Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24]>O>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1C=O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
2. Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Erlenmeyer flask with powdered potassium carbonate (569 g), dimethylformamide (1,000 ml), and methyl chloroacetate (478 g) and mechanically stirred at 65° C. for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25° C. The mixture was poured into cold water (0° C.) while stirring vigorously. An oil separated that suddenly solidified. Stirring was continued for 30 minutes and the solid isolated by filtration. The product was washed with water (2×1,000 ml) and pressed dry. The product can also be dried in vacuo at 25° C. A small sample (approx. 2 g) was purified by distillation. The boiling range of the pure product is 124°-128° C. at 2 mm Hg and has a melting temperature range of about 50.2°-50.6° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[O-:10][CH2:11][CH3:12].[Na+]>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[CH2:11]([O:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9])[CH3:12]
Reactant: CSc1ccccc1Cl
Reactant: CC[O-]
Agent: [Cu]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOc1ccccc1SC

Procedure:
o-Chlorothioanisole (prepared by the procedure of Example 5-A (15.85 g., 0.1 mole) is stirred at reflux in nitrobenzene containing copper powder (100 mg.) and sodium ethoxide (6.8 g., 0.1 mole) for 2 hours. The product is steam distilled and the distillate dried and fractionally distilled under reduced pressure to yield o-ethoxythioanisole.
Reaction SMILES: C([CH:5]([N:9](C(OC(C)(C)C)=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=[C:20]3[C:19]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:18][CH:17]=2)=[CH:12][N:11]=1)[C:6]([O-:8])=[O:7])(C)(C)C.C(Cl)Cl.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>>[F:56][C:55]([F:58])([F:57])[C:53]([OH:59])=[O:54].[O:40]1[CH2:39][CH2:38][N:37]([C:19]2[C:20]3[N:21]([CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=3)[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][CH2:5][C:6]([OH:8])=[O:7])=[N:11][CH:12]=3)=[CH:17][N:18]=2)[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1)C(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Yield: 25 %

Procedure:
A solution of compound 13b (200 mg, 0.300 mmol) in DCM/TFA (4:1 v/v, 10 mL) was stirred at rt for 30 min. Solvent was evaporated, and water (5 mL) was added. The resulting solids were collected by filtration and washed with Et2O to obtain the title compound as a yellow solid (40.2 mg, 25% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.44 (d, J=8.7 Hz, 1H), 8.29-8.23 (m, 1H), 8.18 (s, 1H), 8.03-7.91 (m, 4H), 7.85-7.73 (m, 2H), 7.71 (s, 1H), 7.65-7.52 (m, 2H), 7.51-7.40 (m, 1H), 7.38 (s, 1H), 6.85 (d, J=8.4 Hz, 1H), 4.40-4.20 (m, 4H), 4.18-4.01 (m, 2H), 3.93-3.77 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H25N7O3: 508.2 (M+H). Found 508.3.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][N:6]2[C@H:5]([C:3]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:2])[CH2:9][C@H:8]([NH:10][C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[OH:23])=[O:12])[CH2:7]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Product: O=C(N[C@H]1C[C@@H](C(=O)N2CCCC2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-amide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester and pyrrolidine in an analogous manner to example 12. MS calcd. for C27H36N3O3 [(M+H)4] 450.0, obsd. 450.2.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[F:21][C:22]1[CH:27]=[C:26](F)[C:25]([F:29])=[CH:24][C:23]=1[S:30]([N:33]([CH3:39])[C:34]1[S:38][N:37]=[CH:36][N:35]=1)(=[O:32])=[O:31]>CN(C)C=O.O>[NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[O:18][C:26]3[C:25]([F:29])=[CH:24][C:23]([S:30]([N:33]([CH3:39])[C:34]4[S:38][N:37]=[CH:36][N:35]=4)(=[O:31])=[O:32])=[C:22]([F:21])[CH:27]=3)=[CH:10][C:4]=2[N:3]=1
Reactant: Nc1nc2cc(-c3cc(Cl)ccc3O)ccc2[nH]1
Reactant: CN(c1ncns1)S(=O)(=O)c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ncns1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccc3[nH]c(N)nc3c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 2-(2-amino-1H-benzo[d]imidazol-5-yl)-4-chlorophenol (0.40 g, 1.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added sodium hydride (60% w/w dispersion in mineral oil, 0.07 g, 1.8 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 h. 2,4,5-Trifluoro-N-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.52 g, 1.7 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The mixture was partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed with water (10 mL) and brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in ethyl acetate, followed by trituration in hexanes. The solid thus obtained was suspended in water (5 mL) and lyophilized to afford 4-(2-(2-amino-1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-2,5-difluoro-N-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid in 63% yield (0.344 g): 1H NMR (300 MHz, CDCl3) δ10.78 (br s, 1H), 8.42 (d, J=1.9 Hz, 1H), 7.94-7.86 (m, 1H), 7.52-7.48 (m, 1H), 7.45-7.37 (m, 1H), 7.29 (dd, J=8.7, 1.6 Hz, 1H), 7.13 (s, 1H), 7.10-6.99 (m, 2H), 6.91 (d, J=8.1 Hz, 1H), 6.25 (s, 2H), 3.31 (s, 3H); 19F NMR (282 MHz, DMSO-d6) δ −108.7 (d, J=15.0 Hz, 1F), −135.1 (d, J=15.1 Hz, 1F); MS (ES+) m/z 548.7 (M+1), 550.7 (M+1).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][CH2:28][CH3:29])(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:15]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[S:24](=[O:26])(=[O:25])[NH:27][CH2:28][CH3:29])[CH:10]=1
Reactant: CCNS(=O)(=O)c1ccc(F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCNS(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Product: Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
(Step 2) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.19 g), 2-(aminomethyl)-N-ethyl-4-fluorobenzenesulfonamide obtained in Step 1 (0.23 g) and potassium carbonate (0.34 g) in ethanol (10 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.04 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=O)=[C:4]([S:8](=[O:11])(=[O:10])[NH2:9])[O:5][C:6]=1[CH3:7].P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]2[C:12](=[O:14])[NH:9][S:8](=[O:11])(=[O:10])[C:4]=2[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(S(N)(=O)=O)c(C(=O)O)c1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc2c(c1C)C(=O)NS2(=O)=O
Yield: 73.5 %

