen; Underwood, Tim; Gray, David W.; Fiandor, Jose M.; Gilbert, Ian H.; Wyatt, Paul G.; Read, Kevin D.; Miles, Timothy J. [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1180 - 1202]

36
[ 790184-33-7 ]
[ 2972-52-3 ]
(R)-(2,4-dichloropyrimidin-5-yl)(2-methylmorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With triethylamine In dichloromethane at 0℃; for 3h; Inert atmosphere;

Reference： [1]Thomas, Michael G.; De Rycker, Manu; Ajakane, Myriam; Albrecht, Sébastian; Álvarez-Pedraglio, Ana Isabel; Boesche, Markus; Brand, Stephen; Campbell, Lorna; Cantizani-Perez, Juan; Cleghorn, Laura A.T.; Copley, Royston C.B.; Crouch, Sabrinia D.; Daugan, Alain; Drewes, Gerard; Ferrer, Santiago; Ghidelli-Disse, Sonja; Gonzalez, Silvia; Gresham, Stephanie L.; Hill, Alan P.; Hindley, Sean J.; Lowe, Rhiannon M.; Mackenzie, Claire J.; Maclean, Lorna; Manthri, Sujatha; Martin, Franck; Miguel-Siles, Juan; Nguyen, Van Loc; Norval, Suzanne; Osuna-Cabello, Maria; Woodland, Andrew; Patterson, Stephen; Pena, Imanol; Quesada-Campos, Maria Teresa; Reid, Iain H.; Revill, Charlotte; Riley, Jennifer; Ruiz-Gomez, Jose Ramon; Shishikura, Yoko; Simeons, Frederick R.C.; Smith, Alasdair; Smith, Victoria C.; Spinks, Daniel; Stojanovski, Laste; Thomas, John; Thompson, Stephen; Underwood, Tim; Gray, David W.; Fiandor, Jose M.; Gilbert, Ian H.; Wyatt, Paul G.; Read, Kevin D.; Miles, Timothy J. [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1180 - 1202]

37
[ 32315-10-9 ]
C₂₄H₃₂N₆O₃ [ No CAS ]
[ 790184-33-7 ]
C₃₀H₄₁N₇O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: bis(trichloromethyl) carbonate; C₂₄H₃₂N₆O₃ With triethylamine In dichloromethane at 20℃; for 0.25h; Stage #2: (2R)-2-methyl-morpholine In dichloromethane for 0.5h;

Reference： [1]Chen, Yong; Yuan, Xue; Zhang, Wanhua; Tang, Minghai; Zheng, Li; Wang, Fang; Yan, Wei; Yang, Shengyong; Wei, Yuquan; He, Jun; Chen, Lijuan [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1577 - 1592]

38
lithium 5-amino-7-methoxyimidazo[1,2-c]quinazoline-2-carboxylate [ No CAS ]
[ 790184-33-7 ]
(R)-(5-amino-7-methoxyimidazo[1,2-c]quinazolin-2-yl)(2-methylmorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 20℃;	23 Example 23, General Procedure for preparing amide analogs General procedure: Additional amide analogs were prepared by adding 1.5 equivalents of an amine which will provide the desired substituents into a 1 dram vial (1.5 eq.) along with lithium 5-amino-7- methoxyimidazo[1,2-c]quinazoline-2-carboxylate (30 mg, 0.114 mmol) and a DMF solution (1.0 ml) solution of DIPEA (0.079 ml, 0.454 mmol), shaking the vial for 5 minutes in a Bohdan Miniblock Shaker and then adding 1-propanephosphonic acid cyclic anhydride (50% w/w in EtOAc, 64.7 µl, 0.109 mmol), and continuing to shake the vial at RT overnight. The completed reaction was quenched with 1.0 ml water and the organic layer separated by filtering through a Varian 2 ml Reservior Frit and a Whatman 0.45µm syringe filter to remove emulsion, followed by solvent removal using a Genevac. The crude residue was dissolved in 1.0 ml DMSO and purified by LC/MS.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/118313, 2019, A1 Location in patent: Page/Page column 00140-00141

39
[ 3621-81-6 ]
[ 790184-33-7 ]
C₁₂H₁₃ClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.4%	With triethylamine In dichloromethane at 25℃; for 12h;	56.A Step A To a stirred solution of 2,5-dichloro-1,3-benzoxazole (0.719 g, 0.0038 mol) in DCM (15 mL) TEA (2.67 ml, 0.0191 mol) and (2R)-2-methylmorpholine (0.5 g, 0.00494 mol) and stirred for 12 h at 25°C were added. After completion of the reaction by TLC, the reaction mixture was added DCM and water (50 mL). The organic layer was separated, dried over sodium sulphate filtered and then concentrated to get the title compound (0.6 g, 45.4%) as a white solid. (0715) MS: 253.2 (M+H)+. (0716) 1H-NMR (400 MHz, DMSO- e) d = 7.43 (d, J = 1 1.20 Hz, 1 H), 7.35 (d, J = 2.40 Hz, 1 H), 7.05 (dd, J = 2.80, 11.20 Hz, 1 H), 3.89-3.90 (m, 3H), 3.56-3.59 (m, 2H), 3.17-3.18 (m, 1 H), 2.86-2.89 (m, 1 H), 1.15 (d, J = 8.40 Hz, 3H).

