Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])(=O)=O.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][C:23]=1O.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C=O)C>[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:30][CH3:31])[C:22]=1[O:21][CH3:20])[CH:26]=[O:27])=[N+:18]=[N-:19]
Reactant: COc1cc(C=O)cc(O)c1OC
Reactant: CS(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Temperature: 50 °C
Yield: 68.1 %

Procedure:
A mixture of 5.22 g (17.55 mmol) 2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethyl methanesulfonate 7, 3.20 g (17.55 mmol) 3,4-dimethoxy-5-hydroxybenzaldehyde 1 and 11.5 g (35.20 mmol) caesium carbonate in 120 ml DMF was heated at 50° C. for 17 hrs. The mixture was poured into 100 ml saturated aqueous ammonium chloride solution and extracted with methylene chloride. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (toluene/ethyl acetate 1/1), yielding 4.58 g (11.95 mmol, 68%) of the product as a clear yellow oil. 1H-NMR (CDCl3) δ=9.77 (s, 1H), 7.09 (d, 1H, J=2.2 Hz), 7.06 (d, 1H, J=2.2 Hz), 4.17 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.83 (m, 2H), 3.66 (m, 2H), 3.60 (m, 8H), 3.30 (t, 2H, J=5.4 Hz) ppm. 13C-NMR δ=190.7, 153.6, 152.7, 144.2, 131.5, 109.0, 106.4, 70.7, 70.6, 70.5 (2 signals), 69.8, 69.5, 68.8, 60.8, 56.1, 50.5 ppm. MS: m/z=383 [M]+. Anal. calcd for C17H25N3O7: C, 53.26, H, 6.57, N, 10.96. Found C, 53.15, H, 6.66, N, 10.99.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:19]([CH2:18][O:17][CH3:16])=[N:15][N:14]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: NNc1ccc(-c2cccc(F)c2)nn1
Product: COCc1nnc2ccc(-c3cccc(F)c3)nn12

Procedure:
As for Example 4, 6-(3-fluorophenyl)-3-hydrazinopyridazine (prepared in a manner similar to that described in Example 1) is reacted with methoxyacetyl chloride to give the product of the Example.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.BrC(C1C=CC=CC=1)C(OCC)=O.[CH2:26]([NH2:29])[CH2:27][NH2:28].[O-]CC.[Na+].C(Cl)(Cl)Cl.CO.[NH4+].[OH-]>C(O)C.CCOCC>[O:5]=[C:3]1[CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:29][CH2:26][CH2:27][NH:28]1
Reactant: NCCN
Reactant: O=C(O)C(Br)c1ccccc1
Agent: CCOC(=O)C(Br)c1ccccc1
Agent: CC[O-]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1NCCNC1c1ccccc1
Yield: 62 %

Procedure:
To a solution of α-bromophenylacetic acid (2.15 g, 10 mmol) in ethanol (30 mL) was added 1M HCl in ether (5 mL) and the solution was heated under reflux overnight. The reaction mixture was concentrated to a brown oil (ethyl α-bromophenylacetate), which was used without further purification. A solution of crude ethyl α-bromophenylacetate (2.43 g, 10 mmol) in ethanol (20 mL) was added dropwise to a stirred solution of ethylenediamine (1.2 g, 20 mmol) in 30 mL of ethanol. After the addition was completed, a solution of sodium ethoxide (8.5 mL, 20 mmol, 21 wt. % solution in ethyl alcohol) was added and the reaction was heated under reflux 16 h. The excess ethylenediamine and ethanol were removed under reduced pressure. The residue was extracted with ethyl acetate (200 mL×3), washed with saturated NaCl solution (30 mL×2), dried over MgSO4 and filtered. The crude yellow solid obtained by rotary evaporation of ethyl acetate was purified by silica gel column chromatography. The white solid (1.1 g, 6.2 mmol, 62%) was obtained by elution with CHCl3:MeOH:NH4OH (9:1:0.1). 1H NMR (DMSO-d6): δ 2.75-2.95 (2H, m), 2.95 (1H, br s), 3.10-3.15 (1H, m), 3.21-3.25 (1H, m), 4.29 (1H, s), 7.20-7.37 (5H, m), 7.78 (1H, s). mp: 138°-140° (uncorr.) [lit.] mp: 139°-139.5° (corr.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C@H:9]1[CH2:12][C@H:11]([N:13]=[N+]=[N-])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H].N.CCOC(C)=O>CO.[Pd]>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C@H:9]1[CH2:10][C@H:11]([NH2:13])[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](N=[N+]=[N-])C1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H](N)C1
Yield: 100.5 %

