Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]([CH3:36])([CH3:35])[C@H:10]([NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]#[C:29][C@@H:30]3[CH2:32][C@H:31]3[CH2:33][OH:34])[CH:24]=2)[CH:19]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:8][C:9]([CH3:36])([CH3:35])[C@H:10]([NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]#[C:29][C@@H:30]3[CH2:32][C@H:31]3[CH2:33][OH:34])[CH:24]=2)[CH:19]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@@H](NC(=O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1)C(C)(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirring solution of (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (64) in methanol (10 mL) was added 4N HCl in dioxane (10 mL) and the reaction mixture was stirred at rt for 2 hr, then at 4° C. overnight. The mixture was concentrated under reduced pressure to give a residue, which was partitioned between water and MTBE. The aqueous layer was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-amino-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (6.5, 1.2 g, 3.0 mmol, 79%).
Reaction SMILES: [CH:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].[OH-].[K+].N#N.C(N(CC)CC)C>>[CH3:16][C:14](=[O:15])[CH2:12][CH2:13][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC=O
Reactant: C=CC(C)=O
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)CCC(C)=O
Reaction time: 12 h

Procedure:
78.1 g (0.5 mol) of caprinaldehyde, 35.1 g (0.5 mol) of methyl vinyl ketone and 13.5 g (0.05 mol) of Cat. 1 are introduced into a 250 ml three-necked flask equipped with a stirrer, reflux condenser (high efficiency, KOH drying tube) and N2 inlet. After adding 40.4 g (0.4 mol) of triethylamine, a N2 atmosphere is set up, the mixture is stirred and the surrounding oil bath is brought to 80° C. The initially undissolved catalyst dissolves and after some time triethylamine hydrochloride precipitates. The mixture is kept at 80° C for 12 hours. For working up, it is first cooled, and then the procedure described in Example 21 is followed. Tetradecane-2,5-dione is obtained. Recrystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[C:27]([NH:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])(=[O:29])[CH3:28]
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ncccc2C(F)(F)F)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (0.5 mmol) and pyridine (0.55 mmol) in THF (5 ml) add acetyl chloride (0.55 mmol). Stir the mixture 10 minutes at room temperature. Concentrate under vacuum, extract with EtOAc, wash with brine, dry over Na2SO4, and concentrate under vacuum. Triturate with ether to give 2-acetylamino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[Na+].Cl.[CH:22]([Cl:25])(Cl)Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:1][C:2]1[C:22]([Cl:25])=[C:10]([CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1[nH]c2ccccc2c1CCC1CCNCC1
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Cc1nc2ccccc2c(CCC2CCNCC2)c1Cl

