Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C([O:14][C@@H:15]1[C@@H:28]([O:29]C(=O)C)[C@H:27]([O:33]C(=O)C)[CH2:26][S:25][C@H:16]1[O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Br)[CH:23]=1)(=O)C>>[O:17]([C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:23]=1)[C@@H:16]1[S:25][CH2:26][C@@H:27]([OH:33])[C@H:28]([OH:29])[C@H:15]1[OH:14]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1ccccc1F
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3ccccc3F)c2)SC[C@H]1O

Procedure:
By following a procedure analogous to Example 122 starting from 2-fluoro-phenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 5-(2-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@H:17]1[CH2:22][NH2:23])=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>CC1C=CC=CC=1C.CCOC(C)=O.O>[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@H:17]1[CH2:22][NH:23][C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNc1ncc(Br)cn1
Temperature: 140 °C

Procedure:
5-Bromo-2-chloro-pyrimidine (18.4 mmol) is added to a solution of (1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (14.1 mmol) in o-xylene (30 mL). K2CO3 (42.4 mmol) and DIPEA (42.4 mmol) are added successively and the mixture is heated to 140° C. for 17 h. The mixture is cooled to RT and diluted with EtOAc (100 mL) and water (100 mL). The layers are separated and the aq. layer is extracted with DCM (100 mL). The combined organic layers are dried over MgSO4 and concentrated in vacuo. The obtained brownish solid is stirred in ether (75 mL). The suspension is filtered and washed with ether (25 mL) and the residue is dried in vacuo to give the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]1[C:8](S(C)(=O)=O)=[N:9][CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:6][C:7]1[C:8]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)c1ncccc1Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1cccc1
Temperature: 60 °C
Reaction time: 27 h
Yield: 63.9 %

Procedure:
A mixture of 1.0 g of pyrrole, 3.0 g of 3-chloro-2-methanesulfonylpyridine, 6.6 g of cesium carbonate and 10 ml of N,N-dimethylformamide was stirred at 60° C. for 27 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 1.7 g of 3-chloro-2-(1H-pyrrol-1-yl)pyridine of the formula:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][C:4]1[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([I:1])[CH:3]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a flask containing the product of Step 2 (2.79 g, 7.06 mmol) in AMY (71 mL) were added tert-butyldimethylsilyl chloride (1.60 g, 10.59 mmol), imidazole (0.96 g, 14.12 mmol) and DMAP (86 mg, 0.71 mmol). After two hours, The reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica gel was used for purification to yield N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-iodophenyl]-4-(trifluoromethyl)pyrimidin-2-amine (3.46 g, 6.79 mmol, 96% yield). MS ESI: [M+H]+ m/z 510.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH2:24][CH2:25][CH2:26][OH:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C.Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH2:24][CH2:25][CH:26]=[O:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc(F)c(-c2ccc(OCc3cccc(CCCO)c3)cc2CC(C)(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(CCC=O)c3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)propan-1-ol (357 mg) and triethylamine (0.68 mL) in DMSO (5.0 mL) was added sulfur trioxide pyridine complex (390 mg), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 0.50N hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (167 mg) as a colorless oil.
Reaction SMILES: [F:1][CH:2]([CH2:21][CH2:22][CH3:23])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OCC2C=CC=CC=2)[CH2:6][CH2:5]1>[Pd].CO>[F:1][CH:2]([CH2:21][CH2:22][CH3:23])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1
Reactant: CCCC(F)CN1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCC(F)CN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 134.1 %

