[ CAS No. 5927-18-4 ] {[proInfo.proName]}

Name: 5927-18-4|Methyl 2-(dimethoxyphosphoryl)acetate|98%
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SKU: A184006
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Quality Control of [ 5927-18-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 5927-18-4 ]

Product Details of [ 5927-18-4 ]

CAS No. :	5927-18-4	MDL No. :	MFCD00008452
Formula :	C₅H₁₁O₅P	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SIGOIUCRXKUEIG-UHFFFAOYSA-N
M.W :	182.11	Pubchem ID :	80029
Synonyms :

Calculated chemistry of [ 5927-18-4 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.27
TPSA :	71.64 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) :	-7.84 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.63
Log Po/w (XLOGP3) :	-0.61
Log Po/w (WLOGP) :	0.65
Log Po/w (MLOGP) :	-0.55
Log Po/w (SILICOS-IT) :	-0.57
Consensus Log Po/w :	0.11

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.25
Solubility :	101.0 mg/ml ; 0.556 mol/l
Class :	Very soluble
Log S (Ali) :	-0.42
Solubility :	68.8 mg/ml ; 0.378 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.63
Solubility :	42.3 mg/ml ; 0.232 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.37

Safety of [ 5927-18-4 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P362+P364-P403+P233-P501	UN#:	3082
Hazard Statements:	H302-H315-H318-H335-H411	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 5927-18-4 ]

* 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 [ 5927-18-4 ]
Downstream synthetic route of [ 5927-18-4 ]

[ 5927-18-4 ] Synthesis Path-Upstream 1~19

1
[ 50-00-0 ]
[ 5927-18-4 ]
[ 15484-46-5 ]

Yield	Reaction Conditions	Operation in experiment
44%	With potassium carbonate In water at 20℃; for 2 h;	Example 106: methyl 2-(hydroxymethyl)acrylate44percentA saturated aqueous solution (10 mL) of K₂CO₃ (3.5 g, 117 mmol, 1.6 eq.) was slowly added to a rapidly stirred solution of trimethylphosphonoacetate (5.46 g, 30 mmol, 1.0 eq.) and paraformaldehyde (6.63 g, 48 mmol, 4.0 eq.) at r.t.. After the addition the mixture was stirred for 2 h. Then the mixture was extracted with DCM. The organic layer was concentrated to give the compound (1.5 g, 44percent) as a yellow oil. ¹U NMR (400 MHz, CD₃OD) δ: 6.29 (s, IH), 5.83 (s, IH), 3.75 (s, 3H), 3.72 (s, 2H).

Reference： [1] Angewandte Chemie - International Edition, 2015, vol. 54, # 6, p. 1929 - 1932[2] Angew. Chem., 2015, vol. 127, # 6, p. 1949 - 1952,4
[3] Tetrahedron, 2008, vol. 64, # 17, p. 3701 - 3712
[4] Patent: WO2011/17561, 2011, A1, . Location in patent: Page/Page column 72
[5] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3539 - 3545

2
[ 50-00-0 ]
[ 5927-18-4 ]
[ 15484-46-5 ]
[ 292638-85-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium carbonate In water at 23℃;	Acrylate 20. Synthesized by a method adapted from Villieras and Rambaud.2 To around-bottom flask equipped with a stir bar were added trimethyl phosphonoacetate (S1,9.1 mL, 63 mmol, 1.00 equiv) and formaldehyde (S2, 20.5g, 37percent in water, 252 mmol,4.00 equiv). The flask was lowered into a ambient-temperature water bath. To themixture was added a saturated solution of potassium carbonate in water (15.3 g, 110mmol, 1.75 equiv) dropwise via addition funnel over the course of one hour, and stirringwas continued for an additional hour. The reaction mixture was quenched by addition ofsaturated aqueous ammonium chloride (30 mL), then extracted three times with diethylether. The combined organics were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Methyl acrylate, produced as a side-product,was removed by azeotropic distillation with methanol. The residue was purified byvacuum distillation (~0.5 torr, 44 °C) to afford acrylate 20 as a clear oil (4.07 g, 56percentyield) with minor impurities which were carried forward to the next reaction. Thecharacterization data matched those reported in the literature.3

Reference： [1] Tetrahedron Letters, 2015, vol. 56, # 23, p. 2983 - 2990

3
[ 111-71-7 ]
[ 5927-18-4 ]
[ 111-79-5 ]

Reference： [1] European Journal of Organic Chemistry, 2009, # 4, p. 554 - 563

4
[ 67-56-1 ]
[ 16139-79-0 ]
[ 311-46-6 ]
[ 5927-18-4 ]
[ 625396-69-2 ]
[ 625396-71-6 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 1, p. 131 - 134

5
[ 96-34-4 ]
[ 868-85-9 ]
[ 5927-18-4 ]

Reference： [1] Russian Journal of General Chemistry, 2015, vol. 85, # 10, p. 2441 - 2448[2] Ross. Khim. Zh., 2014, vol. 58, # 1, p. 23 - 30,8

6
[ 67-56-1 ]
[ 88738-78-7 ]
[ 5927-18-4 ]
[ 681123-85-3 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 1, p. 131 - 134

7
[ 6832-16-2 ]
[ 868-85-9 ]
[ 5927-18-4 ]

Reference： [1] Phosphorus, Sulfur and Silicon and the Related Elements, 1992, vol. 73, # 1-4, p. 153 - 160

8
[ 96-32-2 ]
[ 121-45-9 ]
[ 5927-18-4 ]

Reference： [1] Liebigs Annalen der Chemie, 1985, # 2, p. 226 - 238
[2] Canadian Journal of Chemistry, 1968, vol. 46, p. 2225 - 2232

9
[ 96-34-4 ]
[ 121-45-9 ]
[ 5927-18-4 ]

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1996, vol. 35, # 4, p. 312 - 317
[2] Chemische Berichte, 1976, vol. 109, p. 2039 - 2063
[3] Tetrahedron Letters, 1999, vol. 40, # 8, p. 1455 - 1458

10
[ 67-56-1 ]
[ 16139-79-0 ]
[ 311-46-6 ]
[ 5927-18-4 ]
[ 625396-69-2 ]
[ 625396-71-6 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 1, p. 131 - 134

11
[ 67-56-1 ]
[ 42451-44-5 ]
[ 5927-18-4 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1976, vol. 46, p. 529 - 534[2] Zhurnal Obshchei Khimii, 1976, vol. 46, # 3, p. 534 - 540

12
[ 67-56-1 ]
[ 4408-78-0 ]
[ 5927-18-4 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1971, vol. 41, p. 1432 - 1439[2] Zhurnal Obshchei Khimii, 1971, vol. 41, p. 1426 - 1434

13
[ 30361-28-5 ]
[ 5927-18-4 ]
[ 51544-64-0 ]

Reference： [1] Tetrahedron, 2005, vol. 61, # 15, p. 3651 - 3657

14
[ 5927-18-4 ]
[ 33819-10-2 ]
[ 51544-64-0 ]
[ 77761-48-9 ]

Reference： [1] Tetrahedron, 2005, vol. 61, # 15, p. 3651 - 3657

15
[ 5927-18-4 ]
[ 62924-31-6 ]
[ 69877-39-0 ]
[ 69877-38-9 ]

Reference： [1] Journal of Medicinal Chemistry, 1979, vol. 22, # 9, p. 1059 - 1067

16
[ 5927-18-4 ]
[ 1122-91-4 ]
[ 75567-84-9 ]

Reference： [1] Chemistry Letters, 1998, # 3, p. 203 - 204

17
[ 5927-18-4 ]
[ 865-47-4 ]
[ 62327-21-3 ]

Reference： [1] Patent: WO2009/81195, 2009, A1, . Location in patent: Page/Page column 29; 161-162

18
[ 5927-18-4 ]
[ 1095142-51-0 ]
[ 1095142-53-2 ]
[ 1095142-55-4 ]
[ 50650-59-4 ]

Reference： [1] Patent: US2009/5569, 2009, A1, . Location in patent: Page/Page column 7

19
[ 67-56-1 ]
[ 354-32-5 ]
[ 5927-18-4 ]
[ 109-92-2 ]
[ 50650-59-4 ]

Reference： [1] Patent: US2009/5569, 2009, A1, . Location in patent: Page/Page column 6-7

[ 5927-18-4 ] Synthesis Path-Downstream 1~88

1
[ 13330-96-6 ]
[ 5927-18-4 ]
(4aR,4bR,7R,8aR,10aR)-7-Hydroxy-4b-methyl-dodecahydro-phenanthren-2-one [ No CAS ]
[(4aR,4bR,8aR,10aR)-4b-Methyl-7-oxo-dodecahydro-phenanthren-(2Z)-ylidene]-acetic acid 4-dimethylamino-butyl ester [ No CAS ]

Reference： [1]Patent: US3992437,1976,
Chem.Abstr.,1977,vol. 86

2
[ 5927-18-4 ]
[ 53844-02-3 ]
(4aR,4bR,7R,8aR,10aR)-7-Hydroxy-4b-methyl-dodecahydro-phenanthren-2-one [ No CAS ]
[ 14169-97-2 ]

Reference： [1]Patent: US3992437,1976,
Chem.Abstr.,1977,vol. 86

3
[ 104-53-0 ]
[ 5927-18-4 ]
[ 26429-97-0 ]

Yield	Reaction Conditions	Operation in experiment
91.7%		A solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (376 g, 417 mL, 2.07 mol) in THF (750 mL) was stirred at 0 C. in a 3 L 3-neck round bottom flask equipped with a mechanical stirrer and N2 inlet. To the chilled solution, neat tetramethyl guanidine (239 g, 260 mL, 2.07 mol) was added dropwise via an addition funnel. The chilled clear pale yellow solution was stirred for 25 minutes at 0 C. A solution of hydrocinnamaldehyde (90%, 253 g, 248 mL, 1.9 mol) in THF (125 mL) was added dropwise to the reaction solution slowly. Upon completion of addition, the reaction was stirred for 10 h rising to room temperature. GC indicated a 95:5 ratio of product to starting material. 500 ml of water was added to the reaction vessel and the reaction stirred overnight separating into two layers. The organic layer was isolated and the aqueous layer was extracted with t-BuOMe. The organic layers were combined and dried over MgSO4, then concentrated in vacuo to yield an orange oil. The crude product was distilled at 129 C./0.3 mm Hg yielding 360.5 g, 91.7% yield, of a clear slightly yellow oil. [00335] EIMS m/z 190 (13; M+), 159 (410, 158 (39), 131(90), 130(62), 117 (22), 104 (12), 95 (57), 91 (100), 77 (21), 65 (59); HREIMS m/z 190.0998 (C12H14O2 D -0.4 mnu); UV lmax (e) 210 (8400), 260 (230) nm; IR nmax 3027, 2949, 1723, 1658, 1454, 1319, 1203, 978, 700 cm-1; 1H NMR d (CDCl3) 7.15-7.3 (Ph-H5; bm), 7.00 (3-H; dt, 15.6/6.6), 5.84 (2-H; dt, 15.6/1.2), 3.70 (OMe; s), 2.76 (5-H2; t, 7.2), 2.51 (4-H2; bdt, 6.6/7.2); 13C NMR d (CDCl3) 166.9 (1), 148.3 (3), 140.6 (Ph-11'), 128.4/128.2 (Ph2'/3'/5'6'), 126.1 (Ph 4:), 121.4 (2). 51.3 (OMe), 34.2/33.8 (4/5).

Reference： [1]Patent: US6680311,2004,B1 .Location in patent: Page/Page column 47; 53
[2]Journal of the American Chemical Society,1995,vol. 117,p. 2479 - 2490
[3]Angewandte Chemie - International Edition,2014,vol. 53,p. 7634 - 7638
Angew. Chem.,2014,vol. 126,p. 7764 - 7768,5
[4]Chemistry - A European Journal,2016,vol. 22,p. 5767 - 5777
[5]Journal of Organic Chemistry,1990,vol. 55,p. 1928 - 1932
[6]Organic and Biomolecular Chemistry,2015,vol. 13,p. 4255 - 4259
[7]Journal of the American Chemical Society,2019,vol. 141,p. 16983 - 16990

4
[ 60032-57-7 ]
[ 5927-18-4 ]
[ 137146-28-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 1315 - 1324

5
[ 13031-04-4 ]
[ 5927-18-4 ]
[ 86453-60-3 ]
[ 86453-59-0 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 5704 - 5709

6
[ 107-86-8 ]
[ 5927-18-4 ]
[ 52148-91-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 22℃;	To a suspension of NaH (60% in mineral oil, 4.20 g, 24.0 mmol) in anhydrous tetrahydrofuran* (300 mL) cooled to 0 C was added dropwise a solution of trimethylphosphonoacetate (17.0 mL, 19.1 g, 105 mmol) in anhydrous tetrahydrofuran* (40 mL). This solution was stirred at 0 C for 45 min and then treated with 3-methyl-2-butenal (10.0 mL, 8.72 g, 104 mmol) in one portion. The solution was allowed to warm to 22 oC and then stirred for 15 hours. After this time, the reaction mixture was diluted with diethyl ether (300 mL) and 2 N sulfuric acid (100 mL). The organics were separated, washed with saturated aqueous sodium bicarbonate solution (300 mL) and brine (350 mL), dried over magnesium sulfate, filtered and concentrated to a yellow oil. Purification by vacuum distillation afforded 3c (13.32 g, 91 %) of 95% purity by 1H NMR: bp 40-42 C; 1H NMR (500 MHz, CDCl3) d 7.59-7.53 (m, 1H), 5.98 (d, J = 11.6 Hz, 1H), 5.75 (d, J = 15.1 Hz, 1H), 3.73 (s, 3H), 1.88 (q, J = 9.1 Hz, 6H); 13C NMR (125 MHz, CDCl3) delta 168.0, 146.4, 141.1, 123.6, 118.0, 51.3, 26.5, 18.9.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 872 - 874
[2]Heterocycles,1984,vol. 21,p. 309 - 324

7
[ 5927-18-4 ]
[ 5077-67-8 ]
[ 1575-44-6 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 2839 - 2840

8
[ 5927-18-4 ]
[ 51716-63-3 ]
7-((methoxycarbonyl)methylene)-cis-bicyclo<3.3.0>octan-3-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1995,vol. 117,p. 6732 - 6738

9
[ 5927-18-4 ]
[ 53844-02-3 ]
(4aR,4bR,7R,8aR,10aR)-7-Hydroxy-4b-methyl-dodecahydro-phenanthren-2-one [ No CAS ]
[ 14169-96-1 ]

Reference： [1]Journal of medicinal chemistry,1967,vol. 10,p. 582 - 593

10
[ 5927-18-4 ]
[ 1122-91-4 ]
[ 75567-84-9 ]

Reference： [1]Chemistry Letters,1998,p. 203 - 204

11
[ 5927-18-4 ]
[ 128461-65-4 ]
[ 201667-72-3 ]

Yield	Reaction Conditions	Operation in experiment
98%		<strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (5.46 g, 4.9 mL, 30 mmol) was added to a solution of K2CO3(8.3 g, 60 mmol) in water (8.3 mL), cooled at 0 C. The reaction mixture was stirred for 15min, and a solution of the 3-(4-methoxybenzyloxy)propionaldehyde1 (4.9 g, 25 mmol) indiethyl ether (10 mL) was then added. The heterogeneous mixture was stirred overnight atroom temperature and then extracted with diethyl ether. The organic phase was dried withanhydrous Na2SO4 and concentrated to give (E)-methyl 5-(4-methoxybenzyloxy)pent-2-enoate (6.1 g, 98%) as a yellow oil, which was used in the next step without any furtherpurification.

Reference： [1]European Journal of Organic Chemistry,2002,p. 1941 - 1951
[2]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 2446 - 2450
[3]Angewandte Chemie - International Edition,1998,vol. 37,p. 1724 - 1726
[4]Organic Letters,2000,vol. 2,p. 2475 - 2477
[5]Journal of the Brazilian Chemical Society,2012,vol. 23,p. 344 - 348

12
[ 5927-18-4 ]
[ 15971-29-6 ]
methyl-3-(4-methoxy-1-naphthyl)-E-propenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%		<strong>[5927-18-4]Trimethyl phosphonoacetate</strong> VII-b (34.8 mL, 241 mmol) in 300 mL anhydrous CH2Cl2 was cooled to 0 C. and charged with DBU (30.5 mL, 322 mmol), and the mixture was stirred for 15 min. Aldehyde Vika (25.0 g, 134 mmol) in 50 mL CH2Cl2 was charged dropwise. The reaction mixture was brought to room temperature, stirred for 36 h, and quenched with 100 mL of water. The mixture was partitioned, and the aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated, and the residue was purified by silica-gel column chromatography (10:1 hexanes/ethyl acetate) to give the desired trans-alpha,beta-unsaturated ester VII-c (32.0 g, 99%) as a white solid: 1H NMR (400 MHz, CDCl3): delta 8.45 (d, J=16.0 Hz, 1H), 8.29 (dd, J=8.4, 1.5 Hz, 1H), 8.14 (d, J=8.6 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.57 (ddd, J=8.5, 7.0, 1.7 Hz, 1H), 7.49 (ddd, J=8.3, 6.7, 1.2 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.43 (d, J=16.0 Hz, 1H), 3.99 (s, 3H), 3.83 (s, 3H).
99%		<strong>[5927-18-4]Trimethyl phosphonoacetate</strong> Vll-b (34.8 ml_, 241 mmol) in 300 ml_ anhydrous CH2CI2 was cooled to 0 C and charged with DBU (30.5 ml_, 322 mmol), and the mixture was stirred for 15 min. Aldehyde Vll-a (25.0 g, 134 mmol) in 50 ml_ CH2CI2 was charged dropwise. The reaction mixture was brought to room temperature, stirred for 36 h, and quenched with 100 ml_ of water. The mixture was partitioned, and the aqueous layer was extracted with CH2CI2 (3 150 ml_). The combined organics were washed with brine, dried (Na2S04), filtered, and concentrated, and the residue was purified by silica-gel column chromatography (10:1 hexanes/ethyl acetate) to give the desired trans-a,p-unsaturated ester Vll-c (32.0 g, 99%) as a white solid: 1 H NMR (400 MHz, CDCI3): 5 8.45 (d, J = 16.0 Hz, 1 H), 8.29 (dd, J = 8.4, 1.5 Hz, 1 H), 8.14 (d, J = 8.6 Hz, 1 H), 7.70 (d, J = 7.7 Hz, 1 H), 7.57 (ddd, J = 8.5, 7.0, 1 .7 Hz, 1 H), 7.49 (ddd, J = 8.3, 6.7, 1 .2 Hz, 1 H), 6.78 (d, J = 8.2 Hz, 1 H), 6.43 (d, J = 16.0 Hz, 1 H), 3.99 (s, 3H), 3.83 (s, 3H).