Procedure:
A mixture of 1.0 gm (4.6 millimols) of 4.5 -dimethyl-2-sulfamoyl-furan-3-carboxylic acid and 0.96 gm (4.6 millimols) of phosphorus pentachloride in toluene was reacted analogous to Example 1, yielding 0.68 gm (73% of theory) of 4,5-dimethyl-furo[3,2-d]isothiazole-3-(2H)-one-1,1-dioxide. Rf -value: 0.21 (silica gel 60 F254 plates, thickness 0.25 mm, eluant ethylene chloride; ethyl acetate; glacial acetic acid 100:30:5).
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:17])[NH:10][N:9]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C(OCC)C>O>[C:18]1(=[O:23])[N:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:17])[NH:10][N:9]=2)[C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1n[nH]c2cccc(Cl)c12
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(Cl)c12
Yield: 99.1 %

Procedure:
To 50 ml of dioxane were added 5.66 g of 3-amino-4-chloroindazole thus obtained and 6.68 g of phthalic anhydride, and the mixture was stirred for 5 hours at 120° C. After the mixture was condensed under reduced pressure, the condensed residue was added with 30 ml of diethyl ether and stirred under cooling with ice and water for 30 minutes to separate crystals. Then the crystals were obtained by filtration and dried under reduced pressure to give 9.96 g of 3-phthalimido-4-chloroindazole having the following analytical values in a yield of 89%.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCOc2ccccc21
Yield: 63.8 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)chroman-4-amine (0.3 g, 0.93 mmol), piperazine (0.80 g, 9.33 mmol) and N,N-diisopropylethylamine (2.2 mL, 12.74 mmol) in acetonitrile (15 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 0.23 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 144 mg (40%) of N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)chroman-4-amine: 1H NMR (400 MHz, CD3Cl): δ 7.63 (d, 1H), 7.31 (d, 1H), 7.28 (m, 1H), 6.91 (m, 1H), 6.85 (d, 1H), 6.47 (d, 1H), 6.42 (d, 1H), 6.21 (s, 1H), 4.80 (br s, 2H), 4.65 (m, 1H), 4.23 (m, 2H), 3.04 (m, 4H), 2.88 (s, 3H), 2.21 (m, 2H), 2.20 (br d, 1H). MS (ESI) m/z: Calculated: 387.16; Observed: 388.2 (M++1).
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2].[CH3:26][C:27]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:28]=1[C:29](Cl)=[O:30].[Al+3].[Cl-].[Cl-].[Cl-].[F:42][C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45](Cl)=[O:46]>C(Cl)Cl>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:29]([C:28]3[C:27]([CH3:26])=[CH:35][C:34]([CH3:36])=[CH:33][C:32]=3[CH3:37])=[O:30])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:45](=[O:46])[C:44]1[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=1[F:42])[CH:10]=2)[CH3:2]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CCCCC(CC)Cn1c2ccccc2c2ccc3ccccc3c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3F)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 11-(2-ethylhexyl)-11H-benzo[a]carbazole (47.16 g; 143.0 mmol) in CH2Cl2 (400 mL) are added 2,4,6-trimethylbenzoyl chloride (27.45 g; 150.0 mmol) and AlCl3 (20.00 g; 150.0 mmol) at 0° C. After stirring at room temperature for 2 hours, AlCl3 (22.93 g; 172.0 mmol) is added at 0° C. and 2-fluorobenzoyl chloride (23.78 g; 150.0 mmol) is added dropwise, and then the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water, and the crude product is extracted twice with CH2Cl2. The combined organic layer is washed with water and brine, dried over MgSO4. After 230 ml of n-hexane is added there, CH2Cl2 was removed by concentration to give a beige solid. It is collected by filtration, and washed with n-hexane, and then it is dried to give a beige solid (81.81 g; 95.7%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.84 (t), 0.89 (t), 1.18-1.42 (m), 2.20 (s), 2.28-2.31 (m), 2.40 (s), 4.72-4.76 (m), 6.96 (s), 7.19 (t), 7.29 (t), 7.52-7.60 (m), 7.70-7.84 (m), 8.38 (s), 8.63-8.66 (m), 9.56 (d); 19F-NMR spectrum (CDCl3). δ [ppm]: −111.58
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:25]4[CH2:28][CH2:27][CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NC1CCC1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and cyclobutylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 2H) 1.95-2.09 (m, 2H) 2.11-2.24 (m, 2H) 2.36 (s, 3H) 4.28-4.48 (m, 1H) 7.59 (dd, J=8.08, 1.52 Hz, 1H) 7.66 (s, 1H) 7.70 (br. s., 1H) 8.10 (br. s., 1H) 8.35 (d, J=6.57 Hz, 2H) 8.78 (d, J=7.33 Hz, 1H) 8.81-8.91 (m, 1H) 13.12 (br. s., 1H). MS m/z [M+H]+ 374.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.O1CCCC1.CO.C(=O)([O-])O.[Na+]>[Zn].C(O)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Reaction time: 1 h