Reference： [1]Current Patent Assignee: AC IMMUNE SA - WO2019/134978, 2019, A1 Location in patent: Page/Page column 112

40
[ 624-28-2 ]
[ 790184-33-7 ]
C₁₀H₁₃BrN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 100℃; for 5h; Inert atmosphere; Sealed tube;	36.A Step A Commercially available 2,5-dibromopyridine (0.5 g, 2.2 mmol) and (R)-2-methylmorpholine (0.234 g, 2.9 mmol) were added to a reaction tube and degassed toluene (10.0 ml) was added. Then Xantphos (0.073 g, 2.1 mol), Tris(dibenzylideneacetone)dipalladium(0) (0.024 g, 0.4 mmol) and Sodium tert-butoxide (0.608 g, 6.3 mmol) were added and the solution was heated at 100° C for 5 hours in sealed tube filled with Argon gas.The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude purified on HP-Sil column (Biotage), by employing a Petroleum ether/ethyl acetate gradient (100/0 -> 70/30) to afford title compound (0.3 g, 55%) as an off white solid.1H-NMR (400 MHz, DMSO -d6) d 8.18 (d, J = 3.20 Hz, 1 H), 7.69-7.70 (m, 1 H), 6.84 (d, J = 12.00 Hz, 1 H), 3.87-3.88 (m, 3H), 3.48-3.49 (m, 2H), 2.74-2.76 (m, 1 H), 1.14 (d, J = 8.00 Hz, 3H). MS: 257.1 (M +H)+.

Reference： [1]Current Patent Assignee: AC IMMUNE SA - WO2019/233883, 2019, A1 Location in patent: Page/Page column 79

41
[ 141-30-0 ]
[ 790184-33-7 ]
(R)-4-(6-chloropyridazin-3-yl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.5%	With triethylamine In ethanol at 80℃; for 12h;	52.A Step A Step A To a solution of commercially available 3,6-dichloropyridazine (0.500g, 3.36mmol) and (2R)-2- methylmorpholine (0.339g,3.36mmol) in ethanol (15 mL) was added triethylamine (0.509g, 5.03mmol) and the reaction was heated to 80° C for 12 h. The reaction mixture was concentrated under reduced pressure. The crude purified on HP-Sil column (Biotage), by employing a Petroleum ether/ethyl acetate gradient (100/0 -> 70/30) to afford title compound (0.250 g, 34.5%).1H-NMR (400 MHz, DMSO -d6) d 7.57 (d, J = 9.60 Hz, 1 H), 7.40 (d, J = 9.60 Hz, 1 H), 3.91 -3.91 (m, 3H), 3.53-3.54 (m, 2H), 2.89-2.90 (m, 1 H), 2.64-2.67 (m, 1 H), 1.16 (d, J = 6.40 Hz, 3H).MS: 214.2 (M +H)+.

Reference： [1]Current Patent Assignee: AC IMMUNE SA - WO2019/233883, 2019, A1 Location in patent: Page/Page column 88-89

42
2-chloro-4-ethoxy-5-iodobenzonitrile [ No CAS ]
[ 790184-33-7 ]
C₁₄H₁₇ClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃;

Reference： [1]Davidsson, Öjvind; Nilsson, Kristina; Brånalt, Jonas; Andersson, Terese; Berggren, Kristina; Chen, Yantao; Fjellström, Ola; Gradén, Henrik; Gustafsson, Linda; Hermansson, Nils-Olov; Jansen, Frank; Johannesson, Petra; Ohlsson, Bengt; Tyrchan, Christian; Wellner, Annika; Wellner, Eric; Ölwegård-Halvarsson, Maria [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 4]

43
[ 790184-33-7 ]
N-((2S,3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)-2-((R)-2-methylmorpholino)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C / Inert atmosphere; Sealed tube 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0 - 25 °C / Inert atmosphere; Sealed tube 2.2: 25 °C / Inert atmosphere; Sealed tube

Reference： [1]Cen, Shan; Dong, Biao; Dou, Yue; Ma, Ling; Wang, Juxian; Wang, Yucheng; Zhang, Fan; Zhang, Guoning; Zhou, Jinming; Zhu, Mei [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 6, p. 1196 - 1204]

44
[ 790184-33-7 ]
N-((2S,3R)-3-hydroxy-4-((N-isobutyl-4-(trifluoromethyl)phenyl)sulfonamido)-1-phenylbutan-2-yl)-2-((R)-2-methylmorpholino)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C / Inert atmosphere; Sealed tube 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0 - 25 °C / Inert atmosphere; Sealed tube 2.2: 25 °C / Inert atmosphere; Sealed tube

Reference： [1]Cen, Shan; Dong, Biao; Dou, Yue; Ma, Ling; Wang, Juxian; Wang, Yucheng; Zhang, Fan; Zhang, Guoning; Zhou, Jinming; Zhu, Mei [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 6, p. 1196 - 1204]

45
[ 790184-33-7 ]
N-((2S,3R)-4-((4-amino-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-2-((R)-2-methylmorpholino)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C / Inert atmosphere; Sealed tube 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0 - 25 °C / Inert atmosphere; Sealed tube 2.2: 25 °C / Inert atmosphere; Sealed tube 3.1: hydrogen; 5%-palladium/activated carbon / methanol; ethyl acetate / 4 h / 25 °C / 2585.81 Torr / Sealed tube

Reference： [1]Cen, Shan; Dong, Biao; Dou, Yue; Ma, Ling; Wang, Juxian; Wang, Yucheng; Zhang, Fan; Zhang, Guoning; Zhou, Jinming; Zhu, Mei [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 6, p. 1196 - 1204]

46
[ 79-08-3 ]
[ 790184-33-7 ]
(R)-2-(2-methylmorpholino)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 25℃; Inert atmosphere; Sealed tube;

Reference： [1]Cen, Shan; Dong, Biao; Dou, Yue; Ma, Ling; Wang, Juxian; Wang, Yucheng; Zhang, Fan; Zhang, Guoning; Zhou, Jinming; Zhu, Mei [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 6, p. 1196 - 1204]