Reference： [1]Patent: US2014/170244,2014,A1 .Location in patent: Paragraph 0348
[2]Patent: WO2014/99673,2014,A1 .Location in patent: Page/Page column 91; 92; 93
[3]Journal of Organic Chemistry,2001,vol. 66,p. 681 - 688

13
[ 32499-64-2 ]
[ 5927-18-4 ]
[ 548458-81-7 ]

Yield	Reaction Conditions	Operation in experiment
87%		To a dry 500 mL round-bottom flask was added 1.2 equiv (3.4 g, 0.080 mol) LiCl and a stir bar and sealed under a nitrogen balloon. Acetonitrile (180 mL) was added followed by 1.2 equiv of trimethylphosphonoacetate (6.04 mL, 0.037 mol). The mixture was allowed to stir at room temperature for 30 min to dissolve the LiCl. DBU (4.60 mL, 0.031 mol) was added via syringe, drop wise, over 10 min. The protected tropinone 14 (13 g, 0.066 mol) was dissolved in CH3CN (60 mL) and syringed into the flask. The mixture was all allowed to stir at room temperature overnight under N2. The mixture was concentrated under reduced pressure and the light brown oil was dissolved in CH2Cl2 (100 mL) and washed with H2O (50 mL). The layers were separated in a separatory funnel and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The organics were combined and dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, EtOAc/hexane, 1:4) to afford 15 (14.5 g, 87%) as a light yellow oil. 1H NMR: delta 5.79 (s, 1H), 4.39 (br s, 2H), 4.19 (t, J = 6.8 Hz, 2H), 3.69 (s, 3H), 2.69 (br s, 1H), 2.36 (br s, 1H), 2.12 (d, J = 14.4 Hz, 1H), 1.94 (s, 2H), 1.59 (d, J = 7.2 Hz, 2H), 1.28 (t, J = 6.8 Hz, 4H). 13C NMR: delta 165.6, 155.2, 153.2, 118.2, 60.4, 53.6, 53.4, 50.3, 42.1, 35.5, 27.9(2), 14.2. Anal. Calcd for: C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C, 61.46; H, 7.66; N, 5.48.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 7551 - 7558
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 629 - 632

14
[ 5927-18-4 ]
[ 1791-26-0 ]
methyl (E)-3-(4-vinylphenyl)propenoate [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2003,p. 1428 - 1432

15
[ 3731-38-2 ]
[ 5927-18-4 ]
[ 94764-01-9 ]

Yield	Reaction Conditions	Operation in experiment
100%		A stirred solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (7.74 mL,48.0 mmol, 1.2 equiv) in dry tetrahydrofuran (750 mL) under anargon atmosphere at 0 C was treated portionwise with sodiumhydride 60% dispersion in mineral oil (1.92 g, 48.0 mmol, 1.2 equiv).After stirring for 1 h at room temperature (rt), quinuclidin-3-one 35(5.00 g, 40.0 mmol, 1 equiv) was added dropwise via a syringe tothe mixture and stirringwas continued overnight at rt. The reactioncompletionwas confirmed by TLC (dichloromethane/methanol 9:1)and the mixture was cooled to 0 C and quenched with deionizedwater (100 mL). The aqueous layer was extracted with dichloromethane(3 300 mL) and the organic layers were collected andtreated with 1 N HCl (500 mL). The acidic aqueous phase wasseparated and basified to pH 9 by portionwise addition of potassiumcarbonate at 0 C and then extracted with dichloromethane(3 300 mL). The pooled organic phases were dried over anhydrousNa2SO4, filtered and concentrated in vacuo to obtain compound36 as a 1:1 mixture of (E) and (Z) stereoisomers, which wasused without further purification in the next reaction step. Yellow,very viscous oil; yield: 7.25 g, 100%; Rf 0.40 (dichloromethane/methanol 9:1). 1H NMR (300 MHz, CDCl3) d (ppm): 5.63 (t,J 2.5 Hz, 1H), 5.61 (t, J 1.7 Hz, 1H), 3.94e3.85 (m, 3H), 3.66 (s,3H), 3.65 (s, 3H), 3.47e3.41 (m, 2H), 2.98e2.71 (m, 8H), 2.48e2.38(m, 1H), 1.84e1.56 (m, 8H). 13C NMR (75 MHz, CDCl3) d (ppm):169.6, 167.9, 166.8,166.3,110.6, 110.3, 56.4, 50.7, 47.4, 47.2, 33.5, 27.1,26.1, 26.1. Note: in the 13C NMR spectrum, the following pairs ofpeaks, 169.6 and 167.9, 166.8 and 166.3, 110.6 and 110.3, representthe same carbon in the two stereoisomers E and Z.
		To a solution of methyl 2-(dimethoxyphosphoryl)acetate (2.70 g, 14.8 mmol) in THF (200 ml) at 0 C. was added NaH [60% dispersion in mineral oil] (600 mg, 15.0 mmol). After 1 h of stirring, quinuclidin-3-one (2.00 g, 12.4 mmol) was added and the resultant mixture was stirred at room temperature for 18 h. The reaction was quenched with 50 ml water at 0 C. and the mixture was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure to afford crude methyl 2-(quinuclidin-3-ylidene)acetate, which was used in next step without purification (1.2 g, 70%).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 160,p. 207 - 228
[2]Heterocycles,2003,vol. 60,p. 1601 - 1610
[3]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 2403 - 2414
[4]Patent: US9126993,2015,B2 .Location in patent: Page/Page column 103

16
[ 5927-18-4 ]
[ 162752-17-2 ]
(6-tert-butyl-3H-inden-1-yl)-acetic acid methyl ester [ No CAS ]
(6-tert-butyl-indan-1-ylidene)-acetic acid methyl ester [ No CAS ]
methyl (E)-[6-(tert-butyl)-2,3-dihydro-1H-inden-1-ylidene]acetate [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2004,vol. 87,p. 1767 - 1793

17
[ 5927-18-4 ]
[ 162752-17-2 ]
[ 173445-56-2 ]

Reference： [1]Helvetica Chimica Acta,2004,vol. 87,p. 1767 - 1793

18
[ 30361-28-5 ]
[ 5927-18-4 ]
[ 51544-64-0 ]
methyl (E,E,E)-2,4,6-decatrienoate [ No CAS ]

Reference： [1]Tetrahedron,2005,vol. 61,p. 3651 - 3657

19
[ 5927-18-4 ]
[ 33819-10-2 ]
[ 51544-64-0 ]
[ 77761-48-9 ]
Me deca-cis-2, trans-4, trans-6-trienoate [ No CAS ]
methyl (E,E,E)-2,4,6-decatrienoate [ No CAS ]

Reference： [1]Tetrahedron,2005,vol. 61,p. 3651 - 3657

20
[ 67-56-1 ]
[ 16139-79-0 ]
[ 311-46-6 ]
[ 5927-18-4 ]
[ 625396-69-2 ]
[ 625396-71-6 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2005,vol. 53,p. 131 - 134

21
[ 5927-18-4 ]
3-formyl-benzenesulfonate sodium [ No CAS ]
sodium 3-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]benzenesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium carbonate; In water; at 20℃; for 0.5h;	Step 29b: Sodium (E)-3-(3-methoxy-3-oxoprop-l-enyl)benzenesulfonate(Compound 1303)A mixture of 1302 (0.5 g, 2.4mmol), K2CO3 (0.66 g, 4.78 mmol), <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (0.53 g, 2.88 mmol) in water (10 mL) was stirred at room temperature for 30 min. The resulting solid was isolated and washed with ethanol to give product 1303 (0.35 g, 55%) as a white solid: 1H NMR (400MHz, DMSO-d6) delta3.72 (s, IH), 6.59 (d, J= 16 Hz, IH), 7.39 (t, J= 8 Hz, IH), 7.67 (m, 3H), 7.83 (s,IH).
33%	With potassium carbonate; In water; at 20℃; for 15h;	Stage 2 - Preparation of 3-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]benzenesulfonate sodium salt; Stage 1 product (13.8g, 66mmol) and K2CO3 (18.3g, 132mmol) were dissolved in water (7OmL). <strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (14.51g, deltaOmmol) was added dropwise and the reaction stirred at RT for 15h. The resulting precipitate was filtered, washed with MeOH and dried in vacuo to <n="39"/>afford the desired product as a white solid (5.75g, 33%). 1H NMR (300MHz, c/6-DMSO) delta: 7.84 (1 H, s), 7.65-7.70 (3H, m), 7.40 (1 H, t, J=7.5Hz), 6.60 (1 H1 d, J=16.2Hz), 3.73 (1 H1 s).
26 g	With sodium methylate; In methanol; at 0 - 10℃; for 2h;	Method B: Sodium-3-formylbenzenesulfonate (30.Og) was added in methanol (i2OmL) at room temperature and the reaction mass was cooled to 0-10C. Trimethylphophonoacetate (26.2g) and sodium methoxide solution (37.3mL) was added to reaction mass at 0-10Cand stirred for 2 hours. After completion of the reaction, reaction mass was allowed to reach room temperature and then acetone (6OmL) was added. The reaction mass was stirred for 30-40 minutes and filtered the solid. Thus obtained solid was dried under vacuum at 45-50C to give 26g of sodium 3-[(1E)-3-methoxy-3-oxoprop-i-en-i-ylj benzenesulfonate.

Reference： [1]Helvetica Chimica Acta,2005,vol. 88,p. 1630 - 1657
[2]Patent: WO2009/36016,2009,A1 .Location in patent: Page/Page column 84
[3]Patent: WO2008/40934,2008,A1 .Location in patent: Page/Page column 37-38
[4]Patent: WO2018/20406,2018,A1 .Location in patent: Page/Page column 13

22
[ 5927-18-4 ]
[ 1008-72-6 ]
sodium 2-(2-methoxycarbonyl-vinyl)benzenesulfonate [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2005,vol. 88,p. 1630 - 1657

23
[ 777089-26-6 ]
[ 5927-18-4 ]
[ 777089-28-8 ]

Yield	Reaction Conditions	Operation in experiment
87%		Sodium hydride (0.513 g of a 60% dispersion, 12.8 mmol) was placed in a flask and washed three times with hexane. The resulting solid was suspended in DMF (10 mL) and cooled to 0 C. TRIMETHYL phosphonoacetate (2.2 mL, 13.5 mmol) was added dropwise to this suspension to give a clear homogeneous solution. After stirring for another 15 minutes at 0 C, a solution of benzyl 3-fluoro-4- FORMYLPHENYLCARBAMATE (3.5 g, 12.8 mmol) in DMF (10 mL) was added dropwise. The resulting orange suspension was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was poured into 0.5 N HCL and extracted with three portions of dichloromethane. Combined organic phases were washed with saturated NAHC03, H2O, brine, and dried (MGS04) filtered and concentrated. The resulting orange solid was washed sequentially with hexane and then 30% ethyl acetate-hexane to provide the title compound as a yellow-orange solid (2.7 g). The washings were concentrated and purified by column chromatography (0-30% ethyl acetate-hexane) to provide an additional 0.95 g of the product. Yield 3.66 g (87%). H NMR (300 MHz, d6-DMSO): 3.71 (s, 3H), 5.17 (s, 2H), 6. 55 (dd, J = 16, 1 Hz, 1H), 7.26 (d, J= 9 Hz, 1H), 7. 35-7. 50 (m, 6H), 7.63 (d, J= 16 Hz, 1H), 7.79 (t, J =9HZ, 1H), 10.3 (bs, 1 H) MP= 157-158 C.
72%		Sodium hydride (7.2 g of a 60% dispersion, 0. 188 mol) was placed in a flask and washed three times with hexane. The resulting solid was suspended in DMF (140 mL) and cooled to 0 C. <strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (30.7 ML, 0.190 mol) was added dropwise to this suspension to give a clear homogeneous solution. After stirring for another 20 minutes at 0 C, a solution of benzyl 3-fluoro-4- FORMYLPHENYLCARBAMATE (2) (48 g, 0.176 mol) in DMF (140 mL) was added dropwise. The resulting orange suspension was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was poured into 0.5 N HCI (1.5 L) and extracted with three 300 mL portions of dichloromethane. Combined organic phases were washed with saturated NaHCO3, twice with H20, brine, and dried (Na2S04). While concentrating the solution on a rotary evaporator, the product precipitated from solution and these solids were collected on a filter (33.4 g). The filtrate was concentrated to give more solids that were washed with ether (additional 8.4 g obtained). Yield 41.8 g (72%). 'H NMR (300 MHz, d6-DMSO): 3.71 (s, 3H), 5.17 (s, 2H), 6.55 (dd, J= 16,1 Hz, 1H), 7.26 (d, J = 9 Hz, 1H), 7. 35-7. 50 (m, 6H), 7.63 (d, J = 16 Hz, 1H), 7.79 (t, J = 9 Hz, 1H), 10.3 (bs, 1 H) MP= 157-158 C.

Reference： [1]Patent: WO2004/89943,2004,A1 .Location in patent: Page 54
[2]Organic Letters,2005,vol. 7,p. 2627 - 2630
[3]Patent: WO2004/89943,2004,A1 .Location in patent: Page 100

24
[ 498-62-4 ]
[ 5927-18-4 ]
[ 75754-85-7 ]

Yield	Reaction Conditions	Operation in experiment
94%		EXAMPLE 10 3-Thiophen-3-yl-acrylic Acid Methyl Ester To a suspension of sodium hydride (3.65 g 91.22 mmol) in anhydrous THF (250 ML) was added trimethylphosphono acetate (10.16 ML, 62.77 mmol) in THF (50 ML) dropwise.. The thick reaction mixture was then stirred for 1 hour. 3 thiophene carboxaldehyde (5.00 ML, 57.01 mmol) was dissolved in THF (50 ML) and added dropwise, and the reaction stirred at room temp for 18 hours.. The reaction was quenched with half saturated NH4Cl (120 ML).. The layers were separated and the aqueous layer extracted with EtOAc (2*100 ML).. The combined organics were washed with brine (100 ML), dried over MgSO4, filtered and concentrated.. The crude material was chromatographed on silica eluding with hexanes, then 15% EtOAc/heavens to give the title compound 10 as an oil that crystallizes upon standing (9.05 g, 94%). 1H NMR(400MHz, CDCl3) delta7.64(d, 1H, J=15.7 Hz), 7.46 (d, 1H, J=1.47 Hz), 7.30 (dd, 1H, J=5.13, 2.69 Hz), 7.26 (d, 1H, J=5.13 Hz), 6.22 (d, 1H, J=16.1 Hz), 3.76 (s, 3H). MS (APCI) m/z 169 (M++1). Analysis calculated for C8H8O2S: C, 57.12; H, 4.79; S, 19.06. Found: C,57.20; H, 4.77; S, 19.10.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2329 - 2332
[2]Patent: US6710190,2004,B1 .Location in patent: Page column 22
[3]Organic Letters,2016,vol. 18,p. 5716 - 5719

25
[ 5927-18-4 ]
[ 704-13-2 ]
[ 79557-77-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In N,N-dimethyl-formamide; at 20℃; for 16h;	Example 85A 3-(3-hydroxy-4-nitrophenyl)-acrylic acid methyl ester To an ambient solution of <strong>[704-13-2]3-hydroxy-4-nitrobenzaldehyde</strong> (1.00 g, 5.99 mmol) and trimethyl phosphonoacetate (0.950 mL, 6.59 mmol) in DMF (8 mL) was added NaOMe (356 mg, 6.59 mmol). The mixture was stirred at room temperature for 16 h and was then slowly quenched by the addition of 1 N HCl (15 mL). The mixture was acidified to pH~1 with concentrated HCl, and the solid was collected and air-dried to provide the title compound. MS (ESI) m/z 224 (M+H)+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 884 - 889
[2]Patent: US2005/209274,2005,A1 .Location in patent: Page/Page column 48

26
[ 5927-18-4 ]
[ 100-51-6 ]
[ 103-41-3 ]
[ 22767-96-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2006,vol. 4,p. 116 - 125

27
[ 5927-18-4 ]
[ 100-51-6 ]
[ 103-25-3 ]
[ 103-41-3 ]
[ 22767-96-0 ]
[ 103-26-4 ]

Reference： [1]Organic and Biomolecular Chemistry,2006,vol. 4,p. 116 - 125

28
[ 870837-48-2 ]
[ 5927-18-4 ]
C₁₃H₁₁ClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide; In tetrahydrofuran;	To a THF (13 mL) solution of <strong>[870837-48-2]3-chloro-4-(1H-imidazol-1-yl)benzaldehyde</strong> (545 mg) dimethylphosphonoacetic acid methyl ester (513 muL) and lithium hydroxide monohydrate (133 mg) were added one by one, and the reaction solution was agitated overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 442 mg of crude ester product. 2N sodium hydroxide solution (5.0 mL) was added to the reaction solution obtained by which dissolving the obtained ester product in THF (5.0 mL), and the reaction solution was agitated at room temperature overnight. The reaction solution was cooled to 0 C., 2N hydrochloric acid was added to the reaction solution, and the deposited precipitation was separated by filtering with Kiriyama funnel. The obtained precipitation was washed with water and ethyl acetate, and 218 mg of the title compound was obtained. The physical properties of the compound are as follows. 1H-NMR (DMSO-d6) delta (ppm): 8.08 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.82 (dd, J=2.0, 8.4 Hz, 1H), 7.61 (d, J=16 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 6.70 (d, J=16 Hz, 1H).