Procedure:
A mixture of the chiral form (with a shorter retention time) of benzyl N-[1-(2-fluoropentyl)piperidin-4-yl]carbamate obtained in Example 1c (318 mg, 0.986 mmol), 10% Pd/C (100 mg) and methanol (7 ml) was stirred at room temperature for two hours under a hydrogen atmosphere. The atmosphere in the reaction vessel was replaced with nitrogen, 10% Pd/C was filtered off, and the solvent was distilled off to give the title compound (249 mg).
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][C:7]([C:15]3[O:16]C=CC=3)=[CH:6][C:5]=1[NH:4][C:3]2=[O:20].I([O-])(=O)(=O)=[O:22].[Na+]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][C:7]([C:15]([OH:16])=[O:22])=[CH:6][C:5]=1[NH:4][C:3]2=[O:20]
Reactant: O=C1Nc2cc(-c3ccco3)ccc2C2CCCC12F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc2c(c1)NC(=O)C1(F)CCCC21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 0.5 g (1.8 mmol) of 3a-fluoro-7-(2-furanyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 63 ml of acetonitrile-carbon tetrachloride-water (2:1:2) is mixed with 5.9 g (27.6 mmol) of sodium periodate and 0.05 g (0.4 mmol) of ruthenium(IV) oxide, and it is stirred for 4 hours at room temperature. The batch is diluted with water and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is taken up in 0.5 M potassium hydroxide solution. This solution is washed with methyl-tert-butyl ether, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum: 0.31 g of product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:3]=1.BrC1C=CC(C(O)=O)=C(OC2C=CC=CC=2)C=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[C:17]3[C:12]([O:11][C:4]=2[CH:3]=1)=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3
Reactant: COc1ccccc1Oc1cc(Br)ccc1C(=O)O
Agent: O=C(O)c1ccc(Br)cc1Oc1ccccc1
Product: COc1cccc2c(=O)c3ccc(Br)cc3oc12

Procedure:
Using an adaptation of the method described in Procedure 3, substituting 4-bromo-2-(2-methoxy-phenoxy)-benzoic acid, 2k for 4-bromo-2-phenoxybenzoic acid, 2a, the title compound 3-bromo-5-methoxy-xanthen-9-one, 3k was obtained. MS m/z (MH+) 304.8, 306.7.
Reaction SMILES: C1(C)C=CC=CC=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:13]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[CH2:14][CH3:15]>O>[CH2:13]([CH:16]1[CH2:21][CH2:20][C:19]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:18][CH2:17]1)[CH2:14][CH3:15]
Reactant: C1CCNC1
Reactant: CCCC1CCC(=O)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CC=C(N2CCCC2)CC1
Temperature: 25 °C

Procedure:
Toluene (200 ml) and pyrrolidine (90 ml) were added to 4-propylcyclohexanone (53.0 g) in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 3 hours while the water formed was removed by a Dean-Stark apparatus. After the reaction mixture had been cooled to a room temperature, it was washed with brine, and dried over anhydrous magnesium sulfate. The toluene was distilled off under reduced pressure to give 1-(4-propylcyclohex-1-enyl)pyrrolidine (58.2 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][C:22]=4[N:23]3S(C3C=CC(C)=CC=3)(=O)=O)=[CH:19][CH:18]=2)[C:13](=[O:41])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:42].CCOCC>C(Cl)Cl.CO>[ClH:42].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][C:22]=4[NH:23]3)=[CH:19][CH:18]=2)[C:13](=[O:41])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(OCc6ccccc6)cc5=O)cc42)CCN(C)C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CCc2c([nH]c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Reaction time: 2 h
Yield: 34 %