47
[ 7461-50-9 ]
[ 790184-33-7 ]
(R)-2-(2-methylmorpholino)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 150℃; for 36h; Autoclave;	Intermediate 1: (R)-2-(2-Methylmorpholino)pyrimidin-4-amine A mixture of 2-chloropyrimidin-4-amine (60.0 g, 463 mmol, Combi-Blocks, San Diego, CA), (R)- 2-methylmorpholine (65.6 g, 648 mmol, Wuxi Apptec) and DIPEA (243 mL, 1389 mmol) in NMP (600 mL) was taken in an autoclave and heated at 150 °C for 36 h. The reaction mixture was cooled to room temperature and quenched with water (1 L) and extracted with ethyl acetate (3 x 500 mL). The organic layer was washed with brine solution (500 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude material as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with a gradient of 50% to 100% ethyl acetate in hexanes to give a yellow solid. This solid was further triturated with hexanes (300 mL), filtered and dried under vacuum to give the title compound (70 g, 78% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) d ppm 7.75 (d, J = 5.6 Hz, 1H), 6.42 (s, 2H), 5.75 (d, J = 5.6 Hz, 1H), 4.26- 4.49 (m, 2H), 3.83 (ddd, J = 11.4, 3.6, 1.4 Hz, 1H), 3.31- 3.50 (m, 2H), 2.78 (ddd, J = 13.2, 11.8, 3.5 Hz, 1H), 2.42- 2.48 (m, 1H), 1.11 (d, J = 6.2 Hz, 3H). m/z (ESI): 195.2 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132648, 2020, A1 Location in patent: Paragraph 0226; 0227

48
[ 14394-60-6 ]
[ 790184-33-7 ]
(R)-6-methyl-2-(2-methylmorpholino)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine at 150℃; for 12h; Autoclave;	Intermediate 2: (R)-6-Methyl-2-(2-methylmorpholino)pyrimidin-4-amine A mixture of 2-chloro-6-methylpyrimidin-4-amine (30.0 g, 209 mmol, Combi-Blocks, San Diego, CA), (R)-2-methylmorpholine (40.3 g, 293 mmol, Wuxi Apptec, PR China), and DIPEA (109 mL, 627 mmol) was taken in an autoclave (600 mL) and heated at 150 °C for 12 h. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 x 1500 mL). The organic layer was washed with brine solution (500 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel (60-120 mesh) using 50% ethyl acetate in hexanes as an eluent to give the title compound (25.0 g, 57% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) d 6.28 (s, 2H), 5.62 (s, 1H), 4.45- 4.31 (m, 2H), 3.83 (ddd, J = 11.4, 3.5, 1.3 Hz, 1H), 3.42 (ddt, J = 14.4, 9.7, 2.8 Hz, 2H), 2.78- 2.70 (m, 1H), 2.43 (dd, J = 13.0, 10.3 Hz, 1H), 2.05 (s, 3H), 1.11 (d, J = 6.2 Hz, 3H). m/z (ESI): 209.2 (M+H)+.
57%	With N-ethyl-N,N-diisopropylamine at 150℃; for 12h; Autoclave;	(R)-6-Methyl-2-(2-methylmorpholino)pyrimidin-4-amine A mixture of 2-chloro-6-methylpyrimidin-4-amine (30.0 g, 209 mmol, Combi-Blocks, San Diego, CA), (R)-2-methylmorpholine (40.3 g, 293 mmol, Wuxi AppTec, China), and DIPEA (109 mL, 627 mmol) was taken in an autoclave (600 mL) and heated at 150 °C for 12 h. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 x 1500 mL). The organic layer was washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography over silica gel using 50% ethyl acetate in hexanes as an eluent to give the title compound (25.0 g, 57% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) d ppm 6.28 (s, 2H), 5.62 (s, 1H), 4.45- 4.31 (m, 2H), 3.83 (ddd, J = 11.4, 3.5, 1.3 Hz, 1H), 3.42 (ddt, J = 14.4, 9.7, 2.8 Hz, 2H), 2.78- 2.70 (m, 1H), 2.43 (dd, J = 13.0, 10.3 Hz, 1H), 2.05 (s, 3H), 1.11 (d, J = 6.2 Hz, 3H). m/z (ESI): 209.2 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132648, 2020, A1 Location in patent: Paragraph 0228; 0229
[2]Current Patent Assignee: AMGEN INC - WO2020/132649, 2020, A1 Location in patent: Paragraph 0191-0193

49
[ 14394-60-6 ]
[ 790184-33-7 ]
(R)-4-bromo-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 12 h / 150 °C / Autoclave 2.1: sodium hydride / N,N-dimethyl-formamide / 0.17 h / Inert atmosphere 2.2: 2 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132648, 2020, A1

50
[ 1257294-51-1 ]
[ 790184-33-7 ]
(R)-5-fluoro-6-(2-methylmorpholino)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium acetate; copper In dimethyl sulfoxide at 110℃; for 16h;	Intermediate 34: (i?)-5-fluoro-6-(2-methylmorpholino)pyridin-2-amine. A mixture of 6-bromo-5-fluoropyridin-2 -amine (0.90 g, 4.71 mmol), (R)- 2-methylmorpholine (0.48 g, 4.71 mmol), potassium acetate (0.92 g, 9.42 mmol) and copper powder (30 mg, 0.471 mmol) in dimethyl sulfoxide (8.10 mL) was heated at 110 °C for 16 h. The reaction mixture was cooled to RT, diluted with water (mL), and extracted with EtOAc (2 x10 mL). The organic extracts were washed with brine ( 10 mL), dried over Na2SO t, and concentrated in vacuo to give the crude material as a yellow solid. The crude material was purified by silica gel chromatography (0% to 10% EtOAc in hexane) to provide (R)-5-fluoro-6-(2-methylmorpholino)pyridin-2-amine (34, 0.510 g, 2.41 mmol, 51% yield) as a yellow oil. m/z (ESI): 212.0 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132653, 2020, A1 Location in patent: Paragraph 0202-0203

