Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=O)[O:28]C)=[N:24][CH:25]=1>CN(C)C=O>[F:31][C:19]([F:18])([F:32])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[NH:1][C:27]2=[O:28])=[N:24][CH:25]=1
Reactant: COC(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: CCOC(=O)C=C(N)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.1 %

Procedure:
1.27 g of ethyl 3-amino-3-(2-chlorophenyl)-2-propenoate was added dropwise to a 20 ml of dimethylformamide solution of 0.26 g of sodium hydride (purity: 55%). The solution was stirred t room temperature for 15 minutes, then cooled to 0° C. and added with 1.24 g of methyl (5-trifluoromethyl-2-pyridyl)carbamate. The resulting solution was further stirred at 120° C. for 5 hours and then the solvent was distilled away under reduced pressure. The residue was dissolved with 100 ml of water and washed with diethyl ether. The obtained aqueous layer was added into a mixed solution of 20 ml of concentrated hydrochloric acid and 50 g of ice, and the precipitated crystals were filtered out and dried to obtain 0.21 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1ccc(F)cc1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 4-fluoro-benzenesulfonyl chloride (0.054 g) as a light yellow gum (0.08 g). MS (ESI−): 389.1 ([M−H]−)
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([O:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=[O:12])[CH3:9].Br[CH2:27][CH2:28][O:29][CH3:30]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C:13]1([CH2:27][CH2:28][O:29][CH3:30])[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH2:18]1)=[O:12])[CH3:9]
Reactant: COCCBr
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of diisopropylamine (5.68 mL, 0.040 mol) in 100 ml THF at −78° C. was added nBuli (1.6M solution in hexane, 25.9 mL, 0.041 mol) drop-wise. The reaction mixture was warmed to −5° C. and stirring was continued for 30 mins. A solution of 1-benzylpiperidine-4-carboxylic acid ethyl ester (5.00 g, 0.020 mol) in THF (20 mL) was added drop wise and stirring was continued for a further 3 hr followed by the addition of a solution of 1-bromo-2-methoxy-ethane (3.82 g, 0.040 mol) in THF (20 mL) at −5° C. The reaction mixture was then allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was quenched with water and concentrated in vacuo to give a brown residue which was diluted with ethyl acetate and extracted 1NHCl. The aqueous layers were then combined, made basic (with 1N NaOH) and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) to give 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester (5.2 g, 84%) as a brown oil. MS (ESI): 306.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:21]([O:23][C:24](=[O:41])[CH:25]=[C:26]1[CH:35]([CH3:36])[CH:34](Br)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[O:38][CH3:39])[C:27]1=[O:40])[CH3:22]>C1COCC1>[CH2:21]([O:23][C:24](=[O:41])[CH:25]([C:26]1[C:35]([CH3:36])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[O:38][CH3:39])[C:27]=1[OH:40])[O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:22]
Reactant: CCOC(=O)C=C1C(=O)c2cccc(OC)c2C(Br)C1C
Reactant: COc1ccc(CO)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(OC)cccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of 4-methoxybenzyl alcohol (0.27 mL, 4 equiv) in THF (11 mL) at 0° C. was added KHMDS (0.5 M in toluene, 3.4 mL, 3 equiv) and the resulting mixture was allowed to stir for 10 min at 0° C. A solution of (4-bromo-5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-acetic acid ethyl ester (200 mg) in THF (1 mL) was added slowly. After stirring for 3 min at 0° C., the reaction was quenched with citric acid (1 M) and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (5-20% EtOAc/hexanes) to give 157 mg of pale orange oil (68% yield). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H27O6: 411.18. Found: 411.21.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH:36]([OH:39])[CH2:37][OH:38]>>[OH:39][CH:36]([CH2:37][OH:38])[CH2:35][NH:34][C:26]([C:12]1[C:13](=[O:25])[N:14]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[C:15]2[C:10]([C:11]=1[OH:31])=[N:9][CH:8]=[C:7]([CH2:6][C:5]1[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=1)[CH:16]=2)=[O:27]
Reactant: NCC(O)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: O=C(NCC(O)CO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1,2-propanediol using conditions similar to those employed in Example 563 to provide a white solid: ES+ MS: 499 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:27])([F:26])[CH:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH:15]=1)[OH:13].[H-].[Na+]>O1CCOCC1>[Cl:9][C:4]1[CH:5]=[C:6]([O:13][CH:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[C:11]([F:26])([F:27])[F:10])[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: COc1ccc2cc(C(O)C(F)(F)F)ccc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2cc(C(Oc3cc(Cl)nc(N)n3)C(F)(F)F)ccc2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
2-Amino 4,6-dichloro pyrimidine (0.096 g, 0.6 mmol), 2,2,2-trifluoro-1-(6-methoxy-naphthalen-2-yl)-ethanol (0.140 g, 0.55 mmol), and NaH (96 mg, 0.60 mmol) were added to anhydrous dioxane (20 ml) under a nitrogen atmosphere. The reaction was stirred at 80° C. for 12 hours, cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated, and the residue dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml) dried (Na2SO4) and concentrated to afford the crude intermediate, 4-chloro-6-[2,2,2-trifluoro-1-(6-methoxy-naphthalene-2-yl)-ethoxy]-pyrimidin-2-ylamine (0.22 g) which was directly used in the following step.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:13][C:14](=[CH:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22]O)[CH3:20])[CH3:15].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:22][CH2:21][CH:19]([CH3:20])[CH2:18][CH2:17][CH:16]=[C:14]([CH3:15])[CH3:13])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)=CCCC(C)CCO
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccccc1C(=O)OCCC(C)CCC=C(C)C
Reaction time: 75 h
Yield: 81.9 %

