Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([N:36]=[N+:37]=[N-:38])[C@@H:24]([CH3:39])[CH2:23]1)=O)(C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([N:36]=[N+:37]=[N-:38])[C@@H:24]([CH3:39])[CH2:23]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 4 M HCl in dioxane (30.0 equiv.) was added to tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-azido-3-methylcyclohexyl)carbamate (1.0 equiv.). The solution started to go homogeneous for a few minutes, but then a ppt formed and the solution went very thick. After sitting at rt for 1 hour, the volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.15 M), TEA (5.0 equiv.) and Boc2O (1.0 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-azido-3-methylcyclohexylcarbamate in 57% yield. LC/MS (m/z)=347.3 (MH+), Rt=0.70 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.65 Hz, 3H), 1.43-1.58 (m, 11H), 1.79 (d, J=12.52 Hz, 1H), 1.95 (d, J=6.26 Hz, 1H), 2.60 (br. s., 1H), 3.61 (br. s., 2H), 3.77-3.91 (m, 2H), 4.78 (d, J=7.43 Hz, 1H), 6.96 (d, J=4.70 Hz, 1H), 7.97-8.07 (m, 2H).
Reaction SMILES: CO[C:3](=[O:23])[CH2:4][N:5]1[CH2:9][C:8]([OH:10])=[C:7]([C:11]2[CH2:15][N:14]([CH2:16][C:17]([O:19]C)=O)[C:13](=[O:21])[CH:12]=2)[C:6]1=[O:22].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[OH:10][C:8]1[CH2:9][N:5]([CH2:4][C:3]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[C:6](=[O:22])[C:7]=1[C:11]1[CH2:15][N:14]([CH2:16][C:17]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:19])[C:13](=[O:21])[CH:12]=1
Reactant: COC(=O)CN1CC(C2=C(O)CN(CC(=O)OC)C2=O)=CC1=O
Reactant: C1COCCN1
Product: O=C1C=C(C2=C(O)CN(CC(=O)N3CCOCC3)C2=O)CN1CC(=O)N1CCOCC1

Procedure:
Analogously to the procedure described in Example 2, from 4.8 g (0.015 mol) of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dimethyl ester and 25 ml of morpholine there is obtained 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dimorpholide in the form of pale yellow crystals having a melting point of 250° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:14][C:15](=[O:21])[CH:16]([OH:20])[CH2:17][CH2:18]Br)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([OH:20])[CH2:17][CH2:18][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])[CH3:13]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOC(=O)C(O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)CCn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 65 h
Yield: 40 %

Procedure:
2-Amino-6-chloropurine (0.509 g, 3.00 mmole), 4-bromo-2-hydroxybutyric acid ethyl ester (0.633 g, 3.00 mmole; prepared according to Example 1) and anhydrous potassium carbonate (0.415 g, 3.00 mmole) were mixed with 10 g of dimethyl formamide and the mixture stirred at room temperature during 65 hours. The mixture was then filtered and the filtrate evaporated at a pressure of 0.1 mm Hg. The crystalline residue was triturated with 8 ml of chloroform and the undissolved material filtered off and washed with 2 ml of chloroform. The material obtained was then triturated with 5 ml of water and the undissolved material filtered off and washed with 2 ml of water. Recrystallization from 11 ml of ethanol gave 0.360 g product. M.P. 163°-4° C. (uncorr.) UV spectra(ethanol): λmax (nm) 311, 248. Analyses--Found: C 43.90; H 4.78; Cl 11.72; N 23.52; O 15.90%. Calculated for C11H14ClN5O3 : C 44.08; H 4.71; Cl 11.83; N 23.37; O 16.01%.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1C

Procedure:
A mixture of EXAMPLE 31B (1.08 g), ortho-tolylboronic acid (1.1 g), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (140 mg) in dimethoxyethane:2N aqueous Na2CO3 (25 mL:5 mL) was stirred under nitrogen at 80° C. for 16 hours, diluted with ethyl acetate and was washed with water and brine. The organic phase was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][S:12]([CH3:14])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCC1>CO>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19](/[C:20](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][S:12]([CH3:14])=[O:13])/[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: CS(=O)COc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: CS(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 91.3 %

