[ CAS No. 103204-69-9 ] {[proInfo.proName]}

Name: 103204-69-9|4-Acetamido-2-methylbenzoic acid|95%
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Quality Control of [ 103204-69-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 103204-69-9 ]

CAS No. :	103204-69-9	MDL No. :	MFCD02258874
Formula :	C₁₀H₁₁NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AQPDTYYKDYMCTH-UHFFFAOYSA-N
M.W :	193.20	Pubchem ID :	2735224
Synonyms :

Calculated chemistry of [ 103204-69-9 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	52.68
TPSA :	66.4 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.28
Log Po/w (XLOGP3) :	1.0
Log Po/w (WLOGP) :	1.46
Log Po/w (MLOGP) :	1.41
Log Po/w (SILICOS-IT) :	1.28
Consensus Log Po/w :	1.28

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.85

Water Solubility

Log S (ESOL) :	-1.79
Solubility :	3.16 mg/ml ; 0.0163 mol/l
Class :	Very soluble
Log S (Ali) :	-1.98
Solubility :	2.01 mg/ml ; 0.0104 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.55
Solubility :	0.546 mg/ml ; 0.00282 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.25

Safety of [ 103204-69-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313	UN#:	N/A
Hazard Statements:	H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 103204-69-9 ]

* 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 [ 103204-69-9 ]
Downstream synthetic route of [ 103204-69-9 ]

[ 103204-69-9 ] Synthesis Path-Upstream 1~3

1
[ 67-56-1 ]
[ 103204-69-9 ]
[ 6933-47-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: for 3 h; Reflux Stage #2: With sodium hydroxide In waterCooling with ice	4-Acetamido-2-methylbenzoic acid (46 g, 238 mmol) is initially charged in methanol (460 ml), and concentrated sulphuric acid (63 g, 643 mmol) is added. The reaction mixture is heated under reflux for 3 h, cooled, carefully added to ice-water and made alkaline using 5N aqueous sodium hydroxide solution. Extraction with ethyl acetate, drying of the organic phase over sodium sulphate and removal of the solvent under reduced pressure gives ethyl 4-amino-2-methylbenzoate (38.3 g, 232 mmol, 94percent) which is used without further purification for the next step.

Reference： [1] Patent: WO2006/89909, 2006, A1, . Location in patent: Page/Page column 99
[2] Patent: US2011/190365, 2011, A1, . Location in patent: Page/Page column 28
[3] Patent: WO2005/111014, 2005, A1, . Location in patent: Page/Page column 156-157
[4] Patent: WO2011/92140, 2011, A1, . Location in patent: Page/Page column 76
[5] Patent: US2012/28938, 2012, A1, . Location in patent: Page/Page column 44

2
[ 7647-01-0 ]
[ 103204-69-9 ]
[ 2486-75-1 ]

Reference： [1] Archiv der Pharmazie (Weinheim, Germany), 1926, vol. 264, p. 447
[2] Chem. Zentralbl., 1912, vol. 83, # I, p. 136

3
[ 67-56-1 ]
[ 103204-69-9 ]
[ 1149388-04-4 ]
[ 1260848-51-8 ]

Reference： [1] Patent: WO2015/121210, 2015, A1, . Location in patent: Page/Page column 90-91
[2] Patent: WO2017/9325, 2017, A1, . Location in patent: Page/Page column 57-58

[ 103204-69-9 ] Synthesis Path-Downstream 1~54

1
[ 201810-74-4 ]
[ 103204-69-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide

Reference： [1]Kunckell [Chemisches Zentralblatt, 1912, vol. 83, # I, p. 136]

2
[ 2486-75-1 ]
[ 108-24-7 ]
[ 103204-69-9 ]

Reference： [1]Bulletin de la Societe Scientifique de Bretagne,1956,vol. 31,p. Sonderheft S.9,41

3
[ 2198-54-1 ]
[ 103204-69-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium permanganate

Reference： [1]BOYLAND; SIMS [Biochemical Journal, 1959, vol. 73, p. 377 - 380]

4
[ 7647-01-0 ]
[ 103204-69-9 ]
[ 2486-75-1 ]

Reference： [1]Archiv der Pharmazie,1926,vol. 264,p. 447

5
[ 201810-74-4 ]
[ 7722-84-1 ]
[ 103204-69-9 ]

Reference： [1]Richter [Archiv der Pharmazie, 1926, vol. 264, p. 447] Kunckell [Chemisches Zentralblatt, 1912, vol. 83, # I, p. 136]

6
[ 103204-69-9 ]
[ 117523-91-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-acetylamino-2-methylbenzoic acid With borane-THF In tetrahydrofuran at 20℃; Stage #2: With water In tetrahydrofuran	77 Description 77; λ/-[4-(Hydroxymethyl)-3-methylphenyl]acetamide (D77); 4-(Acetylamino)-2-methylbenzoic acid (2 g, 10.4 mmol) was suspended in THF (50 mL) and borane-THF complex (1 M in THF, 26 ml_, 26 mmol) added drop-wise over -15 minutes. The reaction mixture was stirred under argon at room temperature overnight then quenched with water (52 mL) and extracted with ethyl acetate (x3). The combined organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-100% ethyl acetate/petroleum ether yielded the title compound as a cream solid (0.379 g). δH (MeOD, 400MHz) 7.36 (2H, m), 7.25 (1 H1 d), 4.57 (2H, s), 2.31 (3H, s), 2.10 (3H, s). MS (ES): MH+ 180.2.
	With borane-THF In tetrahydrofuran	e N-[4-(Hydroxymethyl)-3-methylphenyl]acetamide (D4)4-(Acetylamino)-2-methylbenzoic acid (2 g, 10.4 mmol) was suspended in THF (50 ml.) and borane-THF complex (1 M in THF, 26 ml_, 26 mmol) added drop-wise over 15 minutes. The reaction mixture was stirred under argon overnight. The reaction mixture was quenched with water (51 ml.) and extracted with EtOAc (x3). The combined organics were dried and concentrated. The crude product was purified by chromatography. Elution with 0-100% EtO Ac/petroleum ether yielded the title compound as a cream solid (0.379 g). δH (MeOD, 400MHz) 7.36 (2H, d), 7.25 (1 H, d), 4.57 (2H, s), 2.31 (3H, s), 2.10 (3H, s). MS (ES+): MH+ 180.2.
	Stage #1: 4-acetylamino-2-methylbenzoic acid With borane-THF In tetrahydrofuran at 20℃; for 0.25h; Stage #2: With water In tetrahydrofuran	51 λ/-[4-(Hydroxymethyl)-3-methylphenyl]acetamide (D51 )4-(Acetylamino)-2-methylbenzoic acid (2 g, 10.4 mmol) was suspended in THF (50 ml) and borane-THF complex (1 M in THF, 26 ml, 26 mmol) added drop-wise over 15 minutes. The reaction mixture was stirred under argon at room temperature overnight then quenched with water (52 ml) and extracted with EtOAc (x3). The combined organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-100% EtOAc/petroleum ether yielded the title compound as a cream solid (0.379 g). δH (CD3OD, 400MHz) 7.36(2H, d), 7.25 (1 H, d), 4.57 (2H, s), 2.31 (3H, s), 2.10 (3H, s). MH+ 180.2.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/729, 2008, A1 Location in patent: Page/Page column 78
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/68552, 2009, A1 Location in patent: Page/Page column 25
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/144400, 2007, A1 Location in patent: Page/Page column 47