Reference： [1]Patent: US2006/4013,2006,A1 .Location in patent: Page/Page column 55

29
[ 870837-70-0 ]
[ 5927-18-4 ]
(E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl)acrylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Dimethylphosphonoacetic acid methyl ester (3.80 mL) and lithium hydroxide monohydrate (1.20 g) were added one by one to a THF (20 mL) solution of the crude aldehyde compound (4.76 g) obtained above, and the reaction solution was agitated overnight at the room temperature. 2N sodium hydroxide solution was added to the reaction solution after confirming disappearance of the starting materials (20 mL), and the reaction solution was agitated at 50 C. for 2 hours. The reaction solution was cooled to 0 C., 2N hydrochloric acid was added to the reaction solution (20 mL), and deposited precipitation was separated by filtering with Kiriyama funnel. The obtained precipitation was washed with water and ethyl acetate, and 4.2 g of the title compound was obtained. The physical properties of the compound are as follows. 1H-NMR (DMSO-d6) delta (ppm): 7.96 (s, 1H), 7.63 (d, J=16 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.39 (dd, J=1.6, 8.0 Hz, 1H), 7.06 (s, 1H), 6.68 (d, J=16 Hz, 1H), 3.90 (s, 3H).

Reference： [1]Patent: US2006/4013,2006,A1 .Location in patent: Page/Page column 77

30
[ 5927-18-4 ]
[ 619-21-6 ]
[ 115974-96-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 5; Stage 1 - Preparation of 3-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]benzoic acid; <strong>[619-21-6]3-Carboxybenzaldehyde</strong> (25g, 0.167mol) and K2CO3 (69g, 0.499mol) were added to water (25OmL) and cooled to 0-50C. Trimethyl phosphonoacetate (32.3mL, 0.2mol) was charged dropwise maintaining the reaction temperature below 15°C. The reaction was warmed and stirred at RT for 17h. The mixture was acidified to pH ~ 1 , filtered and dried in vacuo to afford the product as an off-white solid (37.25g, >100percent - slightly wet). 1H NMR (300MHz, CD3OD) delta: 8.23 (1 H, s), 8.06 (1 H, d, J=7.8Hz), 7.86 (1 H1 d, J=7.5Hz), 7.75 (1 H, d, J=15.9Hz), 6.61 (1 H, d, J=16.2Hz), 7.54 (1 H, t), 3.81 (3H, s).

Reference： [1]Patent: WO2008/40934,2008,A1 .Location in patent: Page/Page column 40
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 312 - 317

31
[ 5927-18-4 ]
[ 34841-47-9 ]
[ 154349-03-8 ]

Yield	Reaction Conditions	Operation in experiment
57%		Stage 2 - Preparation of {4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}acetic acid; To stage 1 product (1.03g, 6.3mmol) in water (10OmL) were added K2CO3 (2.61g, 18.9mmol) then trimethylphosphonoacetate (1.23mL, 7.6mmol) at O0C. Addition was carried out over 10 minutes to avoid the reaction temperature rising above 15C. The reaction mixture was then stirred at RT for 72h. A solution of 1 M HCI was added until pH - 1. The white precipitate was isolated by filtration, washed with water (10OmL), concentrated and dried on the freeze drier to afford the desired product as a white solid (784 mg, 57%). 1H NMR (300MHz, Cf6-DMSO) delta: 12.46 (1 H, br s), 7.69-7.63 (2H, m), 7.31 (2H, d, J=8.1 Hz), 6.74 (1 H, d, J=16.0Hz), 6.63 (1 H, d, J=16.0Hz), 3.72 (3H, s), 3.62 (2H, s).

Reference： [1]Patent: WO2008/40934,2008,A1 .Location in patent: Page/Page column 73

32
[ 5927-18-4 ]
[ 126430-46-4 ]
C₁₆H₂₃O₇P [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2007,vol. 349,p. 432 - 440

33
[ 5927-18-4 ]
[ 73291-09-5 ]
[ 731846-75-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4481 - 4486

34
[ 5927-18-4 ]
[ 1134-43-6 ]
[ 863885-81-8 ]

Yield	Reaction Conditions	Operation in experiment
99%		Step 4; Sodium hydride (95% dry powder; 158 mg; 6.25 mmol) was suspended in anhydrousTHF (10 mL) and <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (0.945 mL; 5.84 mmol) added dropwiseat 0C under a nitrogen atmosphere resulting in a solid white mass which could not bestirred. A solution of the aldehyde 4-4 from above (950 mg; 4.87 mmol) in THF (7 mL+ 3 mL rinse) was then added dropwise resulting in a yellow colour and slowdissolution of the white solid mass. After the addition, the reaction was allowed towarm to ambient temperature. After 15 h, the cloudy reaction mixture was evaporatedto a pale yellow solid which was extracted with ethyl acetate (2 x 50 mL) and washed with saturated NaHCO3 (3 x 75 ml). The combined extracts were dried over MgSO4and evaporated to afford the cinnamate ester 4-5 as pale yellow solid (1.212 g; 99 %)which was used without further purification.
	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 15h;	Step 4:; Sodium hydride (95% dry powder; 158 mg; 6.25 mmol) was suspended in anhydrous THF (10 mL) and <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (0.945 mL; 5.84 mmol) added dropwise at 0C under a nitrogen atmosphere resulting in a solid white mass which could not be stirred. A solution of the aldehyde 12-4 from step 3 (950 mg; 4.87 mmol) in THF (7 mL + 3 mL rinse) was then added dropwise resulting in a yellow colour and slow dissolution of the white solid mass. After the addition, the reaction was allowed to warm to ambient temperature. After 15 h, the cloudy reaction mixture was evaporated to a pale yellow solid which was extracted with ethyl acetate (2 x 50 mL) and washed with saturated NaHC03 (3 x 75 mL). The combined extracts were dried over MgS04 and evaporated to afford the cinnamate ester 12-5 as pale yellow solid (1.212 g; 99 %) which was used in step 5 without further purification.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 10130 - 10143
[2]Patent: WO2006/7693,2006,A1 .Location in patent: Page/Page column 48; 49
[3]Patent: WO2005/80388,2005,A1 .Location in patent: Page/Page column 65-66

35
[ 5927-18-4 ]
[ 79099-07-3 ]
[ 169206-65-9 ]

Yield	Reaction Conditions	Operation in experiment
94%		60% NaH (3.06 g) was washed with dry hexane (2 x 20 mL) and the clear solution was syringed out under N2 atmosphere. The washed NaH was suspended in dry DMF (100 mL) and cooled to 0 C. To this suspension was added slowly <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (14.1 mL) over a period of 20 minutes. Compound HI (14. Og, 78 mmol) in dry DMF (15 mL) was slowly added to the solution. The temperature was maintained at 0 C over a period of 20 minutes, then allowed to stir while warming to RT for 3h. At this point the reaction was diluted with Et20 (250 mL) and washed with water (100 mL). The aqueous layer was back extracted with additional diethyl ether (40 mL), then the combined organic extract was washed with water (4 x 50 mL) and brine (30 mL). The separated organic layer was dried over MgS04,filtered and the solvent was removed under reduced pressure to yield the product as a crystalline solid. Isolated 16.95g (94% yield).
92%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	Methyl dimethylphosphonoacetate (1.8 ml) was dissolved in tetrahydrofuran (40 ml). Under ice cooling, sodium hydride (60% in oil, 450 mg) was added and the resulting mixture was stirred as was. A tetrahydrofuran solution (tetrahydrofuran: 10 ml) of 1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) was added. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate, followed by the addition of 2N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue thus obtained was purified by chromatography (hexane:ethyl acetate = 6:1) on a silica gel column, whereby the title compound (2.35 g, 92%) was obtained.1H-NMR(CDCl3) delta: 1.47(9H,s), 2.28(2H,t,J=5.9Hz), 2.94(2H,t,J=5.9Hz), 3.48(2H,t,J=5.9Hz), 3.50(2H,t,J=5.9Hz), 3.70(3H,s), 5.72(1H,s).
92%		tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-l-carboxylate.; Sodium hydride in mineral oil (60%, 7.92 g, 198.02 mmoles) was washed with hexanes then suspended in dimethylformamide (220 mL). The mixture was cooled to 0C.<strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (29.0 mL, 189.82 mmoles) was added dropwise to the stirred reaction mixture. After 20 min at 0C, a solution of N-tert-butoxycarbonyl-4- piperidone (30.41 g, 152.62 mmoles) in dimethylformamide (80 mL) was added to the mixture dropwise. The reaction was stirred at room temperature for 3 h and then diluted with diethyl ether (650 mL). The mixture was washed once with water and the aqueous layer was extracted once with diethyl ether. The combined organic layers were washed 4 times with water and the aqueous phase was discarded. The organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated to dryness. The title compound was obtained as a white solid in 92% yield. XH-NMR (300 MHz, CDC13): delta = 5.68 (s, 1 H), 3.66 (s, 3 H), 3.40-3.51 (m, 4 H), 2.90 (t, J= 5.49, 2 H), 2.25 (t, J= 5.49, 2 H), 1.44 (s, 9 H).

78.1%		To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.0 g, 15 mmol) in DMF (30 mL) in two neck RB was wadded NaH (56-60 %) (0.54 g, 22.5 mmol) portion wise at 0 C and stirred for 30 mins at RT then methyl 2-(dimethoxyphosphoryl)acetate (3.29 g, 18 mmol) was added and stirred for 16 h at RT. The reaction mixture was quenched with cold water and extracted with ethyl acetate (2 X 100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chomatography using 80 % ethyl acetate in hexane as eluent to afford the title compound (3.0 g, 78.1 %) 1H NMR (400 MHz, DMSO-d6): d 5.77 (s, 1H), 3.61 (s, 3H), 3.41-3.33 (m, 4H), 2.82 (t, / = 6.0 Hz, 2H), 2.26 (t, / = 5.6 Hz, 2H), 1.44 (s, 9H). LC-MS: m/z 255.1 (M+l)+.
72.9%		Sodium hydride in mineral oil (60%, 11.9 g, 297 mmol) was dissolved in DMF (200mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286 mmol) was added dropwise at 0CC. The reaction mixture was stirred at 0 00 for 20 mm then tert-butyl 4-oxopiperidine-1-carboxylate (45.5 g, 228 mmol) in DMF (100 mL) was added drop wiseat 0 00 The reaction mixture was stirred at rt for 2 h, then diluted with ice water (20 mL), filtered and the solvents were removed in vacuo to give tert-butyl 4-(2-methoxy-2- oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) as a yellow solid.LCMS (Method F): mlz 256 (M+H) (ES), at 2.47 mi UV active
72.9%		Sodium hydride in mineral oil (60%, 1 1.9 g, 297 mmol) was dissolved in DMF (200 mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286 mmol) was added drop wise at 0 C. The reaction mixture was stirred at 0 C for 20 min then te/f-butyl 4- oxopiperidine-1-carboxylate (45.5 g, 228 mmol) in DMF (100 mL) was added drop wise at 0C. The reaction mixture was stirred at rt for 2 h, then diluted with ice water (20 mL), filtered and the solvents were removed in vacuo to give te/f-butyl 4-(2-methoxy-2- oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) as a yellow solid. LCMS (Method F): m/z 256 (M+H)+ (ES+), at 2.47 min, UV active
		Intermediate 2a: tert-butyl 4-((methoxycarbonyl)methylene)piperidine-1-carboxylate Sodium hydroxide (4.56 g, 0.114 mol) was dissolved in ethanol (210 mL), and <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (11.4 g, 0.062 mol) added with stirring. The mixture was stirred for 30 min at room temperature. Tert-butyl 4-oxopiperidine-1-carboxylate (11.35 g, 0.057 mol) was added with stirring at room temperature, and the reaction was allowed to stand overnight. Then, the mixture was acidified with diluted hydrochloric acid until the pH was 4, filtered, concentrated, and partitioned into water and chloroform. Phases were separated. The aqueous phase was extracted once with chloroform. Chloroform phases were combined, washed once with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound.
		Sodium hydride (60% in mineral oil, 4.8 g, 120 mmol) was washed with hexanes and then suspended in N,N-dimethylformamide (100 mL). The mixture was cooled to 0 C. <strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (17.0 mL, 111 mmol) was added to the mixture dropwise. The reaction was held at 0 C. for 45 minutes. A solution of N-tert-butoxycarbonyl-4-piperidone (18.5 g, 92.6 mmol) in N,N-dimethylformamide (25 mL) was added to the reaction mixture dropwise. The mixture was held at 0 C. for 1 h and then warmed to room temperature where it was held for 1 h. The reaction was quenched with 1 N hydrochloric acid. The mixture was extracted with diethyl ether (2×). Combined organic layers were washed with water (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in 1:1 ethyl acetate/methanol (60 mL). A catalytic amount of palladium (10% on charcoal) was added to the mixture. The reaction vessel was placed on a Parr apparatus, charged with 55 psi of hydrogen, and shaken at room temperature for 18 h. The reaction mixture was removed from the Parr apparatus and filtered. The filtrate was concentrated in vacuo to give the title compound as lightly colored oil in 94% yield. 1H NMR (300 MHz, CDCl3): delta 4.04 (d, J=10.25, 2H), 3.64 (s, 3H), 2.68 (t, J=14.44, 2H), 2.21 (d, J=6.95, 2H), 1.99-1.80 (m, 1H), 1.64 (d, J=13.54, 2H), 1.41 (s, 9H), 1.25-1.03 (m, 2H).
		Preparation of 2a: tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1- carboxylate Sodium hydroxide (4.56 g, 0.114 mol) was dissolved in alcohol (210 ml), and alcohol solution containing dimethoxy phosphoryl methyl acetate (11.4g, 0.062mol) added with stirring. The mixture was stirred for 30 min at room temperature. 1-(tert-butoxy carboxyl)piperidyl-4-one (11.35g, 0.057mol) was added with stirring at room temperature, and the reaction was allowed to stand overnight. Then, the mixture was acidized with diluted hydrochloric acid until the pH value was 4, filtered, concentrated, dissolved with water and chloroform. The chloroform phase was obtained after layer separation. The water phase was extracted once with chloroform. The chloroform phase was combined, washed once with saturated salt water, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give the title compound.
		Step A: tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine- 1 -carboxylate: A mixture of 60%sodium hydride (1.30 g, 33 mmol) in 145 mL of DMF was cooled to 0C, methyl 2-(dimethoxyphosphoryl)acetate (4.8 mL, 31 mmol) was then added dropwise. After 20 minutes at0C, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25 mmol) in 13 mL of DMFwas added dropwise. The reaction mixture was stirred at r.t. for 3 hours, and then diluted with EtOAc, washed with water; the organic layer was separated and washed with brine, dried over Na2504, filtered and concentrated to afford the title compound. ?H-NMR (400 MHz, CDC13) oe ppm 5.70 (s, 1H), 3.67 (s, 3H), 3.40-3.53 (m, 4H), 2.85-2.95 (t, J= 6.0 Hz, 2H), 2.20-2.30 (t, J=5.2 Hz, 2H), 1.45 (s, 9H).

Reference： [1]Patent: WO2013/166282,2013,A2 .Location in patent: Page/Page column 95
[2]Patent: EP1577302,2005,A1 .Location in patent: Page/Page column 121
[3]Patent: WO2011/123232,2011,A1 .Location in patent: Page/Page column 9
[4]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3157 - 3161
[5]Patent: WO2019/207538,2019,A1 .Location in patent: Page/Page column 73-74
[6]Patent: WO2015/140559,2015,A1 .Location in patent: Page/Page column 41
[7]Patent: WO2016/147011,2016,A1 .Location in patent: Page/Page column 46-47
[8]Patent: US2009/105247,2009,A1 .Location in patent: Page/Page column 12
[9]Patent: US2005/215576,2005,A1 .Location in patent: Page/Page column 49
[10]Patent: EP2045245,2009,A1 .Location in patent: Page/Page column 19
[11]Patent: WO2016/127358,2016,A1 .Location in patent: Page/Page column 54

36
[ 37674-72-9 ]
[ 5927-18-4 ]
6-chloro-3,4-dihydro-2H-1-benzopyran-4-ylidene-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	EXAMPLE 17 In a flame dried flask under nitrogen equipped with a mechanical stirrer, trimethyl phosphonoacetate (10.9 g.) was added dropwise to a slurry of 50% sodium hydride (2.9 g.) in 300 ml. freshly dried tetrahydrofuran and stirred at room temperature for 1 hour. A solution of <strong>[37674-72-9]6-chloro-3,4-dihydro-2H-1-benzopyran-4-one</strong> (10 g.) in 100 ml. of freshly dried tetrahydrofuran was added dropwise, keeping the temperature below 30 C. during the addition. The solution was then heated at reflux for 5 hours and stirred at room temperature for 12 hours. The solution was poured into ice-water, extracted with diethyl ether, washed with water and dried over magnesium suflate. The solution was treated with activated charcoal and evaporated under vacuum to yield a yellow oil (6.3 g.). Chromatography on silica gel (900 ml.) eluted with 1:1 hexane:ethyl acetate yielded 6-chloro-3,4-dihydro-2H-1-benzopyran-4-ylidene-acetic acid methyl ester, (1.6 g., 12%), m.p. 113-115 C.

Reference： [1]Patent: US4210663,1980,A

37
[ 4746-97-8 ]
[ 5927-18-4 ]
[ 172270-85-8 ]

Yield	Reaction Conditions	Operation in experiment
87%		To a DMF (50 mL) solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (26 mL), sodium hydride (purity: 55% or higher, 7.03 g) was added in small portions at 0C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A DMF (50 mL) solution of 1,4-cyclohexanedione monoethylene ketal (25.2 g) was added thereto in small portions at room temperature. This suspension was stirred for 19 hours and diluted with a saturated aqueous solution of ammonium chloride, followed by two extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (29.7 g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta (ppm) = 5.75-5.65 (1H, m), 3.99 (4H, s), 3.70 (3H, s), 3.01 (2H, t, J = 6.7 Hz), 2.39 (2H, t, J = 6.7 Hz), 1.81-1.75 (4H, m);. MS (EI) m/z: 212 (M)+.
87%		(1a) (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester To a DMF (50 mL) solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (26 mL), sodium hydride (purity: 55% or higher, 7.03 g) was added in small portions at 0C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A DMF (50 mL) solution of 1,4-cyclohexanedione monoethylene ketal (25.2 g) was added thereto in small portions at room temperature. This suspension was stirred for 19 hours and diluted with a saturated aqueous solution of ammonium chloride, followed by two extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (29.7 g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta (ppm) = 5.75-5.65 (1H, m), 3.99 (4H, s), 3.70 (3H, s), 3.01 (2H, t, J = 6.7 Hz), 2.39 (2H, t, J = 6.7 Hz), 1.81-1.75 (4H, m) MS (EI) m/z: 212 (M)+.
	With sodium hydride; In tetrahydrofuran; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; at 0 - 20℃; for 12.0833h;	a). To a 0 C. solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (4.8 mL, 34 mmol) in DMPU (12 mL) and THF (30 mL) was added a suspension of NaH (0.74 g, 31 mmol) in THF (45 mL). To the resulting mixture was added a solution 1,4-dioxaspiro[4.5]decane-8-one (4.7 g, 30 mL) in THF (30 mL). After stirring at 0 C. for 5 min the suspension was allowed to reach room temperature and stirred for 12 h. The resulting solution was poured into water (900 mL) and extracted with Et2O (2×200 mL). The combined organics were washed with brine and dried over MgSO4, and organics were removed in vacuo. Silica gel chromatography (gradient of 5 to 7% ethyl acetate in hexanes) afforded the product.

