Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>C(O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of the product of Example 49A (1.00 g, 2.816 mmol), 4-aminothiophenol (529 mg, 4.224 mmol) and anhydrous sodium acetate (1.155 g, 14.08 mmol) in anhydrous ethanol (30 mL) was heated at reflux under a nitrogen atmosphere for 19 hours. The reaction was cooled to room temperature and the ethanol removed by rotary evaporation. The residue was taken up in water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration of the solid with 4% ethyl acetate/methylene chloride (25 mL) afforded the title compound as a yellow solid (1.091 g, 87%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:26]=CC=C[CH:22]=1.CN(C=[O:44])C>[Pd](Cl)Cl.[Cu](I)I>[OH:44][CH2:22][C:21]#[C:26][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Reactant: CN(C)C=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#CCO)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a slurry of tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate (200 mg, 0.515 mmol), triphenylphosphine (1.4 mg, 0.005 mmol), and palladium chloride (0.5 mg, 0.003 mmol) in DEA (2 mL) was added DMF (400 μL) and copper iodide (1 mg, 0.005 mmol). The reaction mixture stirred at room temperature for 24 h. The next day, the reaction mixture was concentrated and purified using silica gel chromatography (gradient method 0%-100% EtOAc in hexanes) to afford tert-butyl 4-(4-(3-hydroxyprop-1-ynyl)phenyl)piperazine-1-carboxylate as a yellow solid (92 mg, 75% yield based on recovered starting material). 1H NMR (300 MHz, CDCl3): δ 7.34 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.9 Hz), 4.48 (d, 2H, J=5.6 Hz), 3.57 (dd, 4H, J=5.5., 4.9 Hz), 3.18 (dd, 4H, J=5.4, 5.0 Hz), 1.87 (t, 1H, J=5.7 Hz), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 154.7, 150.9, 132.8, 115.5, 113.1, 85.9, 80.0, 51.7, 48.4, 44.8, 28.4; FIRMS calcd for C18H24N2O3: 317.18597 found 317.1861.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7].C(N(C(C)C)CC)(C)C>C1COCC1>[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:4][O:3][CH3:2])=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
N-Methoxyamine hydrochloride (123 mg, 1.5 mmol) was added to a solution of 5-(S)-azidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (600 mg, 1.3 mmol) and diisopropylethylamine (0.26 ml, 1.5 mmol) in THF (8 ml), and the mixture stirred overnight at r.t. Solvent was removed under vacuum, and ethyl acetate with 3% aq. citric acid added. Organic layer was washed twice with 3% citric acid, brine, and dried (Na2SO4). Solvent was removed under vacuum, and the crude material crystallized from ethanol-ether to give a white crystalline product (335 mg, 83%). HPLC Rt=4.8. MS (m/z): [M+H]+=310.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[CH3:25][C:26]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:27][OH:28].C(N(CC)CC)C>CC(C)=O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:28][CH2:27][C:26]([CH3:29])([N+:30]([O-:32])=[O:31])[CH3:25])=[O:11]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(CO)[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.8 g, 0.01 mole) in acetone (10 ml) was added 2-methyl-2-nitropropanol (1.19 g, 0.01 mole) in acetone (10 ml) followed by triethylamine (1.01 g, 0.01 mole) in acetone (5 ml). The temperature rose and a white precipitate formed. The reaction was heated to reflux for 2.5 hours and then stirred overnight at room temperature. After dilution with water (75 ml), the solution was extracted twice with methylene chloride (25 ml @). The organic solution was then washed with 5% sodium hydroxide and finally with a brine solution. The dried solution was concentrated to give an amber oil 2.83 g.
Reaction SMILES: [NH2:1][C:2]1C=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:15])(=O)=O.[OH-].[Na+].[CH:19]([Cl:22])(Cl)Cl>>[NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:19]=1[Cl:22]
Reactant: ClC(Cl)Cl
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Reaction time: 2 h

