[ CAS No. 621-50-1 ] {[proInfo.proName]}

Name: 621-50-1|2-(3-Nitrophenyl)acetonitrile|98%
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3d Animation Molecule Structure of 621-50-1

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Quality Control of [ 621-50-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 621-50-1 ]

Product Details of [ 621-50-1 ]

CAS No. :	621-50-1	MDL No. :	MFCD00041249
Formula :	C₈H₆N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WAVKEPUFQMUGBP-UHFFFAOYSA-N
M.W :	162.15	Pubchem ID :	12125
Synonyms :

Calculated chemistry of [ 621-50-1 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.79
TPSA :	69.61 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.16
Log Po/w (XLOGP3) :	1.75
Log Po/w (WLOGP) :	1.66
Log Po/w (MLOGP) :	0.59
Log Po/w (SILICOS-IT) :	-0.04
Consensus Log Po/w :	1.02

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.19
Solubility :	1.06 mg/ml ; 0.00652 mol/l
Class :	Soluble
Log S (Ali) :	-2.83
Solubility :	0.24 mg/ml ; 0.00148 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.26
Solubility :	0.893 mg/ml ; 0.00551 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.65

Safety of [ 621-50-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H312-H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 621-50-1 ]

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

Upstream synthesis route of [ 621-50-1 ]
Downstream synthetic route of [ 621-50-1 ]

[ 621-50-1 ] Synthesis Path-Upstream 1~15

1
[ 621-50-1 ]
[ 621-37-4 ]

Reference： [1] Chemische Berichte, 1884, vol. 17, p. 506[2] Chemische Berichte, 1889, vol. 22, p. 2139

2
[ 621-50-1 ]
[ 14318-64-0 ]

Reference： [1] Bulletin des Societes Chimiques Belges, 1955, vol. 64, p. 87,91

3
[ 621-50-1 ]
[ 52022-77-2 ]

Reference： [1] Patent: WO2011/60196, 2011, A1,
[2] Patent: WO2014/182829, 2014, A1,
[3] Patent: WO2016/191172, 2016, A1,

4
[ 621-50-1 ]
[ 25263-44-9 ]

Reference： [1] Chemische Berichte, 1884, vol. 17, p. 506[2] Chemische Berichte, 1889, vol. 22, p. 2139

5
[ 621-50-1 ]
[ 4623-24-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With iron; ammonium chloride In ethanol; water at 85℃; for 1 h;	General procedure: To a solution of 2 (150.1 mg, 0.66 mmol) and NH₄Cl (183.6 mg, 3.43 mmol) in a mixture of EtOH/H₂O (5:1, 6 mL) was added iron (Fe) powder (184.4 mg, 3.30 mmol) and vigorously stirred at 85 °C for 1 h. After the mixture was allowed to cool to room temperature, the solid was removed by filtration through a Celite pad, and the filtrate was concentrated. The residue was purified by column chromatography (EtOAc/hexane, 20:70) to afford 10a (99.2 mg, 76percent) as a brown oil;
96%	With iron; ammonium chloride In ethanol; water at 85℃; for 1 h;	A. (3-Amino-phenyl)-acetonitrile A mixture of (3-nitro-phenyl)-acetonitrile (2.00 g, 12.35 mmol), iron dust (2.07 g, 37.03 mmol) and ammonia chloride (1.96 g, 37.03 mmol) in EtOH (20 mL) and water (4 mL) was refluxed at 85° C. for 1 h. The reaction mixture was filtered through cellite and rinsed with EtOH. The combined filtrate was concentrated and the residue was purified by silica gel column chromatography (20percent ethyl acetate in petroleum ether) to afford the title compound (1.57 g, 11.89 mmol, 96percent yield) as a pale-yellow solid. MS (ESI) m/z 133.1 [M+H]⁺.
90%	With hydrogen In 1,2-dimethoxyethane at 100℃; for 35 h;	A nanoporous metal cesium catalyst (3.2 mg, 0.03 mmol) Ethylene glycol dimethyl ether (3 mL) and 3-nitrophenylacetonitrile (48.65mg, 0.3mmol) was added to the Reaction kettle, hydrogen (16 bar) was introduced, heated and stirred, the reaction temperature was controlled at 100 ° C, Reaction time control at 35h, column chromatography (baby gel, 200-300 mesh; Developing solvent, petroleum ether: ethyl acetate = 10: 1) to give 35.7 mg of 3-aminophenylacetonitrile in 90percent yield.

