Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10])=O)C.CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:16]([N:7]1[CH2:8][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:10])[C:4](=[O:3])[CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)CC(C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1=O
Reaction time: 3 h
Yield: 93.7 %

Procedure:
60.2 g (0.196 mole) of N-ethoxycarbonylmethyl-N-(2-ethoxycarbonylpropyl)benzylamine [prepared as described in Step (2) above] were added dropwise to a suspension of 24.2 g (0.22 mole) of potassium t-butoxide in 300 ml of toluene over a period of 3 hours, whilst keeping the temperature below 6° C. The mixture was then stirred at the same temperature for 3 hours, after which 13 g of acetic acid were added to it. The toluene layer was separated, washed with water and dried, and the solvent was removed by evaporation under reduced pressure, to give 48.0 g of 1-benzyl-4-ethoxycarbonyl-4-methyl-3-pyrrolidone as a red oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].Br[C:15]1[CH:23]=[C:22]([CH3:24])[C:21]2[N:20]([CH3:25])[C:19]3[CH2:26][CH:27]4[NH:31][CH:30]([C:18]=3[C:17]=2[C:16]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:15]2[CH:23]=[C:22]([CH3:24])[C:21]3[N:20]([CH3:25])[C:19]4[CH2:26][CH:27]5[NH:31][CH:30]([C:18]=4[C:17]=3[C:16]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]5)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Reactant: O=[N+]([O-])c1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Yield: 6 %

Procedure:
Intermediate 12 was coupled to the product of Example 71, step C following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(4-nitro-phenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (44 mg, 6%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.86-8.33 (m, 2H), 8.08-8.16 (m, 2H), 8.03 (s, 1H), 7.34 (s, 1H), 5.23 (br s, 1H), 4.71 (br s, 1H), 3.85 (s, 3H), 3.36 (br s, 1H), 2.76 (s, 3H), 2.46 (d, J=16.2 Hz, 1H), 2.11-2.39 (m, 2H), 1.85-1.97 (m, 1H), 1.53-1.67 (m, 1H), 1.36 (br s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([OH:20])=O)=[CH:11][CH:10]=1.CN(C(ON1N=[N:46][C:41]2[CH:42]=CC=N[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>ClCCl.CN(C=O)C>[CH:41]([NH:46][C:18]([C@@H:16]1[CH2:17][C@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][C:6]2[S:5][C:4]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)=[N:3][C:2]=2[CH3:1])=[CH:10][CH:11]=1)=[O:20])([CH3:42])[CH3:40]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)NC(C)C)cc1
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (I-2m) (0.10 g, 0.231 mmol) in dichloromethane (2 mL) and DMF (1 mL) was added HATU (0.13 g, 0.346 mmol). The mixture was stirred for 15 mins followed by addition of isopropylamine (0.04 g, 0.693 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a yellow ppt which was filtered and dried under high vacuum to give the title compound as a yellow powder (0.062 g, 60%). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 6.96 (d, J=8.1 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 5.29 (d, J=7.8 Hz, 1H), 4.45 (s, 2H), 4.15-4.08 (m, 1H), 4.06 (s, 1H), 2.49 (s, 3H), 2.42-2.34 (m, 1H), 1.54-1.51 (m, 1H), 1.44-1.39 (m, 1H), 1.53-1.10 (m, 7H).
Reaction SMILES: O1CCCCC1ONC([C@H]([C@@:21](C)([CH2:30][CH2:31][CH3:32])[C:22]([NH:24][NH:25]CC(C)C)=[O:23])C/C=C/C1C=CC=CC=1)=O.Cl.[CH2:35](N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:35][CH:31]([CH3:32])[CH2:30][CH2:21][C:22]([NH:24][NH2:25])=[O:23]
Reactant: CCC[C@@](C)(C(=O)NNCC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)CCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.157 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-methylvalerohydrazide in 5 ml of dimethylformamide was treated at room temperature under nitrogen with 0.250 g of 2-[N-(9-fluorenylmethyloxycarbonyl)-4-piperidine]acetic acid and 0.132 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride. The mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution, saturated sodium chloride solution, and then dried over anhydrous magnesium sulphate and evaporated to give 0.500 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-2-(N-(9-fluorenylmethyloxycarbonyl)-4-piperidyl)acetyl]-4-methylvalerohydrazide in the form of a clear oil.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:41][CH2:42][CH2:43][CH3:44])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N+:25]=2[O-:30])=[O:22])[CH2:19][CH2:18][N:17]1C(OCC1C=CC=CC=1)=O)=[O:15])[O:4]CC1C=CC=CC=1)=[O:2]>CCO.[OH-].[OH-].[Pd+2]>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:41][CH2:42][CH2:43][CH3:44])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N+:25]=2[O-:30])=[O:22])[CH2:19][CH2:18][NH:17]1)=[O:15])[OH:4])=[O:2]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2cccc[n+]2[O-])CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCC[C@H](CN(O)C=O)C(=O)N1NCC[C@H]1C(=O)Nc1cccc[n+]1[O-]
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a solution of phenylmethyl (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl]-3-{[(1-oxido-2-pyridinyl)amino]carbonyl}-1-pyrazolidinecarboxylate (85 mg, 0.14 mmol) in EtOH (15 mL) was added Pd(OH)2/C (30 mg). The mixture was degassed and placed under H2 atmosphere for 1 h at rt. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by pre-HPLC to provide the titled compound (22 mg, 40%). LCMS: (M+H)+: 380.2.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[N:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:5][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:12])[CH2:3][CH2:2][N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(CCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(CCC(C)(C)c2ccccc2)CC1
Yield: 81.8 %