51
[ 790184-33-7 ]
(R)-6-fluoro-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 12 h / 150 °C / Autoclave 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132649, 2020, A1

52
[ 790184-33-7 ]
(R)-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-6-(oxetan-3-ylamino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 12 h / 150 °C / Autoclave 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 100 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 16 h / 100 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2020/132649, 2020, A1

53
tert-butyl N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate [ No CAS ]
[ 790184-33-7 ]
(R)-tert-butyl (2-((4-(3-(2-methylmorpholino)phenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.85%	With t-BuXPhos Pd G₃; sodium t-butanolate In 1,4-dioxane at 80℃; for 3h; Inert atmosphere;	86.1 Step 1: Preparation of tert-butyl (2-((4-(3-(2,2-dimethylmorpholino)phenyl)thiazol-2-yl)amino)-2- oxoethyl)carbamate (Intermediate C) To a solution of tert-butyl N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (prepared according to the method in Example 1) (500 mg, 1.21 mmol), 2,2-dimethylmorpholine (209.51 mg, 1.82 mmol), t-BuONa (349.62 mg, 3.64 mmol) in dioxane (10 mL) was added t-BuXPhos-Pd-G3 (96.33 mg, 121.27 mmol). Then the mixture was stirred at 80 °C for 3 h under N2. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 2), the organic layer was washed with brine (10 mL) and concentrated to get the crude product. The crude product was purified by reverse phase column (FA) and lyophilized to give Intermediate C (180 mg, 249.51 mmol, 20.57% yield) as colorless oil. LCMS (ESI) m/z [M+H]+ = 447.1.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2020/160180, 2020, A1 Location in patent: Page/Page column 216

54
C₁₃H₁₁BrFN₃O [ No CAS ]
[ 790184-33-7 ]
C₁₈H₂₁FN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; ruphos In tetrahydrofuran for 6h; Inert atmosphere;	To a solution of 17-2 (32 mg, 0.1 mmol, 1.0 eq) in THF (1 mL) was added RuPhos (0.5 eq), Pd2dba3(0.25 eq), sodium tert-butoxide (2 eq) and (R)-2-methylmorpholine (3 eq). The reaction was heated at 65oC for 6 hours. The reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by FCC to give 17-3 as a white solid (19 mg, 55%).

Reference： [1]Current Patent Assignee: SCENIC HOLDING BV - WO2021/9068, 2021, A1 Location in patent: Page/Page column 438

55
[ 2265-94-3 ]
[ 790184-33-7 ]
(R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 2h; Microwave irradiation;	1 Step 1 A mixture of 1,3-difluoro-5-nitrobenzene (3.0 g, 18.86 mmol, Apollo Scientific), (R)-2- methylmorpholine (2.289 g, 22.63 mmol, Arbor Chemicals), and DIPEA (6.59 mL, 37.7 mmol) in 1,4- dioxane (30.0 mL) was stirred under microwave at 100 °C for 2 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with a gradient of 0 % to 40 % EtOAc in petroleum ether to provide (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine (1.5 g, 6.24 mmol, 33 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): d ppm 7.54 (d, J=2.3 Hz, 1 H), 7.38 (dt, J=8.4, 2.1 Hz, 1 H), 7.27 (dt, J=12.3, 2.3 Hz, 1 H), 3.92 (ddd, J=11.5, 3.7, 1.4 Hz, 1 H), 3.80 (dt, J=12.2, 2.2 Hz, 1 H), 3.68 (ddt, J=12.2, 3.1, 1.6 Hz, 1 H), 3.53 - 3.67 (m, 2 H), 2.79 (td, J=11.9, 3.6 Hz, 1 H), 2.41 - 2.49 (m, 1 H), 1.16 (d, J=6.2 Hz, 3 H). m/z (ESI): 241.1 (M+H)+.
33%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 2h; Microwave irradiation;	1 [0299] Intermediate 1: (R)-3-Fluoro-5-(2-methylmorpholino)aniline. [0300] Step 1: A mixture of 1,3-difluoro-5-nitrobenzene (3.0 g, 18.86 mmol, Apollo Scientific), (R)-2- methylmorpholine (2.29 g, 22.63 mmol, Arbor Chemicals) and DIPEA (6.59 mL, 37.7 mmol) in 1,4-dioxane (30 mL) was stirred under microwave at 100 °C for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with a gradient of 0 - 40% EtOAc in petroleum ether to provide (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine (1.5 g, 6.24 mmol, 33 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): d ppm 7.54 (d, J=2.3 Hz, 1H), 7.38 (dt, J=8.4, 2.1Hz, 1H), 7.27 (dt, J=12.3, 2.3 Hz, 1H), 3.92 (ddd, J=11.5, 3.7, 1.4 Hz, 1H), 3.80 (dt, J=12.2, 2.2 Hz, 1H), 3.68 (ddt, J=12.2, 3.1, 1.6 Hz, 1H), 3.53 - 3.67 (m, 2 H), 2.79 (td, J=11.9, 3.6 Hz, 1H), 2.41 - 2.49 (m, 1H), 1.16 (d, J=6.2 Hz, 3 H). m/z (ESI): 241.1 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26100, 2021, A1 Location in patent: Paragraph 0311-0312
[2]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1 Location in patent: Paragraph 0229-300