7
[ 537-92-8 ]
[ 103204-69-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aluminium chloride; carbon disulfide 2: hydrogen peroxide; alkali

Reference： [1]Kunckell [Chemisches Zentralblatt, 1912, vol. 83, # I, p. 136]

8
[ 110-91-8 ]
[ 103204-69-9 ]
[ 869859-94-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In tetrahydrofuran at 20℃; for 2h;

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2005/111014, 2005, A1 Location in patent: Page/Page column 154-155

9
[ 103204-69-9 ]
C₁₀H₁₀ClNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 50℃; for 4.5h;

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2005/111014, 2005, A1 Location in patent: Page/Page column 133

10
[ 67-56-1 ]
[ 103204-69-9 ]
[ 6933-47-7 ]

Yield	Reaction Conditions	Operation in experiment
94%		4-Acetamido-2-methylbenzoic acid (46 g, 238 mmol) is initially charged in methanol (460 ml), and concentrated sulphuric acid (63 g, 643 mmol) is added. The reaction mixture is heated under reflux for 3 h, cooled, carefully added to ice-water and made alkaline using 5N aqueous sodium hydroxide solution. Extraction with ethyl acetate, drying of the organic phase over sodium sulphate and removal of the solvent under reduced pressure gives ethyl 4-amino-2-methylbenzoate (38.3 g, 232 mmol, 94%) which is used without further purification for the next step.
		Intermediate 7.5.1 4-Amino-2-methyl-benzoic acidTo a stirred solution of 4-acetylamino-2-methyl-benzoic acid (25.5 g) in methanol (250 ml) was added cone. H2S04 (19 ml) dropwise and the reaction heated to reflux. After 2.5 h, the reaction was cooled to rt. NaHC03 (aq) was added until alkaline and the obtained mixture was extracted with EtOAc. The organic extracts were washed with NaOH(aq) (2 M) 3 times, then dried and concentrated affording 17.6 g of the title compound.ESI mass spectrum: [M+H]+ = 166
		Synthesis Example 7.5Intermediate 7.5.14-Amino-2-methyl-benzoic acidTo a stirred solution of 4-acetylamino-2-methyl-benzoic acid (25.5 g) in methanol (250 ml) was added conc. H2SO4 (19 ml) dropwise and the reaction heated to reflux. After 2.5 h, the reaction was cooled to rt. NaHCO3 (aq) was added until alkaline and the obtained mixture was extracted with EtOAc. The organic extracts were washed with NaOH(aq) (2 M) 3 times, then dried and concentrated affording 17.6 g of the title compound.ESI mass spectrum: [M+H]+=166

Reference： [1]Patent: WO2006/89909,2006,A1 .Location in patent: Page/Page column 99
[2]Patent: US2011/190365,2011,A1 .Location in patent: Page/Page column 28
[3]Patent: WO2005/111014,2005,A1 .Location in patent: Page/Page column 156-157
[4]Patent: WO2011/92140,2011,A1 .Location in patent: Page/Page column 76
[5]Patent: US2012/28938,2012,A1 .Location in patent: Page/Page column 44

11
[ 103204-69-9 ]
[ 1149388-03-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; nitric acid at 0℃; for 1h;	22.1 Step 1 : 4-(Acetylamino)-2-methylbenzoic acid (3.93 g, 20.3 mmol) was taken up in concentrated sulfuric acid (20 mL) and warmed to solubilize. The solution was then cooled with an ice bath. Fuming nitric acid (0.86 mL) in sulfuric acid (2.0 mL) was added dropwise and the resultant solution was stirred one hour. The solution was then diluted with water and a yellow solid was collected by filtration and discarded. Upon standing, an orange solid formed in the filtrate, which was collected by filtration to give (0.61 g) of 4-amino-2-methyl-3-nitrobenzoic acid. The aqueous filtrate was then extracted (3 x 100 mL of 10% methanol in ethyl acetate), and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to yield additional 4-amino-2-methyl-3-nitrobenzoic acid (0.90 g). 1H NMR (400 MHz, d6-DMSO): 7.75 (d, IH), 6.75 (d, IH), 2.41 (s, 3H). MS (EI) for C8H8N2O4: 195 (MH+).
	With sulfuric acid; nitric acid at 0 - 20℃;	[0166]Intermediate 9Methyl 3-amino-4 - [(cyclopropylmethyl) amino] -2-methylbenzoate In addition 1.0g of 4-acetamido-2-methyl-benzoic acid (5.2mmol) in concentrated sulfuric acid of 5ml, it was dropped in the continued 0 a mixture of concentrated sulfuric acid of concentrated nitric acid and 0.50ml of 0.22ml. The reaction mixture was allowed to warm to room temperature and placed overnight at room temperature. Then, the mixture was added to ice water, it was taken out by filtration resulting precipitate. It was thus obtained as a crude product 4-amino-2-methyl-3-nitrobenzoic acid 1.47 g.
	With sulfuric acid; nitric acid at 20℃; Cooling with ice;	9.A Step A: 4-Amino-2-methyl-3-nitrobenzoic acid (Compound 9.1) At room temperature, add 4-acetylamino-2-methylbenzoic acid (2.5g, 13.0mmol)Slowly dissolve in 18 mL of concentrated sulfuric acid, drop the mixture of concentrated nitric acid (0.55 mL) and concentrated sulfuric acid (1.3 mL) into the reaction solution under ice bath, and continue to stir at room temperature overnight.LCMS monitors that the raw material has reacted. Add water (40mL) to the reaction solution,A yellow solid precipitated out, filtered and dried to obtain the crude product 9.1(1.12 g, yield: 44.8%, yellow solid).