80%	With iron; ammonium chloride In tetrahydrofuran; methanol; water at 20 - 60℃; for 3 h;	To a stirred solution of NH₄C1 (1.1 g, 19.74 mmol) in H₂0 (16 mL) was added Fe powder (1.01 g, 18.08 mmol) followed by Intermediate BC (800 mg, 4.23 mmol) in a mixture of THF (8.0 mL) and MeOH (8.0 mL) slowly at room temperature. The reaction was then stirred for 3h at 60 °C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through a Celite bed. The organic layer was washed with water (2 χ 25 mL) and brine solution (20 mL), dried over anhydrous Na₂S0₄, and evaporated to afford the crude product. This material was purified by column chromatography (silica gel 100-200 mesh) using 40percent ethyl acetate in petroleum ether as the eluent to afford Intermediate BD (520 mg, 80percent) as a brown gum. NMR (CDC1₃): δ 7.14 (d, J = 7.67 Hz, 1H), 7.68-6.62 (m, 3H), 3.74 (bs, 2H), 3.65 (s, 2H). Mass (M+H): 238.0.
51%	Stage #1: With iron; acetic acid In water at 40℃; for 24 h; Stage #2: With sodium hydroxide In water	Iron powder (517 mg, 9.27 mmol) was added to a solution of 3-nitrophenylacetonitrile (500 mg, 3.09 mmol) in acetic acid (9.5 ml) and water (6.6 ml). The reaction was stirred at 40 ⁰C for 24 h, then cooled to room temperature. The mixture was diluted with water (20 ml), adjusted to pH 8 with 2N NaOH and then filtered trough Celite.(R).. The aqueous filtrate was extracted with ethyl acetate, the combined organic phases were dried (MgSO,)) and evaporated. Purification by flash chromatography on the Biotage SP4, eluting with 0 to 60percent ethyl acetate / petroleum ether gradient, gave the desired product as a colourless oil (51percent). ¹H NMR (400 MHz, DMSO-^₆) δ ppm 3.84 (s, 2 H), 5.22 (br. s, 2 H), 6.40 - 6.44 (m, 1 H), 6.46 - 6.50 (m, 1 H), 6.50 - 6.53 (m, 1 H), 6.96 - 7.03 (m, 1 H); Rf (50percent Ethyl acetate/Petroleum ether) = 0.5.
44%	With hydrogen In methanol; water at 22℃; for 48 h;	To a solution of 3-nitro-phenyl-acetonitrile (3.20 g, 19.7 mmol) in MeOH(50 mL) was added Pd/C (10percent wt, -50percent H₂0, 0.32 g) and the mixture was placed under H₂ (80 psi) and stirred for 2 days at 22 ⁰C. The reaction mixture was filtered through Celite.(R). and the filtrate concentrated in vacuo to give crude product as a yellow oil. The residue was purified by silica gel chromatography (ISCO, elution with 0-10percent ethyl acetate in hexanes) to give xix-1-1 (1.15 g, 44percent): MS m/z = 133 (M-H).
34%	Stage #1: With iron; acetic acid In water at 80℃; for 2 h; Stage #2: With hydrogenchloride In water; ethyl acetate Stage #3: With sodium hydroxide In water	(c) 5-Phenyl-furan-2-carboxylic acid [3-(lH-tetrazol-5- ylmethyl)-phenyl]-amide (75); (i) (3-Amino-phenyl)-acetonitrile (80); A solution of 3-nitrophenyl acetonitrile (500 mg, 3.1 mmol) in 5percent AcOH (10 ml) was heated to 80°C. Iron powder (1.5 g, 27 mmol) was then added and the resulting mixture stirred for 2 h. The reaction mixture was filtered through celite and the filter cake washed with MeCN (4 x 50 ml). The combined MeCN layers were evaporated in vacuo and the residue was re-dissolved in EtOAc (30 ml) followed by 2M HC1 (30 ml). The aqueous layer was separated, basified to pH 10 with 6M NaOH, and extracted with EtOAc (3 x 80 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound. Yield: 140 mg, 34percent ; 1H NMR (400 MHz, CDC13) : 5 3.65 (s, 2H), 3.75 (s, 2H), 6.60-6. 70 (m, 3H), 7.15 (t, 1H)
32%	Stage #1: With tin; hydrogen bromide In water at 0 - 20℃; for 3 h; Stage #2: With sodium carbonate In water	A mixture of nitrobenzene acetic acid (1 g, 5.52 mmoles), 1.66 mL OF SOC12, 10 mL dry CHC13 was refluxed for 14 hours. CHC13 and excess thionyl chlorid were removed in vacuo, and the residue was evaporated twice with 25 mL of toluene to remove traces of thionyl chlorid. The residue was taken into 10 mL of toluene and 30 mL of cold concentrated ammonium hydroxyde were added. The white solid formed was collected and dried with etanol in vacuo. Yield: 79 percent. 'H NMR (DMSO-d6, 300MHZ) 8 : 8.14 (M, 2H), 7.71 (M, 2H), 7.06 (brs, 2H), 3.58 (s, 2H). 2- (3-NITROPHENYL) acetamide was added with 10 mL of POC13 and the mixture was heated at reflux for 2 hours. After cooling, the mixture was poured into ice, basified with NA2CO3 and extracted with CH2C12. The organic layer was dried over NA2S04, filtered and evaporated. Purified by flash chromatography on silica gel CH2C12. Yield : 41percent H NMR (CDC13,300 MHz) 5 : 8. 14 (M, 2H), 7.69 (d, 1H, J = 8HZ), 7.56 (M, 1H), 3.88 (s, 2H). A solution of 15 mL HBr 48percent was cooled to 0°C. (430 mg, 2.65 mmoles) OF 3-NITROBENZONITRILE, (574 mg, 4. 85 mmoles) of Sn were added successively. The mixture was stirred at room temperature for 3 hours, then poured into ice. The solution was basified with NA2C03, extracted with CH2C12, dried, filtered and evaporated. Purified by flash chromatography on silica gel ETOH/CH2CL2 (2: 98). Yield: 32percent H NMR (DMSO-d6, 300MHZ) 8 : 7.37 (M, 2H), 6.81 (M, 2H), 3.86 (s, 2H). 3-AMINOBENZONITRILE was then reacted with 2-chloroethylisocyanate as described in examples 1- 12 to obtain desired product. Purified by flash CHRMATOGRAPHY on silica gel ETOH/CH2CL2 (5: 95). Yield: 78percent H NMR (CDCL3, 300 MHz) 8 : 8.12 (brs, NH, 1H), 7.26 (M, Ar, 4H), 6.97 (brs, NH, 1H), 3.63 (m, CH2,6H).
32%	With tin; hydrogen bromide In water at 0 - 20℃; for 3 h;	A mixture of nitrobenzene acetic acid (1 g, 5.52 mmoles), 1.66 mL OF SOC12, 10 mL dry CHC13 was refluxed for 14 hours. CHC13 and excess thionyl chlorid were removed in vacuo, and the residue was evaporated twice with 25 ML of toluene to remove traces of thionyl chlorid. The residue was taken into 10 mL of toluene and 30 ML of cold concentrated ammonium hydroxyde were added. The white solid formed was collected and dried with etanol in vacuo. Yield: 79 percent. 1H NMR (DMSO-d6, 300MHZ) 8 : 8.14 (M, 2H), 7.71 (M, 2H), 7.06 (brs, 2H), 3.58 (s, 2H). 2- (3-NITROPHENYL) ACETAMIDE was added with 10 mL of POC13 and the mixture was heated at reflux for 2 hours. After cooling, the mixture was poured into ice, basified with NA2C03 and extracted with CH2C12. The organic layer was dried over NA2S04, filtered and evaporated. Purified by flash chromatography on silica gel CH2C12. Yield: 41percent 1H NMR (CDC13, 300 MHz) 8 : 8.14 (M, 2H), 7.69 (d, 1H, J = 8HZ), 7.56 (m, 1H), 3.88 (s, 2H). A solution of 15 mL HBr 48percent was cooled to 0°C. (430 mg, 2.65 mmoles) of 3-nitrobenzonitrile, (574 mg, 4.85 mmoles) of Sn were added successively. The mixture was stirred at room temperature for 3 hours, then poured into ice. The solution was basified with NA2CO3, extracted with CH2CK, dried, filtered and evaporated. Purified by flash chromatography on silica gel ETOH/CH2CL2 (2: 98). Yield: 32percent 1H NMR (DMSO-D6, 300MHZ) B : 7.37 (M, 2H), 6.81 (M, 2H), 3. 86 (s, 2H). 3-AMINOBENZONITRILE was then reacted with 2-chloroethylisocyanate as described in examples 1- 12 to obtain desired product. Purified by flash chrmatography on silica gel ETOH/CH2C12 (5: 95). Yield: 78percent

