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[ CAS No. 438056-69-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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2D 3D

Chemical Structure| 438056-69-0

Chemical Structure| 438056-69-0

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Quality Control of [ 438056-69-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 438056-69-0 ]

Product Details of [ 438056-69-0 ]

CAS No. :	438056-69-0	MDL No. :	MFCD08236742
Formula :	C₁₀H₁₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MHCRLDZZHOVFEE-UHFFFAOYSA-N
M.W :	192.21	Pubchem ID :	11194854
Synonyms :

Calculated chemistry of [ 438056-69-0 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	56.77
TPSA :	55.56 Å²

Pharmacokinetics

GI absorption :	High
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) :	-7.29 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.56
Log Po/w (XLOGP3) :	0.26
Log Po/w (WLOGP) :	0.26
Log Po/w (MLOGP) :	0.29
Log Po/w (SILICOS-IT) :	0.9
Consensus Log Po/w :	0.65

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.45
Solubility :	6.87 mg/ml ; 0.0358 mol/l
Class :	Very soluble
Log S (Ali) :	-0.99
Solubility :	19.8 mg/ml ; 0.103 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.12
Solubility :	1.47 mg/ml ; 0.00766 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.56

Safety of [ 438056-69-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 438056-69-0 ]

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

Upstream synthesis route of [ 438056-69-0 ]
Downstream synthetic route of [ 438056-69-0 ]

[ 438056-69-0 ] Synthesis Path-Upstream 1~15

1
[ 161596-47-0 ]
[ 438056-69-0 ]
[ 446292-07-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	at 65 - 70℃; for 32 h;	4-(4-aminophenyl)morpholinone 100 gm, 0.5202 moles and (S)-(+)glycidyl phthalimide 106.6 gm ( 0.5246 moles) was charged to the mixture of, methanol and water 1000 ml (9: 1) and heated to 65°C-70°C. Continued stirring for next 20 hrs at 65°C-70°C. Add second lot of S)-(+)glycidyl phthalimide 10.6 gm (0.05246 moles) and 200 ml (9: 1) methanol water mixture and stir for next 12 hrs. Cooled the reaction mass to 25°C-30°C and filter the slurry on Buckner funnel, suck dried well. Wet cake washed with 100 ml mixture of methanol and water (9: 1). The solid obtained was dried at 50°C to 55°C to get 190 gm compound of Formula-3 as dry material. Yield-92percent
92%	for 10 h; Reflux	Add 4-(4-aminophenyl)morphin-3-one (192.2 g, 1 mol) to a 1000 ml three-necked flask,2-(2-chloroethoxy)propane(203.2 g, 1 mol), 790 ml of ethanol, stirring was started, the temperature was raised to reflux, and the TLC was detected. It was found that the starting material disappeared after 10 hours of reaction, and the reaction was completed and lowered to room temperature. After suction filtration, 100 ml of ethanol was washed three times, and the compound (4) was dried to obtain 363.78 g, the yield was 92percent, and the HPLC detection was 98.67percent.
89.7%	for 14 h; Reflux	A mixture of 5.68 g(27.9 mmol) of compound V was added compound VI 5.35 g (27.9 mmol) was suspended in 140 ml of 1/9 water - ethanol, stirring reflux for 14 hours, cooled to 20 °C, filter, filter the filter cake with ethanol 3 times. 65-70 °C under reduced pressure, to obtain 9.9 g of the compound of the formula (I) (yield: 89.7percent ) HPLC content 98.5percent (normalization).

87.5%	at 25℃; for 24 h; Reflux	In a four neck round bottom flask charged Isopropyl alcohol (135 ml), 4-(4-aminophenyl) morpholin-3-one (10 g), 2-[(2s)-oxiran-2yl methyl]-lH-isoindole-l,3(2H) dione ((11.6 g) and water (15 ml) at 25 to 30°C. Slowly heated the reaction mixture to reflux and maintained for 24 h at reflux temperature. Reaction mass is cooled to 25 to 30°C after completion of the reaction. Reaction mass then maintained at 25 to 30°C for 30 minutes. Finally obtained solid is filtered off and washed by isopropyl alcohol (25 ml) Yield 87.5percent
87.5%	for 24 h; Reflux	To a 2 litre 4 neck RBF, charge Methanol (1500 ml), 4-(4-aminophenyl)-3-morpholinone Compound (VI), (100 gms), (S)-Glycidyl Phthalimide Compound (V), (127 gms). Reflux the reaction mass for 24 hrs. Cool the reaction mass at 25-30°C and filter. Wash the residue with Methanol (50 ml). Dry the solid at 45-50°C under vacuum. Dry Wt: 180 gms (Theoretical yield: 87.50percent); Purity: 98.20percent
82.6%	Reflux	A suspension of 4-(4-aminophenyl)morpholin-3-one (100 gm) and 2-[(2S)-oxiran-2-ylmethyl}-1H-isoindole-1,3(2H)-dione (116.2 gm) in isopropyl alcohol and water mixture (l700ml :300 ml) is refluxed for 25-30 h. The precipitated solid is filtered off, washed with isopropyl alcohol (100 ml) to obtain solid, which is then dried under vacuum at 50 to 55 °C for 4 to5 hr to obtain 2-[(2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1 H-isoindole-1,3(2H)-dione. [Yield = 170 gm (82.6percent); Purity (H PLC) = 95.0 percent]
82.6%	Reflux	A suspension of 4-(4-aminophenyl)morpholin-3-one (100 gm) and 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (116.2 gm) in isopropyl alcohol and water mixture (1700 ml:300 ml) is refluxed for 25-30 h. The precipitated solid is filtered off, washed with isopropyl alcohol (100 ml) to obtain solid, which is then dried under vacuum at 50 to 55° C. for 4 to 5 hr to obtain 2-[(2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione. [Yield=170 gm (82.6percent); Purity (HPLC)=95.0percent]
82.7%	at 0 - 60℃; for 20 h; Large scale	This example relates to the preparation of 2-{(fl)-2-hydroxy-3-[4-(3-oxo- morpholine-4-yl)-phenylamino]-propyl}isoindol-1 ,3-dione, step a) of the process. 10.0 kg of 4-(4-aminophenyl)morpholine-3-one, 13.0 kg of (S)-(+)-N-(2,3- epoxypropyl)phthalimide and 170 kg of methanol are loaded into a reactor as a single solvent. The mass is heated to around 60 °C and maintained at this temperature for 20 hours, then cooled to 0-10 °C. There is precipitation of the desired product, which is filtered and washed with 30.0 kg of methanol. The product obtained is oven-dried, obtaining 17.0 kg of the desired compound (III), with a reaction yield equal to 82.7percent.
81.4%	at 20 - 60℃; for 36 h;	1173 g of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)dione (II) and 4-(4-aminophenyl)-3-morpholinone (III) are mixed at 20° C. with 6.7 l of water and 14.4 l of ethanol. The suspension is heated to 58 to 60° C., and the resulting solution is stirred for 36 hours. After 2 hours, 5 g of crystalline 2-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (V) are added to the reaction mixture, after which the product starts to crystallize. After cooling to 26° C., the precipitated reaction product is filtered off with suction, washed with ethanol and then dried. Yield: 1522 g; equivalent to 81.4percent of theory. Melting point: 215° C.
80.68%	at 80℃; for 9 h;	238.50 g (1.174 mol) of 2-[(2S)-2-oxiranylmethyl]-1 H-isoindole-1 , 3(2H)-dione (I), 150 g (0.781 mol) of 4-(4-amino phenyl)-3-morpholinone and 3L of ethanol were charged in a 5L flask and the reaction mass was heated at 80 °C for 9 hours. Afterwards the reaction mass was cooled down to 30 °C, and the resulting solid was filtered off and dried under vacuum at 70 °C.Yield: 249 g. Molar yield: 80.68percent. HPLC purity 96.90percent. M.P.: 214 °C. Specific Optical Rotation (S.O.R.): [a ]D25 = +6.24° (c = 1 ,DMSO)
75.4%	With water In ethanol at 60℃; for 36 h; Industry scale	A suspension of (S) -2- (oxiran-2-ylmethyl) isoindoline-1, 3-dione (4.5kg, 1.22eq) and 4- (4-aminophenyl) morpholin-3-one (3.286kg , 17.088 mol) in ethanol/water (42L/16kg), was heated at 60 ⁰C for 36 hours. It was further cooled to room temperature, the precipitate was filtered, and dried in vacuum. An amount of 5.1 kg of the product was obtained (Yield 75,4percent).
203 g	at 80℃; for 8 h;	To 100 gm (0.5208 moles) of 4-(4-Aminophenyl) morpholin-3-one (III) in 2500 ml purified water, 185 gm (0.9104 moles) of (S)- Glycidyl Phthalimide (IV) and 1000ml purified water0 was charged and the reaction mixture was heated to 80 °C for 8 hours. The precipitated products was filtered and washed with purified water. The product was dried under vacuum at 60°C to 65°C for 24 hours. Dried weight = 203 gm

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 19, p. 5900 - 5908
[2] Patent: WO2018/127762, 2018, A1, . Location in patent: Page/Page column 12
[3] Patent: CN108164519, 2018, A, . Location in patent: Paragraph 0014; 0015; 0016; 0017
[4] Patent: CN106588905, 2017, A, . Location in patent: Paragraph 0044; 0046-0047
[5] Patent: WO2014/102820, 2014, A2, . Location in patent: Paragraph 047
[6] Patent: WO2016/199027, 2016, A1, . Location in patent: Page/Page column 18
[7] Patent: WO2013/121436, 2013, A2, . Location in patent: Page/Page column 26
[8] Patent: US2015/11756, 2015, A1, . Location in patent: Paragraph 0117
[9] Patent: WO2015/198259, 2015, A1, . Location in patent: Page/Page column 6
[10] Patent: US2005/182055, 2005, A1, . Location in patent: Page/Page column 1; 3
[11] Patent: WO2005/68456, 2005, A1, . Location in patent: Page/Page column 7
[12] Patent: WO2013/53739, 2013, A1, . Location in patent: Page/Page column 31
[13] Patent: WO2011/12321, 2011, A1, . Location in patent: Page/Page column 31
[14] Patent: WO2013/98833, 2013, A2, . Location in patent: Page/Page column 41
[15] Patent: US2014/378682, 2014, A1, . Location in patent: Paragraph 0209; 0210
[16] Patent: WO2016/30669, 2016, A1, . Location in patent: Page/Page column 28

2
[ 5455-98-1 ]
[ 438056-69-0 ]
[ 446292-07-5 ]

Reference： [1] Patent: US2008/306070, 2008, A1,
[2] Patent: US2010/120718, 2010, A1,
[3] Patent: US2010/160301, 2010, A1,

3
[ 438056-69-0 ]
[ 446292-07-5 ]

Reference： [1] Patent: WO2012/32533, 2012, A2,
[2] Patent: WO2012/32533, 2012, A2,
[3] Patent: WO2012/51692, 2012, A1,
[4] Patent: CN104974105, 2017, B,
[5] Patent: CN104974148, 2017, B,
[6] Patent: CN103951661, 2017, B,
[7] Patent: CN104974149, 2018, B,

4
[ 51594-55-9 ]
[ 1074-82-4 ]
[ 79-22-1 ]
[ 438056-69-0 ]
[ 446292-08-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: at 20℃; Cooling Stage #2: With sodium hydrogencarbonate In butan-1-ol at 0 - 5℃; Stage #3: at 95 - 100℃; for 3 h;	4-(4-Aminophenyl)morpholin-3-one (100 gm) was added in n-butanol (300 ml) and charged Alumia sulfonic acid at ambient temperature. Cool the mass, added (R)-Epichlorohydrin (72 gm) and maintain the reaction mass at below 20°C. Confirmed the completion of reaction, separated the catalyst. Added sodiumbicarbonate, cool the mass temperature to Q-5°C and added methylchloroformate (56 gm) . After completion of reaction, evaporated the n- butanol and charged N,N-dimethylformamide (500 mi), potassium phthalimide (122 gm). The reaction temperature maintained at 95- 100°C for 3 hours. Cool the mass temperature to ambient temperature, quenched the mass into water. Filtered the mass and washed the product with water. Dried the material up to get constant weight. The obtained 2-({(5Sj-2-Qxo-3-[4-(3-Gxo-4- morpholmyl]phenyl ]-- 1 ,3--oxazol.idm-5--yl}methyl)-- 1 H--isoindole-- 1 ,3(2H)--d.ione was 186 gm (85percent yield) .

Reference： [1] Patent: WO2018/55499, 2018, A1, . Location in patent: Page/Page column 12

5
[ 1429334-03-1 ]
[ 438056-69-0 ]
[ 446292-08-6 ]

Yield	Reaction Conditions	Operation in experiment
0.5 g	With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18 h;	To a suspension of (S)-l-phthalimido-2-((phenyloxycarbonyl) oxy)-3-propylchloride (3.595g, 10 mmol) (prepared in Step- I ) and 4-(4-aminophenyl)morpholin-3-one (2.4g, 12.5 mmol, 1.25 eq) in DMF ( 20 ml). Potassium carbonate ( 3.45 gms, 25 mmol, 2.5 eq) and catalytic amount of triethylbenzyl ammonium chloride were added and then stirred for about 18 hrs at 80°C .The reaction mix. is poured into the water ( 50 ml) and then extracted with the DCM ( 25 ml x 3). The combined organics are washed with Dil.HCl (10 ml x2) and water ( 10 ml x 2). Distill off the solvent under reduced pressure to yield a title compound.( (Yield = 0.5 g, 12 percent of the theory).

Reference： [1] Patent: WO2013/46211, 2013, A1, . Location in patent: Page/Page column 71; 72

6
[ 438056-69-0 ]
[ 446292-08-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 19, p. 5900 - 5908
[2] Patent: WO2011/12321, 2011, A1,
[3] Patent: WO2012/32533, 2012, A2,
[4] Patent: WO2012/32533, 2012, A2,
[5] Patent: WO2012/32533, 2012, A2,
[6] Patent: WO2012/32533, 2012, A2,
[7] Patent: WO2013/53739, 2013, A1,
[8] Patent: WO2013/98833, 2013, A2,
[9] Patent: WO2013/46211, 2013, A1,
[10] Patent: WO2013/46211, 2013, A1,
[11] Patent: US2014/378682, 2014, A1,
[12] Patent: US2015/38704, 2015, A1,
[13] Patent: EP2837628, 2015, A1,
[14] Patent: WO2016/30669, 2016, A1,
[15] Patent: CN105085370, 2017, B,
[16] Patent: CN105085431, 2017, B,
[17] Patent: CN105085371, 2017, B,
[18] Patent: CN103951661, 2017, B,
[19] Patent: CN106588905, 2017, A,
[20] Patent: CN105085508, 2017, B,
[21] Patent: CN105085507, 2017, B,

7
[ 161596-47-0 ]
[ 438056-69-0 ]
[ 446292-08-6 ]

Reference： [1] Patent: WO2013/98833, 2013, A2,
[2] Patent: WO2013/121436, 2013, A2,
[3] Patent: US2015/11756, 2015, A1,
[4] Patent: WO2014/102820, 2014, A2,
[5] Patent: US2014/378682, 2014, A1,
[6] Patent: WO2015/198259, 2015, A1,
[7] Patent: WO2016/199027, 2016, A1,
[8] Patent: WO2018/127762, 2018, A1,

8
[ 799012-78-5 ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With magnesium(II) perchlorate In acetonitrile at 25 - 30℃; for 3 h;	4-(4-Aminophenyl)morpholin-3-one (Formula V; 50 g) was dissolved in acetonitnle (500 mL) at 25°C to 30°C. 5-Chloro-N-[(2S)-2-oxiranylmethylj-2- thiophenecarboxamide (from Example 4; Formula IV; 58 g) and magnesium perchlorate (12.5 g) were added to the reaction mixture, and the reaction mixture was stirred at 25°C to 30°C for 3 hours. Toluene (500 mL) and aqueous sodium chloride solution (20percent, 500 mL) were added slowly to the reaction mixture, and the reaction mixture was stirred for 2 hours. The solid was filtered, washed with water (100 mL), and suck dried. The solid was dried at 55°C to 60°C under vacuum for S hours to obtain cmde S-chloro-N-((2R)-2- hydroxy-3 - { [4-(3-oxo-4-morpholinyl)-phenyljamino }propyl)-2-thiophenecarboxamide (90 g, 84.5percent). The cmde material (50 g) was stirred with denatured spirit (500 mL) at 50°C to 55°C for 45 minutes. The reaction mixture was cooled to 25°C to 30°C, filtered, and washed with denatured spirit (100 mL). The solid obtained was suck dried, and then further dried at 55°C to 60°C for 12 hours to obtain 5-chloro-N-((2R)-2-hydroxy-3-[4-(3- oxo-4-morpholinyl)-phenyljamino }propyl)-2-thiophenecarboxamide.Yield: 86percentHPLC Purity: 99.88percent
77%	at 70 - 75℃; for 4 h;	4-Aminophenyl morpholinone-3-one (Formula VI - 1.76 g, 0.00914 moles) was added to a solution of 5-chloro-N-[(2S)-oxiran-2-ylmethyl]thiophene-2-carboxamide (Formula V - 2 g, 0.00919 moles) in ethanol (31.5 mL) and deionized water (3.5 mL) at ambient temperature. The mixture was allowed to heat to 70°C to 75°C and stirred for 4 hours at 70°C to 75°C. The reaction mixture was cooled to 15°C, and the slurry obtained was stirred for 1 hour at 15°C to 20°C. The slurry was filtered and suck dried. The wet solid was dried under vacuum at 40°C to 45°C.
62%	at 75℃;	Step a): 5-Chloro-N-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino}-propyl)-2-thiophenecarboxamide; 6.18 g (32 mmol) of 4-(4-aminophenyl)morpholin-3-one (Example 2A) and 7.00 g (32 mmol) of 5-chloro-N-[(2S)-2-oxiranylmethyl]-2-thiophenecarboxamide (Example 3A) are suspended in 130 ml of ethanol/water (9:1) and stirred at 75° C. overnight (formation of a solution). The solution is cooled in an ice-bath, and the resulting white precipitate is filtered off, washed with diethyl ether and dried under high vacuum. This gives 4.98 g of the title compound. Concentration of the mother liquor, another addition of 3.5 g (16 mmol) of 5-chloro-N-[(2S)-2-oxiranylmethyl]-2-thiophenecarboxamide in 50 ml of ethanol/water (9:1), more stirring at 75° C. overnight and filtration of the precipitate obtained after cooling in an ice-bath gives another 3.44 g of the title compound.Yield: 8.42 g in total (62percent of theory)LC-MS (method 1): R_t=1.46 min;MS (ESIpos): m/z=410 [M+H]⁺;¹H-NMR (300 MHz, DMSO-d₆): δ=8.60 (t, 1H), 7.69 (d, 1H), 7.18 (d, 1H), 7.02 (d, 2H), 6.59 (d, 2H), 5.65 (t, 1H), 5.08 (d, 1H), 4.13 (s, 2H), 3.91 (dd, 2H), 3.87-3.74 (m, 1H), 3.59 (m, 2H), 3.30-2.90 (m, 4H).

Reference： [1] Patent: WO2015/11617, 2015, A1, . Location in patent: Page/Page column 10; 11
[2] Patent: WO2013/156936, 2013, A1, . Location in patent: Page/Page column 17
[3] Patent: US2010/48548, 2010, A1, . Location in patent: Page/Page column 10

9
[ 348626-26-6 ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	at 20 - 60℃;	500 mg (2.6 mmol) of 4-(4-aminophenyl)morpholin-3-one are dissolved in 10 ml of THF and, at RT, 679.47 mg (3.1 mmol) of 5-chloro-N-[(2S)-2-oxiranylmethyl]-2-thiophenecarboxamide and 161.34 mg (0.3 mmol) of ytterbium(III) trifluoromethanesulfonate are added. The solution is stirred at 60° C. overnight. The precipitated white product is filtered off, washed with THF and dried under high vacuum. 574 mg (54percent of theory) of the title compound are obtained. The filtrate is concentrated and the residue is purified by preparative HPLC (column: YMC gel ODS-AQ S-11 μm; mobile phase: water/acetonitrile, gradient 90:10-->5:95). A further 402 mg (38percent of theory) of the desired product are obtained in this way. Yield: total 976 mg (92percent of theory) LC-MS (method 1): R_t=1.67 min. MS (ESIpos): m/z=410 [M+H]⁺ ¹H-NMR (200 MHz, DMSO-d₆): δ=8.62 (t, 1H), 7.68 (d, 1H), 7.18 (d, 1H), 7.02 (d, 2H), 6.59 (d, 2H), 5.66 (t, 1H), 5.09 (d, 1H), 4.13 (s, 2H), 3.96-3.88 (m, 2H), 3.86-3.74 (m, 1H), 3.64-3.55 (m, 1H), 3.30-2.90 (m, 2H).
76%	With magnesium(II) perchlorate In acetone at 50℃; for 18 h; Inert atmosphere	1 g of 4-(4-aminophenyl)-3-morpholinone prepared in Example 4,1.36 g of 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide prepared in Example 7 was charged and placed in a reaction vessel.Then add 200g of dried magnesium perchlorate, then add 10L of acetone.Under nitrogen protection, react at 50 ° C for 18 h to obtain 5-chlorothiophene-2-{(R)-2-hydroxy-3-[4-(3-Oxo-4-morpholinyl)phenylamino]-propyl}amide, separated by column chromatographyObtained a pale yellow solid,The yield was 76percent.

Reference： [1] Patent: US2007/66615, 2007, A1, . Location in patent: Page/Page column 15-16
[2] Patent: CN104788444, 2018, B, . Location in patent: Paragraph 0056; 0057; 0058

10
[ 1325210-61-4 ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 2,3,4-lutidine In ethanol; toluene; butan-1-ol at 20 - 105℃;	Example 4: 5-Chlorothiophen-2-carboxylic acid-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]-propyl}amide To a suspension of 2.55g of 4-[4-[(5R)-5-(chlorothiopheno-2-carboxylic acid ((S)-2-hydroxy-3-tosyloxy)-propyl)-amide (MW = 389.88; 1 eq.) in 15mL toluene were added 1.22 g of 4-(4-amino-phenyl)-morpholin-3-one (MW = 190.22; 1 eq.), 0.73g collidine (MW = 121.18; 0.9 eq.) and 0.29mL ethanol. The reaction mixture was heated to 105°C and stirred at this temperature for 3 hours. Then 2.5mL of n-butanol were added and the mixture was cooled to 22°C. After stirring for at least 1 hour at ambient temperature the product was isolated by filtration and washed with toluene and water. The wet product was dried at 30°C in vacuo to yield 2.00g of the title compound (76percent by theory).
76%	With collidine In ethanol; toluene at 105℃; for 3 h;	To a suspension of 2.55g of 4-[4-[(5R)-5-(chlorothiopheno-2-carboxylic acid ((S)-2-hydroxy- 3-tosyloxy)-propyl)-amide (MW = 389.88; 1 eq.) in 15mL toluene were added 1.22 g of 4-(4- amino-phenyl)-morpholin-3-one (MW = 190.22; 1 eq.), 0.73g collidine (MW = 121.18; 0.9 eq.) and 0.29ml_ ethanol. The reaction mixture was heated to 105°C and stirred at this temperature for 3 hours. Then 2.5mL of n-butanol were added and the mixture was cooled to 22°C. After stirring for at least 1 hour at ambient temperature the product was isolated by filtration and washed with toluene and water. The wet product was dried at 30°C in vacuo to yield 2.00g of the title compound (76percent by theory).

