454-16-0|1-Fluoro-2-methoxy-4-nitrobenzene| Ambeed

Structure of 454-16-0

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Quality Control of [ 454-16-0 ] Purity: 97% SDS Specification

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Product Details of [ 454-16-0 ]

CAS No. :	454-16-0
Formula :	C₇H₆FNO₃
M.W :	171.13
SMILES Code :	COC1=C(C=CC(=C1)[N+]([O-])=O)F
MDL No. :	MFCD07782081
InChI Key :	AZNKKZHZGDZSIF-UHFFFAOYSA-N
Pubchem ID :	14451968

Safety of [ 454-16-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 454-16-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	41.71
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	55.05 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.4
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.25
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.16
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.05
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.1
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.39

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.56
Solubility	0.475 mg/ml ; 0.00278 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.04
Solubility	0.155 mg/ml ; 0.000908 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.18
Solubility	1.13 mg/ml ; 0.00661 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.75 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.99

Application In Synthesis of [ 454-16-0 ]

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

Downstream synthetic route of [ 454-16-0 ]

[ 454-16-0 ] Synthesis Path-Downstream 1~35

1
[ 97-52-9 ]
[ 454-16-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite; In water;	A. 2-Fluoro-5-nitroanisole To a stirred solution of 35 ml. concentrated hydrochloric acid and 40 ml. water is added 48 grams of 2-amino-5-nitroanisole. The mixture is warmed and then cooled to 0°-5° C. To the stirred mixture is added dropwise 20 grams sodium nitrite in 120 ml. water maintaining the temperature at 0° - 5° C. After addition is complete the reaction mixture is filtered and cooled with stirring while 70 ml. fluoboric acid (48percent) is added. The homogeneous solution is allowed to stir in the cold for an additional hour during which time a yellow precipitate forms. The precipitate is filtered, washed with cold water, ethanol and ether and air dried to yield 31.4 grams of the diazonium fluoborate. A mixture of 21.4 grams diazonium fluoborate and 60 grams sand is stirred wile heating in an oil bath. When the evolution of gases commences, the bath is lowered. After the reaction slows down, the bath is applied again. This prodedure is repeated until evolution of gases has ceased. The reaction mixture is then heated at 200° C. for an additional one-half hour. After cooling to room temperature, the residue is extracted with chloroform. The extract is evaporated in vacuo and the residue subjected to a steam distillation. A white solid is formed in the distillate. The solid is extracted with ether, which is removed to yield 2.6 grams of the 2-fluoro-5-nitroanisole. A sample is recrystallized from ethanol to give a pure product with a melting point of 69° - 71° C. Calculated for C7 H6 FNO3: C, 49.13; H, 3.53; N, 819; F, 11.10. Found: C, 49.33; H, 3.60; N, 8.17; F, 10.96.

References: [1]Synthetic Communications,1989,vol. 19,p. 865 - 872.
[2]Synthetic Communications,1989,vol. 19,p. 865 - 872.
[3]Tetrahedron,1996,vol. 52,p. 23 - 36.
[4]Patent: US4044049,1977,A .

2
[ 321-28-8 ]
[ 454-16-0 ]
[ 455-93-6 ]
[ 484-94-6 ]

References: [1]Journal of Organic Chemistry,1998,vol. 63,p. 8448 - 8454.
[2]Journal of Organic Chemistry,1998,vol. 63,p. 8448 - 8454.

4
[ 454-16-0 ]
[ 141699-55-0 ]
[ 960401-34-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.5h;	Dissolve l-fluoro-2-methoxy-4-nitro-benzene (118 g, 689 mmol) and 3-hydroxy- azetidine-1-carboxylic acid tert-bupsilonXyl ester (125 g, 724 mmol) in THF (800 mL) and cool to 0 0C under nitrogen. To the above solution, add dropwise a 1 M THF solution of tert- BuOK (1 L). After the addition is complete, stir the dark brown solution for 30 min at 0 0C and then dilute with water (1 L) over a 10 min period. Stir the mixture for 5 min, then extract with tert-bvAyl methyl ether (2x ). Combine the organic solutions and wash with brine (2 x 700 mL), then dry and concentrate. Dry the solid in vacuo at 45 0C for 20 h to obtain 216 g (95percent) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3) 6.47 (d, IH, J= 8.5), 6.30 (d, IH, J= 2.6), 6.17 (dd, IH, J= 2.4, 8.5), 4.76 (m, IH), 4.18 (m, 2H), 4.04 (m, 2H), 3.80 (s, 3H), 1.42 (s, 9H).
95%	With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.5h;	Preparation 60; 3-(2-Methoxy-4-nitro-phenoxy)-azetidine-l-carboxylic acid tert-butyl ester; Dissolve l-fluoro-2-methoxy-4-nitro-benzene (118 g, 689 mmol) and 3 -hydroxy - azetidine-1-carboxylic acid tert-butyl ester (125 g, 724 mmol) in THF (800 mL) and cool to 0 0C. To the above solution under a nitrogen atmosphere, add dropwise a IM solution of tBuOK (I L, solution in THF). After addition is complete, stir the dark brown solution for 30 min at 0 0C, then dilute with water (1 L) over a 10 min period. Stir the mixture for5 min, then extract with MTBE twice. Combine the organic solutions and wash with brine (2 x 700 mL), then dry and concentrate. Dry the solid in vacuo at 45 0C for 20 h to <n="56"/>obtain 216 g (95percent) of the title compounds as a yellow solid. 1H NMR (300 MHz, CDCl3) .pound. 1.42 (s, 9H), 3.80 (s, 3H), 4.04 (m, 2H), 4.18 (m, 2H), 4.76 (m, IH), 6.17 (dd, IH, J = 2.4, 8.5), 6.30 (d, IH, J= 2.6), 6.47 (d, IH, J= 8.5).