Procedure:
A solution of 1-bromo-3-methyl-3-phenylbutane (0.73 g), ethyl piperazinecarboxylate (0.51 g) and anhydrous potassium carbonate (0.50 g) in tetrahydrofuran (5 ml) was refluxed under heating for 36 hours. To the reaction solution was added water and the solution was extracted with ethyl acetate. After washing with a saturated aqueous solution of sodium chloride, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (15 g) and elution with a hexane-ethyl acetate (2:1) mixture gave 0.80 g of ethyl 4-(3-methyl-3-phenylbutyl)piperazine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:9]([N:7]3[CH2:8][C:4](=[N:3][O:2][CH3:1])[CH2:5][C@H:6]3[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccc(F)cc3)cc2)C1
Yield: 39 %

Procedure:
Following the general methods as outlined in Example 4, starting 1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and 4′-fluoro[1,1′-biphenyl]-4-carboxylic acid, the title compound was isolated, after flash-chromatography, as a mixture of two isomers as an oil in 39% yield (97.6% purity by HPLC).
Reaction SMILES: [C:1]1([C@@H:7]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH2:9][N:8]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[C:32]([F:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl[Pd]Cl>[Cl:28][C:29]1[N:34]=[C:33]([C:10]2[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:32]([F:36])=[CH:31][N:30]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(B2OC(C)(C)C(C)(C)O2)=C[C@H]1c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2nc(Cl)ncc2F)=C[C@H]1c1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Crude 34-1 (0.364 g, 0.98 mmol) was dissolved in anhydrous DMF (10 mL), degassed and filled with an N2 atomsphere. 2,4-dichloro-5-fluoropyrimidine (0.25 g, 1.47 mmol), potassium carbonate (0.40 g, 2.94 mmol) and PdCl2 (dppf) (36 mg, 0.05 mmol) were added to the solution and the mixture was stirred at 80° C. for 2.5 h. The reaction mixture was partitioned between water (3×100 mL) and ethyl acetate (100 mL). The organic layer was then washed with sat. aqueous NaCl, dried over sodium sulfate, filtered, and concentrated. The crude oil was purified using reverse phase HPLC (CH3CN/H2O/TFA 0-90% gradient) to provide tert-butyl (2S)-4-(2-chloro-5-fluoropyrimidinyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (34-2). 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J=2.4 Hz, 1H), 7.35 (m, 5H), 6.96 (m, 1H), 5.82 and 5.66 (m, 1H), 4.82 (m, 2H), 1.50 and 1.22 (s, 9H). LRMS: m/z (M-CH3) 361.3 found, 361.3 required.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][N+:12]([O-])=O)=[CH:6][CH:5]=1.[H][H]>[Pd].C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(CCN)cc1
Yield: 103.9 %