Reference： [1] Patent: EP2354128, 2011, A1, . Location in patent: Page/Page column 15; 16
[2] Patent: WO2011/98501, 2011, A1, . Location in patent: Page/Page column 25; 26

11
[ 721401-52-1 ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Reference： [1] Patent: WO2004/60887, 2004, A1, . Location in patent: Page/Page column 8; 10

12
[ 438056-69-0 ]
[ 721401-53-2 ]

Reference： [1] Patent: CN104817550, 2017, B, . Location in patent: Paragraph 0050

13
[ 721401-52-1 ]
[ 438056-69-0 ]
[ 71-36-3 ]
[ 721401-53-2 ]

Reference： [1] Patent: US2007/149522, 2007, A1,

14
[ 438056-69-0 ]
[ 721401-53-2 ]

Reference： [1] Patent: EP2354128, 2011, A1,
[2] Patent: CN104860904, 2016, B,

15
[ 438056-69-0 ]
[ 898543-06-1 ]

Reference： [1] Patent: WO2013/53739, 2013, A1,
[2] Patent: WO2013/121436, 2013, A2,
[3] Patent: WO2013/46211, 2013, A1,
[4] Patent: WO2013/46211, 2013, A1,
[5] Patent: WO2013/46211, 2013, A1,
[6] Patent: WO2013/46211, 2013, A1,
[7] Patent: WO2013/46211, 2013, A1,
[8] Patent: WO2014/102820, 2014, A2,
[9] Patent: US2015/11756, 2015, A1,
[10] Patent: CN103980221, 2016, B,
[11] Organic Preparations and Procedures International, 2017, vol. 49, # 2, p. 169 - 177
[12] Patent: CN104974105, 2017, B,
[13] Patent: CN105085431, 2017, B,
[14] Patent: CN105085507, 2017, B,

[ 438056-69-0 ] Synthesis Path-Downstream 1~55

1
[ 45121-22-0 ]
[ 438056-69-0 ]
{1-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-propyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5817 - 5822

2
[ 57521-85-4 ]
[ 438056-69-0 ]
{1-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-butyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5817 - 5822

3
[ 446292-04-2 ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
97.8%	With palladium on activated charcoal; hydrogen; In ethanol; at 60℃; under 3000.3 Torr; for 3h;Autoclave;	1.57 g of 4-(4-aminophenyl)-3-morpholinone was added to the autoclave,An additional 0.37 g of palladium on carbon was added followed by 20 mL of absolute ethanol.After replacing the air in the vessel with hydrogen for three times, the oil bath is heated under hydrogen conditions.The mid-term hydrogen pressure is 0.4 MPa, the oil bath temperature is 60 C, and the stirring reaction is 3 h.The target product rivaroxaban intermediate 4-(4-aminophenyl)-3-morpholinone was obtained.After completion of the reaction, palladium carbon was removed by suction filtration, and the filtrate was concentrated under reduced pressure.Recrystallization from ethanol gives 4-(4-aminophenyl)-3-morpholinone,The yield was 97.8%.
96.4%	With hydrogen; In water; isopropyl alcohol; at 50 - 55℃; under 7600.51 - 11400.8 Torr; for 5h;Autoclave;	To a 250 ml stainless steel autoclave, 22.2 g of (0.1 mol) of 4-(4-nitrophenyl)morphin-3-oneprepared in Example 5, 100 g of isopropanol, 6.5 g of a mass content of 50% were added. Rani Nickel (50% water), after nitrogen replacement for 3 times, thereaction is stirred at an internal temperature of 50-55 C, hydrogen pressure of 10-15 atmospheres for 5 hours, cooled to room temperature, and the catalyst is recoveredbyfiltration,using 20 g of isopropanol. The filter cake was washed, the filtrate was taken up in isopropanol, and the residue was washed with 30 g of isopropyl ether to obtain 18.5 g of 4-(4-aminophenyl)morphin-3-one, yield 96.4%, HPLC purity 99.9%.
93%		A solution of 10g of <strong>[446292-04-2]4-<strong>[446292-04-2](4-nitrophenyl)-3-morpholinone</strong></strong> in 75 mL of purified water was stirred at 23C for 30 min. Then, 25.85 g of sodium hydrosulfite was added to the solution, heated to 50 C and then stirred for 2.5 hours. After completion of the reaction, the reaction mixture was heated to 70 C, and dropwise added with 45.5 mL of a 25%(w/w) aqueous hydrochloric acid solution for 3 hours. Thereafter, the reaction mixture was cooled to 23C, and adjusted to a pH of 9-10 by dropwise adding a 30% (w/w) aqueous sodium hydroxide solution thereto. Then, the resulting solution was distilled under a reduced pressure of 40 mmHg to a volume of 80 mL. Then, the remaining solution was subjected to crystallization while stirring for 4 hours at 3 5C. The crystals thus formed were filtered and then washed with 30 mL of purified water at 5C. Finally, the resulting crystals were dried in a vacuum at 40C for 6 hours to obtain 8.04 g (93%) of the title compound as a white solid. Melting point: 171C

93.8%	With 5%-palladium/activated carbon; hydrogen; In methanol;	4- (3-oxomorpholinyl) nitrobenzene(2.2 g, 0.01 mol) was added to 10 mL of methanol, 5% palladium on carbon (0.2 g) was added, hydrogenated at atmospheric pressure until the reaction was complete,The filtrate was concentrated to give 1.8 g of 4- (4-aminophenyl) -3-morpholinone in a yield of 93.8%.
92.75%		1) Weigh 200 g of <strong>[446292-04-2]4-<strong>[446292-04-2](4-nitrophenyl)-3-morpholinone</strong></strong> and add 4 L of anhydrous methanol. After stirring, add8 g of Pd/C catalyst with Pd content of 10%, stir well. The material I is formed, and the material I is sent tothe preheating module 1 of the microchannel reactor for preheating, and after preheating, it enters the reaction module group of the microchannel reactor.
91%	With palladium 10% on activated carbon; hydrazine hydrate; In ethanol; for 1h;Reflux;	General procedure: Toa solution of 4 (19.9 g, 90.4 mmol) in ethanol was added Pd/C (10%, 1.9 g).Then hydrazine hydrate (80%, 33.94g) was added. After addition was complete,the mixture was gently heated at the reflux temperature for 1 h. The reaction mixture was cooled, and dichloromethane (50 ml) was added.The catalyst was filtered off through celite, and the filtrate was concentratedto afford the desired product 5) as a white solid.
91%		A mixture of 4- (4-nitrophenyl) -3-morpholinone111 g (0.5 mol),Methanol 1000ml, ferric chloride hexahydrate 5g, activated carbon 30g added to the reactor, heated to reflux 0.5h, the cooling,Add 80% hydrazine hydrate47 g (1.5 mol), and the mixture was refluxed for 5 h. After filtration, part of the methanol was recovered, cooled and crystallized, and dried by filtration to give 87 g of a white solid in 91% yield.
89%	With hydrogen;5% Pd(II)/C(eggshell); In tetrahydrofuran; water; at 70℃; under 2250.23 Torr; for 6.5h;	Example 3: Preparation of 4-(4-aminophenyl)morpholin-3-one (compound X) To a solution of <strong>[446292-04-2]4-(4-nitrophenyl)morpholin-3-one</strong> (19.9 g, 89.5 mmol) in THF (200 mL) was added Pd/C (5%) (1.7 g.water content: 58%). The reactor was filled with H2 and the mixture was stirred at 70C under a pressure of 3 bars during 6.5 h. As the reaction was not complete (by HPLC-MS) more Pd/C was added (900mg) and the mixture was stirred under the same reaction conditions until all starting material was consumed. The catalyst was filtered off through celite, and the filtrate was concentrated to afford 4-(4- aminophenyl)morpholin-3-one (or compound of formula X) (15.3 g, 89%) as a brown solid. 1H NMR (400 MHz, CDCI3) delta 7.07 (d, J = 8.8 Hz, 2 H), 6.69 (d, J = 8.8 Hz, 2 H), 4.32 (s, 2 H), 4.00 (t, J = 4.8 Hz, 2 H), 3.72 (bs, 2 H), 3.69 (t, J = 4.8 Hz, 2 H).
89%	With palladium 10% on activated carbon; hydrogen; acetic acid; In water; at 20 - 25℃; under 750.075 Torr;Autoclave;	50 ml tap water, 50 ml acetic acid, lO.OOg <strong>[446292-04-2]4-(4-nitrophenyl)morpholin-3-one</strong> are measured into 5 a hydrogenating autoclave. The atmosphere of the autoclave is flushed with nitrogen, then 0.50g (0081) 10% palladium on carbon is measured, then the atmosphere is changed for hydrogen gas and at 1 bar pressure, and at 20-25C is started stirring. The stirring is continued until the loss of hydrogen can be observed . Then the reaction mixture is filtered, at a reduced pressure the filtrate is evaporated to a mass of 20-3 Og, then 100 ml 2-propanole is added, and the suspension 10 obtained is concentrated by evaporation to a mass of 5Q-60g, then it is cooled to 0-5C temperature. The precipitated material is filtered off, washed with 2-propanole then dried at a reduced pressure until constant mass. The mass of the obtained white powder: 7.71g, yield: 89%.
85%	With hydrogen;Raney Ni; In methanol; at 40 - 50℃; for 24h;	In a 5L flask, MeOH (2L), 4- (4-nitrophenyl) -3- morpholinone ( 204g ) , Raney Ni (5Og), was stirred at 40-50 0C under the atmosphere of H2 for 24hours, and the catalyst was filtered off. The solution was concentrated under reduced pressure and remaining solid was dried to constant weight at 50 0C under reduced pressure. An amount of 148.3g of the prod- uct was obtained (Yield 85%) .
37.6%	palladium-carbon; In tetrahydrofuran;	II. 4-(4-Morpholin-3-onyl)Aniline In an autoclave, 63 g (0.275 mol) of 4-(4-morpholin-3-onyl)nitrobenzene are dissolved in 200 ml of tetrahydrofuran, admixed with 3.1 g of Pd/C (5% ig) and hydrogenated at 70 C. and a hydrogen pressure of 50 bar for 8 h. The catalyst is filtered off, the solvent is then distilled off under reduced pressure and the product is purified by crystallization from ethyl acetate. 20 g of product are obtained as a colourless to bluish solid, in a yield of 37.6% of theory. Purification can also be carried out by silica gel chromatography using hexane/ethyl acetate. 1H-NMR (300 MHz, CDCl3): 3.67 (m, 2 H, CH2CH2), 3.99 (m, 2 H, CH2CH2), 4.27 (s, 2 H, CH2CO), 6.68 (d, 2 H, 3J=8.71 Hz, CHCH), 7.03 (d, 2 H, 3J=8.71 Hz, CHCH) MS (r.I. %)=192 (100, M+), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)
	With tin(ll) chloride; In ethanol; ethyl acetate; at 20℃; for 18h;Heating / reflux;	To a solution of 2.6 g 4-(4-Nitro-phenyl)-morpholin-3-one in 350 ml ethyl acetate and 17 ml ethanol 13.2 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 2 h. Then after cooling to RT the mixture was stirred for 16 h. The precipitated product was collected by filtration and was pure enough for the next reaction step. Yield: 2.07 g.
	palladium on activated carbon; In tetrahydrofuran;	Catalytic hydrogenation of (VII) with hydrogen over palladium on activated carbon in tetrahydrofuran as a solvent affords 4-(4-aminophenyl)-3-morpholinone (I):
	With hydrogen;palladium on activated carbon; In ethanol; water;	3rd Step: 4-(4-aminophenyl)-3-morpholinone (I) 60 g (0.27 mol) of <strong>[446292-04-2]4-<strong>[446292-04-2](4-nitrophenyl)-3-morpholinone</strong></strong> (VII) are suspended in 480 g of ethanol, admixed with 3 g of palladium on activated carbon (5%) and contacted with 5 bar of hydrogen at 80 C. for one hour. After hydrogenation has ended, the suspension is admixed with 80 g of ethanol and 270 g of water and heated to 40 C., and the catalyst is filtered off. The solution is concentrated under reduced pressure and the remaining solid is dried to constant weight at 50 C. under reduced pressure. Yield: 48.4 g (93% of theory) of a white to slightly reddish-coloured solid. Melting point: 171 C.
	With ethanol; tin(ll) chloride; In ethyl acetate; at 20℃; for 18h;Heating / reflux;	To a solution of 2.6 g 4-(4-Nitro-phenyl)-morpholin-3-one in 350 ml ethyl acetate and 17 ml ethanol, 13.2 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 2 h. Then after cooling to RT the mixture was stirred for 16 h. The precipitated product was collected by filtration and was pure enough for the next reaction step. Yield: 2.07 g.
	palladium-carbon; In tetrahydrofuran;	II. 4-(4-Morpholin-3-onyl)aniline 63 g (0.275 mol) of 4-(4-morpholin-3-onyl)nitrobenzene are dissolved in 200 ml of tetrahydrofuran in an autoclave, 3.1 g of Pd/C (5%) are added, and the mixture is hydrogenated under a hydrogen pressure of 50 bar at 70 C. for 8 h. After filtration of the catalyst, the solvent is distilled out in vacuo and the product is purified by crystallization from ethyl acetate. The product is obtained as 20 g of a colorless to blueish solid in 37.6% of theory. Purification can also take place by chromatography on silica gel with hexane/ethyl acetate. 1H-NMR (300 MHz, CDCl3): 3.67 (m, 2H, CH2CH2), 3.99 (m, 2H, CH2CH2), 4.27 (s, 2H, CH2CO), 6.68 (d, 2H, 3J=8.71 Hz, CHCH), 7.03 (d, 2H, 3J=8.71 Hz, CHCH) MS (r.I. %)=192 (100, M+), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)
	palladium-carbon; In tetrahydrofuran;	II. 4-(4-Morpholin-3-onyl)aniline In an autoclave, 63 g (0.275 mol) of 4-(4-morpholin-3-onyl)nitrobenzene are dissolved in 200 ml of tetrahydrofuran, treated with 3.1 g of Pd/C (5% strength) and hydrogenated for 8 h at 70 C. and a hydrogen pressure of 50 bar. After filtration of the catalyst, the solvent is distilled off in vacuo and the product is purified by crystallization from ethyl acetate. 20 g of the product are obtained as a colorless to brownish solid in 37.6% of theory. Purification can also be carried out by chromatography on silica gel using hexane/ethyl acetate. 1H-NMR (300 MHz, CDCl3): 3.67 (m, 2H, CH2CH2), 3.99 (m, 2H, CH2CH2), 4.27 (s, 2H, CH2CO), 6.68 (d, 2H, 3J=8.71 Hz, CHCH), 7.03 (d, 2H, 3J=8.71 Hz, CHCH) MS (rel. int. %)=192 (100, M+), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)
	With palladium on activated charcoal; hydrogen; In dichloromethane; at 25 - 80℃;Inert atmosphere; Autoclave;	1.7 L MDC, 100 g <strong>[446292-04-2]4-(4-nitrophenyl)morpholin-3-one</strong> of Formula (B) and 5 g -C were added to 5 L Autoclave The assembly was flushed two times with N2 gas at5 Kg pressure and with H2 gas at 5 Kg pressure at 25C to 35C. The pressure of H2 gas was set at 5 Kg and temperature raised to 75 C to 80C. The reaction mass was cooled to 25C to 35C and H2 gas was released and the assembly was flushed with N2 gas at 5 Kg pressure. Pd-C was filtered off through celite and washed 500 ml MDC. Excess of solvent distilled out under reduced pressure below 45C and further cooled to 25C to 35C. The product was washed filtered and washed with 100 ml mixture of MDC- hexane to afford the title compound as 4-(4-aminophenyl)morpholin-3-one.
	With palladium on activated charcoal; hydrogen; In dichloromethane; at 75 - 80℃; under 3750.38 Torr;Autoclave; Inert atmosphere;	1.7 L MDC, 100 g <strong>[446292-04-2]4-(4-nitrophenyl)morpholin-3-one</strong> of Formula (B) and 5 g Pd-C were added to 5 L Autoclave The assembly was flushed two times with N2 gas at 5 Kg pressure and with H2 gas at 5 Kg pressure at 25 C. to 35 C. The pressure of H2 gas was set at 5 Kg and temperature raised to 75 C. to 80 C. The reaction mass was cooled to 25 C. to 35 C. and H2 gas was released and the assembly was flushed with N2 gas at 5 Kg pressure. Pd-C was filtered off through celite and washed 500 ml MDC. Excess of solvent distilled out under reduced pressure below 45 C. and further cooled to 25 C. to 35 C. The product was washed filtered and washed with 100 ml mixture of MDC-hexane to afford the title compound as 4-(4-aminophenyl)morpholin-3-one.
75 g	With ammonium formate; In water; at 30 - 90℃;	To a reaction mixture of 100 gm (0.45 moles) 4-(4-Nitrophenyl) morpholin-3-one (II) in 5 1000ml of purified water, 30 gm Raney Nickel and 850 gm (13.49 moles) ammonium formate were charged at 30C. The reaction mixture was heated to 90C. After completion of reaction 200 ml dichloromethane was added to reaction mixture. The reaction mixture was filtered through hyflo bed and washed with 200 ml purified water and further extracted with dichloromethane. Dichloromethane was distilled under0 vacuum. 500ml ethyl acetate was charged to the reaction mixture and stirred for lhour at 0C to 5C. The product was filtered and dried under vacuum at 50C to 55C for 10- 12 hours.
	With palladium 10% on activated carbon; hydrogen; In methanol; at 70℃; under 2280.15 Torr; for 10h;	(4) One mole of <strong>[446292-04-2]4-<strong>[446292-04-2](4-nitrophenyl)-3-morpholinone</strong></strong>, 450 ml of methanol 20 g of a 10% palladium carbon catalyst was placed in a reaction cylinder, and a hydrogen atmosphere was introduced in a sealed state.Heating to 70 C, reduction reaction at 3 atmospheres for 10 h,Until the hydrogen is no longer absorbed. Cooling to room temperature, separating the catalyst by filtration, and distilling off the methanol solvent to dryness.4-(4-Aminophenyl)-3-morpholinone was obtained.
	With hydrogenchloride; tin; at 70℃; for 5h;	In a 250 mL round bottom flask,hydrochloric acid (3 V) was taken and cools to 5 C. To thistin metal was added. In this reaction mixture, INT-b (0.01 mol)was added and heat the reaction mixture at 70 C for 5 h.Reaction mixture was cooled and quince in water after thecompletion of the reaction [13]. Neutralize the mixture withNaOH solution until neutral pH. Extract the reaction masswith ethyl acetate and evaporate ethyl acetate to give INT-d(Scheme-I).
	With hydrogen; In ethanol; at 80℃; under 11251.1 Torr; for 5h;Autoclave;	In a 3 liter autoclave with a stirrer, 120 g (0.54 mol) of 4- (4-nitrophenyl) -3-morpholinone,500 g of ethanol and 6 g of developed Raney nickel (catalyst) are added,Contact was made with 1.5 MPa of hydrogen at 80 C. for 5 hours.After the completion of the reaction, the reaction solution was allowed to cool to room temperature and replaced with nitrogen, and then the reaction solution was mixed with a solution composed of 250 g of ethanol and 250 g of ion exchange water. The mixture was heated to 50 C. and the catalyst was removed by filtration. The filtrate is concentrated under reduced pressure, and the solid after concentration is dried to a constant weight at 50 C. under reduced pressure.99.9 g (0.52 mol, yield: 4- (4-aminophenyl) -3-morpholinone96%(Purity: 96%).

Reference： [1]Patent: CN104788444,2018,B .Location in patent: Paragraph 0041; 0042; 0043; 0044
[2]Patent: CN109384738,2019,A .Location in patent: Paragraph 0079; 0080; 0081; 0083
[3]Heterocycles,2007,vol. 74,p. 437 - 445
[4]Patent: WO2005/26135,2005,A1 .Location in patent: Page/Page column 7
[5]Patent: WO2014/175563,2014,A1 .Location in patent: Paragraph 79; 80; 81
[6]Patent: CN104211654,2017,B .Location in patent: Paragraph 0238; 0239; 0245; 0246; 0247
[7]Patent: CN108570015,2018,A .Location in patent: Paragraph 0046-0093
[8]European Journal of Medicinal Chemistry,2015,vol. 95,p. 388 - 399
[9]Patent: CN103804221,2016,B .Location in patent: Paragraph 0047; 0048
[10]Patent: WO2011/80341,2011,A1 .Location in patent: Page/Page column 15; 16
[11]Patent: WO2019/138362,2019,A1 .Location in patent: Page/Page column 11
[12]Patent: WO2011/12321,2011,A1 .Location in patent: Page/Page column 31
[13]Patent: US2003/153610,2003,A1
[14]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5817 - 5822
[15]Patent: EP1479675,2004,A1 .Location in patent: Page 65
[16]Patent: WO2004/87646,2004,A2 .Location in patent: Page/Page column 112
[17]Patent: WO2006/34789,2006,A1 .Location in patent: Page/Page column 41
[18]Patent: US2007/66611,2007,A1
[19]Patent: US2007/66611,2007,A1
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[27]Patent: WO2016/30669,2016,A1 .Location in patent: Page/Page column 28
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[30]Patent: JP2019/108279,2019,A .Location in patent: Paragraph 0071; 0072-0086

4
[ 181140-34-1 ]
[ 438056-69-0 ]
2-((2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 5900 - 5908

5
[ 161596-47-0 ]
[ 438056-69-0 ]
[ 446292-07-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	In methanol; water; at 65 - 70℃; for 32h;	4-(4-aminophenyl)morpholinone 100 gm, 0.5202 moles and (S)-(+)glycidyl phthalimide 106.6 gm ( 0.5246 moles) was charged to the mixture of, methanol and water 1000 ml (9: 1) and heated to 65C-70C. Continued stirring for next 20 hrs at 65C-70C. Add second lot of S)-(+)glycidyl phthalimide 10.6 gm (0.05246 moles) and 200 ml (9: 1) methanol water mixture and stir for next 12 hrs. Cooled the reaction mass to 25C-30C and filter the slurry on Buckner funnel, suck dried well. Wet cake washed with 100 ml mixture of methanol and water (9: 1). The solid obtained was dried at 50C to 55C to get 190 gm compound of Formula-3 as dry material. Yield-92%
92%	In ethanol; for 10h;Reflux;	Add 4-(4-aminophenyl)morphin-3-one (192.2 g, 1 mol) to a 1000 ml three-necked flask,2-(2-chloroethoxy)propane(203.2 g, 1 mol), 790 ml of ethanol, stirring was started, the temperature was raised to reflux, and the TLC was detected. It was found that the starting material disappeared after 10 hours of reaction, and the reaction was completed and lowered to room temperature. After suction filtration, 100 ml of ethanol was washed three times, and the compound (4) was dried to obtain 363.78 g, the yield was 92%, and the HPLC detection was 98.67%.
89.7%	In ethanol; water; for 14h;Reflux;	A mixture of 5.68 g(27.9 mmol) of compound V was added compound VI 5.35 g (27.9 mmol) was suspended in 140 ml of 1/9 water - ethanol, stirring reflux for 14 hours, cooled to 20 C, filter, filter the filter cake with ethanol 3 times. 65-70 C under reduced pressure, to obtain 9.9 g of the compound of the formula (I) (yield: 89.7% ) HPLC content 98.5% (normalization).

