Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:13]([NH2:15])=[O:14])[CH2:5][CH2:4][CH2:3]1.C(O)C.[BH4-].[Na+]>O>[OH:1][C@H:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C@H:6]([NH:12][C:13]([NH2:15])=[O:14])[CH2:5][CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)N[C@@H]1CCC[C@@H](O)c2sccc21
Reaction time: 5.5 h

Procedure:
A sample of 1.72 g. of 5,6,7,8-tetrahydro-8-oxo-4H-cyclohepta[b]thien-4-ylurea is stirred in 120 ml. of absolute ethanol and 0.5 g. of sodium borohydride is added. After 5.5 hours, 50 ml. of water is added to the mixture and the mixture is evaporated to dryness in vacuo. Acetone is added to the residue and the mixture is evaporated to dryness. The residue is then extracted with 3×75 ml. portions of boiling acetone, the acetone solution being decanted each time. The combined acetone solutions are filtered and evaporated to dryness. The residue is then washed with diethyl ether and the insoluble solid (contains some gum) is crystallized from methanol/ethyl acetate to afford 0.148 g. of yellow solid. The mother liquor is evaporated to dryness and chromatographed on preparative thin-layer silica-gel chromatographic plates with 15 parts methanol/85 parts chloroform. A fraction melting at 171°-175° C. is then obtained after separation and recrystallization from methanol/ethyl acetate. This material analyzes acceptably (carbon, hydrogen and nitrogen) for the title compound and the infrared spectrum also supports the structure. A second fraction melting at 169°-172° C. is also obtained and its infrared spectrum is virtually identical with that of the above-mentioned fraction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3C(=O)C4=CC=CC=C4C3=O)[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2=CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(C2=CCN(CCCCN)CC2)cc1
Yield: 150.1 %

Procedure:
A solution of N-[4-{4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]phthalimide (0.98 g), hydrazine hydrate (0.17 g) in methanol (10 ml) was stirred under reflux for 4 hours. After evaporation of the solvent, the crude residue was mixed with chloroform and 1N sodium hydroxide. The chloroform layer was separated, dried over magnesium sulfate and evaporated to give an oil of 4-[4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl]butylamine (0.96 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[C:4]([C:17]([O:19]C)=[O:18])[CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[NH:31][C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=3)=[CH:33][CH:32]=2)=[C:4]([CH:3]=1)[C:17]([OH:19])=[O:18]
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(-c2ccncc2)cc1
Yield: 87.3 %

Procedure:
0.75 g (2.5 mmol) of (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid, 0.43 g (2.5 mmol) of 4-(pyridin-4-yl)aniline, 0.58 g (3.0 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.41 g (3.0 mmol) of 1-hydroxybenzotriazole were stirred in 5.3 mL of DMA for 2 hours. After completion of the reaction, the reaction solution was introduced into an aqueous sodium bicarbonate solution. The solid was separated by filtration, and washed with water to give 0.96 g of 5-chloro-2-([(2-oxo-2-([4-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].CO[C:21]1(OC)[CH2:25][CH2:24][CH2:23]O1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:21]=[CH:25][CH:24]=[CH:23]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N)cc21
Reactant: COC1(OC)CCCO1
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-n3cccc3)cc21

Procedure:
2.5 Grams of 6-fluoro-7-amino-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are suspended in 15 ml of acetic acid, and 1.32 gram of dimethoxytetrahydrofuran is added; the mixture is heated gradually until the solid dissolves, and is then allowed to cool. The precipitate formed is filtered off and washed with ethanol. The product is recrystallized in acetonitrile, and 1.4 gram of needles is obtained, of melting point 251°-252° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][O:30][CH3:31])[S:8][C:7]=2[CH:32]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.CCOC(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][O:30][CH3:31])[S:8][C:7]=2[CH:32]=1
Reactant: COCc1ccccc1-c1sc2cc(OC)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCc1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Yield: 6.3 %