Procedure:
NaOH (644 mg, 16.1 mmol) was added to a solution of the 4-(benzyloxy)-1-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (174 mg, 0.322 mmol) in CH2Cl2/MeOH (10 mL) that had been degassed with N2. The resulting solution was heated at reflux with stirring for 2 h under N2. The solution was allowed to cool, saturated NH4Cl solution and CH2Cl2 were added, and the phases were separated. The organic phase was washed with saturated NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure to yield a white solid. 1 M HCl in Et2O (0.38 ml, 0.38 mmol) was added to a solution of the white solid in 9:1 CH2Cl2/MeOH (10 mL) under N2, and the resulting solution was stirred at 25° C. for 30 min. The solution was concentrated, and the residue was diluted with a small amount of CH2Cl2/CH3CN. The resulting suspension was filtered, and the solid was dried under reduced pressure to yield the title compound (46 mg, 34%) as a white solid: mp 168-170° C.; 1H NMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 10.50-10.41 (m, 1H), 7.58-7.52 (m, 2H), 7.49-7.40 (m, 4H), 7.39-7.35 (m, 2H), 6.96 (br d, J=8.0 Hz, 1H), 6.09 (br d, J=7.5 Hz, 1H), 5.97 (br s, 1H), 5.15 (s, 2H), 4.60 (br d, J=15.0 Hz, 1H), 4.41 (dd, J=15.0, 7.5 Hz, 1H), 3.78-3.71 (m, 1H), 3.45-3.38 (m, 1H), 3.09-2.98 (m, 5H); ESI MS m/z 386 [M+H]+.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=O)C(=O)N2[C@H]1C(O)=O.CC(S[C@@H]1[O:34][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>P([O-])([O-])([O-])=O.C(#N)C1C=CC=CC=1>[C:13]([NH2:20])(=[O:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Product: NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
TG1 /pNHJ10H and TG1/pNHJ20L were inoculated into 10 ml of 2×YT medium containing 50 μg/ml of ampicillin and incubated at 30° C. overnight (12 hours). 1 ml of the resultant culture was added to 100 ml of 2×YT medium (50 μg/ml of ampicillin, 0.1 g of CoCl2.6H2O/l). The mixture was incubated at 30° C. for 4 hours. IPTG was added to the mixture to a final concentration of 1 mM. The mixture was incubated at 30° C. for 10 hours. After harvesting the cells, the cells were suspended in 5 ml of 0.1 M phosphate buffer (pH 7.5). The suspensions were disrupted by sonification for 5 min and centrifuged at 12,000 ×g for 30 min. The resulting supernatants were used for the enzyme assay. The enzyme assay was carried out in a reaction mixture (12 ml) containing 50 mM potassium phosphate buffer (pH 7.5), 6 mM benzonitrile and an appropriate amount of the enzyme. The reaction was carried out at 20° C. for 30 min and stopped by the addition of 0.2 ml 1M HCl. The amount-of benzamide formed in the reaction mixture was determined by EPLC. As a control, the mixture obtained by the same procedure as described above but from E. coli TG1 was used. The levels of nitrile hydratase activity in cell-free extracts of E. coli containing pNHJ10H and pNHJ20L were 1.75×10-3 and 6.99×10-1 units/mg, respectively, when cultured in 2×YT medium in the presence of CoCl2 and IPTG. Benzamide was found in the reaction mixture of TG1/pNHJ10H and pNHJ20L, whereas no benzamide was found in the reaction mixture of TG1. A number of references are cited herein, the disclosures of which are incorporated in their entirities, by reference herein.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CCCCCC.[CH2:30]([N:34]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH3:33].[NH4+].[Cl-]>CCCCCC.C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[CH:43]([C:42]1[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][CH2:35][N:34]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:46][CH:45]=1)[OH:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C=O)cc1
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
2.67 g of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) (0.01 mol, 1 eq) is dissolved in 35 mL of n-hexane and 7 mL of 2.5 M BuLi hexane solution is added in 30 min during which the temperature is kept at 20° C. The reaction mixture is stirred for 2 hours at room temperature and then it is added to the solution of 4.37 g of 4-(3-dibutylamino-propoxy)-benzaldehyde (V) (0.015 mol, 1.5 eq) in 80 mL of THF. The reaction mixture is stirred at room temperature for 2 hours and then 40 mL of NH4Cl solution is added. After 15 min of stirring, the product is extracted with 2×40 mL of diethyl ether. The organic phase is concentrated and the crude product is purified by column chromatography (spheric silica; eluent:toluene:MTBE:methanol=50:40:10) to obtain 2.24 g of compound (VI) (40%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12](C=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([C:17]([CH3:19])=O)[CH3:16]>>[CH:15]([C:17]1[CH:19]=[CH:1][C:14]2[C:8]3[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][C:5]=2[C:4]=1[CH:3]=[CH2:2])=[CH2:16]
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: CCC(C)=O
Product: C=Cc1ccc2c(c1C=C)Cc1ccccc1-2