NaH (9.2 g, 384 mmol, 1.5 eq) was suspended in THF (850 ml). This was cooled to C. and trimethylphosphonoacetate (40 ml, 277 mmol, 1.1 eq) was added dropwise keeping T<10 C. Mixture was then recooled to 0 C. and stirred for 15 min. Then compound 1 (40 g, 256 mmol, 1.0 eq) in THF (300 ml) was added dropwise. The reaction mixture was stirred over night allowing it to warm to room temperature. The mixture was poured into water (500 ml) and EtOAc (300 ml) were added, the layers were separated. The aqueous layer was extracted with EtOAc (400 ml). The combined organic layers were dried (Na2SO4) and evaporated. Yield: 51.6 g of methyl 2-(4-(1,3-dioxalane)cyclohexylidene)acetate; 1H NMR (CDCl3, 300 MHz) delta 1.78 (q, 4H), 2.37 (t, 2H), 2.99 (t, 2H), 3.68 (s, 3H), 3.99 (s, 4H), 5.65 (s, 1H)

Reference： [1]Patent: EP2256105,2010,A1 .Location in patent: Page/Page column 25
[2]Patent: EP2471777,2012,A1 .Location in patent: Page/Page column 10
[3]Patent: US2006/293392,2006,A1 .Location in patent: Page/Page column 62-63
[4]Patent: US2009/36425,2009,A1 .Location in patent: Page/Page column 17-18

38
[ 877267-79-3 ]
[ 5927-18-4 ]
[ 877269-51-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2, 1-a][2]benzazepine-10-carboxylate; A stirred suspension of methyl 11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.61 g, 10 mmol), Cs2CO3 (3.91 g, 12 mmol) and trimethyl 2-phosphonoacetate (2.86g, 14 mmol) in an. DMF (40 mL) was heated at 60 C. under nitrogen for 3 h. The resultant yellow suspension was cooled to rt and water was added with vigorous stirring. A yellow precipitate formed which was collected by filtration. The solid was washed with water, and then air dried overnight to afford the title compound as a yellow powder (4.124 g, 96%). LC/MS: m/e 430 (MH+); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.30-1.46 (m, J=14.86 Hz, 2 H) 1.55 (s, 2 H) 1.77 (s, 2 H) 1.85-2.18 (m, 4 H) 2.76-2.89 (m, 1 H) 3.84 (s, 3 H) 3.95 (s, 3 H) 4.19 (s, 1 H) 5.68 (s, 1 H) 7.38-7.63 (m, 4 H) 7.74 (dd, J=8.44, 1.39 Hz, 1 H) 7.81-7.98 (m, 2 H) 8.29 (d, J=1.0l Hz, 1 H).
96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate.; A stirred suspension of methyl 11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.61 g, 10 mmol), Cs2CO3 (3.91 g, 12 mmol) and trimethyl 2-phosphonoacetate (2.86 g, 14 mmol) in an. DMF (40 mL) was heated at 60 C. under nitrogen for 3 h. The resultant yellow suspension was cooled to rt and water was added with vigorous stirring. A yellow precipitate formed which was collected by filtration. The filtrand was washed with water, and then air dried overnight to afford the title compound as a yellow powder (4.124 g, 96%). LC/MS: m/e 430 (MH+); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.30-1.46 (m, J=14.86 Hz, 2H) 1.55 (s, 2H) 1.77 (s, 2H) 1.85-2.18 (m, 4H) 2.76-2.89 (m, 1H) 3.84 (s, 3H) 3.95 (s, 3H) 4.19 (s, 1H) 5.68 (s, 1H) 7.38-7.63 (m, 4H) 7.74 (dd, J=8.44, 1.39 Hz, 1H) 7.81-7.98 (m, 2H) 8.29 (d, J=1.01 Hz, 1H).
96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Methyl 13-cyclohexyl-6-(methoxycarbonyl)- 7H-indolo[2, 1-a] [2]benzazepine- 10-carboxylate (5; Ri = Rs - Me, R2 = H). A stirred suspension of methyl 11- cyclohexyl-6-hydroxy-6H-isoindolo[2,l-a]indole-3-carboxylate (3.61 g, lOrnmol), Cs2CO3 (3.91 g, 12 mrnol) and trimethyl 2-phosphonoacetate (2.86g, 14 mmol) in an. DMF (40 mL) was heated at 60 0C under nitrogen for 3 h. Resultant yellow suspension was cooled to rt and water was added with vigorous stirring. The yellow precipitate was filtered off , washed with water and then air dried overnight to afford the designated compound (4.124g, 96%). LC/MS: m/e 430 (MH+); IH NMR (400 MHz, CHLOROFORM-D) 6 ppm 1.30 - 1.46 (m, J=14.86 Hz, 2 H) 1.55 (s, 2 H) 1.77 (s, 2 H) 1.85 - 2.18 (m, 4 H) 2.76 - 2.89 (m, 1 H) 3.84 (s, 3 H) 3.95 (s, 3 H) 4.19 (s, 1 H) 5.68 (s, 1 H) 7.38 - 7.63 (m, 4 H) 7.74 (dd, J=8.44, 1.39 Hz, 1 H) 7.81 - 7.98 (m, 2 H) 8.29 (d, J=LOl Hz, I H).

96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate.; A stirred suspension of methyl 11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.61 g, 10 mmol), Cs2CO3 (3.91 g, 12 mmol) and trimethyl 2-phosphonoacetate (2.86 g, 14 mmol) in an. DMF (40 mL) was heated at 60 C. under nitrogen for 3 h. The resultant yellow suspension was cooled to rt and water was added with vigorous stirring. A yellow precipitate formed which was collected by filtration. The solid was washed with water, and then air dried overnight to afford the title compound as a yellow powder (4.124 g, 96%). LC/MS: m/e 430 (MH+); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.30-1.46 (m, J=14.86 Hz, 2 H) 1.55 (s, 2 H) 1.77 (s, 2 H) 1.85-2.18 (m, 4 H) 2.76-2.89 (m, 1 H) 3.84 (s, 3 H) 3.95 (s, 3 H) 4.19 (s, 1 H) 5.68 (s, 1 H) 7.38-7.63 (m, 4 H) 7.74 (dd, J=8.44, 1.39 Hz, 1 H) 7.81-7.98 (m, 2 H) 8.29 (d, J=1.01 Hz, 1 H).
96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Intermediate 23 Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate. A stirred suspension of methyl 11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.61 g, 10 mmol), Cs2CO3 (3.91 g, 12 mmol) and trimethyl 2-phosphonoacetate (2.86 g, 14 mmol) in an. DMF (40 mL) was heated at 60 C. under nitrogen for 3 h. The resultant yellow suspension was cooled to rt and water was added with vigorous stirring. A yellow precipitate formed which was collected by filtration. The solid was washed with water, and then air dried overnight to afford the title compound as a yellow powder (4.124 g, 96%). LC/MS: m/e 430 (MH+); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.30-1.46 (m, J=14.86 Hz, 2H) 1.55 (s, 2H) 1.77 (s, 2H) 1.85-2.18 (m, 4H) 2.76-2.89 (m, 1 H) 3.84 (s, 3H) 3.95 (s, 3H) 4.19 (s, 1H) 5.68 (s, 1H) 7.38-7.63 (m, 4H) 7.74 (dd, J=8.44, 1.39 Hz, 1H) 7.81-7.98 (m, 2H) 8.29 (d, J=11.1 Hz, 1H).

Reference： [1]Patent: US2007/78122,2007,A1 .Location in patent: Page/Page column 176
[2]Patent: US2007/60565,2007,A1 .Location in patent: Page/Page column 72
[3]Patent: WO2007/92000,2007,A1 .Location in patent: Page/Page column 143
[4]Patent: US2008/188458,2008,A1 .Location in patent: Page/Page column 34
[5]Patent: US2008/171015,2008,A1 .Location in patent: Page/Page column 25

39
[ 71690-05-6 ]
[ 5927-18-4 ]
[ 955029-08-0 ]

Yield	Reaction Conditions	Operation in experiment
		2) To a solution of methyl (dimethoxyphosphoryl) acetate (3.4mL) in toluene (103mL) was added portionwise 60% NaH (0.96g) at 20 to 300C under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise above Solution A at 0 to 100C and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into a mixture of AcOEt and water and adjusted to pH 2 with IN- HCl aq. The separated organic layer was washed with saturated sodium hydrogen carbonate aq., dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give methyl (2E) -3- (5, 6-dichloropyridin-3-yl) acrylate (2.83g).

Reference： [1]Patent: WO2008/75757,2008,A1 .Location in patent: Page/Page column 36

40
[ 879016-22-5 ]
[ 5927-18-4 ]
[ 942316-72-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		Methyl 2-(dimethoxyphosphoryl)acetate (1.402 ml,9.72 mmol) was added dropwise to a stirred, 0 C. suspension of sodium hydride (0.359 g, 8.97 mmol) in TRF (60 mE). The reaction mixture was allowed to warm up to room temperature and the stirred for 1 hour. A solution of 5-chloro-2-(1R- tetrazol-1-yl)benzaldehyde (1.56 g, 7.48 mmol) in TRF (10 mE) was then added. The mixture was stirred vigorously for 30 minutes. The mixture was poured into a cold saturated NR4C1 solution. The resulting mixture was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate. The solid was collected and dried in vacuo to give 1.78 g (90%) of (E)-methyl 3-(5-chioro-2- (1 R-tetrazol-1 -yl)phenyl)acrylate as an off white solid.
57%		ID. (E)-3-(5-chloro-2-tetrazol-l-yl-phenyl)-acrylic acid methyl ester: To a cooled (0 C) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to room temperature and stirred at room temperature for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2- tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid (1.76 g). The solid was redissolved in EtOAc and filtered through a plug of silica gel and eluted with EtOAc. The filtrate was concentrated to give a greenish solid (1.36 g). Recrystallization from EtOAc gave an off-white solid (0.476 g). Additional product was obtained by concentrating the filtrate, adding methanol, sonicating, and collecting the resulting solid by filtration. A total of 0.829 g (57%) of ID was obtained. LCMS m/z 265.1 (M+H)+; 287.2(M+Na)+. 1HNMR (500 MHz, CDCl3) delta: 8.80 (s, IH), 7.78 (d, J= 2.2 Hz, IH), 7.58(dd, J= 8.8, 2.2 Hz, IH), 7.42 (d, J= 8.2 Hz, IH), 7.25 (d, J= 16.0 Hz, IH), 6.45 (d,J= 16.0 Hz, IH), 3.78 (s, 3H).
57%		To a cooled(0 0C) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to rt and stirred at rt for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2-tetrazol-l-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid weighing 1.76 g. The solid was dissolved in EtOAc and filtered through a plug of silica gel, eluting with EtOAc. The green filtrate was concentrated to give a greenish solid weighing 1.36 g. Recrystallization from EtOAc gave an off- white solid weighing 0.476 g. Additional product was obtained by concentrating the filtrate from recrystallization, adding methanol, sonicating, and collecting the solid product by filtration. A total of 0.829 g (57%) of (E)-3-(5-chloro-2-tetrazol-l-yl- phenyl)-acrylic acid methyl ester was obtained. LCMS m/z 265.1 (M+H)+; 287.2 (M+Na)+. 1H NMR (CDCl3, 500 MHz) delta: 8.80 (s, IH), 7.78 (d, J= 2.2 Hz, IH), 7.58 (dd, J= 8.8, 2.2 Hz, IH), 7.42 (d, J= 8.2 Hz, IH), 7.25 (d, J= 16.0 Hz, IH), 6.45 (d, J= 16.0 Hz, IH), 3.78 (s, 3H). To a white suspension of this ester (0.140 g, 0.529 mmol) in MeOH (3.0 mL) was added 1.0 M sodium hydroxide (1.587 ml, 1.587 <n="105"/>mmol). The resulting suspension was stirred vigorously at rt for 2.5 h. The yellow suspension was neutralized with 1.0 N HCl (1.60 mL), and concentrated to give a beige solid. The solid was partitioned between 1.0 N HCl and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 0.137 g (100%) of (E)-3-(5-chloro-2-tetrazol-l-yl- phenyl)-acrylic acid as a white solid. LCMS m/z 251.1 (M+H)+. 1H NMR (SOO MHz, DMSO-d6) delta: 12.72 (s, IH), 9.87 (s, IH), 8.24 (d, J= 2.2 Hz, IH), 7.77 (dd, J= 8.8, 2.2 Hz, IH), 7.73 (d, J= 8.2 Hz, IH), 6.98 (d, J= 16.0 Hz, IH), 6.70 (d, J= 16.0 Hz, IH).

57%		1D. (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid methyl ester To a cooled (0 C.) suspension of NaH. (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to room temperature and stirred at room temperature for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2-tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid (1.76 g). The solid was redissolved in EtOAc and filtered through a plug of silica gel and eluted with EtOAc. The filtrate was concentrated to give a greenish solid (1.36 g). Recrystallization from EtOAc gave an off-white solid (0.476 g). Additional product was obtained by concentrating the filtrate, adding methanol, sonicating, and collecting the resulting solid by filtration. A total of 0.829 g (57%) of ID was obtained. LCMS m/z 265.1 (M+H)+; 287.2 (M+Na)+. 1H-NMR (500 MHz, CDCl3) delta: 8.80 (s, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.58 (dd, J=8.8, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.25 (d, J=16.0 Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 3.78 (s, 3H).
57%		To a cooled (0 C) suspension of NaH (0.262 g, 6.56 mmol) inTHF (27.3 mL) was added drop wise methyl 2-(dimethoxyphosphoryl)acetate (1.15 mL, 7.10 mmol). The resulting thick, white suspensionwas diluted with additional THF (15 mL) to facilitatemixing, and then the reaction was allowed to warm to rt. After45 min, a slightly cloudy blue solution of 5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)benzaldehyde39 (1.14 g, 5.46 mmol) in THF (8 mL)was added. The yellow-green suspension was stirred vigorously.After 30 min, the reaction was poured into cold sat. NH4Cl andextracted with EtOAc. The organic layers were combined andwashed with brine, dried over Na2SO4, filtered and concentratedto give a green-blue solid (1.76 g). The solid was dissolved inEtOAc and filtered through a plug of silica gel and eluted withEtOAc. The filtrate was concentrated to give a greenish solid(1.36 g). Recrystallization from EtOAc gave an off-white solid(0.476 g). Additional product was obtained by concentrating thefiltrate, adding methanol, sonicating, and collecting the resultingsolid by filtration. A total of 0.829 g (57% yield) of methyl (2E)-3-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enoate wasobtained. LCMS: 265.1 (M+H)+; 287.2 (M+Na)+. 1H NMR(500 MHz, CDCl3) d: 8.80 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.58 (dd,J = 8.8, 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 16.0 Hz,1H), 6.45 (d, J = 16.0 Hz, 1H), 3.78 (s, 3H)
57%		Intermediate 1; (E)-2,5-Dioxopyrrolidin- 1 -yl 3-(5-chloro-2-(l H-tetrazol-1 -yi)phenyl)acrylate; [00261] Intermediate IA. (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid methyl ester: To a cooled (0 C) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing. The reaction was allowed to warm to rt and stir for 45 min. Next, a solution of 5-cliloro-2-tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem. 2006, 49:1346), in THF (8 mL) was added. The resulting suspension was stirred vigorously. After 30 min, the reaction was poured into cold saturated ammonium chloride and extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated to give a green/blue solid weighing 1.76 g. The solid was dissolved in EtOAc and filtered through a plug of silica gel, eluting with EtOAc. The green filtrate was concentrated to give a greenish solid weighing 1.36 g. Recrystallization from EtOAc gave an off- white solid weighing 0.476 g. Additional product was obtained by concentrating the filtrate from the recrystallization, adding methanol, sonicating, and collecting the solid by filtration. A total of 0.829 g (57%) of Intermediate IA was obtained. 1H NMR(500 MHz, CDCl3) delta: 8.80 (s, 1H), 7.78 (d, J= 2.2 Hz, 1H)5 7.58 (dd, J= 8.8, 2.2 Hz, 1H), 7.42 (d, J= 8.2 Hz, 1H), 7.25 (d, J= 16.0 Hz, 1H), 6.45 (d, J= 16.0 Hz, 1H), 3.78 (s, 3H). MS m/z: 265.1 (M+H)+ and 287.2 (M+Na)+.
		Step 4: (E)-methyl 3-(5-chloro-2-(lH-tetrazol-l-yl)phenyl)acrylate. Methyl 2- (dimethoxyphosphoryl)acetate (1.402 ml, 9.72 mmol) was added dropwise to a stirred, 0 C suspension of sodium hydride (0.359 g, 8.97 mmol) in THF (60 mL). The reaction mixture was allowed to warm up to room temperature and the stirred for 1 hour. A solution of 5-chloro-2-(lH- tetrazol-l-yl)benzaldehyde (1.56 g, 7.48 mmol) in THF (10 mL) was then added. The mixture was stirred vigorously for 30 minutes. The mixture was poured into a cold saturated NH4C1 solution. The resulting mixture was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over MgS04, filtered and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate. The solid was collected and dried in vacuo to give (E)-methyl 3-(5-chloro-2-(lH-tetrazol-l -yl)phenyl)acrylate as an off white solid.