89.3%	In isopropyl alcohol; for 16h;Reflux;	In a 500 ml three-necked flask, add 10 g of 4- (4-aminophenyl) -3-morpholinone, 12.68 g of (S) -N-epoxypropylphthalimide, and 200 ml of isopropyl Propanol, heated to reflux, and refluxed for 16 h. The system was cooled to room temperature, filtered, the solid was washed with 10 ml of isopropanol, and dried at 70 C. for 8 h to obtain 18.37 g of a white solid with a yield of 89.3%.
87.5%	In water; isopropyl alcohol; at 25℃; for 24h;Reflux;	In a four neck round bottom flask charged Isopropyl alcohol (135 ml), 4-(4-aminophenyl) morpholin-3-one (10 g), 2-[(2s)-oxiran-2yl methyl]-lH-isoindole-l,3(2H) dione ((11.6 g) and water (15 ml) at 25 to 30C. Slowly heated the reaction mixture to reflux and maintained for 24 h at reflux temperature. Reaction mass is cooled to 25 to 30C after completion of the reaction. Reaction mass then maintained at 25 to 30C for 30 minutes. Finally obtained solid is filtered off and washed by isopropyl alcohol (25 ml) Yield 87.5%
87.50%	In methanol; for 24h;Reflux;	To a 2 litre 4 neck RBF, charge Methanol (1500 ml), 4-(4-aminophenyl)-3-morpholinone Compound (VI), (100 gms), (S)-Glycidyl Phthalimide Compound (V), (127 gms). Reflux the reaction mass for 24 hrs. Cool the reaction mass at 25-30C and filter. Wash the residue with Methanol (50 ml). Dry the solid at 45-50C under vacuum. Dry Wt: 180 gms (Theoretical yield: 87.50%); Purity: 98.20%
82.6%	In water; isopropyl alcohol;Reflux;	A suspension of 4-(4-aminophenyl)morpholin-3-one (100 gm) and 2-[(2S)-oxiran-2-ylmethyl}-1H-isoindole-1,3(2H)-dione (116.2 gm) in isopropyl alcohol and water mixture (l700ml :300 ml) is refluxed for 25-30 h. The precipitated solid is filtered off, washed with isopropyl alcohol (100 ml) to obtain solid, which is then dried under vacuum at 50 to 55 C for 4 to5 hr to obtain 2-[(2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1 H-isoindole-1,3(2H)-dione. [Yield = 170 gm (82.6%); Purity (H PLC) = 95.0 %]
82.6%	In water; isopropyl alcohol;Reflux;	A suspension of 4-(4-aminophenyl)morpholin-3-one (100 gm) and <strong>[161596-47-0]2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione</strong> (116.2 gm) in isopropyl alcohol and water mixture (1700 ml:300 ml) is refluxed for 25-30 h. The precipitated solid is filtered off, washed with isopropyl alcohol (100 ml) to obtain solid, which is then dried under vacuum at 50 to 55 C. for 4 to 5 hr to obtain 2-[(2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione. [Yield=170 gm (82.6%); Purity (HPLC)=95.0%]
82.7%	In methanol; at 0 - 60℃; for 20h;Large scale;	This example relates to the preparation of 2-{(fl)-2-hydroxy-3-[4-(3-oxo- morpholine-4-yl)-phenylamino]-propyl}isoindol-1 ,3-dione, step a) of the process. 10.0 kg of 4-(4-aminophenyl)morpholine-3-one, 13.0 kg of (S)-(+)-N-(2,3- epoxypropyl)phthalimide and 170 kg of methanol are loaded into a reactor as a single solvent. The mass is heated to around 60 C and maintained at this temperature for 20 hours, then cooled to 0-10 C. There is precipitation of the desired product, which is filtered and washed with 30.0 kg of methanol. The product obtained is oven-dried, obtaining 17.0 kg of the desired compound (III), with a reaction yield equal to 82.7%.
81.4%	In ethanol; water; at 20 - 60℃; for 36h;	1173 g of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)dione (II) and 4-(4-aminophenyl)-3-morpholinone (III) are mixed at 20 C. with 6.7 l of water and 14.4 l of ethanol. The suspension is heated to 58 to 60 C., and the resulting solution is stirred for 36 hours. After 2 hours, 5 g of crystalline 2-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (V) are added to the reaction mixture, after which the product starts to crystallize. After cooling to 26 C., the precipitated reaction product is filtered off with suction, washed with ethanol and then dried. Yield: 1522 g; equivalent to 81.4% of theory. Melting point: 215 C.
80.68%	In ethanol; at 80℃; for 9h;	238.50 g (1.174 mol) of 2-[(2S)-2-oxiranylmethyl]-1 H-isoindole-1 , 3(2H)-dione (I), 150 g (0.781 mol) of 4-(4-amino phenyl)-3-morpholinone and 3L of ethanol were charged in a 5L flask and the reaction mass was heated at 80 C for 9 hours. Afterwards the reaction mass was cooled down to 30 C, and the resulting solid was filtered off and dried under vacuum at 70 C.Yield: 249 g. Molar yield: 80.68%. HPLC purity 96.90%. M.P.: 214 C. Specific Optical Rotation (S.O.R.): [a ]D25 = +6.24 (c = 1 ,DMSO)
75.4%	With water; In ethanol; at 60℃; for 36h;Industry scale;	A suspension of (S) -2- (oxiran-2-ylmethyl) isoindoline-1, 3-dione (4.5kg, 1.22eq) and 4- (4-aminophenyl) morpholin-3-one (3.286kg , 17.088 mol) in ethanol/water (42L/16kg), was heated at 60 0C for 36 hours. It was further cooled to room temperature, the precipitate was filtered, and dried in vacuum. An amount of 5.1 kg of the product was obtained (Yield 75,4%).
	at 75 - 80℃; for 18h;	100 g 4-(4-Aminophenyl)morpholin-3-one and ethanol (1000 ml) were added to RBF at 25C to 35C and heated to 75C to 80C followed by addition of 105 g (S)-2- (Oxiran-2-ylmethyl)isoindoline-l,3-dione of Formula (E). The reaction mass was stirred for 18 hrs. The reaction mass was cooled to 25C to 35C and stirred for 1 hour. The product was filtered and washed with 2 x 200 ml ethanol to afford the title compound as (i?)-2-(2-hydroxy-3-(4-(3-oxomorpholino) phenyl amino) propyl) isoindoline-l,3-dione of Formula (F)
	In ethanol; at 75 - 80℃; for 18h;	100 g 4-(4-Aminophenyl)morpholin-3-one and ethanol (1000 ml) were added to RBF at 25 C. to 35 C. and heated to 75 C. to 80 C. followed by addition of 105 g (S)-2-(Oxiran-2-ylmethyl)isoindoline-1,3-dione of Formula (E). The reaction mass was stirred for 18 hrs. The reaction mass was cooled to 25 C. to 35 C. and stirred for 1 hour. The product was filtered and washed with 2*200 ml ethanol to afford the title compound as (R)-2-(2-hydroxy-3-(4-(3-oxomorpholino)phenylamino) propyl) isoindoline-1,3-dione of Formula (F)
203 g	In water; at 80℃; for 8h;	To 100 gm (0.5208 moles) of 4-(4-Aminophenyl) morpholin-3-one (III) in 2500 ml purified water, 185 gm (0.9104 moles) of (S)- Glycidyl Phthalimide (IV) and 1000ml purified water0 was charged and the reaction mixture was heated to 80 C for 8 hours. The precipitated products was filtered and washed with purified water. The product was dried under vacuum at 60C to 65C for 24 hours. Dried weight = 203 gm
	With water; at 75 - 80℃; for 5h;Large scale;	20 kg of 4-(4-aminophenyl)morphin-3-one, 27.5 kg of (S)-(+)-N-(2,3-ethoxypropyl)-o-benzene Dimethylimide,600kg of purified water was added to a 1000L glass-lined reaction tank, and the mixture was heated to 75-85 C for 5 h.Cool down to room temperature, centrifuge,Drying the filter cake to obtain rivaroxaban intermediate I 39.1kg,The yield was 95.0%, and the purity was 96.90%.

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[2]Patent: WO2018/127762,2018,A1 .Location in patent: Page/Page column 12
[3]Patent: CN108164519,2018,A .Location in patent: Paragraph 0014; 0015; 0016; 0017
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[4]Patent: WO2012/32533,2012,A2
[5]Patent: WO2012/32533,2012,A2
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[7]Patent: WO2012/32533,2012,A2
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Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 92 percent / ethanol; H₂O / 27 h / Heating 2: 87 percent / 4-(dimethylamino)pyridine / tetrahydrofuran / 24 h / 60 °C 3: aq. MeNH₂ / ethanol / 1 h / Heating 4: 86 percent / pyridine / 1 h / 20 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide monohydrate / ethanol / 36 h / 60 °C / Industry scale 2.1: toluene / 3 h / Industry scale; Reflux 3.1: methylamine / ethanol / 4 h / 65 °C / Industry scale 3.2: 58 - 60 °C / pH 2.7 / Industry scale 4.1: 1,1′-carbonyldiimidazole / N,N-dimethyl-formamide / 1 h / 0 - 20 °C / Industry scale 4.2: 2.5 h / 0 - 25 °C
	Multi-step reaction with 6 steps 1.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; propan-2-one / 4 h / 20 °C 2.1: lithium tert-butylate / tetrahydrofuran / 24 h / 20 °C 3.1: triethylamine / dichloromethane / 4 h / 20 °C 4.1: isopropanol / 12 h / 120 °C 5.1: triethylamine / dichloromethane / 24 h / 20 °C 6.1: hydrogenchloride / ethyl acetate / 2 h / 55 °C 6.2: pH 9