Procedure:
The operation is as in Example 1, but starting from 5.9 g of 4-[2-(2-methyl-3-indolyl)-ethyl]-piperidine and 0.12 g of triethylbenzylammonium chloride in 60 ml of chloroform and 7.5 g of sodium hydroxide in 15 ml of water. 2.7 g of 2-methyl-3-chloro-4-[2-(4-piperidyl)-ethyl]-quinoline are finally obtained in the form of the monohydrochloride which melts at 255° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=2[C:18]([F:21])([F:20])[F:19])[CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[C:18]([F:19])([F:21])[F:20])[CH:2]=1
Reactant: COC(=O)c1ccc(Oc2cccnc2)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(Oc2cccnc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
0.9 g of methyl 4-(3-pyridyloxy)-3-trifluoromethylbenzoate was dissolved in 10 ml of THF and 235 mg of LiAlH4 were added at 0° C. The mixture was stirred at RT for 3 h, poured onto 50 ml of 1 N Na2CO3 and extracted 3 times with 50 ml of EA. It was dried over Na2SO4 and the solvent was removed in vacuo. 780 mg of a white solid were obtained, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+](=[CH2:30])=[N-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:23])([F:24])[F:25])[C:15]([O:17][CH3:30])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Product: COC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (1.2 g.) in either (20 ml.) is treated at 0° C. with an excess of an ethereal solution of diazomethane. The solution is evaporated, and the residue is recrystallised from light petroleum (b.p. 40°-60° C.) to give methyl 2-[4(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (1.1 g.), m.p. 61.5°-62.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCOCC1.O>[CH3:12][C:4]1[N:3]=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cc(N2CCNCC2)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
A solution of 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.0 g, 5.11 mmol), piperazine (1.32 g, 15.3 mmol), and triethylamine (0.71 mL, 5.1 mmol) were mixed in 1,4-dioxane (10 mL). After stirring at 100° C. for 5 h, the reaction solution was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (10% MeOH/5% Et3N/EtOAc) to yield the desired product (880 mg, 70.2%). LCMS calculated for C11H15F3N3: (M+1) 246.1; found 246.1.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[C:13](=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C([O-])O
Reactant: Cc1cccc(C(=O)O)c1N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(C)c1N
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of 60.8 g of 2-amino-3-methylbenzoic acid in 900 ml of dry methanol was saturated with anhydrous hydrogen chloride at 0°-10° C., then allowed to stand at room temperature overnight. Then it was refluxed for one hour, cooled to 5° C., resaturated with anhydrous hydrogen chloride, held overnight at room temperature and stripped of solvent. The residue was made neutral with saturated aqueous sodium bicarbonate solution, and extracted with methylene chloride. The extract phase was washed with saturated aqueous sodium bicarbonate solution, dried (MgSO4), filtered and stripped of solvent. The residue was distilled in a kugelrohr apparatus to give methyl 2-amino-3-methylbenzoate (49A), b.p.: 100°-105° C. (1Torr.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:35](=[O:36])[NH:34][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OC(=O)NCc3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
2-Ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (0.36 g; 1.0 mmol) was dissolved in dry dichloromethane (25 ml) and benzylisocyanate (0.20 g; 0.185 ml; 1.5 mmol) was added followed by addition of triethylamine (0.22 ml; 1.5 mmol). The solution was stirred at room temperature for 3 hours. The dichloromethane phase was washed with diluted acid, sodium hydrogen carbonate and brine, dried with sodium sulfate and evaporated to give 0.4 g (81%) of crude 3-{4-[2-(4-benzylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester. The crude material was purified on preparative reversed phase HPLC using a gradient of acetonitrile-water-ammonium acetate as mobile phase. Fractions containing pure product were pooled and the acetonitrile removed in vacuum. The residue was dissolved in dichloromethane, washed with water, dried with sodium sulfate and evaporated to give 0.23 g (48%) of pure 3-{4-[2-(4-benzylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].C(N(CC)CC)C.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(Cl)Cl>[C:16]([O:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C1CC(O)C(=O)O1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CC(=O)OC1=O
Temperature: 0 °C

Procedure:
After equipping a thoroughly dried 200 ml-volume three-necked flask with a dropping funnel, a calcium chloride tube and a nitrogen inlet tube, the system atmosphere was charged with nitrogen gas. A stirrer bar coated with Teflon™ was then added into the flask together with 50 ml of dry methylene chloride, 5.0 g (43.1 millimoles) of 2-hydroxysuccinic anhydride and 4.79 g (47.4 millimoles) of dry triethylamine, and the mixture was stirred at 0° C. under the nitrogen atmosphere. To this solution there was added, dropwise and over the period of an hour, 4.50 g (43.1 millimoles) of methacryloyl chloride that had been already placed in the dropping funnel, and then the mixture was stirred at room temperature for 2 hours. After confirming consumption of the starting materials by thin-layer chromatography, the reaction solution was transferred to a 300 ml separatory funnel and washed with 100 ml of water and saturated saline in that order. The aqueous phase was then extracted 3 times with methylene chloride. The organic layer was collected and dried over sodium sulfate anhydride. The dried organic layer was filtered with filter paper and the solvent in the filtrate was distilled off under reduced pressure. This yielded a brown oil. The oil was purified by silica gel chromatography to obtain methacryloxysuccinic anhydride as a colorless transparent oil. The yield was 6.75 g (85%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8](I)[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:13]([C:16]1[CH:21]=[C:20]([Sn](C)(C)C)[N:19]=[C:18]([C:26]#[N:27])[N:17]=1)[CH2:14][CH3:15]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:6]2[CH:7]=[C:8]([C:20]3[CH:21]=[C:16]([CH2:13][CH2:14][CH3:15])[N:17]=[C:18]([C:26]#[N:27])[N:19]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Ic1cccc(C2CCCC2)c1
Reactant: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1cc(-c2cccc(C3CCCC3)c2)nc(C#N)n1
Temperature: 80 °C
Yield: 36 %