56
[ 2265-94-3 ]
[ 790184-33-7 ]
(R)-3-Fluoro-5-(2-methylmorpholino)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 2 h / 100 °C / Microwave irradiation 2: hydrogen; palladium on activated charcoal / methanol; tetrahydrofuran / 16 h / 724.03 Torr
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 2 h / 100 °C / Microwave irradiation 2: hydrogen; palladium on activated charcoal / methanol; tetrahydrofuran / 16 h / 724.03 Torr

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26100, 2021, A1
[2]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1

57
[ 701-45-1 ]
[ 790184-33-7 ]
(R)-4-(2-fluoro-5-nitrophenyl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 16h;	1 Step 1 A mixture of 2-bromo-1-fluoro-4-nitrobenzene (3.0 g, 13.64 mmol, Apollo Scientific), (R)- 2 methyl morpholine (1.94 g, 19.23 mmol, Arbor chemicals), Pd(OAc)2 (0.36 g, 1.63 mmol), Cs2CO3 (8.89 g, 27.3 mmol) and Xantphos (0.87 g, 1.50 mmol) in 1,4-dioxane (15 mL) was heated at 100 °C for 16 h. The reaction mixture was filtered through a bed of CELITE and washed with EtOAc. The EtOAc layer was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography eluting with 0 % to 20 % EtOAc in hexanes to provide (R)-4-(2-fluoro-5- nitrophenyl)-2-methylmorpholine (0.7 g, 2.91 mmol, 21 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): d ppm 7.89 (ddd, J=8.9, 3.9, 2.8 Hz, 1 H), 7.79 (dd, J=7.6, 2.8 Hz, 1 H), 7.46 (dd, J=12.2, 8.9 Hz, 1 H), 3.90 (ddd, J=11.5, 3.2, 1.5 Hz, 1 H), 3.68 - 3.77 (m, 2 H), 3.27 - 3.40 (m, 2 H), 2.85 (td, J=11.6, 3.2 Hz, 1 H), 2.56 (dd, J=11.6, 10.0 Hz, 1 H), 1.15 (d, J=6.3 Hz, 3 H). m/z (ESI): 241.1 (M+H)+.
21%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 16h;	1 [0302] Intermediate 2: (R)-4-Fluoro-3-(2-methylmorpholino)aniline. [0303] Step 1: A mixture of 2-bromo-1-fluoro-4-nitrobenzene (3.0 g, 13.64 mmol, Apollo Scientific), (R)- 2 methyl morpholine (1.94 g, 19.23 mmol, Arbor chemicals), Pd(OAc)2 (0.36 g, 1.63 mmol), Cs2CO3 (8.89 g, 27.3 mmol) and xantphos (0.87 g, 1.50 mmol) in dioxane (15 mL) was heated at 100 °C for 16 h. The reaction mixture was filtered through a bed of CELITE and washed with EtOAc. The filtrate was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in hexanes to provide (R)-4-(2-fluoro-5-nitrophenyl)-2- methylmorpholine (0.7 g, 2.91 mmol, 21 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): d ppm 7.89 (ddd, J=8.9, 3.9, 2.8 Hz, 1H), 7.79 (dd, J=7.6, 2.8 Hz, 1H), 7.46 (dd, J=12.2, 8.9 Hz, 1H), 3.90 (ddd, J=11.5, 3.2, 1.5 Hz, 1H), 3.68 - 3.77 (m, 2 H), 3.27 - 3.40 (m, 2 H), 2.85 (td, J=11.6, 3.2 Hz, 1H), 2.56 (dd, J=11.6, 10.0 Hz, 1H), 1.15 (d, J=6.3 Hz, 3 H). m/z (ESI): 241.1 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26100, 2021, A1 Location in patent: Paragraph 0314-0315
[2]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1 Location in patent: Paragraph 0302-0303

58
[ 701-45-1 ]
[ 790184-33-7 ]
(R)-4-Fluoro-3-(2-methylmorpholino)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 16 h / 100 °C 2: hydrogen; palladium on activated charcoal / methanol; tetrahydrofuran / 16 h / 724.03 Torr
	Multi-step reaction with 2 steps 1: palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / 1,4-dioxane / 16 h / 100 °C 2: hydrogen; palladium on activated charcoal / methanol; tetrahydrofuran / 16 h / 724.03 Torr

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26100, 2021, A1
[2]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1

59
4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoro-methyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide [ No CAS ]
[ 790184-33-7 ]
1-[({4-((2R)-2-methylmorpholin-4-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19.3 mg	With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate; ruphos In 1,4-dioxane at 100℃; Inert atmosphere;	26 Synthesis of l-[({4-((2R)-2-methylmorpholin-4-yl)-l-[5-(difluoromethyl)(l,3,4-thiadiazol-2- yl)] - 1 H-indazol-6-yl } sulfonyl)amino] cyclopropanecarbonitrile Into a 15-mL sealed tube, were placed 4-chloro-N-(l-cyanocyclopropyl)-l-[5- (difluoromethyl)-l,3,4-thiadiazol-2-yl]-lH-indazole-6-sulfonamide (500.00 mg, 1.161 mmol, 1.00 equiv.), (2R)-2-methylmorpholine (234.78 mg, 2.321 mmol, 2 equiv.), dioxane (5.00 mL),CS2CO3 (756.26 mg, 2.321 mmol, 2 equiv.), RuPhos (108.31 mg, 0.232 mmol, 0.2 equiv.), and RuPhos Palladacycle Gen.3 (97.06 mg, 0.116 mmol, 0.10 equiv.) under nitrogen atmosphere. The resulting solution was stirred for 1 overnight at 100 °C under nitrogen atmosphere and then quenched with saturated NH4CI (aq.). The resulting mixture was extracted with EtOAc and the combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (CEbCkiMeOEMO: 1) to afford the crude product. The crude product (60 mg) was purified by Prep-HPLC (Column: Xbridge Prep OBD Cl 8 Column 30x150 mm 5 um; mobile phase A: water (0.05% NH32O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 27% B to 37% B in 7 min; 254;220 nm; rt: 6.50 min) to afford the title compound (19.3 mg). LCMS (ES, m/z): [M+H]+496; 'H-NMR (300MHz, DMSO-de, ppm) d 9.34 (brs, 1H), 9.00(s, 1H), 8.52 (s, 1H), 7.61 (t, 1H), 7.18 (s, 1H), 3.96-4.02 (m, 1H), 3.68-3.84 (m, 4H), 3.04 (t, 1H), 2.73 (t, 1H), 1.50-1.41 (m, 2H), 1.36-1.28 (m, 2H), 1.21 (d, 3H).

