Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([OH:11])=[C:8]([C:12]([OH:14])=O)[C:7](=[O:15])[N:6]([CH3:16])[C:5]=2[S:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][NH:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33].S(Cl)(Cl)=O>ClCCl.C(Cl)(Cl)Cl>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[N:25]([CH3:24])[C:12]([C:8]1[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:10]=2[C:9]=1[OH:11])=[O:14]
Reactant: Cc1csc2c1c(O)c(C(=O)O)c(=O)n2C
Reactant: CNc1cc(F)ccc1F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1csc2c1c(O)c(C(=O)N(C)c1cc(F)ccc1F)c(=O)n2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To 6,7-dihydro-3,7-dimethyl-4-hydroxy-6-oxo-thieno[2,3-b]pyridine-5-carboxylic acid (4.18. mmol, 1.0 g) in dichloromethane (10 ml), triethylamine (4 equiv., 16.7 mmol, 2.4 ml) and N-methyl-2,5-difluoroaniline (1.2 equiv., 5.0 mmol, 720 mg) were added. To the mixture stirred under nitrogen and cooled to 0° C., a solution of thionyl chloride (1.3 equiv., 5.4 mmol, 0.4 ml) in dichloromethane (5 ml) then was added during 30 min. The stirring was continued at 0° C. for 1 h and then at room temperature for another 20 min. The reaction mixture was diluted with chloroform and quickly washed with cold 1M sulphuric acid. The organic phase then was immediately extracted with 0.5 M NaOH. Remaining traces of chlorinated organic solvents were removed using a rotary evaporator. The pH was adjusted to just above the point where the desired product starts to precipitate (approximately pH 6.5) and the solution was filtered through celite. The product was precipitated by acidification with 1 M HCl until pH was approximately 1-2 and the mixture was allowed to stand for 2 hrs. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (1.26 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([C@@H:58]([NH2:60])[CH3:59])=[N:57][C:53]=2[CH:52]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([C@@H:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([C:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:59])=[N:57][C:53]=2[CH:52]=1
Reactant: COc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 29 %

Procedure:
Prepared analogously to Example 1g from 3-methoxy-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 29%; Rf value: 0.31 (silica gel; dichloromethane/ethanol=9:1); C22H23ClN4O3 (426.90); mass spectrum: (M+H)+=427/429 (chlorine isotope).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:23]1[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Brc1cccc2ccccc12
Reactant: Nc1ccccc1-c1ccccc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2Nc2cccc3ccccc23)cc1
Temperature: 110 °C
Yield: 65 %

Procedure:
Trisdibenzylideneacetonedipalladium (0.276 g, 0.3 mmol) and tri-tert-butylphosphine (0.121 g, 0.6 mmol) were put into a flask, and then dissolved in 40 mL of toluene. Subsequently, 2-biphenylamine (2.53 g, 15 mmol), 1-bromonaphthalene (3.11 g, 15 mol) and tert-butoxy sodium (2.16 g, 22.5 mmol) were added into the flask, and then refluxed at a temperature of 110° C. for 12 hours. After the flask including the reactant mixture was cooled to room temperature, the reactant mixture was washed using an ammonium chloride aqueous solution (150 mL) to separate an organic layer. The separated organic layer was washed with distilled water three times, and was then dried with magnesium sulfate. Thereafter, residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and ethylacetate (1:10), and were then recrystallized in normal hexane to produce 2.88 g of N-(biphenyl-2-yl)naphthalene-1-amine.
Reaction SMILES: F[C:2]1[C:3]([CH3:19])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:5]([O:7][CH3:8])=[O:6].CN(C=O)C.[CH3:25][S-:26].[Na+]>C(OCC)(=O)C>[CH3:19][C:3]1[C:2]([S:26][CH3:25])=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(SC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
2.1 g (7.34 mmol) of methyl 3-fluoro-2-methyl-4-(pentafluoroethyl)benzoate were introduced into 20 ml of DMF and then admixed with 758 mg (95% by weight; 10.3 mmol) of sodium thiomethoxide. The mixture was stirred at RT for 2 hours and then freed from the solvent. The residue was taken up in ethyl acetate and water, the aqueous phase was extracted twice with ethyl acetate, and, finally, the combined organic phases were dried and freed from the solvent. The residue was purified by chromatography, giving 1.28 g of clean product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:16][NH:17][CH3:18]>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([N:17]([CH3:18])[CH3:16])(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNC
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of (4-methanesulfonyl-phenyl)-methanesulfonyl chloride from Step 2 (1.0 g, 3.7 mmol) in CH2Cl2 (40 mL) was added dimethylamine (0.42 g, 9.3 mmol) dropwise. After 18 h, the resulting reaction mixture was diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (HCl 10%, NaHCO3, brine), dried (MgSO4), filtered, and concentrated to provided the C-(4-methanesulfonyl-phenyl)-N,N-dimethyl-methanesulfonamide compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.Cl[CH2:6][CH2:7][CH:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][C:19]([CH3:21])=[N:20][C:10]=2[O:9]1.[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)(C)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:1][N:2]([CH3:3])[CH2:6][CH2:7][CH:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][C:19]([CH3:21])=[N:20][C:10]=2[O:9]1
Reactant: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=O
Reactant: CNC
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc2c(n1)OC(CCN(C)C)CN(C)C2=O
Reaction time: 72 h