	Multi-step reaction with 5 steps 1.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; propan-2-one / 4 h / 20 °C 2.1: lithium tert-butylate / tetrahydrofuran / 24 h / 20 °C 3.1: triethylamine / dichloromethane / 4 h / 20 °C 4.1: isopropanol / 12 h / 120 °C 5.1: triethylamine / toluene / 2 h / 120 °C 5.2: 4 h / 55 °C 5.3: 20 °C / pH 9
	Multi-step reaction with 6 steps 1.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; propan-2-one / 4 h / 20 °C 2.1: lithium tert-butylate / tetrahydrofuran / 24 h / 20 °C 3.1: triethylamine / dichloromethane / 4 h / 20 °C 4.1: N,N-dimethyl-formamide / 24 h / 80 °C 5.1: Sodium hydrogenocarbonate / ethyl acetate 6.1: triethylamine / toluene / 2 h / 120 °C 6.2: 4 h / 55 °C 6.3: 20 °C / pH 9
	Multi-step reaction with 6 steps 1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; propan-2-one / 4 h / 20 °C 2: lithium tert-butylate / tetrahydrofuran / 24 h / 20 °C 3: triethylamine / dichloromethane / 4 h / 20 °C 4: isopropanol / 0 - 120 °C 5: 4-dimethylaminopyridine; triethylamine / toluene / 10 h / Inert atmosphere; Reflux 6: hydrogenchloride / tetrahydrofuran / 2.25 h / 55 °C
	Multi-step reaction with 7 steps 1.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; propan-2-one / 4 h / 20 °C 2.1: lithium tert-butylate / tetrahydrofuran / 24 h / 20 °C 3.1: triethylamine / dichloromethane / 4 h / 20 °C 4.1: N,N-dimethyl-formamide / 24 h / 80 °C 5.1: Sodium hydrogenocarbonate / ethyl acetate 6.1: triethylamine / dichloromethane / 24 h / 20 °C 7.1: hydrogenchloride / ethyl acetate / 2 h / 55 °C 7.2: pH 9
	Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 2 h / 20 °C / Inert atmosphere 2: Tributylphosphine oxide; lithium bromide / toluene / 3 h / Inert atmosphere; Reflux 3: toluene; 1-methyl-pyrrolidin-2-one / 3.5 h / 20 - 110 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 20 - 35 °C / Inert atmosphere 2: Tributylphosphine oxide; lithium bromide / toluene / 3 h / Inert atmosphere; Reflux
	Multi-step reaction with 5 steps 1: toluene / 20 °C / Reflux 2: MgI₂*etherate / tetrahydrofuran / 20 - 80 °C / Inert atmosphere 3: Caswell No_. 744A / N,N-dimethyl-formamide / 12 h / 85 °C 4: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 12 h 5: triethylamine / dichloromethane / 1 h / 0 °C
	Multi-step reaction with 5 steps 1.1: isopropanol / 14 h / 20 °C / Reflux 2.1: N,N-dimethyl-formamide / 3 h / 20 - 100 °C 3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 4.05 h / 20 °C 4.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 3.08 h / 0 °C / Cooling with ice 4.2: 0.08 h / 0 °C 5.1: potassium carbonate; methylamine / isopropanol; lithium hydroxide monohydrate / 15 h / 60 °C
	Multi-step reaction with 6 steps 1: acetonitrile; lithium hydroxide monohydrate / 50 - 60 °C 2: 1-methyl-pyrrolidin-2-one / toluene / 80 °C / Reflux 3: sodium iodide / acetonitrile / 37 h / Reflux 4: Cs₂CO₃ / 35 h / 80 °C 5: hydrogen / palladium 10% on activated carbon / 24 h / 20 °C / 7500.75 Torr 6: anhydrous sodium carbonate; propan-2-one / toluene; lithium hydroxide monohydrate / 8 - 55 °C
	Multi-step reaction with 6 steps 1: ethanol; lithium hydroxide monohydrate / 120 h / 25 °C 2: 1-methyl-pyrrolidin-2-one / toluene / 80 °C / Reflux 3: sodium iodide / acetonitrile / 30 h / Reflux 4: Cs₂CO₃ / 35 h / 80 °C 5: hydrogen / palladium 10% on activated carbon / 24 h / 20 °C / 7500.75 Torr 6: anhydrous sodium carbonate; propan-2-one / toluene; lithium hydroxide monohydrate / 8 - 53 °C
	Multi-step reaction with 6 steps 1: acetonitrile; lithium hydroxide monohydrate / 50 - 60 °C 2: 1-methyl-pyrrolidin-2-one / toluene / 80 °C / Reflux 3: sodium iodide / acetonitrile / 37 h / Reflux 4: Cs₂CO₃ / 35 h / 80 °C 5: hydrogen / palladium 10% on activated carbon / 24 h / 20 °C / 7500.75 Torr 6: potassium carbonate; 1,1′-carbonyldiimidazole / acetonitrile; lithium hydroxide monohydrate / 50 - 55 °C
	Multi-step reaction with 3 steps 1.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; propan-2-one / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: lithium tert-butylate / dichloromethane / 24 h / Reflux 3.1: hydrogenchloride / ethyl acetate; lithium hydroxide monohydrate / 2 h / 20 °C 3.2: 2 h / 20 °C
	Multi-step reaction with 3 steps 1.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; propan-2-one / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: lithium tert-butylate / dichloromethane / 24 h / Reflux 3.1: hydrogenchloride / ethyl acetate; lithium hydroxide monohydrate / 2 h / 20 °C 3.2: 4 h / 20 °C / pH 7 - 8
	Multi-step reaction with 3 steps 1.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; propan-2-one / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: lithium tert-butylate / dichloromethane / 36 h / Reflux 3.1: hydrogenchloride / ethyl acetate; lithium hydroxide monohydrate / 2 h / 20 °C 3.2: 2 h / 20 °C
	Multi-step reaction with 3 steps 1.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; propan-2-one / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: lithium tert-butylate / dichloromethane / 36 h / Reflux 3.1: hydrogenchloride / ethyl acetate; lithium hydroxide monohydrate / 2 h / 20 °C 3.2: 4 h / 20 °C / pH 7 - 8
	Multi-step reaction with 4 steps 1.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; propan-2-one / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: lithium tert-butylate / dichloromethane / 24 h / Reflux 3.1: isobutylamine / toluene / 3 h / Reflux 4.1: triethylamine / tetrahydrofuran / 3 h / 20 °C
	Multi-step reaction with 4 steps 1.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; propan-2-one / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: lithium tert-butylate / dichloromethane / 36 h / Reflux 3.1: isobutylamine / toluene / 3 h / Reflux 4.1: triethylamine / tetrahydrofuran / 3 h / 20 °C
	Multi-step reaction with 3 steps 1.1: ethanol / 9 h / 80 °C 2.1: tetrahydrofuran / 4 h / Reflux 3.1: methylamine / lithium hydroxide monohydrate; methanol / 1 h / Reflux 3.2: 2 h / 25 - 50 °C
	Multi-step reaction with 4 steps 1.1: ethanol / 9 h / 80 °C 2.1: tetrahydrofuran / 4 h / Reflux 3.1: methylamine / lithium hydroxide monohydrate; methanol / 1 h / 65 °C / Autoclave 3.2: 24 h / 25 - 30 °C 4.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 1 h / 50 - 55 °C
	Multi-step reaction with 4 steps 1.1: ethanol / 9 h / 80 °C 2.1: tetrahydrofuran / 4 h / Reflux 3.1: methylamine / lithium hydroxide monohydrate; methanol / 1 h / 65 °C 3.2: 1 h / pH 2 - 3 / Reflux 4.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 1 h / 50 - 55 °C
	Multi-step reaction with 4 steps 1.1: 18 h / 75 - 80 °C 2.1: 4-dimethylaminopyridine / dichloromethane / 40 - 45 °C 3.1: methylamine / methanol / 60 - 65 °C 3.2: 1.5 h / 25 - 65 °C / pH 5.5 - 6.0 4.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; dichloromethane / 0 - 35 °C
	Multi-step reaction with 4 steps 1.1: 18 h / 75 - 80 °C 2.1: 4-dimethylaminopyridine / dichloromethane / 40 - 45 °C 3.1: methylamine / methanol / 60 - 65 °C 3.2: 1.5 h / 25 - 65 °C / pH 5.5 - 6.0 4.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; dichloromethane / 0 - 35 °C
	Multi-step reaction with 7 steps 1.1: ethanol / 12 h / 75 - 80 °C 2.1: 4-dimethylaminopyridine / dichloromethane / 40 - 45 °C 3.1: lithium hydroxide monohydrate; sodium hydroxide / methanol / 1 h / 60 - 65 °C 4.1: triethylamine / dichloromethane / 24 h / 25 - 35 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 25 - 45 °C 6.1: methylamine / methanol / 60 - 65 °C 6.2: 1.5 h / 25 - 65 °C / pH 5.5 - 6.0 7.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; dichloromethane / 0 - 35 °C
	Multi-step reaction with 7 steps 1.1: ethanol / 12 h / 75 - 80 °C 2.1: 4-dimethylaminopyridine / dichloromethane / 40 - 45 °C 3.1: lithium hydroxide monohydrate; sodium hydroxide / methanol / 1 h / 60 - 65 °C 4.1: triethylamine / dichloromethane / 24 h / 25 - 35 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 25 - 45 °C 6.1: methylamine / methanol / 60 - 65 °C 6.2: 1.5 h / 25 - 65 °C / pH 5.5 - 6.0 7.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; dichloromethane / 0 - 35 °C
	Multi-step reaction with 6 steps 1.1: Sodium hydrogenocarbonate / propan-2-one; lithium hydroxide monohydrate; toluene / 4 h / 0 - 30 °C 2.1: lithium tert-butylate; methanol / tetrahydrofuran; N,N-dimethyl-formamide / 0.17 h / 0 °C 2.2: 18 h / 30 °C 3.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4.1: 5 h / 70 °C 5.1: pyridine / 1 h / 0 - 20 °C 6.1: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 50 - 55 °C / 3000.3 - 3750.38 Torr
	Multi-step reaction with 6 steps 1.1: methanol / 14 h / Reflux 2.1: methanol / 48 h / 30 °C 2.2: 2 h / Reflux 3.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4.1: 5 h / 70 °C 5.1: pyridine / 1 h / 0 - 20 °C 6.1: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 50 - 55 °C / 3000.3 - 3750.38 Torr
	Multi-step reaction with 6 steps 1.1: isopropanol / 20 h / Reflux 2.1: methanol / 48 h / 30 °C 2.2: 2 h / Reflux 3.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4.1: 5 h / 70 °C 5.1: pyridine / 1 h / 0 - 20 °C 6.1: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 50 - 55 °C / 3000.3 - 3750.38 Torr
	Multi-step reaction with 6 steps 1: Sodium hydrogenocarbonate / propan-2-one; lithium hydroxide monohydrate; toluene / 4 h / 0 - 30 °C 2: lithium tert-butylate / tetrahydrofuran / 24 h / 30 °C 3: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4: 5 h / 70 °C 5: pyridine / 1 h / 0 - 20 °C 6: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 50 - 55 °C / 3000.3 - 3750.38 Torr
	Multi-step reaction with 7 steps 1: Sodium hydrogenocarbonate / propan-2-one; lithium hydroxide monohydrate; toluene / 4 h / 0 - 30 °C 2: lithium tert-butylate / tetrahydrofuran / 22 h / 0 - 30 °C 3: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 4: triethylamine / dichloromethane / 18 h / 0 - 20 °C 5: 5 h / 70 °C 6: pyridine / 1 h / 0 - 20 °C 7: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 50 - 55 °C / 3000.3 - 3750.38 Torr
	Multi-step reaction with 7 steps 1: ethanol / 20 h / Reflux 2: dichloromethane / 44 h / 30 °C 3: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 4: triethylamine / dichloromethane / 18 h / 0 - 20 °C 5: 5 h / 70 °C 6: pyridine / 1 h / 0 - 20 °C 7: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 50 - 55 °C / 3000.3 - 3750.38 Torr
	Multi-step reaction with 7 steps 1: isopropanol / 20 h / Reflux 2: dichloromethane / 48 h / 30 °C 3: sodium methoxide; methanol / 1 h / 30 °C 4: triethylamine / dichloromethane / 18 h / 0 - 20 °C 5: 5 h / 70 °C 6: pyridine / 1 h / 0 - 20 °C 7: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 50 - 55 °C / 3000.3 - 3750.38 Torr
	Multi-step reaction with 4 steps 1.1: isopropanol; lithium hydroxide monohydrate / Reflux 2.1: potassium carbonate / dichloromethane / 5 h / 20 °C 3.1: methylamine / methanol / 6 h / 25 °C / Reflux 3.2: 1 h / 25 - 30 °C / pH 2 - 3 4.1: potassium carbonate / dichloromethane / 5 h / 25 - 30 °C
	Multi-step reaction with 4 steps 1.1: isopropanol; lithium hydroxide monohydrate / Reflux 2.1: potassium carbonate / dichloromethane / 5 h / 20 °C 3.1: methylamine / methanol / 6 h / 25 °C / Reflux 3.2: 1 h / 25 - 30 °C / pH 2 - 3 4.1: triethylamine / dimethyl sulfoxide / 35 - 40 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / tetrahydrofuran; lithium hydroxide monohydrate / 0.5 h / 0 - 50 °C 2.1: lithium tert-butylate / dichloromethane / 0.17 h / 40 °C 2.2: 18 h / 35 - 45 °C 3.1: lithium hydroxide monohydrate / ethanol / 50 °C 4.1: triethylamine / toluene; 1-methyl-pyrrolidin-2-one / 0.25 h / 50 - 60 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / tetrahydrofuran; lithium hydroxide monohydrate / 0.5 h / 0 - 50 °C 2.1: lithium tert-butylate / dichloromethane / 0.17 h / 40 °C 2.2: 19 h / 30 - 45 °C 3.1: lithium hydroxide monohydrate / ethanol / 60 °C 4.1: triethylamine / toluene; 1-methyl-pyrrolidin-2-one / 0.25 h / 50 - 60 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / tetrahydrofuran; lithium hydroxide monohydrate / 0.5 h / 0 - 50 °C 2.1: lithium tert-butylate / dichloromethane / 0.17 h / 40 °C 2.2: 21 h / 35 - 45 °C 3.1: lithium hydroxide monohydrate / ethanol / 45 °C 4.1: triethylamine / toluene; 1-methyl-pyrrolidin-2-one / 0.25 h / 50 - 60 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / tetrahydrofuran; lithium hydroxide monohydrate / 0.5 h / 0 - 50 °C 2.1: lithium tert-butylate / dichloromethane / 0.17 h / 40 °C 2.2: 21 h / 35 - 45 °C 3.1: triethylamine; hydrogenchloride / lithium hydroxide monohydrate; ethanol / 1 h / 22 - 65 °C 4.1: triethylamine / toluene / 1.5 h / 30 °C
	Multi-step reaction with 2 steps 1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 4 h / 0 - 20 °C 2: lithium tert-butylate / N,N-dimethyl-formamide; tetrahydrofuran / 44 h / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 4 h / 0 - 20 °C 2: lithium tert-butylate / N,N-dimethyl-formamide; methanol; tetrahydrofuran / 21 h / 5 - 21 °C
	Multi-step reaction with 3 steps 1.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 4 h / 0 - 20 °C 2.1: lithium tert-butylate / N,N-dimethyl-formamide; tetrahydrofuran / 44 h / 20 °C / Cooling with ice 3.1: sodium iodide / methanol; acetonitrile / 0.33 h / 20 °C 3.2: 4 h / 0 - 20 °C
	Multi-step reaction with 3 steps 1.1: ethanol / 24 h / Reflux 2.1: dichloromethane / 44 h / 20 °C 3.1: sodium iodide / methanol; acetonitrile / 0.33 h / 20 °C 3.2: 4 h / 0 - 20 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / ethanol / 24 h / Reflux 2.1: dichloromethane / 44 h / 20 °C 3.1: sodium iodide / methanol; acetonitrile / 0.33 h / 20 °C 3.2: 4 h / 0 - 20 °C
	Multi-step reaction with 3 steps 1.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 4 h / 0 - 20 °C 2.1: lithium tert-butylate / N,N-dimethyl-formamide; methanol / 18 h / 0 - 25 °C 3.1: sodium iodide / methanol; acetonitrile / 0.33 h / 20 °C 3.2: 4 h / 0 - 20 °C
	Multi-step reaction with 3 steps 1.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 4 h / 0 - 20 °C 2.1: lithium tert-butylate / tetrahydrofuran / 48 h / 0 - 25 °C 3.1: sodium iodide / methanol; acetonitrile / 0.33 h / 20 °C 3.2: 4 h / 0 - 20 °C
	Multi-step reaction with 3 steps 1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 4 h / 0 - 20 °C 2: lithium tert-butylate / N,N-dimethyl-formamide; tetrahydrofuran / 44 h / 20 °C / Cooling with ice 3: <i>N</i>-methyl-acetamide; NBS / chloroform / 18 h / 30 °C / Reflux
	Multi-step reaction with 3 steps 1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 4 h / 0 - 20 °C 2: lithium tert-butylate / N,N-dimethyl-formamide; tetrahydrofuran / 44 h / 20 °C / Cooling with ice 3: <i>N</i>-methyl-acetamide; NBS / chloroform / 18 h / 30 °C / Reflux
	Multi-step reaction with 3 steps 1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; toluene; propan-2-one / 4 h / 0 - 20 °C 2: lithium tert-butylate / N,N-dimethyl-formamide; methanol; tetrahydrofuran / 21 h / 5 - 24 °C 3: <i>N</i>-methyl-acetamide; NBS / chloroform / 18 h / 30 °C / Reflux
	Multi-step reaction with 3 steps 1.1: toluene / 6.5 h / Inert atmosphere; Reflux 2.1: lithium bromide; Tributylphosphine oxide / 1 h / Inert atmosphere; Reflux 3.1: hydrogenchloride; lithium hydroxide monohydrate / dichloromethane / 1.5 h 3.2: pH 9 - 10 / Cooling with ice 3.3: 0.5 h / 20 °C / Cooling with ice
	Multi-step reaction with 3 steps 1.1: anhydrous sodium carbonate / propan-2-one; lithium hydroxide monohydrate / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: n-butyllithium / dichloromethane / 24 h / Heating; Reflux 3.1: hydrogenchloride / lithium hydroxide monohydrate; ethyl acetate / 2 h / 20 °C 3.2: 2 h / 20 °C / pH 7 - 8
	Multi-step reaction with 3 steps 1.1: anhydrous sodium carbonate / propan-2-one; lithium hydroxide monohydrate / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: n-butyllithium / dichloromethane / 24 h / Heating; Reflux 3.1: hydrogenchloride / lithium hydroxide monohydrate; ethyl acetate / 2 h / 20 °C 3.2: 4 h / 20 °C / pH 7 - 8
	Multi-step reaction with 3 steps 1.1: anhydrous sodium carbonate / propan-2-one; lithium hydroxide monohydrate / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: n-butyllithium / dichloromethane / 36 h / Heating; Reflux 3.1: hydrogenchloride / lithium hydroxide monohydrate; ethyl acetate / 2 h / 20 °C 3.2: 2 h / 20 °C / pH 7 - 8
	Multi-step reaction with 3 steps 1.1: anhydrous sodium carbonate / propan-2-one; lithium hydroxide monohydrate / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: n-butyllithium / dichloromethane / 36 h / Heating; Reflux 3.1: hydrogenchloride / lithium hydroxide monohydrate; ethyl acetate / 2 h / 20 °C 3.2: 4 h / 20 °C / pH 7 - 8
	Multi-step reaction with 4 steps 1.1: anhydrous sodium carbonate / propan-2-one; lithium hydroxide monohydrate / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: n-butyllithium / dichloromethane / 24 h / Heating; Reflux 3.1: isobutylamine / toluene / 3 h / Heating; Reflux 4.1: triethylamine / tetrahydrofuran / 3 h / 20 °C
	Multi-step reaction with 4 steps 1.1: anhydrous sodium carbonate / propan-2-one; lithium hydroxide monohydrate / 0.17 h / 0 °C 1.2: 4 h / 20 °C 2.1: n-butyllithium / dichloromethane / 36 h / Heating; Reflux 3.1: isobutylamine / toluene / 3 h / Heating; Reflux 4.1: triethylamine / tetrahydrofuran / 3 h / 20 °C
	Multi-step reaction with 4 steps 1.1: isopropanol; lithium hydroxide monohydrate / 24 h / 25 °C / Reflux 2.1: dichloromethane / 8 h / 25 - 30 °C 3.1: methylamine / lithium hydroxide monohydrate; methanol / 5 h / 25 - 65 °C 3.2: 0.5 h / 25 - 30 °C / pH 1 - 2 4.1: potassium carbonate / ethanol / 2 h / 25 - 30 °C 4.2: 20 °C / Inert atmosphere; Reflux
	Multi-step reaction with 5 steps 1.1: isopropanol; lithium hydroxide monohydrate / 24 h / 25 °C / Reflux 2.1: dichloromethane / 8 h / 25 - 30 °C 3.1: methylamine / lithium hydroxide monohydrate; methanol / 5 h / 25 - 65 °C 3.2: 0.5 h / 25 - 30 °C / pH 1 - 2 4.1: ammonia / dichloromethane / 0.25 h 4.2: 110 - 120 °C 5.1: sodium hydroxide / lithium hydroxide monohydrate; dichloromethane / 25 - 30 °C
	Multi-step reaction with 5 steps 1.1: isopropanol; lithium hydroxide monohydrate / 24 h / 25 °C / Reflux 2.1: dichloromethane / 8 h / 25 - 30 °C 3.1: methylamine / lithium hydroxide monohydrate; methanol / 5 h / 25 - 65 °C 3.2: 0.5 h / 25 - 30 °C / pH 1 - 2 4.1: ammonia / dichloromethane / 0.25 h 4.2: 110 - 120 °C 5.1: sodium hydride / tetrahydrofuran / 0.5 h / 25 - 30 °C 5.2: 25 - 30 °C
	Multi-step reaction with 6 steps 1.1: isopropanol; lithium hydroxide monohydrate / 24 h / 25 °C / Reflux 2.1: dichloromethane / 8 h / 25 - 30 °C 3.1: methylamine / lithium hydroxide monohydrate; methanol / 5 h / 25 - 65 °C 3.2: 0.5 h / 25 - 30 °C / pH 1 - 2 4.1: ammonia / dichloromethane / 0.25 h 4.2: 110 - 120 °C 5.1: potassium carbonate / dichloromethane / 0.5 h / 25 - 30 °C 5.2: 25 - 30 °C 6.1: hydrogenchloride / lithium hydroxide monohydrate; glacial acetic acid / 70 - 80 °C
	Multi-step reaction with 4 steps 1.1: ethanol / 18 h / 75 - 80 °C 2.1: 4-dimethylaminopyridine / dichloromethane / 40 - 45 °C 3.1: methylamine; methanol / 25 - 65 °C 3.2: 1 h / 25 - 50 °C 4.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; dichloromethane / 0 - 35 °C
	Multi-step reaction with 4 steps 1.1: ethanol / 18 h / 75 - 80 °C 2.1: 4-dimethylaminopyridine / dichloromethane / 40 - 45 °C 3.1: methylamine; methanol / 60 - 65 °C 3.2: 0.5 h / 25 - 50 °C / pH 5.5-6.0 4.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; dichloromethane / 0 - 35 °C
	Multi-step reaction with 7 steps 1.1: lithium hydroxide monohydrate; ethanol / 12 h / 25 - 80 °C 2.1: 4-dimethylaminopyridine / dichloromethane / 25 - 45 °C 3.1: sodium hydroxide; lithium hydroxide monohydrate / methanol / 1 h / 25 - 65 °C 4.1: triethylamine / dichloromethane / 24 h / 25 - 35 °C 5.1: hydrogenchloride; potassium carbonate / N,N-dimethyl-formamide / 10 h / 25 - 45 °C 6.1: methylamine; methanol / 25 - 65 °C 6.2: 1 h / 25 - 50 °C 7.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; dichloromethane / 0 - 35 °C
	Multi-step reaction with 7 steps 1.1: lithium hydroxide monohydrate; ethanol / 12 h / 25 - 80 °C 2.1: 4-dimethylaminopyridine / dichloromethane / 25 - 45 °C 3.1: sodium hydroxide; lithium hydroxide monohydrate / methanol / 1 h / 25 - 65 °C 4.1: triethylamine / dichloromethane / 24 h / 25 - 35 °C 5.1: hydrogenchloride; potassium carbonate / N,N-dimethyl-formamide / 10 h / 25 - 45 °C 6.1: methylamine; methanol / 60 - 65 °C 6.2: 0.5 h / 25 - 50 °C / pH 5.5-6.0 7.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; dichloromethane / 0 - 35 °C
	Multi-step reaction with 4 steps 1.1: isopropanol; lithium hydroxide monohydrate / Reflux 2.1: potassium carbonate / dichloromethane / 5 h / 20 °C 3.1: methylamine / methanol / 6 h / 25 °C / Reflux 3.2: 1 h / 25 - 30 °C 4.1: potassium carbonate / dichloromethane / 5 h / 25 - 30 °C
	Multi-step reaction with 4 steps 1.1: isopropanol; lithium hydroxide monohydrate / Reflux 2.1: potassium carbonate / dichloromethane / 5 h / 20 °C 3.1: methylamine / methanol / 6 h / 25 °C / Reflux 3.2: 1 h / 25 - 30 °C 4.1: triethylamine / dimethyl sulfoxide; acetonitrile / 35 - 40 °C
	Multi-step reaction with 5 steps 1.1: isopropanol; lithium hydroxide monohydrate / Reflux 2.1: potassium carbonate / dichloromethane / 5 h / 20 °C 3.1: methylamine / methanol / 6 h / 25 °C / Reflux 3.2: 1 h / 25 - 30 °C 4.1: potassium carbonate / methanol / 0.5 h / 25 - 30 °C 5.1: potassium carbonate / dichloromethane / 25 - 30 °C
	Multi-step reaction with 5 steps 1.1: lithium hydroxide monohydrate; isopropanol / 17 h / 25 - 35 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 25 - 55 °C 3.1: Caswell No_. 744A / N,N-dimethyl-formamide / 6 h / 80 - 90 °C 3.2: 50 - 60 °C 3.3: 3 h / 50 - 60 °C 4.1: triethylamine / dichloromethane / 25 - 35 °C 5.1: potassium carbonate / dichloromethane / 25 - 35 °C 5.2: 8.5 h / 0 - 35 °C
	Multi-step reaction with 5 steps 1.1: lithium hydroxide monohydrate; isopropanol / 17 h / 25 - 35 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 25 - 55 °C 3.1: Caswell No_. 744A / lithium hydroxide monohydrate; N,N-dimethyl-formamide / 6 h / 100 - 110 °C 3.2: 50 - 60 °C 4.1: triethylamine / dichloromethane / 0 - 10 °C 5.1: potassium carbonate / dichloromethane / 25 - 35 °C 5.2: 8.5 h / 0 - 35 °C
	Multi-step reaction with 5 steps 1.1: lithium hydroxide monohydrate; isopropanol / 17 h / 25 - 35 °C 2.1: potassium iodide; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 8 h / 25 - 70 °C 3.1: Caswell No_. 744A / N,N-dimethyl-formamide / 6 h / 80 - 90 °C 3.2: 50 - 60 °C 3.3: 3 h / 50 - 60 °C 4.1: triethylamine / dichloromethane / 25 - 35 °C 5.1: potassium carbonate / dichloromethane / 25 - 35 °C 5.2: 8.5 h / 0 - 35 °C
	Multi-step reaction with 5 steps 1.1: lithium hydroxide monohydrate; isopropanol / 17 h / 25 - 35 °C 2.1: potassium iodide; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 8 h / 25 - 70 °C 3.1: Caswell No_. 744A / lithium hydroxide monohydrate; N,N-dimethyl-formamide / 6 h / 100 - 110 °C 3.2: 50 - 60 °C 4.1: triethylamine / dichloromethane / 0 - 10 °C 5.1: potassium carbonate / dichloromethane / 25 - 35 °C 5.2: 8.5 h / 0 - 35 °C
	Multi-step reaction with 4 steps 1.1: methanol / 20 h / 0 - 60 °C / Large scale 2.1: chlorobenzene / 4 h / 0 - 100 °C / Large scale 3.1: methylamine / ethanol; lithium hydroxide monohydrate / 3 h / 60 °C / Large scale 3.2: 30 °C / Large scale 4.1: triethylamine / dichloromethane / 1 h / 10 - 20 °C / Large scale
	Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate / 8 h / 80 °C 2: 4-dimethylaminopyridine / 6 h / 80 - 85 °C 3: methylamine / lithium hydroxide monohydrate / 5 h / 35 °C 4: potassium carbonate / 4 h / 10 - 15 °C
	Multi-step reaction with 6 steps 1: isopropanol; lithium hydroxide monohydrate / 30 h / 80 °C 2: triethylamine / chloroform / 1 h / -5 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 10 h / 80 °C 4: Caswell No_. 744A / lithium hydroxide monohydrate; N,N-dimethyl-formamide / 10 h / 0 - 40 °C 5: 5%-palladium/activated carbon; hydrogen / ethanol / 24 h / 40 °C 6: triethylamine / ethyl acetate / 2 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1: methanol / 24 h / Reflux 2: toluene / 2 h / 10 - 110 °C 3: methylamine / methanol; isopropanol / 6 h / 25 - 60 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 30 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / toluene; lithium hydroxide monohydrate / 0 - 20 °C / Industrial scale 2.1: lithium tert-butylate / dichloromethane / 0.5 h / 5 - 20 °C / Reflux; Large scale 2.2: 12 h / Large scale 3.1: hydrogenchloride / lithium hydroxide monohydrate; ethanol / 1.5 h / 20 °C / pH 2 - 3 / Large scale 4.1: anhydrous sodium carbonate / toluene; lithium hydroxide monohydrate / 2 h / 8 - 20 °C / Industrial scale
	Multi-step reaction with 4 steps 1.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; propan-2-one / 1 h / 5 - 30 °C 2.1: lithium tert-butylate / dichloromethane; N,N-dimethyl-formamide / 10 h / Reflux 3.1: hydrogen bromide / lithium hydroxide monohydrate / 8 h / 100 °C 4.1: anhydrous sodium carbonate / dichloromethane / 1 h / 20 °C 4.2: 5 h / 0 - 20 °C
	Multi-step reaction with 4 steps 1.1: dichloromethane / 5 h / 20 - 30 °C 2.1: tetrahydrofuran / 7 h / 0 - 5 °C 3.1: methylamine / ethanol; lithium hydroxide monohydrate / 8 h / 40 - 60 °C 3.2: pH 1-2 4.1: triethylamine / N,N-dimethyl-formamide / 5 h / 30 - 40 °C
	Multi-step reaction with 5 steps 1.1: isopropanol / 17 h / Reflux 2.1: methanol / 10 h / Reflux 3.1: 4-dimethylaminopyridine / tetrahydrofuran / 12 h / Reflux 3.2: 20 °C 4.1: dichloromethane; lithium hydroxide monohydrate / pH 8 5.1: triethylamine / N,N-dimethyl-formamide / 5 h / 20 - 30 °C
	Multi-step reaction with 5 steps 1.1: isopropanol / 12 h / Reflux 2.1: sodium hydroxide / dichloromethane; lithium hydroxide monohydrate / 8 h / 20 °C 2.2: 3 h / 100 °C 3.1: sodium hydride / toluene / 48 h / Reflux 4.1: methylamine / methanol / 1 h / 65 °C 4.2: 1 h / pH 2 - 3 / Reflux 5.1: anhydrous sodium carbonate / lithium hydroxide monohydrate / 1 h / 50 - 55 °C
	Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate; ethanol / 14 h / Reflux 2: <i>N</i>,<i>N</i>-dimethyl-aniline / chloroform / 10 h / -20 - 10 °C / Inert atmosphere 3: methylamine / lithium hydroxide monohydrate; ethanol / 2 h / Reflux 4: pyridine / dichloromethane / 4 h / 0 - 10 °C
	Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate; ethanol / 14 h / Reflux 2: <i>N</i>,<i>N</i>-dimethyl-aniline / chloroform / 10 h / -20 - 10 °C / Inert atmosphere 3: methylamine / lithium hydroxide monohydrate; ethanol / 2 h / Reflux 4: hydrogenchloride; 4-methyl-morpholine / lithium hydroxide monohydrate; N,N-dimethyl-formamide / 2.83 h / 20 °C
	Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.25 h / 20 °C 1.2: 3 h / 20 °C 2.1: potassium-t-butoxide / N,N-dimethyl-formamide / 0.25 h / 25 - 30 °C 2.2: 8.5 h / 120 °C
	Multi-step reaction with 4 steps 1: dichloromethane / 2 h / 20 - 30 °C 2: tetrahydrofuran / 7 h / 0 - 5 °C 3: methylamine; lithium hydroxide monohydrate / ethanol / 8 h / 40 - 60 °C 4: triethylamine / N,N-dimethyl-formamide / 5 h / 30 - 40 °C
	Multi-step reaction with 4 steps 1.1: isopropanol / 17 h / Reflux 2.1: methanol / 10 h / Reflux 3.1: 4-dimethylaminopyridine / tetrahydrofuran / 10 h / Reflux 3.2: pH 1 - 2 3.3: pH 8 4.1: triethylamine / N,N-dimethyl-formamide / 5 h / 20 - 30 °C
	Multi-step reaction with 4 steps 1.1: dichloromethane / 5 h / 20 - 30 °C 2.1: tetrahydrofuran / 7 h / 0 - 5 °C 3.1: methylamine / ethanol; lithium hydroxide monohydrate / 8 h / 40 - 60 °C 3.2: 2 h / 15 °C 4.1: triethylamine / N,N-dimethyl-formamide / 5 h / 30 - 40 °C
	Multi-step reaction with 4 steps 1.1: dichloromethane / 2 h / 20 - 30 °C 2.1: tetrahydrofuran / 7 h / 0 - 5 °C 3.1: methylamine / ethanol; lithium hydroxide monohydrate / 8 h / 40 - 60 °C 3.2: 15 °C / pH 1 - 2 4.1: triethylamine / N,N-dimethyl-formamide / 5 h / 30 - 40 °C
	Multi-step reaction with 4 steps 1.1: isopropanol / 17 h / Reflux 2.1: methanol / 9 h / Reflux 3.1: 1,1′-carbonyldiimidazole; 4-dimethylaminopyridine / tetrahydrofuran / 12 h / Reflux 3.2: 8 h / Reflux 4.1: triethylamine / N,N-dimethyl-formamide / 5 h / 20 - 30 °C
	Multi-step reaction with 4 steps 1.1: methanol; lithium hydroxide monohydrate / 32 h / 65 - 70 °C 2.1: triethylamine / dichloromethane / 0 - 10 °C 3.1: methylamine / 45 - 50 °C 3.2: 1 h / 45 - 50 °C 4.1: anhydrous sodium carbonate / lithium hydroxide monohydrate; propan-2-one / 0.17 h 4.2: 1 h / 0 - 50 °C
	Multi-step reaction with 7 steps 1.1: dichloromethane; lithium hydroxide monohydrate / 2 h / 20 °C / Molecular sieve 1.2: 1 h / 20 °C 2.1: dichloromethane / 0.5 h / 20 °C 2.2: 1 h / 20 °C 3.1: hydrogenchloride / lithium hydroxide monohydrate; acetonitrile / 18 h / 20 °C 4.1: copper (II) acetate; (2R,5S)-5-isopropyl-5-methyl-2-(pyridine-2-yl)imidazolidine-4-one / isopropanol / 168 h / 6 °C 5.1: hydrogen; palladium 10% on activated carbon / methanol / 24 h / 20 °C / 15001.5 Torr 6.1: triethylamine / dichloromethane / 3 h / 20 °C 7.1: potassium carbonate / methanol / 2 h / 20 °C
	Multi-step reaction with 4 steps 1.1: dichloromethane / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 125 °C 2.1: 3-methyl-1-butyl acetate; lithium bromide / 2 h / Heating 3.1: hydrazine hydrate monohydrate / methanol / 2.5 h / 80 °C 4.1: triethylamine / dichloromethane; toluene / 0.67 h / 0 - 20 °C
	Multi-step reaction with 4 steps 1.1: lithium hydroxide monohydrate / 5 h / 75 - 80 °C / Large scale 2.1: 4-dimethylaminopyridine / tetrahydrofuran / 25 h / Reflux; Large scale 3.1: ethanol / 1 h / Reflux; Large scale 3.2: 50 - 60 °C / pH 2 - Ca_. 3 / Large scale 4.1: benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine / dichloromethane / 24 h / 20 °C / pH 8 - 9 / Large scale
	Multi-step reaction with 4 steps 1: isopropanol / 16 h / Reflux 2: tetrahydrofuran / 4 h / Reflux 3: lithium hydroxide monohydrate; methanol / 2 h / Reflux 4: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 3 h / 20 °C
	Multi-step reaction with 4 steps 1.1: ethanol; lithium hydroxide monohydrate / 6 h / 65 °C 2.1: 4-dimethylaminopyridine / tetrahydrofuran / 1.5 h / 60 °C 3.1: 2-aminoethan-1-ol / ethanol / 1.5 h / 65 - 70 °C 3.2: 1 h 4.1: triethylamine / ethyl acetate / 1 h / 10 - 20 °C
	Multi-step reaction with 4 steps 1: isopropanol / 48 h / 80 - 85 °C / Large scale 2: triethylamine / dichloromethane / 12 h / 38 - 45 °C / Large scale 3: methylamine / ethanol; lithium hydroxide monohydrate / 2 h / Heating; Large scale 4: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2.5 h / Heating; Large scale
	Multi-step reaction with 3 steps 1.1: C₂₂H₂₄F₆N₃O⁽¹⁺⁾*Br^(1-) / 1-methyl-pyrrolidin-2-one / 48 h / 100 °C / 760.05 Torr / Green chemistry 2.1: methylamine / methanol / 2 h / Inert atmosphere; Reflux; Green chemistry 2.2: 0 - 20 °C / Inert atmosphere; Green chemistry 3.1: triethylamine / dichloromethane / 1 h / 0 - 20 °C / Inert atmosphere; Green chemistry 3.2: 2 h / 20 °C / Inert atmosphere; Green chemistry
	Multi-step reaction with 4 steps 1: ethanol; lithium hydroxide monohydrate 2: lithium hydroxide monohydrate; toluene 3: methylamine; hydrogenchloride / lithium hydroxide monohydrate; methanol 4: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / N,N-dimethyl-formamide