Reference： [1]Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2021/55744, 2021, A1 Location in patent: Paragraph 0163

60
[ 790184-33-7 ]
(R)-4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium t-butanolate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / toluene / 20 h / 50 °C / Inert atmosphere; Sealed tube 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / 0 °C / Inert atmosphere 2.2: 19 h / 0 °C / Reflux; Inert atmosphere

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]

61
[ 790184-33-7 ]
(R)-4-(2-((1R*,2R*,5S*)-2-benzyl-3-azabicyclo[3.1.0]-hexan-3-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium t-butanolate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / toluene / 20 h / 50 °C / Inert atmosphere; Sealed tube 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / 0 °C / Inert atmosphere 2.2: 19 h / 0 °C / Reflux; Inert atmosphere 3.1: sodium t-butanolate; ruphos; chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butyl ether adduct / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere; Sealed tube

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]

62
[ 790184-33-7 ]
6-((1S,2S,5R)-2-benzyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-((2R)-2-methylmorpholino)pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium t-butanolate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / toluene / 20 h / 50 °C / Inert atmosphere; Sealed tube 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / 0 °C / Inert atmosphere 2.2: 19 h / 0 °C / Reflux; Inert atmosphere 3.1: sodium t-butanolate; ruphos; chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butyl ether adduct / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere; Sealed tube 4.1: 5%-palladium/activated carbon; 2,5-dihydrotoluene / ethanol / 3 h / 75 °C / Inert atmosphere

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]

63
[ 790184-33-7 ]
C₃₀H₃₅N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium t-butanolate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / toluene / 20 h / 50 °C / Inert atmosphere; Sealed tube 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / 0 °C / Inert atmosphere 2.2: 19 h / 0 °C / Reflux; Inert atmosphere 3.1: ruphos; chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butyl ether adduct / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere; Sealed tube

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]

64
[ 790184-33-7 ]
6-((1R,2S,5S)-2-benzyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-((R)-2-methylmorpholino) pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium t-butanolate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / toluene / 20 h / 50 °C / Inert atmosphere; Sealed tube 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / 0 °C / Inert atmosphere 2.2: 19 h / 0 °C / Reflux; Inert atmosphere 3.1: ruphos; chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butyl ether adduct / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere; Sealed tube 4.1: 5%-palladium/activated carbon; 2,5-dihydrotoluene / ethanol / 75 °C / Inert atmosphere

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]

65
[ 790184-33-7 ]
C₃₁H₃₉N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium t-butanolate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / toluene / 20 h / 50 °C / Inert atmosphere; Sealed tube 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / 0 °C / Inert atmosphere 2.2: 19 h / 0 °C / Reflux; Inert atmosphere 3.1: ruphos; chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butyl ether adduct / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere; Sealed tube

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]

66
[ 790184-33-7 ]
6-((R)-2-benzylazepan-1-yl)-4-((R)-2-methylmorpholino)pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium t-butanolate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / toluene / 20 h / 50 °C / Inert atmosphere; Sealed tube 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / 0 °C / Inert atmosphere 2.2: 19 h / 0 °C / Reflux; Inert atmosphere 3.1: ruphos; chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butyl ether adduct / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere; Sealed tube 4.1: 5%-palladium/activated carbon; 2,5-dihydrotoluene / ethanol / 75 °C / Inert atmosphere

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]

67
[ 98027-84-0 ]
[ 790184-33-7 ]
(R)-4-(2,6-dichloropyridin-4-yl)-2-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate In toluene at 50℃; for 20h; Inert atmosphere; Sealed tube;
	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate In toluene at 50℃; for 20h; Inert atmosphere; Sealed tube;	B Method B: A mixture of amine (1.0 eq.), 2,6-dichloro-4-iodopyridine (1.0 eq.), NaOtBu (2 eq.), PdCl2(tBu2Pferrocene)2 (0.025 eq.) in toluene (0.3 M) was placed in a sealed reaction tube under nitrogen and heated at 50 °C for 20 h. The reaction mixture was cooled to rt and filtered through celite. The mixture was concentrated under reduced pressure and purified by silica gel chromatography.

