Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC[C@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (5.0 g) in dimethyl sulfoxide (80 mL) were added L-norvaline (4.52 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 8.12 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:10]([CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH2:33]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:10]([CH2:20][NH:33][CH3:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CC2c2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: CNCC1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
(3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl ester (5.0 g, 0.011 mmol) were dissolved in 2.0 M solution of MeNH2 in THF (36 mL) in an autoclave and heated to 80° C. over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, dichloro methane, dichloro methane/methanol −>4:1) to yield the title compound (2.6 g, 76%) as a light yellow oil.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[CH2:4][N:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:7][OH:8].[OH-].[Na+]>CS(C)=O.O>[CH:9]([N:5]1[CH2:4][C:3]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:2]=2[O:8][CH2:7][CH2:6]1)([CH3:11])[CH3:10]
Reactant: CC(C)N(CCO)Cc1cc([N+](=O)[O-])ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCOc2ccc([N+](=O)[O-])cc2C1
Reaction time: 3 h

Procedure:
To 2-[(2-fluoro-5-nitrobenzyl)(isopropyl)amino]ethanol (31.2 g, 90 mmol) in DMSO (250 ml) was added 25% sodium hydroxide solution (43.2 g, 270 mmol) and the mixture was allowed to stir for 3 h. The reaction was diluted to twice its volume with water and the solids were collected by filtration. The filtrate was extracted with methylene chloride (3×150 ml), washed with water, dried with magnesium sulfate, filtered, and concentrated to an oil. The solid and the oil were dissolved in hot 95% ethanol, then cooled. The solids were collected by filtration (17.47 g, 68%), MS m/z 237 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]12[CH2:18][CH2:17][C:16](=[O:19])[CH:15]=[C:14]1[C:13]1[C:8](=[CH:9][C:10]([O:20]C)=[CH:11][CH:12]=1)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:5]12[CH2:18][CH2:17][C:16](=[O:19])[CH:15]=[C:14]1[C:13]1[C:8](=[CH:9][C:10]([OH:20])=[CH:11][CH:12]=1)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C=C1c1ccc(OC)cc1CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C=C1c1ccc(O)cc1CC2

Procedure:
A solution of 10a-butyl-7-methoxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone (16 mg, 0.056 mmol) in anhydrous CH2Cl2 (0.5 mL) was cooled in an ice bath, stirred, and treated with 1M BBr3 in CH2Cl2 (0.3 mL, 0.3 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 170 minutes. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 5% CH3OH in CH2Cl2. The UV visible product band was eluted with 10% CH3OH in CH2Cl2 and the eluant was evaporated under vacuum to provide 10a-butyl-7-hydroxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[OH:32][N:31]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(C=CC(=O)O)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(C=CC(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-{4-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-acrylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of Z to E isomers (1.7:1) as a colorless oil, MS (ESI+): m/z=401.1859 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:13][C@H:12]([O:14][Si](C(C)(C)C)(C)C)[CH2:11][C:10]2=[O:22])[CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:13][C@H:12]([OH:14])[CH2:11][C:10]2=[O:22])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)N(Cc2cccc(Br)n2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1C[C@@H](O)CN1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4R)-1-[(6-Bromopyridin-2-yl)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-one was dissolved in tetrahydrofuran (33.4 mL), and tetrabutylammonium fluoride (5.84 mL, 5.84 mmol) was added dropwise and the solution stirred at ambient temperature for five minutes. The reaction mixture was concentrated and purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C@H:21]([C:24]([O:26]C)=[O:25])[CH2:22][OH:23])=[O:19])=[C:5]2[OH:28].[OH-].[Na+].O>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C@H:21]([C:24]([OH:26])=[O:25])[CH2:22][OH:23])=[O:19])=[C:5]2[OH:28]
Reactant: COC(=O)[C@H](CO)NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](CO)C(=O)O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Methyl N-((6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)-L-serinate (180 mg, 439 μmol) was dissolved in THF (4392 μL). NaOH in water (4392 μL, 21961 μmol) was added, and the reaction was stirred at ambient temperature for 3 hours. The pH was adjusted to about 3, and the resulting mixture was diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 20 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (95 mg) after it was precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven. MS m/e=396 (M+H)+. Calculated for C18H18NO7 395.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(C(O)c2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(C(Cl)c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-chlorophenyl 1-methylpiperidin-4-yl methanol 1.2 g (5.02 mmol) in toluene (5 ml) was added thionyl chloride (0.45 ml) dropwise. The resulting mixture was stirred at room temperature over night. The mixture was then made alkaline with NaOH solution and extracted with ethyl acetate (3×40). The combined organic solution was dried and concentrated to give 1.2 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[Cl:12][C:13]1[CH:14]=[C:15]([OH:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([CH:16]=[C:15]([O:21][C:7]2[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([F:11])[C:2]=2[Cl:1])[CH:14]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(O)cc(Cl)c1
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(F)nc(F)c2Cl)c1
Temperature: -50 °C