Procedure:
Palladium on carbon (10%, 50 mg) was added to a solution of 4-(2-nitrovinyl)benzoic acid methyl ester (228 mg) in 5 mL of ethyl alcohol and 2 mL of acetic acid. The reaction vessel was saturated with hydrogen and stirred under a 1 atm hydrogen atmosphere for 20 h. The vessel was saturated with nitrogen and filtered through celite. Evaporation of the solvents gave 205 mg of crude 4-(2-amino-ethyl)-benzoic acid methyl ester.
Reaction SMILES: [P:1]([CH2:5][O:6][C:7](CC)(CC)[C:8]([O:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])(CC)CC)([OH:4])([OH:3])=[O:2]>Cl>[P:1]([CH2:5][O:6][CH2:7][CH2:8][O:13][CH2:14][P:15]([OH:17])([OH:18])=[O:16])([OH:3])([OH:4])=[O:2]
Reactant: CCC(CC)(OCP(=O)(O)O)C(CC)(CC)OCP(=O)(O)O
Agent: Cl
Product: O=P(O)(O)COCCOCP(=O)(O)O

Procedure:
The method of claim 6 wherein tetraethyl ethyleneglycol di-(phosphonomethyl) ether is dissolved in concentrated hydrochloric acid, and the resulting solution is refluxed to yield ethyleneglycol di-(phosphonomethyl) ether.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][S-:13].[Na+].O>CN(C=O)C>[CH3:12][S:13][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.3 %

Procedure:
Methyl 6-chloronicotinate (100 mg, 0.583 mmol) in N,N′-dimethylformamide (1.5 mL) was added with sodium thiomethoxide (41 mg) under ice-cold conditions, and then stirred at room temperature for 3 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and methyl 6-(methylthio)nicotinate (120 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([C:24]([O:26]CC)=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([C:24]([OH:26])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CCOC(=O)C1(C)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-c2nnc3n2CCCC3(C)C(=O)O)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.5 g), 1N aqueous sodium hydroxide solution (7.57 mL) and THF (8 mL) was stirred at room temperature for 16 hr. The reaction mixture was acidified with 1N hydrochloric acid, and the organic layer was evaporated under reduced pressure. The mixture was stirred at room temperature for 30 min, and the obtained solid was collected by filtration to give the title compound (1.36 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][C:3]=1[N+:17]([O-])=O>C(O)C.[Pd]>[NH2:17][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(NC(=O)Cn2ccnc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NC(=O)Cn2ccnc2)cc1N
Yield: 108.2 %

Procedure:
To a solution of 1H-imidazole-1-ylacetic acid (284 mg, 2.25 mmol) and 2-nitrobenzene-1,4-diamine (324 mg, 2.12 mmol) in acetonitrile (20 mL) was added 3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4(3H)-one (DEPBT, 632 mg, 2.11 mmol) and triethylamine (600 μL, 4.4 mmol). The mixture was stirred for 4 d at room temperature. The red precipitate was collected by filtration and washed with acetonitrile to give N-(4-amino-3-nitrophenyl)-2-(1H-imidazol-1-yl)acetamide (430 mg, 88% yield), 98% pure. A solution of N-(4-amino-3-nitrophenyl)-2-(1H-imidazol-1-yl)acetamide (430 mg, 1.65 mmol) in ethanol (20 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (100 mg, 0.09 mmol) at room temperature overnight. The mixture was filtered, giving a blue solution. Removal of the solvent under reduced pressure gave N-(3,4-diaminophenyl)-2-(1H-imidazol-1-yl)acetamide (413 mg) as a blue semi-solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)=[O:19]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Yield: 90 %

