Name: 2609-49-6|Diethyl 4-nitrobenzylphosphonate|95%
Brand: Ambeed
SKU: A375447
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1
[ 1080-32-6 ]
[ 2609-49-6 ]

Yield	Reaction Conditions	Operation in experiment
88%		METHOD 1 (Ref. 180,217) The phosphonate (7.3) (5.0 g, 22 mmol) was then added dropwise with cooling to a stirring mixture of concentrated nitric and sulphuric acids [50 ml (1:1 v/v)] at 0°C. The mixture was allowed to warm to room temperature and stirred for a further 1 h. The reaction was poured onto ice and extracted into toluene (3 x 100 ml). The combined organic fractions were washed with water (3 x 50 ml) and saturated NaHCO3(3 x 50 ml) and dried over MgSO4. Removal of toluene under reduced pressure yielded a pale green oil (5.3 g, 88 %) which was found to be a mixture of the title compound and its ortho isomer in a molar ratio of ca. 85:15 respectively (determined by 31P NMR). Analysis by TLC in a range of solvent systems failed to separate the two isomers. Repeated attempts to purify the mixture by silica gel chromatography were of limited success, only increasing the isomeric ratio to 90:10 (overall yield, 71%).
	With sulfuric acid; nitric acid
	With sulfuric acid; nitric acid at 0℃; for 0.666667h;	3 4.1.3 4-Nitrobenzylphosphonic acid (3) Diethyl benzylphosphonate61,62(6, 500 mg, 0.0022 mmol) was treated with a 1:1 mixture of conc. H2SO4 and conc. HNO3 (5 mL) at 0 °C in a round bottom flask. The reaction mixture was stirred at 0 °C for 40 min and then treated with ice/cold water. The crude reaction mixture was extracted with ethyl acetate and then the organic layer washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in silica gel with AcOEt/hexanes (50:50) to yield diethyl 4-nitrobenzylphosphonate 7 as a yellowish oil. This intermediate was hydrolyzed with conc. HCl as described in section 4.1.2 furnishing 4-nitrobenzylphosphonic acid 3 as light yellow crystals in 60% overall yield (mp 224-227 °C).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - EP745673, 1996, A2
[2]Kagan et al. [Journal of the American Chemical Society, 1959, vol. 81, p. 3026,3029]
[3]Fonseca, Emanuella M.B.; Trivella, Daniela B.B.; Scorsato, Valéria; Dias, Mariana P.; Bazzo, Natália L.; Mandapati, Kishore R.; De Oliveira, Fábio L.; Ferreira-Halder, Carmen V.; Pilli, Ronaldo A.; Miranda, Paulo C.M.L.; Aparicio, Ricardo [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4462 - 4471]

2
[ 2609-49-6 ]
[ 20074-79-7 ]

Yield	Reaction Conditions	Operation in experiment
56%	With water; iron; ammonium chloride; In ethanol; for 1h;Reflux;	Into a 100-mL 3-necked round-bottom flask, was placed a solution of diethyl 4-mtrobenzylphosphonate (5 g, 18 32 mmol, 1 00 equiv) in ethanol (50 mL) and a solution of NH4Cl (2 9 g, 54 72 mmol, 2 99 equiv) in water (50 mL) was added This was followed by the addition of Fe (4 1 g, 73 21 mmol, 4 00 equiv), while the temperature was maintained at reflux The resulting solution was heated to reflux for 1 hr The solids were filtered out The resulting mixture was concentrated under vacuum The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined and d?ed over anhydrous sodium sulfate The solids were filtered out The resulting mixture was concentrated under vacuum The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 3) This resulted in 2 5 g (56%) of the title compound as a yellow solid.
	With hydrogen;platinum(IV) oxide; In ethanol; under 3102.97 Torr; for 4h;	Crude 65 was dissolved in abs. EtOH and hydrogenated over PtO2 (200 mg) under H2 (60 psi) for 4 h. The catalyst was filtered off and the solvent removed resulting in the pale-brown solid 66. 1H NMR (400 MHz, CDCl3) delta1.22 (t, J=7.2, 6H), 3.03 (d, J=23.1, 2H), 3.70 (bs, 2H), 3.95-4.03 (m, 4H), 6.61 (d, J=8.4, 2H), 7.15 (dd, J=8.5, 2.4, 2H).
	With palladium on activated charcoal; hydrogen; In ethanol; at 40℃; for 6h;	General procedure: HATU (1.2 equiv) and DIEA (1.5 equiv) were added to a solutionof 2-fluoro-4-nitrobenzoic acid (1 equiv) and R6-NH2 (1 equiv) inCH2Cl2 at rt. The resulting mixture was heated to 25e40 C andstirred until the reaction was complete. The mixture was dilutedwith ethyl acetate, and the organic layer was washed with saline,dried over anhydrous Na2SO4 and filtered. The filtrate wasconcentrated and purified using chromatography to yield the intermediates33a-g. Intermediates 33a-g (1 equiv) were dissolved inethanol, and Pd/C (0.1 equiv)was added. The flask was flushed withH2 and stirred for 6 h at 40 C. The reaction mixture was filteredthrough a Celite pad and the filtrate was concentrated to dryness,yielding intermediates 34a-g.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1845 - 1854
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2015,vol. 190,p. 1958 - 1970
[3]Patent: WO2010/78449,2010,A2 .Location in patent: Page/Page column 152
[4]Journal of the American Chemical Society,1959,vol. 81,p. 3026,3029
[5]Journal of the American Chemical Society,1959,vol. 81,p. 3026,3029
[6]European Journal of Medicinal Chemistry,2015,vol. 101,p. 384 - 390
[7]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 765 - 772
[8]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 6313 - 6321
[9]Patent: US2008/287396,2008,A1 .Location in patent: Page/Page column 75-76
[10]European Journal of Medicinal Chemistry,2020,vol. 188

3
[ 2609-49-6 ]
[ 19734-15-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 4-toluenesulfonyl azide; potassium-t-butoxide In tetrahydrofuran; benzene at 20℃; for 0.0166667h; Inert atmosphere;
	(i) KOtBu, benzene, (ii) TsN₃; Multistep reaction;

Reference： [1]Beletskaya, Irina P.; Titanyuk, Igor D. [Journal of Organic Chemistry, 2022, vol. 87, # 5, p. 2748 - 2757]
[2]Regitz,M. et al. [Chemische Berichte, 1968, vol. 101, # 11, p. 3734 - 3743]

4
[ 455-19-6 ]
[ 2609-49-6 ]
[ 74518-96-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium ethanolate In ethanol for 0.5h; Ambient temperature;

Reference： [1]Hanna, Patrick E.; Gammans, Richard E.; Sehon, Russell D.; Lee, Man-Kil [Journal of Medicinal Chemistry, 1980, vol. 23, # 9, p. 1038 - 1044]

5
[ 939-97-9 ]
[ 2609-49-6 ]
[ 74518-95-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium ethanolate In ethanol for 0.5h; Ambient temperature;

Reference： [1]Hanna, Patrick E.; Gammans, Richard E.; Sehon, Russell D.; Lee, Man-Kil [Journal of Medicinal Chemistry, 1980, vol. 23, # 9, p. 1038 - 1044]

6
[ 2609-49-6 ]
[ 104-87-0 ]
[ 24325-70-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium ethanolate In ethanol for 0.5h; Ambient temperature;
	With sodium hydride In tetrahydrofuran at 50℃; for 0.5h; Inert atmosphere;

Reference： [1]Hanna, Patrick E.; Gammans, Richard E.; Sehon, Russell D.; Lee, Man-Kil [Journal of Medicinal Chemistry, 1980, vol. 23, # 9, p. 1038 - 1044]
[2]Fang, Zhengjun; Cao, Chenzhong; Chen, Guanfan [Journal of Physical Organic Chemistry, 2012, vol. 25, # 12, p. 1343 - 1350]

7
[ 2609-49-6 ]
[ 105-07-7 ]
[ 74518-94-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium ethanolate In ethanol for 0.5h; Ambient temperature;
	With sodium hydride In tetrahydrofuran at 50℃; for 0.5h; Inert atmosphere;

Reference： [1]Hanna, Patrick E.; Gammans, Richard E.; Sehon, Russell D.; Lee, Man-Kil [Journal of Medicinal Chemistry, 1980, vol. 23, # 9, p. 1038 - 1044]
[2]Fang, Zhengjun; Cao, Chenzhong; Chen, Guanfan [Journal of Physical Organic Chemistry, 2012, vol. 25, # 12, p. 1343 - 1350]

8
[ 100-11-8 ]
[ 122-52-1 ]
[ 2609-49-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	at 160℃; for 2h;	(i) Diethyl 4-nitrobenzylphosphonateA mixture of 4-nitrobenzyl bromide (2.05 g, 0.949 mmol) and triethylphosphite (2.23 g, 1.34 mmol) was heated at 1600C under a nitrogen atmosphere for 2 h.The excess triethylphosphite was removed in vacuo to give the sub-title compound as a brown oil (2.50 g, 96%).1H NMR (DMSO-d6): 8.20(2H, d, J=8.1Hz), 7.57(2H, dd, J=2.4Hz & J=8.8Hz),3.97(4H, q, J=7.0Hz), 3.48(2H, d, J=22.4Hz), 1.18(6H, t, J=7.0Hz). IR (KBr): 2982, 2910, 1601, 1521, 1392, 1347, 1254, 1028, 959, 864, 777,695 cm"1.HREIMS: Found 273.0765 calculated for CHHI6O5NP 273.0766
95%	at 160℃; for 2h;Inert atmosphere;	Synthesis of diethyl 4-nitrobenzylphosphonate (1) . Compound 1 was prepared according to a previous report. A mixture of 4-nitrobenzyl bromide (200 mg, 0.93 mmol) and triethylphosphite (216 mg, 1.30 mmol) was heated at 160 under a nitrogen atmosphere for 2 h. Excess triethylphosphite was removed under reduced pressure to provide 1 as a brown oil (241mg, 95%) .1H NMR (400 MHz, CDCl3) : delta 8.19 (dd, J = 8.8, 0.8 Hz, 2H) , 7.48 (dd, J = 8.8, 2.4 Hz, 2H) , 4.07 (dq, J = 7.6, 0.4 Hz, 2H) , 4.05 (dq, J = 7.6, 0.4 Hz, 2H) , 3.25 (d, J = 22.4 Hz, 2H) , 1.27 ppm (t, J = 6.8 Hz, 6H) ;13C NMR (100 MHz, CDCl3) : delta 139.7 (d,2J(C, P)= 8.9 Hz) , 130.6 (d,3J(C, P)= 6.4 Hz) , 123.7 (d,4J(C, P)= 2.9 Hz) , 62.4 (d,2J(C, P)= 6.7 Hz) , 34.0 (d,1J(C, P)= 136.7 Hz) , 16.4 ppm (d,3J(C, P)= 5.9 Hz) ; HRMS (MALDI-TOF) : m/z: calcd for C11H16NO5P 273.0766 [M]+; found: 273.0755.
89%	at 110℃; for 2h;	Into a 250-mL round bottom flask, was placed l-(bromomethyl)-4-mtrobenzene (15 g, 69 77 mmol, 1 OO equiv), t?ethyl phosphite (70 mL) The resulting solution was stirred for 2 h at HO0C in an oil bath The resulting mixture was concentrated under vacuum The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 10-1 1) This resulted in 17 g (89%) of the title compound as a yellow oil.

89%	for 0.666667h;Reflux;	A mixture of 4-nitrobenzyl bromide (1, 10mmol, 2.16g) and triethyl phosphite (30mmol, 4.98g) was heated at reflux in an oil bath for 40min. After the mixture was cooled, the excess triethyl phosphite was removed in vacuo. The intermediate 2 was further used without purification. Yield 89%, brown oil; 1H NMR (500MHz, CDCl3) delta 8.19 (2H, d, J=8.7Hz), 7.58 (2H, dd, J=8.7Hz, 2.3Hz), 4.07 (4H, q, J=7.1Hz), 3.48 (2H, d, J=22.4Hz), 1.19 (6H, t, J=7.1Hz); ESI-MS m/z: 274.1 [M+H]+
66%	In DMF (N,N-dimethyl-formamide); at 155℃; for 1.5h;	lOg (46.3mmol) of 4-nitrobenzylbromide and 10. 03G (60.3mmol) of triethyl phosphite are dissolved in 25ML dimethylformamide. The reaction mixture is held at 155 C for 1.5h, diluted with 20ML water and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated to yield 8. 35G (66%) of the crude title compound. MS: m/e = 274.1 (M++H).
55%	at 97℃; for 1h;	(i) Diethyl 4-nitrobenzylphosphonate (3) A flask with 4-nitrobenzyl bromide (2, 0.997 g, 4.62 mmol) and triethyl phosphite (2.5 mL, 14.08 mmol) was partially immersed in an ultrasonic bath at 25 C, the temperature was gradually raised to 90 C and held at that temperature until the substrate was completely dissolved. Stirring and heating were continued in a metal bath of Wood's alloy at 97 C for 1 h. After cooling, the excess of triethyl phosphite was removed from the reaction mixture by extraction with hexane (4 * 3 mL). The residue was dried under reduced pressure to obtain ester 3 as yellow oil. Yield: 0.626 g (55%). 1H NMR (300.13 MHz, CDCl3): delta 8.23 (d, 3JHH = 8.8 Hz, 2H, arom. H), 7.53 (dd, 3JHH = 8.8 Hz, 4JPH = 2.5 Hz, 2H, arom. H), 3.92 (dq, 3JPH = 7.0 Hz, 3JHH = 7.0 Hz, 4H, O-CH2-CH3), 3.30 (d, 2JPH = 22.4 Hz, 2H, CH2-P), 1.32 ppm (t, 3JHH = 7.0 Hz, 6H, O-CH2-CH3). 31P{1H} NMR (121.50 MHz, CDCl3): delta 25.06 ppm (s).
	In tetrahydrofuran; at 70℃; for 24h;Inert atmosphere;	General procedure: Diphenylbutadiene derivatives utilized in this investigation were prepared by using Horner-Wadsworth-Emmons reaction [23] (Scheme 1a) in about 35-60% yields. In a typical procedure, triethyl phosphite (5.74 mmol) was added to the THF solution of benzyl bromide (2.3 mmol) and refluxed for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and further cooled to 0 C using an ice bath. Sodium hydride (11.5mmol) was added to this mixture and stirred for 5 min. Aldehyde (2.3 mmol) was subsequently added drop wise to the pale/dark pink colored solution and stirring was continued for additional 30 min. In the case of methyl substituted aldehydes, corresponding (E) geometric isomer of alpha-methyl cinnamaldehyde (Aldrich) was used. Thin Layer Chromatography (TLC) was utilized to monitor the progress of the reaction and the reaction was quenched by adding water. The organic layer was extracted using dichloromethane and concentrated under reduced pressure. The crude reaction mixture so obtained was purified by column chromatography using silica gel, 5% ethyl acetate in petroleum ether. Starting materials, 4-methylcinnamaldehyde required for the synthesis of ( 2) and nitro cinnamaldehyde required for synthesis of (3) and (5), were obtained by DDQ oxidation of 4-allyl toluene [40] (Scheme 1b) and by simple nitration using a nitrating mixture generated by mixing KNO3 with H2SO4 of alpha-methyl-cinnamaldehyde (scheme 1c), respectively. Characterization data for all the synthesized dienes were given in the Supplementary information.
	at 120℃; for 2h;sealed tube; Neat (no solvent);	A neat solution of 4-nitrobenzylbromide (8.4 g, 39 mmol) and triethylphosphite (7.5 mL, 43 mmol) was stirred while heating to 120 C. in a sealed tube for 2 h. The mixture was then cooled and excess triethylphosphite was removed under high vacuum. The crude product was used without purification. 1H NMR (400 MHz, CDCl3) delta 1.26 (t, J=7.1, 6H), 3.24 (d, J=23.1, 2H), 4.01-4.10 (m, 4H), 7.47 (dd, J=8.7, 2.4, 2H), 8.18 (d, J=8.3, 2H).

