Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.C(OCC)(=O)C.Br[C:18]1[C:23]([F:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([F:27])[CH:19]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[F:24][C:23]1[CH:22]=[C:21]([O:25][CH3:26])[C:20]([F:27])=[CH:19][C:18]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: C1CNCCN1
Reactant: COc1cc(F)c(Br)cc1F
Agent: COc1ccc(Br)cc1C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(N2CCNCC2)cc1F
Yield: 27.9 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene, 1-(2-phenethyl)piperazine and ethyl acetate (extraction solvent) were replaced with 4-bromo-2,5-difluoroanisole (6.742 g), piperazine (12.404 g) and toluene (extraction solvent), respectively, to provide crude 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (1.926 g).
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.CO.[H][H]>[Pd].C1COCC1>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:11]([OH:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cc(O)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(O)c(F)cc1N
Yield: 85 %

Procedure:
Palladium on carbon (2.5 wt. %, wet, 8.5 g, 0.005 eq) was charged into a 1 L Parr bomb. Then, methyl 4-fluoro-5-hydroxy-2-nitrobenzoate, 62 g, 0.29 mol, 1 eq) and MeOH (300 mL) were charged. The bomb was sealed, and pressurized/vented three times with hydrogen, and pressured with 100 psi hydrogen. The reaction mixture was stirred, until the hydrogen pressure was not dropping. The bomb was opened, and an HPLC sample showed that the reaction was complete. The mixture was diluted with 400 ml of THF and filtered through a Celite pad. The solution was concentrated under vacuum and solvent was switched to MeOH. To the thick suspension in MeOH, water (150 mL) was added in about 30 min. The slurry was filtered. The desired product, methyl 2-amino-4-fluoro-5-hydroxybenzoate, was obtained as off-white solid after drying under vacuum (45.5 g, 85% yield). NMR (DMSO-d6, 400 MHz) δ 9.05 (s, 1H), 7.28 (d, J=10.0 Hz, 1H), 6.54 (d, J=13.4 Hz, 1H), 6.30 (s, 2H), 3.74 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 167.0, 157.0, 154.5, 146.2, 146.1, 134.5, 134.4, 118.2, 104.7, 103.3, 51.4.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[N:25]=CN(C)C)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.NN>C(O)(=O)C>[C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
To 3 (44.64 g, 117 mmol) was added reagent grade ethanol (1200 mL), glacial acetic acid (20.65 mL) and hydrazine (26 mL). The reaction mixture was stirred at 50° C. for 5 hrs. Solvent was removed and to the crude product was added methylene chloride (1,500 ml) and 1 N sodium hydroxide (67 ml) with stirring at room temperature for 15 minutes. The two resulting layers were separated and the organic layer was washed with brine (2×300 mL), dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo to obtain 1-trityl-2-aminoimidazole, 4 (37.2 g, 97%). M.p. 196-199° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:10]Br.O>C(O)(=O)C>[Br:10][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: BrBr
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)CBr
Reaction time: 8 h

