Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH3:3].[O:18]1[CH:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19]1>CO>[OH:18][CH:20]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][N:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:1][CH2:2][N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:17])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:10][CH:11]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Solvent: CO
Product: CCCN(CCN(Cc1ccccc1)CC(O)COc1ccccc1)C(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7.95 9 (20 mmol) N-[2-(phenylmethyl)amino)ethyl]-N-propyl-4-[(methylsulfonyl)amino]benzamide in 20 mL 10% aqueous methanol is added 2.89 mL (21 mmol) 1,2-epoxy-3-phenoxypropane. The solution is stirred at room temperature for 24 h. After this time, the solvents are evaporated and the title compound is obtained as a foamy solid via column chromatography on silica gel (hexane:acetone, 9:1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:23][C:24]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[C:24]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:29]
Reactant: CCOC(=O)C(N)(CC)CC
Reactant: O=C(O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid (Example 234 b) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=432.3 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=O)=O)=[CH:16][CH:15]=2)[C:11]#[N:12])=[CH:6][CH:5]=1.C(=O)/C=C/C>>[F:24][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:23])=[CH:16][CH:15]=2)[C:11]#[N:12])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(NC(C#N)c2ccc(OC(F)F)cc2)cc1
Agent: C/C=C/C=O
Product: CSc1ccc(NC(C#N)c2ccc(OC(F)F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-difluoromethoxyphenyl)-α-(4-methylsulfonylanilino)acetonitrile [prepared as described in step (ii) above] and crotonaldehyde as starting materials, the title compound was obtained as a white powder (yield 31%), melting at 98-99° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: Fc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-fluorophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 324.0 (M+H)+, retention time 1.31 minutes.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Br)cnc1Br
Temperature: 80 °C
Yield: 69.4 %

Procedure:
To the solution of 2,5-Dibromo-3-nitro-pyridine (10.30 g, 35.47 mmol) in the 100 ml of ethanol was added SnCl2 (24.0 g, 106.42 mmol) slowly. The reaction mixture was heated at 80° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (250 mL) was added, white solid separated out, then, basified the reaction mixture with NaOH Solution. To this added the 250 ml of ethyl acetate. Filtered it and washed the residue with ethyl acetate, layers are separated, dried (Na2SO4), filtered, concentrated to give the desired product (6.20 g, 67.39%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][C:3](=[O:13])[CH2:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][CH2:2][C:3]1=[O:13]
Reactant: O=C1CNc2ccccc2C(=O)N1
Reactant: BrCCCCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CNc2ccccc2C(=O)N1CCCCCBr
Reaction time: 2 h
Yield: 52.8 %

Procedure:
In 10 ml of dimethylformamide (DMF) was dissolved 100 mg of 2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione and the solution then ice-cooled. Then, to the resulting solution were added 0.116 ml (1.5 equivalent) of 1,5-dibromopentane and 27.3 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 2 hours with ice-cooling. The reaction solution was poured into ice-cooled water containing citric acid, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate phase was then washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The product was purified in the same manner as in Reference Example 1 to give 97.5 mg (yield: 52.8%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.O[N:17]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl.O>[NH2:17][O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CON)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.2 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5 g, 23 mmol) in CH2Cl2 (250 mL) was added 2-hydroxyisoindoline-1,3-dione (5.6 g, 34.5 mmol) and triphenylphosphine (15 g, 57.5 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (11.1 ml, 57.5 mmol) was slowly added dropwise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture H2O (300 mL) was added and extracted with CH2Cl2. The organic layers were washed with brine. Dried over anhydrous MgSO4, filtered and concentrated to provide clear oil, which was purified by flash chromatography (50% EtOAc-Hexane). The resultant clear oily compound 2S was dissolved in CHCl3:CH3OH (50 ml). Hydrazine hydrate (25 mL, 0.25 mol) was added. The reaction mixture was stirred at ambient temperature overnight. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear oil, which was purified by flash chromatography (10% CH3OH—CH2Cl2) to afford 3 g (56%, over two steps) of tert-butyl 2-(aminooxymethyl)morpholine-4-carboxylate (2T) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9H) 3.46-3.62 (m, 2H) 3.61-3.79 (m, 4H) 3.79-4.04 (m, 3H). [M+H] calc'd for C10H20N2O4, 233; found, 233.
Reaction SMILES: C(O)(=O)C.CCC(C)=O.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[C:22]=2[C:30]2[O:34][CH:33]=[N:32][CH:31]=2)[N:13]=1>[Ag].C(OCC)(=O)C>[NH2:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:14]2[N:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([O:11][CH3:10])[N:13]=2)[C:22]=1[C:30]1[O:34][CH:33]=[N:32][CH:31]=1
Reactant: COc1cc(OC)nc(Oc2cccc([N+](=O)[O-])c2-c2cnco2)n1
Agent: [Ag]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: COc1cc(OC)nc(Oc2cccc(N)c2-c2cnco2)n1
Temperature: 50 °C