Procedure:
To a solution of the product of Example 18A (1.5 g, 4.4 mmol) in 1:1 tetrahydrofuran/methanol (80 mL) at ambient temperature was slowly added zinc power (1.43 g, 22 mmol) and acetic acid (5 mL). The mixture was stirred for 1 hour, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was stirred for 1 hour and filtered, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5/1 petroleum ether/ethyl acetate to give title compound. MS: 312 (M+H+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:28][CH:27]=2)=[N:24][CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(OC1C=CC([Li])=CC=1)CCCCCCC.BrCCCCCCCC>C(Cl)Cl.N1C=CC=CC=1>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:28][CH:27]=2)=[N+:24]([O-:9])[CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)cn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Li]c1ccc(OCCCCCCCC)cc1
Solvent: CCCCCCCCBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c[n+]2[O-])cc1
Yield: 65.2 %

Procedure:
A solution of 3.03 g (12.3 mmol) of 3-chloroperbenzoic acid in 30 ml of methylene chloride is added dropwise at a temperature of 0° to 5° C. to 3.23 g (8.2 mmol) of 5-octyl-2-(4-octyloxyphenyl)pyridine (prepared, for example, analogously to C. S. Giam, J. Staut, J. Chem. Soc., Chem. Commun. 478 (1970) from pyridine, 4-octyloxyphenyllithium and 1-bromooctane) in 30 ml of methylene chloride. After a reaction time of 3 hours at room temperature, the mixture is washed once with 5% sodium carbonate and twice with sodium chloride solution, the organic phase is dried over sodium sulfate, filtered off, and the solvent is removed by distillation. Purification of the residue by chromatography (silica gel, 8:2 methylene chloride/ethyl acetate) gives 2.20 g of 5-octyl-2-(4-octyloxyphenyl)pyridine N-oxide. ##STR13##
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([CH:18]=1)[C@@H:10]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[CH2:11]1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N>C1COCC1>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][C:3]#[C:4][C:5]2[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([CH:18]=2)[C@@H:10]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[CH2:11]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCO
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCOc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
A solution of pre-dried 5-(3-hydroxy-1-propynyl)-2′-deoxyuridine (Robins, M. J. et al. (1983)) (565 mg, 2 mmol) in 40 mL of anhydrous THF under argon was treated with 4-nitrophenol (696 mg, 5 mmol), triphenylphosphine (787 mg, 3 mmol), and diisopropyl azodicarboxylate (590 liters, 3 mmol), and the reaction mixture heated at 60° C. until the solution was clear, and then 1 hour longer. The mixture was allowed to cool to 23° C. and then it was evaporated onto SiO2 and purified by chromatography using MeOH/CH2Cl2 as eluent to afford 107 mg (13%) of the desired ether product: melting point 112–118° C. 1H NMR ((CD3)2SO) δ 11.65 (s, exchanges with D2O, 1, NH), 8.29 (s, 1, H6), 8.24 (d, J=9.3 Hz, 2, m-ArH), 7.23 (d, J=9.3 Hz, 2, o-ArH), 6.09 (pseudo-t, 1, H1′), 5.17 (s, 2, propargyl-CH2), 4.22 (m, 1, H3′), 3.80 (m, 1, H4′), 3.59 (m, 2, 5′-CH2), 2.13 (pseudo-t, 2, 2′-CH2). Low-resolution mass spectrum (DCI-NH3) on per-trimethylsilyated material, m/z 547 [M(TMS)2H+], 565 [M(TMS)2NH4+], 620 [M(TMS)3H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:16][C@@H:15]3[C@H:11]2[CH2:12][N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:14]3)=[CH:6][CH:5]=1)([O-])=O.O>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:16][C@@H:15]3[C@H:11]2[CH2:12][N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:14]3)=[CH:8][CH:9]=1