Procedure:
32.5 g (0.25 mol) of ethyl acetoacetate are dissolved in 64 ml of glacial acetic acid. 40 g (0.25 mol) of bromine are added dropwise to the cooled solution. The mixture is left to stand overnight and then poured into cold water. The oil obtained is washed with water, dried and distilled in a glass filter pump vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[CH:24]=[C:23]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:16]=2[CH3:15])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(CS(C)(=O)=O)ccc1C(=O)O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Cc1cc(CS(C)(=O)=O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
255 mg of methyl 4-(bromomethyl)-2-methylbenzoate was reacted via Procedure O to give methyl 2-methyl-4-(methylsulfonylmethyl)benzoate. 250 mg of methyl 2-methyl-4-(methylsulfonylmethyl)benzoate was then hydrolyzed upon heating to 45° C. for 1 hour via Procedure M to give 2-methyl-4-(methylsulfonylmethyl)benzoic acid. 202 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonylmethyl)benzamide. MS (Q1) 415 (M)+.
Reaction SMILES: C[N:2](C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]([CH2:14][O:15][CH2:16][C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(O)=[O:12].O.N>O1CCCC1>[C:11]([CH2:14][O:15][CH2:16][C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:12])[NH2:2]
Reactant: O=C(O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Agent: N
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: NC(=O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a mixture of dimethylformamide (1.50 ml) and tetrahydrofuran (10 ml) was dropwise added phosphorus oxychloride (1.50 ml) at -5°~5° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of (2S,4R)-2-carboxymethyloxymethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.30 g) in tetrahydrofuran (20 ml) at -5°~5° C., followed by stirring at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (30 ml) at 0°-10° C. with stirring. The mixture was stirred at the same condition for 2 hours. Tetrahydrofuran was evaporated under reduced pressure to give a mixture. The mixture was extracted with ethyl acetate (50 ml×3). The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (3:97 V/V) to give (2S,4R)-2-(carbamylmethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]([C:21]2[S:22][C:23]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][C:25]=2[CH2:26][CH2:27]O)=[O:20])[CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:17])[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CCOCC>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:23]2[S:22][C:21]3[C:19](=[O:20])[N:18]([C:5]4[CH:6]=[CH:7][C:8]([NH:9][C:10](=[O:17])[CH2:11][N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:27][CH2:26][C:25]=3[CH:24]=2)=[CH:34][CH:33]=1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2CCO)ccc1NC(=O)CN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
Dissolve 5-(4-chloro-phenyl)-3-(2-hydroxy-ethyl)-thiophene-2-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-amide (623 μmol, 320 mg) and tri-n-butylphosphine (934 μmol, 233 μL) in tetrahydrofuran (5 mL) then add dropwise via syringe diisopropyl azodicarboxylate (934 μmol, 185 μL). Stir the mixture at room temperature for 4 h. Dilute the mixture with 15 mL of Et2O, filter the resulting solid, and dry under vacuum at 60° C. to afford 195 mg (63%) of N-{4-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenyl}-2-pyrrolidin-1-yl-acetamide. Prepare the hydrochloride salt of the free base using 1N HCl in ethanol. Dilute the salt solution in ether then filter off the product. Dry in vacuo to obtain the title compound. MS/ES m/z (35Cl) 496.2 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:15][C:14](C)=[CH:13][C:12](=[O:17])[CH2:11]1)C1C=CC=CC=1.[CH3:18]COC(C)=O>[Pd]>[CH3:18][C:10]12[O:15][CH:14]([O:8][CH2:9]1)[CH2:13][C:12](=[O:17])[CH2:11]2
Reactant: CCOC(C)=O
Reactant: CC1=CC(=O)CC(COCc2ccccc2)O1
Agent: [Pd]
Product: CC12COC(CC(=O)C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of 4.4 g of the 6-Benzyloxy compound from Step 2 in EtOAc was hydrogenated with H2 and Pd/C (10%). After completion, the reaction was filtrated on a bed of celite and then evaporated to dryness. The cru syrup was then taken up in CH2Cl2 containing 1 g of camphor sulphonic acid. The reaction was stirred at r.t. overnight, filtered and evaporated. Purification by flash chromatography (30% Et2O/pentane) gave 780 mg of the title compound (30%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[CH2:10].N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>C(C(C)=O)C>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:3]1([O:19][S:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:9]=[CH2:10])=[CH:16][CH:15]=2)(=[O:20])=[O:18])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: CCC(C)=O
Solvent: C=Cc1ccccc1
Product: C=Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A three-necked flask having a capacity of 500 ml was charged with 240 g of methyl ethyl ketone and the content was stirred at 65° C in a nitrogen gas stream. A mixture of 93.74 of styrene, 26.64 g of 4-vinylbenzenesulfonic acid cyclohe ester and 1.99 g of 2,2′-azobis(2,4-dimethylvaleronitrile) was dropwise added thereto over 2 hours. After completion of the dropwise addition, 0.5 g of 2,2′-azobis(2,4-dimethylvaleronitrile) was further added, followed by stirring for further 2 hours, thereby a styrene-4-vinylbenzenesulfonic acid cyclohexyl ester copolymer was obtained. After the reaction mixture was poured into an egg-plant type flask having a capacity of 1 liter and concentrated, 300 g of MFG was added thereto, the reaction mixture was heated for 3 hours with refluxing MFG, thereby sulfonic acid cyclohexyl ester was decomposed to obtain a sulfonic acid. The obtained reaction mixture was cooled to room temperature and poured into a beaker containing 3 liters of water, thus an aqueous solution of a high molecular compound was prepared.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:22][C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[CH3:29].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:32])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 40 °C
Yield: 49.6 %