Procedure:
A mixture of 1-cyclopentyl-3-iodo-benzene (158 mg, 0.58 mmol), 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (150 mg, 0.48 mmol) and PdCl2(PPh3)2 (34 mg, 0.05 mmol) in dry DMF (3 ml) was heated to 80° C. for 6 h under a nitrogen atmosphere. More catalyst (40 mg, 0.06 mmol) was added and the mixture was heated for 12 h at 80° C. The solvent was removed under reduced pressure and the residue was partitioned between water (5 ml) and AcOEt (5 ml). The aqueous layer was extracted twice with AcOEt (2×5 ml). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 272 mg of crude product which was purified by silica gel chromatography (eluent:cyclohexane/AcOEt 95/5) to give the above titled compound: 51 mg, yield: 36%, HPLC: 98%.
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]1([C@H:14]2[CH2:16][C@@H:15]2[NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@H:21]2[C:33]([O:35]C)=O)=[O:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[ClH:1].[C:8]1([C@H:14]2[CH2:16][C@@H:15]2[N:17]2[C:33](=[O:35])[C@@H:21]3[CH2:22][NH:23][CH2:24][CH2:25][N:20]3[C:18]2=[O:19])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)N[C@H]1C[C@@H]1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1

Procedure:
4N HCl solution in dioxane (44 eq.) was added at RT to D1. The resulting 0.1 M solution obtained was stirred for 1 h at RT, then the solvent was removed under reduced pressure. The residue was co-evaporated with toluene (×3) and it was used as such in next step without further purification. MS (ES+) C15H17N3O2 requires 271, found: 272 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(N)cc3)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=291.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 4-ethynylaniline.
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:23][C:24]1[N:33]=[C:32]([C:34]([N:36]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[N:25]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:23][C:24]1[N:33]=[C:32]([C:34]([N:36]2[CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:44]2)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:3]=3[CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:30]=2)[N:25]=1
Reactant: Fc1cc(Br)c(CN2CCCC2)cc1F
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CN3CCCC3)ccc2n1
Temperature: 120 °C

Procedure:
129 mg of 1-(2-bromo-4,5-difluorobenzyl)pyrrolidine, 100 mg of potassium carbonate, 7 μl of water and 17 mg of [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 4 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:19]3[N:20]=[CH:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(O)(c1cccc(-c2cccc(F)c2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2cccc(F)c2)c1)c1c[nH]cn1
Yield: 80.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-(3′-fluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (2.55 g) and pyridine hydrochloride (906 mg), the title compound (1.15 g) was obtained as colorless needle crystals.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce].[C:7]([NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23]C)[CH:17]=[CH:18][C:19]=2[O:21]C)[N:14]=[CH:13][CH:12]=1)(=[O:9])[CH3:8].CC#N.O.C([O-])(O)=O.[Na+]>O>[C:7]([NH:10][C:11]1[C:20]2[C:19](=[O:21])[CH:18]=[CH:17][C:16](=[O:23])[C:15]=2[N:14]=[CH:13][CH:12]=1)(=[O:9])[CH3:8]
Reactant: COc1ccc(OC)c2c(NC(C)=O)ccnc12
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccnc2c1C(=O)C=CC2=O
Reaction time: 0.75 h