Procedure:
0.24 g silver powder was suspended in 60% aqueous solution of acetic acid in a volume of 3.2 ml, and MEK solution of 0.6 g 5-[2-(4,6-dimethoxypyrimidine-2-yloxy)-6-nitrophenyl]oxazole was fed dropwise thereto at 50° C. while stirring, then the resulting solution was further stirred for 2 hours at 60-70° C. After completing the reaction, the solution reacted was added with ethyl acetate and was filtrated. The filtrate was washed with water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, affording the objective substance in an amount of 0.45 g.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]([NH2:15])(=[S:14])[CH2:12][CH3:13]>C(O)C>[CH2:6]([O:5][C:3]([C:2]1[S:14][C:11]([CH2:12][CH3:13])=[N:15][C:8]=1[CH3:10])=[O:4])[CH3:7]
Reactant: CCC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(CC)nc1C
Yield: 81.5 %

Procedure:
A solution of ethyl 2-chloroacetoacetate (2.00 g, 10.04 mmol) and thiopropionamide (1.00 g, 11.22 mmol) in ethanol (100 mL) was heated at reflux overnight. The solvent was evaporated and dichloromethane (100 mL) added. The solution was washed with water (2×100 mL) and brine (100 mL), dried (MgSO4), filtered, evaporated and the concentrate was chromatographed over silica gel (10% ethyl acetate/hexanes) to give 2-ethyl-4-methylthiazole-5-carboxylic acid ethyl ester (1.63 g, 81% yield) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:32])[C:21]#[C:22][CH2:23][O:24][Si](C(C)(C)C)(C)C)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:32])[C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(C#CCO)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.9 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide (300 mg, 0.587 mmol) was dissolved in 60 mL of solution (acetic acid:water:tetrahydrofuran=3:1:1) and stirred at room temperature overnight. The reaction solution was treated with cold brine solution and extracted with ethyl acetate. The ethyl acetate solution was washed with sodium bicarbonate solution and brine. Evaporation of the dry ethyl acetate solution yielded 275 mg of the product: HRMS m/z 397.0258 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:11]3[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=3)[C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)N3CCOCC3)c12
Reactant: Oc1ccc(F)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c(Oc3ccc(F)cc3)ncc(C(=O)N3CCOCC3)c12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (1-chloro-5-methylisoquinolin-4-yl)(morpholino)methanone Intermediate-11a (1 equiv) in dry DMF (5 mL) was added, 4-fluorophenol (1.1 equiv), CuI (1.1 equiv) and K2CO3 (2 equiv) in a sealed tube. The reaction mixture was degassed for 20 min and then stirred at 150° C. for 2 h. It was allowed to reach RT and then diluted with EtOAc. The slurry was filtered through celite, and then washed with EtOAc. The solvent was then removed, and the residue was purified by column chromatography (15% EtOAc:Hexane) to afford the title compound; 1H NMR (400 MHz, CDCl3) δ 2.61 (s, 3H), 3.23-4.13 (m, 8H), 7.15-7.20 (m, 4H), 7.55-7.61 (m, 2H), 7.82 (s, 1H), 8.39-8.41 (m, 1H); MS m/z 367 (M+1).
Reaction SMILES: [CH3:1][CH:2]([OH:17])[CH2:3][C:4](=[CH2:16])[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([CH3:13])=[CH:7][C:6]1([CH3:15])[CH3:14].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClCCl>[CH3:14][C:6]1([CH3:15])[CH:7]=[C:8]([CH3:13])[CH2:9][C:10]([CH3:11])([CH3:12])[CH:5]1[C:4](=[CH2:16])[CH2:3][C:2](=[O:17])[CH3:1]
Reactant: C=C(CC(C)O)C1C(C)(C)C=C(C)CC1(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C(CC(C)=O)C1C(C)(C)C=C(C)CC1(C)C
Yield: 74.7 %