Procedure:
In the same manner as that described in Example 1(1), a reaction was carried out using commercially available p-aminoacetophenone (309 mg, 2.3 mmol), triethylamine (0.48 ml, 3.4 mmol), and 4-formylbenzoyl chloride (500 mg, 3.0 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 1(1) to afford a crystalline residue which was recrystallized from a mixture of tetrahydrofuran and hexane to give 4′-acetyl-4-formylbenzanilide (552. mg, yield 90%) as pale yellow powdery crystals.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:40]=[CH:39][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4N=CN[CH:34]=4)=[O:29])=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.C(C1C[CH2:47][C:46](=[O:49])[CH2:45]1)(O)=O.[NH4+].[OH-].[C:52]([C:56]([OH:58])=[O:57])([F:55])([F:54])[F:53]>C(Cl)(Cl)Cl.CO>[F:53][C:52]([F:55])([F:54])[C:56]([OH:58])=[O:57].[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:40]=[CH:39][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([CH:30]4[CH2:34][CH2:47][C:46](=[O:49])[CH2:45]4)=[O:29])=[CH:25][CH:26]=3)=[CH:13][CH:12]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1c[nH]cn1
Reactant: O=C1CCC(C(=O)O)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(C(=O)Nc2ccc(-c3sc4ccccc4c3Cc3ccc(OCCN4CCCC4)cc3)cc2)C1
Yield: 98 %

Procedure:
By essentially following the conditions described in Example 1, Part F, the free base of the title compound was prepared as a foam from 2-(4-aminophenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Example 16; Part D) and 3-carboxycyclopentanone in 98% yield following radial chromatography (SiO2; 1% then 2% then 5% MeOH in CHCl3 sat'd with NH4OH). The solid was taken up in 5 mL of MeOH and was treated with 1.2 eq of CF3CO2H. The solution was concentrated in vacuo to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([NH2:13])=[C:6]([NH2:14])[CH:5]=1)([O-:3])=[O:2].[C:15]1([C:21](=O)[C:22](=O)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH3:23][C:22]1[C:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:14][C:6]2[C:7](=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:13]=1
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Solvent: CCO
Product: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2nc1-c1ccccc1
Yield: 14.3 %

Procedure:
4,5-Dinitro-1,2-phenylenediamine (890 mg, 4.5 mmol) (G. W. H. Cheeseman, J. Org. Soc. 1170-5, 1962) was mixed with 1-phenyl-1,2-propanedione (800 mg, 5.4 mmol) in ethanol (18 ml). The mixture was heated to reflux for 4 hours. The ethanol was removed by evaporation and the remaining brown oil was suspended in dichloromethane (20 ml). Purification by column chromatography on silica gel eluting with dichloromethane followed by recrystallisation from ethanol yielded the title compound (200 mg, 14%).
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: CCOC(C)=NO
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
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: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32](O)=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:17][C:18]1[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccccc2C)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccccc2C)c1

Procedure:
291 mg of compound 31 was obtained in a similar manner to those described in the Examples 1 and 2 using 521 mg of ethyl 4-(2-aminophenoxy)butyrate and 517 mg of 3-[1-(2-methylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ncn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 30 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 3-nitro-1H-1,2,4-triazole (2 g, 17.54 mmol, 1.00 equiv) in dichloromethane (100 mL), 3-(trifluoromethyl)phenylboronic acid (6.66 g, 35.05 mmol, 2.00 equiv), Cu(OAc)2 (4.79 g, 26.32 mmol, 1.50 equiv), pyridine (2.77 g, 35.06 mmol, 2.00 equiv), and molecular sieves (5.2 g). The resulting solution was stirred overnight at 30° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:10) to give 2.2 g (49%) of product as a white solid.