Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:23]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]([NH2:23])=[O:21])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)CCC1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCC(N)=O)CCC1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Next, anhydrous tetrahydrofuran (7 ml) was added to 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionic acid (0.59 g, 2.0 mmol), and the mixture was stirred at −78° C. N-Methylmorpholine (0.22 ml, 2.0 mmol) and then a solution of isobutyl chloroformate (0.38 ml, 2.9 mmol) in tetrahydrofuran (3 ml) were added to the mixture. After one hour, a 28% aqueous ammonia solution (6.0 ml, 9.8 mmol) was added thereto, and the whole was stirred for 1.5 hours. Chloroform (50 ml) was added to the reaction mixture, the temperature was raised to room temperature, and the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (20 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.34 g (58%) of 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionamide as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:5][C:6](=[O:23])[C@@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:29].[H][H]>CO.[Pd]>[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:5][C:6](=[O:23])[C@@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:8]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(C)C

Procedure:
A solution of 1.95 g. of Nα -benzyloxycarbonyl-D-leucyl-L-leucine methyl ester in 50 ml. of absolute methanol containing 2.08 ml. of 2.38N hydrogen chloride in methanol is treated with 250 mg. of 10% palladium on carbon and is shaken in a hydrogen atmosphere until thin layer chromatography of solution samples indicate completion of the reaction. The catalyst is removed by filtration and the filtrate taken to dryness. The product is used without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][CH:25]=[O:26]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:22][CH2:23][CH2:24][C@@H:25]([OH:26])[C@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: O=CCCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)CCCl
Reaction time: 0.5 h

Procedure:
A vigorously stirred solution of 3-propionyl-2-benzoxazolone (19.1 g) in 200 mL of CH2Cl2 at 0° C. was treated with titanium tetrachloride (12.0 mL) followed by slow addition of triethylamine (16.7 mL). After stirring for 30 minutes, the dark red solution was treated with 60 mL of 1.8 M 3-chloropropanal in CH2Cl2 for 30 minutes, then quenched by addition of 200 mL of 2 N HCl. The phases were separated, and the organic phase was filtered through a pad of silica gel. The aqueous phase was extracted with ether, and the extract was used to wash the pad of silica. The combined silica eluate was concentrated under reduced pressure, resulting in crystallization. The white crystals were collected by vacuum filtration and dried to provide 19.9 g of product; mp=116-117° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:24]([O:25][CH3:26])=[CH:23][C:13]2[O:14][C:15](=[O:22])[C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:12]=2[CH:11]=1)(=O)=O.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])(=O)/C=C/C([O-])=O.C(O)C>CC(C)=O>[CH3:26][O:25][C:24]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:36]2[CH2:37][CH2:38][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)=[CH:11][C:12]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[C:15](=[O:22])[O:14][C:13]=2[CH:23]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCCC3
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCC(c2ccccc2)CC1)CCCC3
Yield: 100 %

Procedure:
Method B (20 h at 50° C.); starting materials: 7,8,9,10-tetrahydro-2-[3-(methanesulfonyloxy)propoxy]-3-methoxy-6H-dibenzo[b,d]pyran-6-one (example 80) and 4-phenylpiperidine; yield 100% (raw). Fumarate: method E; yield 72% on the basis of the methanesulfonyl compound; fusion point 184°-186° C. (from ethanol and acetone).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:8])[N:6]=1.Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][O:22][C:21]2=[O:30])[CH2:16][CH2:15]1>>[CH3:11][CH:10]([NH:9][C:7]([C:5]1[N:6]=[C:2]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH2:23][O:22][C:21]3=[O:30])[CH2:18][CH2:19]2)[S:3][CH:4]=1)=[O:8])[CH3:12]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: CC(C)NC(=O)c1csc(Br)n1
Agent: Cl
Product: CC(C)NC(=O)c1csc(N2CCC(N3C(=O)OCc4ccccc43)CC2)n1

Procedure:
The title compound was prepared from the product of step (i) (0.16 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.15 g) using the method of example 115 step (ii). Yield 0.04 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10](O)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.NC1C=CC=C2C=1[CH:24]=[C:23]([OH:26])[CH:22]=[CH:21]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:9]=2[CH:24]=[C:23]([OH:26])[CH:22]=[CH:21]3)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc(O)c2)CC1
Reactant: Nc1cccc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc3ccc(O)cc23)CC1
Yield: 48 %

Procedure:
Compound 16A is prepared according to the same procedure as 13A, using the following reactants: 8-aminonaphthalen-2-ol (1.6 g, 10 mmol) 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (2 g, 10.4 mmol), sodium carbonate (0.54 g, 5 mmol), 1-butanol (20 ml).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[N:6]1[C:17](=[O:18])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:19])[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])ccc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccccc2C1=O
Yield: 83.6 %