Reference： [1]Patent: US2016/229839,2016,A1 .Location in patent: Paragraph 0296
[2]Patent: WO2008/76805,2008,A2 .Location in patent: Page/Page column 118
[3]Patent: WO2008/157162,2008,A1 .Location in patent: Page/Page column 102-103
[4]Patent: US2010/16316,2010,A1 .Location in patent: Page/Page column 60
[5]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 2257 - 2272
[6]Journal of Medicinal Chemistry,2017,vol. 60,p. 9703 - 9723
[7]Patent: WO2009/114677,2009,A1 .Location in patent: Page/Page column 108
[8]Patent: WO2015/54087,2015,A1 .Location in patent: Page/Page column 67

41
[ 5927-18-4 ]
[ 105640-07-1 ]
[ 701232-66-8 ]

Yield	Reaction Conditions	Operation in experiment
97%		60% suspension mixed with NaH mineral oil (7.6 g, 0.19 mol) was added to <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (22.8 mL, 0.15 mol) solution dissolved in anhydrous tetrahydrofuran (655mL) under 0 ? nitrogen gas. 4-(4-hydroxyphenyl)cyclohexanone (25 g, 0.13 mol) solution dissolved in tetrahydrofuran (525 mL) was slowly added thereto at 25?. Then, the reaction mixture was stirred at room temperature for 5 hours, cooled with water, and extracted with ethyl acetate. The mixed organic phase was washed with brine and dried with Na2SO4. The solvent was reduced under reduced pressure to obtain [4-(4-hydroxyphenyl)cyclohexylidene]acetic acid methyl ester as a white solid (31.3 g, 97 %). 1H NMR (300 MHz, DMSO-d6) : delta 9. 14 (s, 1H), 7.00 (d, J = 8 Hz, 2H), 6.65 (d, J = 7.8 Hz), 5.69 (s, 1H), 3.86-3.76 (m, 1H), 3.60 (s, 3H), 2.76- 2.63 (m, 1H), 2.42- 2.24 (m, 2H), 2.07 -1.86 (m, 3 H), 1.57 -1.33 (m, 2H).
94%		a) Methyl 2-r4-(4-hvdroxyphenyl)cvclohexylidenelacetate; <strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (170 mL, 1.05 mol) was added dropwise to a stirred suspension of sodium hydride (60 % in mineral oil, 27.5 g, 1.14 mol) in THF (3.5 L) cooled to 12C. After completion of addition, the reaction mixture was allowed to warm to ambient temperature and stirred for I h. In a separate vessel, N,N-tetramethyl guanidine (144 mL, 1.14 mol) was added to a suspension of 4-(4-hydroxyphenyl)cyclohexan-l-one (235 g, 0.95 mol) in THF (1.2 L) and the reaction mixture was stirred for 1 h at ambient temperature. The phosphonoacetate mixture was cooled to 100C and the guanidine solution added slowly, controlling the temperature between 8 and 120C until no residual exotherm was observed. The temperature was allowed to rise to ambient temperature and the reaction mixture was stirred for 16 h. The mixture was partitioned between a dilute aqueous solution of ammonium chloride (2.4 L) and ethyl acetate (2.4 L). The aqueous phase was separated and extracted with ethyl acetate (1.2 L). The organic phases were combined and washed with brine (2.4 L), dried (MgSO4) and concentrated in vacuo to leave an off- white solid. The solid was slurried in a mixture of ether and hexane (2:1; 470 <n="35"/>mL), filtered and washed with a mixture of ether and isohexane (2:1; 240 mL) to give the product as a white solid (285 g, 94%). 1R NMR delta 1.35 - 1.55 (2H, m), 1.85 - 2.05 (4H, m), 2.25-2.40 (2H, m), 2.65 - 2.75 (IH, m), 3.60 (3H, s), 3.80 (IH, m), 6.66 (2H, d), 6.99 (2H, d), 9.10 (IH, s)
	With sodium hydride; In tetrahydrofuran; mineral oil; at 4 - 20℃; for 18h;Inert atmosphere;	5.1 Synthesis of methyl r4-(4-hydroxyphenyl)cvclohexylidenelacetate 1.69 g of 4-(4-hydroxyphenyl)cyclohexanone (77.22 mmol, 1 eq.) are placed in 100 mL of THF in a 250 mL round-bottomed flask under nitrogen. The solution is cooled to 4C on an ice bath and 3 g of 60% sodium hydride (75.04 mmol, 0.97 eq.) are added portionwise. 16.88 g of methyl dimethylphosphoacetate (92.67 mmol, 1.2 eq.) are placed in 100 mL of THF in another 500 mL round-bottomed flask under nitrogen. This second solution is cooled on an ice bath and 4.41 g of 60% sodium hydride (1 10.30 mmol, 1 .42 eq.) are added portionwise. The ice baths are removed and the media are stirred at room temperature for 30 minutes. The 4-(4-hydroxy- phenyl)cyclohexanone solution is added to the methyl dimethylphosphoacetate solution. The reaction medium is stirred for 18 h. 100 mL of a saturated aqueous ammonium chloride solution is added and the reaction medium is extracted three times with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated to give 17.16 g of methyl [4-(4-hydroxyphenyl)cyclo- hexylidene]acetate.M+H+ = 247.

		Step A: methyl [4~( -hvdroxyphenyl)cyclohexylidene]acetate. A 2 L 4-neck round- bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of sodium hydride (60% in mineral oil, 42.5 g, 1.1 mol, 1.0 equiv) in tetrahydrofuran (500 mL). This was followed by the addition of a solution of 4-(4-hydroxyphenyl)cyclohexanone (200 g, 1.05 mol, LOO equiv) in tetrahydrofuran (1000 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. The resulting solution was assigned as solution A. Into a 5 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (63 g, 1.7 equiv, 60%) in tetrahydrofuran (1000 mL). This was followed by the addition of a solution of methyl 2- (dimethoxyphosphoryl)acetate (229.7 g 1.2 equiv) in tetrahydrofuran (1500 mL) dropwise with stirring at 0C. The resulting solution was stirred for 2 h at room temperature. To this reaction mixture was added solution A dropwise with stirring. The resulting solution was stirred for 1 h at room temperature, then quenched by the addition of water/ice. The resulting solution was extracted with 3 500 mL of ethyl acetate. The combined organic layers were washed with brine (1 L), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by recrystallization from ether to afford the title compound as a white solid.
		Methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate. Sodium hydride (60% suspension in mineral oil, 1.2 g, 30 mmol) was added to a solution of 4-(4- hydroxyphenyl)cyclohexanone (5.7 g, 30 mmol) in anhydrous THF (100 mL) at 0 C under a nitrogen atmosphere. In a separate flask, <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (5.83 mL, 36 mmol) was added to a suspension of sodium hydride (1.8 g, 45 mmol) in anhydrous THF (100 mL) at 0 C under a nitrogen atmosphere. After 30 min., the two mixtures were allowed to warm to rt and were stirred for 30 min. The solution containing the ketone was added to the phosphonate solution via cannula. The reaction mixture was stirred overnight at rt. Water (150 mL) was added, the organic layer was separated, and aqueous phase was extracted with EtOAc (2 x 120 mL). The combined organic layers were washed with brine, dried (MgS04), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (10-20% EtOAc/Hexanes) yielded the title compound as a white solid. :H NMR (DMSO-d6) delta 9.12 (s, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 5.70 (s, 1H), 3.82 (m, 1H), 3.61 (s, 3H), 2.70 (m, 1H), 2.33 (m, 2H), 2.03 (m, 1H), 1.92 (m, 2H), 1.48 (m,2H); (M+l 247.2).
		A 2 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of sodium hydride (60% in mineral oil, 42.5 g, 1.1 mol, 1.0 equiv) in tetrahydrofuran (500 mL). This was followed by the addition of a solution of 4-(4-hydroxyphenyl)cyclohexanone (200 g, 1.05 mol, 1.00 equiv) in tetrahydrofuran (1000 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. The resulting solution was assigned as solution A. Into a 5 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (63 g, 1.7 equiv, 60%) in tetrahydrofuran (1000 mL). This mixture was treated with a solution of methyl 2-(dimethoxyphosphoryl)acetate (229.7 g 1.2 equiv) in tetrahydrofuran (1500 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. To this reaction mixture was added solution A dropwise with stirring. The resulting solution was stirred for 1 h at room temperature then quenched by the addition of water/ice. The resulting solution was extracted with 3x500 mL of ethyl acetate. The combined organic layers were washed with brine (1 L), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by recrystallization from ether to afford the title compound as a white solid.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10610 - 10629
[2]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 544 - 549
[3]Patent: EP2842938,2015,A1 .Location in patent: Paragraph 0056-0058
[4]Patent: WO2008/129319,2008,A1 .Location in patent: Page/Page column 33-34
[5]Patent: WO2012/11081,2012,A1 .Location in patent: Page/Page column 29-30
[6]Patent: WO2012/122075,2012,A1 .Location in patent: Page/Page column 33
[7]Patent: WO2012/138648,2012,A1 .Location in patent: Page/Page column 75
[8]Patent: WO2013/68439,2013,A1 .Location in patent: Page/Page column 34-35
[9]Journal of labelled compounds and radiopharmaceuticals,2014,vol. 57,p. 670 - 673

42
[ 5927-18-4 ]
[ 17429-02-6 ]
[ 1108195-95-4 ]

Yield	Reaction Conditions	Operation in experiment
69%		(4-Methoxy-4 methyl-cyclohexylidene)-acetic acid methyl ester A mixture of trimethyl phosphonoacetate (9.11 mL, 56 mmol) and (40 mL, 64 mmol) of n-BuLi (1.6N) in DME (60 mL) is stirred for 10 minutes at 0 C. <strong>[17429-02-6]4-Hydroxy-4-methyl-cyclohexanon</strong>e (8 g, 56 mmol) was added and the mixture stirred 2.5 hours at 0 C. until TCL indicated complexion of the reaction. Product was obtained after extraction with dichloromethane (7.71 g, 69%).

Reference： [1]Patent: US2009/29977,2009,A1 .Location in patent: Page/Page column 44

43
[ 67-56-1 ]
[ 354-32-5 ]
[ 5927-18-4 ]
[ 109-92-2 ]
[ 50650-59-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 6 Preparation of Mixture of Condensation Products To a 50 milliliter (mL) three neck round bottom flask equipped with a dry-ice acetone condenser was charged with 5.72 g (0.08 mol) of ethyl vinyl ether and the mixture was cooled in an ice-water bath. To this cooled reaction mixture was added 12.2 g (0.09 mol) of trifluoroacetyl chloride (bubbled via sub-surface). After completing addition of the acid chloride, the reaction mixture was allowed to warm to ambient temperature and allowed to stir an additional 30 min. This mixture was then con-added over a 24 min period to an ice-water bath cooled 100 mL (milliliter) round bottom flask charged with 35 mL of methanol. The cold bath was removed and the solution allowed to stir an additional 1 h. The solution was allowed to stand overnight. The reaction mixture was then cooled in an ice-water bath, and to this mixture was slowly added 9.68 g (0.05 mol) of a 30% sodium methoxide in methanol solution. To this mixture was added 14.6 g (0.08 mol) of trimethylphosphonoacetate (TMPA) in one portion. To this mixture was then added 14.41 g (0.08 mol) of 30% sodium methoxide in methanol via addition funnel over a 9 min period. The cold bath was removed and the solution allowed to warm to ambient temperature and stirred an additional 1 h. The reaction mixture was concentrated on a rotovap at 30 C. until a slurry was observed. The residue was partitioned between 30 mL of hexanes and 20 mL of water. The bottom aqueous layer was extracted with 20 mL of hexanes. The combined hexane layers were concentrated on a rotovap at 30 C. to give 9.71 g of condensation products. No further purification was done on this mixture. GC/EIMS analysis indicated the presence of six peaks consisting of olefin products (A:B:C:D:E:F) in a relative ratio of (31:42:5:2:12:6). For olefin A: (relative intensity) m/z. 241 (0.20), 211 (15), 179 (70), 75 (100), 59 (5). For olefin B: (relative intensity) m/z 241 (1), 211 (100), 194 (11), 179 (51), 169 (35), 152 (11), 137 (15), 75 (24), 59 (54). For olefin C: (relative intensity) m/z 255 (0.03), 241 (0.30), 225 (7), 211 (13), 193 (2), 179 (53), 165 (31), 137 (8), 89 (57), 61 (100). For olefin D: (relative intensity) m/z 241 (0.80), 222 (4), 211 (100), 194 (8), 179 (40), 169 (30), 152 (12), 137 (17), 75 (46), 59 (72). For olefin E: (relative intensity) m/z 256 (0.5), 236 (4), 225 (49), 211 (72), 179 (65), 165 (93), 137 (24), 89 (19), 75 (100), 59 (42). For olefin F: (relative intensity) m/z 255 (1), 236 (6), 225 (88), 211 (43), 179 (29), 165 (100), 152 (20), 137 (33), 75 (87), 59 (35).; Example 8 Cyclization to 4-trifluoromethyl-2(1H)-pyridinone) To a 100 mL three-neck round bottom flask equipped with a Dean-Stark trap, thermocouple, nitrogen sweep, and addition funnel was charged 13.4 g (0.173 mol) of ammonium acetate and 14 g (0.312 mol) of formamide. To the addition funnel was charged the mixture of condensation products (Example 7). The reaction mixture was heated to about 140 C. The condensation products were con-added through the addition funnel at a rate so that the internal reaction temperature did not drop below 130 C. The addition took 13 min to complete. The internal solution temperature was heated to 150-160 C. and then distillate was allowed to collect in the Dean-Stark trap. Two layers were observed in the trap, and the bottom layer was added back into the reaction pot. The distillation was allowed to proceed about 3 h 15 min until no more of the starting mixture of condensation products were present. The reaction vessel was cooled to 90 C. and then 20 mL of water was added to the mixture followed by 20 mL of a 10% aqueous brine. The reaction mixture was then cooled in an ice-water bath for 1 h at which time a precipitate formed. The slurry was suction filtered and the filter cake was washed with 15 mL of fresh water. The cake was air-dried in a hood overnight to afford 10.8 g (66% yield [based on starting ethyl vinyl ether molarity] and 97% purity by LC assay) of 4-trifluoromethyl-2(1H)-pyridinone as a light brown solid. mp (uncorrected) 151-157 C. (literature reported value 156-160 C.). 1H NMR (CDCl3, 300 MHz) delta 6.46 (dd, J=6, 3 Hz) 1H), 6.86 (bs, 1H), 7.52 (d, J=6 Hz), 1H), 13.5 (bs, 1H).

Reference： [1]Patent: US2009/5569,2009,A1 .Location in patent: Page/Page column 6-7

44
[ 5927-18-4 ]
[ 1095142-51-0 ]
[ 1095142-53-2 ]
[ 1095142-55-4 ]
[ 50650-59-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 7 Preparation of Mixture of Condensation Products; The acetal/methanolic mixture (Example 5) was chilled using an ice-water bath. To this mixture was con-added 21.1 g (0.12 mol) of 30% sodium methoxide in methanol via addition funnel. The addition rate was maintained to keep the internal reaction temperature below 20 C. After completing base addition, the solution pH was basic as measured by pH paper. To the reaction mixture was added 21.8 g (0.120 mol) of trimethylphosphonoacetate (TMPA) via syringe in one portion. The reaction mixture was allowed to cool down to about 2 C. using ice-water bath cooling and then 21.6 g (0.12 mol) of 30% sodium methoxide in methanol was con-added via addition funnel over 15 min. The internal reaction temperature rose from 2 C. to 8 C. during the base addition. The cold bath was removed and the solution was allowed to warm to ambient temperature with stirring for 2.5 h. The reaction mixture was concentrated on a rotovap and the residue was partitioned between 50 mL hexanes and 50 mL of water. The aqueous layer was separated and extracted with 30 mL of additional hexanes. The combined hexanes layers were then concentrated on a rotovap to give 22.72 g of a mixture of condensation products. This mixture was taken onto the next reaction step without further purification. GC analysis of this mixture of condensation products was similar to that reported for Example 6.Example 8 Cyclization to 4-trifluoromethyl-2(1H)-pyridinone) To a 100 mL three-neck round bottom flask equipped with a Dean-Stark trap, thermocouple, nitrogen sweep, and addition funnel was charged 13.4 g (0.173 mol) of ammonium acetate and 14 g (0.312 mol) of formamide. To the addition funnel was charged the mixture of condensation products (Example 7). The reaction mixture was heated to about 140 C. The condensation products were con-added through the addition funnel at a rate so that the internal reaction temperature did not drop below 130 C. The addition took 13 min to complete. The internal solution temperature was heated to 150-160 C. and then distillate was allowed to collect in the Dean-Stark trap. Two layers were observed in the trap, and the bottom layer was added back into the reaction pot. The distillation was allowed to proceed about 3 h 15 min until no more of the starting mixture of condensation products were present. The reaction vessel was cooled to 90 C. and then 20 mL of water was added to the mixture followed by 20 mL of a 10% aqueous brine. The reaction mixture was then cooled in an ice-water bath for 1 h at which time a precipitate formed. The slurry was suction filtered and the filter cake was washed with 15 mL of fresh water. The cake was air-dried in a hood overnight to afford 10.8 g (66% yield [based on starting ethyl vinyl ether molarity] and 97% purity by LC assay) of 4-trifluoromethyl-2(1H)-pyridinone as a light brown solid. mp (uncorrected) 151-157 C. (literature reported value 156-160 C.). 1H NMR (CDCl3, 300 MHz) delta 6.46 (dd, J=6, 3 Hz) 1H), 6.86 (bs, 1H), 7.52 (d, J=6 Hz), 1H), 13.5 (bs, 1H).

Reference： [1]Patent: US2009/5569,2009,A1 .Location in patent: Page/Page column 7

45
[ 5927-18-4 ]
[ 845823-12-3 ]
(E)-3-(3,5-difluoro-phenyl)-4,4,4-trifluoro-but-2-enoic acid methyl ester [ No CAS ]
(Z)-3-(3,5-difluoro-phenyl)-4,4,4-trifluoro-but-2-enoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1,3,3-tetramethylguanidine; In dichloromethane; at 0 - 20℃; for 22h;	1-(3,5-Difluorophenyl)-2,2,2-trifluoroethanone (1.0 g, 4.8 mmol) was added to CH2Cl2 (5 mL). Trimethylphosphonoacetate (0.87 g, 4.8 mmol) was added and the mixture was cooled to 0 C. Tetramethylguanidine (0.72 mL, 5.7 mmol) was added dropwise by syringe. The mixture was allowed to attain room temperature slowly and was stirred 22 hours. The reaction mixture was poured into a separatory funnel containing CH2Cl2 (40 mL). The organic phase was washed with distilled water (3*), brine, and then dried over Na2SO4. The solution was filtered and the solvents concentrated to a crude oil, which was flash chromatographed using CH2Cl2 as eluent. This gave the desired product as a yellow oil (1.13 g, 89%; mixture of E/Z isomers).