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2009/55077, 2009, A1 Location in patent: Page/Page column 389-390
[2]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - JP2016/501241, 2016, A Location in patent: Paragraph 0166
[3]Current Patent Assignee: WEIQING BIOTECHNOLOGY SHANGHAI - CN111606928, 2020, A Location in patent: Paragraph 0248-0254

12
[ 103204-69-9 ]
[ 1208351-36-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sulfuric acid / 3 h / Reflux 1.2: Cooling with ice 2.1: hydrogenchloride; sodium nitrite / water / 1 h / 0 °C 2.2: 2 h / 0 - 20 °C 2.3: pH 8 - 9 / Cooling with ice

Reference： [1]Current Patent Assignee: BAYER AG - US2011/190365, 2011, A1

13
[ 103204-69-9 ]
[ 1208348-80-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sulfuric acid / 3 h / Reflux 1.2: Cooling with ice 2.1: hydrogenchloride; sodium nitrite / water / 1 h / 0 °C 2.2: 2 h / 0 - 20 °C 2.3: pH 8 - 9 / Cooling with ice 3.1: triethylamine / ethanol / 80 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2011/190365, 2011, A1

14
[ 103204-69-9 ]
[ 1208348-79-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sulfuric acid / 3 h / Reflux 1.2: Cooling with ice 2.1: hydrogenchloride; sodium nitrite / water / 1 h / 0 °C 2.2: 2 h / 0 - 20 °C 2.3: pH 8 - 9 / Cooling with ice 3.1: triethylamine / ethanol / 80 °C 4.1: water; sodium hydroxide / ethanol / 48 h / 20 °C 4.2: pH 3 - 4

Reference： [1]Current Patent Assignee: BAYER AG - US2011/190365, 2011, A1

15
[ 103204-69-9 ]
[ 1208342-20-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sulfuric acid / 3 h / Reflux 1.2: Cooling with ice 2.1: hydrogenchloride; sodium nitrite / water / 1 h / 0 °C 2.2: 2 h / 0 - 20 °C 2.3: pH 8 - 9 / Cooling with ice 3.1: triethylamine / ethanol / 80 °C 4.1: water; sodium hydroxide / ethanol / 48 h / 20 °C 4.2: pH 3 - 4 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 20 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2011/190365, 2011, A1

16
[ 103204-69-9 ]
[ 1208342-39-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sulfuric acid / 3 h / Reflux 1.2: Cooling with ice 2.1: hydrogenchloride; sodium nitrite / water / 1 h / 0 °C 2.2: 2 h / 0 - 20 °C 2.3: pH 8 - 9 / Cooling with ice 3.1: triethylamine / ethanol / 80 °C 4.1: water; sodium hydroxide / ethanol / 48 h / 20 °C 4.2: pH 3 - 4 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 20 °C 6.1: tert.-butylnitrite; iodoform / chloroform / 20 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2011/190365, 2011, A1

17
[ 103204-69-9 ]
[ 1015435-34-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuric acid / 2.5 h / Reflux 2: 1,4-dioxane / 3 h / 20 °C
	Multi-step reaction with 2 steps 1.1: sulfuric acid / 2.5 h / Reflux 1.2: 20 °C 2.1: dmap / 1,4-dioxane / 10 - 20 °C

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2011/92140, 2011, A1
[2]Current Patent Assignee: GOSSAMER BIO INC - US2012/28938, 2012, A1

18
[ 103204-69-9 ]
[ 1303931-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sulfuric acid / 2.5 h / Reflux 2: 1,4-dioxane / 3 h / 20 °C 3: sodium hydroxide; methanol / tetrahydrofuran; methanol / 5 h
	Multi-step reaction with 3 steps 1.1: sulfuric acid / 2.5 h / Reflux 1.2: 20 °C 2.1: dmap / 1,4-dioxane / 10 - 20 °C 3.1: sodium hydroxide / tetrahydrofuran; methanol / 5 h 3.2: 0.5 h / Cooling with ice

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2011/92140, 2011, A1
[2]Current Patent Assignee: GOSSAMER BIO INC - US2012/28938, 2012, A1

19
[ 103204-69-9 ]
[ 1322083-18-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sulfuric acid / 2.5 h / Reflux 2: 1,4-dioxane / 3 h / 20 °C 3: sodium hydroxide; methanol / tetrahydrofuran; methanol / 5 h 4: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C
	Multi-step reaction with 4 steps 1.1: sulfuric acid / 2.5 h / Reflux 1.2: 20 °C 2.1: dmap / 1,4-dioxane / 10 - 20 °C 3.1: sodium hydroxide / tetrahydrofuran; methanol / 5 h 3.2: 0.5 h / Cooling with ice 4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2011/92140, 2011, A1
[2]Current Patent Assignee: GOSSAMER BIO INC - US2012/28938, 2012, A1

20
[ 103204-69-9 ]
[ 1322083-19-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: sulfuric acid / 2.5 h / Reflux 2: 1,4-dioxane / 3 h / 20 °C 3: sodium hydroxide; methanol / tetrahydrofuran; methanol / 5 h 4: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C 5: triethylamine / tetrahydrofuran / 2 h / 20 °C
	Multi-step reaction with 5 steps 1.1: sulfuric acid / 2.5 h / Reflux 1.2: 20 °C 2.1: dmap / 1,4-dioxane / 10 - 20 °C 3.1: sodium hydroxide / tetrahydrofuran; methanol / 5 h 3.2: 0.5 h / Cooling with ice 4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C 5.1: triethylamine / tetrahydrofuran / 2 h / 0 °C

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2011/92140, 2011, A1
[2]Current Patent Assignee: GOSSAMER BIO INC - US2012/28938, 2012, A1

21
[ 103204-69-9 ]
[ 1322083-20-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: sulfuric acid / 2.5 h / Reflux 2: 1,4-dioxane / 3 h / 20 °C 3: sodium hydroxide; methanol / tetrahydrofuran; methanol / 5 h 4: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C 5: triethylamine / tetrahydrofuran / 2 h / 20 °C 6: potassium carbonate / acetonitrile / 72 h / 20 °C
	Multi-step reaction with 6 steps 1.1: sulfuric acid / 2.5 h / Reflux 1.2: 20 °C 2.1: dmap / 1,4-dioxane / 10 - 20 °C 3.1: sodium hydroxide / tetrahydrofuran; methanol / 5 h 3.2: 0.5 h / Cooling with ice 4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C 5.1: triethylamine / tetrahydrofuran / 2 h / 0 °C 6.1: potassium carbonate / acetonitrile / 72 h / 20 °C