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]
[2]Current Patent Assignee: CHDI FOUNDATION - WO2021/113506, 2021, A1 Location in patent: Paragraph 0185; 0189

68
4-chloro-6-(7-methoxy-9H-thioxanthen-4-yl)-1H-pyridin-2-one [ No CAS ]
[ 790184-33-7 ]
(R)-6-(7-methoxy-9H-thioxanthen-4-yl)-4-(2-methylmorpholino)pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-chloro-6-(7-methoxy-9H-thioxanthen-4-yl)-1H-pyridin-2-one With sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In toluene for 0.333333h; Inert atmosphere; Stage #2: (2R)-2-methyl-morpholine With palladium diacetate In toluene at 110℃; for 16h; Inert atmosphere; Sealed tube;

Reference： [1]Van De Poël, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Muñoz-Sanjuan, Ignacio; Dominguez, Celia [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5018 - 5036]

69
C₂₄H₂₂O₅ [ No CAS ]
[ 790184-33-7 ]
C₂₉H₃₁NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₂₄H₂₂O₅ With trifluoromethylsulfonic anhydride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Stage #2: (2R)-2-methyl-morpholine

Reference： [1]Babbar, Palak; Sato, Mizuki; Manickam, Yogavel; Mishra, Siddhartha; Harlos, Karl; Gupta, Swati; Parvez, Suhel; Kikuchi, Haruhisa; Sharma, Amit [ChemBioChem, 2021, vol. 22, # 14, p. 2468 - 2477]

70
[ 1079649-94-7 ]
[ 36160-82-4 ]
[ 790184-33-7 ]
4-[4-(4-fluorophenoxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.5%	Stage #1: 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-(4-fluorophenoxy)aniline With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 40℃; for 16h; Stage #2: (2R)-2-methyl-morpholine In dimethyl sulfoxide at 100℃; for 16h;	51 Example 51: (R)-4-((4-(4-fluorophenoxy)phenyl)amino)-6-isopropyl-2- (2-methylmorpholino)-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one 4-(4-Fluorophenoxy /aniline (83 mg, 0.41 mmol) was added to 2,4-dichloro-6-isopropyl-5,6-dihydro-7H- pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.41 mmol) and DIEA (0.213 mL, 1.22 mmol) in DMSO (2 mL) at rt. The resulting mixture was stirred at 40 °C for 16 hours. (// ) -2 - m c thy 1 m o rp ho 1 i nc (41.1 mg, 0.41 mmol) was added to the reaction at rt. The resulting mixture was stirred at 100 °C for 16 hours. The crude product was purified by preparative HPLC conditions A. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-((4-(4-fluorophenoxy)phenyl)amino)-6-isopropyl-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4- d]pyrimidin-7 -one (63.0 mg, 32.5 %) as a yellow solid. NMR (400 MHz, DMSO) d 1.15 (d, J = 6.2 Hz, 3H), 1.24 (d, J = 6.7 Hz, 6H), 2.61 (dd, J = 13.1, 10.4 Hz, 1H), 2.88 - 3.00 (m, 1H), 3.44 - 3.54 (m, 2H), 3.89 (d, J = 9.3 Hz, 1H), 4.26 (s, 2H), 4.31 - 4.46 (m, 3H), 6.99 - 7.11 (m, 4H), 7.18 - 7.29 (m, 2H), 7.74 (dd, J = 9.2, 3.0 Hz, 2H), 9.30 (s, 1H). m/z (ES+), [M+H]+: 478; HPLC tR= 1.946 min (98%).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2021/180952, 2021, A1 Location in patent: Page/Page column 59

71
[ 848398-41-4 ]
[ 6373-50-8 ]
[ 790184-33-7 ]
N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.1%	Stage #1: 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine; p-cyclohexylaniline With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 50℃; for 7h; Stage #2: (2R)-2-methyl-morpholine In dimethyl sulfoxide at 100℃; for 16h;	90 Example 90: (/?)-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)-5,7- dihydrofuro[3,4-d]pyrimidin-4- amine 4-Cyclohexylaniline (0.918 g, 5.24 mmol) was added to 2,4-dichloro-5, 7-dihydroiuro[3,4-d]pyrimidine (1 g, 5.24 mmol) and DIEA (2.74 mL, 15.71 mmol) in DMSO (15 mL) at RT. The resulting mixture was stirred at 50 °C for 7 hours. (// ) - 2 - m c thy 1 m o rp ho 1 i nc (0.635 g, 6.28 mmol) was added to above mixture and stirred at 100 °C for 16 hours. The reaction mixture was purified by flash C18-flash chromatography with elution gradient 10 to 85% MeCN in water (0.1% FA). Pure fractions were evaporated to dryness to afford (R)-N- (4-cyclohexylphenyl)- 2- (2-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (0.932 g, 45.1 %) as a white solid. NMR (400 MHz, DMSO) d 1.13 (d, J = 6.1 Hz, 3H), 1.18 - 1.25 (m, 1H), 1.27 - 1.44 (m, 4H), 1.70 (d, J = 12.7 Hz, 1H), 1.78 (d, J = 9.7 Hz, 4H), 2.42 - 2.46 (m, 1H), 2.57 (dd, J = 13.0, 10.3 Hz, 1H), 2.90 (td, J = 12.4, 3.5 Hz, 1H), 3.37 - 3.56 (m, 2H), 3.86 (dd, J = 11.3, 3.2 Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H), 4.38 (d, J = 12.6 Hz, 1H), 4.68 (t, J = 2.3 Hz, 2H), 4.87 (t, J = 2.4 Hz, 2H), 7.12 - 7.19 (m, 2H), 7.52 - 7.60 (m, 2H), 8.76 (s, 1H). ES+m/z [M + H]+: 395, HPLC tR= 1.78 min (99.6%).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2021/180952, 2021, A1 Location in patent: Page/Page column 71-72

72
[ 6373-50-8 ]
[ 790184-33-7 ]
[ 15783-48-9 ]
4-[(4-cyclohexylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 16 h / 23 °C 1.2: 16 h / 100 °C 2.1: hydrogenchloride / water / 4 h / 190 °C