Procedure:
To the mixture of tert-butyl(trans-3-azidocyclobutyl)methylcarbamate (1.8 g, 7.95 mmol) and Pd/C (200 mg) in MeOH (5 mL) under hydrogen atmosphere (hydrogen balloon) was added NH3(g)/MeOH (saturated, 50 mL) via syringe. The resulting mixture was stirred at rt for three hours until TLC analysis (EtOAc:petroleum ether=1:2) showed the reaction was complete. Pd/C was filtered off and the resulting solution was concentrated and dried in vacuum to afford crude title compound (1.6 g), which was used for the next steps without further purification.
Reaction SMILES: NN1CCCC1.S(=O)(=O)(O)O.O=[C:13]([CH3:29])[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)=[O:16]>O>[CH3:29][C:13]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=2)[NH:17][C:15](=[O:16])[CH:14]=1
Reactant: CC(=O)CC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: NN1CCCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(=O)[nH]c2ccc(OC(F)(F)F)cc12
Temperature: 95 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
4-(Trifluoromethoxy)aniline (10 mL) was added dropwise to ethyl acetoacetate (44 mL) at 160° C., and the mixture was stirred at the same temperature for 1 h. The mixture was left stand for cooling to room temperature and crystallized with hexane to obtain 3-oxo-N-(4-(trifluoromethoxy)phenyl)butane amide (6.5 g). (2) To concentrated sulfuric acid (32.5 mL) was added 3-oxo-N-(4-(trifluoromethoxy)phenyl)butane amide (6.5 g), and the mixture was stirred at 95° C. for 3 h. The reaction solution was added dropwise to water with ice cooling, and the precipitated crystals were collected by filtration. The resulting crystals were suspended in water, the suspension was made basic with aqueous ammonia, and the precipitated crystals were collected by filtration to obtain 4-methyl-6-(trifluoromethoxy)quinoline-2(1H)-one (1.87 g). (3) A mixture of 4-methyl-6-(trifluoromethoxy)quinoline-2(1H)-one (1.87 g) and phosphorus oxychloride (19 mL) was stirred at 105° C. for 2.5 h. The reaction solution was added dropwise to water with ice cooling, and the precipitated crystals were collected by filtration to obtain 2-chloro-4-methyl-6-trifluoromethoxyquinoline (1.98 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>O1CCCC1>[F:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([CH:11]2[C:10]([CH3:24])([CH3:25])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)ccc1C)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1Nc2ccc(C(=O)O)cc2CC1(C)C
Temperature: 60 °C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
A mixture of 2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.70 g, 2.05 mmol), lithium hydroxide hydrate (0.86 g, 20.5 mmol), water (3 mL) in tetrahydrofuran (30 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (260 mg, 40%) as a white solid: LC/MS m/e calcd for C19H20FNO2 (M+H)+: 314.4, observed: 314.3.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([NH:8][CH3:9])=[N:6][N:7]=1.[C:10]([Cl:13])(Cl)=[O:11]>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:4][C:5]([N:8]([CH3:9])[C:10]([Cl:13])=[O:11])=[N:6][N:7]=1
Reactant: O=C(Cl)Cl
Reactant: CNc1nnc(SC)s1
Solvent: c1ccccc1
Product: CSc1nnc(N(C)C(=O)Cl)s1

Procedure:
2-Methylthio-5-methylamino-1,3,4-thiadiazole (0.1 mole) and a solution of phosgene (0.11 mole) in benzene (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of benzene and unreacted phosgene to yield the desired product N-(2-methylthio-1,3,4-thiadiazol-5-yl)-N-methylcarbamoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCCOc1ccccc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4ccccc4)CC3)noc2c1
Yield: 47 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 18.2 mmol), K2CO3 (3.0 g, 21.8 mmol), KI (100 mg), 3-chloropropoxybenzene (3.4 g, 20.0 mm and acetonitrile was stirred at reflux under nitrogen for 30 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO4 and concentrated to afford 6.2 g of a damp, beige solid. The compound was recrystallized twice from ethanol to yield (47%) of 6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole as a light beige solid, m.p.=78-80° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:18]1CCO[CH:19]1[C:23]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:47])[N:28]2[CH2:35][C:36]1[CH:37]=[N:38][C:39]([C:42]2[CH:46]=[CH:45][S:44][CH:43]=2)=[CH:40][CH:41]=1>CC(C)=O.O>[CH3:34][O:33][C:30]1[C:29]2[N:28]([CH2:35][C:36]3[CH:37]=[N:38][C:39]([C:42]4[CH:46]=[CH:45][S:44][CH:43]=4)=[CH:40][CH:41]=3)[C:27](=[O:47])[CH2:26][CH2:25][C:24]=2[C:23]([CH:19]=[O:18])=[CH:32][CH:31]=1
Reactant: COc1ccc(C2OCCO2)c2c1N(Cc1ccc(-c3ccsc3)nc1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C=O)c2c1N(Cc1ccc(-c3ccsc3)nc1)C(=O)CC2
Yield: 111.6 %