Procedure:
A mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 3-chloro-4-methylphenyl isocyanate (0.26 g, 1.6 mmol) and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at this temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.35 g of the product in 50% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.22 (s, 3H), 2.36-2.43 (m, 1H), 2.57-2.64 (m, 1H), 2.86-2.98 (m, 1H), 4.36 (d, J=5.6 Hz, 2H), 4.40 (d, J=17.3 Hz, 1H), 4.54 (d, J=17.3 Hz, 1H), 5.15 (dd, J=13.1 Hz, J=5.0 Hz, 1H), 6.77 (t, J=5.6 Hz, 1H), 7.09-7.19 (m, 2H), 7.48-7.57 (m, 2H), 7.61-7.64 (m, 2H), 8.72 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 18.7, 22.6, 31.2, 39.7, 46.2, 51.6, 116.5, 117.7, 121.6, 127.5, 128.3, 130.4, 131.0, 131.7, 133.0, 135.5, 139.5, 139.9, 155.1, 168.1, 171.0, 172.8; Anal. calcd for C22H21ClN4O4.0.2H2O: C, 59.45; H, 4.85; N, 12.60. Found: C, 59.28; H, 4.83; N, 12.39.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:20]=1.[OH:21]CC1C=CC2CCC3C=CC=CC=3SC=2C=1>>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=3[S:8](=[O:21])[C:7]=2[CH:20]=1
Reactant: OCc1ccc2c(c1)Sc1ccccc1CC2
Reactant: O=[N+]([O-])c1ccc2c(c1)C=Cc1ccc(CO)cc1S2
Product: O=[N+]([O-])c1ccc2c(c1)C=Cc1ccc(CO)cc1S2=O

Procedure:
Repeat the process of Example 2, substituting an equivalent quantity of 3-hydroxymethyl-8-nitro-dibenzo[b,f]thiepin for the 3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin, to obtain the title product.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:4]2[N:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:2]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:4]2[N:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Cc1cc2nc(Cl)c3cnccc3n2n1
Reactant: CCCCN
Product: CCCCNc1nc2cc(C)nn2c2ccncc12

Procedure:
2.2 g. of 5-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of Example 18 are refluxed in 10 ml. of n-butylamine for 12 hours. The excess amine is evaporated and the residue treated with 10 ml. of water. N-Butyl-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5-amine is filtered off, yield: 2 g. (80%); m.p. 116.1° (methanol).
Reaction SMILES: [Cl-:1].[CH2:2]([O:4][C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][NH+:10]([CH3:12])[CH3:11])[CH3:3].Cl.[CH2:15](O)[CH2:16]CC>>[Cl-:1].[CH2:2]([O:4][C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][NH+:10]([CH3:11])[CH3:12])[CH2:3][CH2:15][CH3:16]
Reactant: CCOC(=O)NCCC[NH+](C)C
Reactant: CCCCO
Agent: Cl
Agent: [Cl-]
Product: CCCCOC(=O)NCCC[NH+](C)C

Procedure:
21.0 g (0.1 mole) of N-(3-dimethylammoniopropyl)-carbamic acid ethyl ester chloride are suspended in 100 ml of n-butanol. Dry HCl gas is introduced into the suspension for a short time and the mixture is heated for 6 hours at 100° to 115° C while stirring, the hydrochloride going into solution and some ml of liquid distilling off. Then concentrate and drag the residue in vacuum. One obtains 18.0 g of nD20 = 1.4750.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br.Br[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>CO>[N:1]([CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCCCC1CCNCC1
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCCC1CCNCC1

Procedure:
Sodium azide (1 g) was added to a mixture of 4-(3'-bromopropyl)-piperidine hydrobromide (2 g), water (7 ml) and methanol (7 ml). The pH of the mixture was adjusted to 6.3, and the resulting solution was refluxed for 2 hours. After cooling, methanol was evaporated, 30 percent aqueous sodium hydroxide was added and the mixture was extracted several times with ether. The ether extracts were dried and evaporated to leave the desired compound as an oil. The IR-spectrum (CHCl3) showed strong bands at 2925, 2100 and 1450 cm-1.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:4].O[NH:19][C:20](=[NH:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:20]2[N:19]=[C:3]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[O:4][N:29]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(C(=N)NO)c1
Reactant: COC(=O)C1CCCCN1Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc(-c2noc(C3CCCCN3Cc3ccccn3)n2)c1