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2011/92140, 2011, A1
[2]Current Patent Assignee: GOSSAMER BIO INC - US2012/28938, 2012, A1

22
[ 103204-69-9 ]
[ 1322083-21-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: sulfuric acid / 2.5 h / Reflux 2: 1,4-dioxane / 3 h / 20 °C 3: sodium hydroxide; methanol / tetrahydrofuran; methanol / 5 h 4: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C 5: triethylamine / tetrahydrofuran / 2 h / 20 °C 6: potassium carbonate / acetonitrile / 72 h / 20 °C 7: trifluoroacetic acid / dichloromethane / 2 h / 20 °C
	Multi-step reaction with 7 steps 1.1: sulfuric acid / 2.5 h / Reflux 1.2: 20 °C 2.1: dmap / 1,4-dioxane / 10 - 20 °C 3.1: sodium hydroxide / tetrahydrofuran; methanol / 5 h 3.2: 0.5 h / Cooling with ice 4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C 5.1: triethylamine / tetrahydrofuran / 2 h / 0 °C 6.1: potassium carbonate / acetonitrile / 72 h / 20 °C 7.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2011/92140, 2011, A1
[2]Current Patent Assignee: GOSSAMER BIO INC - US2012/28938, 2012, A1

23
[ 103204-69-9 ]
4-amino-2-methyl-5-nitrobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: nitric acid; sulfuric acid; acetic acid / water / 3 h / 0 - 20 °C 2: hydrogenchloride; water; acetic acid / 1 h / Reflux

Reference： [1]Current Patent Assignee: CRYSTAL GENOMICS INC.; KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - WO2011/99832, 2011, A2

24
[ 103204-69-9 ]
4-acetylamino-2-methyl-5-nitro-benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With sulfuric acid; nitric acid; acetic acid In water at 0 - 20℃; for 3h;	111.1 Example 111 : Preparation of 7-chloro-2-(2-chloro-6-fluoro-phenyl)-6- methyI-lH-benzimidazole-5-carboxyIic acid (l-methyl-5-trifluoromethyI-lH- benzimidazol-2-yl)-amide; The title compound was prepared as follows:; Step 1 ; Preparation of 4-acetylamino-2-methyl-5-nitro-benzoic acid; 15ml con. H2S04 was allowed to cool between 0- 5 °C with ice bath added 3.3 g of 4-acetylamino-2-methyl-benzoic acid (3.30 g). Added acetic acid 10 ml and con. H 03 1.6 ml. The reaction mixture was stirred 3h at room temperature. The solution was added ice water, filtration to give the title compound: 1.20 g (30 %) NMR ((DMSO-d6, 300 MHz) : 5(ppm) 10.10 (br, OH), 7.78 (d, J=8.7 Hz, 1 H), 7.70-7.45 (m, 2H), 2.47 (s, 3H), 2.04 (s, 3H)

Reference： [1]Current Patent Assignee: CRYSTAL GENOMICS INC.; KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - WO2011/99832, 2011, A2 Location in patent: Page/Page column 102

25
[ 103204-69-9 ]
[ 1329119-38-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid; acetic acid / water / 3 h / 0 - 20 °C 2: hydrogenchloride; water; acetic acid / 1 h / Reflux 3: acetic acid; sulfuryl dichloride / 3 h / 20 °C

Reference： [1]Current Patent Assignee: CRYSTAL GENOMICS INC.; KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - WO2011/99832, 2011, A2

26
5-chloro-4-(1-(phenylsulfonyl)-1-indol-3-yl)-N-(piperidin-4-yl)pyrimidin-2-amine [ No CAS ]
[ 103204-69-9 ]
N-(4-(4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)-3-methylphenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 23℃;	15 N-(4-(4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)-3-methylphenyl)acetamide N-(4-(4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)-3-methylphenyl)acetamideA solution of 5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)-N-(piperidin-4-yl)pyrimidin-2- amine (220 mg, 0.47 mmol), 4-acetamido-2-methylbenzoic acid (91mg, 0.47mmol), HBTU (357mg, 0.94mmol) and DIPEA (0.25mL, 1.41mmol) in DCM (3.1mL) was stirred overnight at 23°C before being concentrated under reduced pressure. The residue was purified by flash chromatography (Hex/EtOAc 50 to 100% gradient) and afforded the title compound (240mg, 0.37mmol, 83%) as a white solid.

Reference： [1]Current Patent Assignee: SYROS PHARMACEUTICALS INC - WO2015/58163, 2015, A2 Location in patent: Paragraph 217

27
[ 67-56-1 ]
[ 103204-69-9 ]
[ 1149388-04-4 ]
[ 1260848-51-8 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9]; 20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0 C and treated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51 mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192 mmol). The reaction mixture was warmed to rt and stirred for 1 h. It was poured in small portions on ice water, the formed orange precipitate filtered off and air-dried to give a mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid (ca 2:3, 17 g, 84%) which was used in the next step without further purification. (0521) 1H-NMR (300MHz, DMSO-d6, major isomer): [ppm] = 2.46 (s, 3H), 6.82 (s, 1 H), 8.58 (s, 1H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1H), 7.73 (d, 1H)]. (0522) UPLC-MS (ESI+): [M + H]+ = 197; Rt = 0.73 min. Step 2: methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5- nitrobenzoate A mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5- nitrobenzoic acid (ca 2:3; 40.6 g, 207 mmol) from step 1 in methanol (323 mL) was treated dropwise with concentrated sulfuric acid (9.5 eq., 105 mL, 2.0 mol) and stirred at 60 C for 7 h. The reaction mixture was poured on ice water, the formed precipitate filtered off and washed with cold water. The obtained material was dried in vacuo at 40 C overnight to give a mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5-nitrobenzoate (ca 2:3, 44 g, quant.) which was used in the next step without further purification. (0523) 1H-NMR (300MHz, DMSO-d6, major isomer): [ppm] = 2.46 (s, 3H), 3.78 (s, 3H), 6.84 (s, 1H), 7.83 (br. s., 2H), 8.58 (s, 1 H) [minor isomer: 2.37 (s, 3H), 3.75 (s, 3H), 6.51 (br. s., 2H), 6.75 (d, 1H), 7.73 (d, 1 H)]. (0524) UPLC-MS (ESI+): [M + H]+ = 211 ; Rt = 1.00 min.
		A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9]; 20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0 C and treated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51 mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192 mmol). The reaction mixture was warmed to rt and stirred for 1 h. It was poured in small portions on ice water, the formed orange precipitate filtered off and air-dried to give a mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4- amino-2-methyl-5-nitrobenzoic acid (ca 2:3, 17 g, 84%) which was used in the next step without further purification. H-NMR (300MHz, DMSO-d6, major isomer): delta [ppm] = 2.46 (s, 3H), 6.82 (s, 1 H), 8.58 (s, 1 H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1 H), 7.73 (d, 1 H)]. UPLC-MS (ESI+): [M + H]+ = 197; Rt = 0.73 minA mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid (ca 2:3; 40.6 g, 207 mmol) from step 1 in methanol (323 ml_) was treated dropwise with concentrated sulfuric acid (9.5 eq., 105 mL, 2.0 mol) and stirred at 60 C for 7 h. The reaction mixture was poured on ice water, the formed precipitate filtered off and washed with cold water. The obtained material was dried in vacuo at 40 C overnight to give a mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2- methyl-5-nitrobenzoate (ca 2:3, 44 g, quant.) which was used in the next step without further purification. 1H-NMR (300MHz, DMSO-de, major isomer): delta [ppm] = 2.46 (s, 3H), 3.78 (s, 3H), 6.84 (s, 1 H), 7.83 (br. s., 2H), 8.58 (s, 1 H) [minor isomer: 2.37 (s, 3H), 3.75 (s, 3H), 6.51 (br. s., 2H), 6.75 (d, 1 H), 7.73 (d, 1 H)]. UPLC-MS (ESI+): [M + H]+ = 21 1 ; Rt = 1.00 min.