Reference： [1]Macromolecules,2004,vol. 37,p. 2460 - 2470
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 6116 - 6125
[3]Patent: WO2008/38018,2008,A1 .Location in patent: Page/Page column 53
[4]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1845 - 1854
[5]Patent: WO2019/141246,2019,A1 .Location in patent: Paragraph 00242-00243
[6]Tetrahedron,1998,vol. 54,p. 1691 - 1714
[7]Patent: WO2010/78449,2010,A2 .Location in patent: Page/Page column 152
[8]Journal of Medicinal Chemistry,2013,vol. 56,p. 9982 - 10002
[9]European Journal of Medicinal Chemistry,2016,vol. 124,p. 1006 - 1018
[10]Chemistry - A European Journal,2002,vol. 8,p. 4470 - 4474
[11]Journal of the Chemical Society. Perkin Transactions 2 (2001),1996,vol. 4,p. 713 - 718
[12]Synthetic Communications,2011,vol. 41,p. 3462 - 3468
[13]Journal of the American Chemical Society,1996,vol. 118,p. 6841 - 6852
[14]Tetrahedron Letters,2012,vol. 53,p. 7108 - 7112
[15]ChemPhysChem,2019,vol. 20,p. 2836 - 2851
[16]Patent: WO2003/99763,2003,A1 .Location in patent: Page 34
[17]Journal of Molecular Structure,2014,vol. 1074,p. 240 - 249
[18]Journal of the Chemical Society. Perkin transactions II,1973,p. 25 - 33
[19]Tetrahedron,1985,vol. 41,p. 427 - 434
[20]Journal of the Chemical Society. Chemical communications,1986,p. 1516 - 1517
[21]Journal of the Chemical Society. Perkin transactions II,1994,p. 2101 - 2108
[22]Journal of Organic Chemistry,1998,vol. 63,p. 3706 - 3716
[23]Journal of Physical Organic Chemistry,2000,vol. 13,p. 587 - 590
[24]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2001,vol. 40,p. 965 - 973
[25]Journal of Materials Chemistry,2002,vol. 12,p. 868 - 878
[26]Journal of Organic Chemistry,2004,vol. 69,p. 719 - 726
[27]Angewandte Chemie - International Edition,2007,vol. 46,p. 4481 - 4485
[28]ChemBioChem,2010,vol. 11,p. 2125 - 2131
[29]Journal of Medicinal Chemistry,2013,vol. 56,p. 5843 - 5859
[30]Journal of Photochemistry and Photobiology A: Chemistry,2014,vol. 293,p. 40 - 49
[31]European Journal of Medicinal Chemistry,2015,vol. 95,p. 220 - 229
[32]Photochemistry and Photobiology,2015,vol. 91,p. 1324 - 1331
[33]Journal of Photochemistry and Photobiology A: Chemistry,2016,vol. 321,p. 55 - 62
[34]Dyes and Pigments,2016,vol. 132,p. 291 - 305
[35]Patent: US2008/287396,2008,A1 .Location in patent: Page/Page column 75-76

9
3-(4-dimethylamino-phenyl)-propenal [ No CAS ]
[ 2609-49-6 ]
[ 67309-70-0 ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium hydroxide In ethanol at 23℃;
48%	With sodium ethanolate In ethanol; N,N-dimethyl-formamide for 3h; Ambient temperature;
25%	Stage #1: diethyl p-nitrobenzylphosphonate With sodium methylate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-(4-dimethylamino-phenyl)-propenal In N,N-dimethyl-formamide at 20℃;

With sodium hydroxide; tetra-(n-butyl)ammonium iodide

Reference： [1]Kukkonen, Esa; Lahtinen, Elmeri; Myllyperkiö, Pasi; Haukka, Matti; Konu, Jari [New Journal of Chemistry, 2021, vol. 45, # 15, p. 6640 - 6650]
[2]Akiyama, Shuzo; Tajima, Kunihiko; Nakatsuji, Shin'ichi; Nakashima, Kenichiro; Abiru, Kazuko; Watanabe, Miwa [Bulletin of the Chemical Society of Japan, 1995, vol. 68, # 7, p. 2043 - 2052]
[3]Singh, Anil K.; Mahalaxmi, Ganapati R. [Photochemistry and Photobiology, 2000, vol. 71, # 4, p. 387 - 396]
[4]Fialkov,Yu.A. et al. [Journal of Organic Chemistry USSR (English Translation), 1978, vol. 14, p. 939 - 946][Zhurnal Organicheskoi Khimii, 1978, vol. 14, # 5, p. 1005 - 1012]

10
[ 2609-49-6 ]
[ 1205-62-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	With hydrogenchloride; In water; for 8h;Reflux;	Compound 3 (0.626 g, 2.56 mmol) was hydrolyzed by refluxingwith concentrated hydrochloric acid (10 mL) for 8 h. After cooling,beige fine crystalline product 1 was collected by vacuum filtration,washed with ice-cold water (2 3 mL) and dried under reducedpressure. Yield: 0.348 g (62%). 1H NMR (300.13 MHz, D2O-Na2CO3):d 7.98 (d, 3JHH = 8.9 Hz, 2H, arom. H), 7.31 (dd, 4JPH = 2.3 Hz,3JHH = 8.9 Hz, 2H, arom. H), 2.92 ppm (d, 2JPH = 20.8 Hz, 2H, CH2AP).31P{1H} NMR (121.50 MHz, D2O-Na2CO3): d 18.16 ppm (s).
	With hydrogenchloride; water; at 120℃; for 6h;	A mixture of diethyl (4-nitrobenzyl)phosphonate (I, 700 mg, 2.56 mmol) and 5 mL concentrated HCI was heated at 1200C for 6 hours. The cooled mixture was then diluted with water, the suspended solid isolated by filtration, washed with water and dried in vacuo to afford 500mg of (4-nitrobenzyl)phosphonic acid (II) which was used without further purification. This material was mixed with oxalyl chloride (5 mL) and heated at 650C under nitrogen for 12hr after which time the mixture was concentrated in vacuo to afford crude (4- nitrobenzyl)phosphonic dichloride (III). This dichloride was dissolved in dry methylene chloride(5 mL), cooled in ice under nitrogen and treated with n-butanol (1.05 mL, 11.5mmol) andDIPEA (0.88 mL, 5.07 mmol). After 1 hr at room temperature the mixture was concentrated in vacuo and chromatographed over silica gel eluting with EtOAc:hexane 30-70% to yield 498mg of dibutyl (4-nitrobenzyl)phosphonate (IV, R = nBu) yield: 66%). A solution of this phosphonate ester in methanol (5 mL) was hydrogenated in the presence of 5% Pd/C (32mg) for 2h The suspension was filtered and the filtrate concentrated in vacuo to afford 368mg of dibutyl (4-aminobenzyl)phosphonate (yield: 82%).A mixture of dibutyl (4-aminobenzyl)phosphonate (18mg, O.Obetammol), Lambda/-[3-([2-chloro- 5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-Lambda/-methylmethanesulfonamide XLIa (20mg, O.Odeltammol), TFA (12uL, 0.15mmol) and TFE (0.5mL) was heated at 105Cunder nitrogen in a microwave reactor for 40 minutes. The resulting mixture was concentrated in vacuo and the residue purified by preparative HPLC (MDP) to afford 24mg of dibutyl [4-({4- [({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzyl]phosphonate trifluoroacetate (Example 26, yield 73%). 1H NMR (400 MHz, CD3OD) delta = 0.91 (t, J = 7.5 Hz, 6 H), 1.30 - 1.42 (m, 4 H), 1.53 - 1.65 (m, 4 H), 3.1 1 (s, 3 H), 3.17 (s, 3 H), 3.22 (d, J = 21.7 Hz, 2 H), 3.91 - 4.02 (m, 4 H), 4.94 (s, 2 H), 7.25 (dd, J = 8.5, 2.4 Hz, 2 H), 7.33 - 7.41 (m, 3 H), 7.73 (d, J = 7.3 Hz, 1 H), 8.20 (s, 1 H), 8.45 (dd, J = 4.7, 1.9 Hz, 1 H). MS (ES+): m/z 659.30 (100) [MH+]; HPLC: tR = 1.16 min (UPLC, purity).
	With hydrogenchloride; water; for 24h;Reflux;	General procedure: Diethyl benzylphosphonate 59 (6, 500 mg, 0.0022 mmol) was treated with conc. HCl (8 mL) and stirred under reflux for 24 h in a round bottom flask. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered, washed with cold water and dried in vacuum. Benzylphosphonic acid (2) was isolated in 70% yield (mp 160-163 C).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9982 - 10002
[2]Journal of Molecular Structure,2014,vol. 1074,p. 240 - 249
[3]Journal of the Chemical Society. Perkin transactions II,1973,p. 25 - 33
[4]Journal of the Chemical Society. Perkin transactions II,1994,p. 2101 - 2108
[5]Patent: WO2010/141406,2010,A2 .Location in patent: Page/Page column 61-62
[6]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4462 - 4471

11
[ 2609-49-6 ]
[ 100-52-7 ]
[ 1694-20-8 ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: To a solution of CH3ONa (1.350 g, 7.5 mmol) in DMF (10 mL), 2 (1.296 g, 5 mmol) was added. After the mixture was stirred at 0 C under nitrogen for 1 h, a substituted benzaldehyde (7.5 mmol) in DMF (5 mL) was added dropwise to the solution. The reaction mixture was slowly warmed to room temperature and stirred overnight. Ice water was added, and the mixture was filtered to yield the crude product. Purification of the crude product by recrystallisation from ethyl acetate provided the target product.

Reference： [1]Bulletin of the Chemical Society of Japan,1995,vol. 68,p. 2043 - 2052
[2]European Journal of Medicinal Chemistry,2015,vol. 95,p. 220 - 229
[3]Journal of the American Chemical Society,2005,vol. 127,p. 11720 - 11726
[4]Journal of Physical Organic Chemistry,2012,vol. 25,p. 1343 - 1350

12
[ 2609-49-6 ]
[ 123-11-5 ]
[ 4648-33-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium etoxide In ethanol; N,N-dimethyl-formamide for 3h; Ambient temperature;
66%	With sodium hydroxide In ethanol at 23℃;
39%	With 18-crown-6 ether; sodium methoxide In N,N-dimethyl-formamide at 0 - 120℃; for 21h;	7 Example 7: Synthesis of (E)-4-(4-methoxystyryl)-N-methylaniline (control B) NaOMe (3.24 g, 60 mmol) and 18-Crown-6 (3.17 g, 12 mmol) were added to a solution of diethyl (4-nitrobenzyl)phosphonate (8.0 g, 30 mmol) in DMF (60 mL). The reaction mixture was stirred at rt for 5 minutes and a solution of 4-methoxybenzaldehyde (4.9 g, 36 mmol) in DMF (25 mL) was added dropwise at 0°C. The mixture was stirred at rt for 1 hour and then at 120°C for 20 hours. The mixture was quenched with water and the precipitate was filtered and washed with water to give (E)-1-methoxy-4-(4-nitrostyryl)benzene as a yellow solid (3.0 g, 39%).

39%	With 18-crown-6 ether; sodium methoxide In N,N-dimethyl-formamide at 0 - 120℃; for 21h;	7 Example 7: Synthesis of (E)-4-(4-methoxystyryl)-N-methylaniline (control B) NaOMe (3.24 g, 60 mmol) and 18-Crown-6 (3.17 g, 12 mmol) were added to a solution of diethyl (4-nitrobenzyl)phosphonate (8.0 g, 30 mmol) in DMF (60 mL). The reaction mixture was stirred at rt for 5 minutes and a solution of 4-methoxybenzaldehyde (4.9 g, 36 mmol) in DMF (25 mL) was added dropwise at 0°C. The mixture was stirred at rt for 1 hour and then at 120°C for 20 hours. The mixture was quenched with water and the precipitate was filtered and washed with water to give (E)-1-methoxy-4-(4-nitrostyryl)benzene as a yellow solid (3.0 g, 39%).
	Stage #1: diethyl p-nitrobenzylphosphonate With sodium methoxide In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: 4-methoxy-benzaldehyde In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;
	With sodium hydride In tetrahydrofuran at 50℃; for 0.5h; Inert atmosphere;
	With sodium methoxide In N,N-dimethyl-formamide

Reference： [1]Akiyama, Shuzo; Tajima, Kunihiko; Nakatsuji, Shin'ichi; Nakashima, Kenichiro; Abiru, Kazuko; Watanabe, Miwa [Bulletin of the Chemical Society of Japan, 1995, vol. 68, # 7, p. 2043 - 2052]
[2]Kukkonen, Esa; Lahtinen, Elmeri; Myllyperkiö, Pasi; Haukka, Matti; Konu, Jari [New Journal of Chemistry, 2021, vol. 45, # 15, p. 6640 - 6650]
[3]Current Patent Assignee: MASS GENERAL BRIGHAM INC; DANA-FARBER CANCER INSTITUTE - WO2021/257650, 2021, A1 Location in patent: Paragraph 00147-00148
[4]Current Patent Assignee: MASS GENERAL BRIGHAM INC; DANA-FARBER CANCER INSTITUTE - WO2021/257650, 2021, A1 Location in patent: Paragraph 00147-00148
[5]Lu, Chuanjun; Guo, Yueyan; Yan, Jun; Luo, Zonghua; Luo, Hai-Bin; Yan, Ming; Huang, Ling; Li, Xingshu [Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5843 - 5859]
[6]Fang, Zhengjun; Cao, Chenzhong; Chen, Guanfan [Journal of Physical Organic Chemistry, 2012, vol. 25, # 12, p. 1343 - 1350]
[7]Pankova, Alena S.; Sorokina, Mariia V.; Kuznetsov, Mikhail A. [Tetrahedron Letters, 2015, vol. 56, # 40, p. 5381 - 5385]

13
[ 2609-49-6 ]
[ 100-10-7 ]
[ 2844-15-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.25h; Stage #2: 4-dimethylamino-benzaldehyde In N,N-dimethyl-formamide; mineral oil for 1h;
68%	With sodium hydroxide In ethanol at 23℃;
63%	With sodium ethanolate In ethanol; N,N-dimethyl-formamide for 3h; Ambient temperature;

