Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccn2cc(C=Cc3ccc([N+](=O)[O-])cc3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccn2cc(CCc3ccc(N)cc3)nc2c1
Yield: 92.8 %

Procedure:
A solution of 2-[2-(4-nitrophenyl)vinyl]-7-methylimidazo[1,2-a]pyridine (3.1 g) in a solution of methanol (100 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (1.0 g) under atmospheric pressure of hydrogen gas at ambient temperature for 3 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with n-hexane to give a precipitate, which was collected by filtration and dried to give 2-[2-(4-aminophenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (2.59 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[N:7]=1.[OH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([C:23]2[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:12][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:7][N:6]2[CH:8]=1
Reactant: OCc1cn2nc(I)ccc2n1
Reactant: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(CO)cn4n3)c2)n(C)n1
Temperature: 150 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of (6-iodoimidazo[1,2-b]pyridazin-2-yl)methanol (400 mg, 1.45 mmol) in N,N-dimethylformamide (4.0 mL) were added N-(3-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (504 mg, 2.18 mmol) and potassium carbonate (402 mg, 2.91 mmol), and the mixture was stirred at 150° C. for 16 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol=100/0→10/1) to give the title compound (70 mg, 13%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])=[O:21])=[CH:17][CH:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)cc1
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1ccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)cc1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield (10.1 mg) prepared from 4-(4-(4-chlorophenoxy)piperidine-1-carbonyl)benzoic acid (Step-2) according to the procedure similar to that described in Step-2 of Example 349, using 2-methoxy-N-methylethanamine instead of 25% ammonium water.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH:25]3[CH2:27][CH2:26]3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH:25]3[CH2:27][CH2:26]3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(C#CCO)cc2c1=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(CCCO)cc2c1=O
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-1-cyclopropyl-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.17 g) from Example No. 25 in THF (3 mL) and methanol (3 mL) is added platinuim oxide (0.01 g). The mixture is placed under an atmosphere of hydrogen gas. After 1 hour, the mixture is filtered through Celite with THF:methanol washes. The filtrate is concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 4% methanol in dichloromethane. The product-containing fractions are concentrated under reduced pressure to afford 0.13 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Br:17])[C:15]=1[OH:16])[C:11]#[N:12].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:16][C:15]1[C:14]([Br:17])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[Br:7])=[O:4]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: C=C(F)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1c(Br)cc(C#N)cc1Br
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
10 g (0.092 mol) α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 5 minutes, to a solution of 24.8 g (0.09 mol) of 3,5-dibromo-4-hydroxybenzonitrile and 9.1 g (0.09 mol) of triethylamine in 200 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-heptane. 17.5 g (55% of theory) of 2,6-dibromo-4-cyanophenyl α-fluoroacrylate were obtained, melting point 135° to 138° C.
Reaction SMILES: Br[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4][CH2:3]1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:24]1[C:31]2[CH2:30][CH2:29][CH2:28][N+:27]=2[CH2:26][CH2:25]1.Cl>CCOCC.CCCCC>[C:8]1([C:2]2[CH:7]=[C:6]([C:31]34[CH2:30][CH2:29][CH2:28][N:27]3[CH2:26][CH2:25][CH2:24]4)[CH:5]=[N:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: BrC1(c2ccccc2)C=CC=NC1
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: c1ccc(-c2cncc(C34CCCN3CCC4)c2)cc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
3-Bromo-3-phenylpyridine (200 mg, 0.85 mmol) was dissolved in Et2O and cooled to -30° C. A solution of 2.5M t-BuLi (1.1 mL, 1.90 mmol) in pentane was added, and the reaction was stirred for 10 minutes. 1,2,3,5,6,7-Hexahydropyrrolizinium perchlorate (230 mg, 1.30 mmol) was added, and the reaction mixture was allowed to stir for 30 minutes at -30° C. then allowed to warm to room temperature and stir for 1 hour. Then 2N HCl was added, the phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The organic phases were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 95:5) to afford a clear oil (32.5 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([Cu])#[N:13]>N1C=CC=CC=1.CCOC(C)=O>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:12]#[N:13])[CH:3]=1
Reactant: N#C[Cu]
Reactant: Brc1cnc2ccccc2c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccccc2c1
Temperature: 250 °C