References: [1]Patent: WO2008/76562,2008,A1 .Location in patent: Page/Page column 25.
[2]Patent: WO2007/146758,2007,A2 .Location in patent: Page/Page column 54-55.

5
[ 454-16-0 ]
[ 64465-53-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	To a solution of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (101) (5.0 g, 29.0 mmol) in methanol (25 mL) was added 10 percent Pd/C (500 mg) at room temperature under H2 atmosphere. After reaction completion (monitored by TLC), the mixture was filtered and the filtrate was evaporated under vacuo to afford title compound 202 (4.0 g, 97 percent yield). ?H NIVIR (400 1VIHz, DMSO-d6): 3.72 (s, 3H), 4.93 (s, 2H), 6.02-6.05 (m, 1H), 6.33 (dd, J7.6, 2.4 Hz, 1H),6.81 (dd,J 11.6, 8.8 Hz, 1H).
93%		N-(4-fluoro-3-methoxyphenyl)pivalamide Step 1 : 4-fluoro-3-methoxyanilineNitro compound Il (6.5 g, 0.038 mol) and iron powder (10.6 g, 0.19 mol) were suspended in ethanol (90 ml) at O0C. HCI cone. (120 ml) was added drop wise to the reaction mixture. The reaction mixture was stirred at 2O0C for 18hr. The reaction mixture was then filtered through celite and washed repeatedly with ethanol. Then ethanol was concentrated and the residue was basified with solid Na2CO3. Then it was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuum to get the product (5 g, Y= 93percent). HPLC-MS: Purity 97percent, M+1 = 142.1
	palladium-carbon; In 1,4-dioxane;	C. 4-Fluoro-3-methoxyaniline A suspension of 10 grams of <strong>[454-16-0]2-fluoro-5-nitroanisole</strong> and 100 ml. of dioxane is reduced catalytically under 40 p.s.i. of hydrogen and 1.0 gram of 5percent Pd/C. After the uptake of hydrogen ceases, the catalyst is filtered, and the filtrate is concentrated in vacuo to yield 4-fluoro-3-methoxyaniline. Alternatively, the compound may be prepared as follows:

With hydrogenchloride; In methanol;

B. 4-Fluoro-3-methoxyaniline A solution of 5.4 grams <strong>[454-16-0]2-fluoro-5-nitroanisole</strong> in 125 ml. methanol is reduced by hydrogen at room temperature and 40 p.s.i. pressure using 100 mg. platinum oxide catalyst. After the required uptake of hydrogen, the mixture is filtered, 50 ml. 2.5 N hydrochloric acid added and the resulting solution is evaporated in vacuo. After washing the residue with ether, it is dissolved in methanol, filtered and diluted with excess ether. The precipitate is filtered, washed with ether and dried in vacuo at room temperature. The 4-fluoro-3-methoxyaniline hydrochloride darkens at 250° C. and melts 260° - 265° C. Calculated for C7 H8 FNO.HC1: C, 47.33; H, 5.11; N, 7.89; F, 10.70; Cl, 19.96. Found: C, 47.35; H, 5.14; N, 7.66; F, 10.9; Cl, 20.05.

References: [1]Patent: WO2017/132928,2017,A1 .Location in patent: Paragraph 000101.
[2]Patent: WO2010/145989,2010,A1 .Location in patent: Page/Page column 12-13.
[3]Patent: US4044049,1977,A .
[4]Patent: US4044049,1977,A .

6
[ 109-01-3 ]
[ 454-16-0 ]
[ 209482-01-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 18h;	2-Fluoro-5-nitroanisole (1.0 mmol) and N-methyl-piperazine (1.0 mmol)It was added to a 25 ml dry eggplant-shaped flask and dissolved in 4 ml of dry dimethyl sulfoxide.Potassium carbonate (2.0 mmol) was then added, and the mixture was heated to 120 C for 18 h, and the reaction was completely converted by TLC.Add water after cooling to room temperature.It was extracted three times with ethyl acetate and the organic phases were combined.Wash the organic phase with saturated brine.It was then dried over anhydrous sodium sulfate.Concentrated under reduced pressure to obtain crude product and then purified by column chromatography(dichloromethane: methanol = 100:1 ? dichloromethane: methanol = 50:1),A yellow solid S5 was obtained (yield 93%).
69%	In dimethyl sulfoxide; at 120℃; for 12h;	A mixture of scheme 2 compound 1 (2.00 g, 11.68 mmol) and scheme 2 compound 2 (1.17 g, 11.68 mmol) in dry DMSO (5 mL) was heated to 120 C for 12 h. After TLC showed the starting material was consumed completely, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5 x 50 mL). The organic layer was dried over Na2S04, filtered and concentrated to give scheme 2 compound 3 (2.00 g, 69% yield) as a brown solid which was used without further purification. *H NMR (400 MHz, CDCls): delta 7.87 (dd, J= 8.8, 2.6 Hz, 1H), 7.71 (d, J= 2.5 Hz, 1H), 6.90 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H), 3.26 (d, J= 4.9 Hz, 4H), 2.61 (t, J= 4.9 Hz, 4H), 2.37 (s, 3H). MS [ESI, MH+] = 252.13.