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2021/180952, 2021, A1

73
[ 6373-50-8 ]
[ 790184-33-7 ]
[ 15783-48-9 ]
(R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: p-cyclohexylaniline; 2,4-dichlorofuro[3,4-d]pyrimidin-7(5H)-one With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 23℃; for 16h; Stage #2: (2R)-2-methyl-morpholine In dimethyl sulfoxide at 100℃; for 16h;	Intermediate 15 (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino) furo[3,4-d]pyrimidin-7(5H)- one DIEA (0.598 mL, 3.42 mmol) was added to 2,4-dichlorofuro[3,4-d]pyrimidin-7(5H)-one (234 mg, 1.14 mmol) and 4-cyclohexylaniline (200 mg, 1.14 mmol) in DMSO (2 mL) at rt. The resulting mixture was stirred at rt for 16 h. (R)-2- me thy 1 mo rplio line (115 mg, 1.14 mmol) was added to above mixture. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered with water and ethyl acetate and evaporated to afford (A)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)iuro[3,4-d]pyrimidin-7(5H)-one (412 mg,88 %) as a yellow solid. NMR (400 MHz, DMSO) d 1.16 (d, J = 6.1 Hz, 3H), 1.31 - 1.46 (m, 5H), 1.77 - 1.82 (m, 5H), 2.60 - 2.71 (m, 1H), 2.99 (t, J = 11.4 Hz, 1H), 3.43 - 3.55 (m, 3H), 3.91 (d, J = 10.8 Hz, 1H), 4.40 (dd, J = 13.2, 30.2 Hz, 2H), 5.23 (s, 2H), 7.23 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 9.53 (s, 1H).ES+ m/z [M + H]+: 409, HPLC tR= 1.50 min (81.4%).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2021/180952, 2021, A1 Location in patent: Page/Page column 40; 47-48

74
C₂₁H₂₄ClF₃N₆O₂ [ No CAS ]
[ 790184-33-7 ]
C₂₆H₃₄F₃N₇O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride In dimethyl sulfoxide at 150℃; for 2h; Microwave irradiation;	1 Intermediate A1-1 (0.68 mmol, 330 mg) and (R)-2-methylmorpholine (1.36 mmol, 138 mg) were dissolved in 5 mL of DMSO, KF (2.04 mmol, 118 mg) was added, and the temperature was raised to 150 ° C by microwave for the reaction 2 hours.The reaction was stopped, 30 mL of water was added, and the mixture was extracted with dichloromethane.It was dried over anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A1-2 (220 mg, yield: 59%)

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - WO2022/12484, 2022, A1 Location in patent: Page/Page column 34

75
[ 99898-84-7 ]
[ 790184-33-7 ]
C₁₁H₁₄N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	In 1-methyl-pyrrolidin-2-one; at 190.0℃; for 6.0h;Microwave irradiation;	Intermediate a1-2 (47.3 mmol, 8 g) and (R)-2-methylmorpholine (94.6 mmol, 9.56 g) were added to a microwave reaction flask.After 30 mL of N-methylpyrrolidone NMP was dissolved, the reaction was heated at 190C by microwave for 6 hours.The reaction was stopped, the solvent was evaporated under reduced pressure, and separated by flash column chromatography to obtain intermediate a1-3 (6.4 g, yield: 58%),

Reference： [1]Patent: WO2022/12484,2022,A1 .Location in patent: Page/Page column 30

76
[ 3764-01-0 ]
[ 790184-33-7 ]
(R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 2h;	Preparation of key intermediates a1-a13: 2,4,6-trichloropyrimidine (13.74 mmol, 2.5 g), (R)-2-methylmorpholine (13.8 mmol, 1.4 g) and DIPEA (30 mmol, 3.87 g) were added to a reaction flask, after dissolving in 50 mL of acetonitrile, the mixture was reacted at 90°C for 2 hours. The reaction was stopped, the solvent was dried by rotary evaporation, 50 mL of water was added, extracted with ethyl acetate, dried over anhydrous Na2SO4, and separated by column chromatography to afford intermediate a1 (2.3 g, yield: 68%), LC-MS: [M+H]+: 248.

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; BEIJING TIDE PHARMACEUTICAL CO LTD - EP3967694, 2022, A1 Location in patent: Paragraph 0146-0147

77
[ 6693-08-9 ]
[ 790184-33-7 ]
C₉H₁₀Cl₂FN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	In ethanol at -20 - 20℃; for 12h;	At -20°C, the raw material c6-1 (1.0 mmol, 200 mg) was added to a reaction flask, dissolved in 12 mL of ethanol. A solution of (R)-2-methylmorpholine (1.1 mmol, 111 mg) in 2 mL ethanol was added dropwise, and the mixture was reacted at room temperature for 12 hours. The reaction was stopped, the solvent was evaporated under reduced pressure, and separated by column chromatography to afford intermediate c6 (127 mg, yield: 48%), LC-MS: [M+H]+: 266

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; BEIJING TIDE PHARMACEUTICAL CO LTD - EP3967694, 2022, A1 Location in patent: Paragraph 0206

78
[ 108-77-0 ]
[ 790184-33-7 ]
2,4-dichloro-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -50℃; for 1h;	5 At -50°C, cyanuric chloride (110 mmol, 1.97 g) and DIPEA (210 mmol, 2.76 g) were dissolved in 70 mL of dichloromethane, and (R)-2-methyl morpholine (110 mmol, 1.08 g) was slowly added dropwise. After the mixture was stirred at -50°C for 1 hour, 50 mL of 1N HCl aqueous solution was added to quench the reaction, extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was dried by rotary evaporation to afford C1-3 (2.5 g, yield: 92%). LC-MS: [M+H]+: 249.

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; BEIJING TIDE PHARMACEUTICAL CO LTD - EP3967694, 2022, A1 Location in patent: Paragraph 0257-0258

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

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