Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:24][CH:25]=2)[C@H:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(OCc2ccccc2)cc1
Temperature: 95 °C
Yield: 92.2 %

Procedure:
(3R)-1-tert-Butoxycarbonyl-3-methylpiperazine (3.0 g, 15.0 mmol), 4-benzyloxybromobenzene (4.73 g, 18.0 mmol), sodium tert-butoxide (2.02 g, 21.0 mmol) and toluene (30 ml) were mixed, and the atmosphere was replaced with nitrogen. tri-tert-Butylphosphine tetrafluoroborate (0.52 g, 1.8 mmol) and palladium acetate (0.34 g, 1.5 mmol) were added thereto and heated at 90 to 100° C. for 4 hours. Water and ethyl acetate were added to the brown reaction mixture, and insoluble matter was removed by filtration. The filtrate was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a colorless oil (5.29 g, 92%).
Reaction SMILES: CC(N)(C)C[C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>CCO>[OH:20][C@@H:21]([CH2:22][N:30]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:16][CH:17]=1)[CH2:29][CH:37]([CH3:25])[CH3:36])[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(O)cc2)cc1
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 60 °C

Procedure:
4-(4-(2-Methyl-2-aminopropyl)phenoxy)phenol (0.40 g, 1.55 mmol) was combined with (S)-4-(oxiranylmethoxy)-9H-carbazole (0.250 g, 1.0 mmol) in EtOH (50 mL) and the mixture heated at 60° C. for 20 hours. The mixture was then concentrated in vacuo and the resulting residue chromatographed over silica (1–10% MeOH/CHCl3) which allowed for isolation of the product as the free base. The free base was then dissolved in minimal EtOAc and treated with diethyl ether (25 mL) saturated with HCl. Filtration and drying netted 0.410 g (76%) of product as the HCl salt. MS (FD+): 497. m.p. 80–85° C. (dec). Anal. Calcd for C31H32N2O4.1.3HCl: C, 68.31; H, 6.16; N, 5.14. Found: C, 68.30; H, 6.75; N, 4.62.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C@H:11]1[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]1
Reactant: Fc1ccc2[nH]cc([C@H]3CC[C@H](NCc4ccccc4)C3)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N[C@H]1CC[C@H](c2c[nH]c3ccc(F)cc23)C1
Yield: 87.9 %

Procedure:
A mixture of trans-benzyl-3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.45 g, 1.46 mmol), 0.20 g 10% Pd/C, and ammonium formate (1.0 g, 15.9 mmol) in methanol (30 mL) were refluxed under nitrogen for 4 hours. The reaction mixture was cooled, filtered through celite, and concentrated. The residue was diluted with 1 N aqueous NaOH (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.28 g (100%) of the title compound as a thick oil: MS (ESI) m/z 219 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]2[N:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]2[S:5][CH:6]=1.[C:20]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25](B(O)O)=[C:24]([O:33][CH3:34])[CH:23]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C.O.COCCOC>[C:15]([O:14][C:13](=[O:19])[NH:12][C:7]1[C:8]([O:10][CH3:11])=[N:9][N:3]2[C:2]([C:25]3[C:24]([O:33][CH3:34])=[CH:23][C:22]([C:20]#[N:21])=[CH:27][C:26]=3[O:28][CH3:29])=[CH:6][S:5][C:4]=12)([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1cc(C#N)cc(OC)c1B(O)O
Reactant: COc1nn2c(Br)csc2c1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1cc(C#N)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
To a mixture of tert-butyl (3-bromo-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl)carbamate (461 mg, 1.33 mmol), DME (49 mL) and water (16 mL) were added (4-cyano-2,6-dimethoxyphenyl)boronic acid (412 mg, 2.00 mmol), potassium carbonate (366 mg, 2.66 mmol), triphenylphosphine (174 mg, 0.659 mmol) and palladium acetate (29.8 mg, 0.132 mmol) in that order, and the mixture was stirred at 90° C. (internal temperature) for 2 hours. Water was added to the mixture, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=2/1 then 1/1) to obtain the title compound (296 mg, 0.688 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 6.5 h
Yield: 97.4 %