Procedure:
To a solution of (E)-3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (45.9 mg, 0.103 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was added thiophenol (0.016 mL, 0.154 mmol) and K2CO3 (14.21 mg, 0.103 mmol). The resulting mixture was subjected to microwave irradiation at 200° C. for 90 min after which time the reaction was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo and the crude material was purified by was purified by reverse phase HPLC (basic condition, 0.1% NH4OH in CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (3.0 mg, 0.00645 mmol, 6% yield). 1H NMR (400 MHz, CD3OD) δ ppm=7.47 (d, J=7.7 Hz, 1H), 7.40-7.31 (m, 4H), 7.31-7.21 (m, 4H), 6.86 (dd, J=8.7, 2.1 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.35 (d, J=15.9 Hz, 1H), 4.53 (s, 2H), 3.29 (s, 3H). HRMS (m/z. M+H2O): 450.1355.
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:18][N:17]=1.[I:29]I>C1COCC1>[I:29][C:20]1[C:19]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:18][N:17]=[C:16]([O:15][CH3:14])[CH:21]=1
Reactant: II
Reactant: COc1ccc(OC2CCCCO2)cn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(I)c(OC2CCCCO2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., 13.6 ml (90.1 mmol, 1.2 eq.) of 1,2-bis(dimethylamino)ethane and 54.0 ml (86.4 mmol, 1.15 eq.) of n-butyllithium were added to a solution of 16.2 g (75.1 mmol) of 2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine in 250 ml of THF, and the mixture was stirred at −78° C. for 1 h. 24.8 g (97.6 mmol, 1.3 eq.) of iodine were then added, and the reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to RT overnight. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium thiosulphate solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 25.1 g (purity 82%, 82% of theory)
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.[CH3:8][C:9]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C=O)C>[Si:12]([O:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)([C:9]([CH3:11])([CH3:10])[CH3:8])([CH3:14])[CH3:13]
Reactant: O=C1C[C@@H](O)CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a suspension of (R)-4-hydroxypyrrolidin-2-one (purchased from Asta Tech or Aldrich) (5.030 g, 48.26 mmol) in DMF (24 mL) at 0° C. was added TBDMS-Cl (7.637 g, 50.67 mmol) followed by imidazole (4.978 g, 72.39 mmol). The resulting mixture was warmed to ambient temperature and stirred for 1 hour, then poured into 100 mL of water with stirring. The resulting suspension was filtered and the solids were washed with water and dried under reduced pressure to afford (R)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one (10.14 g, 97.56% yield) that was used directly without further purification.
Reaction SMILES: [C:1]([CH:3]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>[Ni].C(OCC)(=O)C>[C:25]([NH:2][CH2:1][CH:3]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:27])[CH3:26]
Reactant: CCOC(=O)C(C#N)c1cn(C(=O)OCC)c2ccc(OC)cc12
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CNC(C)=O)c1cn(C(=O)OCC)c2ccc(OC)cc12
Reaction time: 20 h

Procedure:
A solution of Compound 1A, prepared above, (7.4 g, 0.022 mole) in 150 ml of acetic anhydride was hydrogenated for 20 hours at 50 psi, using about 10 g of Raney nickel as a catalyst. The catalyst was then removed by filtration, and the solvent was evaporated in vacuo to leave a thick syrup. This syrup was dissolved in 200 ml of ethyl acetate which was then washed five times with 6% aqueous potassium carbonate solution and dried over MgSO4. The solvent was then evaporated in vacuo, and the syrup which remained was crystallized from ethyl acetate:petroleum ether. One recrystallization from the same solvent pair yielded 4.6 g (56% theory) of product, mp. 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1COCC1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1Cl
Reactant: Fc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)cn2)c(Cl)cc1Cl
Yield: 67 %