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (10-1; 1.0 g; 5.39 mmol) and Compound 1-4 (0.83 g; 5.39 mmol) were dissolved in DMF and the solution cooled to −50° C. under a nitrogen atmosphere, after which potassium carbonate (1.12 g; 8.09 mmol) was added and the mixture allowed to slowly warm to 25° C. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic extract was concentrated and purified on a silica column eluted with ethyl acetate:hexane to give the title product 10-2 as a clear oil. Rf=0.6 (EtOAc:hx, 5:95). 1H NMR (CDCl3): δ 7.50 (s, 1H), 7.24 (s, 1H), 7.17 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([S:13]([OH:16])(=[O:14])=[O:15])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)O)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)N1CCc2cc([N+](=O)[O-])c(S(=O)(=O)O)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
16.0 g (66 mmol) of 1-acetylindoline-6-sulfonic acid (Compound 2-2 in Scheme II) was dissolved in 160 mL of cone, sulfuric acid. The solution was cooled to 0° C. using ice/water bath. Nitric acid (90%, furming) (3.0 mL, 1.1 eqv.) was added dropwise over 10 min. The resulting pale yellow solution was stirred at 0° C. for 2 h and then slowly poured onto 200 g of ice. The crystals formed were collected by filtration and washed successively with cold water acetone and ether. Drying under vacuum over P2O5 afforded 18.2 g of the title compound. 1H MNR (d6-DMSO) δ: 8.47 (s, 1H), 7.40 (s, 1H), 5.54 (OH+H2O), 4.12 (t, J=8.5 Hz, 2H), 3.13 (t, J=8.5 HZ, 2H) and 2.17 (s, 3H). 13C NMR (d6-DMSO) δ: 169.19, 144.18, 143.17, 139.54, 133.54, 119.10, 115.23, 48,67, 26.75 and 24.01.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:22]([F:25])([F:24])[F:23])=[C:18]([CH:21]=1)[CH2:19]Br>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:22]([F:23])([F:24])[F:25])=[C:18]([CH:21]=1)[CH2:19][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(F)ccc1C(F)(F)F
Yield: 51 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.07 g) was reacted with 5-fluoro-2-trifluoromethylbenzyl bromide as in General Procedure 1 to give the title compound as an off-white solid (51% yield). M.p. 244-245° C., LCMS: m/z=453.03 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.21 (s, 2H), 5.15 (s, 2H), 6.97 (s, 1HO, 7.12 (d, J=9.8 Hz, 1H), 7.25 (s, 1H), 7.36 (dd, J=8.3 Hz, 1H), 7.84 (s, 1H), 7.88-7.94 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13]([F:16])([F:15])[F:14])[C:11]=1F)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:11]=1[N:27]1[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]1)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C(F)(F)F)c21
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C)c3c2C(F)(F)F)CCN1
Temperature: 105 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
In 30 ml of pyridine were dissolved 1.5 g (0.0049 mole) of 6,7-difluoro-8-trifluoromethyl-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 1.5 g (0.015 mole) of 2-methylpiperazine, the mixture was stirred at 105° C. for 3 hours, and then the solvent was removed by evaporation under reduced pressure. Ethanol was added to the residue, precipitated crystals were collected by filtration, the crystals obtained were washed with ethanol and dried, and then 1.49 g of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-(3-methylpiperazin-1-yl)quinoline-3-carboxylic acid was obtained as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[C:17](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[C:17]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[CH:14]1[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2cc(Cl)c(F)c(Cl)c2c1=O
Temperature: 0 °C
Yield: 91.7 %

Procedure:
6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-cyclopropylamino-acrylate are heated in 100 ml of dimethylformamide at 150° C. with 2.75 g of potassium carbonate for 2.5 hours. The mixture is poured into 600 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 5.2 g of ethyl 5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 227°-229° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:11]
Reactant: O=C(Cl)Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(F)cc1Cl
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of 2-chloro-4-fluorophenylacetyl chloride (10 mmol) in dry DCM (15 ml) was added over 20 min to a mixture of t-butyl carbazate (1.32 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (20 ml). After stirring for a further 2 h, the mixture was washed with 1M HCl then with aqueous NaHCO3. A white solid precipitated at this point, which was filtered off, washed with water and DCM then dried to yield 1,1-dimethylethyl 2-[(2-chloro-4-fluorophenyl)acetyl]hydrazinecarboxylate (1.94 g).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH3:41])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CC1>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22](=[O:23])[C:17]=4[C:16]=3[CH3:41])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Solvent: O
Product: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 91.9 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 1.54 g (2.53 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 4-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=19:1→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.11 g of the title compound as a white solid. (Yield: 92%)
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[O:10][N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:28]([N:31]1[C:38]([NH2:39])=[C:37]([NH2:40])[C:35](=[O:36])[N:34]([CH2:41][CH2:42][CH3:43])[C:32]1=[O:33])[CH2:29][CH3:30]>CO>[CH2:41]([N:34]1[C:35](=[O:36])[C:37]2[NH:40][C:13]([C:11]3[O:10][N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:39][C:38]=2[N:31]([CH2:28][CH2:29][CH3:30])[C:32]1=[O:33])[CH2:42][CH3:43]
Reactant: CCC(Oc1cc(C(=O)O)on1)C(=O)O
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)no3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxyisoxazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yl)oxyacetic acid.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[CH:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: C#Cc1sc(N)nc1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1sc(N)nc1-c1ccccc1
Yield: 74.4 %