Procedure:
To a solution of 4.5 g of 6,11-dihydro-5-(4-nitrobenzoyl)-5H-dibenz[b,e]azepine in 230 ml of glacial acetic acid is added 0.58 g of 10% palladium-on-carbon and the mixture under hydrogen (38 psi) shaken in a Parr hydrogenator for 6.5 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated to give 4.0 g of solid. The solid is extracted with 100 ml of dichloromethane and the extract washed with water, dried (Na2 SO4). The solvent is removed to give 4.0 g of yellow crystals, m.p. 168°-175° C. A sample chromatographed on a thick layer silica gel plate with hexane-ethyl acetate (8:7) as solvent gives yellow crystals, m.p. 173°-175° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH:32]1[CH:39]=[CH:38][C:36]([NH2:37])=[N:35][C:33]1=[O:34]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:37][C:36]3[NH:35][C:33](=[O:34])[N:32]=[CH:39][CH:38]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: Nc1cc[nH]c(=O)n1
Product: Cc1cc(F)ccc1-c1nc(Nc2ccnc(=O)[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (100 mg, 0.22 mmol) and cytosine (124 mg, 1.12 mmol) were reacted to give the crude material. Preparative HPLC afforded the title compound, 27 mg (20%). LC-MS: 477.2 (MH+, m/z), 1.77 (Rt, min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3C=N[C:19](OC)=[CH:20][CH:21]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:25]=[C:26](Cl)C1C=CC=CN=1>CO.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:26][N:25]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cn1
Reactant: ON=C(Cl)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccccn3)[C@@H]2C1

Procedure:
The title compound was prepared in an analogous manner as the 4-methoxy-3-pyridyl cycloadduct 3c using chloro oxime 2e. 3e was isolated as a white solid after chromatography with 1.5% methanol/methylene chloride.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][NH:6][N:7]([CH3:18])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][N:6]1[C:1](=[S:2])[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8](=[O:9])[N:7]1[CH3:18]
Reactant: CNN(C)C(=O)Nc1ccc(Cl)cc1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.5 %

Procedure:
A solution of 3.8 g (0.033 mol) thiophosgene in 10 ml chloroform was added dropwise to a stirred solution of 7 g (0.033 mol) 1,2-dimethyl-4-(4-chlorophenyl)semicarbazide and 6.67 g (0.066 mol) triethylamine in 200 ml chloroform. After completion of the addition, the reaction mixture was heated under reflux for 2 hours and stirred at about 25° C. for 3 days. The reaction mixture was then washed with water, dilute hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 10 g of a semi-solid residue. The residue was diluted with 100 ml dichloromethane and filtered. The filtate was chromatographed on 200 g of silica gel. Elution with 1% methanol in dichloromethane gave the product, 3.9 g, as light tan crystals, m.p. 143°-144° C. Infrared analysis showed strong carbonyl absorption at 5.8 micron. The product is tabulated in Table I as Compound No. 2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[C:17]([NH2:19])=[O:18])[C:8]2=O)=[CH:4][CH:3]=1.Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[N:12]4[CH:16]=[CH:15][N:14]=[C:13]4[C:17](=[O:18])[NH:19][C:8]=3[C:9]=2[CH:10]=1
Reactant: NC(=O)c1nccn1C1Cc2ccc(Cl)cc2C1=O
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)Cc1ccc(Cl)cc1-2
Yield: 75 %

Procedure:
The procedure is carried out as in Example 1 but starting with 1 g of 1-(6-chloro-1-oxo-2-indanyl)imidazole-2-carboxamide, a total of 75 ml of methanol and 15 ml of 12N aqueous hydrochloric acid solution. 0.4 g of 7-chloro-5H, 10H-imidazo [1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride is obtained which decomposes without melting above 300° C. [NMR spectrum: (300 MHz; DMSO-d6 ; δ in ppm): 4.12 (s, 2H: --CH2-- in position 10); 7.44 (dd, J=8 and 1 Hz 1H: --H8); 7.66 (d, J=8 Hz, 1H: --H9); 7.95 and 8.25 (2s broad, 1H each: --H of imidazole); 8.05 (d, j=1 Hz, 1H: --H6); 12.97 (unresolved complex, 1H: --CONH--)].
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1cccc(N)c1C
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Cc1cccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c1C
Yield: 58.8 %