	With sodium hydride In N,N-dimethyl-formamide
	With sodium methylate In ethanol; N,N-dimethyl-formamide for 3h; Reflux;
	Stage #1: diethyl p-nitrobenzylphosphonate With sodium methylate In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: 4-dimethylamino-benzaldehyde In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;
	With sodium hydride In tetrahydrofuran at 50℃; for 0.5h; Inert atmosphere;

Reference： [1]Cullinane, Carleen; Donnelly, Paul S.; Hayne, David J.; Lim, SinChun; McLean, Catriona A.; Noor, Asif; Roselt, Peter D.; Van Zuylekom, Jessica K.; White, Jonathan M. [Inorganic Chemistry, 2020, vol. 59, # 16, p. 11658 - 11669]
[2]Kukkonen, Esa; Lahtinen, Elmeri; Myllyperkiö, Pasi; Haukka, Matti; Konu, Jari [New Journal of Chemistry, 2021, vol. 45, # 15, p. 6640 - 6650]
[3]Akiyama, Shuzo; Tajima, Kunihiko; Nakatsuji, Shin'ichi; Nakashima, Kenichiro; Abiru, Kazuko; Watanabe, Miwa [Bulletin of the Chemical Society of Japan, 1995, vol. 68, # 7, p. 2043 - 2052]
[4]Yang, Jye-Shane; Hwang, Chung-Yu; Hsieh, Chia-Chun; Chiou, Shih-Yi [Journal of Organic Chemistry, 2004, vol. 69, # 3, p. 719 - 726]
[5]Location in patent: experimental part Wu, Chunying; Wei, Jinjun; Tian, Donghua; Feng, Yue; Miller, Robert H.; Wang, Yanming [Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6682 - 6688]
[6]Lu, Chuanjun; Guo, Yueyan; Yan, Jun; Luo, Zonghua; Luo, Hai-Bin; Yan, Ming; Huang, Ling; Li, Xingshu [Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5843 - 5859]
[7]Fang, Zhengjun; Cao, Chenzhong; Chen, Guanfan [Journal of Physical Organic Chemistry, 2012, vol. 25, # 12, p. 1343 - 1350]

14
[ 2609-49-6 ]
[ 104-88-1 ]
(E)-4-chloro-4'-nitrostilbene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		64.a a a 4-[2-(4-Chloro-phenyl)-vinyl]-1-nitro-benzene Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 4-chloro-benzaldehyde. Yellow solid. Yield=95%. MS: m/e=259.1 (M+).
65%	With ethanol; sodium ethanolate for 16h;
	With sodium hydride In N,N-dimethyl-formamide

With sodium hydride In tetrahydrofuran at 50℃; for 0.5h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2003/232883, 2003, A1
[2]Kuo, Elizabeth A.; Hambleton, Philip T.; Kay, David P.; Evans, Phillip L.; Matharu, Saroop S.; Little, Edward; McDowall, Neil; Jones, C. Beth; Hedgecock, Charles J. R.; Yea, Christopher M.; Chan, A. W. Edith; Hairsine, Peter W.; Ager, Ian R.; Tully, W. Roger; Williamson, Richard A.; Westwood, Robert [Journal of Medicinal Chemistry, 1996, vol. 39, # 23, p. 4608 - 4621]
[3]Yang, Jye-Shane; Hwang, Chung-Yu; Hsieh, Chia-Chun; Chiou, Shih-Yi [Journal of Organic Chemistry, 2004, vol. 69, # 3, p. 719 - 726]
[4]Fang, Zhengjun; Cao, Chenzhong; Chen, Guanfan [Journal of Physical Organic Chemistry, 2012, vol. 25, # 12, p. 1343 - 1350]

15
[ 2609-49-6 ]
[ 99970-84-0 ]
4,4'-bis(p-nitrostyryl)-[2,2']-bipyridine [ No CAS ]

Reference： [1]Tetrahedron Letters,1996,vol. 37,p. 7503 - 7506
[2]New Journal of Chemistry,2001,vol. 25,p. 1553 - 1566

16
[ 2609-49-6 ]
[ 104-55-2 ]
[ 27370-90-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium methylate In N,N-dimethyl-formamide
	With sodium ethanolate In ethanol at 20℃;	4.3. Synthesis of aniline analogues General procedure: With the exception of 10c, 10d and 10i all the anilines required for the synthesis of the isatin analogues were commercially available. Sodium (105 mmol) was allowed to react with ethanol (109 mL) in small portions over a period of 2 h. The resulting mixture was added at room temperature to diethyl 4- or diethyl 3-nitrobenzylphosphonate (11a, b, 100 mmol)26 and benzaldehyde (12, 100 mmol) or cinnamaldehyde (14, 100 mmol) dissolved in ethanol (164 mL) over a period of 1.5 h. Stirring was continued for 20 h and the thick yellow precipitate was collected by vacuum filtration and washed with 40 mL ethanol followed by 40 mL petroleum ether.27 The nitro-functionalized intermediates 13a, 13b and 15 thus obtained (yield 69-71%) were used without further purification in the following reaction. The nitro derivatives (25 mmol) were suspended in 400 mL methanol and the reaction flask was purged with argon. A quantity of 3% (of the weight of the nitro derivative) of Pd/C (10%) was prewet with 2 mL water and added to 10 mL methanol. This mixture was carefully added to the reaction. The atmosphere was replaced by hydrogen and the reaction was stirred at room temperature for 24 h during which the reaction became a clear solution. The catalyst was removed by filtration through a bed of Celite and the methanol solvent was evaporated under reduced pressure. The resulting aniline derivative was converted to the corresponding hydrochloride salt in CH2Cl2 (70 mL). A volume of 150 mL diethyl ether may be added to the acidic CH2Cl2 solution to facilitate precipitation of the salt (yield 41-95%).

Reference： [1]Singh, Anil K.; Darshi, Manjula; Kanvah, Sriram [Journal of Physical Chemistry A, 2000, vol. 104, # 3, p. 464 - 471]
[2]Location in patent: experimental part Manley-King, Clarina I.; Bergh, Jacobus J.; Petzer, Jacobus P. [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 261 - 274]

17
[ 2609-49-6 ]
[ 118688-53-2 ]
C₄₈H₃₃N₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydride In tetrahydrofuran at 20℃; for 4h;

Reference： [1]Brunel; Ledoux; Zyss; Blanchard-Desce [Chemical Communications, 2001, # 10, p. 923 - 924]

18
[ 2609-49-6 ]
4-carboxaldehyde-16-(4'-dihexylaminostyryl)[2.2]paracyclophane [ No CAS ]
4-(4'-dihexylaminostyryl)-16-(4''-nitrostyryl)-[2.2]paracyclophane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium ethanolate In N,N-dimethyl-formamide at 0 - 20℃; for 12h;

Reference： [1]Zyss; Ledoux; Volkov; Chernyak; Mukamel; Bartholomew; Bazan [Journal of the American Chemical Society, 2000, vol. 122, # 48, p. 11956 - 11962]

19
(E)-2-methyl-3-(4-nitrophenyl)acrylaldehyde [ No CAS ]
[ 2609-49-6 ]
1,4-di(4-nitrophenyl)-2-methylbuta-1E,3E-diene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	Stage #1: diethyl p-nitrobenzylphosphonate With sodium methylate In N,N-dimethyl-formamide for 0.333333h; Stage #2: (E)-2-methyl-3-(4-nitrophenyl)acrylaldehyde In N,N-dimethyl-formamide at 20℃; for 0.5h;
	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: (E)-2-methyl-3-(4-nitrophenyl)acrylaldehyde In tetrahydrofuran at 0℃; for 0.5h;	2.1 Synthesis General procedure: Diphenylbutadiene derivatives utilized in this investigation were prepared by using Horner-Wadsworth-Emmons reaction [23] (Scheme 1a) in about 35-60% yields. In a typical procedure, triethyl phosphite (5.74 mmol) was added to the THF solution of benzyl bromide (2.3 mmol) and refluxed for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and further cooled to 0 °C using an ice bath. Sodium hydride (11.5mmol) was added to this mixture and stirred for 5 min. Aldehyde (2.3 mmol) was subsequently added drop wise to the pale/dark pink colored solution and stirring was continued for additional 30 min. In the case of methyl substituted aldehydes, corresponding (E) geometric isomer of α-methyl cinnamaldehyde (Aldrich) was used. Thin Layer Chromatography (TLC) was utilized to monitor the progress of the reaction and the reaction was quenched by adding water. The organic layer was extracted using dichloromethane and concentrated under reduced pressure. The crude reaction mixture so obtained was purified by column chromatography using silica gel, 5% ethyl acetate in petroleum ether. Starting materials, 4-methylcinnamaldehyde required for the synthesis of ( 2) and nitro cinnamaldehyde required for synthesis of (3) and (5), were obtained by DDQ oxidation of 4-allyl toluene [40] (Scheme 1b) and by simple nitration using a nitrating mixture generated by mixing KNO3 with H2SO4 of α-methyl-cinnamaldehyde (scheme 1c), respectively. Characterization data for all the synthesized dienes were given in the Supplementary information.

Reference： [1]Singh; Kanvah [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 10, p. 965 - 973]
[2]Agnihotri, Harsha; Palakollu, Veerabhadra; Kanvah, Sriram [Journal of Photochemistry and Photobiology A: Chemistry, 2014, vol. 293, p. 40 - 49]

20
[ 2609-49-6 ]
[ 15174-47-7 ]
1-phenyl-2-methyl-4-(4-nitrophenyl)buta-1E,3E-diene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: diethyl p-nitrobenzylphosphonate With sodium methylate In N,N-dimethyl-formamide for 0.333333h; Stage #2: α-methyl-trans-cinnamaldehyde In N,N-dimethyl-formamide at 20℃; for 0.5h;
	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: α-methyl-trans-cinnamaldehyde In tetrahydrofuran at 0℃; for 0.5h;	2.1 Synthesis General procedure: Diphenylbutadiene derivatives utilized in this investigation were prepared by using Horner-Wadsworth-Emmons reaction [23] (Scheme 1a) in about 35-60% yields. In a typical procedure, triethyl phosphite (5.74 mmol) was added to the THF solution of benzyl bromide (2.3 mmol) and refluxed for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and further cooled to 0 °C using an ice bath. Sodium hydride (11.5mmol) was added to this mixture and stirred for 5 min. Aldehyde (2.3 mmol) was subsequently added drop wise to the pale/dark pink colored solution and stirring was continued for additional 30 min. In the case of methyl substituted aldehydes, corresponding (E) geometric isomer of α-methyl cinnamaldehyde (Aldrich) was used. Thin Layer Chromatography (TLC) was utilized to monitor the progress of the reaction and the reaction was quenched by adding water. The organic layer was extracted using dichloromethane and concentrated under reduced pressure. The crude reaction mixture so obtained was purified by column chromatography using silica gel, 5% ethyl acetate in petroleum ether. Starting materials, 4-methylcinnamaldehyde required for the synthesis of ( 2) and nitro cinnamaldehyde required for synthesis of (3) and (5), were obtained by DDQ oxidation of 4-allyl toluene [40] (Scheme 1b) and by simple nitration using a nitrating mixture generated by mixing KNO3 with H2SO4 of α-methyl-cinnamaldehyde (scheme 1c), respectively. Characterization data for all the synthesized dienes were given in the Supplementary information.

Reference： [1]Singh; Kanvah [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 10, p. 965 - 973]
[2]Agnihotri, Harsha; Palakollu, Veerabhadra; Kanvah, Sriram [Journal of Photochemistry and Photobiology A: Chemistry, 2014, vol. 293, p. 40 - 49]

21
[ 2609-49-6 ]
[ 217655-10-2 ]
N,N-bis(2-hexyloctyl)-4-[(E)-2-(4-nitrophenyl)ethenyl]aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h;
	With sodium hydride In 1,2-dimethoxyethane

Reference： [1]Meier, Herbert; Gerold, Juergen; Kolshorn, Heinz; Muehling, Bastian [Chemistry - A European Journal, 2004, vol. 10, # 2, p. 360 - 370]
[2]Meier, Herbert; Gerold, Juergen; Kolshorn, Heinz; Baumann, Wolfram; Bletz, Michael [Angewandte Chemie - International Edition, 2002, vol. 41, # 2, p. 292 - 295]

22
[ 2609-49-6 ]
[ 532948-22-4 ]
N,N-bis(2-hexyloctyl)-4-((E)-2-{4-[(E)-2-(4-nitrophenyl)ethenyl]phenyl}ethenyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hydride In 1,2-dimethoxyethane at 20℃; for 0.25h; Stage #2: 4-((E)-2-{4-[bis(2-hexyloctyl)amino]phenyl}ethenyl)benzaldehyde In 1,2-dimethoxyethane for 3h; Heating; Further stages.;
	With sodium hydride In 1,2-dimethoxyethane

Reference： [1]Meier, Herbert; Gerold, Juergen; Kolshorn, Heinz; Muehling, Bastian [Chemistry - A European Journal, 2004, vol. 10, # 2, p. 360 - 370]
[2]Meier, Herbert; Gerold, Juergen; Kolshorn, Heinz; Baumann, Wolfram; Bletz, Michael [Angewandte Chemie - International Edition, 2002, vol. 41, # 2, p. 292 - 295]

23
[ 2609-49-6 ]
[ 532948-29-1 ]
N,N-bis(2-hexyloctyl)-4-[(E)-2-(4-{(E)-2-[4-((E)-2-{4-[(E)-2-(4-nitrophenyl)ethenyl]phenyl}ethenyl)phenyl]ethenyl}phenyl)ethenyl]aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hydride In 1,2-dimethoxyethane at 20℃; for 0.25h; Stage #2: 4-[(E)-2-(4-{(E)-2-[4-((E)-2-{4-[bis(2-hexyloctyl)amino]phenyl}ethenyl)phenyl]ethenyl}phenyl)ethenyl]benzaldehyde In 1,2-dimethoxyethane for 3h; Heating; Further stages.;
	With sodium hydride In 1,2-dimethoxyethane

Reference： [1]Meier, Herbert; Gerold, Juergen; Kolshorn, Heinz; Muehling, Bastian [Chemistry - A European Journal, 2004, vol. 10, # 2, p. 360 - 370]
[2]Meier, Herbert; Gerold, Juergen; Kolshorn, Heinz; Baumann, Wolfram; Bletz, Michael [Angewandte Chemie - International Edition, 2002, vol. 41, # 2, p. 292 - 295]

24
[ 2609-49-6 ]
[ 433719-66-5 ]
(4,12)-bis(4'-dihexylaminostyryl)-(7,15)-bis(4''-nitrostyryl)[2.2]paracyclophane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃;

Reference： [1]Bartholomew, Glenn P.; Bazan, Guillermo C. [Journal of the American Chemical Society, 2002, vol. 124, # 18, p. 5183 - 5196]

25
[ 2609-49-6 ]
[ 433719-63-2 ]
(4,7,12)-tris(4'-dihexylaminostyryl)-15-(4''-nitrostyryl)[2.2]paracyclophane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃;