Procedure:
A stirred mixture of 15.0 g (10.1 mole) of 2-ethoxy-4-nitroaniline and 13.4 g (0.09 mole) of phthalic anhydride in 100 ml of glacial acetic acid was heated at reflux for approximately 18 hours. The reaction mixture was cooled then poured into 700 ml of water to produce a solid which was collected by filtration. The solid was dissolved in methylene chloride, and the resultant solution washed first with an aqueous 10% potassium carbonate solution followed by an aqueous sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to yield 23.5 g of 2-(2-ethoxy-4-nitrophenyl)-1H-isoindol-1,3-(2H)-dione as a solid (mp 204°-206° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: COc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Yield: 86.7 %

Procedure:
In the same manner as in Example 259 and using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (80 mg, 0.52 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (160 mg, 85%) was obtained as a white solid. melting point 224° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
A mixture of 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyl-1,3-oxazole (2.10 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-benzyl-3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate as colorless crystals (3.04 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 99-100° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:16]=O>O1CCOCC1>[N:10]1([CH2:16][CH2:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C=O
Reactant: C1CCNCC1
Reactant: CC(=O)c1ccccn1
Solvent: C1COCCO1
Product: O=C(CCN1CCCCC1)c1ccccn1

Procedure:
2-acetylpyridine (121 mg), piperidine (65 mg), and paraformaldehyde (36 mg) were reacted in dioxane (0.2 ml) at 150° C. for 2 hours.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=O)=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[NH2:29][OH:30].Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([NH:29][OH:30])=[O:24])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NO)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A mixture of 1-benzyl-3-(5-hydroxycarbonyl-2-furyl)-1H-indazole (0.40 g, 1.257 mmol), DMF (cat., 2 drops) and SOCl2 (5 mL) was heated to reflux for 2 h. After cooling, the excess SOCl2 was removed under reduced pressure and the almost black oil was dissolved in DME (8 mL). A portion of this acid chloride solution (2 mL, approx. 0.314 mmol) was mixed with a solution of NH2OH.HCl (0.20 g, 2.88 mmol) and K2CO3 (excess) in H2O (2 mL) and allowed to stir at rt overnight A precipitate formed while stirring. The reaction mixture was poured onto water (50 mL) and extracted four times with EtOAc. The combined organic material was dried (MgSO4) and concentrated under reduced pressure to give the crude product (77.4 mg, 74%) as an orange/brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:34]([CH3:48])[CH2:35][CH2:36][N:37]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:37][CH2:36][CH2:35][CH:34]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[C:31]#[N:32])[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[CH3:48]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CS(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CC(CCN)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(S(C)=O)cc2)CC1

Procedure:
Using general procedure C with 4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.57 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (270 mg, 1.2 mmol) followed by general procedure D afforded 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methanesulfinyl-phenyl)-amino]-methyl}-benzonitrile as a white solid (133 mg, 55% over 3 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (430 mg, 2.0 mmol) in CH2Cl2 (20 mL) was added CDl (356 mg, 2.2 mmol). The mixture was stirred at room temperature for 20 minutes, N,O-dimethylhydroxylamine hydrochloride (234 mg, 2.4 mmol) and DIPEA (258 mg, 2.6 mmol) were then added subsequently at 0° C. The mixture was stirred at 0° C. for 0.5 hour, then warmed up and stirred at ambient temperature overnight. The mixture was washed with HCl (1 N), saturated aqueous NaHCO3 and water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound for the next step.
Reaction SMILES: [OH-].[Na+].CO.[SH2:5].Br[CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]>O>[CH3:16][C:9]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:8][CH2:7][SH:5]
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)=CCCC(C)=CCS

Procedure:
To a solution of 2 g. of sodium hydroxide in 40 ml. of methanol saturated with hydrogen sulfide is added 14 g. of 1-bromo-3,7-dimethylocta-2,6-diene. The mixture is stirred at about 25° for about five hours with continued introduction of hydrogen sulfide. The mixture is diluted with water and then extracted with petroleum ether. The organic phase is washed well with water, dried over sodium sulfate and evaporated under reduced pressure to yield 3,7-dimethylocta-2,6-dienylmercaptan which is purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:36]1([CH2:42][CH2:43][S:44][CH:45]([C:49](O)=[O:50])[C:46](O)=[O:47])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[OH:50][C:49]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[C:12]([CH3:20])[CH:13]=2)[O:19][C:46](=[O:47])[C:45]=1[S:44][CH2:43][CH2:42][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccccc1COc1ccc(C(C)=O)cc1C
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1C

Procedure:
The title compound was prepared by Method A using 4'-[(2-methoxyphenyl)methoxy]-3'-methylacetophenone (1.36 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ2.25 (s, 3 H), 2.77 (t, 2 H), 2.97 (t, 2 H), 3.84 (s, 3 H), 5.17 (s, 2 H), 6.67 (s, 1 H), 6.98 (t, 1 H), 7.70 (d, 1 H), 7.27 (m, 6 H), 7.41 (t, 1 H), 7.43 (d, 1 H), 7.65 (m, 2 H), 11.81 (bs, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S-:12][C:13]#[N:14].[K+].O>CN(C)C=O>[CH3:10][C:4]([CH3:11])([CH2:3][CH2:2][S:12][C:13]#[N:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)(C)CCCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)CCSC#N
Temperature: 100 °C
Reaction time: 7 h
Yield: 65.9 %