References: [1]Patent: CN110092784,2019,A .Location in patent: Paragraph 0103; 0120-0123.
[2]Patent: WO2014/151871,2014,A2 .Location in patent: Page/Page column 52.
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 1637 - 1648.

7
[ 822-36-6 ]
[ 454-16-0 ]
[ 958245-17-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Autoclave; Inert atmosphere;	2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-lH- imidazole (36.0 g, 0.44 mol) and K2C03 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125 °C for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H20 (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40(79 percent).
79%	With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere;	2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-lH- imidazole (36.0 g, 0.44 mol) and K2C03 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125 °C for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H20 (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40 (79 percent).
79%	With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere;	2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-1H-imidazole (36.0 g, 0.44 mol) and K2CO3 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125° C. for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H2O (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40 (79percent).

78.9%	With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere; Autoclave;	Example A2 a) Preparation of intermediate 3. (NOTE: this reaction was carried out in 4 batches of 50 g of <strong>[454-16-0]2-fluoro-5-nitroanisole</strong>). A mixture of <strong>[454-16-0]2-fluoro-5-nitroanisole</strong> (200 g, 1.17 mol), 4-methyl- IH- imidazole (143.9 g, 1.75 mol) and K2CO3 (161.5 g, 1.17 mol) in DMSO (600 ml) was prepared in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. heated at 125 0C for 16 h. The contents were allowed to cool and the solvent was evaporated under reduced pressure. H2O (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 215 g ofintermediate 3 (78.9 percent).
	With potassium carbonate; In acetonitrile; at 20℃;	Step C:; Two equivalent of 4-methylimidazole, 1 equivalent of 3-methoxy-4-fluoro- nitrobenzene and 5 eq. of K2CO3 were stirred in CH3CN at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product 5.1 d.
	With potassium carbonate; In acetonitrile; at 20℃;	Step F: Two equivalent of 4-methylimidazofe, 1 equivalent of 3-rnethoxy-4-fluoro- nitrobenzene and 5 eq. of K2CO3 were stirred in CH3CN at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product E1i.
	With potassium carbonate; In acetonitrile; at 20℃;	4-methylimidazole (2.0 mmol), <strong>[454-16-0]3-methoxy-4-fluoro-nitrobenzene</strong> (1.0 mmol) and K2CO3 (5 mmol) were stirred in CH3CN (10 mL) at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystallized with EtOAc to give desired product 1a.
	With potassium carbonate; In acetonitrile; at 20℃;	EXAMPLE 1Step A: 4-methylimidazole (2.0 mmol), <strong>[454-16-0]3-methoxy-4-fluoro-nitrobenzene</strong> (1.0 mmol) and K2CO3 (5 mmoi) were stirred in CH3CN (10 mL) at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product 1a.
	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃;Sealed tube;	Example 34 a. 3-methoxy-4-(5-methyl-lH-imidazol-l-yl)anilineA mixture of 4-methyl imidazole (500 mg, 6.1 mmol), 2-fluoro-5-nitro anisole (1.02 g, 5.9 mmol) and potassium carbonate (1.68 g, 12 mmol) in DMF (15 mL) was heated overnight at 85°C in a sealed tube. The reaction mixture was cooled, transferred into a round bottom flask using ethyl acetate and concentrated under high vacuum to 5 mL volume. The residue was suspended in water and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was dissolved in dichloromethane (10 mL) and diluted with hexane until the solution became slightly turbid. The turbid solution was left at room temperature. The separated solid was filtered, washed with hexane to give l-(2-methoxy-4-nitro-phenyl)-4- methyl-lH-imidazole. The mother liquor was purified by preparative HPLC giving 0.20 g of l-(2-methoxy-4-nitro-phenyl)-5-methyl-lH-imidazole.10 percent Pd/C (0.28 g, 2.6 mmol) was added to a solution of l-(2-methoxy-4-nitro-phenyl)-5- methyl-lH-imidazole (0.61 g, 2.6 mmol) in ethyl acetate (20 mL). The mixture was hydrogenated at 35 psi over night. The mixture was filtrated through celite and concentrated to about 10 mL. Diethylether (50 mL) was added and the solution was cooled to 00C. 4M HCl in dioxane (2 mL) was added and the solution was stirred for 15 min then warmed up to rt and stirred for 30 min. The excess solvent was decanted off and more diethylether was added and the mixture stirred for 15 min. This was repeated once more with a large amount of diehtylether. The wet solid was dried under vacuum giving 0.60 g of the title compound (16 percent Yield).1H NMR (400 MHz, METHANOL-d4) ppm 2.15 (s, 3 H), 3.92 (s, 3 H), 7.07 (dd, 1 H), 7.19 (d, 1 H), 7.49 (s, 1 H), 7.59 (d, 1 H), 9.03 (d, 1 H)

References: [1]Patent: WO2011/86098,2011,A1 .Location in patent: Page/Page column 71; 72.
[2]Patent: WO2011/86099,2011,A1 .Location in patent: Page/Page column 61.
[3]Patent: US2012/295891,2012,A1 .Location in patent: Page/Page column 28-29.
[4]Patent: WO2011/6903,2011,A1 .Location in patent: Page/Page column 117.
[5]Patent: WO2009/32277,2009,A1 .Location in patent: Page/Page column 413.
[6]Patent: WO2009/76337,2009,A1 .Location in patent: Page/Page column 242.
[7]Patent: US2010/137320,2010,A1 .Location in patent: Page/Page column 48.
[8]Patent: WO2009/108766,2009,A1 .Location in patent: Page/Page column 274.
[9]Patent: WO2010/132015,2010,A1 .Location in patent: Page/Page column 108-109.