Procedure:
A solution of α,2,2,4,6,6-hexamethyl-γ-methylene-3-cyclohexene-1-propanol (2.36g, 0.01 mol) in dichloromethane (10 mL) was added over a 30 min period to a mixture of pyridinium chlorochromate (3.25g, 0.015 mol), sodium acetate (2.30g, 0.03 mol) and dichloromethane (15 mL) at 25° C. The mixture was filtered and the filtrate washed with water (100 mL) and 5% sodium carbonate solution (100 mL). The solvents were evaporated and the residue chromatographed to provide after kugelrohr distillation 1.75g (75% yield) of 4-(2,2,4,6,6 -pentamethyl-3-cyclohexen-1-yl)-4-penten-2-one (GLC purity: 94%). 1H-NMR 6 0.93 (3H, s) 0.95 (3H, s), 1.02 (6H, s), 1.62 (3H, s), 1.6-1.8 (2H, m), 1.97 (1H, s), 2.18 (3H, s), 3.15 (2H, s), 5.05 (2H, broad s); IR (film) vmax 2950, 1710, 1630, 1430, 1380, 1350 cm-1; MS m/e 234, 219, 201, 191, 176, 161, 149, 123, 96.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@@H:2]([CH3:4])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of known tert-butyl D-(-)-lactate (160 mg), 4-chlorophenol (108 μl) and triphenylphosphine (287 mg) in dry tetrahydrofuran (6 ml) on an ice bath, diethylazodicarboxylate (173 μl) was added dropwise over about 5 minutes. After the addition, the ice bath was removed and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was then evaporated with a rotary evaporator (water bath temperature 25° C.). The residue thus obtained was purified by silica gel chromatography [silica gel 30 g, eluant:ethyl acetate-hexane (1:10)] to give tert-butyl (2S)-(-)-2-(4'-chlorophenoxy)-propionate (173 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N=Cc2ccccc2)ccc1O
Solvent: c1ccncc1
Product: COC(=O)c1cc(N=Cc2ccccc2)ccc1OC(C)=O
Reaction time: 48 h
Yield: 49 %

Procedure:
Methyl 2-hydroxy-5-benzylideneaminobenzoate (23.5 g, 92.2 mmole) was dissolved in pyridine (50 ml) and acetic anhydride (11 ml) was added after which the reaction mixture was left at room temperature for 48 hours and evaporated to dryness, in vacuo. The remaining material was recrystallized from hexane to give the title compound (13.4 g, 49%), m.p. 101°-103° C. Found (Calc. for C17H15NO4) C 68.57 (68.69), H 4.98 (5.05) N 4.80 (4.71).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:36]=[C:37]([C:45]([F:47])([F:46])[F:48])[CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=3)=[CH:32][CH:33]=2)[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([Cl:25])[CH:9]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: FC(F)(F)c1cc(Sc2ccc(Br)cc2)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Yield: 27.5 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-3,5-bis-trifluoromethyl-benzene (0.334 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to provide {4-[4-(3,5-bis-trifluoromethyl-phenylsulfanyl)-phenyl]-6-chloro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.083 g, 27%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[NH2:16][C:17]1[CH:26]=[C:25]([OH:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[NH2:16][C:17]1[CH:26]=[C:25]([O:27][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=3)[O:11][C:2]([CH3:1])([CH3:15])[CH:3]2[OH:14])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: Nc1cc(O)c2ccccc2n1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(Oc2cc(N)nc3ccccc23)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 2-amino-quinolin-4-ol as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:32])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccncc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 mL (0.061 mMol) 4-pyridinecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]([N:9]([CH3:11])[CH3:10])[CH3:8])=[O:4].S(=O)(O)[O-:25].C(O)C(N)(CO)CO>>[CH3:10][N:9]([CH3:11])[CH:7]([CH3:8])[CH2:6][C:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][C:15]([OH:25])=[CH:16][CH:17]=1)[C:3](=[O:4])[CH2:2][CH3:1]
Reactant: O=S([O-])O
Reactant: CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Agent: NC(CO)(CO)CO
Product: CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccc(O)cc1
Reaction time: 0.03 h

Procedure:
The procedure of Example 5 is repeated using the methadone derivative 6-methylamino-4-phenyl-4-(4-hydroxyphenyl)heptan-3-one except for the following modifications. Instead of mixing the NaI125 reaction mixture on a Vortex mixer the mixture is shaken gently for 90 seconds and after addition of the bisulfite the mixture is shaken gently for 30 seconds. Finally 2.0 ml of 0.1 M Tris buffer pH 7.0 is used prior to the column chromatography step. The resulting above-captioned labeled antigen is obtained in Fractions #22-27 at a radioactive concentration of 10.5μCi/ml. EXAMPLE 7
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([O:44][CH:45]([CH2:53][O:54][C:55](=[O:71])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:46][S:47][CH2:48][CH2:49][C:50](O)=[O:51])(=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:50](=[O:51])[CH2:49][CH2:48][S:47][CH2:46][CH:45]([O:44][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:53][O:54][C:55](=[O:71])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-aminobenzoylaspartic acid di-t-butyl ester (168 mg) in pyridine (2.3 ml), phosphorus trichloride (0.02 ml) was added, followed by stirring at room temperature for 2 hours. To the mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (150 mg) was added, followed by stirring at room temperature for 64 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate =3:1) to yield the title compound (197 mg, yield 85%) as a wax-like substance.