Reference： [1]Bartholomew, Glenn P.; Bazan, Guillermo C. [Journal of the American Chemical Society, 2002, vol. 124, # 18, p. 5183 - 5196]

26
[ 2609-49-6 ]
(E,E)-4-{4-(3,4,5-tridodecyloxystyryl)-2,5-bis[(S)-2-methylbutoxy]styryl}-2,5-bis[(S)-2-methylbutoxy]benzaldehyde [ No CAS ]
(E,E,E)-4-[4-{4-(3,4,5-tridodecyloxystyryl)-2,5-bis[(S)-2-methylbutoxy]styryl}-2,5-bis[(S)-2-methylbutoxy]styryl]nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: diethyl p-nitrobenzylphosphonate With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: (E,E)-4-{4-(3,4,5-tridodecyloxystyryl)-2,5-bis[(S)-2-methylbutoxy]styryl}-2,5-bis[(S)-2-methylbutoxy]benzaldehyde In N,N-dimethyl-formamide at 20℃; for 4h; Further stages.;

Reference： [1]Peeters, Emiel; Van Hal, Paul A.; Meskers, Stefan C. J.; Janssen, Rene A. J.; Meijer [Chemistry - A European Journal, 2002, vol. 8, # 19, p. 4470 - 4474]

27
[ 2609-49-6 ]
[ 506417-48-7 ]
[ 506417-53-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: diethyl p-nitrobenzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5h; Stage #2: 4-benzyloxy-hept-6-enal In tetrahydrofuran; hexane at 20℃;

Reference： [1]Guo, Xin; Basu, Kallol; Cabral, Jose A.; Paquette, Leo A. [Organic Letters, 2003, vol. 5, # 6, p. 789 - 792]

28
[ 2609-49-6 ]
(E)-4-{4-methyl-2,5-bis[(S)-2-methylbutoxy]styryl}-2,5-bis[(S)-2-methylbutoxy]benzaldehyde [ No CAS ]
[ 626255-53-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: diethyl p-nitrobenzylphosphonate With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: (E)-4-{4-methyl-2,5-bis[(S)-2-methylbutoxy]styryl}-2,5-bis[(S)-2-methylbutoxy]benzaldehyde In N,N-dimethyl-formamide at 20℃; for 4h;

Reference： [1]Precup-Blaga; Garcia-Martinez; Schenning; Meijer [Journal of the American Chemical Society, 2003, vol. 125, # 42, p. 12953 - 12960]

29
[ 2609-49-6 ]
[ 123415-45-2 ]
[ 1026092-57-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hydride In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 1,4-di(n-dodecyloxy)benzene-2,5-dicarboxaldehyde In tetrahydrofuran at 20℃; for 4h;

Reference： [1]Varghese, Reji; George, Subi J.; Ajayaghosh, Ayyappanpillai [Chemical Communications, 2005, # 5, p. 593 - 595]

30
[ 2609-49-6 ]
[ 90134-10-4 ]
[ 122258-50-8 ]

Reference： [1]Macromolecules,2004,vol. 37,p. 2460 - 2470

31
[ 98-01-1 ]
[ 2609-49-6 ]
[ 2827-56-7 ]
[ 68-12-2 ]
1-[[[[5-(4-nitrobenzene)ethenyl]-2-furanyl]-methylene]-amino]-2,4-imidazolidinedione [ No CAS ]

Reference： [1]Pharmacy and Pharmacology Communications,1998,vol. 4,p. 477 - 479

32
[ 23100-12-1 ]
[ 2609-49-6 ]
[ 938435-66-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium methylate; In methanol; for 1h;Heating / reflux;	Sodium methoxide (1 M in methanol, 5.0 ml) was added slowly into a solution of diethyl-(4-nitro-benzyl)-phosphonate (546 mg, 2.0 mmol) and 2- chloro-5-rhoyridyl aldehyde (283 mg, 2.0 mmol) in methanol (5.0 ml). The <n="44"/>reaction mixture was then refluxed for 1 h. After cooled down to 0 0C, yellow precipitate was filtered and washed with cold methanol to obtain product 3 (458 mg, Yield: 88%), which was used directly for next step without further purification. 3: 1H NMR (200 MHz, CDCl3): delta.8.53 (IH, d, J= 2.4 Hz), 8.25 (2H, d, J= 8.8 Hz), 7.85 (IH, d, d, J1 = 8.4 Hz, J2 = 2.4 Hz), 7.65 (2H, d, J= 8.8 Hz), 7.36 (IH, d, J = 8.4 Hz), 7.19 (2H, s), HRMS (EI) mlz calcd. for [C13H9ClN2theta2]+ 260.0353.
75%	With sodium methylate; In methanol; at 0℃; for 2h;Reflux;	Sodium methoxide (IM in methanol, 10.0 ml) was added slowly into a solution of <strong>[2609-49-6]diethyl 4-nitrobenzylphosphonate</strong> (1.092 g, 4.0 mmol) and 6- chloropyridine-3-carboxaidehyde (566 mg, 4.0 mmoi) in methanol (10.0 mL), The reaction mixture was refluxed for 2 h, then cooled down to 0 0C. Yellow precipitate was collected by filtration and washed with cold methanol and dried over vacuum to give (E)-2-chioro-5-(4- nitrosty1yI)p7ridine, 782 mg, yield 75%. Orbitrap ESI-MS caicd. for C13H9C1N2O2 260.04 Found 261.08.

Reference： [1]Patent: WO2007/126733,2007,A2 .Location in patent: Page/Page column 31; 42-43
[2]Patent: WO2017/31239,2017,A1 .Location in patent: Paragraph 0150

33
[ 2609-49-6 ]
[ 649712-39-0 ]
(E,E)-4-{4-(3,4,5-tridodecyloxystyryl)-2,5-bis[(S)-2-methylbutoxy]styryl}nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 1.5h;

Reference： [1]Hoeben, Freek J. M.; Wolffs, Martin; Zhang, Jian; De Feyter, Steven; Leclere, Philippe; Schenning, Albertus P. H. J.; Meijer [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9819 - 9828]

34
[ 2609-49-6 ]
[ 22525-43-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaH / dimethylformamide 2: SnCl₂ / H₂O; ethanol
	Multi-step reaction with 2 steps 1.1: sodium methylate / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere 1.2: 12 h / 20 °C / Inert atmosphere 2.1: tin(ll) chloride / ethyl acetate / 4 h / 90 °C
	Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 0.5 h / 50 °C / Inert atmosphere 2: hydrogenchloride; tin(II) chloride dihdyrate / ethanol; water / 7 h / 20 °C / Reflux

Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.25 h 1.2: 1 h 2.1: tin(ll) chloride / ethanol / 1.5 h / Inert atmosphere; Reflux

Reference： [1]Yang, Jye-Shane; Hwang, Chung-Yu; Hsieh, Chia-Chun; Chiou, Shih-Yi [Journal of Organic Chemistry, 2004, vol. 69, # 3, p. 719 - 726]
[2]Lu, Chuanjun; Guo, Yueyan; Yan, Jun; Luo, Zonghua; Luo, Hai-Bin; Yan, Ming; Huang, Ling; Li, Xingshu [Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5843 - 5859]
[3]Fang, Zhengjun; Cao, Chenzhong; Chen, Guanfan [Journal of Physical Organic Chemistry, 2012, vol. 25, # 12, p. 1343 - 1350]
[4]Cullinane, Carleen; Donnelly, Paul S.; Hayne, David J.; Lim, SinChun; McLean, Catriona A.; Noor, Asif; Roselt, Peter D.; Van Zuylekom, Jessica K.; White, Jonathan M. [Inorganic Chemistry, 2020, vol. 59, # 16, p. 11658 - 11669]

35
[ 32723-67-4 ]
[ 2609-49-6 ]
[ 120191-48-2 ]

Yield	Reaction Conditions	Operation in experiment
47.6%	With sodium ethanolate In ethanol	1 EXAMPLE 1 EXAMPLE 1 Sodium ethoxide (prepared from 0.70 g of Na and 30 mL of ethanol) was added to an ice-cold mixture of diethyl p-nitrobenzylphosphonate (9.09 g, 0.033 mole) and 3-methyl-p-anisaldehyde (5.0 g, 0.033 mole) in ethanol (about 100 mL). The resulting mixture was stirred overnight. The solid product was filtered, washed with ethanol and vacuum dried to give MMONS, 3-methyl-4-methoxy-4'-nitrostilbene (4.946 g, 0.0157 mole, 47.6% yield, m.p. 109°-111° C.).

Reference： [1]Current Patent Assignee: DUPONT DE NEMOURS INC - US4985178, 1991, A

36
[ 2609-49-6 ]
[ 185457-34-5 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus pentachloride In tetrachloromethane; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran	Ethyl (4-nitrophenyl)methylphosphonochloridate (7.15) Ethyl (4-nitrophenyl)methylphosphonochloridate (7.15) This method is a modification of that outlined by Doak and Freedman (Ref.178). Diethyl (p-nitrophenyl)methylphosphonate (7.16) (1.0 g, 3.6 mmol) in DCM (10 ml) was added dropwise to a solution of PCl5(0.9 g, 4.32 mmol) in CCl4(20 ml) under an inert atmosphere. The reaction was stirred at 30°C and the progress of the chlorination was followed by 31P NMR which showed the reaction was complete after 24 h. Solvent and phosphoryl chloride were removed in vacuo to yield a pale yellow, moisture-sensitive oil (0.8 g, 90 %) which was used without further purification. δH (250 MHz, CDCl3) 1.40 (3H, t, J 7.5 Hz, CH3), 3.60 (2H, d, 2JPH22.5 Hz, Ar-CH2), 4.25-4.43 (2H, m, JHP8.5 Hz, J 7.5 Hz,CH2), 7.5 (2H, d, J 7.5 Hz, Ar-H), 8.20 (2H, d, J 7.5 Hz, Ar-H); δP (101 MHz, CDCl3) 35.94 (s).
	With oxalyl dichloride; N,N-dimethyl-formamide at 60℃; for 2h;	2.2. General procedure for the synthesis of 11a,b General procedure: A mixture of 9a,b (9.43 mmol), (COCl)2 (20 mL), and a catalytic quantity of DMF was heated to 60 °C and stirred for 2 h. Evaporation of the excess (COCl)2 yielded 11a,b as a rufous oil (95-98%).
	With chlorinating agent In N,N-dimethyl-formamide at 60℃; for 2h;

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - EP745673, 1996, A2
[2]Ge, Yang; Yang, Haijun; Wang, Changyuan; Meng, Qiang; Li, Lei; Sun, Huijun; Zhen, Yuhong; Liu, Kexin; Li, Yanxia; Ma, Xiaodong [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 765 - 772]
[3]Liu, He; Wu, Bin; Ge, Yang; Huang, Jiaxin; Song, Shijie; Wang, Changyuan; Yao, Jihong; Liu, Kexin; Li, Yanxia; Li, Yongming; Ma, Xiaodong [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6313 - 6321]

37
[ 2609-49-6 ]
[ 456-48-4 ]
[ 38694-04-1 ]

Yield	Reaction Conditions	Operation in experiment
82%		a 4-[2-(3-Fluoro-phenyl)-vinyl]-1-nitro-benzene Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 3-fluoro-benzaldehyde. Yellow solid. Yield=82%. MS: m/e=243.0 (M+).
82%		A suspension of 677 mg of sodium hydride (55% dispersion in oil) in 10 ml of N,N-di-methylformamide is cooled to 0C. Thereupon, 5.61 g (20.5 mmol) of diethyl(4-nitro-benzyl)phosphonate are added portionwise. The reaction mixture is left to warm to RT and stirred for 1.5 hours. Thereafter, the mixture is cooled to -10C and a solution of 1.5 g (12.1 mmol) of 3-fluorobenzaldehyde in 5 ml N,N-dimethylformamide is added dropwise. Stirring is continued for 30 min at 0C, then at RT. For the working-up, ice and ethyl acetate are added to the reaction mixture. The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure to yield the crude crystalline product, which after recrystallisation from a mixture of ether and heptane gives 2.41 g (82% of theory) of (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS: m/e=243(M)+.

Reference： [1]Patent: US2003/232883,2003,A1
[2]Patent: WO2004/26825,2004,A1 .Location in patent: Page 25; 26

38
[ 100-11-8 ]
[ 2609-49-6 ]

Yield	Reaction Conditions	Operation in experiment
8.35 g (66%)	With triethyl phosphite In <i>N</i>-methyl-acetamide	56.a a a (4-Nitro-benzyl)-phosphonic Acid Diethyl Ester 10 g (46.3 mmol) of 4-nitrobenzylbromide and 10.03 g (60.3 mmol) of triethyl phosphite are dissolved in 25 ml dimethylformamide. The reaction mixture is held at 155° C. for 1.5 h, diluted with 20 ml water and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated to yield 8.35 g (66%) of the crude title compound. MS: m/e=274.1 (M++H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2003/232883, 2003, A1

39
[ 66507-25-3 ]
[ 2609-49-6 ]
(E)-1-ruthenocenyl-2-(4-nitro-phenyl)ethylene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With NaOC₂H₅ In ethanol NaOC2H5 was added to a mixt. of phosphonate and ruthenocene in ethanol (cooled in an ice bath), mixt. was stirred overnight; product was filtered off, washed with ethanol; elem. anal.;

Reference： [1]Calabrese, Joseph C.; Cheng, Lap-Tak; Green, Jennifer C.; Marder, Seth R.; Tam, Wilson [Journal of the American Chemical Society, 1991, vol. 113, # 19, p. 7227 - 7232]

40
[ 2609-49-6 ]
[ 459-57-4 ]
[ 1996-67-4 ]

Yield	Reaction Conditions	Operation in experiment
91%		2.63g of sodium hydride are added to 50ML of dimethylformamide. The mixture is cooled to 0o C and 16g (58. 6mmol) of (4-nitro-benzyl) -phosphonic acid diethyl ester is added portionwise. The solution is stirred at room temperature for 1.5 h, then cooled to - 10o. A solution OF 6. 09G (50mmol) 4-fluoro-benzaldehyde in 10ML dimethylformamide is slowly added to the mixture AT-10o. Stirring at room temperature for 45 min followed by additon of 250ML water yields a precipitate which is filtered and to yield 10. 81G (91%) of a yellow solid. MS: m/e = 243.1 (M+).
	With sodium ethanolate; In ethanol; at 0℃; for 12h;	The FONS (C14H10FNO2) material was prepared by the addition of high purity diethyl p-nitrobenzyl phosphonate (C11H16NO4P), 4-fluoro benzaldehyde (C7H5FO) and sodium ethoxide (C2H5ONa) in equimolar ratio. The mixture was dissolved in 35 ml of ethanol and kept inside the ultra cryostat water bath and stirred for 12 h at 0 C [6]. The ethanol was removed by filtration and the resulting green coloured FONS were dried and the powdered material was collected after one day. The FONS material was 10 times recrystallized for purification. The reaction mechanism is as follows (Scheme 1).