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 4, p. 577 - 583
[2] Patent: US2015/175557, 2015, A1, . Location in patent: Paragraph 0347
[3] Patent: CN107098786, 2017, A, . Location in patent: Paragraph 0049-0050
[4] Patent: WO2011/47156, 2011, A1, . Location in patent: Page/Page column 82
[5] Patent: WO2009/122180, 2009, A1, . Location in patent: Page/Page column 95
[6] Patent: WO2006/41773, 2006, A2, . Location in patent: Page/Page column 368
[7] Patent: WO2005/80367, 2005, A1, . Location in patent: Page/Page column 129-130
[8] Patent: WO2004/106292, 2004, A1, . Location in patent: Page 94-95
[9] Patent: WO2004/106291, 2004, A1, . Location in patent: Page 92
[10] Journal of the American Chemical Society, 1943, vol. 65, p. 437
[11] Chemische Berichte, 1884, vol. 17, p. 506[12] Chemische Berichte, 1889, vol. 22, p. 2139
[13] Journal of Medicinal Chemistry, 2003, vol. 46, # 9, p. 1661 - 1669
[14] Patent: US5910495, 1999, A,
[15] Patent: US2008/214558, 2008, A1, . Location in patent: Page/Page column 16
[16] Patent: WO2011/60196, 2011, A1, . Location in patent: Page/Page column 141
[17] Medicinal Chemistry Research, 2017, vol. 26, # 5, p. 975 - 986
[18] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 7146 - 7165
[19] Patent: WO2008/135525, 2008, A2, . Location in patent: Page/Page column 49-50

6
[ 621-50-1 ]
[ 619-23-8 ]
[ 4623-24-9 ]

Reference： [1] Patent: US5952362, 1999, A,
[2] Patent: EP887346, 1998, A2,

7
[ 621-50-1 ]
[ 4623-24-9 ]

Reference： [1] Patent: US2010/29675, 2010, A1,

8
[ 621-50-1 ]
[ 4623-24-9 ]

Reference： [1] Patent: US5405826, 1995, A,

9
[ 621-50-1 ]
[ 14338-36-4 ]

Reference： [1] Chemische Berichte, 1883, vol. 16, p. 2066

10
[ 621-50-1 ]
[ 52273-77-5 ]

Reference： [1] Patent: WO2014/182829, 2014, A1,
[2] Patent: WO2016/191172, 2016, A1,

11
[ 621-50-1 ]
[ 83304-13-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: With dimethylsulfide borane complex In tetrahydrofuran for 2 h; Heating / reflux Stage #2: With hydrogenchloride In tetrahydrofuran; ethanol at 20℃; for 0.5 h;	A solution of (3-nitro-phenyl)-acetonitrile (11.4 g, 70.4 mmol) in THF (100 ml) was heated to reflux and borane dimethylsulfide (2M in THF, 77.34 mmol) was added.The mixture was stirred for 2 h under reflux. After complete conversion the mix.not. ture was allowed to come to room temperature and a solution of HCI in ethanolM/45293 EPO <DP n="101"/>(1 M) was added. After stirring the mixture for 30 min it was concentrated under reduced pressure. The residue was triturated with diethylether, filtered, washed with diethylether and dried in vacuo to give the product as a yellow powder (13.1 g, 92percent).

Reference： [1] Chemical Communications, 2011, vol. 47, # 11, p. 3242 - 3244
[2] Patent: WO2006/40179, 2006, A1, . Location in patent: Page/Page column 99-100
[3] Patent: EP2096105, 2009, A1, . Location in patent: Page/Page column 16
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1545 - 1548
[5] Patent: US2002/169192, 2002, A1,
[6] Patent: EP2168966, 2010, A1, . Location in patent: Page/Page column 60-61

12
[ 621-50-1 ]
[ 52913-11-8 ]

Reference： [1] Patent: WO2011/60196, 2011, A1,

13
[ 621-50-1 ]
[ 180079-94-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 9, p. 1661 - 1669
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1545 - 1548

14
[ 621-50-1 ]
[ 74-88-4 ]
[ 915394-28-4 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydride In tetrahydrofuran at 0℃;	To an ice-cold slurry of 50percent sodium hydride (2.17g, 90.4mmol) in anhydrous THF (15ml), was slowly added a solution of (3-nitro-phenyl)-acetonitrile (2.2g, 13.58mmol) in anhydrous THF (5ml). After 30 min, methyl iodide (6.67ml, 107mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was then quenched with ice- water. The compound was then extracted with ethyl acetate, the organic layer separated and washed with water, dried over anhydrous sodium sulphate, filtered and concentrated to oil. Column chromatography over silica gel by eluting with ethyl acetate/pet ether (5:95) gave 2-methyl-2-(3-nitrophenyl)- propionitrile (1. Ig, 43percent) as a solid.
30%	With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 16 h; Inert atmosphere	To a solution of 3 (400.0 mg, 2.47 mmol) in anhydrous THF (5 mL) was slowly added a suspension of 60percent sodium hydride in mineral oil (641.4 mg, 16.03 mmol) in anhydrous THF (4.2 mL) under argon at 0 °C. Methyl iodide (1.23 mL, 19.74 mmol) was added to the mixture. The temperature was allowed to rise to room temperature and stirred for 16 h. After being quenched by the addition of water, the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 5:95 to 10:90) to afford 4 (141.3 mg, 30percent) as a brown solid; ¹H NMR (CDCl₃, 400 MHz) 8.31 (1 H, t, J = 2.3 Hz), 8.21–8.19 (1 H, m), 7.90–7.87 (1 H, m), 7.61 (1 H, t, J = 7.8 Hz), 1.79 (6 H, s); ¹³C NMR (CDCl₃, 100 MHz) 148.5, 143.5, 131.6, 130.1, 123.3, 123.0, 120.1, 37.1, 28.9.
23%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 20℃; for 12 h;	NaH (4.34 g, 90.4 mmol) was stirred in a solvent of tetrahydrofuran (20 mL) at 0°C. The reaction solution was slowly added with 2-(3-nitrophenyl)acetonitrile (2.2 g, 13.6 mmol), and stirred for about 30 minutes at 0°C. The reaction solution was added with MeI (6.67 mL, 107 mmol), followed by stirring for about 12 hours at room temperature. The reaction mixture was added with an ice water. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (EA:HEX = 1:9) to obtain the title compound (0.6 g, 23 percent). ¹H-NMR Spectrum (300 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.22 (d, 1H), 7.91 (d, 1H), 7.65 (t, 1H), 1.81 (s, 6H). MS (ESI⁺, m/z): 191 [M+H]⁺