Procedure:
The above prepared 5-ethynyl-4-phenyl-thiazol-2-ylamine (0.665 g, 3.321 mmol) was dissolved in 12 mL of ethyl acetate and hydrogenated over 0.330 g of Pd on charcoal (10%) at atmospheric pressure and ambient temperature over night. Filtration over a pad of Celite and evaporation off all solvents, followed by flash chromatography (SiO2, hexane/ethyl acetate=65/35), yielded 0.505 g of the title product as yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[Na+]>O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: BrCCCCCCBr
Reactant: Oc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(OCCCCCCBr)c1
Reaction time: 24 h
Yield: 50 %

Procedure:
To a stirred mixture of 32.1 parts of 3-fluorophenol, 122 parts of 1,6-dibromohexane and 200 parts of water was dropwise added a solution of 20 parts of sodium hydroxide in 100 parts of water at reflux temperature. Upon completion, stirring was continued for 24 hours at reflux. After cooling, the product was extracted three times with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was distilled, yielding 40 parts (50%) of 1-[(6-bromohexyl)oxy]-3-fluorobenzene; bp. 45°-90° C. at 0.05 mm pressure (107).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:16][NH:17][O:18][CH3:19].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:17]([O:18][CH3:19])[CH3:16])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Yield: 99.5 %

Procedure:
Prepared according to Method A step A from 2-fluoro-3-trifluoromethylbenzoic acid (5.0 g, 24 mmol), N,O-dimethylhydroxylamine hydrochloride (3.4 g, 35 mmol), oxalyl chloride (2.18 mL, 25 mmol) and 6 mL of pyridine to give the title compound (6.0 g) as an oil. Used as is in the next prep
Reaction SMILES: C[N:2](C)CC=C.O.[S:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[CH:14][CH:13]=1)([OH:11])(=[O:10])=[O:9].[Na:21]>O>[S:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH2:2])=[S:20])=[CH:16][CH:17]=1)([OH:11])(=[O:9])=[O:10].[Na:21]
Reactant: C=CCN(C)C
Reactant: O=S(=O)(O)c1ccc(N=C=S)cc1
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1ccc(S(=O)(=O)O)cc1

Procedure:
Trifluoroacetic acid (4 ml) was added to a suspension of BHAlyslys2lys4lys8DBL16 (0.73 g; 0.1 mmol) in dry dichloromethane (4 ml) under nitrogen. A vigorous evolution of gas was observed for a short time and the resulting solution was stirred at room temperature for two hours and then concentrated. The residual syrup was dissolved in water (5 ml), the solution passed through a column of Amberlite IRA-401(OH) and the filtrate concentrated to give BHAlyslys2lys4lys8lys16 as a viscous oil (0.49 g). The oil was redissolved in water (5 ml) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 3 ml) added. Solid sodium 4-sulfophenylisothiocyanate monohydrate (1.30 g; 5.1 mmol) was then added and the resulting solution heated under nitrogen at 53° for two hours and then cooled. The solution was concentrated and the brownish solid residue purified by gel filtration (Sephadex LH20; water). The pure fractions were combined, passed through a column of Amberlite IR 120(Na) and freeze dried to give the sodium 4-sulfophenylthiourea terminated BHAlyslys2lys4lys8lys16 dendrimer as a fluffy white solid (374 mg). 1H nmr (D2O): δ 1.40; 1.72; 3.08; 3.42; 4.24; 4.60; 7.30; 7.40 (d, J=9 Hz); 7.78 (d, J=9 Hz). 13C nmr (D2O): δ 27.3; 32.5; 35.9; 43.7; 48.9; 58.6; 63.3; 128.8; 131.0; 143.7; 144.7; 145.1; 177.7; 178.1; 183.8; 185.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of 2-iodonitrobenzene (2.0 g, 8.0 mmol), bis(triphenylphosphine)palladium(II) chloride (0.30 g, 0.40 mmol) and copper(I) iodide (0.080 g, 0.40 mmol) in 25 mL of Et3N was degassed by freeze/pump/thaw technique (three times). Trimethylsilylacetylene (1.0 g, 10 mmol) was added and the mixture was stirred for 18 hours. The reaction mixture was filtered through a celite pad and the pad was rinsed with CH2Cl2. The filtrate was washed with sat. NH4Cl (aq.) and brine and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (Hexane, then EtOAc;Hexane=1:60, 1:30) to afford trimethyl((2-nitrophenyl)ethynyl)silane (1.33 g, 76%): 1H-NMR (300 MHz, CDCl3) δ 8.02 (dd, J=8.1, 1,2 Hz, 1H), 7.66 (dd, J=7.5, 1.5 Hz, 1H), 7.56 (ddd, J=7.2, 7.2, 1.2 Hz, 1H), 7.45 (ddd, J=8.1, 8.1, 1.5 Hz, 1H) , 0.28 (s, 9H).