Reference： [1]Patent: US2009/23801,2009,A1 .Location in patent: Page/Page column 25

46
[ 5927-18-4 ]
[ 386704-12-7 ]
[ 1119807-17-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 24h;	26A. (E)-Methyl 3-(6-(trifluoromethyl)pyridin-3-yl)acrylate To a stirring solution of trimethyl phosphonoacetate (0.510 mL, 3.14 mmol) in THF (15 mL) at 0 C. was added NaH (88.0 mg, 3.3 mmol). After stirring for ca. 20 min, the slurry was allowed to warm to ambient temperature for 10 min, then cooled again to 0 C. To this was added dropwise 6-(trifluoro-methyl)nicotinaldehyde (500 mg, 2.86 mmol), which is commercially available from Oakwood Products, Inc. (1741 Old Dunbar Rd., West Columbia, S.C. 29172), in THF (5 mL) over 2 min. The bath was allowed to expire and the reaction stirred at ambient temperature for ca. 24 h. The reaction was quenched with H2O (50 mL) then diluted with EtOAc (100 mL). The phases were separated and the organics further washed with H2O (2×20 mL), brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 670 mg 26A in ca. 85% purity as a white solid (86% yield). This was taken forward without further purification. m/z (ES+) M+1=232. 1; HPLC tR=1.07 min. 1H NMR (500 MHz, CDCl3) delta 8.84 (dd, J=2.1, 0.6 Hz, 1H), 7.99 (dt, J=8.2, 1.2 Hz, 1H), 7.77-7.65 (m, 2H), 6.59 (d, J=16.2 Hz, 1H), 3.85 (s, 3H).

Reference： [1]Patent: US2009/76020,2009,A1 .Location in patent: Page/Page column 41

47
[ 5927-18-4 ]
[ 865-47-4 ]
[ 62327-21-3 ]

Yield	Reaction Conditions	Operation in experiment
	In 2-MeTHF; at 5 - 20℃;	Intermediate 64-8: Methyl 2-fn r.4rWU4-f4A5.5-tetramethyl-T .3.2-rtioxahorolan-2- vDnhenylkvclohexyDacetateTrimethylphosphonoacetate (1.05X-1.06X) was added dropwise to a suspended solution of t-BuOK (0.70X-0.71X) in 2-MeTHF (10 vol) at 5-1O0C. The resulting solution was stirred at 15-2O0C for 3.5-4.0 hours. The reaction mixture was cooled to 5-1O0C and DIPEA (0.81-0.82X) was added to the reaction at 10-150C. 4-(4-Hydroxyphenyl)cyclohexanone (1.0 X) was added in portions to the above reaction mixture at 10-150C and the resulting solution was stirred at 15-2O0C for 3-6 hours and then sampled for HPLC analysis. NH4C1- sol (5.0X-6.0X) was added to the reaction mixture at 0-150C, and the reaction was quenched. The organic layer was separated and the aqueous layer was extracted with 2- MeTHF (2.5X-3.0X). The two organic extracts were combined and washed with NaHSO3 aq. and then NaCl-solution (2.5X-3.0X) twice. The organic layer was concentrated to 2~3 vol and n-heptane was added to give a suspended solution, and the above mixture was <n="163"/>concentrated to below 3percent of 2-MeTHF residue to give a suspended solution. The mixture was cooled to 0-5 0C, stirred for 1.0-2.0 h, filtered and the cake washed with n-heptane (2 vol X2). Dry in vacuum at below 450C to give the desired phenoxyacrylate product.

Reference： [1]Patent: WO2009/81195,2009,A1 .Location in patent: Page/Page column 29; 161-162

48
[ 111-71-7 ]
[ 5927-18-4 ]
[ 111-79-5 ]

Reference： [1]European Journal of Organic Chemistry,2009,p. 554 - 563

49
[ 5927-18-4 ]
[ 14615-72-6 ]
[ 64793-98-2 ]

Reference： [1]Chemistry - A European Journal,2009,vol. 15,p. 2278 - 2288

50
[ 5927-18-4 ]
[ 22515-18-0 ]
[ 1189770-25-9 ]

Yield	Reaction Conditions	Operation in experiment
95%		400 mg (10.0 mmol) sodium hydride (60 % in mineral oil) was suspended in 10 ml THF and cooled to 4C. While being stirred, a solution of 1.3 ml (8.99 mmol) trimethylphosphono acetate in 10 ml THF was added. The mixture was stirred for 1 h at the same temperature. After this, a solution of 4,4-difluorocyclohexanone in 10 ml THF was added at 00C. The mixture was allowed to warm to room temperature and stirred for 14 h. THF and water was added and the THF evaporated. The remainder was diluted with ethyl acetate, washed with water and saturated sodium hydrogen carbonate solution and evaporated to yield 1.49 g (95 %) of the product. <n="152"/>MS (El): m/z = 190 (M)
57%		To a stirred suspension of 60% NaH (0.4 g, 10 mmol) in THF (10 mL), methyl 2-(dimethoxyphosphoryl)acetate (1.3 mL, 9 mmol) in 10 mL THF was added at 0C and stirred for lh at 0-5 0C. 4,4-difluorocyclohexanone 67 (1 g, 7.5 mmol) in 10 mL THF was then added slowly at 0C and allowed to stir at room temperature for about 1 5h. The reaction mixture was diluted with 20 mL THF and 50 mL ice-water, THF layer was separated and concentrated, residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), saturated NaHCO3 solution (10 mL) and dried over Na2SO4 andconcentrated under reduced ?pressure to obtain methyl 2-(4,4-difluorocyclohexylidene)acetate 68 as light brown liquid (0.8 g, 57% yield). ?HNMR (400 MHz, CDC13): oe 5.73 (s, 1H), 3.70 (s, 3H), 3.04 (t, 2H), 2.41 (t, 2H), 2.09-1.97 (m, 4H).
		Example 1F 400 mg (10.0 mmol) NaH suspended in 30 mL THF were cooled to 5 C. and 1.30 mL (9.00 mmol) methyl-2-(dimethoxyphosphoryl)acetate were added. The reaction mixture was stirred for 1 h at this temperature. 1.00 g (7.50 mmol) 4,4-difluorocyclohexanone was added to the mixture. The reaction mixture was warmed to room temperature and stirred over night at ambient temperature. The mixture was hydrolysed with water and THF and concentrated under reduced pressure. The product was obtained as an oil.

Reference： [1]Patent: WO2009/121919,2009,A1 .Location in patent: Page/Page column 149-150
[2]Patent: WO2015/25197,2015,A1 .Location in patent: Paragraph 000141
[3]Patent: US2012/115863,2012,A1 .Location in patent: Page/Page column 39

51
[ 5927-18-4 ]
[ 99-61-6 ]
[ 659-04-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium methylate; In N,N-dimethyl-formamide;	Step 95a: (E)-Methyl 3-(3-(chlorosulfonyl)phenyl)acrylate (1006-218)To a solution of 3-nitro-benzaldehyde (15 g, 0.1 mol), (dimethoxy- phosphoryl)-acetic acid methyl ester (27 g, 0.148 mol) in DMF (100 ml) was added NaOMe (10.7 g 0.198 mol). The reaction was mornitored by TLC. After reaction was completed, the reaction mixture was adjusted to pH = 1 with aquous HCl solution and evaporated. The resulting solid was washed with water to afford (E)-methyl 3-(3-nitrophenyl)acrylate as a yellow solid (20.14 g, 98%).
98%	With sodium methylate; In N,N-dimethyl-formamide;	Step 95a: (E)-Methyl 3-(3-(chlorosulfonyl)phenyl)acrylate (1006-218)[0624]To a solution of 3-nitro-benzaldehyde (15 g, 0.1 mol), (dimethoxy-phosphoryl)-acetic acid methyl ester (27 g, 0.148 mol) in DMF (100 ml) was added NaOMe (10.7 g 0.198 mol). The reaction was monitored by TLC. After reaction was completed, the reaction mixture was adjusted to pH=1 with aqueous HCl solution and evaporated. The resulting solid was washed with water to afford (E)-methyl 3-(3-nitrophenyl)acrylate as a yellow solid (20.14 g, 98%).
85 g	With potassium carbonate; In water; at 20℃; for 1h;	To a mixture of compound 115 (82.4 g, 452 mmol) and K2CO3 (96 g, 696 mmol) in H20 (160 mL) was added compound 114 (52.4 g, 348 mmol). The reaction was stirred at room temperature for 1 hour. Then the solution was filtered and the filter cake was washed with 1 N HCl and water, and the solid was concentrated to give compound 116 (85 g, crude) as a white solid. The product was used directly in the next step without further purification. (0943) NMR: H20619-001-1Q1 (DMSO- 6, 400 MHz) delta 8.56 (s, 1 H), 8.25-8.19 (m, 2 H), 7.80 (d, J=16 Hz, 1 H), 7.71 (t, J=8 Hz, 1 H), 6.86 (d, J=16 Hz, 1 H), 3.75 (s, 3 H).

183.5 g

A mixture of methanol (450 ml), 3-nitrobenzaldehyde (150 gms) and methyl-2- (dimethoxyphosphoryl)acetate (234.9 gms) was stirred for 10 minutes at 25-30C. Cooled the reaction mixture to 15-20C. Triethyl amine (276 ml) was slowly added to the reaction mixture at 15-20C. Heated the reaction mixture to 60-65C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 25-30C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 183.5 gms; M.R: 120-127C.

Reference： [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 238
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0623; 0624
[3]Synthetic Communications,2010,vol. 40,p. 2520 - 2524
[4]Patent: WO2015/138969,2015,A1 .Location in patent: Page/Page column 120
[5]Patent: WO2018/29699,2018,A1 .Location in patent: Page/Page column 14

52
[ 5927-18-4 ]
[ 81172-89-6 ]
[ 7560-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; lithium bromide; In tetrahydrofuran; at 5 - 25℃;	Intermediate 29; Methyl (2£)-3-(4-formylphenyl)acrylateLithium bromide (159g, 2.5eq) was dissolved in THF (2L) and cooled to <;5C. Trimethyl phosphonoacetate (1.3eq, 138mL) then triethylamine (204mL, 2eq) were charged at <;10C. 4-Diethoxybenzaldehyde (152.8g, 1eq) was charged over25mins and the reaction allowed to warm to 20 +/- 5C, then the cooling was removed. After 1 h 40min, the reaction was quenched with water, separated, and the aqueous layer extracted with EtOAc. The combined organic phases were washed three times with brine then concentrated to dryness in vacuo. Methanol (0.5L) was charged to the residue and again concentrated to dryness. Methanol (0.75L) and 1 N HCI (0.75L) were charged to the residue and stirred at ambient temperature for 45 min. Water (0.75L) was charged and the product isolated by filtration (128.5g). 1H NMR (30OMHz1CDCI3) delta(ppm): 10.06 (1 H, s), 7.93 (2H, d), 7.71 (3H, m), 6.58 (1 H, d), 3.85 (3H, s).

Reference： [1]Patent: WO2010/97586,2010,A1 .Location in patent: Page/Page column 45

53
[ 5927-18-4 ]
[ 1243634-45-8 ]
[ 1243634-46-9 ]

Yield	Reaction Conditions	Operation in experiment
95%		[00207] In a 50 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed trimethylphosphonoacetate (2.11 g, 11.60 mmol) in anhydrous acetonitrile (20 mL) under argon. To this solution 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (1.76 g, 11.60 mmol) was added at room temperature and stirred for 15 minutes. At this time, a solution of (4) (1.89 g, 5.80 mmol) in dry acetonitrile (20 mL) was added to the above reaction mixture via cannula and monitored for completion by checking TLC (typically 2 hours). At this time the reaction mixture was quenched by addition of water (80 mL), the phases were separated, and the aqueous phase was extracted with EtOAc (4 x 60 mL). Combined organic phases were washed with brine (2 x 100 mL), dried (MgS04), and concentrated. Chromatography (80% EtOAc-hexanes) afforded 2.10 g (95%) of a colorless oil. IR (film) 3440,1720,1660 cm"1; [oc]20D +34.95 (c 1.07, CHC13); 1H NMR (CDC13) delta 1.31 (s, 3H), 1.57 (m, 1H), 1.74 (m, 2H), 1.84 (m, 1H), 2.30 (m, 1H), 2.39 (s, 3H), 3.49 (m, 1H), 3.71 (s, 3H), 3.94 (m, 4H), 4.07 (d, J= 8.0 Hz, 1H), 5.80 (td, J= 1.6 Hz, J= 15.2 Hz, 1H), 6.80 (td, J= 7.2 Hz, J= 15.6 Hz, 1H), 7.27 (bd, J- 8.0 Hz, 2H), 7.56 (td, J= 2.0 Hz, J= 8.4 Hz, 2H); 13C NMR (CDC13) delta 21.2, 23.8, 29.7, 35.0, 39.0, 51.4, 53.2, 64.5, 64.6, 109.6, 123.9, 125.5, 129.4, 141.2, 141.9, 144.2, 166.4; HRMS calcd for C19H28N05S (M+H) 382.1683. Found 382.1695.

Reference： [1]Organic Letters,2010,vol. 12,p. 4118 - 4121
[2]Journal of Organic Chemistry,2012,vol. 77,p. 2345 - 2359
[3]Patent: WO2012/9263,2012,A1 .Location in patent: Page/Page column 77

54
[ 5927-18-4 ]
[ 100-06-1 ]
[ 99142-77-5 ]

Yield	Reaction Conditions	Operation in experiment
83%		NaH (0.37 g, 60% dispersion in oil, 9.19 mmol) was suspended in anhydrous hexane (10 mL), stirred under a nitrogen atmosphere for 10 minutes, and the solvent was removed. THF (4 mL) was added to oil-free NaH and cooled to 0. Trimethylphosphonoacetates (1.55 ml, 9.59 mmol) were dipped and the reaction mixture was stirred for 30 minutes. 4- methoxy acetophenone (compound 15) (1.20 g, 7.99 mmol) solution among the drying THF (5 mL) was dipped to the reaction mixture and the mixture was heated at the room temperature and it was stirred for 14 hours. The saturation NH 4 Cl aqueous solution was gradually added after the completion of reaction and it extracted in the EtOAc (2 × 40 mL). It dried to the anhydrous Na 2 SO 4 and the mixed organic solvent layer was the vacuum concentration to the saline solution (25 mL), and the purified water (25 mL) after doing washing. The crude product was refined to the column chromatography (EtOAc/Hexane=1/20) and pure products (1.37 g, 83%) of the oil phase were obtained.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 50 - 53
[2]Patent: KR101799305,2017,B1 .Location in patent: Paragraph 0106; 0107
[3]Journal of Organic Chemistry,2010,vol. 75,p. 8319 - 8321
[4]Organic Letters,2016,vol. 18,p. 4451 - 4453
[5]Chinese Journal of Chemistry,2017,vol. 35,p. 397 - 400
[6]Chemical Communications,2017,vol. 53,p. 9258 - 9261

55
[ 5927-18-4 ]
[ 60032-63-5 ]
methyl 4-hydroxy-3-iodocinnamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; In methanol; at 70℃; for 24h;	Na (5.0 mmol) was dissolved in dry MeOH (7 ml) and to the resulting solution methyl trimethylphosphonacetate (3.0 mmol) and a solution of the aldehyde (1.0 mmol) in dry MeOH (1 ml) were added in sequence. The resulting mixture was allowed to react for 24 h at 70 C. The solution was then acidified with HCl (aq) 10%, and extracted with Et2O (3 x 10 ml). The combined organic phases were dried over Na2SO4 and evaporated to dryness yielding the desired product that was used for the next reaction without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 769 - 772

56
[ 5927-18-4 ]
[ 405-05-0 ]
[ 1207954-10-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; In methanol; at 70℃; for 24h;	Na (5.0 mmol) was dissolved in dry MeOH (7 ml) and to the resulting solution methyl trimethylphosphonacetate (3.0 mmol) and a solution of the aldehyde (1.0 mmol) in dry MeOH (1 ml) were added in sequence. The resulting mixture was allowed to react for 24 h at 70 C. The solution was then acidified with HCl (aq) 10%, and extracted with Et2O (3 x 10 ml). The combined organic phases were dried over Na2SO4 and evaporated to dryness yielding the desired product that was used for the next reaction without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 769 - 772

57
[ 5927-18-4 ]
[ 94651-33-9 ]
[ 1202578-19-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		(63A) Methyl (2E)-3-[2-(trifluoromethoxy)phenyl]acrylate A tetrahydrofuran (40 mL) solution of methyl dimethyl phosphonoacetate (7.3 mL, 50.6 mmol) was slowly added to a suspension of sodium hydride (about 63%, oily, 1.93 g, 50.6 mmol) and tetrahydrofuran (80 mL) at 0 C., and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. A tetrahydrofuran (40 mL) solution of <strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> (8.01 g, 42.1 mmol) was slowly added thereto, and the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 85:15 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (12.2 g, quantitative). 1H NMR (CDCl3, 500 MHz): delta3.83 (3H, s), 6.49 (1H, d, J=16.1 Hz), 7.35-7.28 (2H, m), 7.40-7.45 (1H, m), 7.66 (1H, dd, J=7.8, 1.5 Hz), 7.92 (1H, d, J=16.1 Hz)

Reference： [1]Patent: US2011/53974,2011,A1 .Location in patent: Page/Page column 80

58
[ 5927-18-4 ]
[ 60611-24-7 ]
[ 1313426-19-5 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide monohydrate; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere;	Under nitrogen at room temperature trimethylphosphonoacetate (355 g, 1 .95 mol) was added to a sti rred sol uti on of <strong>[60611-24-7]2-fluoro-6-trifluoromethyl-benzaldehyde</strong> (250 g , 1 .3 mol) and lithiumhydroxide monohydrate (82 g, 1 .95 mol) in tetrahydrofurane (3 L). After stirring for 24 hours the mixture was partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum to yield (£)-3-(2-fluoro-6-trifluoromethyl-phenyl)-acrylic acid methyl ester (329 g). 1H-NMR (CDCIs, 400 MHz): 3.82 (s , 3H); 6.57 - 6.66 (m , 1 H) 7.24 - 7.58 (m, 3H); 7.72 - 7.83 (m, 1 H).UPLC-MS (ESI+): [M + H]+ = 249

Reference： [1]Patent: WO2011/76687,2011,A1 .Location in patent: Page/Page column 183

59
[ 5927-18-4 ]
[ 156866-52-3 ]
3-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-acrylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		To a solution of trimethyl phosphino acetate (4.64 mL, 23.5 mmol) in dry DMF (20 mL) was added potassium tert-butoxide (2.14 g, 19.13 mmol) at 0° C. and the mixture was stirred at same temperature over a period of 15 min.To the above mixture a solution of <strong>[156866-52-3](4-Formyl-benzyl)-carbamic acid tert-butyl ester</strong> (3.0 g, 12.75 mmol) in DMF (10 mL) was added drop wise at ice temperature.The reaction mixture was stirred at ice temperature over a period of 45 min.The resulting reaction mixture diluted with ethyl acetate, washed with water, brine and dried over sodium sulfate.The residue obtained upon evaporation of volatiles was purified by column chromatography to give 3-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-acrylic acid methyl ester as colourless solid (1.5 g, 40percent).