Procedure:
22 g (40.1 mmol) of cerium ammonium nitrate are added, at 0° C., to a solution of 5 g (20.3 mmol) of 4-acetamido-5,8-dimethoxyquinoline in a CH3CN/H2O mixture (50 mL/50 mL). The reaction medium is stirred for 1 h 45 min and is then basified with 500 mL of saturated NaHCO3 solution. 200 mL of H2O are added and the mixture is extracted with CHCl3 (3 times 500 mL) After drying over MgSO4 and evaporating off the solvent, 3.4 g of expected product are obtained in the form of a brown-yellow powder, which is used rapidly for the following step since the product is unstable.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCN(c2ccccc2)CC1)C(F)(F)F
Product: O=C(N1CCN(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 155 °C
Yield: 72 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(4-phenylpiperazin-1-yl)ethanone (1.0 g, 3.9 mmol) and chlorosulfonic acid (6 mL) was heated at 155° C. for 15 min. After cooling to RT, the mixture was poured into ice water and extracted with EtOAc. The organic layer was concentrated and purified via silica gel chromatography using 7/3 hexanes/EtOAc to obtain 4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride as a yellow solid (1.0 g, 72%). 1H NMR (400 MHz, CDCl3) δ 7.93-7.89 (m, 2H), 6.96-6.92 (m, 2H), 3.88 (t, J=5.3 Hz, 2H), 3.83 (t, J=5.1 Hz, 2H), 3.55-3.52 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[O:7][CH2:13][C:9](=[O:10])[N:8]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C=NC(=O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Product: O=C1COC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.4 %

Procedure:
To a solution of 4-fluorobenzoyl isocyanate (1.2 g, 7.2 mmol) in DCM (25 mL) was added (trimethylsilyl)diazomethane (2.0 M in hexane, 4.3 mL, 8.6 mmol) at 0° C. The reaction mixture was stirred for 45 min at rt. The mixture was diluted with water and the separated aqueous phase was extracted with DCM (3×). The combined organic layers were dried over (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 100:0-80:20 DCM-methanol) to afford 870 mg of 2-(4-fluorophenyl)oxazol-4(5H)-one: LCMS (m/z): 180.0 (MH+), tR=0.39 min
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15]>CO>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:15]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CO
Product: COC(=O)c1ccc(CN(C)C)cc1
Reaction time: 0.42 h
Yield: 99 %

Procedure:
Methyl 4-(bromomethyl)benzoate (2.0 g, 8.73 mmol) was added to a saturated solution of dimethylamine in methanol. After stirring for 25 min, the solution was concentrated and the residue was partitioned between 1N NaOH and ethyl acetate. The organic layer was washed with saturated brine, dired (MgSO4), filtered, and concentrated to provide the title compound as a colorless liquid (1.67 g, 99%). 1H NMR (250 MHz, CDCl3) δ8.00 (d, 2H), 7.39 (d, 2H), 3.91 (s, 3H), 3.47 (d, 2H), 2.25 (s, 6H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22](COC(CCCCCCC/C=C\CCCCCCCC)=O)OC(CCCCCCC/C=C\CCCCCCCC)=O)=[O:19]>C(O)C>[C:18]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCCCCCC/C=C\CCCCCCCC
Solvent: CCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC
Temperature: 80 °C

Procedure:
A mixture of ethanol and oleic acid triglyceride (ethanol: 0.1 mol, oleic acid triglyceride: 0.01 mol) was added with 0.2 g of the sulfonate-group-introduced amorphous carbon synthesized in Example 1, and the resulting mixture was maintained at 80° C. for 12 hours to produce ethyl oleate. The amount of ethyl oleate produced was quantified on a gas chromatography-mass spectrometer. The yield of ethyl oleate was 30%, and the rate of production of ethyl oleate was 10 to 100 times greater than that achieved using the same weight of each of already-existing solid strong acids (hydrated niobic acid, a polymeric solid acid “Nafion”, and a polymeric solid acid “Amberlyst-15”) as a catalyst.