Reference： [1]Patent: WO2015/121210,2015,A1 .Location in patent: Page/Page column 90-91
[2]Patent: WO2017/9325,2017,A1 .Location in patent: Page/Page column 57-58

28
[ 67-56-1 ]
[ 14376-79-5 ]
[ 103204-69-9 ]
methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate [ No CAS ]
methyl 2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-acetylamino-2-methylbenzoic acid With sulfuric acid; nitric acid at 0 - 20℃; Stage #2: methanol With sulfuric acid at 60℃; for 7h; Stage #3: 3,3,5,5-tetramethylcyclohexanone Overall yield = 39 %; Overall yield = 667 g; Further stages;	1-3 methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate and methyl 2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9]; 20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0 °C and treated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51 mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192 mmol). The reaction mixture was warmed to rt and stirred for 1 h. It was poured in small portions on ice water, the formed orange precipitate filtered off and air-dried to give a mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid (ca 2:3, 17 g, 84%) which was used in the next step without further purification. (0521) 1H-NMR (300MHz, DMSO-d6, major isomer): [ppm] = 2.46 (s, 3H), 6.82 (s, 1 H), 8.58 (s, 1H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1H), 7.73 (d, 1H)]. (0522) UPLC-MS (ESI+): [M + H]+ = 197; Rt = 0.73 min. Step 2: methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5- nitrobenzoate A mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5- nitrobenzoic acid (ca 2:3; 40.6 g, 207 mmol) from step 1 in methanol (323 mL) was treated dropwise with concentrated sulfuric acid (9.5 eq., 105 mL, 2.0 mol) and stirred at 60 °C for 7 h. The reaction mixture was poured on ice water, the formed precipitate filtered off and washed with cold water. The obtained material was dried in vacuo at 40 °C overnight to give a mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5-nitrobenzoate (ca 2:3, 44 g, quant.) which was used in the next step without further purification. (0523) 1H-NMR (300MHz, DMSO-d6, major isomer): [ppm] = 2.46 (s, 3H), 3.78 (s, 3H), 6.84 (s, 1H), 7.83 (br. s., 2H), 8.58 (s, 1 H) [minor isomer: 2.37 (s, 3H), 3.75 (s, 3H), 6.51 (br. s., 2H), 6.75 (d, 1H), 7.73 (d, 1 H)]. (0524) UPLC-MS (ESI+): [M + H]+ = 211 ; Rt = 1.00 min. A mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5- nitrobenzoate (ca 2:3; 1.00 g, 4.76 mmol) from step 2 and 3,3,5,5-tetramethylcyclo- hexanone (CAS No. [14376-79-5]; 1.00 eq., 734 mg, 4.76 mmol) in 1 ,2-dichloroethane (10 mL) was treated dropwise with trifluoroacetic acid (5 mL) and stirred at rt for 5 minutes upon which sodium triacetoxyborohydride ([56553-60-7]; 1.5 eq., 1.5 g, 7.1 mmol) were added in portions and stirring at rt was continued for 2 days. An additional amount of trifluoroacetic acid (1 mL) and sodium triacetoxyborohydride (1.0 eq., 1.0 g, 4.8 mmol) were added and stirring at rt was continued for 6 days. The ice-cooled reaction mixture was quenched with an aqueous ammonia solution (25%) and partitioned between water and dichloromethane. The phases were separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give a mixture of methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate and methyl 2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate (ca 4:1 , 667 mg, 39%). (0526) 1H-NMR (400MHz, DMSO-d6, major isomer): [ppm] = 0.89- 1.17 (m, 14H), 1.20- 1.29 (m, 2H), 1.59- 1.62 (m, 2H) [minor isomer: 1.74- 1.77 (m, 2H)], 2.36 (s, 3H) [minor isomer: 2.57 (s, 3H)], 3.65- 3.74 (m, 1 H), 3.77 (s, 3H) [minor isomer: 3.80 (s, 3H)], 5.98 (d, 1H), 6.81 (d, 1 H), 7.84 (d, 1 H) [minor isomer: 6.93 (s, 1 H), 8.05 (d, 1 H), 8.66 (s, 1H)]. (0527) UPLC-MS (ESI+): [M + H]+ = 349; Rt = 1.73 / 1.76 min.
	Stage #1: 4-acetylamino-2-methylbenzoic acid With sulfuric acid; nitric acid at 0 - 20℃; for 1h; Stage #2: methanol With sulfuric acid at 60℃; for 7h; Stage #3: 3,3,5,5-tetramethylcyclohexanone With sodium tris(acetoxy)borohydride; trifluoroacetic acid In 1,2-dichloro-ethane at 20℃; for 192h; Overall yield = 39 %; Overall yield = 667 mg;	3 Step 3: methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate and methyl 2-methyl-5-nitro-4-[(3,3.5,5-tetramethylcyclohexyl)amino]benzoate A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9]; 20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0 °C and treated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51 mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192 mmol). The reaction mixture was warmed to rt and stirred for 1 h. It was poured in small portions on ice water, the formed orange precipitate filtered off and air-dried to give a mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4- amino-2-methyl-5-nitrobenzoic acid (ca 2:3, 17 g, 84%) which was used in the next step without further purification. H-NMR (300MHz, DMSO-d6, major isomer): δ [ppm] = 2.46 (s, 3H), 6.82 (s, 1 H), 8.58 (s, 1 H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1 H), 7.73 (d, 1 H)]. UPLC-MS (ESI+): [M + H]+ = 197; Rt = 0.73 minA mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid (ca 2:3; 40.6 g, 207 mmol) from step 1 in methanol (323 ml_) was treated dropwise with concentrated sulfuric acid (9.5 eq., 105 mL, 2.0 mol) and stirred at 60 °C for 7 h. The reaction mixture was poured on ice water, the formed precipitate filtered off and washed with cold water. The obtained material was dried in vacuo at 40 °C overnight to give a mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2- methyl-5-nitrobenzoate (ca 2:3, 44 g, quant.) which was used in the next step without further purification. 1H-NMR (300MHz, DMSO-de, major isomer): δ [ppm] = 2.46 (s, 3H), 3.78 (s, 3H), 6.84 (s, 1 H), 7.83 (br. s., 2H), 8.58 (s, 1 H) [minor isomer: 2.37 (s, 3H), 3.75 (s, 3H), 6.51 (br. s., 2H), 6.75 (d, 1 H), 7.73 (d, 1 H)]. UPLC-MS (ESI+): [M + H]+ = 21 1 ; Rt = 1.00 min. A mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5- nitrobenzoate (ca 2:3; 1.00 g, 4.76 mmol) from step 2 and 3,3,5,5-tetramethylcyclo- hexanone (CAS No. [14376-79-5]; 1.00 eq., 734 mg, 4.76 mmol) in 1 ,2-dichloroethane (10 mL) was treated dropwise with trifluoroacetic acid (5 mL) and stirred at rt for 5 minutes upon which sodium triacetoxyborohydride ([56553-60-7]; 1 .5 eq., 1.5 g, 7.1 mmol) were added in portions and stirring at rt was continued for 2 days. An additional amount of trifluoroacetic acid (1 mL) and sodium triacetoxyborohydride (1.0 eq., 1.0 g, 4.8 mmol) were added and stirring at rt was continued for 6 days. The ice-cooled reaction mixture was quenched with an aqueous ammonia solution (25%) and partitioned between water and dichloromethane. The phases were separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiC hexane/ ethyl acetate) to give a mixture of methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate and methyl 2- methyl-5-nitro-4-[(3,3.5,5-tetramethylcyclohexyl)amino]benzoate (ca 4:1 , 667 mg, 39%). H-NMR (400MHz, DMSO-de, major isomer): δ [ppm] = 0.89 - 1.17 (m, 14H), 1.20 - 1 .29 (m, 2H), 1.59 - 1 .62 (m, 2H) [minor isomer: 1 .74 - 1.77 (m, 2H)], 2.36 (s, 3H) [minor isomer: 2.57 (s, 3H)], 3.65 - 3.74 (m, 1 H), 3.77 (s, 3H) [minor isomer: 3.80 (s, 3H)], 5.98 (d, 1 H), 6.81 (d, 1 H), 7.84 (d, 1 H) [minor isomer: 6.93 (s, 1 H), 8.05 (d, 1 H), 8.66 (s, 1 H)].