Procedure:
1-Pyridin-2-ylmethyl-piperidine-2-carboxylic acid methyl ester (50 mg, 0.213 mmol) was mixed with N-hydroxy-3-methoxy-benzamidine (29 mg, 0.174 mmol) and sodium tert-butoxide (19 mg, 0.20 mmol) in toluene (0.5 mL) in a sealed vial at 130° C. for 10 min. The reaction mixture was cooled down and diluted with dichloromethane, washed with water. The title compound was purified by silica gel colomn chromatography with 20˜30% ethyl acetate in hexanes to give a colorless oil, 20 mg (32.7%). 1H NMR (CDCl3), δ(ppm): 8.50 (d, 1H), 7.66 (m, 3H), 7.47 (d, 1H), 7.38 (t, 1H), 7.13 (dd, 1H), 7.03 (dd, 1H), 4.11 (t, 1H), 3.88 (s, 3H), 3.73 (dd, 2H), 3.04 (m, 1H), 2.42 (m, 1H), 2.03 (m, 2H), 1.46-1.90 (m, 4H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([O:36][CH3:37])[CH2:31][C:32](OC)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:30]([O:36][CH3:37])[O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: COC(=O)CC(OC)OC
Agent: Cl
Product: COC(CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)OC

Procedure:
The title compound, white solid (101 mg, 91%), MS (ISP) m/z=447.4 [(M+H)+], mp 220° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl 3,3-dimethoxy-propanoate.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[Br:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Br:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:25]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)cc2Br)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
2-(2-bromo-4-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (445 mg, 1.11 mmol) is dissolved in EtOH (15 mL), and solid KOH (1.42 g, 24.7 mmol) and water (1.5 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with conc. HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (277) as white solid (415 mg, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1CCN2C(=NCCC2)CC1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>[OH-].[Na+]>[CH:19]1([NH:25][C:26](=[O:27])[NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC1CCCCC1
Reactant: NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CCCNC(=O)NC1CCCCC1
Yield: 76 %

Procedure:
To a cold solution of 4-aminobutyric acid (2.16 g, 21 mmol) and catalytic amount of DBU in 22 mL of 1.0 N NaOH, 2.5 g (20 mmol) of cyclohexyl isocyanate were added in one time. The mixture was strongly mixed at room temperature overnight. The reaction was then acidified with concentrated HCl. The formed white solid was collected by filtration. The mixture was purified by chromatography on a silica column (8×3 cm). Elution with a mixture 50:50:1 of hexane:ethyl acetate: acetic acid gave the pure targeted product. The resulting white crystal (3.46 g; yield: 76%) had a mp of 153.0-154.0° C. [M+H]+ 281.18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][NH:16][N:15]=1)=O.[N+](C1C(N2C3C=CC=CC=3N=C2)=NNC=1)([O-])=O>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:11][C:12]([C:14]3[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][NH:16][N:15]=3)=[N:1][C:2]=2[CH:7]=1)[CH3:10]
Reactant: CCOc1ccc(NC(=O)c2n[nH]cc2[N+](=O)[O-])c(N)c1
Agent: O=[N+]([O-])c1c[nH]nc1-n1cnc2ccccc21
Product: CCOc1ccc2[nH]c(-c3n[nH]cc3[N+](=O)[O-])nc2c1

Procedure:
By proceeding in a manner similar to Example 252(b) above but using 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethoxy-phenyl)-amide [824 mg, Reference Example 36(e)] there was prepared 5-ethoxy-2-(4-nitro-1H-pyrazol-3-yl-1H-benzoimidazole (407 mg) as a light brown powder. LC-MS (Method H): RT=1.82 minutes, 274.26 (M+H)+, 272.30 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:39][CH:36]3[CH2:38][CH2:37]3)=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1
Reactant: BrCC1CC1
Product: COc1ccc(CC2c3cc(OC)c(OCC4CC4)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with cyclopropylmethyl bromide
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1.[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:36](=[O:37])[CH2:35][CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1
Reactant: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](NC(=O)CC4CCOCC4)CC3)CC2)n1

Procedure:
The title compound, off-white solid (131 mg, 93%), MS (ISP) m/z=469.5 [(M+H)+], mp 212.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate D) (136 mg, 0.3 mmol) and tetrahydropyran-4-yl-acetic acid.