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[55]Current Patent Assignee: FERRER INTERNACIONAL SA - US2014/128601, 2014, A1
[56]Current Patent Assignee: FERRER INTERNACIONAL SA - US2014/128601, 2014, A1
[57]Current Patent Assignee: FERRER INTERNACIONAL SA - US2014/128601, 2014, A1
[58]Current Patent Assignee: WANBURY LIMITED - WO2014/102820, 2014, A2
[59]Current Patent Assignee: WANBURY LIMITED - WO2014/102820, 2014, A2
[60]Current Patent Assignee: WANBURY LIMITED - WO2014/102820, 2014, A2
[61]Current Patent Assignee: WANBURY LIMITED - WO2014/102820, 2014, A2
[62]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2014/378682, 2014, A1
[63]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2014/378682, 2014, A1
[64]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2014/378682, 2014, A1
[65]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2014/378682, 2014, A1
[66]Current Patent Assignee: MEGAFINE PHARMA (P) LTD. - US2015/11756, 2015, A1
[67]Current Patent Assignee: MEGAFINE PHARMA (P) LTD. - US2015/11756, 2015, A1
[68]Current Patent Assignee: MEGAFINE PHARMA (P) LTD. - US2015/11756, 2015, A1
[69]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC - WO2015/26761, 2015, A1
[70]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC - WO2015/26761, 2015, A1
[71]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC - WO2015/26761, 2015, A1
[72]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC - WO2015/26761, 2015, A1
[73]Current Patent Assignee: ERREGIERRE SPA. - WO2015/198259, 2015, A1
[74]Current Patent Assignee: CIPLA LTD - WO2016/30669, 2016, A1
[75]Current Patent Assignee: CHANGZHOU NUOBEILANG BIOMEDICAL TECH - CN105566310, 2016, A
[76]Current Patent Assignee: MEHTA API PVT - WO2016/199027, 2016, A1
[77]Tian, Shaixiao; Tang, Bo; Zhang, Minzhong; Gao, Qingjiao; Chen, Bo; Zhang, Qinghua; Xu, Guangyu [Organic Preparations and Procedures International, 2017, vol. 49, # 2, p. 169 - 177]
[78]Current Patent Assignee: BEIJING JINGWEI XINKANG PHARMACEUTICAL TECHNOLOGY - CN103864773, 2017, B
[79]Current Patent Assignee: PEKING UNIVERSITY - CN105085370, 2017, B
[80]Current Patent Assignee: PEKING UNIVERSITY - CN104974105, 2017, B
[81]Current Patent Assignee: SPRINGPHARMA - CN103951661, 2017, B
[82]Current Patent Assignee: CHONGQING ENSKY CHEMICAL; CHONGQING KERUI PHARMACEUTICAL GROUP - CN106588905, 2017, A
[83]Current Patent Assignee: CHONGQING ENSKY CHEMICAL; CHONGQING KERUI PHARMACEUTICAL GROUP - CN106588905, 2017, A
[84]Current Patent Assignee: KAIFENG PHARMACEUTICAL GROUP; FUREN MEDICINES GROUP; HENAN FUREN MEDICAL TECH DEVELOPMENT - CN107089974, 2017, A
[85]Current Patent Assignee: PEKING UNIVERSITY - CN105085508, 2017, B
[86]Current Patent Assignee: PEKING UNIVERSITY - CN104974148, 2017, B
[87]Current Patent Assignee: PEKING UNIVERSITY - CN105085431, 2017, B
[88]Current Patent Assignee: PEKING UNIVERSITY - CN105085507, 2017, B
[89]Current Patent Assignee: PEKING UNIVERSITY - CN104974149, 2018, B
[90]Current Patent Assignee: UNICHEM LABORATORIES LIMITED - WO2018/127762, 2018, A1
[91]Drabina, Pavel; Feixová, Viola; Sedlák, Miloš [Tetrahedron Letters, 2019, vol. 60, # 2, p. 99 - 101]
[92]Yu, Jun; Qiu, Peng-Cheng; Ke, Bin; Chen, Hui; Zhao, Chuan-Meng; Zhang, Fu-Li [Journal of Heterocyclic Chemistry, 2018, vol. 55, # 12, p. 2852 - 2858]
[93]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN109553611, 2019, A
[94]Current Patent Assignee: HUNAN JIUDIAN PHARMACEUTICAL - CN110818700, 2020, A
[95]Current Patent Assignee: NANJING CHICO PHARMACEUTICAL - CN110938069, 2020, A
[96]- CN114105970, 2022, A
[97]Current Patent Assignee: THE FOURTH MILITARY MEDICAL UNIV - CN114163395, 2022, A
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8
[ 438056-69-0 ]
[ 446292-08-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 5900 - 5908
[2]Patent: WO2011/12321,2011,A1
[3]Patent: WO2012/32533,2012,A2
[4]Patent: WO2012/32533,2012,A2
[5]Patent: WO2012/32533,2012,A2
[6]Patent: WO2012/32533,2012,A2
[7]Patent: WO2013/53739,2013,A1
[8]Patent: WO2013/98833,2013,A2
[9]Patent: WO2013/46211,2013,A1
[10]Patent: WO2013/46211,2013,A1
[11]Patent: US2014/378682,2014,A1
[12]Patent: US2015/38704,2015,A1
[13]Patent: EP2837628,2015,A1
[14]Patent: WO2016/30669,2016,A1
[15]Patent: CN105085370,2017,B
[16]Patent: CN105085371,2017,B
[17]Patent: CN103951661,2017,B
[18]Patent: CN106588905,2017,A
[19]Patent: CN105085508,2017,B
[20]Patent: CN105085507,2017,B
[21]Journal of Heterocyclic Chemistry,2018,vol. 55,p. 2852 - 2858

9
[ 797804-53-6 ]
[ 438056-69-0 ]
3-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-indazole-5-carboxylic acid methyl ester hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine In dichloromethane at 20℃; for 16h;	47.iv (iv) 3-[4-(3-Oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-indazole-5-carboxylic acid methyl ester To a solution of 60 mg 1 H-indazole-3,5-dicarboxylic acid 5-methyl ester and 52 mg 4-(4-Amino-phenyl)-morpholin-3-one in 2 ml DCM, 68 mg BOP-Cl and 0.15 ml NEt3 were added and the mixture was stirred for 16 h at RT. Then after the reaction mixture was diluted with 20 ml DCM, the solution was washed with 15 ml of water. The organic phase was dried over MgSO4 and after filtration concentrated under reduced pressure. The crude product was subjected to the next reaction step without further purification. Yield: 71 mg.

Reference： [1]Current Patent Assignee: SANOFI - EP1479675, 2004, A1 Location in patent: Page 65

10
[ 721401-52-1 ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Reference： [1]Patent: WO2004/60887,2004,A1 .Location in patent: Page/Page column 8; 10

11
[ 144701-24-6 ]
[ 438056-69-0 ]
[ 749250-57-5 ]

Reference： [1]Patent: WO2004/76429,2004,A1 .Location in patent: Page/Page column 19-20

12
[ 109-11-5 ]
[ 540-37-4 ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
53.45%	With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃; for 12h;Inert atmosphere;	General procedure: Compound 1 (5g, 22.83mmol) was dissolved in DMSO (120mL), followed by the addition of 2-Piperidinone (4.53g, 45.66mmol), CuI (0.43g, 2.28mmol), 8-hydroxy-quinoline (0.66g, 4.57mmol) and K2CO3 (9.46g, 68.49mmol). The mixture was heated to 130C under N2 for 12h, cooled, and quenched with water (120mL). The organics were extracted with ethyl acetate (2×150mL) and dried (Na2SO4). Purification by silica gel column chromatography (n-hexane/ethyl acetate, 5/1 to 3/1, as eluent) afforded compound 2 as faint yellow (2.80g, 64.47%).
50%	With copper(l) iodide; N,N-dimethyl-formamide; at 120℃;Inert atmosphere;	Under nitrogen, 8 (21.3 g, 0.21 mol), K3C0349.2 g,Catalytic amount of Cul,P-iodoaniline (35.5 g, 0.16 mil) was added to DMF and heated to 120 C. The color of the reaction solution was gradually changed from yellow to dark brown. Reaction time 30 ~ 40h. The reaction is completed, add anhydrous methanol 142ml, reflux lh, hot filter, evaporated the filtrate, add 355ml water, stirring lh, filter, evaporated the filtrate, add 142ml anhydrous ethanol, activated carbon decolorization, reflux lh, hot Filtration, the filtrate cooling crystallization, pale yellow solid 15.5g, yield 50%.
	With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 110℃;	To a blue solution of 3 -morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 0C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.l (M+H).

	With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃;	B. Preparation of 4-(3-oxo-morpholin-4-yl)phenylamine;[0440] To a blue solution of 3-morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H).
	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃;	A. Preparation of 4-(3-oxo-morpholin-4-yl)phenylamine; [0169] NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane. To the flask cooled in an ice-bath, a solution of ethanolamine (4.4 mL, 73 mmol) in dioxane (40 mL) was added. The mixture was heated at reflux for 10 min until no H2 gas evolved. The thick slurry was then cooled in an ice-bath, and a solution of ethyl chloroacetate (8.9 g, 73 mmol) in dioxane (15 mL) was added. The reaction mixture was heated at reflux for Ih. It was then filtered. The filtrate was concentrated in vacuo to give an oil, which was purified by a short flash column, eluted with EtOAc/MeOH (95/5) to give a white solid (1.9 g), as 3-morphorinone.[0170] To a blue solution of 3-morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H).

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 411 - 422
[2]Patent: CN104513239,2017,B .Location in patent: Paragraph 0197; 0238; 0251; 0252
[3]Patent: WO2006/55951,2006,A2 .Location in patent: Page/Page column 44
[4]Patent: WO2006/63113,2006,A2 .Location in patent: Page/Page column 99
[5]Patent: WO2006/63293,2006,A2 .Location in patent: Page/Page column 43

13
[ 348626-26-6 ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	ytterbium(III) triflate; In tetrahydrofuran; at 20 - 60℃;	500 mg (2.6 mmol) of 4-(4-aminophenyl)morpholin-3-one are dissolved in 10 ml of THF and, at RT, 679.47 mg (3.1 mmol) of 5-chloro-N-[(2S)-2-oxiranylmethyl]-2-thiophenecarboxamide and 161.34 mg (0.3 mmol) of ytterbium(III) trifluoromethanesulfonate are added. The solution is stirred at 60 C. overnight. The precipitated white product is filtered off, washed with THF and dried under high vacuum. 574 mg (54% of theory) of the title compound are obtained. The filtrate is concentrated and the residue is purified by preparative HPLC (column: YMC gel ODS-AQ S-11 mum; mobile phase: water/acetonitrile, gradient 90:10?5:95). A further 402 mg (38% of theory) of the desired product are obtained in this way. Yield: total 976 mg (92% of theory) LC-MS (method 1): Rt=1.67 min. MS (ESIpos): m/z=410 [M+H]+ 1H-NMR (200 MHz, DMSO-d6): delta=8.62 (t, 1H), 7.68 (d, 1H), 7.18 (d, 1H), 7.02 (d, 2H), 6.59 (d, 2H), 5.66 (t, 1H), 5.09 (d, 1H), 4.13 (s, 2H), 3.96-3.88 (m, 2H), 3.86-3.74 (m, 1H), 3.64-3.55 (m, 1H), 3.30-2.90 (m, 2H).
76%	With magnesium(II) perchlorate; In acetone; at 50℃; for 18h;Inert atmosphere;	1 g of 4-(4-aminophenyl)-3-morpholinone prepared in Example 4,1.36 g of 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide prepared in Example 7 was charged and placed in a reaction vessel.Then add 200g of dried magnesium perchlorate, then add 10L of acetone.Under nitrogen protection, react at 50 C for 18 h to obtain 5-chlorothiophene-2-{(R)-2-hydroxy-3-[4-(3-Oxo-4-morpholinyl)phenylamino]-propyl}amide, separated by column chromatographyObtained a pale yellow solid,The yield was 76%.

Reference： [1]Patent: US2007/66615,2007,A1 .Location in patent: Page/Page column 15-16
[2]Patent: CN104788444,2018,B .Location in patent: Paragraph 0056; 0057; 0058

14
[ 721401-52-1 ]
[ 438056-69-0 ]
[ 71-36-3 ]
[ 721401-53-2 ]

Yield	Reaction Conditions	Operation in experiment
	In 2,3,5-trimethyl-pyridine; ethanol; toluene;	4th Step N-{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chloro-thiophene-2-carboxamide (X) 55 g of N-((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) and 29.4 g of 4-(4-aminophenyl)-3-morpholinone (III) (a preparation method is described, for example, in WO-A 01/47919 on pages 55 to 57) are suspended at from 20 to 25 C. in 500 ml of toluene and admixed with 18.5 g of collidine and 10 ml of ethanol. The reaction mixture is heated to from 103 to 105 C. for 6 hours and then admixed while hot with 50 ml of 1-butanol. After cooling to 30 C., the precipitated reaction product is filtered off with suction, washed with toluene and water and dried. Yield: 42.0 g; corresponds to 61.8% of theory. Melting point: 198.5 C.

Reference： [1]Patent: US2007/149522,2007,A1

15
SnCl₂ dihydrate [ No CAS ]
[ 446292-04-2 ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; ethyl acetate;	(v) 4-(4-Amino-phenyl)-morpholin-3-one To a solution of 2.6 g 4-(4-Nitro-phenyl)-morpholin-3-one in 350 ml ethyl acetate and 17 ml ethanol, 13.2 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 2 h. Then, after cooling to RT the mixture was stirred for 16 h. The precipitated product was collected by filtration and was pure enough for the next reaction step. Yield: 2.07 g.

Reference： [1]Patent: EP1571154,2005,A1

16
[ 799012-78-5 ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With magnesium(II) perchlorate; In acetonitrile; at 25 - 30℃; for 3h;	4-(4-Aminophenyl)morpholin-3-one (Formula V; 50 g) was dissolved in acetonitnle (500 mL) at 25C to 30C. 5-Chloro-N-[(2S)-2-oxiranylmethylj-2- thiophenecarboxamide (from Example 4; Formula IV; 58 g) and magnesium perchlorate (12.5 g) were added to the reaction mixture, and the reaction mixture was stirred at 25C to 30C for 3 hours. Toluene (500 mL) and aqueous sodium chloride solution (20%, 500 mL) were added slowly to the reaction mixture, and the reaction mixture was stirred for 2 hours. The solid was filtered, washed with water (100 mL), and suck dried. The solid was dried at 55C to 60C under vacuum for S hours to obtain cmde S-chloro-N-((2R)-2- hydroxy-3 - { [4-(3-oxo-4-morpholinyl)-phenyljamino }propyl)-2-thiophenecarboxamide (90 g, 84.5%). The cmde material (50 g) was stirred with denatured spirit (500 mL) at 50C to 55C for 45 minutes. The reaction mixture was cooled to 25C to 30C, filtered, and washed with denatured spirit (100 mL). The solid obtained was suck dried, and then further dried at 55C to 60C for 12 hours to obtain 5-chloro-N-((2R)-2-hydroxy-3-[4-(3- oxo-4-morpholinyl)-phenyljamino }propyl)-2-thiophenecarboxamide.Yield: 86%HPLC Purity: 99.88%
77%	In ethanol; water; at 70 - 75℃; for 4h;	4-Aminophenyl morpholinone-3-one (Formula VI - 1.76 g, 0.00914 moles) was added to a solution of 5-chloro-N-[(2S)-oxiran-2-ylmethyl]thiophene-2-carboxamide (Formula V - 2 g, 0.00919 moles) in ethanol (31.5 mL) and deionized water (3.5 mL) at ambient temperature. The mixture was allowed to heat to 70C to 75C and stirred for 4 hours at 70C to 75C. The reaction mixture was cooled to 15C, and the slurry obtained was stirred for 1 hour at 15C to 20C. The slurry was filtered and suck dried. The wet solid was dried under vacuum at 40C to 45C.
62%	In ethanol; water; at 75℃;	Step a): 5-Chloro-N-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino}-propyl)-2-thiophenecarboxamide; 6.18 g (32 mmol) of 4-(4-aminophenyl)morpholin-3-one (Example 2A) and 7.00 g (32 mmol) of 5-chloro-N-[(2S)-2-oxiranylmethyl]-2-thiophenecarboxamide (Example 3A) are suspended in 130 ml of ethanol/water (9:1) and stirred at 75 C. overnight (formation of a solution). The solution is cooled in an ice-bath, and the resulting white precipitate is filtered off, washed with diethyl ether and dried under high vacuum. This gives 4.98 g of the title compound. Concentration of the mother liquor, another addition of 3.5 g (16 mmol) of 5-chloro-N-[(2S)-2-oxiranylmethyl]-2-thiophenecarboxamide in 50 ml of ethanol/water (9:1), more stirring at 75 C. overnight and filtration of the precipitate obtained after cooling in an ice-bath gives another 3.44 g of the title compound.Yield: 8.42 g in total (62% of theory)LC-MS (method 1): Rt=1.46 min;MS (ESIpos): m/z=410 [M+H]+;1H-NMR (300 MHz, DMSO-d6): delta=8.60 (t, 1H), 7.69 (d, 1H), 7.18 (d, 1H), 7.02 (d, 2H), 6.59 (d, 2H), 5.65 (t, 1H), 5.08 (d, 1H), 4.13 (s, 2H), 3.91 (dd, 2H), 3.87-3.74 (m, 1H), 3.59 (m, 2H), 3.30-2.90 (m, 4H).

Reference： [1]Patent: WO2015/11617,2015,A1 .Location in patent: Page/Page column 10; 11
[2]Patent: WO2013/156936,2013,A1 .Location in patent: Page/Page column 17
[3]Patent: US2010/48548,2010,A1 .Location in patent: Page/Page column 10

17
[ 51594-55-9 ]
[ 438056-69-0 ]
[ 1252018-10-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	In ethanol; for 12h;Reflux;	Preparation of 4- [4- (N- (3-chloro- (2R) -2-hydroxy-1 -propyl) amino) phenyl] morpholin-3-one In a 500 mL reaction flask, 4- (aminophenyl) -3-morpholinone (36. 5 g, 0.19 mol) and R-epichlorohydrin (18.5 g, 0.2 mol) was heated in 300 mL of ethanol to reflux for 12 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure The organic layer was washed with 100 mL of saturated aqueous sodium chloride, and the solvent was evaporated under reduced pressure. The organic layer was washed with water and extracted with ethyl acetate Concentrated to dryness and dried to give 4- [4- (N- (3-chloro- (2R)-2-hydroxy-1-propyl)amino)phenyl] (5 L 4 g), 95% yield, 98% purity.
90%	In water; isopropyl alcohol; at 25 - 35℃; for 17h;	R-Epichlorohydrin (60.3 g; 0.65 mol) was added to a heterogeneous mixture of 4-(4- aminophenyl)-morpholin-3-one (100 g; 0.52 mol) in water (400 ml) and isopropyl alcohol (100 ml) at 25-35C within 1 hour. The reaction mass was stirred at 25-35C for 16 hours. The suspension was filtered and washed twice with 100 ml isopropyl alcohol: water (2:8) mixture. The solid was dried at 25-35C for 2 hours, at 35-55C for 2 hours and then at 50-60C for 12 hours. The solid was added in isopropyl alcohol (300 ml) at 25-35C. The reaction mass was stirred at 25-35C for 2 hours. The suspension was filtered and washed with isopropyl alcohol (100 ml x 4). The solid obtained was dried at 25-35C for 2 hours, at 35-55C for 2 hours and then at 50-60C for 12 hours to give the title product (80-100 g). Yield: 90 %. HPLC Purity: 98.95 %. 1H NMR (DMSO)5: 3.0-3.07 (1H, m), 3.15-3.21 (1H, m), 3.58-3.71 (4H, m), 3.82-3.86 (1H, q), 3.91-3.93 (2H, t), 4.13 (2H, s), 5.36-5.37 (1H, d), 5.72-5.75(lH, t), 6.59-6.61 (2H,d), 7.02- 7.04 (2H,d) Mass: 285.1 [M+H] +
90%	In isopropyl alcohol; for 12h;Reflux;	1L three-neck flask was added 60g (0.31mol) 4- (4- aminophenyl) morpholin-3-one and 420mL isopropylalcohol was heated to reflux in batches dropwise 39.1mL (0.499mol) R- ring Thesolid was washed twice with 2 x 60mL of isopropanol and dried at 50 C for 12 h to give white crystalline intermediate 4 about 80 g(90% yield, the same below), and the mixture was heated to room temperature for2 h.