Procedure:
Methyl 4-aminobenzoate (25 g.) in dry chloroform (250 ml.) was treated dropwise with sulphuryl chloride (10 ml.) and the mixture heated at reflux for 4 hours. A further supply of sulphuryl chloride (10 ml.) was added and heating continued for a further 2 hours. The reaction mixture was poured onto ice and 2N sodium hydroxide solution was added. The organic solution was separated and the aqueous phase extracted with ethyl acetate. The combined organic solution was dried (anhydrous magnesium sulphate) and evaporated to give methyl 4-amino-3,5-dichlorobenzoate as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([CH3:31])[CH:26]=[CH:25][CH:24]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=1>>[C:21]1([CH3:31])[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]4)[CH2:3][CH2:2]2)(=[O:29])=[O:28])[CH:22]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Cc1cccc(S(=O)(=O)N2CCC(COc3cccc4nc(N)nc(N)c34)CC2)c1
Yield: 83 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and m-toluenesulfonyl chloride (71 mg; 0.37 mmol) via Method AA to yield 131 mg. (83% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.54 (m, 4H), 7.47 (t, J=8.4 Hz, 1H), 7.10 (br s, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.0 Hz, 1H), 5.93 (br s, 2H), 3.95 (d, J=6.0 Hz, 2H), 3.69 (br d, J=11.6 Hz, 2H), 2.42 (s, 3H), 2.23 (t, J=12.0 Hz, 2H), 1.86 (m, 3H), 1.36 (m, 2H). MS m/z (ESI) 428 (M+H)+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.[OH:11][C:12]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=1[NH2:14].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.CCCP(=O)=O>ClCCl>[C:20]12([CH2:30][C:31]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:12]=3[OH:11])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.05 ml of N-ethyl-diisopropylamine is added to a solution of 323 mg 2,4-dihydroxyaniline hydrochloride (formula V), 388 mg (adamantan-1-yl)acetic acid (formula R3COOH) and 1.2 ml of propylphosphonic anhydride (50% in ethyl acetate) in 20 ml of dry dichloromethane at 0°. The mixture obtained is stirred for about 18 hours at room temperature and the solvent is evaporated off. The residue is dissolved in 50 ml of ethyl acetate and extracted with 1 M aqueous hydrochloric acid, saturated aqueous NaHCO3 solution and brine. The organic layer is dried and the solvent is evaporated off. The title compound is obtained (m.p. 195-197°).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].C([O-])(=O)CC([O-])=O.[CH3:29][O:30][C:31]([C:33]1[S:45][C:36]2[N:37]=[C:38](S(C)(=O)=O)[N:39]=[CH:40][C:35]=2[CH:34]=1)=[O:32]>C1COCC1.C1COCC1.CN(C=O)C>[CH3:29][O:30][C:31]([C:33]1[S:45][C:36]2[N:37]=[C:38]([CH:10]([C:11](=[O:12])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8](=[O:9])[NH:7][C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[N:39]=[CH:40][C:35]=2[CH:34]=1)=[O:32]
Reactant: O=C(CC(=O)Nc1ccccc1)Nc1ccccc1
Reactant: COC(=O)c1cc2cnc(S(C)(=O)=O)nc2s1
Agent: O=C([O-])CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc2cnc(C(C(=O)Nc3ccccc3)C(=O)Nc3ccccc3)nc2s1
Reaction time: 0.17 h

Procedure:
To a solution of malondianilide (102 mg, 0.40 mmol) in THF (2 mL) was added of NaH (16.3 mg, 60% wt. dispersion in mineral oil, 0.41 mmol). After 10 min, the malonate salt solution was added to a solution of 2-methanesulfonyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg, 0.367 mmol) in THF/DMF (2/0.5 mL). After 1 h, the reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was washed with brine (1×), dried over MgSO4, filtered, and concentrated. The residue was triturated with EtOAc and H2O, and the solid was filtered.: ESIMS calcd 447 (W+H), found 447 M++H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C>CO.C(O)(=O)C>[CH:39]1([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:41][CH2:40]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)C3CC3)c(SC)nn12
Temperature: 25 °C