Reference： [1]Patent: WO2003/99763,2003,A1 .Location in patent: Page 34
[2]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2013,vol. 105,p. 509 - 515

41
[ 1132941-18-4 ]
[ 2609-49-6 ]
1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium tert-butylate; In dichloromethane; at 20℃; for 1.5h;	Part H. Preparation of l-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydro- pyrimidine- 2,4(lH,3H)-dione.; [001004] The product prepared in Part G (1.0Og, 3.29mmol) and diethyl 4-nitrobenzyl- phosphonate (0.853g, 3.12mmol) were dissolved in dichloromethane (5OmL). Solid potassium tert-bupsilontoxide (0.737g, 6.57mmol) was added portion wise at room temperature. The resultant dark red solution was stirred for 1.5h at room temperature. IN aqueous HCl (5OmL) solution was added and the mixture was stirred 30min, and then diluted with dichloromethane (5OmL). The resultant organic layer was separated and dried. The material was purified by column chromatography on silica gel using 99/1 dichloromethane/methanol as eluent to obtain the title compound as a solid (1.12g, 80%).

Reference： [1]Patent: WO2009/39127,2009,A1 .Location in patent: Page/Page column 211

42
[ 1132941-18-4 ]
[ 2609-49-6 ]
1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium t-butanolate; In dichloromethane; at 20℃; for 1.5h;	Part H. Preparation of l-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydro- pyrimidine- 2,4(lH,3H)-dione.; [00517] The product prepared in Part G (1.0Og, 3.29mmol) and diethyl 4-nitrobenzyl- phosphonate (0.853g, 3.12mmol) were dissolved in dichloromethane (5OmL). Solid potassium tert-butoxide (0.737g, 6.57mmol) was added portion wise at room temperature. The resultant dark red solution was stirred for 1.5h at room temperature. IN aqueous HCl (5OmL) solution was added and the mixture was stirred 30min, and then diluted with dichloromethane (5OmL). The resultant organic layer was separated and dried. The material was purified by column chromatography on silica gel using 99/1 dichloromethane/methanol as eluent to obtain the title compound as a solid (1.12g, 80%). [00518] Part I. Preparation of Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

Reference： [1]Patent: WO2009/39135,2009,A1 .Location in patent: Page/Page column 107

43
[ 1132941-10-6 ]
[ 2609-49-6 ]
[ 1132942-04-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium tert-butylate; In dichloromethane; at 20℃; for 1.5h;	Part E. Preparation of (E)-l-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)pyrimidine-2,4(lH,3H)-dione.; [00582] The product of Part D (0.634g, 2.1mmol) and <strong>[2609-49-6]diethyl 4-nitrobenzylphosphonate</strong> (0.573g,2.1mmol) were combined in dichloromethane (25mL) at ambient temperature. Potassium tert- butoxide(0.494g, 4.4mmol) was added portion wise and the resulting red/brown heterogeneous mixture was stirred for 1.5h. This mixture was quenched with IM HCl (15mL), poured into water and extracted into ethyl acetate, and the crude product was purified by column chromatography on silica gel, eluting with 1% methanol/dichloromethane to give the title compound (0.735g , 83%).

Reference： [1]Patent: WO2009/39135,2009,A1 .Location in patent: Page/Page column 117
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1153 - 1163

44
[ 957120-32-0 ]
[ 2609-49-6 ]
[ 96042-30-7 ]
[ 1206772-42-0 ]

Yield	Reaction Conditions	Operation in experiment
0.127 g (59%)	With NaH; ammonium chloride; iron; sodium carbonate In tetrahydrofuran; methanol; water; ethyl acetate; mineral oil	37.142 N-(4-{(E)-2-[3-tert-Butyl-5-(5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl)-2-methoxy-phenyl]-vinyl}-phenyl)-methanesulfonamide (I-142) step 1-To a suspension of NaH (0.3493 g, 8.73 mmol, 60% mineral oil dispersion) and dry THF (9 mL) was added 15-crown-5 (0.27 mL, 1.36 mmol) and the resulting mixture cooled to 0° C., A solution of diethyl (4-nitro-benzyl)-phosphonate (2.33 g, 8.53 mmol) in dry THF (10.5 mL) was added slowly while maintaining the temperature at 0° C. The reaction was stirred for 15 min then a solution of D-2 (1.93 g, 7.12 mmol) and dry THF (21 mL) was added. The reaction mixture was stirred at 0° C. for 2 h then allowed to warm to RT and stirred overnight. The reaction mixture was quenched with H2O (50 mL) and the resulting solution thrice extracted with Et2O (3*60 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluding with 5% EtOAc/hexane to afford 2.70 g (98%) of 202a. step 2-A mixture of 202a (0.7883, 2.02 mmol), iron (0.471 g, 8.44 mmol), NH4Cl (0.8667 g, 16.2 mmol), MeOH (25 mL) and H2O (25 mL) was heated at reflux for 4 h. The reaction mixture was cooled to RT and filtered. The filtrate was thrice extracted with EtOAc and the combined extracts washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 0.709 g (95%) of 202b as a yellow solid which was used without further purification. step 3-The conversion of 202b to the sulfonamide 202c in accord with the procedure described in step 3 of example 6. step 4-A microwave vial was charged with 202c (0.193 g, 0.442 mmol), 5-fluoro-2-methoxy-pyridin-3-yl boronic acid (0.0771 g, 0.451 mmol), Na2CO3 (0.1228, 1.16 mmol), Pd(PPh3)4 (0.027 g, 0.023 mmol), MEOH (1.2 mL) and DCM (0.3 mL), sealed and irradiated in a microwave synthesizer at 115° C. for 35 min. The vial was cooled to RT, filtered and the solid washed with EtOAc. The filtrate was washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluding with a EtOAc/hexane gradient (20 to 50% EtOAc) to afford 0.127 g (59%) of 204 as a yellow oil.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/21423, 2010, A1

45
2-oxo-1,2-dihydropyridine-3-boronic acid [ No CAS ]
[ 1206774-54-0 ]
[ 1206774-55-1 ]
[ 2609-49-6 ]
[ 1206774-56-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In tetrahydrofuran; methanol; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran	18.108.4 N-(4-{2-[2-Methoxy-3-(1-methyl-cyclopropyl)-5-(2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-ethyl}-phenyl)-methanesulfonamide step 4: Sodium hydride (60% dispersion, 0.10 g, 2.6 mmol) and 15-crown-5 (0.038 g, 0.17 mmol) were added to THF (5 mL) at 0° C. and stirred for 5 min. To the reaction mixture was then added dropwise over 5 min a solution of diethyl (4-nitrobenzyl)phosphonate (0.52 g, 1.9 mmol) in THF (5 mL), and stirring was continued at 0° C. for 5 min. To this reaction mixture was then added dropwise over 10 min a solution of 132 (0.47 g, 1.7 mmol) in THF (10 mL). The reaction mixture was stirred for 30 min at 0° C. then for 90 min at RT. Water was carefully added, and the mixture was partitioned between water and EtOAc. The EtOAc layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluding with EtOAc/hexane to afford 0.67 g (94%) of 5-bromo-2-methoxy-1-(1-methylcyclopropyl)-3-[(E)-2-(4-nitrophenyl)vinyl]benzene(134) as a yellow solid (0.67 g, 94%). step 5-A mixture of 134 (0.17 g, 0.44 mmol), 112 (0.073 g, 0.53 mmol), Pd(PPh3)4 (0.051 g, 0.044 mmol) and Na2CO3 (0.14 g, 1.3 mmol) in DCM/MeOH (3:1, 6 mL) was irradiated in a microwave synthesizer at 115° C. for 30 min. The reaction mixture was partitioned between DCM and water and the DCM layer was then washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue obtained was purified by SiO2 chromatography eluding with EtOAc/hexane to afford 0.15 g (79%) of 3-{4-methoxy-3-(1-methylcyclopropyl)-5-[(E)-2-(4-nitrophenyl)vinyl]phenyl}-1H-pyridin-2-one (136) as a yellow solid.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/21423, 2010, A1

46
[ 1178892-65-3 ]
[ 2609-49-6 ]
C₂₅H₃₅NO₇Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		a. Protected Stilbene 214. A suspension of NaH (109 mg, 2.6 mmol, 60% in oil), and 15- crown-5 (1 drop, cat.) in THF (10 mL) was cooled to 0 0C. To this was added aldehyde 212 (245 mg, 0.66 mmol) and the known phosphonate 213 (181 mg, 0.66 mmol) in THF (1.5 mL). After the mixture was allowed to stir for 45 mins, water was added dropwise and the solution was extracted with EtOAc. The resulting organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Final purification by column chromatography (2:1 hexanes:ethyl acetate) gave the stilbene 214 (197 mg, 61%) as a bright yellow oil: 1H NMR (CDCl3) delta 8.21 - 8.18.(m, 2H), 7.65 - 7.62 (m, 4H), 6.88 (s, 2H), 5.30 (s, 4H), 4.74 (s, 2H), 3.53 (s, 6H), 0.98 (s, 9H), 0.13 (s, 6H); 13C NMR (CDCl3) delta 156.4 (2C), 146.1, 145.9, 143.8, 129.5, 126.4 (2C), 124.7, 123.9 (2C), 113.9, 105.6 (2C), 94.7 (2C), 64.5, 56.1 (2C), 25.7 (3C), 18.2, -5.4 (2C); HRMS (EI) calcd for C25H35O7NSi (M+) 489.2183 found 489.2173.

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 6734 - 6741
[2]Patent: WO2009/158516,2009,A1 .Location in patent: Page/Page column 35

47
[ 1202637-29-3 ]
[ 2609-49-6 ]
C₁₈H₁₉NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%		c. Benzyl Alcohol 222. To a solution of aldehyde 221 (128 mg, 0.57 mmol) in THF (12 mL) at room temperature was added 15-crown-5 (0.01 mL), diethyl-4-nitro-benzylphosphonate (213, 203 mg, 0.74 mmol), followed by NaH (220 mg, 5.5 mmol, 60% in oil), which resulted in the rapid appearance of a maroon color. After 8 min, the reaction was quenched by slow addition of water. The resulting solution was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO4), and concentrated in vacuo. Final purification by column chomatography (6:4 hexanes/THF) afforded compound 222 (191 mg, 98%) as an orange solid: 1H NMR (CDCla)delta 8.20 - 8.18 (m, 2H), 7.64 - 7.61 (m, 4H), 6.80 (s, IH), 6.69 (s, IH), 5.29 (s, 2H), 4.70 (s, 2H), 3.94 (s, 3H), 3.53 (s, 3H); 13C NMR (CDCl3) delta 159.2, 156.6, 145.9, 142.9, 129.8, 126.6 (2C), 124.5, 124.3, 124.0 (2C), 113.8, 105.5, 103.1, 94.8, 65.2, 56.4, 55.8; HRMS (EI) calcd for Ci8Hi9NO6 (M+) 345.1212 found 345.1216.

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 6734 - 6741
[2]Patent: WO2009/158516,2009,A1 .Location in patent: Page/Page column 38

48
[ 2609-49-6 ]
[ 1232361-55-5 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; acetic acid In ethyl acetate	31.A.T N-(4-{(E)-2-[5-(2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-2-methoxy-3-(2,2,2-trifluoro-ethyl)-phenyl]-vinyl}-phenyl)-methanesulfonamide (I-38) step 2-To a solution of 238a (1.678 g, 8.219 mmol) and HOAc (8.2 mL) at RT was added dropwise Br2 (0.844 mL, 16.439 mmol). The reaction mixture was stirred at RT for 72 h. The mixture was diluted with DCM and 10% Na2S2O3 was added and the mixture stirred for several min. The organic layer was washed with sat'd. aq. NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluding with an EtOAc/hexane gradient (0 to 10% EtOAc) to afford 1.845 g of 238b as a yellow solid. step 3-O-methylation of 238b was carried out in accord with the procedure described in step 9 of example 18. The crude product was purified by SiO2 chromatography eluding with 10% EtOAc/hexane to afford 239. step 4-Condensation of 239 with diethyl (4-nitro-benzyl)-phosphonate (step 4) was carried out in accord with the procedures in step 1 of example 1. step 5-Palladium-catalyzed coupling of 240 (0.16 g, 0.364 mmol) and 137 (0.085 g, 0.546 mmol) was carried out in accord with the procedure described in example 14. The crude product was purified by SiO2 chromatography eluding with 10% MeOH/DCM to afford 242a. step 6-Reduction of the nitro moiety was carried out with iron in accord with the procedure in step 5 of example 15 and the crude product was purified by column chromatography to afford 242b. step 7-Sulfonylation of the amine was carried out in accord with the procedure described in step 3 of example 1 to afford I-38. The crude product was purified by HPLC.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/158860, 2010, A1

49
[ 2609-49-6 ]
[ 119646-68-3 ]
[ 1252662-35-3 ]

Yield	Reaction Conditions	Operation in experiment
65%		To a solution of 15-crown-5 in THF (20 mL) cooled to 0 0C was added NaH (1.56 g,3.9 mmol, 60% mineral oil dispersion) followed by a solution of diethyl (4-nitro-benzyl)- phosphonate (10.65 g, 3.9 mmol) and THF (20 mL). After stirring for 10 min a solution of 36a (5.0 g, 19.5 mmol) was added slowly. After 10 min at 0 0C the reaction was warmed to RT then heated at reflux for 6 h. The reaction was cooled to RT then quenched with IN HCl and the resulting solution was extracted with EtOAc. The combined extracts were dried, filtered and evaporated. The crude product was purified by SiO2 chromatography eluting with 5% EtOAc/hexane to afford 44a in a 65% yield.

Reference： [1]Patent: WO2010/122082,2010,A1 .Location in patent: Page/Page column 40

50
[ 1206774-54-0 ]
[ 2609-49-6 ]
[ 1206774-55-1 ]

Yield	Reaction Conditions	Operation in experiment
94%		Sodium hydride (60% dispersion, 0.10 g, 2.6 mmol) and 15-crown-5 (0.038 g, 0.17 mmol) were added to THF (5 mL) at 0 C and stirred for 5 min. To the reaction mixture was then added dropwise over 5 min a solution of diethyl (4-nitrobenzyl)phosphonate (0.52 g, 1.9 mmol) in THF (5 mL), and stirring was continued at 0 C for 5 min. To this reaction mixture was then added dropwise over 10 min a solution of 76 (0.47 g, 1.7 mmol) in THF (10 mL). The reaction mixture was stirred for 30 min at 0 C then for 90 min at RT. Water was carefully added, and the mixture was partitioned between water and EtOAc. The EtOAc layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.67 g (94%) of5- bromo-2-methoxy-l-(l-methylcyclopropyl)-3-[(£)-2-(4-nitrophenyl)vinyl]benzene (75) as a yellow solid (0.67 g, 94%).