89.8%	In isopropyl alcohol; for 17h;Reflux;	he reaction flask was added Example 4 Preparation of 24.5g (0.128mol) 4- (4- aminophenyl) -3-morpholinone (Formula IV), 48.3g (0.525mol) (R) -2- (chloromethyl yl) oxirane and isopropanol 450ml, stir, the reaction was warmed to reflux for 17 hours, the TLC control (dichloromethane: methanol = 20: 1, volume ratio) reaction was complete, the reaction mixture was concentrated to give intermediate V the crude product, was added 220ml of acetone heated to reflux for 20 minutes natural cooling crystallization was stirred for 3 hours and filtered, and dried under reduced pressure to give intermediate V about 32.7g (0.115mol), intermediate IV preparation of intermediate molar yield of approximately V 89.8%.
89.8%	In isopropyl alcohol; for 17h;Reflux;	24.5 g (0.128 mol) of 4-(4-aminophenyl)-3-morpholinone (Formula IV) prepared in Example 4 was added to the reaction flask.48.3 g (0.525 mol) of (R)-2-(chloromethyl)oxirane and 450 ml of isopropanol were stirred well and heated to reflux for 17 hours.TLC control (dichloromethane:methanol = 20:1, volume ratio) was completed. The reaction solution was concentrated to obtain the crude product of Intermediate V. Then 220 ml of acetone was added to the mixture and the mixture was warmed and refluxed for 20 minutes. The mixture was crystallized with natural cooling for 3 hours, filtered, and reduced. After pressure drying, about 32.7 g (0.115 mol) of Intermediate V was obtained, and the intermediate IV produced approximately 89.8% of the molar yield of Intermediate V.
82%	In water; acetonitrile; at 50 - 60℃;	Example 24Preparation of 4-{4-[((2R)-3-chIoro-2-hydroxypropyI)-amino]-phenyI}- morpholine-3-one of the Formula 9a10.4 g (0.0544 mole) of 4-(4-aminophenyl)-morpholine-3-one (5) are suspended in a mixture of 84 ml of acetonitrile and 17 ml of distilled water under stirring whereupon 4.4 ml (5.0 g, 0.054 mole) of (R)-epichlorohydrine ( 11) are added. The reaction mixture is warmed to 50-52C, the light brown solution is stirred for 6 hours, whereupon a further 4.4 ml of (R)-epichlorohydrine are added. After 6 hours in intervals of 6 hours four times 1.1 ml (1.25 g, 00.0135 mole) of (R)- epichlorohydrine are added. After introduction of the last portion the reaction is continued for a further period of 3 hours. The mixture is warmed to 60C and stirred at this temperature for a further 3 hours. The acetonitrile is distilled off in vacuo, to the two-phase residue ethyl acetate is added and azeotopic distillation is carried out. On advancement of the distillation the product precipitates in the form of a light yellow suspension. Crystallization is carried out at a temperature between (-15) and (-20) C overnight. The product is filtered, washed with 0-5 C ethyl acetate and dried under an infrared lamp to constant weight. Thus 10.3 g (67 %( of the desired crude product are obtained, mp.: 132-134C, chemical purity 95.1 %, chiral purity (HPLC) 98.2 %.The crude product is suspended in 35 ml of hexane, the suspension is warmed and to the hot suspension 169 ml of acetone are added dropwise under stirring until the product is dissolved. The mixture is allowed to cool to 25 C and crystallization is performed at 0-2 C under stirring for an hour. The product is filtered and dried under an infrared lamp to constant weight. Thus 8.16 g (82 %) of the title compound are obtained, mp.: 137-139C, chemical purity 98 %, chiral purity (HPLC) 98.2 %.The IR, JH NMR and 13C NMR spectral characteristically data of the product are identical with those of the compound 9aS.Elementary analysis for the Formula C13H17ClN2O3 (M: 284,75): C 54,84 %; H 6,02 %; CI 12,45 %; N 9,84 %. Found: C 54,77 %; H 6,09 %; CI 12,50; N 9,87 % Rotation: [a]20D = -2,5 (588 nm /20 C; c = 0,1 g / 10 ml DMSO)
70%	In isopropyl alcohol; at 20℃; for 14h;Reflux;	Example 1 :Preparation of 4-[4-(N-(3-chloro-2f?-hydroxy-1- propyl)amino)phenyl]morpholin-3-one(4a): (R)-(-)-Epichlorohydrin (39.1 mL, 499.45 mmoL) was added in 6 portions over a period of 8 h to a refluxing suspension of 4-(4-aminophenyl)-3-morpholinone (60 g, 312.158 mmoL) in IPA (420 mL) under stirring. The reaction mixture was cooled to room temperature over a period of 4 h, and stirred further at room temperature for 2 h. The thick white suspension was filtered through a Buchner funnel. The solid was washed with IPA (2 x 60 mL) and dried under vacuum at 50C for 12 h to obtain 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3- one (62.22 g, 70%) as a crystalline white solid.1HNMR (300MHz, CDCI3) delta 2.80 (d, J=5.1 Hz, 1 H), 3.15-3.22 (m, 1 H), 3.33- 3.38 (m, 1 H), 3.57-3.71 (m, 4H), 3.96-4.05 (m, 3H), 4.17 (br s, 1 H), 4.32 (s,2H), 6.60-6.65 (m, 2H), 7.07-7.11 (m, 2H).
	In ipa; for 24h;Reflux;	Example 5 Preparation of 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl] morpholin-3-one (7, L2 is chloro): R-(-)-epichlorohydrin (2.12 mL, 27.053 mmol) was added to a refluxing solution of 4-(4-aminophenyl)-3-morpholinone (2, 4.0 g, 20.81 mmol) in IPA (125 mL). The mixture was refluxed for 24 h and the solvent was evaporated in vacuo. The residue was purified by flash chromatography over silica gel (4*22 cm) using 90% EtOAc-hexane to obtain 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl] morpholin-3-one (7, L2 is chloro, 4.89 g, 83%) as a crystalline white solid. Alternatively the crude residue can be purified by crystallization in EtOAc-hexane (2:1). 1H-NMR (300 MHz, CDCl3) d 2.80 (d, J=5.1 Hz, 1H), 3.15-3.22 (m, 1H), 3.33-3.38 (m, 1H), 3.57-3.71 (m, 4H), 3.96-4.05 (m, 3H), 4.13 (br s, 1H), 4.17 (s, 2H), 6.60-6.65 (m, 2H), 7.07-7.11 (m, 2H).
	In methanol; for 16h;Reflux;	Example 1: Preparation of 4-[4-(3-chloro-2(R)-hydroxypropyl amino)-phenyI]- morpholin-3-one (V)4-(4-Morpholin-3-onyl) aniline (39 g), R-epichlorohydrin (18.5 g) and methanol (200 ml) were charged into a clean and dry 4 neck R.B. flask followed by heating to about reflux for about 16 hours. After completion of the reaction, the solvent was distilled completely to give 57 gms of the title compound.
42.5 g	In isopropyl alcohol; for 17h;Reflux;	32.7 g (0.17 mol) prepared in Example 3 was added to the reaction flask4-(4-Aminophenyl)-3-morpholinone (Formula IV),64.4 g (0.70 mol) of (R)-2-(chloromethyl)oxirane and 600 ml of isopropanol,Stir and heat up to reflux for 17 hours.TLC control (dichloromethane:methanol = 20:1, volume ratio) reacted completely.The reaction solution was concentrated to obtain crude Intermediate V, followed by the addition of 300 ml of acetone and warmed to reflux for 20 minutes.The crystals were stirred and cooled for 3 hours under natural cooling, filtered, and dried under reduced pressure.About 42.6 g (0.15 mol) of the intermediate V was obtained, and the intermediate IV produced approximately 88.2% of the molar yield of the intermediate V.

Reference： [1]Patent: CN103980221,2016,B .Location in patent: Paragraph 0058; 0061; 0062
[2]Patent: WO2015/26761,2015,A1 .Location in patent: Page/Page column 18; 19
[3]Patent: CN103951661,2017,B .Location in patent: Paragraph 0041-0042
[4]Patent: CN104974105,2017,B .Location in patent: Paragraph 0072
[5]Patent: CN104974149,2018,B .Location in patent: Paragraph 0074; 0075; 0076; 0081; 0082
[6]Patent: WO2012/153155,2012,A1 .Location in patent: Page/Page column 64-65
[7]Patent: WO2012/51692,2012,A1 .Location in patent: Page/Page column 41-42
[8]Patent: US7816355,2010,B1 .Location in patent: Page/Page column 40
[9]Patent: WO2012/32533,2012,A2 .Location in patent: Page/Page column 14
[10]Patent: CN104974148,2017,B .Location in patent: Paragraph 0073; 0074; 0075; 0081

18
[ 79-22-1 ]
[ 438056-69-0 ]
[ 1252018-07-7 ]

Yield	Reaction Conditions	Operation in experiment
95%		Example 1 Preparation of methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b): N,N-Diisopropylethylamine (27.2 mL, 156.08 mmol) was added over 3 min to a stirred suspension of 4-(4-aminophenyl)-3-morpholinone (2, 25 g, 130.07 mmol) in CH2Cl2 (750 mL). The reaction mixture was stirred at room temperature for 15 min and methyl chloroformate (11.6 mL, 149.58 mmol) was added drop-wise over 10 min. The resulting thick suspension was stirred for another 1 h and filtered through a Buchner funnel. The solid was washed with CH2Cl2 (2*75 mL) and dried under vacuum to obtain methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 30.92 g, 95%) as a crystalline solid. 1H-NMR (300 MHz, DMSO-d6) delta 3.66-3.69 (m, 2H), 3.67 (s, 3H), 3.93-3.97 (m, 2H), 4.17 (s, 2H), 7.28 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 9.72 (brs, 1H).

Reference： [1]Patent: US7816355,2010,B1 .Location in patent: Page/Page column 39

19
[ 29518-11-4 ]
[ 438056-69-0 ]

Reference： [1]Patent: WO2011/12321,2011,A1
[2]Patent: WO2011/80341,2011,A1
[3]Journal of Chemical Research,2011,vol. 35,p. 400 - 401
[4]Patent: WO2013/98833,2013,A2
[5]Patent: US2014/378682,2014,A1
[6]European Journal of Medicinal Chemistry,2015,vol. 95,p. 388 - 399
[7]Patent: CN103804221,2016,B
[8]Patent: CN104788444,2018,B
[9]Asian Journal of Chemistry,2019,vol. 31,p. 1461 - 1464

20
[ 501-53-1 ]
[ 438056-69-0 ]
[ 1313613-18-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydrogencarbonate; In water; acetone; toluene; at 0 - 30℃; for 4h;	Example 1: Preparation of [4-(3-oxo-morpholin-4-yl)phenyl]carbamic acid benzyl ester (Compound-VIII, R = -OCH2Ph): 3.73g, (19.40 mmol ) of <strong>[438056-69-0]4-(4-aminophenyl)morpholin-3-one</strong> and 80ml of acetone were charged in a clean and dry R.B. flask and stirred. A mixture of 40 ml of water and sodium bicarbonate (3.26g,38.80 mmol) was added. The resultant reaction mixture was cooled to about 0C and benzyl chloroformate ( 50% w/w in toluene, 20.60 mmol) was added drop-wise. The reaction mixture was stirred at about 30C for about 4 hours. After the completion of reaction, the reaction mixture was quenched by pouring into ice-water. The separated solid product was filtered and the solid was washed with water followed by n- hexane and dried to afford title compound as a white solid. Yield: 6.2 g, (% Yield: 98%).
98%	With sodium hydrogencarbonate; In water; acetone; toluene; at 0 - 20℃; for 4h;	To a solution of <strong>[438056-69-0]4-(4-aminophenyl)morpholin-3-one</strong>(3.73 g, 19.40 mmol) in acetone (80ml) were added water (40 ml) and NaHC03 (3.26g, 38.80 mmol). The mixture was cooled to 0C and benzyl chloro formate (50% in toluene, 20.60 mmol) was added dropwise. The mixture was stirred at R.T for 4 hrs and poured into ice/water. The product was filtered, washed with water and hexane and dried, affording the title compound as a white solid (6.2 g, 98%).
96.2%	With sodium hydrogencarbonate; In water; acetone; at 0℃; for 3.5h;	Example 12: [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid benzyl ester 3.17g of sodium bicarbonate (MW = 84.01; 2.1 eq.) and then 3.28g of benzyl chloroformate (MW = 170.60; 1.03 eq.) were added to a solution of 3.53g of APMO (MW = 192.22; 1 eq.) in 68mL of acetone and 34mL of water at 0 C over 5 min via syringe. The reaction mixture was stirred for two hours and then poured onto 110mL of water. After stirring for 1.5 hours at 0C the resulting suspension was filtered and the filter cake washed with 100mL of water. The wet product was dried at 30C in vacuo to yield 5.76g (MW = 326.36) of the title compound (96.2 % of theory).

96.2%	With sodium hydrogencarbonate; In water; acetone; at 0℃; for 2h;	3.17g of sodium bicarbonate (MW = 84.01 ; 2.1 eq.) and then 3.28g of benzyl chloroformate (MW = 170.60; 1.03 eq.) were added to a solution of 3.53g of APMO (MW = 192.22; 1 eq.) in 68mL of acetone and 34ml_ of water at 0 C over 5 min via syringe. The reaction mixture was stirred for two hours and then poured onto 110ml_ of water. After stirring for 1.5 hours at 0C the resulting suspension was filtered and the filter cake washed with 100ml_ of water. The wet product was dried at 30C in vacuo to yield 5.76g (MW = 326.36) of the title compound (96.2 % of theory).
96%		Example 1 : Obtaining benzyl (4-(3-oxomorpholin)phenyl)carbamate (19a)Prepare a dissolution of 20 g of <strong>[438056-69-0]4-(4-aminophenyl)morpholin-3-one</strong> (1) (104 mmol) in a mixture of 439 ml_ of acetone and 220 ml_ of water. Cool the solution to 0 C and add 18.5 g of sodium carbonate (175 mmol). After 10 min slowly add over the mixture 15.9 mL of benzyl chloroformate (18a) (1 1 1 mmol) and stir at room temperature for 4 h. Filter the solid obtained and wash with water. Vacuum dry at room temperature, obtaining 32.5 g (96% yield) of the intended product (19a) as a white solid. Mp: 198C. MS: m/z= 349 (M+Na). IR(cm"1)= 1650, 1725. 1H RMN (500 MHz, CDCI3) delta 7.38 (m, 7H), 7.23 (d, J = 8.7 Hz, 2H), 6.87 (s, 1 H), 5.20 (s, 2H), 4.32 (s, 2H), 4.04 - 3.97 (m, 2H), 3.75 - 3.68 (m, 2H).
96%		Example 1 Obtaining benzyl (4-(3-oxomorpholin)phenyl)carbamate (19a) Prepare a dissolution of 20 g of <strong>[438056-69-0]4-(4-aminophenyl)morpholin-3-one</strong> (1) (104 mmol) in a mixture of 439 mL of acetone and 220 mL of water. Cool the solution to 0 C. and add 18.5 g of sodium carbonate (175 mmol). After 10 min slowly add over the mixture 15.9 mL of benzyl chloroformate (18a) (111 mmol) and stir at room temperature for 4 h. Filter the solid obtained and wash with water. Vacuum dry at room temperature, obtaining 32.5 g (96% yield) of the intended product (19a) as a white solid. Mp: 198 C. MS: m/z=349 (M+Na). IR (cm-1)=1650, 1725. 1H NMR (500 MHz, CDCl3) delta 7.38 (m, 7H), 7.23 (d, J=8.7 Hz, 2H), 6.87 (s, 1H), 5.20 (s, 2H), 4.32 (s, 2H), 4.04-3.97 (m, 2H), 3.75-3.68 (m, 2H).
89.6%	With sodium hydrogencarbonate; In water; acetone; at 5 - 30℃; for 1h;	To the reaction flask, <strong>[438056-69-0]4-(4-aminophenyl)morpholin-3-one</strong> (150 g, 0.78 mol) was added followed by acetone (600 mL) and water (300 mL) and stirred. Cooling to 5 to 10 C, and adding sodium bicarbonate (128.4 g, 1.53 mol). Followed by the dropwise addition of benzyl chloroformate (185.9 g, 1.09 mol), and the temperature was raised to 25 to 30 C. After stirring for 1 hour, the reaction was completed and water (1500 mL) was added and stirring was continued for 1 hour. The solid was filtered, the filter cake was washed with cyclohexane, and dried to give N-[4-(3-oxomorpholino)phenyl]carbamate benzyl ester 228.9 g, yield 89.6%.
86%	With sodium hydrogencarbonate; In water; acetone; at 20℃; for 4h;	Example 4: Preparation of benzyl 4-(3-oxomorpholino)phenylcarbamate (compound VIII) To a solution of <strong>[438056-69-0]4-(4-aminophenyl)morpholin-3-one</strong> (3.73 g, 19.40 mmol) in acetone (80 mL) were added H20 (40 mL) and NaHCO3 (3.26 g, 38.80 mmol). The mixture was cooled to 0 C and CbzCI (2.90 mL, 20.60 mmol) was added dropwise. The mixture was stirred at room temperature for 4 h and poured onto ice/H20. The precipitate was filtered, washed with H20 and hexane and dried, affording benzyl 4-(3-oxomorpholino)phenylcarbamate (or compound VIII) (5.44 g, 86%) as a white solid.1H NMR (200 MHz, CDCI3) delta 7.44-7.36 (m, 7 H), 7.25-7.22 (m, 2 H), 6.86 (bs, 1 H), 5.20 (s, 2 H), 4.32 (s, 2 H), 4.01 (t, J = 5.4 Hz, 2 H), 3.72 (t, J = 5.4 Hz, 2 H).
52.1 g	With triethylamine; In tetrahydrofuran; water; at 0 - 50℃; for 0.5h;	4-(4-aminophenyl)-3-morpholinone (38.5 g) was dissolved in a mixture of 400 ml of water and 400 ml of tetrahydrofuran at 45-50C, then 32 ml of triethylamine were added and the obtained solution was maintained at 45C. In parallel, a solution of benzylchloroformate (36 ml) in 100 ml of tetrahydrofuran was prepared under stirring and cooling to ca. 0C. The solution of 4-(4-aminophenyl)-3-morpholinone was added dropwise to the cooled solution of benzylchloroformate during 15 minutes, the reaction mixture was stirred under cooling in an ice bath for 15 minutes, then heptane (200 ml) was added and the obtained suspension was thoroughly stirred up. The separated product was aspirated, washed with water (2 x 100 ml), heptane (2 x 100 ml) and dried in vacuo. 52.1 g of a white crystalline powder with the melt, point of 190-192C was obtained. NMR (250 MHz, DMSO-D6), delta (ppm): 2.68 (m, 2H, CH2); 3.97 (m, 2H, CH2); 4.29 (s, 2H, CH2); 5.18 (s, 2H, CH2); 7.10-7.45 (m, 10H, 9xCH + NH). 13C NMR (250 MHz, CDC13), delta (ppm): 49.8; 64.1; 66.9; 68.5; 1 19.4; 126.1 ; 128.2; 128.6; 136.1; 136.3; 137.0; 153.3; 166.9.
312.6 g	With sodium hydrogencarbonate; In dichloromethane; at 25℃; for 4h;	192.2 g of 4- (4-aminophenyl) morpholin-3-one (1.0 mol) obtained above was sequentially added to a clean and dry 1 L reaction flask,168.02 g (2.0 mol) of sodium bicarbonate and 800 mL of dichloromethane, stir well; then at room temperature (25 C), 179.1 g (dissolved in 200 ml of DCM) benzyl chloroformate was dropped into the reaction system within 1 h. After stirring at room temperature for 3h, the reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to distill off without dichloromethane, and then 500ml of H2O was added. After stirring, the mixture was filtered, and the filter cake was dried at 50 C in a vacuum oven to obtain 312.6 g of a white solid.Yield, 95.8%.

Reference： [1]Patent: WO2013/105100,2013,A1 .Location in patent: Page/Page column 49-50
[2]Patent: WO2013/46211,2013,A1 .Location in patent: Page/Page column 48
[3]Patent: EP2354128,2011,A1 .Location in patent: Page/Page column 19; 20
[4]Patent: WO2011/98501,2011,A1 .Location in patent: Page/Page column 31
[5]Patent: WO2012/159992,2012,A1 .Location in patent: Page/Page column 13-14
[6]Patent: US2014/128601,2014,A1 .Location in patent: Paragraph 0048
[7]Patent: CN103864773,2017,B .Location in patent: Paragraph 0067; 0074; 0088; 0089; 0090; 0091; 0092; 0093
[8]Patent: WO2011/80341,2011,A1 .Location in patent: Page/Page column 16
[9]Patent: WO2013/120465,2013,A1 .Location in patent: Page/Page column 23; 24
[10]Patent: CN110551111,2019,A .Location in patent: Paragraph 0040; 0041; 0042; 0047; 0048; 0049

21
[ 438056-69-0 ]
[ 721401-53-2 ]

Reference： [1]Patent: EP2354128,2011,A1
[2]Patent: CN104860904,2016,B

22
[ 1325210-61-4 ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 2,3,4-lutidine; In ethanol; toluene; butan-1-ol; at 20 - 105℃;	Example 4: 5-Chlorothiophen-2-carboxylic acid-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]-propyl}amide To a suspension of 2.55g of 4-[4-[(5R)-5-(chlorothiopheno-2-carboxylic acid ((S)-2-hydroxy-3-tosyloxy)-propyl)-amide (MW = 389.88; 1 eq.) in 15mL toluene were added 1.22 g of 4-(4-amino-phenyl)-morpholin-3-one (MW = 190.22; 1 eq.), 0.73g collidine (MW = 121.18; 0.9 eq.) and 0.29mL ethanol. The reaction mixture was heated to 105C and stirred at this temperature for 3 hours. Then 2.5mL of n-butanol were added and the mixture was cooled to 22C. After stirring for at least 1 hour at ambient temperature the product was isolated by filtration and washed with toluene and water. The wet product was dried at 30C in vacuo to yield 2.00g of the title compound (76% by theory).
76%	With collidine; In ethanol; toluene; at 105℃; for 3h;	To a suspension of 2.55g of 4-[4-[(5R)-5-(chlorothiopheno-2-carboxylic acid ((S)-2-hydroxy- 3-tosyloxy)-propyl)-amide (MW = 389.88; 1 eq.) in 15mL toluene were added 1.22 g of 4-(4- amino-phenyl)-morpholin-3-one (MW = 190.22; 1 eq.), 0.73g collidine (MW = 121.18; 0.9 eq.) and 0.29ml_ ethanol. The reaction mixture was heated to 105C and stirred at this temperature for 3 hours. Then 2.5mL of n-butanol were added and the mixture was cooled to 22C. After stirring for at least 1 hour at ambient temperature the product was isolated by filtration and washed with toluene and water. The wet product was dried at 30C in vacuo to yield 2.00g of the title compound (76% by theory).