Reference： [1]Current Patent Assignee: Helmholtz Association - WO2015/121210, 2015, A1 Location in patent: Page/Page column 90-92
[2]Current Patent Assignee: Helmholtz Association - WO2017/9325, 2017, A1 Location in patent: Page/Page column 57-58

29
[ 67-56-1 ]
[ 14376-79-5 ]
[ 103204-69-9 ]
methyl 3-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate [ No CAS ]
methyl 5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 59% 2: 17%	Stage #1: 4-acetylamino-2-methylbenzoic acid With sulfuric acid; nitric acid at 0 - 20℃; Stage #2: methanol With sulfuric acid at 60℃; for 7h; Stage #3: 3,3,5,5-tetramethylcyclohexanone Overall yield = 39 %; Overall yield = 667 g; Further stages;	1-4 methyl 3-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9]; 20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0 °C and treated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51 mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192 mmol). The reaction mixture was warmed to rt and stirred for 1 h. It was poured in small portions on ice water, the formed orange precipitate filtered off and air-dried to give a mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid (ca 2:3, 17 g, 84%) which was used in the next step without further purification. (0521) 1H-NMR (300MHz, DMSO-d6, major isomer): [ppm] = 2.46 (s, 3H), 6.82 (s, 1 H), 8.58 (s, 1H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1H), 7.73 (d, 1H)]. (0522) UPLC-MS (ESI+): [M + H]+ = 197; Rt = 0.73 min. Step 2: methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5- nitrobenzoate A mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5- nitrobenzoic acid (ca 2:3; 40.6 g, 207 mmol) from step 1 in methanol (323 mL) was treated dropwise with concentrated sulfuric acid (9.5 eq., 105 mL, 2.0 mol) and stirred at 60 °C for 7 h. The reaction mixture was poured on ice water, the formed precipitate filtered off and washed with cold water. The obtained material was dried in vacuo at 40 °C overnight to give a mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5-nitrobenzoate (ca 2:3, 44 g, quant.) which was used in the next step without further purification. (0523) 1H-NMR (300MHz, DMSO-d6, major isomer): [ppm] = 2.46 (s, 3H), 3.78 (s, 3H), 6.84 (s, 1H), 7.83 (br. s., 2H), 8.58 (s, 1 H) [minor isomer: 2.37 (s, 3H), 3.75 (s, 3H), 6.51 (br. s., 2H), 6.75 (d, 1H), 7.73 (d, 1 H)]. (0524) UPLC-MS (ESI+): [M + H]+ = 211 ; Rt = 1.00 min. A mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5- nitrobenzoate (ca 2:3; 1.00 g, 4.76 mmol) from step 2 and 3,3,5,5-tetramethylcyclo- hexanone (CAS No. [14376-79-5]; 1.00 eq., 734 mg, 4.76 mmol) in 1 ,2-dichloroethane (10 mL) was treated dropwise with trifluoroacetic acid (5 mL) and stirred at rt for 5 minutes upon which sodium triacetoxyborohydride ([56553-60-7]; 1.5 eq., 1.5 g, 7.1 mmol) were added in portions and stirring at rt was continued for 2 days. An additional amount of trifluoroacetic acid (1 mL) and sodium triacetoxyborohydride (1.0 eq., 1.0 g, 4.8 mmol) were added and stirring at rt was continued for 6 days. The ice-cooled reaction mixture was quenched with an aqueous ammonia solution (25%) and partitioned between water and dichloromethane. The phases were separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give a mixture of methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate and methyl 2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate (ca 4:1 , 667 mg, 39%). (0526) 1H-NMR (400MHz, DMSO-d6, major isomer): [ppm] = 0.89- 1.17 (m, 14H), 1.20- 1.29 (m, 2H), 1.59- 1.62 (m, 2H) [minor isomer: 1.74- 1.77 (m, 2H)], 2.36 (s, 3H) [minor isomer: 2.57 (s, 3H)], 3.65- 3.74 (m, 1 H), 3.77 (s, 3H) [minor isomer: 3.80 (s, 3H)], 5.98 (d, 1H), 6.81 (d, 1 H), 7.84 (d, 1 H) [minor isomer: 6.93 (s, 1 H), 8.05 (d, 1 H), 8.66 (s, 1H)]. (0527) UPLC-MS (ESI+): [M + H]+ = 349; Rt = 1.73 / 1.76 min. A mixture of methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate and methyl 2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate (ca 4:1 ; 660 mg, 1.89 mmol) from step 3 in ethyl acetate (30 mL) was treated with Pd/C (10wt%; 0.25 eq., 50 mg, 0.47 mmol) and stirred under a hydrogen atmosphere at rt overnight. The reaction mixture was filtrated over Celite, washed with ethyl acetate and the filtrate concentrated in vacuo. The obtained regioisomeric mixture was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give methyl 3-amino-2-methyl-4- [(3,3,5,5-tetramethylcyclohexyl)amino]benzoate (intermediate 1 -22; 357 mg, 59%) along with the minor isomer methyl 5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclo- hexyl)amino]benzoate (intermediate 1 -24; 111 mg, 17%). (0528) 1H-NMR (400MHz, DMSO-d6): [ppm] = 0.91 (s, 6H), 1.01 (t, 2H), 1.07- 1.09 (m, 7H), 1.25- 1.29 (m, 1 H), 1.72- 1.75 (m, 2H), 2.30 (s, 3H), 3.56- 3.65 (m, 1 H), 3.69 (s, 3H), 4.44 (br. s., 2H), 4.84 (d, 1 H), 6.37 (d, 1 H), 7.17 (d, 1 H). (0529) UPLC-MS (ESI+): [M + H]+ = 319; Rt = 1.55 min.