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in methanol (10 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane (60 μL), acetic acid (298 μL) and sodium cyanoborohydride (171 mg) were added and the mixture was heated to reflux for 6 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogencarbonate was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (74 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N+:11]([O-])([OH:13])=[O:12].C(O)(=[O:17])C>>[CH3:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:17])=[O:4]
Reactant: CC(=O)O
Reactant: O=C(CO)c1ccccc1
Reactant: O=[N+]([O-])O
Product: CC(=O)c1cc([N+](=O)[O-])ccc1O
Temperature: 35 °C
Reaction time: 8 h

Procedure:
2-Hydroxyacetophenone (25.0 g, 183.62 mmol) (B6) was taken up in acetic acid (150 mL) and heated to 35° C. To this solution was then added concentrated nitric acid (26 mL) dropwise over 1.5 hours. After the addition the reaction mixture was stirred overnight at room temperature and worked up by pouring into ice water. The oil so obtained was extracted with ethyl acetate. The ethyl acetate layer was then dried (MgSO4), filtered, concentrated to an oil under reduced pressure and coevaporated with heptane to remove residual acetic acid. The residue was taken up in 50% dichloromethane in heptane and subjected to flash chromatography eluting with the same solvent mixture. The first major band was collected and concentrated to give the desired 2-hydroxy-5-nitroacetophenone, yield 12.0 g (39%). The 2-hydroxy-3-nitroacetophenone isomer was also formed in this reaction and could readily be isolated from the same chromatography column.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.C1(C)C(C)=CC=CC=1.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[N:30][N:29]=1>O>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]3=[N:10][N:9]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:29]3[N:30]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2nn3c(-c4ccccc4)nnc3c3ccccc23)cc1
Yield: 99.3 %

Procedure:
163 mg (1.2 mmol) of benzohydrazide and 165 mg (1.2 mmol) of triethylamine hydrochloride were added to a xylene solution (5 ml) of 271 mg (1.0 mmol) of the obtained 1-chloro-4-(4-methoxyphenyl)-phthalazine, and then stirred under reflux for 2 hours. Water was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 350 mg of a crude product of 6-(4-methoxyphenyl)-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CC(C)=O.O>[C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:2]([F:1])[CH:3]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 28.91 g of 3-fluoro-4-morpholinyl-aniline and 27.88 g of sodium bicarbonate in 500 mL of acetone and 250 mL of water at 0° C. was added 28.68 g of benzyl chloroformate. After stirring the mixture for 1.5 hours, the mixture was poured onto 1000 cc of ice and water, and the ice allowed to melt. The precipitated solid was collected by filtration and washed with 3×250 ml of water, and then dried in a vacuum oven at 750° C. to give a gray-purple solid. This was recrystallized from acetone-water to give a cream-colored solid, mp=123°-124° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: COc1ccc(C(=O)NCc2c(C(=O)N(C)C)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
7-Chloro-3-[(4-methoxy-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 4-methoxybenzoic acid. MS calcd. for C27H24ClN3O4 [(M+H)+] 490.2, obds. 490.0.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][OH:23].[C]=O.CN(C)[CH:28]=[O:29]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([C:22]([O:29][CH3:28])=[O:23])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: CO
Reactant: CN(C)C=O
Reactant: Ic1ccc(Cc2ccncc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(Cc2ccncc2)cc1

Procedure:
1.03 g (3.49 mmol) of 4-(4-iodobenzyl)pyridine was dissolved in 15 ml of dimethylformamide. 39 mg (0.18 mmol) of palladium acetate, 0.97 ml (6.98 mmol) of triethylamine and 2.82 ml (69.8 mmol) of methanol were added to the solution, and the resultant mixture was stirred in the presence of carbon monoxide at 70° C. for 6 hours. The reaction solution was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with water and then with a saturated Aqueous NaCl solution. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17](O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: COc1ccccc1-c1nc(O)c2ccccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Yield: 93 %