23%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 20℃; for 12 h;	NaH (4.34 g, 90.4 mmol) was stirred in a solvent of tetrahydrofuran (20 mL) at 0° C. The reaction solution was slowly added with 2-(3-nitrophenyl)acetonitrile (2.2 g, 13.6 mmol), and stirred for about 30 minutes at 0° C. The reaction solution was added with MeI (6.67 mL, 107 mmol), followed by stirring for about 12 hours at room temperature. The reaction mixture was added with an ice water. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (EA:HEX=1:9) to obtain the title compound (0.6 g, 23percent). ¹H-NMR Spectrum (300 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.22 (d, 1H), 7.91 (d, 1H), 7.65 (t, 1H), 1.81 (s, 6H). MS (ESI⁺, m/z): 191 [M+H]⁺
2.1 g	Stage #1: With sodium hydride In tetrahydrofuran for 0.5 h; Cooling with ice Stage #2: at 20℃;	To an ice-cold slurry of 50 percent NaH (6.84 g, 171 mmol) in anhydrous THF (30.0 ml) was slowly added a solution of 2-(3-nitrophenyl) acetonitrile (4.2 g, 25.9 mmol) in anhydrous THF (30 ml). After 30 min, methyl iodide ( 12.63 ml, 202 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was then quenched with ice-water. The reaction mixture was then extracted with ethyl acetate, the organic layer was separated and washed with water, dried over anhydrous sodium sulphate; filtered and concentrated to get crude oil. The crude oil was purified by column chromatography over silica gel by eluting with ethyl acetate/ hexane (5:95) gave 2-methyl-2-(3-nitro phenyl) propanenitrile (2.1 g). ⁱHNMR (400 MHz, CDC13), 8 8.33-8.32 (m, IH), 8.24-8.21 (m, IH), 7.92-7.89 (m, IH), 7.63 (t, J= 8.00 Hz, IH), 1.82(s, 6H).GCMS: 190.11 [M+]
2.1 g	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil for 0.5 h; Cooling with ice Stage #2: at 22 - 26℃; Cooling with ice	Step a: Synthesis of 2-methyl-2-(3-nitrophenyl)propanenitrile To an ice-cold slurry of 50percent NaH (6.84 g, 171 mmol) in anhydrous THF (30.0 ml) was slowly added a solution of 2-(3-nitrophenyl)acetonitrile (4.2 g, 25.9 mmol) in anhydrous THF (30 ml). After 30 min, methyl iodide (12.63 ml, 202 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was then quenched with ice-water. The reaction mixture was then extracted with ethyl acetate, the organic layer was separated and washed with water, dried over anhydrous sodium sulphate; filtered and concentrated to get crude oil. The crude oil was purified by column chromatography over silica gel by eluting with ethyl acetate/hexane (5:95) gave 2-methyl-2-(3-nitrophenyl) propanenitrile (2.1 g). ¹HNMR (400 MHz, CDCl₃), δ 8.33-8.32 (m, 1H), 8.24-8.21 (m, 1H), 7.92-7.89 (m, 1H), 7.63 (t, J=8.00 Hz, 1H), 1.82 (s, 6H). GCMS:190.11[M+]

Reference： [1] Patent: WO2006/123145, 2006, A1, . Location in patent: Page/Page column 49
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 4, p. 577 - 583
[3] Patent: EP2876107, 2015, A1, . Location in patent: Paragraph 0085
[4] Patent: US2015/191450, 2015, A1, . Location in patent: Paragraph 0176-0178
[5] Patent: WO2013/136249, 2013, A1, . Location in patent: Page/Page column 49-50
[6] Patent: US2015/133424, 2015, A1, . Location in patent: Paragraph 0248-0249

15
[ 621-50-1 ]
[ 71-91-0 ]
[ 74-88-4 ]
[ 915394-28-4 ]

Reference： [1] Patent: US2009/137595, 2009, A1,

[ 621-50-1 ] Synthesis Path-Downstream 1~88

1
[ 108-73-6 ]
[ 621-50-1 ]
[ 876487-63-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; diethyl ether; zinc(II) chloride Erhitzen des Reaktionsprodukts mit Wasser;
	Stage #1: 3,5-dihydroxyphenol; (3-nitrophenyl)acetonitrile With hydrogenchloride; zinc(II) chloride In diethyl ether at 20℃; Stage #2: With hydrogenchloride; edetate disodium Heating;

Reference： [1]Yamashita [1929, vol. <I> 18, p. 615,616]
[2]Stachulski, Andrew V.; Berry, Neil G.; Low, Lilian A.C.; Moores, Shelley L.; Row, Eleanor; Warhurst, David C.; Adagu, Ipemida S.; Rossignol, Jean-François [Journal of Medicinal Chemistry, 2006, vol. 49, # 4, p. 1450 - 1454]

2
[ 621-50-1 ]
[ 1877-73-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sulfuric acid; water; acetic acid; at 110℃; for 5h;Inert atmosphere; Schlenk technique;	2-(3-nitrophenyl)acetonitrile (27) (1.95 g, 12.0 mmol, 1.00 eq) was dissolved in H2O (7 mL) before concentrated H2SO4 (7 mL) and AcOH (7 mL) were added dropwise. The solution was stirred at 110 C for 5 h. After cooling to room temperature, H2O (40 mL) was added carefully. The solution was extracted with EtOAc (3 * 50 mL), then washed with H2O (90 mL) and saturated aqueous NaCl (90 mL), dried over MgSO4 and concentrated. The off-white solid 28 (2.15 g, 11.9 mmol, 99%) thus obtained was pure enough for further transformations. 1H NMR (400 MHz, CDCl3) delta = 8.17 (d, J = 7.0, 2H), 7.63 (d, J = 7.6, 1H), 7.58-7.48 (m, 1H), 3.79 (s, 2H).
94%	With sulfuric acid; acetic acid; In water; at 110℃;	Into a 50-mi. round-bottom flask, was placed a mixture of 2-(3-nitrophenyl)acetonitrile24.67 mmol, 1.00 equiv), water (8 mL), sulfuric acid (8 mL), and acetic acid (8 mL). The resulting solution was stirred overnight at 1100 C, and then it was diluted with water. The resulting solution was extracted with ethyl acetate, and the combined organic layers wereconcentrated under vacuum to yield 4.2 g (94%) of 2-(3-nitrophenyl)acetic acid as a yellow solid
94%	With sulfuric acid; acetic acid; In water; at 110℃;	Step 1 Into a 50-mL round-bottom flask, was placed a mixture of 2-(3-nitrophenyl)acetonitrile (4 g, 24.67 mmol, 1.00 equiv), water (8 mL), sulfuric acid (8 mL), and acetic acid (8 mL). The resulting solution was stirred overnight at 110 C, and then it was diluted with water. The resulting solution was extracted with ethyl acetate, and the combined organic layers were concentrated under vacuum to yield 4.2 g (94%) of 2-(3-nitrophenyl)acetic acid as a yellow solid.