Reference： [1]Current Patent Assignee: Helmholtz Association - WO2015/121210, 2015, A1 Location in patent: Page/Page column 90-92

30
[ 103204-69-9 ]
[ 1149388-03-3 ]
4-amino-2-methyl-5-nitrobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; nitric acid at 0 - 20℃; Overall yield = 84 %; Overall yield = 17 g;	1 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9]; 20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0 °C and treated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51 mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192 mmol). The reaction mixture was warmed to rt and stirred for 1 h. It was poured in small portions on ice water, the formed orange precipitate filtered off and air-dried to give a mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid (ca 2:3, 17 g, 84%) which was used in the next step without further purification. (0521) 1H-NMR (300MHz, DMSO-d6, major isomer): [ppm] = 2.46 (s, 3H), 6.82 (s, 1 H), 8.58 (s, 1H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1H), 7.73 (d, 1H)]. (0522) UPLC-MS (ESI+): [M + H]+ = 197; Rt = 0.73 min.
	With sulfuric acid; nitric acid at 0 - 20℃; for 1h; Overall yield = 84 %; Overall yield = 17 g;	1 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9]; 20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0 °C and treated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51 mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192 mmol). The reaction mixture was warmed to rt and stirred for 1 h. It was poured in small portions on ice water, the formed orange precipitate filtered off and air-dried to give a mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4- amino-2-methyl-5-nitrobenzoic acid (ca 2:3, 17 g, 84%) which was used in the next step without further purification. H-NMR (300MHz, DMSO-d6, major isomer): δ [ppm] = 2.46 (s, 3H), 6.82 (s, 1 H), 8.58 (s, 1 H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1 H), 7.73 (d, 1 H)]. UPLC-MS (ESI+): [M + H]+ = 197; Rt = 0.73 min.

Reference： [1]Current Patent Assignee: Helmholtz Association - WO2015/121210, 2015, A1 Location in patent: Page/Page column 90
[2]Current Patent Assignee: Helmholtz Association - WO2017/9325, 2017, A1 Location in patent: Page/Page column 57

31
[ 103204-69-9 ]
methyl 3-amino-4-[(cyclopropylmethyl)amino]-2-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sulfuric acid; nitric acid / 0 - 20 °C 2.1: sulfuric acid / 18 h / 20 °C / Reflux 3.1: trifluoroacetic acid; sodium tris(acetoxy)borohydride / 0.17 h / -15 °C 3.2: 0.08 h 4.1: palladium 10% on activated carbon; hydrogen

Reference： [1]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - JP2016/501241, 2016, A

32
[ 103204-69-9 ]
1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-4-methyl-1H-benzimidazole-5-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sulfuric acid; nitric acid / 0 - 20 °C 2.1: sulfuric acid / 18 h / 20 °C / Reflux 3.1: trifluoroacetic acid; sodium tris(acetoxy)borohydride / 0.17 h / -15 °C 3.2: 0.08 h 4.1: palladium 10% on activated carbon; hydrogen 5.1: acetic acid / 1 h / Cooling with ice; Reflux 6.1: sodium hydroxide / methanol / 5 h / Reflux

Reference： [1]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - JP2016/501241, 2016, A

33
[ 103204-69-9 ]
methyl 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-4-methyl-1H-benzimidazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sulfuric acid; nitric acid / 0 - 20 °C 2.1: sulfuric acid / 18 h / 20 °C / Reflux 3.1: trifluoroacetic acid; sodium tris(acetoxy)borohydride / 0.17 h / -15 °C 3.2: 0.08 h 4.1: palladium 10% on activated carbon; hydrogen 5.1: acetic acid / 1 h / Cooling with ice; Reflux

Reference： [1]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - JP2016/501241, 2016, A

34
[ 103204-69-9 ]
methyl 3-nitro-4-[(cyclopropylmethyl)amino]-2-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sulfuric acid; nitric acid / 0 - 20 °C 2.1: sulfuric acid / 18 h / 20 °C / Reflux 3.1: trifluoroacetic acid; sodium tris(acetoxy)borohydride / 0.17 h / -15 °C 3.2: 0.08 h

Reference： [1]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - JP2016/501241, 2016, A

35
[ 103204-69-9 ]
[ 1149388-04-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuric acid; nitric acid / 0 - 20 °C 2: sulfuric acid / 18 h / 20 °C / Reflux