Procedure:
A solution of 6.49 g (30.0 mmol) 2-acetylbenzoic acid, 3.81 g (31.2 mmol) DMAP and 12.48 g (80.0 mmol) citronellol in 60 ml dichloromethane was cooled in an ice bath before adding a solution of 8.84 g (42.9 mmol) DCC in 40 ml dichloromethane over 5 min. The reaction mixture was maintained with stirring at 40° for 75 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×). The organic phase was dried (Na2SO4), and the solvent evaporated. The excess citronellol was distilled (1 Torr, 60-80°), and the residue chromatographed (SiO2, 9:1 toluene/ethyl acetate) and distilled (0.6 Torr, 150-155°), to give 7.43 g (63%) of 3,7-dimethyl-6-octenyl 2-acetylbenzoate in the form of a colourless oil.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:32])[C@H:17]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:28]([O:27][C:25]([NH:24][C@H:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:32])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reaction time: 3 h
Yield: 62 %

Procedure:
A mixture of compound 2a (2 mmol) and Pd/C (20 w %) in ethanol (30 mL) was hydrogenated for 3 hrs at atmospheric pressure. The reaction mixture was filtered off and concentrated in vacuo. The crude was taken in toluene and concentrated again, and then in Et2O/petroleum ether and concentrated once more to give compound 3a as a glassy solid in 62% yield over two steps. MS (ESI, EI−) m/z=347 (MH−).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][C:13](OCC)(OCC)OCC)[CH3:11]>C(OCC)(=O)C>[CH2:10]([O:12][C:13]1[NH:1][C:2]2[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1)[CH3:11]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: Cc1cccc(N)c1N
Solvent: CCOC(C)=O
Product: CCOc1nc2cccc(C)c2[nH]1
Temperature: 130 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
2,3-Diaminotoluene (6.09 g, 49.8 mmol) and tetraethoxymethane (25 mL, 119 mmol) were mixed, and the mixture was stirred at 130° C. for 16 hr. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give the title compound (6.89 g, 78%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@@:3]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1)(O)[CH2:4][C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]2)[N:9]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(O)(=O)C>[F:31][C:2]([F:1])([F:30])/[C:3](/[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)=[CH:23][CH:24]=1)=[CH:4]\[C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:15])([F:16])[F:17])[CH2:12][CH2:13]2)[N:9]=1
Reactant: O[C@](Cc1nc(CC2(C(F)(F)F)CC2)c[nH]1)(c1ccc(-n2cccn2)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: FC(F)(F)/C(=C\c1nc(CC2(C(F)(F)F)CC2)c[nH]1)c1ccc(-n2cccn2)cc1