With sulfuric acid; water; acetic acid; at 110℃; for 4h;

b. 2-(3-nitrophenyl)ethanol; A solution of 3-nitro-phenyl acetonitrile (220 g, 1.078 moles) in water (440 imL), H2SO4 (440 ml_), and acetic acid (440 ml_) was heated at 110 0C for 4 hours. The reaction mixture was diluted with water, and extracted with EtOAc (3 x 1 L). The combined organics were washed with water and brine, dried (Na2SO4), filtered and concentrated to give the product carboxylic acid (20Og). This crude acid was dissolved in THF (3L), cooled to 0 0C, and treated with borane dimethyl sulfide (150 mL, 1.618 moles), allowed to warm to room temperature, and stirred overnight. The reaction mixture was evaporated to dryness and the resulting syrup was dissolved in EtOAc (3L), washed with water and brine, dried (Na2SO4), filtered and concentrated to a brown liquid (175 g).

Reference： [1]Tetrahedron,2017,vol. 73,p. 4905 - 4912
[2]Patent: WO2014/182829,2014,A1 .Location in patent: Page/Page column 55
[3]Patent: WO2016/191172,2016,A1 .Location in patent: Page/Page column 78
[4]Chemische Berichte,1883,vol. 16,p. 2066
[5]Journal of Biological Chemistry,1926,vol. 68,p. 508
[6]Scientia Pharmaceutica,2001,vol. 69,p. 329 - 350
[7]Patent: WO2007/18941,2007,A2 .Location in patent: Page/Page column 44

3
[ 621-50-1 ]
[ 14318-64-0 ]

Reference： [1]Bulletin des Societes Chimiques Belges,1955,vol. 64,p. 87,91

4
[ 621-50-1 ]
[ 4623-24-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With iron; ammonium chloride; In ethanol; water; at 85℃; for 1.0h;	General procedure: To a solution of 2 (150.1 mg, 0.66 mmol) and NH4Cl (183.6 mg, 3.43 mmol) in a mixture of EtOH/H2O (5:1, 6 mL) was added iron (Fe) powder (184.4 mg, 3.30 mmol) and vigorously stirred at 85 C for 1 h. After the mixture was allowed to cool to room temperature, the solid was removed by filtration through a Celite pad, and the filtrate was concentrated. The residue was purified by column chromatography (EtOAc/hexane, 20:70) to afford 10a (99.2 mg, 76%) as a brown oil;
96%	With iron; ammonium chloride; In ethanol; water; at 85℃; for 1.0h;	A. (3-Amino-phenyl)-acetonitrile A mixture of (3-nitro-phenyl)-acetonitrile (2.00 g, 12.35 mmol), iron dust (2.07 g, 37.03 mmol) and ammonia chloride (1.96 g, 37.03 mmol) in EtOH (20 mL) and water (4 mL) was refluxed at 85 C. for 1 h. The reaction mixture was filtered through cellite and rinsed with EtOH. The combined filtrate was concentrated and the residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (1.57 g, 11.89 mmol, 96% yield) as a pale-yellow solid. MS (ESI) m/z 133.1 [M+H]+.
90%	With hydrogen; In 1,2-dimethoxyethane; at 100℃; under 12001.2 Torr; for 35.0h;	A nanoporous metal cesium catalyst (3.2 mg, 0.03 mmol) Ethylene glycol dimethyl ether (3 mL) and 3-nitrophenylacetonitrile (48.65mg, 0.3mmol) was added to the Reaction kettle, hydrogen (16 bar) was introduced, heated and stirred, the reaction temperature was controlled at 100 C, Reaction time control at 35h, column chromatography (baby gel, 200-300 mesh; Developing solvent, petroleum ether: ethyl acetate = 10: 1) to give 35.7 mg of 3-aminophenylacetonitrile in 90% yield.