Reference： [1]Patent: EP2354128,2011,A1 .Location in patent: Page/Page column 15; 16
[2]Patent: WO2011/98501,2011,A1 .Location in patent: Page/Page column 25; 26

23
[ 32315-10-9 ]
[ 1325210-61-4 ]
[ 438056-69-0 ]
[ 1325210-63-6 ]

Yield	Reaction Conditions	Operation in experiment
78%		Under an atmosphere of nitrogen to a suspension of 20. Og of 4-[4-[(5R)-5-(chlorothiopheno- 2-carboxylic acid ((S)-2-hydroxy-3-tosyloxy)-propyl)-amide (MW = 389.88; 1 eq.) in 400mL of methylene chloride were added at 10C 12.2g of pyridine (MW = 79.10; 3 eq.) and 5.1g of bis(trichloromethyl)carbonate (MW = 296.75; 0.34 eq.). After stirring for 15 minutes 10. Og of <strong>[438056-69-0]4-(4-amino-phenyl)-morpholin-3-one</strong> (MW = 192.22; 1 eq.), 4.1g pyridine (MW = 79.10; 1 eq.) and 0.19g dimethylaminopyridine were added. The reaction mixture was allowed to warm to 22C. After stirring for 75 minutes at this temperature the reaction was quenched by addition to a mixture of 2L of a saturated aqueous solution of ammonium chloride and 1 L of methylene chloride. Then the organic layer was separated and the aqueous layer was extracted once more with 400mL of methylene chloride. The combined methylene chloride layers were washed with 400mL of water, dried with sodium sulfate and concentrated in vacuo to a weight of 86g. The concentrate was dissolved in 200mL of acetonitrile at 40C and then allowed to cool to ambient temperature. The resulting slurry was stirred for 1 hour at ambient temperature and cooled to 0C. After stirring for 2 hours at this temperature the suspension was filtered and the filter cake was washed with 50ml_ of acetonitrile. The wet product was dried at 30C in vacuo to yield 21.1g of the title compound in form of crystalline powder (78 % by theory). mp: 142 C1H-NMR (DMSO-d6, 300Mz) delta (ppm) = 2.29 (s, CH3, 3H), 3.49 (m, CH2N, 2H), 3.68 (m, CH2, 2H), 3.95 (m, CH2, 2H), 4.18 (s, CH2CO, 2H), 4.18-4.32 (m, CH2, 2H), 5.07 (m, CH, 1 H), 7.18 (d, J=1.9Hz, CH, 1 H), 7.22-7.48 (m, CH, 6H), 7.59 (d, J=3.9Hz, CH, 1 H), 7.77 (d, J=1.9Hz, CH, 1 H), 8.75 (t. J 5.1 Hz, NH.1 H), 9.81 (s, NH.1 H). 13C-NMR (DMSO-d6, 300Mz) delta (ppm) = 49.98, 64.34, 68.59, 70.16, 70.80, 119.34, 126.81 , 128.49, 128.92, 129.15, 131.02, 132.52, 134.03, 137.08, 137.94, 139.31 , 145.99, 153.23, 161.42, 166.76.

Reference： [1]Patent: WO2011/98501,2011,A1 .Location in patent: Page/Page column 27; 28

24
[ 146824-93-3 ]
[ 438056-69-0 ]
[ 1403383-47-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In acetonitrile; at 20℃; for 24h;Inert atmosphere;	Example 3: Sulfuric acid mono-{(R)-1-chloromethyl-2-[4-{3-oxo-morphoiin-4-yi)- phenylaminoj-ethy.} ester potassium saltUnder an atmosphere of nitrogen to a solution of a 7.11 g of (R)-4-chloromethyl- [1 ,3,2]dioxathioiane 2,2-dioxide (MW = 156.59; 1.38 eq.) in 95 mL of acetonitrile were added 6.34 g of 4-(4-aminophenyl)-morphoiin-3-one (APMO) (MW=192.22; 1 eq.) and 3.29 g (MW=138.21 ; 0.72 eq.) of potassium carbonate. The reaction mixture was stirred for 24 h at room temperature. Then the resulting suspension was cooied to 0 C. After stirring for at least 2 h at this temperature, the product was isolated by filtration and the filter cake was washed with 50 mL of acetonitriie. After drying in vacuo at 30 C, 12.09 g of the crystalline title compound (MW = 402.90) were isolated. Yield = 91.0 %.m.p.: 147 C1H-NM (D SO-de, 300Mz) § (ppm) = 2.70 (m, CH2, 2H), 3.61 (dd, CH2, 2H, J 4.7, J 5.7Hz), 3.81 (dd, CH2, 2H, J 2.1 Hz, J 4.3Hz), 3.92 (dd, CH2, 2H, J 4.7Hz, J 6.2Hz), 4.14 (s, CH2, 2H), 4.44 (m, CHO, 1 H), 5.78 (t, NH, 1 H), 6.62 (d, CH, 2H, J 8.9Hz), and 7.04 (d, CH, 2H, J 8.9Hz).13C-N R (DMSO-d6, 300Mz) delta (ppm) = 44.81 , 46.26, 50.43, 64.43, 68.59, 112.27, 127.37, 131.34, 148.02, 166.68.

Reference： [1]Patent: WO2012/140061,2012,A1 .Location in patent: Page/Page column 25-26

25
[ 1412905-05-5 ]
[ 438056-69-0 ]
[ 1412905-15-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With HATU; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	General procedure: 2-[(2-Oxo-2H-chromen-7-yl)oxy]propanoic acid 4 (1 mmol), amnie (1.1 mmol), HATU (1.1 mmol) in DMF (3 mL) were stirred at room temparature for overnight. After completion of the reaction water (10 mL) was added to the reaction mixture. The solid separated was filtered and dried to give the desired product.

Reference： [1]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6745 - 6749,5

26
[ 88285-82-9 ]
[ 438056-69-0 ]
4-(4-[3-dibenzylamino-2-hydroxy-propyl]-amino}-phenyI)-morfoIine-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With lithium bromide; In water; isopropyl alcohol; at 25 - 62℃;	Example 7Preparation of racemic 4-(4-[(3-dibenzyIamino-2-hydroxy-propyl]-amino}- phenyI)-morfoIine-3-one of the Formula 18 (racemic form of the compound of the Formula 18)10.0 g (50 millimoles) of 4-amino-phenyl-morpholinone (compound of the Formula 5) and 2.o g of lithium bromide are suspended in a mixture of 65 ml of 2-propanol and 26 ml of distilled water at 25C whereupon 13.0 g (50 millimoles) ofNN-dibenzyl-l-oxirane-2-yl-methaneamine (racemic form of the compound of the Formula 17) are added. The reaction mixture is warmed to 58- 62C and stirred at this temperature for 48 hours. In the 18th hour a further 4.0 g (15.7 millimoles) and in the 42nd hour a further 2.,0 g (7.9 millimoles) ofN,N- dibenzyl-l-oxirane-2-yl-methaneamine are added. After 48 hours the reaction mixture is allowed to cool to room temperature, the precipitated product is filtered, washed with 15 ml of a 2:5 mixture of distilled water and 2-propanol and dried under an infrared lamp to constant weight. Thus 18.8 g (84 %) of a white solid product are obtained. Mp.: 154-155C.

Reference： [1]Patent: WO2012/153155,2012,A1 .Location in patent: Page/Page column 50

27
[ 24460-74-0 ]
[ 438056-69-0 ]
[ 1414932-71-0 ]

Yield	Reaction Conditions	Operation in experiment
94%		Example 2: Obtaining dodecyl (4-(3-oxomorpholin)phenyl)carbamate 09a} Prepare a dissolution of 1 g of <strong>[438056-69-0]4-(4-aminophenyl)morpholin-3-one</strong> (1 ) (5.2 mmol) in a mixture of 22 mL of acetone and 1 1 mL of water. Cool the solution to 0 C and add 0.93 g of sodium carbonate (8.8 mmol). After 10 min slowly add over the mixture 1 .5 mL of dodecyl chloroformate (18b) (5.6 mmol) and stir at room temperature for 4 h. Filter the solid obtained and wash with water. Redissolve the solid in dichloromethane, add anhydrous sodium carbonate, filter, and remove the dissolvent at reduced pressure. Vacuum dry at room temperature, obtaining 1 .98 g (94% yield) of the intended product (19b) as a white solid. Mp: 152C. MS: m/z= 405 (M+1 ). IR(cm"1)= 1650, 1725. 1H NMR (500 MHz, CDCIs) delta 7.44 (d, J = 8.3 Hz, 2H), 7.26 (s, 2H), 6.71 (s, 1 H), 4.35 (s, 2H), 4.17 (t, J = 6.7 Hz, 2H), 4.04 (dd, J = 5.7, 4.3 Hz, 2H), 3.78 - 3.72 (m, 2H), 1 .72 - 1 .64 (m, 2H), 1 .42 - 1 .23 (m, 18H), 0.89 (t, J = 6.9 Hz, 3H)
94%		[0049] Prepare a dissolution of 1 g of <strong>[438056-69-0]4-(4-aminophenyl)morpholin-3-one</strong> (1) (5.2 mmol) in a mixture of 22 mL of acetone and 11 mL of water. Cool the solution to 0 C. and add 0.93 g of sodium carbonate (8.8 mmol). After 10 min slowly add over the mixture 1.5 mL of dodecyl chloroformate (18b) (5.6 mmol) and stir at room temperature for 4 h. Filter the solid obtained and wash with water. Redissolve the solid in dichloromethane, add anhydrous sodium carbonate, filter, and remove the dissolvent at reduced pressure. Vacuum dry at room temperature, obtaining 1.98 g (94% yield) of the intended product (19b) as a white solid. Mp: 152 C. MS: m/z=405 (M+1). IR (cm-1)=1650, 1725. 1H NMR (500 MHz, CDCl3) delta 7.44 (d, J=8.3 Hz, 2H), 7.26 (s, 2H), 6.71 (s, 1H), 4.35 (s, 2H), 4.17 (t, J=6.7 Hz, 2H), 4.04 (dd, J=5.7, 4.3 Hz, 2H), 3.78-3.72 (m, 2H), 1.72-1.64 (m, 2H), 1.42-1.23 (m, 18H), 0.89 (t, J=6.9 Hz, 3H)

Reference： [1]Patent: WO2012/159992,2012,A1 .Location in patent: Page/Page column 14
[2]Patent: US2014/128601,2014,A1 .Location in patent: Paragraph 0049

28
[ 438056-69-0 ]
[ 898543-06-1 ]

Reference： [1]Patent: WO2013/53739,2013,A1
[2]Patent: WO2013/121436,2013,A2
[3]Patent: WO2013/46211,2013,A1
[4]Patent: WO2013/46211,2013,A1
[5]Patent: WO2013/46211,2013,A1
[6]Patent: WO2013/46211,2013,A1
[7]Patent: WO2013/46211,2013,A1
[8]Patent: WO2014/102820,2014,A2
[9]Patent: US2015/11756,2015,A1
[10]Patent: CN103980221,2016,B
[11]Organic Preparations and Procedures International,2017,vol. 49,p. 169 - 177
[12]Patent: CN104974105,2017,B
[13]Patent: CN105085431,2017,B
[14]Patent: CN105085507,2017,B
[15]Patent: CN109553611,2019,A
[16]Patent: CN110551111,2019,A

29
[ 161596-47-0 ]
[ 438056-69-0 ]
[ 446292-08-6 ]

Reference： [1]Patent: WO2013/98833,2013,A2
[2]Patent: WO2013/121436,2013,A2
[3]Patent: WO2014/102820,2014,A2
[4]Patent: US2014/378682,2014,A1
[5]Patent: WO2015/198259,2015,A1
[6]Patent: WO2016/199027,2016,A1
[7]Patent: WO2018/127762,2018,A1
[8]Patent: CN109553611,2019,A
[9]Patent: CN110818700,2020,A

30
[ 1429333-87-8 ]
[ 438056-69-0 ]
[ 366789-02-8 ]

Yield	Reaction Conditions	Operation in experiment
1.63 g	With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;	8.II Step- II : Preparation of Rivaroxaban (I): To a solution of N-[(2S)-3-chloro-2-((phenyloxycarbonyl)-oxy)propyl]-5- chlorothiophene-2-carboxamide (7.0 gms, 18.7 mmol) (prepared in step - I) and 4-(4- aminophenyl)morpholin-3-one (4.5 gms , 1.25eq) commercially available) in DMF (35 ml), Potassium carbonate (6.5 gms, 2.5 eq ) and catalytic amount of triethylbenzyl amm.chloride were added and stirred at 80°C for 12 hrs. The reaction mixture was poured into water (150 ml) and extracted with dichloromethane (3 x 50 ml). The combined org. extract was washed with water (2 x 50 ml) and evaporated to get the crude compound. Upon recrystallization from acetone to yield a title compound as a white crystalline solid (Yield = 1.63 gms, 20 % of the theory).

Reference： [1]Current Patent Assignee: SYMED LABS LIMITED - WO2013/46211, 2013, A1 Location in patent: Page/Page column 51; 52

31
[ 415684-05-8 ]
[ 438056-69-0 ]
[ 1429333-95-8 ]

Yield	Reaction Conditions	Operation in experiment
23 g	With potassium carbonate In ethanol for 24h; Reflux;	20 Example 20: Alternative Preparation of tert. Butyl -N- [(R)-2-hydroxy-3-{4-(3- oxomo holin-4-yl)phenylamino}propyl]carbamate ( compound - VII, R⁶= -H, R⁷= -C0₂tBu): To a suspension of 19.2 gms (0.1 mol) of 4-(4-aminophenyl)-morpholin-3-one and tert.butyl-(2S)-3-chloro-2-hydroxypropyl carbamate ( 23 gms, 1.05 eq) in ethanol ( 200 ml) was added potassium carbonate(27.6 gms, 2 eq) and refluxed for 24 hrs. Filter the undissolved solid and washed with ethanol (50 ml). Distill off the solvent completely and to the semi solid added water (200 ml) and adjusted pH = 2 with dil. HC1 and washed the aq. layer with 50 ml of dichloromethane. Acidic aq. layer taken and pH =10 adjusted with 10 % NaOH solution and then extracted with dichloromethane (100 ml x 2) and washed dichloromethane layer with water ( 50 ml x 2).Distill off the solvent and then used for the further reactions without further purifications.(Yield=23 gms, 63% of the theory).

Reference： [1]Current Patent Assignee: SYMED LABS LIMITED - WO2013/46211, 2013, A1 Location in patent: Page/Page column 62

32
[ 161513-47-9 ]
[ 438056-69-0 ]
[ 1429333-95-8 ]

Yield	Reaction Conditions	Operation in experiment
36.5 g	In ethanol for 24h; Reflux;	19.I Step - I: Preparation of tert. Butyl -N- [(R)-2-hydroxy-3-{4-(3-oxomorpholin-4-yl)phenylamino}propyl]carbamate (compound -IX, R6 -H, R7 -CO-Ot Bu): To a suspension of 4-(4-aminophenyl)-morpholin-3-one (19.2 gms 0.1 mol) in ethanol ( 200 ml) added teit-butyl-(2S)-oxiranyl methyl carbamate ( 17. 3 gms, 0.1 mol, 1 eq) ( prepared as per US6,998,420 B2) and refluxed for 24 hrs . Distill - off solvent completely and used for the next reaction without further purification (Yield =36.5 gms, 100 % of the theory).

Reference： [1]Current Patent Assignee: SYMED LABS LIMITED - WO2013/46211, 2013, A1 Location in patent: Page/Page column 61

33
[ 183905-31-9 ]
[ 438056-69-0 ]
[ 1429334-00-8 ]

Yield	Reaction Conditions	Operation in experiment
1.072 g	With lithium tert-butoxide; In tetrahydrofuran; methanol; N,N-dimethyl-formamide; at 5 - 24℃; for 21h;	To a suspension of [4-(3-oxo-morpholin-yl)phenyl]carbamic acid benzyl ester (3.26 gms, 10 mmol) in DMF (10 ml) and methanol (0.64 g, 20 mmol, 2 eq) at 20 C is added to a solution of Lithium-t-Butoxide ( 2.4 g, 30mmol, 3 eq) in THF (13.5 ml) while keeping less than 24C . The suspension is cooled to about 5C, and (S)-N-[2-(acetyloxy)-3- chloropropyl]acetamide (3.87g, 20 mmol, 2 eq) ( prepared as per US7,087,784B2). The resulting suspension is allowed to stand at about 21C for 21 hrs. Sat. NH4C1 solution ( 25 ml) is added followed by water ( 30 ml), sat.aq. NaCl ( 25 ml) and methylene chloride ( 50 ml). The phases are separated and the aq. washed with DCM ( 20 ml x3) . The organics are dried on MgS04 and concentrated in the vacuum and then recrystallized from methanol to yield a title compound as a white-crystalline solid. (Yield = 1.072 g, 32% of the theory).

Reference： [1]Patent: WO2013/46211,2013,A1 .Location in patent: Page/Page column 66; 67

34
[ 1429334-03-1 ]
[ 438056-69-0 ]
[ 446292-08-6 ]

Yield	Reaction Conditions	Operation in experiment
0.5 g	With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;	To a suspension of (S)-l-phthalimido-2-((phenyloxycarbonyl) oxy)-3-propylchloride (3.595g, 10 mmol) (prepared in Step- I ) and 4-(4-aminophenyl)morpholin-3-one (2.4g, 12.5 mmol, 1.25 eq) in DMF ( 20 ml). Potassium carbonate ( 3.45 gms, 25 mmol, 2.5 eq) and catalytic amount of triethylbenzyl ammonium chloride were added and then stirred for about 18 hrs at 80C .The reaction mix. is poured into the water ( 50 ml) and then extracted with the DCM ( 25 ml x 3). The combined organics are washed with Dil.HCl (10 ml x2) and water ( 10 ml x 2). Distill off the solvent under reduced pressure to yield a title compound.( (Yield = 0.5 g, 12 % of the theory).

Reference： [1]Patent: WO2013/46211,2013,A1 .Location in patent: Page/Page column 71; 72

35
[ 17823-69-7 ]
[ 438056-69-0 ]
[ 1456732-79-8 ]

Yield	Reaction Conditions	Operation in experiment
		Dissolved 0.500 g <strong>[17823-69-7]2-cyano-3,3-bis(methylthio)acrylamide</strong> in 15 mL EtOH and added 4-(4-aminophenyl)morpholin-3-one (1.0 eq.) . Stirred reaction at 75 C until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75 C until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(2-oxomorpholino)phenyl)amino)-lH- razole-4-carboxamide as a yellow powder . Product was allowed to dry under vacuum for 1 5-amino-3-((4-(2-oxomorpholino)phenyl)amino)-lH-pyrazole-4-carboxamide

Reference： [1]Patent: WO2013/138613,2013,A1 .Location in patent: Paragraph 00427

36
[ 161596-47-0 ]
[ 438056-69-0 ]
2-[2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 g	In water; at 55 - 60℃; for 15h;	In a clean round bottom flask, 100 gm of 4-(4-aminophenyl) morpholin-3-one, 126.9 gm of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-drone and 2 liter water were charged. The reaction mixture was heated to a temperature of about 55-60 C. and maintained for about 15 hours. The reaction mass was cooled to about room temperature and stirred for about one hour, filtered, washed with water and dried in air oven at about 50 C.-55 C. to yield 200 gm of titled compound.

Reference： [1]Patent: US2016/52919,2016,A1 .Location in patent: Paragraph 0109; 0127; 0142

37
[ 161596-47-0 ]
[ 438056-69-0 ]
2-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione [ No CAS ]

Reference： [1]Patent: US2016/52919,2016,A1

38
[ 50654-94-9 ]
[ 438056-69-0 ]
(R)-tert-butyl-3-(1H-imidazol-5-yl)-1-oxo-1-(4-(3-oxomorpholino)phenylamino)propan-2-ylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 3.25h; Cooling with ice;	6.1 1. Preparation of intermediate (R)-tert-butyl-3-(1H-imidazol-5-yl)-1-oxo-1-(4-(3-oxomorpholino)-phenylamino)-propan-2-ylcarbamate 4- (4-aminophenyl) morpholin-3-one (2.0g,10.41mmol) was dissolved in N,N- dimethylformamide (10ml) and tetrahydrofuran(20ml). Add under ice-cooling N,N- diisopropylethylamine (5.4g, 41.64mmol) and Boc-D-histidine-OH (2.66g, 10.41mmol), and finally added 2- (7-azo BTA) -N, N,N ' , N'- tetramethyluronium hexafluorophosphate (HATU) (4.75g, 12.49mmol), The reaction was stirred at ice bath for 15 minutes, then go to room temperature for 3 hours. LCMS the reaction was complete, quenched with small amount of water, washed with ethyl acetate and extracted three times, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (dichloromethane: methanol = 50: 1 to 15: 1) to afford an off-white solid, 1.21 g of, purity: 94%, yield: 27%.

Reference： [1]Current Patent Assignee: SHANDONG KAISEN PHARMA - CN105294669, 2016, A Location in patent: Paragraph 0080; 0081

39
4-(4-nitrosophenyl)-3-morpholinone [ No CAS ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
89.5%	With ethanol; 5%-palladium/activated carbon; hydrogen; at 40℃; under 2068.65 Torr; for 2h;Inert atmosphere; Heating;	Add 30g (0.15mol) 4- (4- nitrosophenyl) in 500ml hydrogenation vessel -3- morpholinone () and 200g of ethanol, replacement of air with nitrogen was added 5% Pd / C 1.5g, on Stirring , warmed to 40 , leads to 40psi hydrogen, stirred 2h.After completion of the reaction, the reaction solution was added 40g ethanol and 150g water, heated to 40 , filtered and the filtrate was concentrated to dryness under reduced pressure, added 100ml of methanol was heated to reflux and stirred clear solution, after cooling to 10 deg.] C stirred 1h, filtered and the filter cake 50 drying under reduced pressure to give white to pink solid 25.0g, 89.5% yield, mp 169-170 ,

Reference： [1]Patent: CN104478820,2016,B .Location in patent: Paragraph 0082; 0083; 0084

40
[ 42518-98-9 ]
[ 438056-69-0 ]
N-[4-(3-morpholinon-4-yl)phenyl]-5-chloro-2-thiophenecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.5%	With triethylamine; In tetrahydrofuran; at 20℃; for 5h;	A reaction flask was successively added 4-(3-morpholinon-4-yl)aniline (0.01 mol), THF 60 ml, triethylamine (0.015 mol), stirred well, added 5-chloro-2-thenoyl chloride (0.012 mol), stirred at room temperature for 5 hours, the reaction was completed, solvent was evaporated under reduced pressure and the residue was dissolved in 100 ml of dichloromethane, washed with deionized water, washed with saturated aqueous NaHCO3, and saturated sodium chloride solution, dried over anhydrous sodium, after drying the filtrate solvent was evaporated under reduced pressure, the residue was recrystallized from ethanol to give N-[4-[(3-morpholinon-4-yl)phenyl]-5-chloro-2-thiophenecarboxamide, yield 97.5 %;

Reference： [1]Patent: CN104860904,2016,B .Location in patent: Paragraph 0048

41
[ 112-05-0 ]
[ 438056-69-0 ]
C₁₉H₂₈N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h; Inert atmosphere;	Synthesis procedures General procedure: This second reaction was carried out using the precursors with fatty acids in peptide coupling conditions: a mixture of 1-hydroxybenzotriazole (HOBt) (2 equiv.) and N-ethyl-N’-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDAC.HCl) (2 equiv.), as carboxylic acid activating agents, and arylamines (1 equiv.) were weighed and transferred into a dried reaction tube. The tube was evacuated and back filled with dry N2. Fatty acids (1.2 equiv.), N,N-diisopropylethylamine (2.5 equiv.), pyridine (Py) (0.01 equiv.) and dry dichlorometane (DCM)(5 mL) were injected into the tube and stirred at room temperature (r.t.) for 6 h. After this time, all compounds were isolated using flash chromatography techniques (for complete methodology description see Supplementary Information).