Procedure:
A solution of 2-(2-methoxy-phenyl)-quinazolin-4-ol (2.94 g, 11.65 mmol) in phosphorus oxychloride (60 mL) was heated to reflux for 4.5 hours. The orange reaction mixture was concentrated and the resulting gum was treated with ice-cold saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried (MgSO4) and concentrated to give the title compound as a yellow solid (2.92 g, 93%).
Reaction SMILES: CCO[CH:4]1N(C(OCC)=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.CCN(C(C)C)[CH:22]([CH3:24])[CH3:23].CN1C(=[O:34])CCC1>>[CH:8]1[C:7]2[C:6]3[CH:23]=[CH:22][CH:24]=[CH:4][C:5]=3[O:34][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: CN1CCCC1=O
Product: c1ccc2c(c1)oc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dbf-BAE (0.022 mmol), prepared above (F246), and EEDQ (0.024 mmol) are dissolved in NMP (0.3 mL). After 2 h of stirring at ambient temperature, N-glycylfluoresceinamine (0.022 mmol) and DIEA (0.012 mL, 0.067 mmol) are added as in examples 17 and 19 above. After about 18 h at ambient temperature, protected from light, the solvent is removed under reduced pressure and the residue purified by preparative TLC (reversed phase C18, 1 mm, methanol/500 mM NaCl, 6:4) giving the tracer shown below. ##STR15## D. Production of Antisera
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Cl:19])[C:3]=1[NH2:20].[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33])#[N:22].N1C=CC=CC=1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:20][C:3]2[C:4]([Cl:19])=[CH:5][C:6]([C:9]([F:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])=[C:7]([F:8])[C:2]=2[Cl:1])=[O:28])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33])#[N:22]
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)c(F)c1Cl
Reactant: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)c(F)c2Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a solution of 2,6-dichloro-3-fluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)-phenylamine (Example 3.2) (3.48 g, 10 mmol) and 4-cyano-3-nitrobenzoic acid (made as in WO 2008/074427) (3.84 g, 20 mmol) in dichloromethane (40 ml) was added pyridine (4.17 ml, 30 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (5.09 g, 20 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of aqueous hydrochloric acid (1N) (50 ml). The mixture was then extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent:cyclohexane/ethyl acetate 7:3) to give 4-cyano-N-[2,6-dichloro-3-fluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)phenyl]-3-nitrobenzamide (4.76 g, 91% yield). LC-MS (Method 2): RT=2.08, [M−H]−=520.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: O=C(O)c1nc(N2CCOCC2)ccc1Cl
Temperature: 80 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
3,6 Dichloropyridine-2-carboxylic acid (0.55 g, 2.86 mmol), morpholine (1.37 g, 15.7 mmol) and N,N dimethylacetamide (1.37 mL) were combined and stirred for 24 h at 80° C. An additional volume of morpholine (1.39 g, 15.7 mmol) was added and heating continued for 40 hours more. After cooling the DMA was removed in the presence of toluene. The residue was dissolved in water and extracted with ether to remove excess morpholine. The aqueous was acidified to pH=2 and the product extracted into ether. Crystallization from water gave a white solid, 369 mg (53% yield). 1H NMR (CD3OD): δ 3.52 (t, 4H), 3.78 (t, 4H), 6.97 (d, 1H), 7.65 (d, 1H). LC-MS, M+H: 243.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=1>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=2)=[CH:8][CH:9]=1
Reactant: Cc1cncc(C)c1
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Product: Cc1cc(C)c[n+](CCCCCc2ccc(-c3ccccc3)cc2)c1
Product: [Br-]
Temperature: 65 °C
Yield: 85 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (352 mg, 1.16 mmol) and 3,5-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resulting mixture was washed with diethyl ether and then dissolved in water (15 mL). The aqueous solution was extracted with diethyl ether (30 mL×3). Water was removed by lyophilization to afford 406 mg of the title compound. Yield: 85%. 1H NMR (300 MHz, CDCl3) δ 1.45 (m, 2H), 1.70 (m, 2H), 2.08 (m, 2H), 2.53 (s, 6H), 2.63 (t, J=7.8 Hz, 2H), 4.84 (t, J=7.5 Hz, 2H), 7.18-7.58 (m, 9H), 7.93 (s, 1H), 9.21 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 18.6, 25.8, 30.8, 31.9, 35.2, 61.3, 126.8, 126.9, 127.0, 128.7, 128.8, 138.4, 138.7, 140.7, 141.1, 141.7, 146.0 ppm.