Procedure:
To 50 ml of freshly collected dimethylamine was added 5.0 g (0.020 mole) of 2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one hydrate [1:1]. The reaction flask was sealed tightly and left standing at room temperature for 3 days. The dimethylamine was evaporated in a stream of air. The residue was taken up in methylene chloride, washed twice with 1N sodium hydroxide and once with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The syrupy residue was treated with 2 equivalents of fumaric acid in isopropyl alcohol which yield 5.2 g (52%) of white crystals, m.p. 164°-165° C.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:38]1[C:43]([OH:54])([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)[CH2:42][CH2:41][NH:40][CH2:39]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:53][C:50]([F:51])([F:52])[C:46]1[CH:45]=[C:44]([C:43]2([OH:54])[CH2:42][CH2:41][N:40]([C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:2])([F:25])[F:24])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:23][CH:22]=3)[CH2:39][CH2:38]2)[CH:49]=[CH:48][CH:47]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: O=C(O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 1.0 mmol of 4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoic acid hydrochloride in dry dimethylformamide is stirred in a nitrogen atmosphere at 20°-25° C.; 1.1 mmol of carbonyl diimidazole is added and the mixture stirred further for 1 hour. 4-Hydroxy-4-[(3-trifluoromethyl)phenyl]piperidine (1.1 mmol) is then added and the reaction mixture is stirred for 20 hours, then poured into aqueous sodium bicarbonate and is extracted with methylene chloride. The organic extract is dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate is crystallized and recrystallized from methylene chloride to give 86% yield of 4-[3-(trifluoromethyl)phenyl]-4-hydroxy-1-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperidine of m.p. 278°-279° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:13]=1[F:12])=[O:6]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1c(I)ccnc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1F)c1c(I)ccnc1Cl
Reaction time: 63 h
Yield: 54.5 %

Procedure:
To a homogeneous mixture of 2-chloro-4-iodonicotinic acid (CB Research & Development, Inc., 0.58 g, 2.0 mmol) and 2,4-difluoroaniline (Aldrich, 0.21 mL, 2.0 mmol) in anhydrous DMF (7 mL) was added PyBroP (Novabiochem, 1.4 g, 3.1 mmol) followed by DIPEA (1.1 mL, 6.6 mmol). The mixture was stirred for 63 hours, and then partitioned between chloroform and 10% LiCl (aq). After the aqueous layer was extracted with chloroform, the combined organic layers were washed twice with 10% LiCl (aq), dried over anhydrous MgSO4, and then concentrated in vacuo. Purification of the residue by flash column chromatography (SiO2, eluting with 1:1 hexane/EtOAc) afforded the desired compound (0.43 g, 53%). MS(ESI+) m/z 395 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:12][CH2:13][CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:18])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCS(=O)(=O)c1nc[nH]n1
Reactant: CCCCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCN(CCC)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
A mixture of 4.83 g. 3-ethylsulphonyl-1,2,4-triazole, 6.0 g. N-n-pentyl-N-propylcarbamoyl chloride, 40 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The cooled reaction mixture was filtered. The filtrate was distilled under reduced pressure to give 1-(N-n-pentyl-N-propylcarbamoyl)-3-ethylsulphonyl-1,2,4-triazole as a residual oil, nD25 1.4967. (96.5% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13]Br)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(COc1ccc(F)cc1)OCC
Temperature: 120 °C
Reaction time: 48 h