Reference： [1]Patent: US2012/101099,2012,A1 .Location in patent: Page/Page column 18-20

60
[ 5927-18-4 ]
[ 138555-58-5 ]
C₁₄H₁₈BrO₆P [ No CAS ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 10348 - 10354

61
[ 5927-18-4 ]
[ 35344-95-7 ]
[ 1295583-21-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃;	(E)-methyl 3-(l -methyl- lH-pyrazol-4-yl)acrylateCs2C03 (1.304g, 4 mmol) was added to a solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100°C overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3 -(1 -methyl- lH-pyrazol-4- yl)acrylate (0.278 g). ES+ (M+H)+ 167
0.278 g	With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃;	Cs2CO3 (1.304 g, 4 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364 g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100° C. overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3-(1-methyl-1H-pyrazol-4-yl)acrylate (0.278 g). ES+(M+H)+167

Reference： [1]Patent: WO2012/118782,2012,A1 .Location in patent: Page/Page column 74-75
[2]Patent: US2013/317003,2013,A1 .Location in patent: Paragraph 0429

62
[ 790667-49-1 ]
[ 5927-18-4 ]
[ 1338821-09-2 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2. Synthesis of tert-butyl (2S,4E)- and tert-butyl (2S,4Z)-4-(2-methoxy-2-oxoethylidene)-2-methylpiperidine-1-carboxylate (C20) Sodium hydride (60% in mineral oil, 1.35 g, 33.6 mmol) was washed with hexanes (25 mL), suspended in N,N-dimethylformamide (40 mL) and cooled to 0 C. Methyl (dimethoxyphosphoryl)acetate (4.66 mL, 32.3 mmol) was added to the reaction in a drop-wise manner, and the mixture was held at 0 C. with vigorous stirring for 20 minutes. A solution of <strong>[790667-49-1]ter<strong>[790667-49-1]t-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate</strong></strong> (C19) (5.52 g from the previous experiment, ?24.3 mmol) in N,N-dimethylformamide (10 mL) was added drop-wise, and the resulting solution was allowed to warm to room temperature over 16 hours. The reaction was then diluted with diethyl ether (400 mL) and washed with water (300 mL). The aqueous layer was extracted with diethyl ether (200 mL) and the combined organic layers were washed with water (4200 mL) and saturated aqueous sodium chloride solution (200 mL), then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was obtained as a colorless oil, composed of a roughly 1:1 mixture of olefin isomers. Yield: 6.63 g, 24.6 mmol, quantitative. 1H NMR (400 MHz, CDCl3) delta 5.83 and 5.72 (2 br s, 1H), 4.44-4.61 (m, 1H), 3.98-4.14 (m, 1H), 3.71 and 3.70 (2 s, 3H), 3.58-3.70 (m, 1H), 2.93-3.03 (m, 1H), 2.06-2.11, 2.18-2.33 and 2.53-2.59 (multiplets, total 3H), 1.47 (2 s, 9H), 1.08 (d, J=6.7 Hz) and 1.07 (d, J=6.9 Hz, total 3H).

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256
[2]Patent: US2013/150376,2013,A1 .Location in patent: Paragraph 0271

63
[ 5927-18-4 ]
N-acetoxymethyl-N-(N-fluorenylmethyloxycarbonyl-L-leucyl)-4-oxo-L-homoalanine methyl ester [ No CAS ]
dimethyl N-acetoxymethyl-N-(N-fluorenylmethyloxycarbonyl-L-leucyl)-N-acetoxymethyl-4,5-dehydro-L-homoglutamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		[0103] Dimethyl N-Acetoxymethyl-N-(N-fluorenylmethyloxycarbonyl-L-leucyl)-N-acetoxymethyl-4,5-dehydro-L-homoglutamate(60). A suspension of sodium hydride (60 % in mineral oil, 6 mg, 0.15 mmol) in dry THF (1.5 mL) was cooledto -10 C and a solution of methyl 2-(dimethoxyphosphoryl)acetate (27 mg, 0.15 mmol) in dry THF (1 mL) was addeddropwise. The mixture was stirred for 45 minutes, and then a solution of the aldehyde (41) (54 mg, 0.10 mmol) in dryTHF (1 mL) was slowly added, while the temperature was mantained at -10 C for 35 minutes. The reaction mixture waspoured into water and extracted with diethyl ether. The organic layer was dried, filtered and evaporated as usual, andthe residue was purified by rotatory chromatography (hexane/EtOAc, 80:20), affording the olefin (60) (49 mg, 82%) asa yellowish slurry: [alpha]D = -22.30 (c 0.38, CHCl3); IR (CHCl3) vmax. 3431, 1745, 1721, 1674, 1511 cm-1; 1H NMR (500MHz, CDCl3, 26 C) deltaH 0.94 (3H, d, J = 6.7 Hz, Me), 0.98 (3H, d, J = 6.6 Hz, Me), 1.42-1.56 (2H, m, 3?-H2), 1.70 (1 H,m, 4?-H), 2.10 (3H, s, Ac), 2.92 (2H, dd, J = 7.3, 7.4 Hz, 3-H2), 3.67 (3H, s, OMe), 3.68 (3H, s, OMe), 4.21 (1 H, dd, J =7.2, 7.2 Hz, CHFmoc), 4.34 (1 H, dd, J = 7.0, 10.6 Hz, OCHa-fluorenyl), 4.40 (1 H, dd, J = 7.4, 10.6 Hz, OCHb-fluorenyl),4.55 (1 H, dd, J = 7.0, 8.3 Hz, 2-H), 4.83 (1 H, ddd, J = 4.2, 9.1, 9.4 Hz, 2?-H), 5.34 (1 H, d, J = 9.1 Hz, NH), 5.43 (1 H, d, J = 12.4 Hz, NCHaO), 5.55 (1 H, d, J = 12.4 Hz, NCHbO), 5.85 (1 H, d, J = 15.6 Hz, 5-H), 6.80 (1 H, ddd, J = 7.6, 8.1,15.6 Hz, 4-H), 7.30 (2H, dd, J = 7.5, 7.5 Hz, Ar), 7.39 (2H, dd, J = 7.4, 7.5 Hz, Ar), 7.58 (1 H, d, J = 7.5 Hz, Ar), 7.75 (1H, d, J = 7.6 Hz, Ar); 13C NMR (125.7 MHz, CDCl3, 26 C) deltaC 20.6 (CH3), 21.6 (CH3), 23.2 (CH3), 24.7 (CH), 31.6 (CH2),42.9 (CH2), 47.2 (CH), 49.9 (CH), 51.4 (CH3), 52.6 (CH3), 59.6 (CH), 67.1 (CH2), 71.7 (CH2), 120.0 (2 x CH), 124.0(CH), 125.1 (2 x CH), 127.0 (2 x CH), 127.7 (2 x CH), 141.3 (2 x C), 143.8 (CH), 143.9 (2 x C), 156.5 (C), 166.3 (C),169.9 (C), 170.5 (C), 174.9 (C); MS (EI) m/z (relative intensity) 594 (M+, <1), 339 (M+ - fluorenylmethyl -OCO - HOMe,<1), 308 ([Fmoc-NH-CHCH2CHMe2]+, 3), 279 ([Fmoc-NH-CHCO]+, 3), 200 ([CH2=NH-CH(CO2Me)CH2CH=CHCO2Me+ H]+, 6), 179 ([fluorenyl-CH2]+, 60), 178 ([fluorenyl-CH2 - H]+, 100), 165 ([fluorenyl]+, 25); HRMS calcd for C32H38N2O9,594.2577, found 594.2573; calculated for C16H23N2O6, 339.1556, found 339.1564; calculated for C20H22NO2, 308.1651,found 308.1647; calculated for C14H11, 179.0861, found 179.0857; calculated for C14H10, 178.0783, found 178.0790;calculated for C13H9, 165.0704, found 165.0707. Elemental analysis: Calculated for C32H38N2O9: C, 64.63; H, 6.44; N,4.71; found C, 64.75; H, 6.68; N, 4.88.

Reference： [1]Organic Letters,2013,vol. 15,p. 5778 - 5781
[2]Journal of Organic Chemistry,2015,vol. 80,p. 9379 - 9391
[3]Patent: EP2957555,2015,A1 .Location in patent: Paragraph 0098; 0103

64
[ 5927-18-4 ]
[ 43192-33-2 ]
[ 1528736-48-2 ]

Yield	Reaction Conditions	Operation in experiment
56%		General procedure: To a suspension of potassium tert-butoxide (7.83g, 70mmol, 3.0equiv) in THF (300mL) at 0C was added trimethyl phosphonoacetate (10.6g, 58mmol, 2.5equiv). The resulting clear yellow solution was stirred for 15min at 0C, then a solution of (4-bromo-2-methoxy)benzaldehyde (31b; 5.00g, 23mmol) in THF (20mL) was added dropwise. The resulting mixture was warmed from 0C to room temperature over 16h. The solvent was removed under vacuum, then the crude mixture was diluted with water (50mL) and extracted with EtOAc (2×100mL). The combined organic extracts were washed with water (1×50mL), brine (1×50mL), dried (MgSO4), filtered, and concentrated to provide a dark residue. The residue was purified by flash chromatography using 5% EtOAc in hexanes to obtain 3.53g (56%) of product as a white solid: Rf 0.19 (5% EtOAc/hexane; 1H NMR (CDCl3) delta 8.02 (d, 1H), 7.47 (dd, 1H), 7.26-7.22 (m, 1H), 6.93 (t, 1H), 6.84 (d, 1H), 6.62 (d, 1H), 6.2 (s, 1H), 3.83 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 419 - 434

65
[ 5927-18-4 ]
[ 82257-15-6 ]
[ 1528736-54-0 ]

Yield	Reaction Conditions	Operation in experiment
65%		To a suspension of potassium t-butoxide (819 mg, 7.3 mmol, 2.5 equiv) in THF (20 mL) at 0 C was added trimethyl phosphonoacetate (1.30 g, 7.3 mmol, 2.5 equiv). The clear yellow solution was stirred for 10 minutes at 0 C, then <strong>[82257-15-6]4-methoxynicotinaldehyde</strong> (400 mg, 2.92 mmol) was added over 5 min. The resulting suspension was allowed to warm to room temperature over 1.5 h.. The mixture was then diluted with water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated to yield a crude solid that was purified by flash chromatography (1:1 hexanes:EtOAc). Product-containing fractions were combined, evaporated and dried under high vacuum to yield 368 mg (65%) of product as a pale yellow oil: Rf 0.33 (1:1 hexane:EtOAc); 1H NMR (CDCl3) delta 8.58 (s, 1H), 8.46 (d, 1H), 7.81 (d, 1H), 6.85 (d, 1H), 6.60 (d, 1H), 3.96 (s, 3H), 3.82 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 419 - 434

66
[ 5927-18-4 ]
[ 53581-86-5 ]
methyl 3-(4-chloro-2-methoxyphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a suspension of potassium tert-butoxide (7.83g, 70mmol, 3.0equiv) in THF (300mL) at 0C was added trimethyl phosphonoacetate (10.6g, 58mmol, 2.5equiv). The resulting clear yellow solution was stirred for 15min at 0C, then a solution of (4-bromo-2-methoxy)benzaldehyde (31b; 5.00g, 23mmol) in THF (20mL) was added dropwise. The resulting mixture was warmed from 0C to room temperature over 16h. The solvent was removed under vacuum, then the crude mixture was diluted with water (50mL) and extracted with EtOAc (2×100mL). The combined organic extracts were washed with water (1×50mL), brine (1×50mL), dried (MgSO4), filtered, and concentrated to provide a dark residue. The residue was purified by flash chromatography using 5% EtOAc in hexanes to obtain 3.53g (56%) of product as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 419 - 434

67
[ 5927-18-4 ]
[ 893724-10-2 ]
[ 1628783-86-7 ]

Yield	Reaction Conditions	Operation in experiment
93%		To a suspensionof NaH (60% in mineral oil, 4.36 g, 0.109 mol), in THF (180 mL), a solution of trimethylphosphonoacetate (18.2 g, 0.1 mol) in THF (90 mL) was added dropwise at 15 C upon stirring. Themixture was stirred for 1 h, and then a solution of 13 (22.0 g, 0.091 mmol) was added. The resultingmixture was stirred at rt overnight, then most of the solvent was removed in vacuo, the residue wasquenched with 10% aq NH4Cl (50 mL) and extracted with Et2O (3300 mL). The combined organicphases were dried over MgSO4 and evaporated in vacuo to give 15 (25.3 g, 93%) pure enough for thenext step. An analytical sample was obtained by column chromatography (Hexanes - EtOAc (5 : 1) aseluent). Colourless oil. Rf = 0.49 (Hexanes - EtOAc (5 : 1)). MS (m/z, CI): 299 (MH+). IR (neat, cm-1):1718 ((C=O)), 1626, 1625, 1101, 1082. Anal. calc. for C15H22O6 C 60.39, H 7.43. Found C 60.18,H 7.64. 1H NMR (CDCl3) 5.69 (t, J = 2.0 Hz, 1H), 5.05 (sept, J = 6.2 Hz, 2H), 3.67 (s, 3H), 3.58 (d,J = 2.0 Hz, 2H), 3.30 (s, 2H), 1.22 (d, J = 6.2 Hz, 12H). 13C NMR (CDCl3) 170.3 (C), 166.3 (C), 157.7(C), 114.7 (CH), 69.4 (CH), 51.2 (CH3), 49.9 (C), 41.2 (CH2), 39.1 (CH2), 21.6 (CH3).

Reference： [1]Synlett,2014,vol. 25,p. 355 - 358

68
[ 5927-18-4 ]
[ 3453-33-6 ]
[ 744241-46-1 ]

Yield	Reaction Conditions	Operation in experiment
92%		To the Trimethyl phosphonoacetate (55.6 mL, 381 mmol) in 250 mL anhydrous CH2Cl2 cooled to 0 C. was added DBU (48.8 mL, 322 mmol) and the mixture was stirred for 15 min. Aldehyde 59 (40.0 g, 215 mmol) in 50 mL CH2Cl2 was added dropwise. The temperature of the reaction mixture brought to rt and resulting reaction mixture was stirred at rt for 16 h, and then quenched with 100 mL of Water. The mixture was partitioned, and the aq. layer was extracted with CH2Cl2 (3×150 mL). The combined organics were washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel column chromatography (10:1 hexanes/ethyl acetate) to give the desired trans-alpha,beta-unsaturated ester 62 (48.0 g, 92%) as a white solid.

Reference： [1]Patent: US2014/171447,2014,A1 .Location in patent: Paragraph 0321; 0323

69
[ 20098-14-0 ]
[ 5927-18-4 ]
[ 110511-31-4 ]

Yield	Reaction Conditions	Operation in experiment
90%		To a solution of trimethyl phosponoacetate 21 (699.58 mg, 3.842 mmol) in anhydrous tetrahydrofuran (15 mL) 60% suspension in minral oil of sodium hydride (200 mg, 4.802 mmol) was added at 0 C under nitrogen atmosphere and stirred for 1 h at the same temperature. Added solution of 5-hydroxy-2-adamantanone 20 (500 mg, 3.201 mmol) in tetrahydrofuran (5 mL) slowly at room temperature. The reaction mixture was stirred for 5 h, quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to provide (5-hydroxy-adamantan-2-ylidene)acetic acid methyl ester 22 (641 mg, 90%). 1H NMR (300 MHz, DMSO-d6): delta 5.60 (s, 1H), 4.53 (s, 1H), 3.58 (s, 3H), 2.67-2.54 (m, 1H), 2.16-2.08 (m, 1H), 1.80-1.52 (m, 11H); LC-MS (m/z): 223 [M+H]+.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 101,p. 716 - 735

70
[ 5927-18-4 ]
[ 1550-35-2 ]
[ 186758-21-4 ]

Yield	Reaction Conditions	Operation in experiment
99%		(E)-Methyl 3-(2,4-difluorophenyl)acrylateTo a solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (1.425 mL, 8.80 mmol) in THF (30 mL) was added KOtBu (0.987 g, 8.80 mmol) and stirred at RT for 10 min before was added 2,4-difluorobenzaldehyde (0.875 mL, 8 mmol) in THF (5 mL). The resulting reaction mixture was stirred at RT for 160 min. To the reaction mixture was added more <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (0.648 mL, 4.00 mmol) then KOtBu (0.449 g, 4.00 mmol). The resulting reaction mixture was stirred at RT for 30 min. To the reaction mixture was added H20 (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over MgS04, filtered, evaporated down under vacuum to afford desired intermediate (E)-methyl 3-(2,4-difluorophenyl)acrylate (1.5710 g, 7.93 mmol, 99 % yield). LC-MS m/z 199.1 (M+H)+, 0.94 min (ret. time).
86%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 5.5h;	Step1 To a stirred solution of methyl (dimethoxyphosphoryl) acetate (12.8 mL, 77.46 mmol, 1.1 eq) in THF (70.0 mL)) was added KOtBu (8.69 g, 77.46 mmol, 1.1 eq) at RT and the reaction mixture was stirred for 10 min. Then 2,4-difluorobenzaldehyde (10.0 g, 70.42 mmol, 1.0 eq) in THF (20 mL) was added drop wise stirred at RT for 2 h. Methyl (dimethoxyphosphoryl) acetate (5.8 mL, 35.21 mmol, 0.5) and KOtBu (3.95 g, 35.21 mmol, and 0.5 eq) was added as lot-2 and stirred for 30 minutes. After 3 h, reaction mixture was diluted with water (200 mL) extracted with EtOAc (2*100 mL), organic layer was dried over anhydrous Na2SO4, and evaporated under reduced pressure gave crude compound, which was purified by column chromatography on silica gel (100-200 mesh) using EtOAc/pet ether (1:9) as eluent to get (E)-methyl 3-(2,4-difluorophenyl)acrylate (12.0 g, 86%) as a white solid. TLC system: EtOAc: Pet ether (1:9), Rf: 0.5.