Procedure:
Using the procedure of example 1, 2,3-dimethylaniline (98 mg) was reacted with compound 1f (100 mg) to provide compound 34 (50 mg, 59%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=8.0 Hz, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.18-7.13 (m, 3H), 7.02 (dd, J=8.0 Hz, 4.8 Hz, 1H), 2.37 (s, 3H), 2.20 (s, 3H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([O:20]C)[CH:13]=2)=[N:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>>[CH2:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:20])[CH:13]=2)=[N:7][C:6]=1[C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1sc(NC(=O)c2ccc(OC)c(OC)c2)nc1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Product: CCCCc1sc(NC(=O)c2ccc(O)c(O)c2)nc1-c1ccc(O)cc1
Yield: 43.6 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-n-butyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-3,4-dimethoxy-benzamide prepared in Example 63 and boron tribromide were used as starting materials, the crude product was purified by recrystallization with acetone to give a product as a white solid in a yield of 43.6%, mp: 189-190 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.88 (3H, t, J=7.2 Hz, CH3), 1.35 (2H, sextuple, J=7.20 Hz, CH2), 1.62 (2H, quintuple, J=7.20 Hz, CH2), 2.82 (2H, t, J=7.2 Hz, CH3), 6.07 (3H, br, OH), 7.65˜7.85 (3H, m, ArH), 7.32˜7.52 (4H, m, ArH), 12.12 (1H, br, CONH); EI-MS m/e (%): 384.1 (M+, 37), 248.2 (83), 205.1 (100); HREI-MS Calcd. for C20H20N2O4S: 384.1144. found: 384.1146.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]=[CH:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: C(C=Cc1ccccc1)=CCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: OCCCCCCc1ccccc1
Yield: 88 %

Procedure:
The whole of this 1-benzyloxy-6-phenyl-3,5-hexadiene was then treated with hydrogen in the presence of 250 mg of 5% w/w palladium-on-carbon in 40 ml ethanol at room temperature for 15 hours, the catalyst was removed by filtration and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.14 g (yield 88%) of 6-phenylhexanol as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[N+:21]([O-])=O)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[H][H]>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[NH2:21])(=[O:10])=[O:9])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2N)CC1