8
[ 822-55-9 ]
[ 454-16-0 ]
[ 1077629-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile;Reflux;	Example 27(l-{4-[4-(2-Chloro-pyridin-3-yloxy)-6-methoxy-[l,3,5]triazin-2-ylamino]-2-methoxy- phenyl}-lH-imidazol-4-yl)-methanola) [ 1 -(2-Methoxy-4-nitro-phenyl)- 1 H-imidazo 1-4-yl] -methano 1A mixture of l-fluoro-2-methoxy-4-nitro-benzene (1.0 g, 5.8 mmol), (1 H-imidazo 1-4-yl)- methanol (602 mg, 6.1 mmol) and cesium carbonate (2.86 g, 8.8 mmol) in 40 ml of acetonitrile was refluxed overnight. The reaction mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. Chromatography on Si-NH2 (Isolute) using ethyl acetate as an eluent gave the title compound as a yellowish solid.MS ISP (m/e): 250.1 (51) [(M+H)+]1H NMR (CDCl3, 300 MHz): delta (ppm) = 8.00-7.85 (m, 3H), 7.45 (d, 1 H), 7.26 (d, IH), 4.70 (s, 2H), 4.01 (s, 3H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;	Example A37 a) Preparation of intermediate 98 A mixture of l-fluoro-2-methoxy-4-nitrobenzene (2.45 g, 14.3 mmol), 4- hydroxymethyl- IH- imidazole (1.54 g, 15.7 mmol) and K2CO3 (3.95 g, 28.6 mmol) in DMF (20 ml) was stirred at 100 0C for 16 h. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and water. Undissolved material was collected by filtration and dissolved in a mixture of TEtaF and CEta3CN. The combined organic layers were dried (MgSO4), filtered and the solvent was evaporated. The residue was triturated in DIPE/2-propanol, filtered off and dried. Yield: 1.2 g of intermediate 98 which was used as such in the next reaction step.

References: [1]Patent: WO2010/40661,2010,A1 .Location in patent: Page/Page column 30.
[2]Patent: WO2010/94647,2010,A1 .Location in patent: Page/Page column 95.

9
[ 179236-79-4 ]
[ 454-16-0 ]
[ 1221420-76-3 ]

Yield	Reaction Conditions	Operation in experiment
51.3%	In dichloromethane; at 110℃;Irradiation;	Example 65 A. Ethyl 3-(2-methoxy-4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6- carboxylate [00259] l-Fluoro-2-methoxy-4-nitrobenzene (258 mg, 1.5 mmol) and ethyl 3- azabicyclo[3.1.0]hexane-6-carboxylate (232 mg, 1.5 mmol) were placed in a microwave vial using minimal amount of DCM and heated to 110 0C, allowing the DCM to evaporate off. The mixture was allowed to stir at this temperature O.N. Flash chromatography (12O g, 0percent to 100percent EtOAc-Etaexanes) yielded Example 65 A (235 mg, 0.767 mmol, 51.3 percent yield) as a yellow oil which solidified on standing. LC- MS, [M+Eta]+ = 307.1.

References: [1]Patent: WO2010/42682,2010,A1 .Location in patent: Page/Page column 122.

10
[ 822-36-6 ]
[ 454-16-0 ]
[ 958245-17-5 ]
[ 1255701-91-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃;	A mixture of 4-methyl imidazole (500 mg, 6 mmol), 2-fluoro-5-nitro anisole (1.02 g, 5.9 mmol) and potassium carbonate (1.68 g, 12 mmol) in DMF (15 mL) was heated overnight at 850C in a sealed tube. The reaction mixture was cooled, transferred into a round bottom flask using ethyl acetate and concentrated under high vacuum to 5 mL volume. The residue was suspended in water and extracted with dichloromethane (3 x 25 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give an orange solid. The solid was dissolved in dichloromethane (10 mL) and diluted with hexane until the solution became slightly turbid. The turbid solution was left at room temperature. The separated orange solid was filtered, washed with hexane to give l-(2-methoxy-4-nitro-phenyl)-4-methyl-lH-imidazole and l-(2-methoxy-4-nitro- phenyl)-5 -methyl- lH-imidazole (577 mg, 43 percent).1H NMR (400 MHz, methanol- d4) delta ppm 2.25 (s, 3 H) 4.02 (s, 3 H) 7.21 (s, 1 H) 7.62 (d, 1 H) 7.92 - 8.02 (m, 2 H) 8.04 (s, 1 H)

References: [1]Patent: WO2010/53438,2010,A1 .Location in patent: Page/Page column 63.

11
[ 454-16-0 ]
[ 33631-05-9 ]
[ 1229607-64-0 ]

Yield	Reaction Conditions	Operation in experiment
50%		To a suspension of 2-aminopyridin-4-ol (0.251 g, 2.28 mmol) in MeCN (4.0 ml.) at RT was added DB U (423 mul , 2.80 mmol) and after 30 min a solution of 1-fluoro-2-methoxy-4- nitrobenzene (300 mg, 1.75 mmol) in DMF (2.0 ml.) was added dropwise. The reaction mixture was maintained at RT for 1 hr and was then heated to 800C for 16 hr. After cooling to RT water (2.0 ml.) was added and the mixture was evaporated in vacuo. The residue was partitioned between DCM (30 ml.) and brine (20 ml.) and the organic layer was separated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 20-100percent, gradient elution) to afford 4-(2- methoxy-4-nitrophenoxy)pyridin-2-amine as a bright yellow solid (234 mg, 50percent); R' 1.25 min (Method 2); m/z 262 (M+H)+ (ES+).