Procedure:
Pyridinium p-toluenesulfonate (PPTS) (0.24 g) was added to a mixed solution of 5-(1,3-dioxolan-2-yl)-8-methoxy-1-(6-thiophen-3-ylpyridin-3-ylmethyl)-3,4-dihydro-1H-quinolin-2-one (0.4 g) in acetone (8 ml) and water (4 ml), followed by heating under reflux 1.5 hours. The resulting mixture was concentrated under reduced pressure, subjected to extraction with dichloromethane, washed with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtrated, and concentrated under reduced pressure to thereby obtain 0.4 g (yield: quantitative) of 8-methoxy-1-(6-thiophen-3-ylpyridin-3-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a light brown amorphous solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=[O:6])[CH3:5].O.C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(OCC)(=O)C>[C:20]([NH:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=[O:6])[CH3:5])(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(=O)Cl
Reactant: CC(=O)C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCC(=O)NC(C(C)=O)c1ccccc1

Procedure:
To a mixture of 1-amino-1-phenyl-2-propanone hydrochloride (5.55 g), water (40 ml), ethyl acetate (75 ml) and potassium carbonate (4.55 g) was added dropwise hexanoyl chloride (4.42 g) under ice-cooling and stirring. The mixture was further stirred for an hour with ice-cooling. The ethyl acetate layer was separated, washed with water, diluted hydrochloric acid and water in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was recrystallized from isopropyl ether to give crystals of 1-hexanoylamino-1-phenyl-2-propanone, yield 5.80 g (78.2%), m.p. 77°-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[N:11]([CH3:19])[C:10]=1[CH3:20].[CH3:21][O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH3:21][O:22][C:23](=[O:28])[C:24]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH3:20])=[C:9]2[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:26])[CH3:25]
Reactant: COc1ccccc1-c1c(C)n(C)c2ccc(O)cc12
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccc1OC)c(C)n2C

Procedure:
A mixture of 5.34 g (0.02 mole) of 3-(2-methoxy-phenyl)-1,2-dimethyl-1H-indole-5-ol, 5.4 g (0.03 mole) of 2-bromo-2-methyl-propanoic acid methylester, and 14 g (0.1 mole) of potassium carbonate was refluxed for 16 hours in 250 ml of methyl-ethylketone. The precipitate was filtered off, the filtrate was evaporated, and the residue obtained was chromatographed on silicagel (solvent: toluene/acetone (30:1)).
Reaction SMILES: [CH2:1]1[C:9]2[C:8](=O)[C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[O:5][C:4]=2[C:3](=[O:15])[O:2]1.[H][H]>C(O)(=O)C.[Pd].C(OCC)(=O)C>[CH2:1]1[C@H:9]2[C@H:4]([O:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[CH2:8]2)[C:3](=[O:15])[O:2]1
Reactant: [H][H]
Reactant: O=C1OCc2c1oc1ccccc1c2=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1OC[C@@H]2Cc3ccccc3O[C@H]12
Yield: 67.1 %

Procedure:
A suspension of 1H-furo[3,4-b][1]benzopyran-3,9-dione (6.1 g) in glacial acetic acid (300 ml) was hydrogenated over 10% palladium on charcoal (1 g) until hydrogen uptake ceased. The catalyst was filtered off and the solvent evaporated from the filtrate to give an oil. The oil was dissolved in ethyl acetate and the solution washed with aqueous sodium bicarbonate and brine. The organic layer was separated, dried (MgSO4) and the solvent evaporated. Crystallisation of the residue from ethyl acetate/ether gave the title compound (3.85 g) m.p. 107°-111°.
Reaction SMILES: COC1C=CC(CCC2C=CC(OC)=CC=2)=C(C=1)OC1C=CC(O)=CC=1.Cl.ClCCN1CCCCC1.C[O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69]C)=[CH:65][CH:64]=2)=[C:43]([CH:60]=1)[O:44][C:45]1[CH:59]=[CH:58][C:48]([O:49][CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)=[CH:47][CH:46]=1.Cl.N1C=CC=CC=1>O1CCCC1>[OH:69][C:66]1[CH:67]=[CH:68][C:63]([CH2:62][CH2:61][C:42]2[CH:41]=[CH:40][C:39]([OH:38])=[CH:60][C:43]=2[O:44][C:45]2[CH:59]=[CH:58][C:48]([O:49][CH2:50][CH2:51][N:52]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]3)=[CH:47][CH:46]=2)=[CH:64][CH:65]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Oc1ccc(CCc2ccc(O)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
Synthesized from 4-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenoxy}phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, to 1-{2-{4-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenoxy}phenoxy}ethyl}piperidine (344 mg) was added pyridine hydrochloride (1.2 g), and the solution was stirred for 3 hours and 10 minutes at 170° C. To the reaction solution were added tetrahydrofuran and an aqueous solution of 1N sodium hydroxide, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (111 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][NH:23]1.C1CCN2C(=NCCC2)CC1.CN(C=O)C>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][N:23]1[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[C:9]([NH2:17])[C:10]=1[F:16]
Reactant: c1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3ccccc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 54 %