80%	With iron; ammonium chloride; In tetrahydrofuran; methanol; water; at 20 - 60℃; for 3.0h;	To a stirred solution of NH4C1 (1.1 g, 19.74 mmol) in H20 (16 mL) was added Fe powder (1.01 g, 18.08 mmol) followed by Intermediate BC (800 mg, 4.23 mmol) in a mixture of THF (8.0 mL) and MeOH (8.0 mL) slowly at room temperature. The reaction was then stirred for 3h at 60 C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through a Celite bed. The organic layer was washed with water (2 chi 25 mL) and brine solution (20 mL), dried over anhydrous Na2S04, and evaporated to afford the crude product. This material was purified by column chromatography (silica gel 100-200 mesh) using 40% ethyl acetate in petroleum ether as the eluent to afford Intermediate BD (520 mg, 80%) as a brown gum. NMR (CDC13): delta 7.14 (d, J = 7.67 Hz, 1H), 7.68-6.62 (m, 3H), 3.74 (bs, 2H), 3.65 (s, 2H). Mass (M+H): 238.0.
51%		Iron powder (517 mg, 9.27 mmol) was added to a solution of 3-nitrophenylacetonitrile (500 mg, 3.09 mmol) in acetic acid (9.5 ml) and water (6.6 ml). The reaction was stirred at 40 0C for 24 h, then cooled to room temperature. The mixture was diluted with water (20 ml), adjusted to pH 8 with 2N NaOH and then filtered trough Celite. The aqueous filtrate was extracted with ethyl acetate, the combined organic phases were dried (MgSO,)) and evaporated. Purification by flash chromatography on the Biotage SP4, eluting with 0 to 60% ethyl acetate / petroleum ether gradient, gave the desired product as a colourless oil (51%). 1H NMR (400 MHz, DMSO-^6) delta ppm 3.84 (s, 2 H), 5.22 (br. s, 2 H), 6.40 - 6.44 (m, 1 H), 6.46 - 6.50 (m, 1 H), 6.50 - 6.53 (m, 1 H), 6.96 - 7.03 (m, 1 H); Rf (50% Ethyl acetate/Petroleum ether) = 0.5.
44%	With hydrogen;palladium 10% on activated carbon; In methanol; water; at 22℃; under 4137.29 Torr; for 48.0h;	To a solution of 3-nitro-phenyl-acetonitrile (3.20 g, 19.7 mmol) in MeOH(50 mL) was added Pd/C (10% wt, -50% H20, 0.32 g) and the mixture was placed under H2 (80 psi) and stirred for 2 days at 22 0C. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to give crude product as a yellow oil. The residue was purified by silica gel chromatography (ISCO, elution with 0-10% ethyl acetate in hexanes) to give xix-1-1 (1.15 g, 44%): MS m/z = 133 (M-H).
34%		(c) 5-Phenyl-furan-2-carboxylic acid [3-(lH-tetrazol-5- ylmethyl)-phenyl]-amide (75); (i) (3-Amino-phenyl)-acetonitrile (80); A solution of 3-nitrophenyl acetonitrile (500 mg, 3.1 mmol) in 5% AcOH (10 ml) was heated to 80C. Iron powder (1.5 g, 27 mmol) was then added and the resulting mixture stirred for 2 h. The reaction mixture was filtered through celite and the filter cake washed with MeCN (4 x 50 ml). The combined MeCN layers were evaporated in vacuo and the residue was re-dissolved in EtOAc (30 ml) followed by 2M HC1 (30 ml). The aqueous layer was separated, basified to pH 10 with 6M NaOH, and extracted with EtOAc (3 x 80 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound. Yield: 140 mg, 34% ; 1H NMR (400 MHz, CDC13) : 5 3.65 (s, 2H), 3.75 (s, 2H), 6.60-6. 70 (m, 3H), 7.15 (t, 1H)
32%		A mixture of nitrobenzene acetic acid (1 g, 5.52 mmoles), 1.66 mL OF SOC12, 10 mL dry CHC13 was refluxed for 14 hours. CHC13 and excess thionyl chlorid were removed in vacuo, and the residue was evaporated twice with 25 mL of toluene to remove traces of thionyl chlorid. The residue was taken into 10 mL of toluene and 30 mL of cold concentrated ammonium hydroxyde were added. The white solid formed was collected and dried with etanol in vacuo. Yield: 79 %. 'H NMR (DMSO-d6, 300MHZ) 8 : 8.14 (M, 2H), 7.71 (M, 2H), 7.06 (brs, 2H), 3.58 (s, 2H). 2- (3-NITROPHENYL) acetamide was added with 10 mL of POC13 and the mixture was heated at reflux for 2 hours. After cooling, the mixture was poured into ice, basified with NA2CO3 and extracted with CH2C12. The organic layer was dried over NA2S04, filtered and evaporated. Purified by flash chromatography on silica gel CH2C12. Yield : 41% H NMR (CDC13,300 MHz) 5 : 8. 14 (M, 2H), 7.69 (d, 1H, J = 8HZ), 7.56 (M, 1H), 3.88 (s, 2H). A solution of 15 mL HBr 48% was cooled to 0C. (430 mg, 2.65 mmoles) OF 3-NITROBENZONITRILE, (574 mg, 4. 85 mmoles) of Sn were added successively. The mixture was stirred at room temperature for 3 hours, then poured into ice. The solution was basified with NA2C03, extracted with CH2C12, dried, filtered and evaporated. Purified by flash chromatography on silica gel ETOH/CH2CL2 (2: 98). Yield: 32% H NMR (DMSO-d6, 300MHZ) 8 : 7.37 (M, 2H), 6.81 (M, 2H), 3.86 (s, 2H). 3-AMINOBENZONITRILE was then reacted with 2-chloroethylisocyanate as described in examples 1- 12 to obtain desired product. Purified by flash CHRMATOGRAPHY on silica gel ETOH/CH2CL2 (5: 95). Yield: 78% H NMR (CDCL3, 300 MHz) 8 : 8.12 (brs, NH, 1H), 7.26 (M, Ar, 4H), 6.97 (brs, NH, 1H), 3.63 (m, CH2,6H).
32%	With tin; hydrogen bromide; In water; at 0 - 20℃; for 3.0h;	A mixture of nitrobenzene acetic acid (1 g, 5.52 mmoles), 1.66 mL OF SOC12, 10 mL dry CHC13 was refluxed for 14 hours. CHC13 and excess thionyl chlorid were removed in vacuo, and the residue was evaporated twice with 25 ML of toluene to remove traces of thionyl chlorid. The residue was taken into 10 mL of toluene and 30 ML of cold concentrated ammonium hydroxyde were added. The white solid formed was collected and dried with etanol in vacuo. Yield: 79 %. 1H NMR (DMSO-d6, 300MHZ) 8 : 8.14 (M, 2H), 7.71 (M, 2H), 7.06 (brs, 2H), 3.58 (s, 2H). 2- (3-NITROPHENYL) ACETAMIDE was added with 10 mL of POC13 and the mixture was heated at reflux for 2 hours. After cooling, the mixture was poured into ice, basified with NA2C03 and extracted with CH2C12. The organic layer was dried over NA2S04, filtered and evaporated. Purified by flash chromatography on silica gel CH2C12. Yield: 41% 1H NMR (CDC13, 300 MHz) 8 : 8.14 (M, 2H), 7.69 (d, 1H, J = 8HZ), 7.56 (m, 1H), 3.88 (s, 2H). A solution of 15 mL HBr 48% was cooled to 0C. (430 mg, 2.65 mmoles) of 3-nitrobenzonitrile, (574 mg, 4.85 mmoles) of Sn were added successively. The mixture was stirred at room temperature for 3 hours, then poured into ice. The solution was basified with NA2CO3, extracted with CH2CK, dried, filtered and evaporated. Purified by flash chromatography on silica gel ETOH/CH2CL2 (2: 98). Yield: 32% 1H NMR (DMSO-D6, 300MHZ) B : 7.37 (M, 2H), 6.81 (M, 2H), 3. 86 (s, 2H). 3-AMINOBENZONITRILE was then reacted with 2-chloroethylisocyanate as described in examples 1- 12 to obtain desired product. Purified by flash chrmatography on silica gel ETOH/CH2C12 (5: 95). Yield: 78%
	palladium; In ethanol;	3-Aminobenzeneacetonitrile A solution of 3-nitrobenzeneacetonitril (8.0 g) in EtOH (100 ml) was hydrogenated at 1 atm and room temperature over 5% palladium on carbon (0.8 g) for 4 hrs. The catalyst was removed by filtration through Hyflo and the filtrate was evaporated. The residue was chromatographed, eluding with EA:Hexane (1:2) to give the title compound (5.25 g) as an orange oil.
		2-(3-aminophenyl)acetonitrile (11) 3-Nitrophenyl acetonitrile (10) was dissolved in a mixture of concentrated HCl (15 ml) and ethanol (15 ml). A solution of SnCl2 dihydrate in ethanol (25 ml) was added gradually dropwise under ice-cooling and the mixture was stirred at room temperature for 5 hours. TLC (EtOAc/Hexane 1:1) Rf=0.1 showed 80% completion. After the solvent was evaporated, the residue was treated with NaOH to pH 9. Extraction with EtOAc and combiflash (12 g, Hexane/EtOAc 10% to 50%, 70 min) afforded 1.182 g of compound (11) as a yellow oil. 1H-NMR(400 Mhz, CDCl3) 7.12(t, J=7.5 Hz, 1H), 6.65(m, 3H), 3.72(br-s, 1 H), 3.64(s, 2H).
	With iron; In ethanol; water; for 4.0h;Reflux;	[0308] To the mixture of solution of 3-nitrophenylacetonitrile (16.2g, 0. lmol) and ion powder (56g, lmol) in ethanol (160ml) and water (40ml), added hydrochloride (25ml, 6N), heated to reflux for 4 hours. Filtered through celite, concentrated, extracted with EtOAc, washed with water and brine, dried over sodium sulfate.Removed solvent, got crude product as oil.
	With palladium on activated charcoal; hydrogen; In methanol; under 1551.49 Torr; for 2.0h;	Pd/C (0.48 g) was added to a solution of 3-nitrophenylacetonitrile (1.0 mol, 3.80 g,) in methanol (130mL) and the suspension was hydrogenated for 2 h at 30 psi.At the end of the reaction the suspension was filtered overCelite and the solvent removed under reduced pressure.The oil thus obtained was used in the next step withoutpurification. Scheme S9. Yield 98%. 1H-NMR (CDCl3,200 MHz): delta = 7.20-7.10 (m, 1H), 6.7-6.6 (m, 3H); 13CNMR(CDCl3, 100 MHz): delta = 130.05, 117.84, 114.53,114.17, 23.50. Anal. calcd. for C8H8N2: C, 72.7; H, 6.1; N,21.2. Found: C, 72.63; H, 6.08; N, 21.12.
	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 825.0830000000001 Torr; for 0.583333h;	Example 19; (2R,3R)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(1 R)-(1 ,2-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide] (as the trifluoroacetate salt); (a) 3-amino-phenyl-acetonitrile; Palladium/charcoal 10% (4.5g) is added to a solution of 3-nitro-phenyl- acetonitrile (46 g, 284 mmol) in methanol (644 ml_). The mixture is hydrogenated at 1.1 bar hydrogen atmosphere and at 200C for 35 minutes. Then it is filtered to remove the catalyst and evaporated down i.vaalpha. Rt value: 0.22 min (Method C) <n="51"/>C8H8N2 (132.16)Mass spectrum: (M+H)+ = 133