Reference： [1]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - JP2016/501241, 2016, A

36
[ 67-56-1 ]
[ 14376-79-5 ]
[ 103204-69-9 ]
methyl 5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate [ No CAS ]
methyl 5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 59% 2: 17%	Stage #1: 4-acetylamino-2-methylbenzoic acid With sulfuric acid; nitric acid at 0 - 20℃; for 1h; Stage #2: methanol With sulfuric acid at 60℃; for 7h; Stage #3: 3,3,5,5-tetramethylcyclohexanone Overall yield = 39 %; Overall yield = 667 mg; Further stages;	4 Step 4: methyl 5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9]; 20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0 °C and treated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51 mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192 mmol). The reaction mixture was warmed to rt and stirred for 1 h. It was poured in small portions on ice water, the formed orange precipitate filtered off and air-dried to give a mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4- amino-2-methyl-5-nitrobenzoic acid (ca 2:3, 17 g, 84%) which was used in the next step without further purification. H-NMR (300MHz, DMSO-d6, major isomer): δ [ppm] = 2.46 (s, 3H), 6.82 (s, 1 H), 8.58 (s, 1 H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1 H), 7.73 (d, 1 H)]. UPLC-MS (ESI+): [M + H]+ = 197; Rt = 0.73 minA mixture of 4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoic acid (ca 2:3; 40.6 g, 207 mmol) from step 1 in methanol (323 ml_) was treated dropwise with concentrated sulfuric acid (9.5 eq., 105 mL, 2.0 mol) and stirred at 60 °C for 7 h. The reaction mixture was poured on ice water, the formed precipitate filtered off and washed with cold water. The obtained material was dried in vacuo at 40 °C overnight to give a mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2- methyl-5-nitrobenzoate (ca 2:3, 44 g, quant.) which was used in the next step without further purification. 1H-NMR (300MHz, DMSO-de, major isomer): δ [ppm] = 2.46 (s, 3H), 3.78 (s, 3H), 6.84 (s, 1 H), 7.83 (br. s., 2H), 8.58 (s, 1 H) [minor isomer: 2.37 (s, 3H), 3.75 (s, 3H), 6.51 (br. s., 2H), 6.75 (d, 1 H), 7.73 (d, 1 H)]. UPLC-MS (ESI+): [M + H]+ = 21 1 ; Rt = 1.00 min. A mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl 4-amino-2-methyl-5- nitrobenzoate (ca 2:3; 1.00 g, 4.76 mmol) from step 2 and 3,3,5,5-tetramethylcyclo- hexanone (CAS No. [14376-79-5]; 1.00 eq., 734 mg, 4.76 mmol) in 1 ,2-dichloroethane (10 mL) was treated dropwise with trifluoroacetic acid (5 mL) and stirred at rt for 5 minutes upon which sodium triacetoxyborohydride ([56553-60-7]; 1 .5 eq., 1.5 g, 7.1 mmol) were added in portions and stirring at rt was continued for 2 days. An additional amount of trifluoroacetic acid (1 mL) and sodium triacetoxyborohydride (1.0 eq., 1.0 g, 4.8 mmol) were added and stirring at rt was continued for 6 days. The ice-cooled reaction mixture was quenched with an aqueous ammonia solution (25%) and partitioned between water and dichloromethane. The phases were separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiC hexane/ ethyl acetate) to give a mixture of methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate and methyl 2- methyl-5-nitro-4-[(3,3.5,5-tetramethylcyclohexyl)amino]benzoate (ca 4:1 , 667 mg, 39%). H-NMR (400MHz, DMSO-de, major isomer): δ [ppm] = 0.89 - 1.17 (m, 14H), 1.20 - 1 .29 (m, 2H), 1.59 - 1 .62 (m, 2H) [minor isomer: 1 .74 - 1.77 (m, 2H)], 2.36 (s, 3H) [minor isomer: 2.57 (s, 3H)], 3.65 - 3.74 (m, 1 H), 3.77 (s, 3H) [minor isomer: 3.80 (s, 3H)], 5.98 (d, 1 H), 6.81 (d, 1 H), 7.84 (d, 1 H) [minor isomer: 6.93 (s, 1 H), 8.05 (d, 1 H), 8.66 (s, 1 H)]. A mixture of methyl 2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate and methyl 2-methyl-5-nitro-4-[(3.3.5 5-tetramethylcyclohexyl)amino]benzoate (ca 4: 1 ; 660 mg, 1 .89 mmol) from step 3 in ethyl acetate (30 mL) was treated with palladium on carbon ( 10wt%; 0.25 eq., 50 mg, 0.47 mmol) and stirred under a hydrogen atmosphere at rt overnight. The reaction mixture was filtrated over Celite, washed with ethyl acetate and the filtrate concentrated in vacuo. The obtained regioisomeric mixture was purified by flash chromatography (SiCb-hexane/ ethyl acetate) to give methyl 3-amino-2-methyl- 4-[(3,3,5.5-tetramethylcyclohexyl)amino]benzoate (357 mg, 59%) along with the minor isomer methyl 5-amino-2-methyl-4-[(3,3.5,5-tetramethylcyclohexyl)amino]benzoate (intermediate 1 -3; 1 1 1 mg, 17%). 1 H- MR (300MHz, DMSO-de): δ [ppm] = 0.91 (s, 6H), 0.99 (t, 2H), 1 .06 - 1 .1 1 (m, 7H), 1 .25 - 1 .30 (m, 1 H), 1 .72 - 1 .76 (m, 2H), 2.38 (s, 3H), 3.56 - 3.64 (m, 1 H), 3.69 (s, 3H), 4.54 (br. s., 2H), 4.79 (d, 1 H), 6.26 (s, 1 H), 7.16 (s, 1 H). UPLC-MS (ESI+): [M + H]+ = 319; Rt = 1 .52 min.

Reference： [1]Current Patent Assignee: Helmholtz Association - WO2017/9325, 2017, A1 Location in patent: Page/Page column 59

37
[ 103204-69-9 ]
[ 84257-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: borane-THF / tetrahydrofuran / 0.25 h / 20 °C 2: manganese(IV) oxide / acetonitrile / 0.12 h / 120 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/144400, 2007, A1

38
[ 103204-69-9 ]
6-carboxy-7-methylbenzo[c][1,2,5]oxadiazole-1-oxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuric acid; nitric acid / 20 °C / Cooling with ice 2: sodium hypochlorite solution; potassium hydroxide / water; ethanol / 0.5 h / 20 °C / Cooling with ice