Procedure:
A suspension of 3-bromoquinoline (1-Im-10, 1.5 g) and CuCN (3 eq) in 10 mL of pyridine in a 25 mL microwave tube was heated at 250° C. for 30 min in a microwave. This was repeated 10 times and the reactions were combined and diluted with 200 mL of EtOAc. The solids were removed by filtration and the EtOAc solution concentrated. The residue was taken up in a solution prepared from 80 mL of 30% aqueous NH3 and 800 mL of water. This was extracted with EtOAc (4×800 mL) then the combined extracts were dried with anhydrous Na2SO4, concentrated and purified by silica gel chromatography (PE:EtOAc=3:1) to give quinoline-3-carbonitrile (2-Im-10).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([OH:16])([C:14]#[CH:15])[CH3:13]>>[Cl:9][C:5]1[C:4]([CH3:10])=[CH:3][C:2]([C:15]#[C:14][C:12]([CH3:13])([OH:16])[CH3:11])=[C:7]([F:8])[CH:6]=1
Reactant: C#CC(C)(C)O
Reactant: Cc1cc(Br)c(F)cc1Cl
Product: Cc1cc(C#CC(C)(C)O)c(F)cc1Cl

Procedure:
By the method of Example (IV-1), 100 mmol of 3-bromo-6-chloro-4-fluoro-toluene are reacted with 2-methyl-3-butin-2-ol to give 1-(4-chloro-2-fluoro-5-methyl-phenyl) -3-methyl-1-butin-3-ol, except that the mixture is only filtered after the reaction and not concentrated. The filtrate is then admixed with 1.5 g of sodium hydroxide (powder) and the mixture is heated to the boil in a distillation apparatus (with Vigreux column). Distillate is continuously removed, until the boiling point of triethylamine (89° C.) is reached. The mixture is then allowed to cool, filtered and washed with some ml of triethylamine. The filtrate is subsequently subjected to fractional distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].CCO>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:7]2=[O:14])([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 65.5 %

Procedure:
To a solution of 5-nitroisoindoline-1,3-dione (2 g, 10.41 mmol) in DMF (10 ml), K2CO3 (1.439 g, 10.41 mmol) and methyl 2-bromoacetate (1.930 ml, 20.82 mmol) were added, and the mixture was reacted under MW irradiation for 2 hr at 140° C. Then the solid K2CO3 was filtered off, the solvent was evaporated and the resulting crude was triturated with EtOH obtaining the title compound as a pale brown solid (1.8 g, 6.82 mmol, 65.5% yield, UPLC-MS purity 90%, MS/ESI+ 265.1 [MH]+) which was used without any additional purification.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>C(OCC)(=O)C>[CH2:7]([O:6][C:4]([CH:3]1[CH2:9][CH2:10][CH2:11][N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:2]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Combine Ethyl nipecotate (9.9 mL, 63.6 mmol), K2CO3 (13.2 g, 95.4 mmol), and DMF (300 mL) at room temperature under a Nitrogen atmosphere. Heat reaction mixture to 70° C. for 30 minutes then add 4-Methoxybenzyl chloride (9.5 mL, 69.9 mmol). Stir the reaction for 5 hours at 70° C. then cool the reaction mixture to room temperature and stir for an additional 12 hours. Add Ethyl acetate to the reaction mixture and extract with water and then brine. Dry the organic layer over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 3:1 Hexanes:Ethyl acetate to give 14.6 g (82% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.2 (3H, t), 1.4-1.6 (2H, m), 1.6-1.7 (1H, m), 1.9-2.1 (2H, m), 2.2 (1H, t), 1.5-1.8 (2H, m), 2.9 (1H, d), 3.5 (2H, q), 3.8 (3H, s), 4.1 (2H, dd), 6.8 (2H, d), 7.2 (2H, d); MS m/z 278 (M+1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=O.[NH2:14]N.O>C(O)C>[O:10]1[CH2:11][CH2:12][CH:7]([C:5]2[CH:4]=[CH:3][NH:2][N:14]=2)[CH2:8][CH2:9]1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)C1CCOCC1
Solvent: O
Solvent: CCO
Product: c1cc(C2CCOCC2)n[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-3-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one (compound 294.1, 4.3 g, 23.4 mmol) in ethanol (20 mL) was added NH2NH2.H2O (1.41 g, 28.2 mmol). The reaction mixture was stirred for 3 h at 80° C. The resulting mixture was concentrated under reduced pressure to yield 4.45 g (crude) of the title compound as a light yellow solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].O.[NH2:25][NH2:26]>O1CCOCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:1][C:2]([NH:25][NH2:26])=[S:3])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(NC(=S)NN)cc3)CC2)cc1
Yield: 89 %