Reference： [1]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 566
[2]Patent: WO2016/202253,2016,A1 .Location in patent: Page/Page column 314; 315
[3]Patent: US2018/78541,2018,A1 .Location in patent: Paragraph 0377; 0379

71
[ 499770-67-1 ]
[ 5927-18-4 ]
methyl (2E)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)prop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere;	(E)-3-(1 -Methyl-1 H-benzotriazol-5-yl)-acrylic acid methyl esterA stirred solution of t-BuOK (2.10 g, 18.6 mmol) in THF (100 ml_) at 0 C under N2was treated with trimethyl phosphonoacetate (4.30 g, 23.3 mmol). After 30 mins, 1- methyl-1 H-1 ,2,3-benzotriazole-5-carbaldehyde (2.50 g, 15.5 mmol) was added slowly in portions. After 1 h, the mixture was treated with NH4CI (aq., sat.), diluted with water and then extracted with n-heptane (x3), resulting in a precipitate which was isolated by filtration. The combined organic layers were washed with water and brine, dried over MgS04, filtered and concentrated to dryness, giving a beige solid which was washed with toluene and dried under vacuum. This material was combined with the precipitate above to give the product as a beige solid (3.1 g, 92%). LCMS (M+H)+218, RT 1.12 min.
92%		Intermediate 2 (E)-3-(1 -Methyl-1 H-benzotriazol-5-yl)-acrylic acid methyl ester A stirred solution of t-BuOK (2.10 g, 18.6 mmol) in THF (100 ml) at 0C under N2 was treated with trimethyl phosphonoacetate (4.30 g, 23.3 mmol). After 30 mins, 1 -methyl-1 H-1 ,2,3- benzotriazole-5-carbaldehyde (2.50 g, 15.5 mmol) was added slowly in portions. After 1 hour, the mixture was treated with NH4CI (aq., sat.), diluted with water and then extracted with n- heptane (x3), resulting in a precipitate which was isolated by filtration. The combined organic layers were washed with water and brine, dried over MgS04, filtered and concentrated to dryness, giving a beige solid which was washed with toluene and dried under vacuum. This material was combined with the precipitate above to give the product as a beige solid (3.1 g, 92%). LC-MS m/z 218 (M+H)+ 1 .12 min (ret. time).

Reference： [1]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 135; 278; 328; 329
[2]Patent: WO2016/203400,2016,A1 .Location in patent: Page/Page column 44; 45
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 3991 - 4006

72
[ 5927-18-4 ]
[ 34097-60-4 ]
(E)-methyl-4-(phenylsulfonyl)but-2-enoate [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 5792 - 5795

73
[ 5927-18-4 ]
[ 711-33-1 ]
3-(4-trifluoromethylphenyl)pent-2-enoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		Example 21 Preparation of Compound AA [3-(4-Trifluoromethylphenyl)-pentanamide] To a chilled (0 C.) solution of lithium bis(trimethylsilyl)amide (1.0 M, 50 mL) was dropwise added a solution of trimethylphosphonoacetate, keeping the temperature below 10 C. The solution was then allowed to warm to room temperature and stirred for an additional five minutes, after which a solution of <strong>[711-33-1]4'-(trifluoromethyl)propiophenone</strong> in THF (25 mL) was added in one portion. The solution was slowly heated to 50 C. for eight hours. The solution was cooled to room temperature, then diluted with a 10% NH4Cl solution (100 mL), and extracted with ethyl acetate (2*100 mL). The organic layers were combined and dried over MgSO4, filtered, and the filtrate concentrated to a white solid which was recrystallized from hexane/ethyl acetate to give 5.42 grams of 3-(4-trifluoromethylphenyl)pent-2-enoic acid methyl ester intermediate (85% yield).

Reference： [1]Patent: US9206143,2015,B2 .Location in patent: Page/Page column 26

74
[ 2476-37-1 ]
[ 5927-18-4 ]
C₁₁H₁₀Cl₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7 g		3. To a solution of tri methyl phosphonoacetate (11.6 g, 63.5 mmol) in dry THF (300 mL) at 0 C was added 60% NaH (2.55 g, 63.5 mmol) portionwise. After 2 hours stirring at RT, a solution of Compound 3 (10 g, 52.9 mmol) in dry THF (20 mL) was added dropwise. The resulting mixture was stirred at RT for 1 hour and reflux for 2 hours. The mixture was diluted with saturated NH4C1 solution and extracted with EA. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give an oil which was purified by silica gel chromatography to give 7 g of Compound 4.

Reference： [1]Patent: WO2016/77240,2016,A2 .Location in patent: Page/Page column 95; 96

75
[ 5927-18-4 ]
[ 52010-98-7 ]
C₁₁H₁₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride; In acetonitrile; at 0 - 20℃; for 17.33h;	Lithium chloride (1.1906 g, 1.56 eq.) in acetonitrile (20 mL) solution of 3-hydroxy-methyl-benzaldehyde (2.4528 g) in acetonitrile (10 mL) , phosphonoacetic acid trimethyl (5.1150g, 1.56 eq.) in acetonitrile (10 mL) was mixed at room temperature, the resulting mixed solution, 0 C. with DBU (1,8-diazabicyclo [5.4.0] -7-undecene) (4.2682g, 1.56 eq) in acetonitrile (10 mL ) solution was added over a period of 2 minutes, 20 minutes at 0 C, and the mixture was stirred at room temperature for 17 hours. Was added water (50 mL), extracted with ethyl acetate (250 mL), the organic layer was washed with brine (100 mL), dried over magnesium sulfate. The residue obtained by distilling off the solvent, column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (2.5720 g, 74%, colorless oil)
74%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride; In acetonitrile; at 0 - 20℃; for 17.36h;	Lithium chloride (1.1906 g, 1.56 eq.) In acetonitrile (20 mL) solution of acetonitrile (10 mL) solution of <strong>[52010-98-7]3-hydroxymethyl benzaldehyde</strong> (2.4528 g), trimethyl phosphonoacetate (5.1150g, 1.56 eq.) In acetonitrile (10 mL) was mixed at room temperature, the resulting mixed solution, 0 C. with DBU (1,8-diazabicyclo [5.4.0] -7-undecene) (4.2682g, acetonitrile (10 mL of 1.56 eq.)) the solution was added over a period of 2 minutes, 20 minutes at 0 , and the mixture was stirred at room temperature for 17 hours. Was added water (50 mL), extracted with ethyl acetate (250 mL), the organic layer was washed with brine (100 mL), dried over magnesium sulfate. The residue obtained by distilling off the solvent, column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (2.5720 g, 74%, colorless oil).

Reference： [1]Patent: JP2016/17036,2016,A .Location in patent: Paragraph 0351; 0353-0355
[2]Patent: JP2016/17037,2016,A .Location in patent: Paragraph 0307

76
[ 5927-18-4 ]
[ 130753-13-8 ]
benzyl 3-(2-methoxy-2-oxoethylidene)-8-azabicyclo[3,2,1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.6%		Sodium hydride (0.344g, 8.60mmol, 60%) in tetrahydrofuran (20.0mL) suspension of trimethyl phosphono acetic acid (0.908mL, 5.61mmol) was added at 0C. After stirring for 20 minutes at the same temperature, <strong>[130753-13-8]benzyl 3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate</strong> (0.970g, 3.74mmol) in tetrahydrofuran(20.0mL) was added a solution of room temperature and the mixture was stirred after raising the temperature 22 hours.Distilled water was added to the reaction mixture, and the mixture was distilled off under reduced pressure of tetrahydrofuran,and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by column chromatography (silica gel, nhexane/ ethylacetate = 94 / 665/ 35), 3(2methoxy2oxoethylidene)8azabicyclo[3,2,1] octane8carboxylicacid benzyl (below,reference example compound of 13) (0.645g, 2.05mmol, 54.6%) was obtained as a colorless oily product.

Reference： [1]Patent: JP2015/124178,2015,A .Location in patent: Paragraph 0145

77
[ 60032-57-7 ]
[ 5927-18-4 ]
[ 137146-28-2 ]

Yield	Reaction Conditions	Operation in experiment
75%		Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (60%, 1.09 g, 1.10 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of methyl 2-(dimethoxyphosphoryl)acetate (5.41 g, 29.71 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 30 min at 0 C. To this was added a solution of <strong>[60032-57-7]2-methylpyridine-3-carbaldehyde</strong> (3 g, 24.77 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 100 mL of water, extracted with 2×300 mL of ethyl acetate, washed with 1×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). The collected fraction was concentrated under vacuum to give (E)-methyl 3-(2-methylpyridin-3-yl)acrylate (3.3 g, 75%) as yellow oil. MS: (ES, m/z): 178[M+H]+.

Reference： [1]Patent: US2016/264518,2016,A1 .Location in patent: Paragraph 0862; 0863

78
[ 5927-18-4 ]
[ 70201-43-3 ]
(E)-methyl 3-(3-bromopyridin-4-yl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (60%, 476 mg, 19.83 mmol, 1.10 equiv) in tetrahydrofuran (70 mL). To this was added a solution of methyl 2-(dimethoxyphosphoryl)acetate (2.36 g, 12.96 mmol, 1.20 equiv) in tetrahydrofuran (70 mL). The resulting solution was stirred for 30 min at 0 C., then to this was added a solution of 3-bromopyridine-4-carbaldehyde (2 g, 10.75 mmol, 1.00 equiv) in tetrahydrofuran (60 mL). The resulting solution was allowed to react with stirring for 2 h at room temperature. Then was poured into 100 mL of water, extracted with 100 mL of ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). The collected fraction was concentrated under vacuum to give (E)-methyl 3-(3-bromopyridin-4-yl)acrylate (1.5 g, 58%) as a white solid. MS: (ES, m/z): 242[M+H]+.

Reference： [1]Patent: US2016/264518,2016,A1 .Location in patent: Paragraph 0865; 0866

79
[ 13490-32-9 ]
[ 5927-18-4 ]
2-(4-amino-1,2,5-oxadiazol-3-yl)-4-dimethoxyphosphoryl-1,4-dihydroimidazol-5-one [ No CAS ]
3-amino-3-(4-amino-1,2,5-oxadiazol-3-yl)-4-dimethoxyphosphoryl-isoxazolidin-5-one [ No CAS ]
4-amino-N'-methoxy-1,2,5-oxadiazole-3-carboxamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%; 30%; 15%	With sodium hydride; In toluene; for 6h;Reflux;	General procedure: Trialkylphosphonoacetate (2a or b) (1 mmol) was dissolved inrigorously dried toluene (25 mL) then sodium hydride (1mmol)was added carefully with stirring. Thence, the startingmaterial 1(1 mmol) was added to the mixture which then was refluxed for6 h., the volatile materials were evaporated under reduced pressureand the remaining residue was purified on silica gel columnchromatograph to give compounds 5a,b, 6a,b, and 7a,b

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2016,vol. 191,p. 1000 - 1008

80
[ 5927-18-4 ]
[ 24078-12-4 ]
methyl (E)-3-(4-bromo-2-methylphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; at 20℃; for 19h;	To a mixture of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (5.87 mL, 44 mmol, 1 equiv.) and trimethyl phosphonoacetate (7.62 mL, 53 mL, 1.2 equiv.) was added potassium carbonate (12.1 g, 88 mmol, 2 equiv.) and DBU (0.2 mL, 1.3 mmol, 0.03 equiv.). The reaction was stirred at room temperature for 19 h before being quenched with water. It was extracted three times with ether, the combined organic extracts were dried over sodium sulfate and the solvent was evaporated. The residue was purified by bulb-to-bulb distillation (135-140C, 0.15 mbar) to afford methyl (E)-3-(4-bromo-2-methylphenyl)acrylate (10.3 g, 92 % yield).1H NMR: 2.40 (s, 3H), 3.81 (s, 3H), 6.34 (d, / = 15.9, 1H), 7.32.7.40 (m, 3H), 7.87 (d, / =15.9, 1H). 13C NMR: 167.2 (s), 141.3 (d), 139.6 (s), 133.6 (d), 132.4 (s), 129.6 (d), 127.8 (d), 124.1 (s), 119.5 (d), 51.8 (q), 19.6 (q).

Reference： [1]Patent: WO2017/9175,2017,A1 .Location in patent: Page/Page column 15

81
[ 204339-72-0 ]
[ 5927-18-4 ]
[ 1007862-08-9 ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 145,p. 235 - 251

82
[ 256417-10-4 ]
[ 5927-18-4 ]
(E)-methyl 3-(2,6-difluoro-4-methoxyphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 24h;	Step1 To a stirred solution of <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (5 g, 29.05 mmol, 1 eq) in THF (100 mL) was added trimethylphosphonoacetate (5.03 mL, 34.86 mmol, 1.2eq) and DBU (5.65 mL, 37.76 mmol, 1.3eq). The solution was stirred at RT for 24 h. It was then concentrated in vacuo and dissolved in 1:2 EtOAc/Hexane (250 mL). The resulting solution was washed sequentially with 1 N aq. HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and finally with brine (100 mL). The organic phase was then dried over sodium sulfate, filtered and evaporated under reduced pressure to yield the crude (E)-methyl 3-(2,6-difluoro-4-methoxyphenyl)acrylate as off white solid (5.8 g, 87%). It was used for the next step without further purification.

Reference： [1]Patent: US2018/78541,2018,A1 .Location in patent: Paragraph 0355; 0357

83
[ 189442-92-0 ]
[ 5927-18-4 ]
(E)-tert-butyl 4-(3-methoxy-3-oxoprop-1-enyl)-4-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		A mixture of methyl 2- (dimethoxyphosphoryl) acetate (1.82 g, 10 mmol) and t-BuOK (1.2 g, 10 mmol) in dry THF (15 mL) was stirred at 0 for 2h under N2. Then a solution of <strong>[189442-92-0]tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate</strong> (2.2 g, 9 mmol) was added to the mixture at 0 under N2. And the resulting mixture was stirred at rt overnight, quenched with aq. NH4Cl (100 mL) and extracted with EtOAc (100 mL × 3) . The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc20/1 to 5/1) to give (E) -tert-butyl 4- (3-methoxy-3-oxoprop-1-enyl) -4-methylpiperidine-1-carboxylate (2 g, 78) . LRMS m/z (M-55) 228.2 found, 228.1 required

Reference： [1]Patent: WO2018/68297,2018,A1 .Location in patent: Page/Page column 95

84
[ 5927-18-4 ]
[ 304873-65-2 ]
C₁₄H₁₈N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.62%	With potassium carbonate; In tetrahydrofuran; for 15h;Inert atmosphere;	To a mixture of compound 21.8 (2.50 g, 11.25 mmol, 1 eq) and methyl 2- dimethoxyphosphorylacetate 21.7 (2.05 g, 11.25 mmol, 1.63 mL, 1 eq) in THF (30 mL) was added K2C03 (3.11 g, 22.50 mmol, 2 eq) in one portion at 50C under N2. The mixture was stirred at 50 C for 15 hours. The reaction mixture was diluted with H20 30 mL and extracted with EtOAc 90 mL (30 mL x 3). The combined organic layers were washed with brine 50 mL(50 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=5:1) to give compound 21.6 (2.40 g, 8.62 mmol, 76.62% yield) as a white solid.[02921 LCMS (ESI): m/z: [M + H] calcd for C14H18N204: 278; found 279; RTO.739 mm.

Reference： [1]Patent: WO2018/209132,2018,A1 .Location in patent: Paragraph 0291; 0292

85
[ 5927-18-4 ]
[ 13670-99-0 ]
C₁₁H₁₀F₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		General procedure: Trimethyl phosphonacetate (5.21 mmol) was added dropwise to a suspension of NaH (5.21 mmol) in dry THF (8 mL) at 0 C under inert atmosphere (N2). After 30 min, the appropriate ketone(4.17 mmol) was added to the reaction mixture. The reaction mixture was let to warm slowly to room temperature. The system was kept stirring at room temperature overnight. The next morning the reaction was quenched by addition 1M NH4Cl (10 mL) and the product was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography eluting with n-hexane: EtOAc, 50:1 to give the pure 3a-d, 3f-l.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 163,p. 722 - 735

86
[ 21778-81-4 ]
[ 5927-18-4 ]
C₁₃H₁₃NO₃ [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 5026 - 5029

87
[ 5927-18-4 ]
[ 213682-04-3 ]
C₁₃H₁₃NO₃ [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 5026 - 5029

88
[ 53590-49-1 ]
[ 5927-18-4 ]
C₁₂H₁₀ClNO₂ [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 5026 - 5029

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[ 99-61-6 ]

3-Nitrobenzaldehyde

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
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Prevention
Code	Phrase
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P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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P285	In case of inadequate ventilation wear respiratory protection.
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Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
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P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
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P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
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Storage
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P401
P402	Store in a dry place.
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P411
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P413
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P422
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Disposal
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Physical hazards
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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
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H226	Flammable liquid and vapour
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H228	Flammable solid
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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
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H312	Harmful in contact with skin
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H314	Causes severe skin burns and eye damage
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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

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[ 5927-18-4 ] Synthesis Path-Upstream 1~19

[ 5927-18-4 ] Synthesis Path-Downstream 1~88

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