Reactant: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc([N+](=O)[O-])cc3)[C@@H]2C1
Solvent: O
Solvent: CO
Product: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc(N)cc3)[C@@H]2C1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
1.21 g of 1-((1R,5S,6R)-6-(4-nitro-phenyl)-3-aza-bicyclo[3.2.0]hept-3-yl)-propan-1-one (4.44 mmol) were dissolved in 50 ml of methanol, 8.0 g of stannous dichloride SnCl2×H2O (35.46 mmol) were added, and the reaction was stirred under refluxing conditions for 2 h. The solvent was evaporated and the residue portioned between 1 N aqueous sodium hydroxide and ethyl acetate. This mixture was filtered, the two phases were separated, and the aqueous layer was extracted with ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 0.94 g of the product as a mixture of 72% para and 28% ortho substituted product which was used in the next step without further separation.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C(N(CC)CC)C.[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19](Cl)=[C:20]([N+:26]([O-:28])=[O:27])[C:21]([Cl:25])=[N:22]2)=[CH:17][CH:16]=1.O>CN(C=O)C>[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[C:20]([N+:26]([O-:28])=[O:27])[C:21]([Cl:25])=[N:22]2)=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2cc(Br)ccc2c1Cl
Reactant: CC(C)(O)CN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
1-Amino-2-methylpropan-2-ol (575 mg, 6.45 mmol) and triethylamine (889 mg, 8.79 mmol) were added to a solution of 7-bromo-2,4-dichloro-3-nitroquinoline (1.9 g, 5.9 mmol) in DMF (25 mL), and the reaction was stirred at room temperature for two hours and poured into water (750 mL). A precipitate formed and was isolated by filtration, washed with water (500 mL), and dried under vacuum for two hours to provide 1.94 g of 1-[(7-bromo-2-chloro-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: O[CH2:2][CH:3]([OH:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[BrH:20].[C:21]([OH:24])(=O)[CH3:22].C(=O)(O)[O-].[Na+]>ClCCl>[C:21]([O:19][CH:3]([CH2:2][Br:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:24])[CH3:22]
Reactant: OCC(O)CCCCCCCCCN1CCCCC1
Reactant: CC(=O)O
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(CBr)CCCCCCCCCN1CCCCC1
Reaction time: 0.17 h

Procedure:
A mixture of N-(11,10-dihydroxyundecyl)piperidine (2.0 g, 7.4 mmol) and a 30% solution of hydrogen bromide in acetic acid (4.45 mL, 22 mmol) was stirred for 90 minutes. The mixture was then added to a flask containing aqueous sodium bicarbonate solution (15 g in 40 mL) and dichloromethane (50 mL). After 10 minutes of vigorous stirring, the layers were separated and the aqueous portion extracted with dichloromethane (2×50 mL). The combined organic portions were dried over sodium sulfate. The solvent was evaporated to give 1-(10-acetoxy-11-bromoundecyl)piperidine which was used without further purification. Bromoacetate was dissolved in methanol (10 mL) and treated with a 1 M solution of sodium methoxide (8 mL). After 30 minutes, the reaction mixture was added to water (30 mL) and extracted with dichloromethane (3×50 mL). The organic extracts were combined, washed with water (25 mL) and brine solution (25 mL) and then dried over anhydrous magnesium sulphate solution and concentrated under reduced pressure. The crude product obtained was further purified by column chromatography over alumina (grade-II) using 10% methanol/ethyl acetate eluant to yield 1.5 g (80.6%) N-(9,10-Oxidodecyl)piperidine.