References: [1]Patent: WO2010/67130,2010,A1 .Location in patent: Page/Page column 60.

12
[ 13466-43-8 ]
[ 454-16-0 ]
[ 1093183-39-1 ]

Yield	Reaction Conditions	Operation in experiment
72%		Example 19A3-Bromo-1-(2-methoxy-4-nitrophenyl)pyridin-2(1H)-one 70 g (403 mmol) of 3-bromopyridin-2(1H)-one are dissolved in 1 l of anhydrous dimethyl sulphoxide, and 54 g (484 mmol) of potassium tert-butoxide are added at room temperature. The suspension is stirred at this temperature for 1 h. 69 g (403 mmol) of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> are added, and the reaction solution is heated at 80° C. for 20 h. Carefully, the mixture is diluted with 5 l of water. The precipitated solid is filtered off, washed with water and dried under reduced pressure. This gives 103 g (72percent of theory) of the desired product.1H-NMR (400 MHz, DMSO-d6, delta/ppm): delta=8.05 (dd, 1H), 8.1 (d, 1H), 7.95 (dd, 1H), 7.7 (d, 1H), 7.6 (dd, 1H), 6.3 (t, 1H), 3.9 (s, 3H).MS (ESIpos): m/z=342 (M+NH4)+
	With potassium tert-butylate; In water; dimethyl sulfoxide;	Example 28A 3-Bromo-1-(2-methoxy-4-nitrophenyl)pyridin-2(1H)-one 70 g (403 mmol) of 3-bromopyridin-2(1H)-one are dissolved in 1 l of anhydrous dimethyl sulphoxide, and 54 g (484 mmol) of potassium tert-butoxide are added at room temperature. The suspension is stirred at this temperature for 1 h. 69 g (403 mmol) of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> are added, and the reaction solution is heated at 80° C. for 20 h. Carefully, the mixture is diluted with 5 l of water. The precipitated solid is filtered off, washed with water and dried under reduced pressure. This gives 103 g (72percent of theory) of the desired product. 1H-NMR (400 MHz, DMSO-d6, delta/ppm): delta=8.05 (dd, 1H), 8.1 (d, 1H), 7.95 (dd, 1H), 7.7 (d, 1H), 7.6 (dd, 1H), 6.3 (t, 1H), 3.9 (s, 3H). MS (ESIpos): m/z=342 (M-FNH4)+
38.7 g	With potassium phosphate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 6h;	Example 5 Preparation of 3-bromo-1-(2-methoxy-4-nitrophenyl)pyridin-2(1H)-one 36.2 g of 3-bromopyridone (87percent purity, 0.18 mol) and 29.4 g of <strong>[454-16-0]<strong>[454-16-0]4-fluoro-3-methoxynitrobenze</strong>ne</strong> (0.17 mol) were introduced as initial charge in 180 ml of N-methylpyrrolidone; 46.1 g of anhydrous potassium phosphate (0.22 mol) were added and the reaction mixture was carried out at 120° C. for 6 h. After cooling to 90° C., water was added and the mixture was cooled to room temperature. The precipitate was filtered off, washed with water and stirred with a methanol/water mixture (1:1). The solid was filtered off, washed and dried in the air. This gave 38.7 g (66percent) of the desired target compound.[0098] HPLC (method 3): Rt=3.50 min. [0099] LC-MS (method 4): Rt=0.84 min. [0100] 1H NMR (400 MHz, DMSO-d6): delta [ppm]=3.91 (s, 3H), 6.30 (t, 1H), 7.64 (dd, 1H), 7.70 (d, 1H), 7.96 (dd, 1H), 8.00 (m, 1H), 8.04 (dd, 1H). [0101] MS (ES+): [M+H]+ 327 or 325.

References: [1]Patent: US2010/184740,2010,A1 .Location in patent: Page/Page column 28.
[2]Patent: US2010/261759,2010,A1 .
[3]Patent: US2013/116443,2013,A1 .Location in patent: Paragraph 0096; 0097; 0098; 0099; 0100; 0101.

13
[ 288-88-0 ]
[ 454-16-0 ]
[ 267648-19-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In dimethyl sulfoxide; at 75℃; for 2h;Sealed tube; Inert atmosphere;	To a 100 mL dried sealed tube were added <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (0.6 g, 3.5 mmol), 1,2,4-triazole (0.36 g, 5.2 mmol) and potassium carbonate (0.9 g, 6.5 mmol), then DMSO (10 mL) was added. The sealed tube was sealed with teflon nut under nitrogen protection, then the mixture was heated to 75 °C and stirred for 2 h. The mixture was cooled to rt and to the residue was added water (60 mL). The mixture was stirred for 10 min and filtered. The filter cake was dried to give a light yellow solid (0.7 g, 90percent). MS(ESI, pos.ion) m/z: 221.1 (M+1);
	With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 1h;	A mixture of l-fluoro-2-methoxy-4-nitrobenzene (7 g, 40 mmol), IH-I, 2,4-triazole (4.28 g, 60 mmol), K2CO3 (8.3 Ig, 60 mmol) and DMF (50 ml) was stirred for 1 h at 75 0C. The solvent was evaporated and the residue was taken up in EtOAcZH2O. The aq. layer was extracted 3 times with EtOAc. The combined organic layers were dried (MgSO4), filtered and the solvent was evaporated in vacuo. Yield: 4.4 g of intermediate 13. The crude product was used as such in the next reaction step

References: [1]Patent: EP3342765,2018,A1 .Location in patent: Paragraph 0363.
[2]Patent: WO2010/70008,2010,A1 .Location in patent: Page/Page column 48.