Procedure:
To a solution of 10.0 g of 4-fluorophenol and 16.1 ml of bromoacetaldehyde diethylacetal in 100 ml dimethylformaldehyde was added 18.5 g of potassium carbonate at room temperature, and the mixture was stirred at 120° C. for two days. The reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=0:10 to 1:20), to give 17.3 g of the title compound as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([N:17]([CH2:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][C:29]=2[O:30][CH3:31])[N:26]=[CH:25][N:24]=[C:23]3[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])[CH3:18])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([NH:32][C:23]2[C:22]3[C:27](=[CH:28][C:29]([O:30][CH3:31])=[C:20]([CH2:19][N:17]([CH3:18])[C:11]4([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:21]=3)[N:26]=[CH:25][N:24]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCNCC1

Procedure:
1-(tert-butoxycarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxylic acid (prepared as described in Example 16) was deprotected by treating the compound with hydrogen chloride in dioxane using an analogous method to that described for the equivalent step in Example 7 to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxylic acid; 1H NMR Spectrum: (DMSO-d6+CD3COOD) 2.06 (m, 2H); 2.15 (m, 2H); 2.26 (s, 3H); 3.04 (m, 2H); 3.27 (m, 2H); 3.75 (s, 2H); 3.96 (s, 3H); 7.21 (s, 1H); 7.28 (m, 1H); 7.48 (m, 1H); 7.54 (m, 1H); 8.32 (s, 1H); 8.42 (S, 1H). Mass Spectrum: (M+H)+ 474.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:29][NH:30][OH:31].Cl>CN(C)C=O.ClCCl.CC(C)=O.C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([N:30]([CH3:29])[OH:31])=[O:8]
Reactant: CNO
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COc1ccc(OC)c(C=CC(=O)N(C)O)c1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 40.5 %

Procedure:
A solution of 2,5-dimethoxycinnamic acid (2.08 g, 10 mmol), oxalyl chloride (0.96 ml, 11 mmol) and N,N-dimethylformamide (two drops) in 25 ml dichloromethane was stirred for 20 minutes. The resulting solution was evaporated to leave a yellow solid, which was then dissolved in 10 ml of acetone. This solution was added slowly to a stirred mixture of water (20 ml), sodium carbonate (2.5 g, 24 mmol), and N-methylhydroxylamine hydrochloride (1.06 g, 12.7 mmol), cooled to 5° C. The resulting mixture was stirred for 20 minutes, then poured into excess 1M hydrochloric acid and extracted twice with ethyl acetate. The extracts were washed wth water and 1N NaHCO3, dried over MgSO4, and evaporated to leave an orange oil. Chromatography on silica gel with 7:3 ethyl acetate-hexane provided 0.96 g (40% yield) of the named compound, mp 111°-112° C., after recrystallization from hexane-1,2-dichloroethane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].Cl>O>[CH:3]1[C:2]([NH:1][NH2:12])=[CH:7][CH:6]=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:4]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
4-Aminobenzenesulfonamide (52 g, 0.3 mol) was dissolved in 200 ml H2O containing 30 ml 30% NaOH and added to 75 ml 4N NaNO2. The resulting solution was poured over 100 g crushed ice containing 100 ml 30% HCl at a rate needed to maintain a reaction temperature of 5° C. The diazotization step was carried out for 40 min and the resultant diazonium salt was then added slowly to a stirred solution of 99.95 g Na2 SO3 in 250 ml water at 10° C., and the reaction was continued for 1 h. At this point, the reaction temperature was raised to 70° C. and 300 ml 30% HCl was added over 30 min. The precipitated product was stirred overnight, collected by filtration, washed with cold water and dried. The phenylhydrazine-4-sulfonamide obtained (47 g) was dissolved in 600 ml H2O containing 40 ml 30% NaOH, and to this solution 27.5 g (0.26 mol) of benzaldehyde was added at 50°-55° C. After stirring for 1 h, the temperature was reduced to 30° C. and 24 ml 30% HCl was added. The precipitated product was collected by filtration, washed with cold water and dried, to give 47.2 g of benzaldehyde phenylhydrazone-4-sulfonamide (m.p. 199° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[CH3:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([CH3:48])=[C:26]([NH:25][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=5)=[O:9])[CH:27]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C(F)(F)F)nn1C
Yield: 77.5 %