Procedure:
To a solution of 2,7-Bis(diethylphosphonatomethyl)-9,9-dipropylfluorene (4) (26.8 g) and 3,5-dimethoxy-4-(1-methylpropoxy)-benzaldehyde (6) (26.2 g) in tetrahydrofuran (200 mL) was added potassium hydroxide (8.4 g) and dimethylsulfoxide (5.0 mL). The suspension was stirred at 70° C. for 4 hours and then isopropanol (150 mL) was added. The solvent of the supernatant solution was removed at reduced pressure and the resultant oil was stirred in methanol (200 mL). The precipitate was filtered off and purified by stirring in boiling ethanol (200 mL) two times. After drying, (II-2) was obtained as a pale yellow powder (25.8 g, 72%). The UV/VIS spectrum of (II-2) in methyl ethyl ketone (MEK) has two maxima at 382 nm and at 402 nm with a molar extinction coefficient of 93092 Mol−1 cm−1 and 75139 Mol−1 cm−1 respectively. Under UV irradiation in MEK, (II-2) shows a strong blue fluorescence with fluorescence peaks at 419 nm and 444 nm. The fluorescence quantum yield of (II-2) relative to the anthracene standard is 0.66 (in MEK solvent, not degassed). The 1H-NMR data in CDCl3 are summarized in table 2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].C(Cl)(Cl)Cl.CCCCCC>C(Cl)Cl>[C:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCCCCCCCCC(=O)O

Procedure:
16-Hydroxyhexadecanoic acid (0.5 g) was suspended in methylene chloride (15 ml), and triethylamine (1.03 ml) was added to the suspension. To the mixture, while ice-cooled and stirred, was added dropwise acetyl chloride (0.39 ml). After 8 hours ice was added, and extracted with chloroform. The chloroform layer was washed with a saturated sodium hydrogen carbonate solution and then twice with water and dried with anhydrous sodium sulfate. The chloroform layer was concentrated and the residue thus obtained was subjected to chromatography on a silica gel column with an eluent system of chloroform-hexane (2:1) to give 16-acetoxyhexadecanoic acid (0.58 g).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1O.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: Oc1ccc2ccccc2c1
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Oc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (47.1 g), β-naphthol (28.8 g) and dicyclohexylcarbodiimide (45.4 g) in pyridine (400 ml) was stirred at room temperature for 24 hours. After evaporation of solvent, to the residue was added water (500 ml), and the mixture was acidified with hydrochloric acid. The resulting white crystals were dissolved in methanol (500 ml). After evaporation of methanol, the residue was recrystallized from methanol to give β-naphtyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride (49.1 g, 67.8%), m.p. 195°-202° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:17]1([CH:23]2[CH2:24][CH2:25][N:26]([CH:14]3[C:15]4[C:10](=[N:9][C:8]5[C:3]([C:2]=4[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:11][CH2:12][CH2:13]3)[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCC(c2ccccc2)CC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 48 hours in 300 ml of toluene that contained 4-phenylpiperidine (8.06 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was concentrated and the residue purified by flash chromatography (5% Et3N/toluene) to give, after concentration of theproduct-containing fractions and recrystallization from EtOAc/pentane, 3.22g of analytically pure product, m.p. 189°-190°.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][NH:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: CCOC(=O)c1ccc(N2CCNS2(=O)=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNS4(=O)=O)cc3)CC2)c(C)c1
Yield: 72.9 %

Procedure:
Using ethyl 4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)benzoate (198 mg) described in Preparation Example 46 and 1-(3,5-dimethylpyridin-2-yl)piperazine (141 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (222 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH:8]([CH2:19][OH:20])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:23]I>ClCCl.[Ag]=O>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH:8]([CH2:19][O:20][CH3:23])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1nc2c(s1)C(CO)COc1ccc(Br)cc1-2
Reactant: CI
Agent: O=[Ag]
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)C(COC)COc1ccc(Br)cc1-2
Temperature: 50 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
A suspension of ethyl 9-bromo-4-(hydroxymethyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (200 mg, 0.52 mmol, 1.00 equiv), MeI (750 mg, 5.28 mmol, 10.00 equiv) and silver oxide (480 mg, 2.07 mmol, 4.00 equiv) in dichloromethane (15 mL) was stirred for 6 h at 50° C. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give 110 mg (53%) of the titled compound as an off-white solid; LC-MS (ES, m/z) 398,400 [M+H]+.