14
[ 454-16-0 ]
[ 7170-01-6 ]
[ 1185019-82-2 ]
[ 1232038-78-6 ]

Yield	Reaction Conditions	Operation in experiment
49%; 13%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h;	A mixture of l-fluoro-2-methoxy-4-nitrobenzene (821.414 mg, 4.8 mmol), 5-methyl- lH-l,2,4-triazole (800 mg, 9.63 mmol), K2CO3 (4.8 mmol) and DMSO (8 ml) was stirred at 120 0C for 1 h. After cooling to r.t., the r.m. was poured into ice H2O. The solid was filtered off, washed with H2O and dried in vacuo at 50 0C. Yield: 0.554 g of intermediate 9 (49 percent). The aq. layer was sat. with NaCl, extracted with DCM and the organic layer was dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography over silicagel (eluent: DCM). The desired fraction was collected and the solvent was evaporated in vacuo. Yield: 0.147 g of intermediate 10 (13 percent).
49%; 13%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h;	a) Preparation of intermediate 3 and intermediate 4 (regioisomers) A mixture of l-fluoro-2-methoxy-4-nitrobenzene (821 mg, 4.8 mmol), 5 -methyl- IH- 1,2,4-triazole (800 mg, 9.63 mmol), K2CO3 (4.8 mmol) and DMSO (8 ml) was stirred at 120 0C for 1 h. After cooling, the r.m. was poured into ice water. The solid was filtered off, washed with water and dried in vacuo at 50 0C. Yield: 0.554 g of intermediate 3 (49 percent). The aq. layer was saturated with NaCl, extracted with DCM and the organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fraction was collected and the solvent was evaporated. Yield: 0.147 g of intermediate 4 (13 percent).
49%; 13%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h;	Example A2 a) Preparation of intermediate 3 and intermediate 4A mixture of l-fluoro-2-methoxy-4-nitrobenzene (821 mg, 4.8 mmol), 5-methyl-lH- 1,2,4-triazole (800 mg, 9.63 mmol), K2CO3 (4.8 mmol) and DMSO (8 ml) was stirred at 120 0C for 1 h. After cooling, the r.m. was poured into ice water. The solid was filtered off, washed with H2O and dried (in vacuo; 50 0C). Yield: 0.554 g of intermediate 3 (49 percent). The aq. layer was sat. with NaCl, extracted with DCM and the organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fraction was collected and the solvent was evaporated. Yield: 0.147 g of intermediate 4 (13 percent).

49%; 13%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h;	A mixture of l-fluoro-2-methoxy-4-nitrobenzene (821 mg, 4.80 mmol), 5-methyl-lH- 1,2,4-triazole (800 mg, 9.63 mmol), K2C03 (4.80 mmol) and DMSO (8 ml) was stirred at 120 °C for 1 h. After cooling, the r.m. was poured into ice water. The solid was filtered off, washed with water and dried in vacuo at 50 °C. Yield: 0.55 g ofintermediate 37 (49 percent). The aq. layer was saturated with NaCl, extracted with DCM and the organic layer was dried (MgSC^), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fraction was collected and the solvent was evaporated. Yield: 0.15 g ofintermediate 38 (13 percent).
49%; 13%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h;	A mixture of l-fluoro-2-methoxy-4-nitrobenzene (821 mg, 4.80 mmol), 5-methyl-lH-1,2,4-triazole (800 mg, 9.63 mmol), K2C03 (4.80 mmol) and DMSO (8 ml) was stirred at 120 °C for 1 h. After cooling, the r.m. was poured into ice water. The solid was filtered off, washed with water and dried in vacuo at 50 °C. Yield: 0.55 g ofintermediate 37 (49 percent). The aq. layer was saturated with NaCl, extracted with DCM and the organic layer was dried (MgS04), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fraction was collected and the solvent was evaporated. Yield: 0.15 g of intermediate 38 (13 percent).
49%; 13%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h;	A mixture of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (821 mg, 4.80 mmol), 5-methyl-1H-1,2,4-triazole (800 mg, 9.63 mmol), K2CO3 (4.80 mmol) and DMSO (8 ml) was stirred at 120° C. for 1 h. After cooling, the r.m. was poured into ice water. The solid was filtered off, washed with water and dried in vacuo at 50° C. Yield: 0.55 g of intermediate 37 (49percent). The aq. layer was saturated with NaCl, extracted with DCM and the organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fraction was collected and the solvent was evaporated. Yield: 0.15 g of intermediate 38 (13percent).

References: [1]Patent: WO2010/70008,2010,A1 .Location in patent: Page/Page column 48.
[2]Patent: WO2010/94647,2010,A1 .Location in patent: Page/Page column 62.
[3]Patent: WO2010/145883,2010,A1 .Location in patent: Page/Page column 46.
[4]Patent: WO2011/86098,2011,A1 .Location in patent: Page/Page column 71.
[5]Patent: WO2011/86099,2011,A1 .Location in patent: Page/Page column 60.
[6]Patent: US2012/295891,2012,A1 .Location in patent: Page/Page column 28.