Procedure:
To the solution of methyl 2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in anhydrous THF (Preparation 45, 10 mL, 1.61 g, 4.88 mmol) was added 2-bromo-5-fluoropyridine (856 mg, 4.88 mmol), sodium carbonate (1.55 g, 14.59 mmol) and water (2 mL). The reaction was degassed with nitrogen for 15 minutes followed by the addition of Pd(PPh3)4 (280 mg, 0.244 mmol) with further degassing for 5 minutes. The reaction was heated to reflux under a nitrogen atmosphere for 2 hours. The reaction was concentrated in vacuo and the residue partitioned between EtOAc (35 mL) and water (35 mL). The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-20% EtOAc in heptanes to afford the title compound as a white solid (1 g, 67%).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH:35]([CH3:37])[CH3:36])[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH:35]([CH3:37])[CH3:36])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1oc(-c2ccccc2OC(C)C)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3OC(C)C)oc2C)c1)C(=O)O
Yield: 60 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(2-isopropoxy-phenyl)-5-methyl-oxazole, the title compound was obtained in 60% yield as a brown oil. MS: (M+H)+ 463.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH3:17])[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH3:17])[C:5]([OH:7])=[O:6])(=[O:26])[CH3:25]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C(=O)O)ccc1N1CCCCC1C
Temperature: 40 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a suspension of 3-amino-4-(2-methylpiperidin-1-yl)benzoic acid obtained in step 2 (100 mg; 0.43 mmol) in pyridine (69.04 μL, 0.85 mmol) and DCM (4 mL), was added acetyl chloride (36.42 μL; 0.51 mmol). The reaction mixture was then stirred at 40° C. for 5 h after which solvents were evaporated under vacuum, solid residue was triturated with ethylacetate and re-evaporated. Finally, water was added to the reaction mixture which was sonicated, filtered, dried under vacuum to give the title compound as a white solid (95 mg, 81%). 1H NMR (DMSO-d6, 300 MHz) δ 12.76 (bs, 1H), 8.97 (s, 1H), 8.66 (s, 1H), 7.64 (dd, J=8.2, 2.1 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.07-3.01 (m, 1H), 2.86-2.82 (m, 1H), 2.57-2.51 (m, 1H), 2.15 (s, 3H), 1.82-1.77 (m, 4H), 1.47-1.42 (m, 2H), 0.78 (d, J=6 Hz, 3H). LC/MS (Method B): 277.2 (M+H)+. HPLC (Method A) Rt 1.77 min (purity: 91.3%).
Reaction SMILES: [OH-].[Na+].N[C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([C:13]([OH:15])=[O:14])=[C:6]([C:16]([OH:18])=[O:17])[CH:5]=1.C(Cl)(=O)C(C)=C.Cl(O)(=O)=O>O>[C:6]1([C:16]([OH:18])=[O:17])[CH:5]=[CH:4][CH:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]=1[C:13]([OH:15])=[O:14]
Reactant: Nc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1
Agent: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [O-][Cl+2]([O-])O
Solvent: O
Product: O=C(O)c1cccc(C(=O)O)c1C(=O)O
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
A 2 litter flask equipped with a magnetic stirrer, a thermometer, and 250 ml dripping funnel were filled with 1 litter of water and 71 g of sodium hydroxide pellet. When this was dissolved, 100 g of 1-aminobenzene-3,4,5-tricarboxylic acid was added and dissolved. After neutralization heat ceased, the reaction result was cooled down to 10° C. The dripping funnel was filled with 40.23 g of methacryloyl chloride. While this was maintained below 15° C., the liquid was dripped to the reaction container in 15 minutes. 40 g of sodium hydroxide was dissolved in 150 g of water in another container. This solution was added to the reaction mixture 20 minutes after the addition of methacryloyl chloride was complete. After the reaction product was cooled down to 10° C., 40 g of methacryloyl chloride was dripped from the dripping funnel in 15 minutes while the temperature was maintained below 15° C. 20 minutes after the dripping was complete, the reaction mixture was acidized to pH 3 by strong chloric acid. The thus-produced solid portion was extracted by vacuum filtration followed by washing with ethanol and dried at 60° C. for 14 hours in a vacuum oven.
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34](O)=[O:35])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34]([NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:35])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCc1ccccc1)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 67 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-phenylethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-phenethylisonicotinamide was obtained as a colorless solid in 67% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.90-8.86 (m, 1H), 8.55-8.50 (m, 2H), 8.06-8.03 (m, 2H), 7.64-7.47 (m, 4H), 7.34-7.18 (m, 5H), 3.54-3.48 (m, 2H), 2.87 (t, J=7.4 Hz, 2H); MS (ES+) m/z 346.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH2:9][CH2:8]2.[CH3:15][O:16]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[N:11]([CH3:13])[C:10](=[O:14])[CH2:9][CH2:8][C:7]=2[C:6]([CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1N(C)C(=O)CC2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
8-Methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (1.5 g) was dissolved in dichloromethane (15 ml), and dichloromethyl methyl ether (0.86 ml) was added at room temperature, followed by cooling with ice water. Titanium tetrachloride (10.5 ml) was added dropwise, and the resulting mixture was stirred at room temperature overnight. Further, dichloromethyl methyl ether (1.29 ml) and titanium tetrachloride (15.8 ml) were added, and stirring was carried out at room temperature for 5 hours. The reaction mixture was poured into ice water, and the aqueous layer was subjected to extraction with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Hexane was added to the residue, and the produced insoluble matter was collected by filtration and dried to thereby obtain 1.37 g (yield: 80%) of 8-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde.
Reaction SMILES: [N+](C1C=CC=CC=1N=NC1C=C(C)C=CC=1O)([O-])=[O:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[N:30]=[N:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:33]=1O)([O-])=O>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]2=[N:20][N:31]([C:32]3[CH:37]=[C:36]([C:38]([CH3:40])([CH3:39])[CH3:41])[CH:35]=[C:34]([C:42]([CH3:45])([CH3:43])[CH3:44])[C:33]=3[OH:2])[N:30]=[C:24]2[CH:25]=1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Reactant: CC(C)(C)c1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
When in Example 1, the 2-nitro-2'-hydroxy-5'-methylazobenzene is replaced by an equivalent amount of 2-nitro-5-chloro-2'-hydroxy-3',5'-di-tert-butylazobenzene, the above noted product is obtained.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([NH:20][S:2]([C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (1.0 g, 4.02 mmol) in N,N-dimethylacetamide (5 mL) was added 3-fluoroaniline (1.79 g, 16.08 mmol) dropwise over 30 seconds at room temperature. The mixture was stirred at room temperature for 4 hours, and then it was diluted with ethyl acetate (33 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (8 mL) was added, and the mixture concentrated to give ethyl 3-{[(3-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.O[CH2:12][NH:13][C:14](=[O:18])[CH:15]([Cl:17])[Cl:16]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:18])[CH:15]([Cl:17])[Cl:16]
Reactant: O=C(NCO)C(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Cl)c(CNC(=O)C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.4 %