Procedure:
A suspension of (2R)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol in acetic acid (10 mL)/acetic anhydride (10 mL) was heated to reflux. The reaction mixture was poured into 1M sodium hydroxide solution until basic and extracted with diethyl ether. The crude product was dissolved in a mixture of methanol and acetonitrile and charged with 1M sodium hydroxide. It was heated to reflux overnight, and the reaction mixture was extracted with diethyl ether. The combined organic extracts were washed with brine, dried (potassium carbonate) and concentrated in vacuo to afford 1-{4-[(Z)-1-(trifluoromethyl)-2-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)vinyl]phenyl}-1H-pyrazole, which was used without further purification.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:11][CH:12]=2)[CH2:4][O:3]1.C([O-])(=O)C.[NH4+:42].Cl>C(O)(=O)C.C(OCC)(=O)C.O1CCCC1>[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:17]([C:16]2[NH:42][C:13]([C:10]3[N:11]=[CH:12][C:7]([CH:5]([OH:6])[CH2:4][OH:3])=[CH:8][CH:9]=3)=[CH:14][CH:15]=2)[CH2:18][CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:30][CH:29]=1)(=[O:33])=[O:32]
Reactant: [NH4+]
Reactant: CC1(C)OCC(c2ccc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)nc2)O1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
To a solution of 1-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-2-yl]-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (232 mg) in acetic acid (5 mL) was added ammonium acetate (540 mg), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated to give a crude product (218 mg). To a solution of the obtained crude product in tetrahydrofuran (5 mL) was added 1M hydrochloric acid (5 mL), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (155 mg, yield 78%) as a colorless amorphous solid. MS: 471 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Cc1cccnc1N
Reactant: O=C(CBr)c1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccn2cc(-c3ccc(I)cc3)nc12
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A mixture of crude 2-bromo-1-(4-iodophenyl)ethanone (18.2 g), 2-amino-3-picoline (1.1 equiv, 61.6 mmol), and sodium bicarbonate (1.3 equiv, 72.8 mmol) in isopropanol (160 mL) was heated at 80° C. for 16 h. After concentrating the reaction mixture in vacuo, water (100 mL) was added and the resultant tan slurry was filtered, rinsing with water (2×50 mL). The brown solid was recrystallized from hot isopropanol and further dried in vacuo to provide the title product as a brown solid (13.2 g, 71%). ESMS [M+H]+: 335.0.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([I:20])=[C:5]([C:7]([I:19])=[C:8]([C:11]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[O:12])[C:9]=1[I:10])[NH2:6].C(O[C:25](=[O:27])[CH3:26])(=O)C.S(=O)(=O)(O)O.C(Cl)Cl>C(O)(=O)C.O>[C:2]([NH:6][C:5]1[C:7]([I:19])=[C:8]([C:11]([NH:13][CH2:14][CH:15]([O:18][C:16](=[O:17])[CH3:15])[CH2:16][O:17][C:11](=[O:12])[CH3:8])=[O:12])[C:9]([I:10])=[C:3]([CH2:2][O:1][C:25](=[O:27])[CH3:26])[C:4]=1[I:20])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3-Hydroxymethyl-5-(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodoaniline (3.3 g, 5.3 mmol) was suspended in glacial acetic acid (12 ml) containing acetic anhydride (48 ml) and concentrated sulfuric acid (0.08 ml). The mixture was stirred at 60° C. for 3 h, allowed to cool to room temperature, and CH2Cl2 (100 ml) and water (100 ml) were added. The organic phase was washed with water (3×50 ml) and a saturated aqueous solution of NaHCO3 (2×50 ml). After drying (MgSO4) and evaporation, the residue was dissolved in a mixture of CH2Cl2 and methanol (9:1) and filtered through a short silica pad and evaporated. Yield: 3.0 g (71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:24]([OH:26])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:21]([F:20])=[C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1F
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Product: CCCCCCCCCCOc1ccc(C(=O)O)c(-c2ccc(C(=O)C(C)CCCCCCC)c(F)c2)c1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methyloctanoyl) phenol in Example 20 and 3-fluoro-4-decyloxy benzoic acid was used instead of 3-fluoro-4-heptyloxy benzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC1CCN(C(=O)n2cc[n+](C)c2)CC1
Agent: [I-]
Product: CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(4-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (73%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.4 min.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=[O:32].[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([F:27])[CH:29]=1)[OH:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1F
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.54 M, 6.79 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.5 g, 9.50 mmol) in THF (30 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 3-fluoro-4-methoxybenzaldehyde (1.32 g, 8.56 mmol) in THF (8 mL) was added dropwise at −78° C. The mixture was stirred at the same temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.79 g, 96%).
Reaction SMILES: [Cl:1]C1N=CC=CN=1.[NH2:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[CH:11][C:10]=1[F:24]>>[ClH:1].[NH2:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[CH:11][C:10]=1[F:24]
Reactant: Clc1ncccn1
Agent: N#Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Product: Cl

Procedure:
Starting from chloropyrimide 1A and aniline 2G, this material was prepared by a method analogous to that described for Example 1. After the reaction was complete, the solid was filtered and washed with MeOH to provide the title compound. 1H NMR (DMSO-d6) δ 12.99 (s, broad, 1H, 10.51 (s, broad, 1H) 8.63 (d, J=6.0 Hz, 1H), 8.07 (s, broad, 1H), 7.88 (m, 2H), 7.79 (d, J=2.4 Hz, 1H), 7.66 (m, 3H), 7.45 (dd, J=11.2 Hz, 2.4 Hz, 1H), 7.30 (d, J=3.2 Hz, 1H), 7.16 (dd, J=8.8 Hz, 1.6 Hz, 1H), 6.82 (s, broad, 1H); MS ES: 399 (M+H)+, calcd 399, RT=2.24 min.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[NH2:13][NH2:14]>O1CCOCC1>[NH:13]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)[NH2:14]
Reactant: NN
Reactant: O=C1NCCc2cc(F)ccc21
Solvent: C1COCCO1
Product: NNc1ccc2c(c1)CCNC2=O

Procedure:
A solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (3.6 g, 0.022 mole) and hydrazine (17.3 mL, 0.55 mole) was stirred at reflux in dioxane (150 mL) under nitrogen for 48 hours. The reaction mixture was concentrated under vacuo, water added (150 mL), and the product isolated by filtration. The product was thoroughly washed with diethyl ether to give the titled compound quantitatively as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[CH:3]1.[CH:18](OC)=[O:19]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[N:16]([CH:18]=[O:19])[CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[CH:3]1
Reactant: Cn1cc(C2NCCNC2=O)c2ccccc21
Reactant: COC=O
Product: Cn1cc(C2C(=O)NCCN2C=O)c2ccccc21

Procedure:
22.9 g (0.1 mol) of 3-(1-methylindol-3-yl)-piperazin-2-one, prepared in accordance with Example 34, are reacted with methyl formate, as described in Example 5.