Reference： [1]Patent: WO2010/122082,2010,A1 .Location in patent: Page/Page column 45-46

51
[ 2609-49-6 ]
3-bromo-5-formyl-tert-butylbenzene [ No CAS ]
[ 1252662-17-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a slurry of NaH (0.38 g, 9.46 mmol) and 15-crown-5 (0.17 g, 0.79 mmol) in THF (5 mL) cooled to 0 0C was added slowly a solution of diethyl (4-nitro-benzyl)-phosphonate (2.58 g, 9.46 mmol) and THF (8 mL). The resulting solution was stirred at 0 0C until the bubbling ceased. To the resulting solution maintained at 0 0C was added slowly a solution of 20 (1.90 g, 7.88 mmol) and THF (20 mL). The reaction was stirred at 0 0C for 20 min then quenched with H2O. The solution was extracted with Et2O and the organic extracts washed with brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 2.64 g of 22 as a yellow solid.

Reference： [1]Patent: WO2010/122082,2010,A1 .Location in patent: Page/Page column 34-35

52
[ 100-14-1 ]
[ 122-52-1 ]
[ 2609-49-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	In ethanol at 140℃; for 14h;
85.9%	at 140℃; for 5h;
	at 130℃; for 5h;

at 130℃; for 10h;

5.1.12. General procedure for the synthesis of intermediates 38 and40 General procedure: To a solution of 1-(chloromethyl)-4-nitrobenzene (1 equiv) intriethyl phosphite (1.5 equiv). The reaction mixture was stirred at130 C for 10 h. Upon completion, the mixture was diluted withwater and extracted with CH2Cl2. The organic phases were combined,washed with saline, dried over anhydrous Na2SO4 andevaporated to afford crude product 35. Oxalyl chloride (3 equiv)was added to a solution of compound 35 (1 equiv) in CH2Cl2, towhich a catalytic amount of DMF (2 drops) was added. The reactionwas stirred at 60 C for 4 h. The reaction mixture was concentratedand dried under a vacuum. A suspension of CH3NH2HCl (1.2 equiv)or morpholine (1.2 equiv) and Et3N (1.5 equiv) in anhydrous CH2Cl2was then added. The mixture was stirred at 25 C for 4 h and thendiluted with CH2Cl2, and the organic layer was washed with saline,dried over anhydrous Na2SO4 and filtered. The filtrate wasconcentrated and purified using chromatography to yield intermediate37 or 39. Intermediate 37 or 39 (1 equiv) was dissolved inethanol, and Pd/C (0.1 equiv)was added. The flask was flushed withH2 and stirred for 6 h at 40 C. The reaction mixture was filteredthrough a Celite pad, and the filtrate was concentrated to dryness,yielding intermediate 38 or 40.38: MS (ESI) m/z(%): 285.1 [MH];40: MS (ESI) m/z(%): 229.1 [MH].

Reference： [1]Yu, Jia; Li, Minglei; Yu, Yong; Gao, Yanjing; Liu, Jiancheng; Sun, Fang [Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 11, p. 1958 - 1970]
[2]Location in patent: experimental part Liu, Xiaofeng; Liu, Huibiao; Zhou, Weidong; Zheng, Haiyan; Yin, Xiaodong; Li, Yuliang; Guo, Yanbing; Zhu, Mei; Ouyang, Canbin; Zhu, Daoben; Xia, Andong [Langmuir, 2010, vol. 26, # 5, p. 3179 - 3185]
[3]Ge, Yang; Yang, Haijun; Wang, Changyuan; Meng, Qiang; Li, Lei; Sun, Huijun; Zhen, Yuhong; Liu, Kexin; Li, Yanxia; Ma, Xiaodong [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 765 - 772]
[4]Chen, Yixuan; Cheng, Maosheng; Hao, Chenzhou; Wang, Ruifeng; Wu, Tianxiao; Yang, Bowen; Yu, Sijia; Zhao, Dongmei; Zhao, Xiangxin [European Journal of Medicinal Chemistry, 2020, vol. 188]

53
[ 2609-49-6 ]
[ 100-52-7 ]
4-nitrostilbene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate In ethanol at 20℃;	4.3. Synthesis of aniline analogues General procedure: With the exception of 10c, 10d and 10i all the anilines required for the synthesis of the isatin analogues were commercially available. Sodium (105 mmol) was allowed to react with ethanol (109 mL) in small portions over a period of 2 h. The resulting mixture was added at room temperature to diethyl 4- or diethyl 3-nitrobenzylphosphonate (11a, b, 100 mmol)26 and benzaldehyde (12, 100 mmol) or cinnamaldehyde (14, 100 mmol) dissolved in ethanol (164 mL) over a period of 1.5 h. Stirring was continued for 20 h and the thick yellow precipitate was collected by vacuum filtration and washed with 40 mL ethanol followed by 40 mL petroleum ether.27 The nitro-functionalized intermediates 13a, 13b and 15 thus obtained (yield 69-71%) were used without further purification in the following reaction. The nitro derivatives (25 mmol) were suspended in 400 mL methanol and the reaction flask was purged with argon. A quantity of 3% (of the weight of the nitro derivative) of Pd/C (10%) was prewet with 2 mL water and added to 10 mL methanol. This mixture was carefully added to the reaction. The atmosphere was replaced by hydrogen and the reaction was stirred at room temperature for 24 h during which the reaction became a clear solution. The catalyst was removed by filtration through a bed of Celite and the methanol solvent was evaporated under reduced pressure. The resulting aniline derivative was converted to the corresponding hydrochloride salt in CH2Cl2 (70 mL). A volume of 150 mL diethyl ether may be added to the acidic CH2Cl2 solution to facilitate precipitation of the salt (yield 41-95%).

Reference： [1]Location in patent: experimental part Manley-King, Clarina I.; Bergh, Jacobus J.; Petzer, Jacobus P. [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 261 - 274]

54
[ 1274931-86-0 ]
[ 2609-49-6 ]
[ 1274931-87-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.25h; Stage #2: C₂₃H₂₁N₃O₂ In tetrahydrofuran at 0 - 20℃; for 5h;	6.3 To a solution of diethyl (4-nitrobenzyl)phosphonate (132 mg, 0.48 mmol) in THF (5 mL) at 0° C. was added dropwise a solution of 1M NaHMDS (485 μL, 0.48 mmol) in THF. The mixture was stirred at 0° C. for 15 min then a solution of 34c (100 mg, 0.27 mmol) in THF (4 mL) was added. The resulting mixture was stirred from 0° C. to RT over 5 h before it was quenched with sat'd. aq. NH4Cl. The reaction mixture was extracted with EtOAc. The organic extract was washed with H2O, brine, dried (MgSO4) and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 78 mg of 36a as a mixture of E,Z-isomers.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/70189, 2011, A1 Location in patent: Page/Page column 18

55
[ 619-73-8 ]
[ 122-52-1 ]
[ 2609-49-6 ]

Yield	Reaction Conditions	Operation in experiment
79.9%	With tetrabutylammomium bromide; potassium iodide at 165℃; for 8.5h;	11 example 11 A mixture of 7.65 g (0.05 mol) of p-nitrobenzyl alcohol,1.61 g (5.0 mmol) of tetrabutylammonium bromide and 0.17 g (1.0 mmol) of KI were added to a three-necked flask, and the mixture was stirred at 165 ° C for 4 hours. Of triethyl phosphite was added and the reaction was continued at 165 & lt; 0 & gt; C for 4.5 h. After cooling to room temperature, the mixture was extracted with a 1: 3 by volume mixture of ethyl acetate and petroleum ether, and concentrated under reduced pressure to give 16.35 g of product. The yield of p-nitrobenzylphosphonic acid diethyl ester was 79.9%.
15%	With zinc(II) iodide In tetrahydrofuran for 12h; Inert atmosphere; Reflux;

Reference： [1]Current Patent Assignee: HEBEI UNIVERSITY OF TECHNOLOGY - CN105237567, 2016, A Location in patent: Paragraph 0040; 0041
[2]Barney, Rocky J.; Richardson, Rebekah M.; Wiemer, David F. [Journal of Organic Chemistry, 2011, vol. 76, # 8, p. 2875 - 2879]

56
[ 2609-49-6 ]
[ 79099-07-3 ]
[ 1299487-36-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In tetrahydrofuran at 20℃; Cooling with ice;	6.A Diethyl 4-nitrobenzylphosphonate (36g, 132mmol) and tert-butyl 4-oxopiperidine-1 - carboxylate (26.3g, 132mmol) were stirred in tetrahydrofuran (230ml_) and cooled in an ice bath. Sodium hydride was added (6.85g, 171 mmol) and the reaction was taken off the ice bath and stirred for 3 hours at room temperature. The reaction was quenched with water and extracted with dichloromethane, dried (magnesium sulphate), filtered and evaporated under reduced pressure. The crude material was purified by silica chromatography using a dichloromethane solvent system. The oil obtained was triturated with heptane and filtered to give the title compound as a yellow solid (34.24g). 1H NMR (CDCI3, 400 MHz): δ 8.18 (d, 2H), 7.33 (d, 2H), 6.40 (s, 1 H), 3.54 (t, 2H), 3.43 (t, 2H), 2.46 (t, 2H), 2.38 (t, 2H), 1.48 (s, 9H)

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2011/51282, 2011, A1 Location in patent: Page/Page column 28

57
[ 2609-49-6 ]
[ 59379-02-1 ]
[ 1312565-70-0 ]

Yield	Reaction Conditions	Operation in experiment
58%		Example 109 (RS)- 4-Chloro-N- [4-(2-pyrrolidin-3-yl-ethyl)-phenyl] -benzamide hydrochloridea) (RS)-3-[(E)-2-(4-Nitro-phenyl)- vinyl] -pyrrolidine- 1-carboxylic acid tert-butyl esterTo a stirred solution of N,N-diisopropylamine (3.36 ml) in tetrahydrofuran (20 ml) at -78 C was added dropwise a solution of n-butyllithium (14.9 ml, 1.6 M in hexane) and the reaction mixture was then warmed to 0 C for 15 min. After re-cooling to -78C, a solution of diethyl (4-nitrobenzyl) phosphonate (5.00 g, CAS 2609-49-6) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at -78 C for 60 min and then a solution of (RS)-3- formyl-pyrrolidine- 1-carboxylic acid tert-butyl ester (4.01 g, CAS 59379-02-1) intetrahydrofuran (10 ml) was added dropwise over 30 min. The mixture was then allowed to warm to room temparature and stirring continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and acidified to pH 6 by addition of aqueous hydrochloric acid (I N). The mixture was washed sequentially with water and with saturated brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography (Si02, heptane/EtOAc gradient) to yield (RS)-3-[(E)-2-(4-nitro-phenyl)-vinyl]-pyrrolidine- 1-carboxylic acid tert-butyl ester (3.39 g, 58%) as a yellow oil.
58%		To a stirred solution of N,N-diisopropylamine (3.36 ml) in tetrahydrofuran (20 ml) at -78 C. was added dropwise a solution of n-butyllithium (14.9 ml, 1.6 M in hexane) and the reaction mixture was then warmed to 0 C. for 15 min. After re-cooling to -78 C., a solution of diethyl (4-nitrobenzyl) phosphonate (5.00 g, CAS 2609-49-6) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at -78 C. for 60 min and then a solution of (RS)-<strong>[59379-02-1]3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester</strong> (4.01 g, CAS 59379-02-1) in tetrahydrofuran (10 ml) was added dropwise over 30 min. The mixture was then allowed to warm to room temperature and stirring continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and acidified to pH 6 by addition of aqueous hydrochloric acid (1 N). The mixture was washed sequentially with water and with saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield (RS)-3-[(E)-2-(4-nitro-phenyl)-vinyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.39 g, 58%) as a yellow oil.
58%		EXAMPLE 3 [(RS)-1-(4-Chloro-phenyl)-2,2,2-trifluoro-ethyl]-[(RS)-4-(2-pyrrolidin-3-yl-ethyl)-phenyl]-aminea) (RS)-3-[(E)-2-(4-Nitro-phenyl)-vinyl]-pyrrolidine-1-carboxylic acid tert-butyl esterTo a stirred solution of N,N-diisopropylamine (3.36 ml) in tetrahydrofuran (20 ml) at -78 C. was added dropwise a solution of n-butyllithium (14.9 ml, 1.6 M in hexane) and the reaction mixture was then warmed to 0 C. for 15 min. After re-cooling to -78 C., a solution of diethyl (4-nitrobenzyl) phosphonate (5.00 g, CAS 2609-49-6) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at -78 C. for 60 min and then a solution of (RS)-3-formyl-pyrrolidine-l-carboxylic acid tert-butyl ester (4.01 g, CAS 59379-02-1) in tetrahydrofuran (10 ml) was added dropwise over 30 min. The mixture was then allowed to warm to room temparature and stirring continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and acidified to pH 6 by addition of aqueous hydrochloric acid (1 N). The mixture was washed sequentially with water and with saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, gradient: heptane/EtOAc) to yield (RS)-3-[(E)-2-(4-nitro-phenyl)-vinyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.39 g, 58%) as a yellow oil.

58%

To a stirred solution of N,N-diisopropylamine (3.36 ml) in tetrahydrofuran (20 ml) at-78 C was added dropwise a solution of n-butyllithium (14.9 ml, 1.6 M in hexane) and the reaction mixture was then warmed to 0 C for 15 min. After re-cooling to -78C, a solution of diethyl (4-nitrobenzyl) phosphonate (5.00 g, CAS 2609-49-6) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at -78 C for 60 min and then a solution of (RS)-3- formyl-pyrrolidine-l-carboxylic acid tert-butyl ester (4.01 g, CAS 59379-02-1) intetrahydrofuran (10 ml) was added dropwise over 30 min. The mixture was then allowed to warm to room temparature and stirring continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and acidified to pH 6 by addition of aqueous hydrochloric acid (1 N). The mixture was washed sequentially with water and with saturated brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, gradient: heptane/EtOAc) to yield (RS)-3-[(E)-2-(4-nitro-phenyl)-vinyl]-pyrrolidine- 1-carboxylic acid tert-butyl ester (3.39 g, 58%) as a yellow oil.