Procedure:
The title compound was prepared by modification of procedures previously reported in the literature (Felder et al (1965) Helv. Chim. Acta, 48: 259). To a solution of 4-chlorobenzoic acid (15.7 g, 100 mmol) in 150 ml of concentrated sulfuric acid was added N-hydroxymethyl dichloroacetamide (23.7 g, 150 mmol) in portions. The reaction mixture was stirred at room temperature for 2 days, poured onto 375 g of ice, stirred for 1 hour, the solid was collected by filtration, and washed with H2O. The moist solid was dissolved in 5% sodium bicarbonate solution, filtered, and acidified to pH 1 with concentrated HCl. The solid was collected by filtration, washed with H2O, and air-dryed overnight to give 4-chloro-3-dichloroacetylaminomethylbenzoic acid (26.2 g, 89%) as a white powder.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCOCC1.O>[CH2:21]([O:20][C:18]([NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCOc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Sodium hydroxide (222 mg) was added to a solution of 2-[4-(2-aminoethoxy)-phenyl]acetic acid (394 mg) (see DE-A-2250400) in 1,4-dioxane: water (1:1, by volume) (20 ml) at 0° C. The reaction mixture was stirred for 20 minutes then benzyl chloroformate (319 mg) was added to the mixture and the solution was stirred for 4 hours. Additional benzyl chloroformate (70 mg) was added to the reaction mixture and it was stirred for a further 1 hour. The solvent was removed under reduced pressure. The resulting solid was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and the product was extracted with ethyl acetate. The organic solution was dried over magnesium sulphate and the solvent removed under reduced pressure to afford 2-[4-(2-[benzyloxycarbonylamino]ethoxy)phenyl]acetic acid (375 mg) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: Nc1ccccc1O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccccc2O)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromo-4-methylbenzoic acid (1.0 g, 4.7 mmol) and thionyl chloride (18 mL) was refluxed for 1 h and then cooled to rt. The excess thionyl chloride was removed in vacuo, the residue was dissolved in THF (10 mL), and was added to a cooled (0° C.) mixture of 2-aminophenol (510 mg, 4.7 mmol) and diisopropylethylamine (0.90 mL, 5.1 mmol) in THF (18 mL). The resulting mixture was stirred at rt for 4 h. The solvent was then removed and the residue was purified by flash chromatography on silica gel eluting with EtOAc:hexane (1:5 to 1:4) to afford 3-bromo-N-(2-hydroxyphenyl)-4-methylbenzamide.