15
[ 108-43-0 ]
[ 454-16-0 ]
[ 1253962-06-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 95℃; for 48h;	Example 6: 1 -(3 -chlorophenoxy)-2-methoxy-4-nitrobenzeneIn a 25OmL round-bottom flask was added 3-chlorophenol (4.13g, 32.1mmol), 1- fluoro-2-methoxy-4-nitrobenzene (5.00g, 29.2mmol), potassium carbonate (6.06g, 43.8mmol) and acetonitrile (25mL). The reaction was heated to 950C for 48 hours. The reaction was cooled to room temperature and was purified by column chromatography on silica gel (hexane/ethyl acetate = 3:1). The reaction was poured into sodium hydroxide (2mol) and extracted with ethyl acetate. The ethyl acetate layers were washed with sodium hydroxide (2mol), water and brine. The combined organic layers were dried over sodium sulfate, filtered and solvent removed. A small amount of methanol added and oil was triturated to obtain the title compound (7.5g) having the following physical data. 1H NMR (400 MHz, CDCl3) delta 7.84 (dt, J = 8.7, 2.6, 2H), 7.28 (t, J = 8.1, IH), 7.13 (ddd, J = 8.0, 1.9, 0.9, IH), 6.99 (t, J = 2.2, IH), 6.96 (s, IH), 6.91 - 6.86 (m, IH), 3.94 (d, J = 3.8, 3H).

References: [1]Patent: WO2010/126960,2010,A1 .Location in patent: Page/Page column 58-59.

16
[ 7170-01-6 ]
[ 454-16-0 ]
[ 1185019-82-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃;	Example 41 b. l-(2-methoxy-4-nitrophenyl)-3-methyl-lH-l,2,4-triazoleA mixture of 3-methyl-lH-[l,2,4]triazole (2.4 g, 29.21 mmol), l-fluoro-2-methoxy-4- nitrobenzene (5.0 g, 29.21 mmol) and potassium carbonate (8.06 g, 58.42 mmol) in DMF (50 mL) was heated overnight at 85°C in a pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in water and the mixture extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in dichloromethane (50 mL) and hexane was added in small portions until the solution become slightly turbid. The turbid solution was left at room temperature. The precipitation was collected by filtration, washed with hexane to give 2.5 g of title compound (37 percent Yield).1U NMR (400 MHz, CHLOROFORM-J) delta ppm 2.51 (s, 3 H) 4.10 (s, 3 H) 7.90 - 8.06 (m, 2 H) 8.10 (d, I H) 8.87 (s, I H)
35%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 85℃; for 16h;Sealed tube; Inert atmosphere;	To a stirred solution of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (2.5 g, 14.60 mmol) in DMF (25 mL) under an argon atmosphere were added potassium carbonate (4 g, 29.20 mmol) and 3-methyl-1H-1, 2, 4-triazole (1.2 g, 14.60 mmol) at room temperature. The reaction mixture was stirred at 85 oC for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 15-25percent EtOAc:hexane to afford <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (1.2 g, 35percent) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): delta 8.87 (s, 1H), 8.10 (d, 1H), 8.00-7.97 (m, 2H), 4.10 (s, 3H), 2.50 (s, 3H); LCMS: 234.9 (M+1); (column; Ascentis Express C-18 (50 × 3.0 mm, 2.7 mum); RT 2.02 min. 0.025percent Aq TFA+5percent ACN: ACN+5percent 0.025percent Aq TFA; 1.2 mL/min); TLC: 30percent EtOAc:hexane (Rf: 0.2).
35%	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 16h;Inert atmosphere; Sealed tube;	Synthesis of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (1023) To a stirred solution of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (2.5 g, 14.60 mmol) in DMF (25 mL) under an argon atmosphere were added potassium carbonate (4 g, 29.20 mmol) and 3-methyl-1H-1,2,4-triazole (1.2 g, 14.60 mmol) at room temperature. The reaction mixture was stirred at 85° C. for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 15-25percent EtOAc:hexane to afford <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (1.2 g, 35percent) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): delta 8.87 (s, 1H), 8.10 (d, 1H), 8.00-7.97 (m, 2H), 4.10 (s, 3H), 2.50 (s, 3H); LCMS: 234.9 (M+1); (column; Ascentis Express C-18 (50×3.0 mm, 2.7 mum); RT 2.02 min. 0.025percent Aq TFA+5percent ACN: ACN+5percent 0.025percent Aq TFA; 1.2 mL/min); TLC: 30percent EtOAc:hexane (Rf: 0.2).

References: [1]Patent: WO2010/132015,2010,A1 .Location in patent: Page/Page column 120.
[2]Patent: WO2015/109109,2015,A1 .Location in patent: Paragraph 0740.
[3]Patent: US2017/44182,2017,A1 .Location in patent: Paragraph 1023.

17
[ 454-16-0 ]
[ 22510-08-3 ]

Yield	Reaction Conditions	Operation in experiment
30%		116 ml (116 mmol) of boron tribromide (1 molar solution in dichloromethane) are added dropwise at -10° C. over a period of 1 h to a solution of 5.00 g (29.2 mmol) of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> at such a rate that the temperature does not exceed -5° C. The solution is left at 0° C. for 5 h, then added slowly to 600 ml of ice-water and diluted with 100 ml of ethyl acetate. After phase separation, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (10:1 cyclohexane/ethyl acetate). This affords 1.45 g (30percent of theory) of the desired compound. 1H NMR (400 MHz, DMSO-d6, delta/ppm): 10.99 (s, 1H), 7.78 (dd, 1H), 7.73 (ddd, 1H), 7.44 (dd, 1H). HPLC (Method 1): Rt=3.60 min. MS (DCI, m/z): 174 (M+NH4)+.