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 577 - 583
[2]Patent: US2015/175557,2015,A1 .Location in patent: Paragraph 0347
[3]Patent: CN107098786,2017,A .Location in patent: Paragraph 0049-0050
[4]Patent: WO2011/47156,2011,A1 .Location in patent: Page/Page column 82
[5]Patent: WO2009/122180,2009,A1 .Location in patent: Page/Page column 95
[6]Patent: WO2006/41773,2006,A2 .Location in patent: Page/Page column 368
[7]Patent: WO2005/80367,2005,A1 .Location in patent: Page/Page column 129-130
[8]Patent: WO2004/106292,2004,A1 .Location in patent: Page 94-95
[9]Patent: WO2004/106291,2004,A1 .Location in patent: Page 92
[10]Journal of the American Chemical Society,1943,vol. 65,p. 437
[11]Chemische Berichte,1884,vol. 17,p. 506
Chemische Berichte,1889,vol. 22,p. 2139
[12]Journal of Medicinal Chemistry,2003,vol. 46,p. 1661 - 1669
[13]Patent: US5910495,1999,A
[14]Patent: US2008/214558,2008,A1 .Location in patent: Page/Page column 16
[15]Patent: WO2011/60196,2011,A1 .Location in patent: Page/Page column 141
[16]Medicinal Chemistry Research,2017,vol. 26,p. 975 - 986
[17]Journal of Medicinal Chemistry,2017,vol. 60,p. 7146 - 7165
[18]Patent: WO2008/135525,2008,A2 .Location in patent: Page/Page column 49-50

5
[ 621-50-1 ]
[ 100-52-7 ]
[ 54648-43-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With dimethyl 3-methyl-9-oxo-7-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)-2,4-di(pyridin-2-yl)-3,7-diazabicyclo-[3.3.1]nonane-1,5-dicarboxylate In water at 60℃; for 24h;
	With sodium ethanolate

Reference： [1]Ang, Wei Jie; Chng, Yong Sheng; Lam, Yulin [RSC Advances, 2015, vol. 5, # 99, p. 81415 - 81428]
[2]Schonne et al. [Bulletin des Societes Chimiques Belges, 1953, vol. 62, p. 155,156, 159] Bruylants et al. [Helvetica Chimica Acta, 1952, vol. 35, p. 1127,1135]

6
[ 7647-01-0 ]
[ 621-50-1 ]
tin [ No CAS ]
[ 4623-24-9 ]

Reference： [1]Chemische Berichte,1884,vol. 17,p. 506
Chemische Berichte,1889,vol. 22,p. 2139

7
[ 6940-76-7 ]
[ 621-50-1 ]
5-chloro-2-(3-nitro-phenyl)-pentanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium diisopropyl amide In tetrahydrofuran; cyclohexane at -78 - 20℃; for 1h;