Reference： [1]Núñez-Navarro, Nicolás E.; Segovia, Gerardine F.; Burgos, Renato A.; Lagos, Carlos F.; Fuentes-Ibacache, Nataly; Faúndez, Mario A.; Zacconi, Flavia C. [Journal of the Brazilian Chemical Society, 2017, vol. 28, # 2, p. 203 - 207]

42
[ 109-11-5 ]
4-haloaniline [ No CAS ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 2h;Microwave irradiation;	General procedure: We initially investigated the microwave-promoted Ullmann type coupling reaction of 4-C, 4-O and 4-S lactams (1.2 equiv.) using CuI (0.05 equiv.) as catalyst with 4-iodoaniline (or 4-bromoaniline) (1 equiv.) in dry toluene (PhMe) in the presence of N,N’-dimethlyethylenediamine (DMEN) (0.1 equiv.) as ligand, and K3PO4 (2 equiv.) as the base and irradiated with power (4-6 bar, 850 watts) at 110 C for 2 hours (2 h). This new microwave (MW) assisted approach decreased the reaction time from 16-72 to 2 h to produce the precursors of interest 6-8. The second step of the synthesis was carried out through a modified peptide coupling reaction at room temperature between lactams 6-8, which have different heteroatoms at position 4, and fatty acids with varying chain lengths (n = 4-7) in order to modify the lipophilicity characteristics of the novel compounds (Scheme 1).

Reference： [1]Journal of the Brazilian Chemical Society,2017,vol. 28,p. 203 - 207

43
[ 141-43-5 ]
[ 446292-04-2 ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With iron; acetic acid; In acetonitrile; at 30℃; for 3h;	In a 500 mL reaction flask, <strong>[446292-04-2]4-(nitrophenyl)-3-morpholinone</strong> (44.4 g, 0.2 mol) and iron powder (54.8 g, 0 & gt; 8 [deg.] 1) was heated to 300 [deg.] C in glacial acetic acid to 30 [deg.] C for 3 hours. After completion of the reaction, the filter cake is washed with water, dried, To give 4- (aminophenyl) -3-morpholinone (36. 5 g) in 95% yield

Reference： [1]Patent: CN103980221,2016,B .Location in patent: Paragraph 0058; 0059; 0060

44
[ 42518-98-9 ]
[ 530-62-1 ]
[ 161596-47-0 ]
[ 438056-69-0 ]
[ 366789-02-8 ]

Yield	Reaction Conditions	Operation in experiment
3.41 g		To a 250 ml reaction flask was added 5. 37 g of 4- (4-aminophenyl) -3-morpholinone,5. 68 g of S-glycidyl phthalimide,140 ml of ethanol-water (nu: nu = 9: 1), heated to reflux for 12 hours,filter,The filter cake was washed with ethanol,dry,Get solid 7. 50g,The mother liquor is concentrated under reduced pressure,Add 5.68 g of S-glycidyl phthalimide,140 ml of ethanol-water (nu: nu = 9: 1),Heated to reflux for 13 hours. filter,The filter cake was washed with ethanol,Dried to give 2.80 g of solid,A total of 10. 30 g was obtained as a white solid. 5.23 g of the above white solid was added to a 100 ml reaction flask,Further, 20 ml of N, N-dimethylformamide,4. 29 g N, N-carbonyl imidazole ( I),Temperature rise of 100 C agitation, TLC monitoring reaction process,6 hours reaction is complete. Add 100 ml of water,Stirring and filtering,dry,White solid 5. 08g,4.45 g of the 5. 08 g white solid was charged into a 250 ml reaction flask,Add lml of ethanol,10 ml of a 40% aqueous solution of methylamine was added dropwise,Heating up,After 1 hour, the solvent was evaporated under reduced pressure,50 ml of tetrahydrofuran was added,Stir,0-5 C by adding 1. 92 g of triethylamine,A solution of 2.30 g of 5-chlorothiophene-2-carboxylic acid chloride,5 minutes drop finished,Stir at room temperature,TLC monitors the reaction process,2 hours after the reaction is complete. Vacuum drying solvent,A white solid was added, stirred with 50 ml of water,filter,The filter cake was washed with ethanol,dry,A white solid is rivabhaban 3. 41g.

Reference： [1]Patent: CN103382200,2016,B .Location in patent: Paragraph 0076; 0077

45
[ 161596-47-0 ]
[ 438056-69-0 ]
C₃₂H₃₀N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	In ethanol; for 36h;Reflux;	17.5 g of compound R3, 88.0 g of compound R4, 500 mL of anhydrous ethanol, opened in an oil bath and heated to reflux. After stirring, the reaction was continued for 36 hours. The reaction was monitored by HPLC. After completion of the reaction, the reaction was allowed to cool to room temperature , Allowed to stand overnight, filtered, and the filtrate was collected and evaporated to dryness to give 34.3 g of a yellow solid.The crude impurities R5-1, into the reaction flask, inward into the 240mL 95% ethanol, stirring to warm to reflux, stirring 10min, hot filter, filter the pale yellow solid, drying, impurity R5-1: 27.8g, Yield 51%,

Reference： [1]Patent: CN106588903,2017,A .Location in patent: Paragraph 0040-0042

46
[ 50-00-0 ]
[ 438056-69-0 ]
4-[4-(methylideneamino)phenyl]morpholin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.1%	In dichloromethane; at 20 - 30℃; for 2h;	The reaction flask was charged with 192.2 g (1.0 mol) of 4- (4-aminophenyl) -3-morpholinone,With 700ml dichloromethane stirring dissolved, cooled to 25 ,75.0 g (2.5 mol) of formaldehyde was added dropwise, the dropping temperature was controlled at 20 C to 30 C,After completion of the dropwise addition, the reaction was stirred for 2 hours,TLC medium (dichloromethane: methanol: triethylamine = 20: 1: 0.5, volume ratio)The reaction is complete, stop stirring,Decompression (-0.1MPa ~ -0.09MPa) distillation of dichloromethane, add 600ml ethyl acetate temperature reflux,Stirring natural cooling, down to 10 to 15 crystallization for 8 hours, filtration, vacuum drying,A mixture of 188.1 g of the white intermediate III product was obtained, the molar yield was 92.1%, and the HPLC purity was 98.3%.
92.1%	In dichloromethane; at 20 - 30℃; for 2h;	192.2 g (1.0 mol) of 4-(4-aminophenyl)-3-morpholinone was added to the reaction flask and stirred with 700 ml of dichloromethane.Mix and dissolve, cool to 25C, add 75.0g (2.5mol) formaldehyde dropwise, control the dropping temperature at 20C to 30C, add dropwiseAfterwards, the reaction was stirred for 2 hours and controlled by TLC (dichloromethane: methanol: triethylamine = 20:1:0.5, volume ratio). The reaction was complete and stopped.Stirring, distilling off the methylene chloride under reduced pressure (-0.1 MPa to -0.09 MPa), adding 600 ml of ethyl acetate, warming and refluxing, stirring naturallyCool down to 10C to 15C, crystallize for 8 hours, filter, dry under reduced pressure,The product is 188.1 g of white intermediate III with a molar yield of 92.1% and HPLC purity of 98.3%.
92.1%	In dichloromethane; at 20 - 30℃; for 5h;	192.2 g (1.0 mol) of 4-(4-aminophenyl)-3-morpholinone was added to the reaction flask.Dissolve and dissolve with 700ml methylene chloride, cool down to 25C, add 75.0g (2.5mol) formaldehyde dropwise, and control the dropping temperature at 20C to 30C. Add dropwise and stir the reaction for 2 hours. TLC control (dichlorobenzene) Methane:methanol:triethylamine=20:1:0.5,volume ratio). The reaction was complete. Stirring was stopped. Dichloromethane was distilled off under reduced pressure (-0.1 MPa to -0.09 MPa). 600 ml ethyl acetate was added to warm the mixture under reflux. Cool down naturally, drop to 10C to 15C, crystallize for 8 hours, filter and dry under reduced pressure to obtain 188.1 g of white intermediate III product with a molar yield of 92.1% and HPLC purity of 98.3%.

185.4 g	In dichloromethane; at 20 - 30℃; for 5h;	The reaction flask was charged with 192.28 (1.0 mol) of 4-(4-aminophenyl)-3-morpholinone (Test II). After stirring with 700 ml of methylene chloride, the solution was cooled to 25 C and 45.0 g (1.5 mol) of formaldehyde was added dropwise. The dropping temperature was controlled at 20 C to 30 C, Completion of the dropwise addition, the reaction was stirred for 5 h, TLC in the control (dichloromethane: methanol: triethylamine = 20: 1: 0.5, by volume), the reaction was complete, stirring was stopped, under reduced pressure (-0.1MPa~-0.09MPa) dichloromethane was evaporated, 600ml of ethyl acetate was added heated to reflux, with stirring natural cooling down to 10 C to 15 C crystallization 8 hours, filtered, and dried under reduced pressure, Afforded 185.4 g of the white intermediate III product, the molar yield was 90.8%, and the HPLC purity was 98.8%.
188.1 g	In dichloromethane; at 20 - 30℃; for 2h;	192.2 g (1.0 mol) of 4-(4-aminophenyl)-3-morpholinone (formula II) was added to the reaction flask, and the mixture was stirred and dissolved with 700 ml of dichloromethane, cooled to 25 C., and 75.0 g was added dropwise (2.5muM) formaldehyde, the dropping process temperature is controlled between 20C and 30C, the addition is complete, the reaction is stirred for 2 hours, TLC is controlled (dichloromethane: methanol: triethylamine = 20:1:0.5, volume ratio), the reaction Completely, stirring is stopped. Dichloromethane is distilled off under reduced pressure (-0.1MPa to -0.09MPa). 600ml of ethyl acetate is added to the mixture and the mixture is heated to reflux. Under natural conditions, the mixture is cooled to 10C to 15C and crystallized for 8 hours. After pressure drying, 188.1 g of a white intermediate III product was obtained with a molar yield of 92.1% and an HPLC purity of 98.3%.

Reference： [1]Patent: CN105085371,2017,B .Location in patent: Paragraph 0071-0073
[2]Patent: CN105085508,2017,B .Location in patent: Paragraph 0076; 0077-0079; 0081-0083
[3]Patent: CN105085431,2017,B .Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066; 0067; 0068
[4]Patent: CN105085370,2017,B .Location in patent: Paragraph 0066-0068
[5]Patent: CN105085507,2017,B .Location in patent: Paragraph 0085-0087; 0089; 0090

47
N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide [ No CAS ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
92.4%	With tetrabutylammomium bromide; potassium carbonate; In dichloromethane; at 0 - 20℃; for 5h;	The reaction flask was added Example 1 Preparation of 45.6g (0.2mol) N- (4- aminophenyl) -2- (2-chloroethoxy) acetamide (Formula III), 250ml of dichloromethane, 82.8g (0.6 mol) of potassium carbonate, 6.4g (0.02mol) of tetrabutylammonium bromide, stir, the reaction system was cooled to 0 to 20 , incubated for 5 h, TLC in the control (dichloromethane: methanol = 20: 1, volume ratio) starting material disappeared.The insolubles were filtered, the organic layer was washed with water to remove purified liquid separation, and the organic layer under reduced pressure (-0.08MPa ~ -0.06MPa) was evaporated to dryness, added to 150ml of acetone for 3 hours, precipitated crystals were filtered and dried under reduced pressure with 80ml, to give 4- (4-aminophenyl) -3-morpholinone 35.2g, molar yield 91.6%, HPLC purity 98.5%.Mass spectrometry detection data obtained the title product are as follows: HR-MS (ESI): C10H12N2O2Molecular weight: 192.1, [M + H]+Measured: 193.5.
92.4%	With tetrabutylammomium bromide; potassium carbonate; In dichloromethane; at 0 - 20℃; for 3h;	The reaction flask was charged with 34.2 g (0.15 mol) of N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide (Formula III) prepared in Example 2, 200 ml of dichloromethane, 62.1 g (0.45 mol) potassium carbonate, 4.8 g (0.015 mol) tetrabutylammonium bromide, stirring evenly, cooling the reaction system to 0 C. to 20 C., and stirring while stirring for 3 hours,In the TLC control (dichloromethane:methanol=20:1, volume ratio), the raw materials disappeared. Insoluble matter was removed by filtration, and the organic layer was washed with 60 ml of purified water, and the organic layer was depressurized (-(0.08 MPa to -0.06 MPa) was evaporated to dryness, 110 ml of acetone was added and the mixture was stirred for 3 hours. The crystals were precipitated, filtered, and dried under reduced pressure to obtain 26.6 g of 4-(4-aminophenyl)-3-morpholinone in a molar yield of 92.4. %, HPLC purity 98.2%.
35.2 g	With tetrabutylammomium bromide; potassium carbonate; In dichloromethane; at 0 - 20℃; for 5h;	45.6 g (0.2 mol) prepared in Example 1 was added to the reaction flaskN-(4-aminophenyl)-2-(2-chloroethoxy)acetamide (Formula III),250ml dichloromethane, 82.8g (0.6mol) potassium carbonate,6.4g (0.02mol) tetrabutylammonium bromide, stirring evenly, the reaction system is cooled to 0 C to 20 C,The mixture was stirred for 5 hours and controlled by TLC (dichloromethane:methanol=20:1, volume ratio). The raw materials disappeared. Insoluble material was removed by filtration, and the organic layer was washed with 80 ml of purified water, and the organic layer was evaporated to dryness under reduced pressure (-0.08 MPa to -0.06 MPa), stirred for 150 minutes with 150 ml of acetone, precipitated crystals, filtered, and dried under reduced pressure.35.2 g of 4-(4-aminophenyl)-3-morpholinone are obtained in a molar yield of 91.6% and the HPLC purity is 98.5%.

Reference： [1]Patent: CN104974105,2017,B .Location in patent: Paragraph 0061-0063
[2]Patent: CN104974149,2018,B .Location in patent: Paragraph 0067; 0068; 0069; 0071; 0072
[3]Patent: CN104974148,2017,B .Location in patent: Paragraph 0066-0068; 0071

48
5-chlorothiophene-2-carboxylic acid [(S)-3-iodo-2-hydroxypropyl]amide [ No CAS ]
[ 438056-69-0 ]
[ 721401-53-2 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; water; for 10h;Reflux; Large scale;	(2) 50 L of tetrahydrofuran, 6L purified water was added to the reactor, Open the stir, The intermediate I was added to the previous step and 4- (4-aminophenyl) -3-morpholinone 4.2 kg, Heated to reflux for 10 hours, Down to room temperature, get 5-Chlorothiophene-2-carboxylic acid {(R) -2-hydroxy-3- [4- (3-oxomorpholin-4-yl) phenylamino] -propyl} (Intermediate II);

Reference： [1]Patent: CN104817550,2017,B .Location in patent: Paragraph 0050

49
4-(4-aminophenyl)-3-morpholinone hydrochloride [ No CAS ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydroxide; In dichloromethane; at 0 - 20℃; for 2h;	4- (4-aminophenyl) -3-morpholinone hydrochloride (22.8 g, 0.10 mol) was added 100 mL of water and 100 mL of dichloromethane The mixture was cooled to 0 C by adding 4N sodium hydroxide to 30 mL, and the reaction was carried out at room temperature for 2 hours. The aqueous layer was extracted with 100 mL of dichloromethane, The organic layer was washed with water, dried, filtered and concentrated to give 18.6 g of 4- (4-aminophenyl) -3-morpholinone in 96% yield.

Reference： [1]Patent: CN104211654,2017,B .Location in patent: Paragraph 0225; 0226; 0227; 0228

50
[ 181140-34-1 ]
[ 438056-69-0 ]
C₃₂H₃₀N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	In ethanol; for 24h;Reflux;	A solution of 22.6 g (111.21 mmol) of S - (+) - N- (2,3-ethoxypropyl) phthalimide (SM1)5.34 g (27.80 mmol) of 4- (4-aminophenyl) morpholin-3-one (SM2) was added to 250 ml of a three-necked flask, followed by addition of 110 ml of absolute ethanol and the reaction was refluxed for 24 h.With tap water to 50 ~ 55 C , filter, remove the insoluble matter, collecting the filtrate, continue to cool to 10 ~ 15 C crystallization, filtration, a yellow solid. The yellow solid was dissolved in 80 ml of absolute ethanol and cooled to 5 to 10 The filter cake was dried at 50 to 60 C for 5 hours under reduced pressure. The product was obtained in a yield of 60.0% and a purity of 96.2%.

Reference： [1]Patent: CN106432218,2017,A .Location in patent: Paragraph 0056; 0057

51
[ 51594-55-9 ]
[ 1074-82-4 ]
[ 79-22-1 ]
[ 438056-69-0 ]
[ 446292-08-6 ]

Yield	Reaction Conditions	Operation in experiment
85%		4-(4-Aminophenyl)morpholin-3-one (100 gm) was added in n-butanol (300 ml) and charged Alumia sulfonic acid at ambient temperature. Cool the mass, added (R)-Epichlorohydrin (72 gm) and maintain the reaction mass at below 20C. Confirmed the completion of reaction, separated the catalyst. Added sodiumbicarbonate, cool the mass temperature to Q-5C and added methylchloroformate (56 gm) . After completion of reaction, evaporated the n- butanol and charged N,N-dimethylformamide (500 mi), potassium phthalimide (122 gm). The reaction temperature maintained at 95- 100C for 3 hours. Cool the mass temperature to ambient temperature, quenched the mass into water. Filtered the mass and washed the product with water. Dried the material up to get constant weight. The obtained 2-({(5Sj-2-Qxo-3-[4-(3-Gxo-4- morpholmyl]phenyl ]-- 1 ,3--oxazol.idm-5--yl}methyl)-- 1 H--isoindole-- 1 ,3(2H)--d.ione was 186 gm (85% yield) .

Reference： [1]Patent: WO2018/55499,2018,A1 .Location in patent: Page/Page column 12

52
[ 51673-84-8 ]
[ 438056-69-0 ]
N-4-[(2,2-dimethoxyethylamino)phenyl]morpholine-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		To a suspension of N-4-aminophenylmorpholine-3-one (2) (960 mg; 5 mmol) in dry CH2Cl2 (20 mL) and 4 A molecular sieves (0.5 g) was added the solution of <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (60%) in water (1.13 mL, 7.5 mmol). The mixture was stirred at room temperature for 2 hours. Then, solid NaBH(OAc)3 (1.59 g; 7.5 mmol) was added portionwise during 20 min and the slurry was stirred for 1 hour at room temperature. Afterwards, the mixture was filtered through a plug of Celite and washed with CH2Cl2 (30 mL). The filtrate was evaporated under reduced pressure and the crude product 3 was purified by column chromatography (SiO2; acetone/hexanes/TEA 2/1/0.001, Rf 0.47).1 Yield: 1.32 g (94%); mp: 99-101 C; 1H NMR (CDCl3; 400 MHz): delta 7.09 (m, 2H), 6.65 (m, 2H), 4.56 (t, J = 4.4 Hz, 1H), 4.32 (s, 2H), 4.00 (m, 2H), 3.95 (br, 1H), 3.69 (m, 2H), 3.41 (s, 6H), 3.24 (d, J = 4.4 Hz, 2H); 13C NMR (CDCl3; 100 MHz): delta 167.1, 147.2, 131.6, 127.0, 113.6, 102.5, 68.8, 64.4, 54.1, 50.4, 45.5; FT-IR (ATR, cm-1): 3343, 3054, 2951, 2910, 2857, 2834, 1741, 1639, 1608, 1525, 1478, 1342, 1323, 1121 (100%), 1043, 995, 915, 831, 544; HR-MALDI-MS (DHB): m/z calcd. for C14H21N2O4 ([M+H]+) 281.15014, found 281.15024

Reference： [1]Tetrahedron Letters,2019,vol. 60,p. 99 - 101

53
[ 1313613-18-1 ]
[ 438056-69-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; In methanol; water; for 3h;Reflux;	In 100ml reaction flask equipped with a condenser, was added 3.30 g Step 2) Compound of structure (II) resulting formula, was dissolved in 20 mL of methanol; 2 ml of concentrated hydrochloric acid was added and heated under reflux for 3 hours; concentrated and the crude product was 3 ml of concentrated ammonia water was stirred, cooled and precipitated solid was filtered, the filter cake was washed with a little ice water, and dried in vacuo to give the desired compound of formula (I) structure. Analysis of the product: the product obtained weighed and yield was calculated, the result is: the desired structure of the compound of formula (I) weight 1.77 g, 90% yield.

Reference： [1]Patent: CN108997247,2018,A .Location in patent: Paragraph 0076-0080

54
[ 161596-47-0 ]
[ 438056-69-0 ]
2-((2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.6%	In water; toluene; at 30 - 85℃;	At room temperature, the reaction flask was added 2000ml of 4- (4-aminophenyl) morpholin-3-one 100g (0.52mol) and S- glycidyl phthalimide 125g (0.62mol), toluene 250ml, Water 1000ml.Heat, warm to 80-85 C, reflux for 1.5-2 hours. Add 100 ml of toluene, 400 ml of water, continue refluxing for 3.5-4 hours, reduce to 30-40 C, stir for 1-2 hours, filter by suction, rinse with water at 30-40 C, drain, wet dry, 2-[(2S)-2-Hydroxy-3-[[4-(3-oxo-4morpholinyl)phenyl]amino]propyl]-1H-isoindole-1,3(2H) -Dione] (III) 194.55 g, yield 94.6%. Ee: 99.96%

Reference： [1]Patent: CN110054623,2019,A .Location in patent: Paragraph 0021-0029

55
C₁₀H₁₁Cl₂NO₄S [ No CAS ]
[ 438056-69-0 ]
[ 366789-02-8 ]

Yield	Reaction Conditions	Operation in experiment
96.4%	In ethanol at 36℃; for 7h;	1.4; 2.4 (4) Weigh 40.0g of compound ,4-(4-aminophenyl)morpholin-3-one() 98.5 g, dissolved in 300 ml of 10% ethanol, turn on the stirring, turn on the heating,The system was heated to 36 and stirred for 7 h.Stop heating, ice-water bath system, and stir for 1 hour.Filter with suction, and rinse the filter cake with 40 ml 10% ethanol.After washing, the solids were collected and dried in a blast drying oven at 50°C.After drying, the white powder obtained is rivaroxaban ().53.8 g of product is obtained,The yield was 96.4%, and the purity was 99.2%.

Reference： [1]Current Patent Assignee: BEIJING VENTUREPHARM BIOTECH - CN112538080, 2021, A Location in patent: Paragraph 0013; 0017

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Code	Phrase
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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