References: [1]Patent: US2010/298293,2010,A1 .Location in patent: Page/Page column 39.

18
[ 454-16-0 ]
[ 10166-54-8 ]
[ 1093656-11-1 ]

Yield	Reaction Conditions	Operation in experiment
43%		450 mg (3.94 mmol) of 1-methyltetrahydropyrimidin-2(1H)-one in 15 ml of DMF are admixed at 0° C. with 663 mg (5.91 mmol) of potassium tert-butoxide, and the mixture is stirred at room temperature for 30 min. 742 mg (4.33 mmol) of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> are added and the mixture is stirred at RT. After 2 h, the mixture is admixed with 150 ml of water and 8 ml of saturated aqueous sodium chloride solution, and extracted three times with 30 ml each time of ethyl acetate. The combined organic phases are washed with 30 ml of water and then dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (1:5-->1:10 cyclohexane/ethyl acetate). This affords 457 mg (43percent of theory) of the desired compound. 1H NMR (400 MHz, DMSO-d6, delta/ppm): 7.85 (m, 2H), 7.44-7.39 (m, 1H), 3.90 (s, 3H), 3.48 (t, 2H), 3.38-3.31 (m, 2H), 2.84 (s, 3H), 2.05-1.93 (m, 2H). HPLC (Method 1): Rt=3.57 min. MS (DCI, m/z): 266 (M+H)+.

References: [1]Patent: US2010/298293,2010,A1 .Location in patent: Page/Page column 32.

19
[ 454-16-0 ]
3-propyl-pyridin-2(1H)-one [ No CAS ]
[ 1093656-01-9 ]

Yield	Reaction Conditions	Operation in experiment
15%		500 mg (3.65 mmol) of the product from example 51A are dissolved in 7.3 ml of DMF and cooled to 0° C. To this are added 613 mg (5.47 mmol) of potassium tert-butoxide, and the mixture is left to stir at RT for 30 min. Then 624 mg (3.65 mmol) of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> are added. The mixture is stirred at RT for 6 h, water is added and the mixture is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. Purification is effected by preparative HPLC. The resulting product fraction is purified further by chromatography on silica gel (eluent: dichloromethane, then 10:1 dichloromethane/methanol). This affords 158 mg (15percent of theory) of the desired compound as a solid. 1H NMR (400 MHz, DMSO-d6, delta/ppm): 7.97 (d, 1H), 7.93 (dd, 1H), 7.61 (d, 1H), 7.40-7.33 (m, 2H), 6.26 (t, 1H), 3.89 (s, 3H), 2.43-2.36 (m, 2H), 1.60-1.48 (m, 2H), 0.91 (t, 3H). HPLC (Method 5): Rt=2.19 min. MS (ESIpos, m/z): 289 (M+H)+.

References: [1]Patent: US2010/298293,2010,A1 .Location in patent: Page/Page column 30.

20
[ 454-16-0 ]
[ 870838-56-5 ]

References: [1]Patent: WO2011/6903,2011,A1 .
[2]Patent: WO2011/86098,2011,A1 .
[3]Patent: WO2011/86099,2011,A1 .
[4]Patent: US2012/295891,2012,A1 .

21
[ 454-16-0 ]
[ 958245-18-6 ]

References: [1]Patent: WO2011/6903,2011,A1 .
[2]Patent: WO2011/86098,2011,A1 .
[3]Patent: WO2011/86099,2011,A1 .
[4]Patent: US2012/295891,2012,A1 .
[5]Patent: WO2009/108766,2009,A1 .

22
[ 454-16-0 ]
[ 1262193-88-3 ]

References: [1]Patent: WO2011/6903,2011,A1 .

23
[ 454-16-0 ]
[ 1263868-21-8 ]

References: [1]Patent: WO2011/14535,2011,A1 .

24
[ 454-16-0 ]
[ 57090-88-7 ]
[ 1263868-22-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	To a solution of lH-Imidazole-4-carbonitrile (300 mg, 3.22 mmol) and 4-Fluoro- 3-methoxynitrobenzene (552 mg, 3.22 mmol) in DMF (Volume: 6446 mul) was added K2CO3 (891 mg, 6.45 mmol). The resulting mixture was brought to 120 0C and stirred overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 x 10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to give 1- (2-methoxy-4-nitrophenyl)-lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> (698 mg, 2.86 mmol, 89 percent yield). LC-MS (M+H)+ = 245.0. IH NMR (500 MHz, MeOD) delta ppm 8.30 - 8.34 (1 H), 8.19 - 8.23 (1 H), 8.09 - 8.12 (1 H), 8.00 - 8.05 (1 H), 7.71 - 7.79 (1 H), 4.02 - 4.10 (3 H).

References: [1]Patent: WO2011/14535,2011,A1 .Location in patent: Page/Page column 38-39.

25
[ 454-16-0 ]
[ 937026-26-1 ]

References: [1]Patent: WO2011/86098,2011,A1 .
[2]Patent: WO2011/86099,2011,A1 .
[3]Patent: US2012/295891,2012,A1 .

26
[ 454-16-0 ]
[ 1185019-85-5 ]

References: [1]Patent: WO2011/86098,2011,A1 .
[2]Patent: WO2011/86099,2011,A1 .
[3]Patent: US2012/295891,2012,A1 .
[4]Patent: WO2015/109109,2015,A1 .
[5]Patent: US2017/44182,2017,A1 .
[6]Patent: WO2010/132015,2010,A1 .

27
[ 454-16-0 ]
[ 1314786-46-3 ]