Procedure:
A mixture of 47.8 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 100 parts of hydrazine hydrate and 400 parts of 1,4-dioxane is stirred and refluxed for 1 hour. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off, washed with water and with methanol and dried, yielding 46 parts (89%) of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarbothioamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCNCC1
Reactant: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Product: CC1CCN(c2nc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 145 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
A flask was charged with 6′-chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (210 mg, 0.820 mmol) (as prepared in the previous step), and 1-methylpiperazine (182 μL, 1.65 mmol) and the mixture was stirred at 145° C. for 3 h. Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane yielded 202 mg (77%) of the title compound as yellow glass. 1H-NMR (400 MHz, CDCl3): δ 8.19 (d, 1H, J=9.2 Hz), 6.03 (d, 1H, J=9.2 Hz), 3.82 (m, 2H), 3.70 (m, 4H), 2.98 (m, 2H), 2.48 (m, 2H), 2.34 (s, 3H), 1.71-1.60 (m, 3), 1.35 (m, 2H), 0.97 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. for C16H26N5O2, 320.2 (M+H); found: 320.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH:11]=1)[NH2:10].[O-:20][C:21]#[N:22].[Na+]>C(O)(=O)C.O.Cl>[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([NH:10][C:21]([NH2:22])=[O:20])[CH:11]=1
Reactant: N#C[O-]
Reactant: NCCc1ccc(OCc2ccccc2)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NCCc1ccc(OCc2ccccc2)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
2.4 g of 5-(2-aminoethyl)-2-benzyloxyaniline, hydrochloride, is dissolved in a mixture of 20 ml of acetic acid, 5 ml of water and 0.5 ml of 2N hydrochloric acid. A solution of 0.72 g of sodium cyanate in 5 ml of water is added and the mixture is stirred for one hour at room temperature. Thereafter, the mixture is diluted with 100 ml of water, the product is extracted by shaking with methylene chloride and recrystallized from isopropanol, thus obtaining 0.56 g of N-[5-(2-aminoethyl)-2-benzyloxyphenyl]urea, mp 176°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)=[O:4].Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].O>C(OCCO)CCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:17])[NH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=C(O)c1cccnc1Cl
Solvent: CCCCOCCO
Solvent: O
Product: COC(=O)c1ccc2c(c1)NC(=O)c1cccnc1N2
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 1.66 g (0.010 mol) of 4-methoxycarbonyl-o-phenylene-diamine and 1.58 g (0.010 mol) of 2-chloronicotinic acid in 5 ml of 2-butoxyethanol was heated to 140° C. for 2 h, during which time a dark solution, followed by formation of a green solid, was observed. The reaction mixture was poured into 50 ml of water and the solid collected and stirred in 10% sodium carbonate solution for 1 h. The resulting solid was collected, washed thoroughly with water, dried and crystallized from DMF to yield 1.1 g (40% of theory) of a beige crystalline product, m.p. 344°-349° C.
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH2:43][CH3:44])[CH:42]=1)[C:37]([OH:39])=O)=[O:33].[CH2:45]([C:47]1[CH:62]=[C:61]([C:63](=[NH:66])[NH:64]O)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]>>[CH2:45]([C:47]1[CH:62]=[C:61]([C:63]2[N:66]=[C:37]([C:36]3[CH:40]=[C:41]([CH2:43][CH3:44])[CH:42]=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:64]=2)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]
Reactant: CCc1cc(C=O)cc(C(=O)O)c1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(C=O)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)c1
Yield: 34.1 %