Procedure:
A mixture of 200 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 87 mg of isoindoline, 200 mg of DBU, and 1.5 ml of anhydrous DMF was heated at 110°-115° C. for 20 minutes while stirring. After cooling, 30 ml of chloroform and 10 ml of 5% acetic acid were added to the resulting reaction mixture. The mixture was thoroughly stirred and the organic layer was separated. The water layer was extracted once more with 20 ml of chloroform. The extract, mixed with the organic layer, was dried over magnesium sulfate, and condensed. The residue was recrystallized from a mixed solvent of chloroform and methanol to obtain 144 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](=O)[NH:9][N:10]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[NH4+]>CC(C)=O.O>[Cl:18][C:8]1[N:9]=[N:10][C:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[CH3:1])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1Cc1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccccc1Cc1ccc(Cl)nn1

Procedure:
2,3-Dihydro-6-(2-methylbenzyl)pyridaz-3-one (prepared as described above; 36 g.) and phosphorus oxychloride (120 ml.) were heated together on a steam bath to 90° C. The dark red solution thus obtained was immediately cooled to 10°-15° C., diluted with acetone (125 ml.) and added to a stirred solution of acetone and aqueous ammonium hydroxide solution (s.g. 0.880) (1:1; 1000 ml.) maintained at a temperature of from 0° to 20° C. by strong cooling. The mixture was then diluted with water (1000 ml.). A light brown coloured solid was precipitated, filtered off, dried and dissolved in toluene (200 ml.). The toluene solution was filtered and the filtrate evaporated to dryness to give 3-chloro-6-(2-methylbenzyl)pyridazine (34 g.) in the form of an off-white coloured solid, m.p. 73.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:11]([CH3:20])[C:10]=2[CH:21]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C.[OH-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO>[CH:17]1([C:15]([NH:14][C:12]2[N:11]([CH3:20])[C:10]3[CH:21]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:24]=[CH:23][CH:22]=4)[CH:7]=[CH:8][C:9]=3[N:13]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl]cyclopropanecarboxamide (200 mg, 620 μmol) in pyridine (5 mL) were added 3-(trifluoromethyl)benzoic acid (241 mg, 1.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (479 mg, 2.50 mmol) and N,N-dimethylpyridine-4-amine (28.3 mg, 232 μmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added methanol (2 mL) and 8N aqueous sodium hydroxide solution (2 mL), and the mixture was further stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and methanol (1 mL). This solution was washed with water (50 ml), 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=2/98→80/20), and further purified by reversed phase silica gel column chromatography (containing 0.1% trifluoroacetic acid, water/acetonitrile=95/5→0/100). The fraction containing the object product was concentrated, and the residue was dissolved in ethyl acetate (50 mL) and methanol (10 mL). The mixture was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was recrystallized from acetone and diisopropyl ether to give the title compound (139 mg, 45%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[CH:38]1([C:41]2[C:46]([C:47](O)=[O:48])=[CH:45][N:44]=[C:43]([C:50]3[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=3)[N:42]=2)[CH2:40][CH2:39]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:47]([C:46]2[C:41]([CH:38]3[CH2:40][CH2:39]3)=[N:42][C:43]([C:50]3[CH:51]=[CH:52][C:53]([C:56]([F:58])([F:59])[F:57])=[CH:54][CH:55]=3)=[N:44][CH:45]=2)=[O:48])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[3-chloro-4-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])[CH3:17].[O-]CC.[Na+]>C(O)C>[CH2:16]([O:18][C:19](=[O:25])[C:20](=[O:21])[CH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 4-methyl-3-nitrobenzoate (80 g, 0.38 mol) and oxalic acid diethyl ester (57 mL, 0.42 mol) in ethanol (1000 mL) is added sodium ethoxide (430 mL, 1.15 mol, 21% in ethanol). The resulting brown solution is stirred at room temperature for 16 h. The reaction is quenched with 3N HCl to neutral pH and diluted with water (2000 mL). The resulting white precipitate is filtered and dried in vacuum to afford the title compound (91 g, 77%).