Procedure:
22.1 g of ethyl 4-chloro-2,2-dimethylbutyrate and 14.5 g of potassium thiocyanate were dissolved in 100 ml of dimethylformamide, followed by stirring at 100° C. for 7 hours. The reaction mixture was added to 500 ml of water and extracted with ethyl ether. After the extract was washed with water and dried over MgSO4, the solvent was distilled off. The residue was distilled under reduced pressure to yield 16.4 g of the title compound in the form of a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:20]([O:19][C:17]([N:13]1[CH2:12][CH2:11][N:10]([C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Cl:1])[CH:9]=2)[CH2:15][CH2:14]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: O=Cc1ccc(N2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(c2ccc(C=O)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
2-Chloro-4-(1-piperazinyl)benzaldehyde (4) (560 mg; 2.5 mmol) is dissolved in THF (20 ml), ClCO2Et (500 mg; 4.5 mmol) and 2N Na2CO3 (20 ml) added and the reaction mixture stirred at room temperature for 20 min. The mixture is extracted with TBME three times, the combined organic phases are dried over Na2SO4 and evaporated to dryness yielding the title compound as white crystals (700 mg; 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([O:10]CC)=[O:9])=[C:4]([CH3:7])[S:5][CH:6]=1.[OH-].[Na+]>CCO>[Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[C:4]([CH3:7])[S:5][CH:6]=1
Reactant: CCOC(=O)c1c(Cl)csc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1scc(Cl)c1C(=O)O
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-chloro-2-methylthiophene-3-carboxylate (F-6) (4.98 g, 24.3 mmol, 1.0 eq) in EtOH (50 mL) ar RT, aqueous NaOH solution (20%, 14.6 g, 73.0 mmol, 3.0 eq) is added and the resulting mixture is stirred at reflux for 1 h. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is poured into ice water (30 mL) and neutralized with concentrated HCl to adjust the pH to 1-2 while keeping the temperature below 5° C. The precipitate is collected by filtration, rinsed with H2O (80 mL) and dried in vacuo to afford the product, 4-chloro-2-methylthiophene-3-carboxylic acid (F-7).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[O:21][N:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl.CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:6]([C:5]4[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=4)=[O:7])[CH2:25]3)[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C3CCCNC3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCCC(c2nc(-c3ccc(F)cc3)no2)C1
Yield: 30 %

Procedure:
The compound was prepared following the procedure described in the Example 3 (D), using 4-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (already prepared before in the Example 4 (B)). Yield: 30% (white powder); mp=82-83° C.; Rf=0.25 DCM/MeOH:98/2);
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21][NH:22][CH3:23]>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:23])[C:2]1[C:11]([CH:12]=[O:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1c(Cl)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Reaction time: 14 h

Procedure:
2-Chloro-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde (5.28 g) and 15 ml of dimethylamine are dissolved in 75 ml of toluene. This mixture is autoclaved for 14 hours at 123°-136° C. The mixture is cooled, evaporated to dryness, and partitioned between ethyl acetate and a saturated aqueous solution of potassium carbonate. The ethyl acetate layer is dried (magnesium sulfate) and evaporated to give an orange oil. Chromatography (silica, 10% ethyl acetate/hexanes) gives 4.20 g of 2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde as an orange solid; 1H NMR (chloroform-d): δ 9.73 (s, 1H), 7.78-6.96 (m, 8H), 3.10 (s, 6H) ppm.
Reaction SMILES: C1C(=O)N(OC(CCCCCN[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]2[S:27][CH2:26][C@@H:25]3[NH:28][C:29]([NH:31][C@H:24]23)=[O:30])=[O:18])=O)C(=O)C1.P([O-])([O-])([O-])=[O:33]>>[OH:33][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:24]2[C@@H:25]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:27]1)=[O:18]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
OA (manufactured by Sigma Co., 30 mg) was dissolved in 0.1M phosphate buffer (pH 7.0 , 1 ml), thereto was added an NHS-LC-biotin solution (manufactured by Pierce Chemical Co., 12.6 mg/ml 0.1M phosphate buffer, pH 7.0; 100 μl) and the mixture was reacted at 30° C. for 1 hour. Thereafter, the procedure in Example 5 (a) was repeated to give a biotin-OA fraction.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH2:44]>C1COCC1>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH:44][C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=1)=[O:26]
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Yield: 74.3 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (3-dimethylamino-propyl)-amide was prepared as described in example 1. 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.6 g, 1.65 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.27 g, 1.68 mmol, 1.02 eq.). The resulting acyl imidazole was then treated with 3-(dimethylamino)propylamine (0.20 g, 1.98 mmol, 1.2 eq.). When complete, the reaction was worked up and the resulting yellow oil purified as described in example 3 to give 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid (3-dimethylamino-propyl)-amide (0.55 g, 74% yield) as a white solid.