Reference： [1]Patent: WO2011/76678,2011,A1 .Location in patent: Page/Page column 82-83
[2]Patent: US2011/152245,2011,A1 .Location in patent: Page/Page column 49
[3]Patent: US2012/245172,2012,A1 .Location in patent: Page/Page column 28
[4]Patent: WO2012/126922,2012,A1 .Location in patent: Page/Page column 49

58
[ 2609-49-6 ]
[ 95715-87-0 ]
[ 1302579-22-1 ]

Yield	Reaction Conditions	Operation in experiment
77%		Example 6(S)-4-{2-[4-(4-Chloro-phenylamino)-phenyl]-ethyl}-4,5-dihydro-oxazol-2-ylaminea) (S)-2,2-Dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylic acid tert-butyl esterTo a stirred solution of diisopropylamine (10.9 ml) in THF (350 ml) cooled to -78 C. was added dropwise a solution of n-butyllithium in hexane (48.3 ml, 1.6 M). The cooling bath was removed and the reaction mixture was allowed to warm up to 10 C. before being re-cooled to -78 C. A solution of (4-nitro-benzyl)-phosphonic acid diethyl ester (16.3 g, CAS 2609-49-6) in THF (300 ml) was then added dropwise and the reaction mixture stirred at -78 C. for 1 hour. A solution of (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (15.0 g, CAS 95715-87-0) in THF (250 ml) was then added dropwise over 1 hour and the mixture was then allowed to warm to room temperature overnight. The mixture was then diluted with ethyl acetate and acidified by addition of 2 N aq. hydrochloric acid. The mixture was then washed sequentially with water and saturated brine. The organic phase was separated and dried over sodium sulphate and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylic acid tert-butyl ester (15.9 g, 77%) as a yellow oil. MS (EI): 333 ([M-CH3]+), 292 ([M-C4H8]+), 277 ([M-CH3-C4H8]+), 57 ([C4H9]+).
77%		a) (S)-2,2-Dimethyl-4-r(E)-2-(4-nitro-phenyl)-vinyll-oxazolidine-3-carboxylic acid tert-butyl esterTo a stirred solution of diisopropylamine (10.9 ml) in THF (350 ml) cooled to -78 C was added dropwise a solution of n-butyllithium in hexane (48.3 ml, 1.6 M). The cooling bath was removed and the reaction mixture was allowed to warm up to 10 C before being re-cooled to -78 C. A solution of (4-nitro-benzyl)-phosphonic acid diethyl ester (16.3 g, CAS 2609-49-6) in THF (300 ml) was then added dropwise and the reaction mixture stirred at -78 C for 1 hour. A solution of (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (15.0 g, CAS 95715- 87-0) in THF (250 ml) was then added dropwise over 1 hour and the mixture was then allowed to warm to room temperature overnight. The mixture was then diluted with ethyl acetate and acidified by addition of 2 N aq. hydrochloric acid. The mixture was then washed sequentially with water and saturated brine. The organic phase was separated and dried over sodium sulphate and concentrated in vacuo. The reside was purified by column chromatography (Si02; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3- carboxylic acid tert-butyl ester (15.9 g, 77%) as a yellow oil. MS (EI): 333 ([M-CH3]+), 292 ([M- C4H8]+), 277 ([M-CH3-C4H8]+), 57 ([C4H9]+).
64%	With n-butyllithium; aq. hydrochloric acid; diisopropylamine; In tetrahydrofuran; hexane;	a) S-2,2-Dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylic acid tert-butyl ester To a stirred solution of diisopropylamine (1.81 ml) in THF (50 ml) cooled to -78 C. was added dropwise a solution of n-butyllithium in hexane (8.05 ml, 1.6 M). The cooling bath was removed and the reaction mixture was allowed to warm up to 10 C. before being re-cooled to -78 C. A solution of (4-nitro-benzyl)-phosphonic acid diethyl ester (2.71 g, CAS 2609-49-6) in THF (60 ml) was then added dropwise and the reaction mixture stirred at -78 C. for 1 hour. A solution of (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.50 g, CAS 95715-87-0) in THF (50 ml) was then added dropwise over 30 min and the mixture was then allowed to warm to room temperature over 90 min. The mixture was then diluted with ethyl acetate and acidified by addition of 1 N aq. hydrochloric acid. The mixture was then washed sequentially with water and with saturated brine. The organic phase was separated and was dried over sodium sulphate and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylic acid tert-butyl ester (2.21 g, 64%) as a yellow oil. MS (EI): 333 ([M-CH3]+), 292 ([M-C4H8]+), 277 ([M-CH3-C4H8]+), 57 ([C4H9]+).

64%

To a stirred solution of diisopropylamine (1.81 ml) in THF (50 ml) cooled to -78 C. was added dropwise a solution of n-butyllithium in hexane (8.05 ml, 1.6 M). The cooling bath was removed and the reaction mixture was allowed to warm up to 10 C. before being re-cooled to -78 C. A solution of (4-nitro-benzyl)-phosphonic acid diethyl ester (2.71 g, CAS 2609-49-6) in THF (60 ml) was then added dropwise and the reaction mixture stirred at -78 C. for 1 hour. A solution of (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.50 g, CAS 95715-87-0) in THF (50 ml) was then added dropwise over 30 min and the mixture was then allowed to warm to room temperature over 90 min. The mixture was then diluted with ethyl acetate and acidified by addition of 1 N aq. hydrochloric acid. The mixture was then washed sequentially with water and with saturated brine. The organic phase was separated and was dried over sodium sulphate and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylic acid tert-butyl ester (2.21 g, 64%) as a yellow oil. MS (EI): 333 ([M-CH3]+), 292 ([M-C4H8]+), 277 ([M-CH3-C4H8]+), 57 ([C4H9]+).

Reference： [1]Patent: US2012/108609,2012,A1 .Location in patent: Page/Page column 15
[2]Patent: WO2012/59371,2012,A1 .Location in patent: Page/Page column 27-28
[3]Patent: US2012/28964,2012,A1
[4]Patent: US9132136,2015,B2 .Location in patent: Page/Page column 22; 23

59
[ 2609-49-6 ]
[ 59379-02-1 ]
[ 1312565-72-2 ]

Reference： [1]Patent: US2012/245172,2012,A1

60
[ 2609-49-6 ]
[ 155380-49-7 ]
[ 1398047-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 1-Formyl-1-methylcyclobutanecarboxylate In tetrahydrofuran at 20℃; for 1h;	[00390] Synthesis of compound 71d[00391] The mixture of diethyl 4-nitrobenzylphosphonate (2.5g, 9.16mmol) in THF(50mL) was cooled down to 0°C,then NaH (0.73g, 18.3mmol) was added carefully and the mixture was stirred for 10 minutes. Compound 71b (3g, 21mmol) in THF (lOmL) was added dropwise. After addition, the mixture was allowed to warm to r.t and stirred for 1 hour at r.t The reaction was quenched with IN HC1 (40mL). The mixture was extracted with EA (100mLx2). Dried and removed the EA to get crude product. The crude material was purified by flash chromatography (silica gel, PE:EA=8: 1) to give 71d (1.6g, yield 70%>) as a white solid.

Reference： [1]Current Patent Assignee: SUZHOU KINTOR PHARMACEUTICALS INC - WO2012/119559, 2012, A1 Location in patent: Page/Page column 117

61
[ 13865-20-8 ]
[ 2609-49-6 ]
[ 1398047-38-5 ]

Yield	Reaction Conditions	Operation in experiment
70%		00322] Preparation of compound 61d[00323] A mixture of diethyl 4-nitrobenzylphosphonate (2.5 g, 9.16 mmol) in THF (50 mL) was cooled down to 0C,then NaH (0.5 g, 11.2 mmol) was added carefully and the mixture was tirred for 10 minutes. Compound 61b (1.6 g, 11.2 mmol) in THF (10 mL) was added dropwise. After addition, the mixture was allowed to warm to r.t and stirred for 1 hour at r.t The reaction was quenched with IN HC1 (40 mL). The mixture was extracted with EA (100 mLx2). Dried and removed the EA to get crude product. The crude material was purified by flash chromatography (silica gel, PE: EA=8: 1) to give 61d (1.6 g, 70%) as a white solid.

Reference： [1]Patent: WO2012/119559,2012,A1 .Location in patent: Page/Page column 105-106

62
[ 2609-49-6 ]
[ 117241-32-4 ]
[ 1415488-17-3 ]

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 7108 - 7112

63
[ 2609-49-6 ]
[ 1571-08-0 ]
[ 136827-59-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium methylate; In tetrahydrofuran; at 0℃; for 0.333333h;	A solution of <strong>[2609-49-6]diethyl 4-nitrobenzylphosphonate</strong> (200 mg, 0.73 mmol) and methyl 4-formylbenzoate (120 mg, 0.73 mmol) in THF (3 ml) was added to a suspension of sodium methoxide (79 mg, 1.46 mmol) in THF (6 ml) . The mixed solution was stirred for 20 min at 0 . The solvent was removed under reduced pressure. H2O (100 ml) was added, and the resulting aqueous solution was neutralized with HCl (0.1 N) , followed by extraction with DCM (3 × 50 mL) . The combined organic phases were dried over anhydrous MgSO4and filtered. Then, the solvents were removed under reduced pressure. The pure product 3 (yellow solid) was obtained by filtering the crude material through silica gel with DCM as the eluent (182 mg, 88%) .1H NMR (400 MHz, CDCl3) : delta 8.25 (dd, J1= 6.8, 2 Hz, 2H) , 8.07 (dd, J1= 6.8, 1.6 Hz, 2H) , 7.67 (dd, J1= 7.2, 2 Hz, 2H) , 7.61 (d, J = 8.4 Hz, 2H) , 7.28-7.26 (2H, coincided with residual CHCl3) , 3.94 ppm (s, 3H) ;13C NMR (100 MHz, CDCl3) : delta 166.7, 147.2, 143.2, 140.5, 132.1, 130.2, 130.0, 128.7, 127.2, 126.9, 124.2, 52.2 ppm; HRMS (MALDI-TOF) : m/z: calcd for C16H14NO4284.0923 [M+H]+; found: 284.0895.
48.8 g	With sodium methylate; In methanol; at 20℃; for 16h;Cooling with ice;	(1) To a mixture of 50.3 g of diethyl (4-nitrobenzyl)phosphonate and 500 mL of methanol was added dropwise a solution of sodium methylate in methanol (ca. 5 mol/L, 73.7 mL) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture was added dropwise a mixture of 30.6 g of methyl 4-formylbenzoate and 300 mL of methanol for 1 hour under ice-cooling, followed by stirring at room temperature for 15 hours after the addition dropwise. The precipitate was collected by filtration to obtain 48.8 g of methyl 4-[(E)-2-(4-nitrophenyl)vinyl]benzoate as a yellow solid. EI: 283

Reference： [1]Langmuir,2014,vol. 30,p. 11375 - 11385
[2]Patent: WO2019/141246,2019,A1 .Location in patent: Paragraph 00197; 00246-00247
[3]Patent: EP2565190,2013,A1 .Location in patent: Paragraph 0102

64
[ 7311-34-4 ]
[ 2609-49-6 ]
[ 586410-18-6 ]

Yield	Reaction Conditions	Operation in experiment
76%		The solution of intermediate 2 in 15mL of dry dimethyl formamide was stirred and then sodium methoxide (60mmol, 3.24g) was added, which was stirred at 0C for 30min, and the 3,5-dimethoxybenzaldehyde (3, 12mmol, 1.99g) dissolved in 10mL of dimethyl formamide was added dropwise at 0C. The mixture was stirred at room temperature overnight. The reaction was quenched by pouring into 200mL of ice water. After stewing for 10-20min, the solid precipitated was collected by filtration, washed with water and petroleum ether and then recrystallized from ethanol. Yield 76%, yellow solid; 1H NMR (500MHz, CDCl3) delta 8.20 (d, J=8.7Hz, 2H), 7.61 (d, J=8.7Hz, 2H), 7.18 (d, J=16.2Hz, 1H), 7.09 (d, J=16.2Hz, 1H), 6.68 (d, J=1.8Hz, 2H), 6.43 (t, J=2.1Hz, 1H), 3.83 (s, 6H); ESI-MS m/z: 286.1 [M+H]+.
74%		General procedure: To a solution of CH3ONa (1.350 g, 7.5 mmol) in DMF (10 mL), 2 (1.296 g, 5 mmol) was added. After the mixture was stirred at 0 C under nitrogen for 1 h, a substituted benzaldehyde (7.5 mmol) in DMF (5 mL) was added dropwise to the solution. The reaction mixture was slowly warmed to room temperature and stirred overnight. Ice water was added, and the mixture was filtered to yield the crude product. Purification of the crude product by recrystallisation from ethyl acetate provided the target product.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 124,p. 1006 - 1018
[2]European Journal of Medicinal Chemistry,2015,vol. 95,p. 220 - 229
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 5843 - 5859

65
[ 56578-35-9 ]
[ 2609-49-6 ]
[ 1428963-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: diethyl p-nitrobenzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: 4-methyl-cinnamaldehyde In tetrahydrofuran at 0℃; for 0.5h;	2.1 Synthesis General procedure: Diphenylbutadiene derivatives utilized in this investigation were prepared by using Horner-Wadsworth-Emmons reaction [23] (Scheme 1a) in about 35-60% yields. In a typical procedure, triethyl phosphite (5.74 mmol) was added to the THF solution of benzyl bromide (2.3 mmol) and refluxed for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and further cooled to 0 °C using an ice bath. Sodium hydride (11.5mmol) was added to this mixture and stirred for 5 min. Aldehyde (2.3 mmol) was subsequently added drop wise to the pale/dark pink colored solution and stirring was continued for additional 30 min. In the case of methyl substituted aldehydes, corresponding (E) geometric isomer of α-methyl cinnamaldehyde (Aldrich) was used. Thin Layer Chromatography (TLC) was utilized to monitor the progress of the reaction and the reaction was quenched by adding water. The organic layer was extracted using dichloromethane and concentrated under reduced pressure. The crude reaction mixture so obtained was purified by column chromatography using silica gel, 5% ethyl acetate in petroleum ether. Starting materials, 4-methylcinnamaldehyde required for the synthesis of ( 2) and nitro cinnamaldehyde required for synthesis of (3) and (5), were obtained by DDQ oxidation of 4-allyl toluene [40] (Scheme 1b) and by simple nitration using a nitrating mixture generated by mixing KNO3 with H2SO4 of α-methyl-cinnamaldehyde (scheme 1c), respectively. Characterization data for all the synthesized dienes were given in the Supplementary information.

Reference： [1]Agnihotri, Harsha; Palakollu, Veerabhadra; Kanvah, Sriram [Journal of Photochemistry and Photobiology A: Chemistry, 2014, vol. 293, p. 40 - 49]

66
[ 2609-49-6 ]
[ 120-14-9 ]
[ 51042-54-7 ]

Yield	Reaction Conditions	Operation in experiment
63.8%		General procedure: To a solution of CH3ONa (1.350 g, 7.5 mmol) in DMF (10 mL), 2 (1.296 g, 5 mmol) was added. After the mixture was stirred at 0 C under nitrogen for 1 h, a substituted benzaldehyde (7.5 mmol) in DMF (5 mL) was added dropwise to the solution. The reaction mixture was slowly warmed to room temperature and stirred overnight. Ice water was added, and the mixture was filtered to yield the crude product. Purification of the crude product by recrystallisation from ethyl acetate provided the target product.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 95,p. 220 - 229

67
[ 2609-49-6 ]
[ 86-81-7 ]
[ 134029-66-6 ]

Yield	Reaction Conditions	Operation in experiment
57%		General procedure: To a solution of CH3ONa (1.350 g, 7.5 mmol) in DMF (10 mL), 2 (1.296 g, 5 mmol) was added. After the mixture was stirred at 0 C under nitrogen for 1 h, a substituted benzaldehyde (7.5 mmol) in DMF (5 mL) was added dropwise to the solution. The reaction mixture was slowly warmed to room temperature and stirred overnight. Ice water was added, and the mixture was filtered to yield the crude product. Purification of the crude product by recrystallisation from ethyl acetate provided the target product.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 95,p. 220 - 229

68
[ 2609-49-6 ]
[ 591-31-1 ]
[ 14064-58-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: diethyl p-nitrobenzylphosphonate With sodium methylate In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: 3-methoxy-benzaldehyde In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	4.1.1 General procedure for the preparation of 3 General procedure: To a solution of CH3ONa (1.350 g, 7.5 mmol) in DMF (10 mL), 2 (1.296 g, 5 mmol) was added. After the mixture was stirred at 0 °C under nitrogen for 1 h, a substituted benzaldehyde (7.5 mmol) in DMF (5 mL) was added dropwise to the solution. The reaction mixture was slowly warmed to room temperature and stirred overnight. Ice water was added, and the mixture was filtered to yield the crude product. Purification of the crude product by recrystallisation from ethyl acetate provided the target product.