Procedure:
1-methyl-4-(2-nitro-4-(trifluoromethyl)phenylsulfonyl)piperazine was dissolved in EtOH (20 mL) and the solution was purged with argon. Pd/C (365 mg, 0.34 mmol, 10%) was added to the solution, which was stirred for 3 days in an atmosphere of hydrogen gas. The mixture was again purged with argon, filtered through Celite and concentrated under reduced pressure to afford 2-(4-methylpiperazin-1-ylsulfonyl)-5-(trifluoromethyl)benzenamine. MS m/z=324 [M+H]+. Calc'd for C12H16F3N3O2S: 323.
Reaction SMILES: [CH2:1]([C:4]1([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:8](=[O:11])[O:7][C:5]1=[O:6])[CH2:2][CH3:3].P([O-])([O-])([O-])=[O:16]>C1COCC1>[CH2:1]([C:4]([CH2:10][CH2:9][C:8]([OH:7])=[O:11])([CH2:12][CH2:13][CH3:14])[C:5]([OH:16])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC1(CCC)CCC(=O)OC1=O
Reactant: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCCC(CCC)(CCC(=O)O)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of BSA (300 mg, 5×10-4 mmole) in 20 ml of phosphate buffer was added the hapten, 2,2-dipropylglutaric anhydride as prepared in Example 5 (55 mg, 0.25 mmole in 200 ml THF) in 4 μl portions over an hour. The resulting clear solution was stirred at 4° overnight, after which it was dialyzed in 7×2 liter of water adjusted to pH8 with phosphate buffer, followed by one time with deionized water. The dialysis took 5 days. Lyophilization gave 320 mg of conjugate having a hapten number of 40 as estimated by the amino group precipitation method.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:16]([C:22]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:17][C:18](Cl)=[CH:19][CH:20]=1.O>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:15]1[C:16]([C:22]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:17][C:18]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][CH:20]=1
Reactant: Sc1ccccn1
Reactant: Cc1csc(NC(=O)c2nc(Cl)ccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2nc(Sc3ccccn3)ccc2Sc2ccccn2)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
2-Mercaptopyridine (24 mg; 0.205 mmol) and 68 g (0.492 mmol) of potassium carbonate were added to a solution (2 ml) of 3,6-dichloro-N-(4-methyl-thiazole-2-yl)-2-pyridine carboxamide produced by the same method as in Production Example 1 in N,N-dimethylformamide followed by stirring at 100° C. for 15 hours. Water was added to the reaction solution followed by extracting with ethyl acetate and washing with a saturated aqueous saline solution. After drying and concentrating, the resulting residue was purified by a thin-layer silica gel chromatography (chloroform:methanol=20:1) to give 15 mg (yield: 23%) of the title compound as a yellow solid.
Reaction SMILES: [O-]CC.[Na+].[CH:5]1([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19](=[O:28])[CH2:20][C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[CH:18][C:13]=3[N:12]([CH3:29])[C:11]2=[O:30])[CH2:9][CH2:8][CH2:7][CH2:6]1.[N:31](OCCCC)=[O:32]>C(O)C.O>[CH:5]1([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19](=[O:28])[C:20]([C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[N:31][OH:32])=[CH:18][C:13]=3[N:12]([CH3:29])[C:11]2=[O:30])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Cc1cccc(CC(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Reactant: CCCCON=O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=NO)C(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium ethoxide (9.27 mL of a 21% solution in ethanol, 28.6 mmol) was added to ethanol (12 mL) at 0 deg C. After 5 minutes, 1-cyclopentyl-3-methyl-5-m-tolylacetyl-1,3-dihydro-benzoimidazol-2-one (prepared as described in the general procedure, 5 gm, 14.3 mmol) was added. n-Butyl nitrite (3.34 mL, 28.6 mmol) was then added dropwise over 5 minutes. When the addition was complete, the flask was covered with a septum and allowed to stand in the refrigerator overnight, after which time LCMS of an aliquot showed essentially complete reaction. The reaction mixture was diluted with 300 mL of water and allowed to stir at room temperature overnight. The resulting precipitate was filtered and dried in vacuo. The yellow solid was slurried with benzene for 2 hours and filtered to afford 4.0 gm of a pale tan solid. The title oxime is formed a ca. 10:1 mixture of isomers.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[NH3:30].O1CCOCC1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15]([NH2:30])(=[O:17])=[O:16])[CH2:9]1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Reactant: N
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol, 1.0 eq.) in DCM (1.0 mL) was combined with 0.5 M of ammonia in 1,4-dioxane (874 μL, 4.0 eq.) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (16.3 mg). MS m/z: [M+H1]+ calcd for C13H17F3N2O3S, 339.09; found 339.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][N:27]2[C:23](=[O:33])[C:24]3=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]3[C:26]2=[O:28])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-bromo-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-bromo-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17](S(C3C=CC(C)=CC=3)(=O)=O)=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12].[OH-:30].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:30])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12]
Reactant: CCC(C)COc1ccc(-c2ccc(S(=O)(=O)c3ccc(C)cc3)cc2)cc1Br
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1Br

Procedure:
A mixture of 3'-bromo-4'-(2-methylbutyloxy)-4-p-toluenesulfonylbiphenyl (40 g) prepared in the above step (iii), a 50% aqueous solution (20 g) of NaOH and ethanol (350 ml) was heated under reflux for 4 hours, followed by distilling off ethanol, adding toluene, further adding 6N hydrochloric acid, separating the resulting liquid layer, washing with water to make the solution neutral, drying and distilling off toluene to obtain a raw product of oily 3'-bromo-4'-(2-methylbutyloxy)-4-hydroxybiphenyl, which was then dissolved in pyridine (200 ml), followed by adding benzoyl chloride (20 g), heating the mixture on a water bath, allowing to stand overnight, adding toluene, washing with 6N hydrochloric acid, washing with water, further washing with an aqueous solution of 2N NaOH, washing with water to make the solution neutral, drying and distilling off toluene to obtain 3'-bromo-4'-(2-methylbutyloxy)-4-biphenylylbenzoate (25 g). M.p.: 93.6° C.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+].CO>O>[OH:14]/[N:13]=[C:1]1\[CH2:2][CH2:3][CH2:4][C:5]2[C:10]\1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NO
Reactant: O=C1CCCc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O/N=C1\CCCc2ccccc21

Procedure:
A mixture of 3,4-dihydro-1-(2H)-naphthalenone (72.4 g, 0.495 mol), hydroxylamine hydrochloride (139 g, 1.98 mol), sodium acetate (162 g, 1.98 mol), methanol (500 mL) and water (100 mL) was refluxed for 6 hours. The reaction mixture was diluted with water (2 L), and extracted with ether (800 mL). The organic layer was washed with water, dried and concentrated. The residue was crystallized from ether/hexane to give the title compound: LCMS m/z=162.0 [M+H]+.