Procedure:
The title compound (538 mg) was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-5-ethyl-benzoic acid (600 mg, 3.37 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (1096 mg, 3.37 mmol). LC-MS**: tR=0.74 min; [M+1]+=468.26; 1H NMR (D6-DMSO): δ 1.24 (t, J=7.5 Hz, 3H), 1.30 (t, J=7.5 Hz, 3H), 2.36 (s, 3H), 2.71-2.78 (m, 5H), 2.88 (q, J=7.8 Hz, 2H), 2.90 (s, 3H), 3.21-3.28 (m, 1H), 3.41-3.48 (m, 1H), 3.72-3.82 (m, 2H), 3.84 (s, 2H), 3.94-4.01 (m, 1H), 5.31 (br s, 1H), 5.55 (br s, 1H), 7.70 (t, J=6.0 Hz, 1H), 7.83 (s, 2H), 7.96 (s, 1H), 8.10 (s, 1H), 8.35 (s, 1H), 8.52 (s, 1H), 10.16 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[O:10][C:11]=1[CH2:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[O:10][C:11]=1[CH2:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid (145 mg, 0.57 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (219 mg, 0.57 mmol)[prepared according to Preparation 6] and N,N-diisopropylethylamine (0.50 ml, 2.85 mmol) in dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (292 mg, 0.63 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide (250 mg, 0.41 mmol, 71% yield) as a white solid: LCMS (ES) m/e 585, 587 (M, M+2)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[OH:17][N:18]=[C:19]([O:21][CH2:22][CH3:23])[CH3:20]>O1CCCC1>[C:10]1(=[O:11])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:17][N:18]=[C:19]([O:21][CH2:22][CH3:23])[CH3:20])[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CCOC(C)=NO
Solvent: C1CCOC1
Product: CCOC(C)=NOCCCCN1C(=O)c2ccccc2C1=O

Procedure:
Briefly, N-(4-bromobutyl)phthalimide was treated with the anion of ethyl N-hydroxyacetimidate in tetrahydrofuran to yield ethyl N-[(4-phthalimidobutyl)oxy]acetimidate. The product was then treated with hydrazine to release the desired amine, ethyl N-[(4-aminobutyl)oxy]acetamidate, from the phthalimide. The desired amine was isolated from the crude product by removal of phthalazine-1,4-dione by filtration, and was coupled to biotin using dicyclohexyl carbodiimide and N-hydroxy succinimide in dimethylformamide. Acidic hydrolysis of the coupled product, ethyl N-[(4-biotinamidobutyl)oxy]acetamidate, gave the final product, N-(4-aminooxybutyl)biotinamide, V. Other analogous aminooxy linkers may be prepared by variations of the above synthetic procedure. The synthesis of biotin aminooxy linker V is described in more detail and summarized in the reaction scheme presented in Example 1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH2:6][NH:5][C:4]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@@H:3]1[CH2:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][NH:5][C:4]1=[O:14])=[O:26])=[CH:19]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H]1Cc2ccccc2CNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1Cc2ccccc2CNC1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 16 h
Yield: 44 %

Procedure:
(R)-4-amino-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one hydrochloride salt (387 mg) (amine free base prepared in U.S. Pat. No. 5,545,735) was added to a mixture of tetrahydrofuran (40 mL), 5-chloroindole-2-carboxylic acid (356 mg), 1-hydroxy-7-azabenzotriazole (272 mg), and 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (382 mg) at room temperature. Diisopropylethylamine (202 mg) was added, and the resulting yellow suspension was stirred under argon for 16 h, during which a solution formed. The solution was evaporated under vacuum and the residue was redissolved in ethyl acetate (100 mL). This was washed sequentially with 1.0 M aqueous hydrochloric acid (50 mL), 1.0 M aqueous sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with 20% methanol in diethyl ether (20 mL four times). Drying under vacuum provided pure title compound (283 mg). HPLC/MS [M+H]+, 354.