Reference： [1]Yan, Jun; Guo, Yueyan; Wang, Yali; Mao, Fei; Huang, Ling; Li, Xingshu [European Journal of Medicinal Chemistry, 2015, vol. 95, p. 220 - 229]

69
[ 2609-49-6 ]
4-nitrophenylphosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: diethyl p-nitrobenzylphosphonate With trimethylsilyl bromide In acetonitrile at 20℃; for 24h; Stage #2: In methanol at 20℃; for 24h;

Reference： [1]Jorge, Ana Rita; Chernobryva, Mariya; Rigby, Stephen E.J.; Watkinson, Michael; Resmini, Marina [Chemistry - A European Journal, 2016, vol. 22, # 11, p. 3764 - 3774]

70
[ 2609-49-6 ]
[ 69610-41-9 ]
C₁₇H₂₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: diethyl p-nitrobenzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.08333h; Stage #2: Boc-L-Pro-H In tetrahydrofuran; hexane at -78 - 20℃;

Reference： [1]Chen, Qian; Li, Liang; Zhou, Guangli; Ma, Xiaoli; Zhang, Lu; Guo, Fang; Luo, Yi; Xia, Wujiong [Chemistry - An Asian Journal, 2016, vol. 11, # 10, p. 1518 - 1522]

71
[ 2609-49-6 ]
2-(2-(5-formyl-2-nitrophenoxy)ethoxy)ethyl 4-methylbenzenesulfonate [ No CAS ]
(E)-2-(2-(2-nitro-5-(4-nitrostyryl)phenoxy)ethoxy)-ethyl-4-methylbenzene-sulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		Synthesis of (E)-2-(2-(2-Nitro-5-(4-nitrostyryl)phenoxy)ethoxy)-ethyl-4-methylbenzene- sulfonate 23 (Scheme 4) (0231) [00110] To an oven-dried 100 mL round-bottom flask purged with argon and fitted with a magnetic stirring bar was added sodium hydride (0.80 g, 2.0 mmol, 60% dispersion in mineral oil). The flask was purged with argon, and dry DMF 2.0 mL was added. The diethyl (4-nitrobenzyl) phosphonate (15, 0.30 g, 1.1 mmol) was dissolved in dry DMF (2.0 mL), and the NaH-DMF mixture was transferred via syringe to a flask. The mixture was then stirred under argon at 0C for 1 h. The tosylated 4- nitrobenzaldehyde (4, 0.360 g 1.0 mmol) was dissolved in dry DMF (2 mL) and added to the reaction mixture via syringe under argon at 0C. The reaction was stirred again for 2 h at 0C in the dark under argon. The reaction was quenched with 25 mL of ice cold water, and the compound precipitated out. It was then filtered under vacuum, washed with water several times followed by diethyl ether, and used for the next step without further purification. The yellow amorphous compound was dried under high vacuum, yield 0.390 g (80%). 1H NMR (400 MHz, DMSO-d6) delta 8.31-8.25 (m, 2H), 7.95 (d, J = 8.4 Hz, 1H), 7.92-7.87 (m, 2H), 7.79-7.74 (m, 2H), 7.68 (d, J = 16.5 Hz, 1H), 7.64-7.55 (m, 2H), 7.42 (dd, J = 9.1, 3.0 Hz, 3H), 4.30 (t, J = 4.6 Hz, 2H), 4.19-4.09 (m, 2H), 3.79-3.62 (m, 4H), 2.37 (s, 3H). 13C NMR (101 MHz, DMSO) delta 151.8, 146.7, 144.8, 143.1, 142.6, 138.5, 132.3, 131.2, 130.4, 130.1, 127.8, 127.6, 125.9, 124.2, 119.4, 113.1, 70.0, 69.1, 68.5, 68.2, 21.1.

Reference： [1]Patent: WO2017/156303,2017,A1 .Location in patent: Paragraph 00110
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 3705 - 3718

72
[ 2609-49-6 ]
[ 120475-79-8 ]
(E)-(2,5-dimethoxy-4-(4-nitrostyryl)phenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide Inert atmosphere;	3.1.1. Synthesis of (E)-(2,5-dimethoxy-4-(4-nitrostyryl)phenyl)methanol: b In a three-necked flask under nitrogen, diethyl-4-nitrobenzylphosphonate (348 mg, 1.274 mmol) was suspended indry DMF (10 ml), a solution of t-BuOK (355 mg, 3.17 mmol) wasadded dropwise. The mixture was stirred for few minutes then, asolution of 4-(hydroxymethyl)-2,5-dimethoxybenzaldehyde(250 mg, 1.274 mmol) was added. The mixture was stirred overnightand 50 ml ofwaterwas then added, the resulting mixturewasstirred for additional 10 min. The orange solid was filtered andpurified by column chromatography (petroleum ether/ethyl acetate7/3) to give compound b as an orange powder in 49%. Mp 130 °C; 1HNMR (300 MHz, CDCl3) δ 8.25 (d, 2H, J 8.79 Hz), 7.70 (s, 1H),7.66 (d, 2H, J 6.83 Hz), 7.15 (m, 2H), 6.98 (s, 1H), 4.75 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.80 (s, 1H). Selected IR bands (cm1): 3279,2833, 1628, 1588, 1507,1462,1411,1337, 1318,1285,1209, 1176, 1109,1041, 968, 955, 870, 829, 749, 681, 669, 502. Anal. calcd forC17H17NO5: C, 64.75; H, 5.43; N, 4.44, found: C, 63.83; H, 5.72; N,4.04. MALDI-TOF MS calcd: m/z 315.32 Da found: m/z 315.

Reference： [1]Ayadi, Awatef; Szukalski, Adam; El-Ghayoury, Abdelkrim; Haupa, Karolina; Zouari, Nabil; Myśliwiec, Jaroslaw; Kajzar, Francois; Kulyk, Bohdan; Sahraoui, Bouchta [Dyes and Pigments, 2017, vol. 138, p. 255 - 266]

73
[ 556-18-3 ]
[ 2609-49-6 ]
[ 4629-58-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium hydroxide at 40℃; for 4h;	16 A batch of stilbene type compound was prepared by using the following reaction conditions in substantially the same manner as in Example 2, and the reaction conditions and the results are shown in Table 1.

Reference： [1]Current Patent Assignee: SOUTHEAST UNIVERSITY - CN104591959, 2016, B Location in patent: Paragraph 0074-0080

74
[ 2609-49-6 ]
4-methoxy-3-(4-methoxycarbonylpyridin-2-yl)b enzaldehyde [ No CAS ]
(E)-2-(2-methoxy-5-(4-nitrostyryl)phenyl)isonicotinic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 3h; Cooling with ice;	9 Example 9 Methyl (E) -methyl 2- (2-methoxy-5- (4-nitrostyryl) phenyl) isonicotinate (2d) Compound 1d (406.9 mg, 1.50 mmol) and diethyl 4-nitrobenzylphosphonate (430.3 mg,1.575 mmol) was dissolved in anhydrous DMF (6 mL), Under ice bath, potassium tert-butoxide (336.6 mg, 3.0 mmol) was added slowly and the mixture was stirred at room temperature for 3 hours. The reaction system was slowly poured into ice water to precipitate a solid, The solid was collected and recrystallized from ethyl acetate to give 245.9 mg of a yellow solid with a yield of 42.0%

Reference： [1]Current Patent Assignee: XINXIANG MEDICAL UNIVERSITY - CN107501169, 2017, A Location in patent: Paragraph 0050; 0051; 0052

75
[ 2609-49-6 ]
2-(2-methoxyphenyl)isonicotinaldehyde [ No CAS ]
(E)-2-(2-methoxyphenyl)-4-(4-nitrostyryl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.7%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 4h;Cooling with ice;	In 25 ml two-neck flask adding compound 1 a (319.8 mg, 1 . 50 mmol) and <strong>[2609-49-6]diethyl 4-nitrobenzylphosphonate</strong>(430.3 mg, 1 . 575 mmol), dissolved in anhydrous DMF (6 mL), and placed on an ice bath. Potassium tert-butoxide (336.6 mg, 3.Ommol) was added slowly, and the reaction was stirred for 4 hours at room temperature. The reaction was slowly poured into ice water to precipitate a solid which was filtered off with suction and the solid was collected and recrystallized from ethyl acetate. White solid 352 mg, yield 70.7%
70.7%		General procedure: To a solution of t-BuOK (3.0 equiv) in dry DMF was added a substituted diethyl benzylphosphonate (1.1 eq). After the mixture was stirred at 0 C under nitrogen for 0.5 h, compound 1 or 5 (1.0 eq) in dry DMF was added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 0.5-2 h. Ice-water was added, and the precipitate was filtered to afford the crude product. Purification of the crude product by recrystallization from ethyl acetate or by silica gel column chromatography provided the target products 2 and 6

Reference： [1]Patent: CN107474011,2017,A .Location in patent: Paragraph 0032-0034
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 6000 - 6014

76
[ 2609-49-6 ]
[ 619-66-9 ]
4-[(E)-2-(4-nitrophenyl)ethenyl]benzoic acid sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With sodium ethanolate; In ethanol; at 90℃; for 1h;	To a solution of sodium ethoxide (15 mmol) in 25 ml of anhydrous ethanol was added 0.75 g (5 mmol) of 4-carboxybenzaldehyde followed by 1.5 g (5.8 mmol) of diethyl (4-nitrobenzyl)phosphonate (3a). The reaction was stirred at 90C for 1 h then cooled and diluted with 20 ml of ethyl acetate. The resultant solid was collected by filtration, washed with ethyl acetate and dried. The obtained crude product was re- crystallized from hot water (10-15 ml) to afford 0.89 g (61% yield) of nitrostilbenecarboxylic acid (sodium salt) 16 as yellow crystals. 1H N MR (DMSO-d6) 5 8.23 (d, J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.54 (skewed d, J=16.5 Hz, 1H), 7.41 (skewed d, J=16.5 Hz, 1H).

Reference： [1]Patent: WO2018/162986,2018,A2 .Location in patent: Paragraph 0167

77
[ 2609-49-6 ]
ethyl 4-[[4-[(E)-2-[4-(formyl)phenyl]ethenyl]phenyl] methylamino]butanoate [ No CAS ]
ethyl 4-[[4-[(E)-2-[4-[(E)-2-[4-nitrophenyl]ethenyl]phenyl]ethenyl]phenyl] methylamino]butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydride In tetrahydrofuran; ethanol for 4h;	11 Example 11. Ethyl 4-[[4-[(E)-2-[4-[(E)-2-[4-nitrophenyl]ethenyl]phenyl]ethenyl]phenyl] methylamino]butanoate (12) To a solution of aldehyde 11 (0.4 g, 1.13 mmol) and diethyl (4-nitrobenzyl)phosphonate (3a) (0.33 g, 1.2 mmol) in 10 mL of anhydrous THF was added a solution of sodium hydride (55 mg, 2.3 mmol) in 10 ml of anhydrous ethanol. After being agitated for 4 h the reaction was filtered and the collected solid was washed with methanol. Drying in vacuo afforded 0.497 g (93% yield) of the desired bis-stil bene 12 as a brown-red solid. 1H NMR (DMSO-d6) 5 8.23 (d, J=9 H, 2H), 7.87 (d, J=9H, 2H), 7.7-7.3 (m, 8H), 7.21 (skewed d, J=16 Hz, 1H), 6.99 (skewed d, J=16 Hz, 1H), 6.72 (d, J=9 Hz, 2H), 4.06 (q, J=7.2 Hz, 2H), 2.92 (s, 3H), 3.4 (m, 2H), 2.35 (t, J=7.2 Hz, 2H), 1.78 (p, J=7.5 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H).

Reference： [1]Current Patent Assignee: PAI PARTNERS - WO2018/162986, 2018, A2 Location in patent: Paragraph 0159

78
[ 628711-22-8 ]
[ 2609-49-6 ]
(E)-2-(2-methoxy-5-(4-nitrostyryl)phenyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.3%		General procedure: To a solution of t-BuOK (3.0 equiv) in dry DMF was added a substituted diethyl benzylphosphonate (1.1 eq). After the mixture was stirred at 0 C under nitrogen for 0.5 h, compound 1 or 5 (1.0 eq) in dry DMF was added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 0.5-2 h. Ice-water was added, and the precipitate was filtered to afford the crude product. Purification of the crude product by recrystallization from ethyl acetate or by silica gel column chromatography provided the target products 2 and 6

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 6000 - 6014

79
[ 2609-49-6 ]
4-methoxy-3-(pyrimidin-2-yl)benzaldehyde [ No CAS ]
(E)-2-(2-methoxy-5-(4-nitrostyryl)phenyl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.1%		General procedure: To a solution of t-BuOK (3.0 equiv) in dry DMF was added a substituted diethyl benzylphosphonate (1.1 eq). After the mixture was stirred at 0 C under nitrogen for 0.5 h, compound 1 or 5 (1.0 eq) in dry DMF was added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 0.5-2 h. Ice-water was added, and the precipitate was filtered to afford the crude product. Purification of the crude product by recrystallization from ethyl acetate or by silica gel column chromatography provided the target products 2 and 6

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 6000 - 6014

80
[ 2609-49-6 ]
2-(5-fluoro-2-methoxyphenyl)isonicotinaldehyde [ No CAS ]
(E)-2-(5-fluoro-2-methoxyphenyl)-4-(4-nitrostyryl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.1%	Stage #1: diethyl p-nitrobenzylphosphonate With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-(5-fluoro-2-methoxyphenyl)isonicotinaldehyde In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	18 4.1.3. General procedure for synthesis of compounds 2 and 6 General procedure: To a solution of t-BuOK (3.0 equiv) in dry DMF was added a substituted diethyl benzylphosphonate (1.1 eq). After the mixture was stirred at 0 °C under nitrogen for 0.5 h, compound 1 or 5 (1.0 eq) in dry DMF was added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 0.5-2 h. Ice-water was added, and the precipitate was filtered to afford the crude product. Purification of the crude product by recrystallization from ethyl acetate or by silica gel column chromatography provided the target products 2 and 6

Reference： [1]Duan, Yingchao; Qin, Wenping; Suo, Fengzhi; Zhai, Xiaoyu; Guan, Yuanyuan; Wang, Xiaojuan; Zheng, Yichao; Liu, Hongmin [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 23-24, p. 6000 - 6014]

81
[ 872-85-5 ]
[ 2609-49-6 ]
[ 1023-66-1 ]