Reference： [1]Ng, Howard P.; Karen, May; Bauman, John G.; Ghannam, Ameen; Islam, Imadul; Liang, Meina; Horuk, Richard; Hesselgesser, Joseph; Snider, R. Michael; Perez, H. Daniel; Morrissey, Michael M. [Journal of Medicinal Chemistry, 1999, vol. 42, # 22, p. 4680 - 4694]

8
[ 67-56-1 ]
[ 621-50-1 ]
[ 618-95-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With iodine; oxygen; potassium iodide at 20℃; for 72h;
38%	With samarium; potassium iodide at 20℃; for 72h;

Reference： [1]Wang, Zhiyuan; Kang, Junhui; Yu, Mingxin [Journal of Chemical Research, 2007, # 6, p. 323 - 324]
[2]Yu, Mingxin; Wen, Weijiang; Wang, Zhiyuan [Synthetic Communications, 2006, vol. 36, # 19, p. 2851 - 2857]

9
[ 71-23-8 ]
[ 621-50-1 ]
[ 59265-70-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With iodine; oxygen; potassium iodide at 20℃; for 72h;

Reference： [1]Wang, Zhiyuan; Kang, Junhui; Yu, Mingxin [Journal of Chemical Research, 2007, # 6, p. 323 - 324]

10
[ 64-17-5 ]
[ 621-50-1 ]
[ 618-98-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With iodine; potassium iodide at 20℃; for 72h;

Reference： [1]Wang, Zhiyuan; Kang, Junhui; Yu, Mingxin [Journal of Chemical Research, 2007, # 6, p. 323 - 324]

11
[ 621-50-1 ]
[ 67-63-0 ]
[ 6268-23-1 ]

Yield	Reaction Conditions	Operation in experiment
65%	With iodine; oxygen; potassium iodide at 60℃; for 30h;

Reference： [1]Wang, Zhiyuan; Kang, Junhui; Yu, Mingxin [Journal of Chemical Research, 2007, # 6, p. 323 - 324]

12
[ 621-50-1 ]
[ 100-51-6 ]
[ 136322-11-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With iodine; oxygen; potassium iodide at 60℃; for 24h;

Reference： [1]Wang, Zhiyuan; Kang, Junhui; Yu, Mingxin [Journal of Chemical Research, 2007, # 6, p. 323 - 324]

13
[ 621-50-1 ]
[ 100-51-6 ]
cyclohexyl 3-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With iodine; oxygen; potassium iodide at 50℃; for 21h;

Reference： [1]Wang, Zhiyuan; Kang, Junhui; Yu, Mingxin [Journal of Chemical Research, 2007, # 6, p. 323 - 324]

15
[ 621-50-1 ]
[ 501124-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: ZnCl₂; HCl (gas) / diethyl ether / 20 °C 1.2: aq. HCl; EDTA sodium salt / Heating 2.1: 74 percent / BF₃*Et₂O; MeSO₂Cl / 1.5 h / Heating

Reference： [1]Stachulski, Andrew V.; Berry, Neil G.; Low, Lilian A.C.; Moores, Shelley L.; Row, Eleanor; Warhurst, David C.; Adagu, Ipemida S.; Rossignol, Jean-François [Journal of Medicinal Chemistry, 2006, vol. 49, # 4, p. 1450 - 1454]

16
[ 621-50-1 ]
5,7-dihydroxy-3-(3-nitro-phenyl)-4-oxo-4<i>H</i>-chromene-2-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: ZnCl₂; HCl (gas) / diethyl ether / 20 °C 1.2: aq. HCl; EDTA sodium salt / Heating 2.1: 74 percent / BF₃*Et₂O; MeSO₂Cl / 1.5 h / Heating 3.1: K₂CO₃ / acetone / 20 - 50 °C

17
[ 621-50-1 ]
[ 76935-75-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: BH₃ / tetrahydrofuran / 25 °C 1.2: aq. HCl / tetrahydrofuran / 0 °C 2.1: SnCl₂*2H₂O / ethanol / 70 °C
81% (1.5 g, brown liquid, over two steps)		32 Example 32 Example 32 3-(2-Aminoethyl)aniline (40). This compound was prepared as described above using (3-nitrophenyl)acetonitrile (2.2 g, 13.6 mmol). Evaporation of the solvent gave the product in a yield of 81% (1.5 g, brown liquid, over two steps): 1H NMR (400 MHz, CD3OD) 7.02 (t, J=7.2 Hz, 1H), 6.59 (m, 2H), 6.56 (m, 1H), 2.84 (t, J=7.2 Hz, 2H), 2.64 (t, J=7.2 Hz, 2H). HRMS (EI) m/z (M+) calcd for C8H12N2 136.1000, found 136.0980.
	Multi-step reaction with 2 steps 1: borane-THF / tetrahydrofuran / 7 h / Reflux 2: palladium 10% on activated carbon; hydrogen / isopropyl alcohol / 24 h / 20 °C / Inert atmosphere

Multi-step reaction with 4 steps 1: dimethylsulfide borane complex / tetrahydrofuran / 2 h / Reflux 2: sodium hydroxide / tetrahydrofuran / 20 °C 3: hydrogen; 20% palladium hydroxide-activated charcoal / tetrahydrofuran; methanol 4: trifluoroacetic acid / 1 h / 20 °C

Reference： [1]Hah, Jung-Mi; Martásek, Pavel; Roman, Linda J.; Silverman, Richard B. [Journal of Medicinal Chemistry, 2003, vol. 46, # 9, p. 1661 - 1669]
[2]Current Patent Assignee: NORTHWESTERN UNIVERSITY (ILLINOIS) - US2003/119751, 2003, A1
[3]Pesnot, Thomas; Gershater, Markus C.; Ward, John M.; Hailes, Helen C. [Chemical Communications, 2011, vol. 47, # 11, p. 3242 - 3244]
[4]Current Patent Assignee: NUVATION BIO INC - US2019/106427, 2019, A1

18
[ 621-50-1 ]
[ 180079-94-1 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1661 - 1669
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1545 - 1548
[3]Patent: US2019/106427,2019,A1

19
[ 621-50-1 ]
C₁₄H₂₅N₇O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: BH₃ / tetrahydrofuran / 25 °C 1.2: aq. HCl / tetrahydrofuran / 0 °C 2.1: SnCl₂*2H₂O / ethanol / 70 °C 3.1: 100 percent / dioxane 4.1: 3A molecular sieves / methanol / 1 h / 20 °C 5.1: 314 mg / sodium triacetoxyborohydride / methanol 6.1: 90 percent / TFA / CH₂Cl₂ / 2 h