Procedure:
In the same manner as in Example 259 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (160 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (240 mg, 76%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][C:46](=[O:48])[CH3:47])=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[O:45][C:46](=[O:48])[CH3:47])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
3-Aminopyridine (0.424 g, 4.492 mmol), triethylamine (0.440 g, 4.342 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.735 g, 4.342 mmol) were added to a methylene chloride solution (200 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (1.120 g, 2.995 mmol) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.710 g, 1.576 mmol, 53%).
Reaction SMILES: CN1C=CC(C(O)=O)=C1.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11]1.[CH:22]1([N:26]2[CH2:31][CH2:30][CH:29]([O:32][C:33]3[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)[CH2:25]C[CH2:23]1.IC1C=CC(OC2CCN(C(C)C)CC2)=CC=1>>[CH:22]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N:10]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])=[CH:11]3)=[CH:37][CH:38]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:23]
Reactant: O=C(c1cc[nH]c1)N1CCCC1
Reactant: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: CC(C)N1CCC(Oc2ccc(I)cc2)CC1
Agent: Cn1ccc(C(=O)O)c1
Product: CC(C)N1CCC(Oc2ccc(-n3ccc(C(=O)N4CCCC4)c3)cc2)CC1

Procedure:
The titled compound was prepared as a colorless amorphous substance by repeating the procedure of Example 1, except that the methyl 1H-pyrrole-3-carboxylic acid was replaced by (1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanone and the 1-cyclobutyl-4-(4-iodophenoxy)piperidine by 4-(4-iodophenoxy)-1-isopropylpiperidine (which can be synthesized in accordance with the method described in WO2004089373).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>CC(=O)CC>[CH2:2]([C:3]1([CH3:4])[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[O:1]1)[CH3:10]
Reactant: NC(=O)c1ccccc1O
Solvent: CCC(C)=O
Product: CCC1(C)NC(=O)c2ccccc2O1

Procedure:
2-Hydroxybenzamide was transformed by Method G (using 2-butanone). M.p. 76–78° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](OCC)=[O:17].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][OH:17]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
14 grams (50 mmol) of ethyl 4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylate was suspended in 400 ml THF, and 9.5 grams (250 mmol) lithium aluminum hydride were added slowly. The mixture was stirred at room temperature for 12 hours, cooled, 250 ml water were added and the resulting mixture was stirred overnight. The solvent was thereafter evaporated, and water (300 ml) was again added. The aqueous suspension was extracted with dichloromethane. The organic extract was evaporated, and the remaining residue was purified by column chromatography on silica gel, using a 9:1 mixture of ethylacetate and methanol as eluent, to yield 4-hydroxy-7-trifluoromethyl-3-(hydroxymethyl)-quinoline (12 grams, 82% yield).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>O>[N+:18]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:11])[CH:3]=[CH:2][C:1]2=[O:12])([O-:20])=[O:19]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
The same procedure as in Example 1 was repeated except that 10.0 g of 1,4-naphthoquinone was added to 200 g of a mixed acid consisting of 83 percent by weight of sulfuric acid, 4 percent by weight of nitric acid and 13 percent by weight of water with maintaining a temperature of 5° to 10°C, to obtain 8.9 g of brown-colored crude 5-nitro-1,4-naphthoquinone of a melting point of 140°C. The D.V.S. of the reaction mixture after reaction was 6.1. The crude product was purified to obtain the similar results with Example 1.