Procedure:
In a manner similar to the method described in Example 9b, 5-chloro-2-methanesulfinylmethoxy-benzaldehyde (0.4 g, 1.72 mmol) was reacted with 6-chlorooxindole (0.31 g, 1.86 mmol) and pyrrolidine (0.13 g, 1.86 mmol) in methanol (10 mL) to give the title compound as a yellow solid (0.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)c1
Yield: 44.5 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0314 g, 0.0680 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-methoxybenzenesulfonyl chloride (0.0403 g, 0.195 mmol) to obtain 4-(3-methoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0191 g, yield 44%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([C:14]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[O:16][N:15]=1)([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[CH:11]([C:14]1[N:18]=[C:17]([N:19]2[CH2:20][CH2:21][C:22](=[O:25])[CH2:23][CH2:24]2)[O:16][N:15]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)c1noc(N2CCC(=O)CC2)n1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A solution of dimethylsulfoxide (1.07 g, 13.7 mmol) in anhydrous dichloromethane (30 mL) was added dropwise over 10 min to oxalyl chloride (2M in dichloromethane; 5.44 mL, 10.9 mmol) which had been cooled to −60° C. The reaction mixture was stirred at −60° C. for 20 min, and then a solution of crude 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (from Step 2; 2.00 g, ˜9.5 mmol) in anhydrous dichloromethane (100 mL) was added dropwise over 20 min. The reaction mixture was stirred at −60° C. for 1 h, and then triethylamine (2.68 g, 26.5 mmol) was added. The reaction mixture was stirred at −60° C. for 30 min, then allowed to warm to room temperature and stir for 1 h. Dichloromethane (200 mL) was added, and then the mixture was washed with water (3×150 mL) and brine (150 mL). The organic layer was dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one (1.75 g, 88%) as a light tan solid. Mass spectrum (ES) MH+=209.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1CC(CCO)CCN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CC(CC=O)CCN1C(=O)OC(C)(C)C

Procedure:
A solution of 11.8 g of ethyl 1-tert-butoxycarbonyl-4-(2-hydroxyethyl)-piperidine-2-carboxylate and 12.6 g of pyridinium chlorochromate in 175 ml methylene chloride is stirred under nitrogen at room temperature for 80 minutes. Mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (25:75) to yield 1-(tert-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4-acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH3:12][N:13]([CH3:15])[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:14][N:13]([CH3:15])[CH3:12])[CH2:6][CH2:5]2
Reactant: CN(C)N
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C)N=C1CCc2cc(Cl)ccc21
Reaction time: 4 h

Procedure:
20 g of 5-chloroindan-1-one are dissolved in 600 ml of dry toluene and, after addition of 27.4 ml of N,N-dimethylhydrazine and 1 g of p-toluenesulfonic acid, boiled with a water trap for 4 h. The reaction mixture is concentrated in vacuo, and the residue is dissolved in ethyl acetate and washed with sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulfate and concentrated in vacuo, and the residue is chromatographed on silica gel with ethyl acetate/heptane ½. N′-(5-chloroindan-1-ylidene)-N,N-dimethylhydrazine is obtained as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C@@H:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[O:9])[CH2:3]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[O-][Si]([O-])=O.[Mg+2].C(OCC)C>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C@@H:11]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])=[O:9])[CH2:3]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCCC(O)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCCN(C(=O)O[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of benzyl 2(S)-(3-hydroxypiperidinocarbonyloxy)-3-phenylpropionate (477 mg) in methylene chloride (10 ml) was added pyridinium dichromate (0.99 g) and the mixture was stirred at ambient temperature overnight. The mixture was passed through a Florisil (Trademark : manufactured by Floridin Co.) (60-100 mesh) column with diethyl ether and then methylene chloride as eluent. Concentration under reduced pressure gave benzyl 2(S)-(3-oxopiperidinocarbonyloxy)-3-phenylpropionate (278 mg).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][O:3][CH3:2])[CH2:11][CH2:10]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COCCN1CCN(CC(=O)O)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COCCN1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 41.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-methoxyethyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 241, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)propanamide (18.8 mg, 41.6%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.59 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.03-6.97 (m, 4H), 4.68 (m, 1H), 4.52 (s, 2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.41 (t, 4H), 3.22 (s, 3H), 2.96 (s, 2H), 2.44 (t, 8H). MS (EI) for C31H37FN4O5. found 565.7 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=O)[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].P(Cl)(OCC)(OCC)=O.[N+:38]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])#[C-:39]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:39]=[N:38][C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:12]3[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C1CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1F)c1cc([N+](=O)[O-])ccc1-2
Reaction time: 0.08 h

Procedure:
A stirred solution of 2.99 g (0.01 mol) of 7-nitro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 50 ml of tetrahydrofuran was cooled in an ice bath under an atmosphere of nitrogen. Potassium t-butoxide, 1.29 g (0.0115 mol) was added, and after stirring for 5 minutes, 2.59 g (0.015 mol) of diethyl chlorophosphate was added and the stirring was continued for an additional 5 minutes. A mixture of 2.26 g (0.02 mol) of ethyl isocyanoacetate in 50 ml of tetrahydrofuran that has been treated with 2.24 g (0.02 mol) of potassium t-butoxide, just prior to the addition, was then added. After 5 min, the ice bath was removed and the stirring was continued for 1 hour. The mixture was acidified with 2 ml of glacial acetic acid, diluted with 200 ml of saturated sodium bicarbonate solution and extracted with two 125 ml portions of toluene which were dried and evaporated. Crystallization from ethyl acetate yielded end product with mp 228°-231°. For analysis, the material was chromatographed over a column of 60 g of silica gel using ethyl acetate/methylene chloride 1:1 (v/v) and recrystallized from ethyl acetate/ether to give colorless crystals with mp 229°-232°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([C:17](OC)=[O:18])[N:14]=[C:13]([C:21](OC)=[O:22])[CH:12]=2)[CH:8]=[C:7]([C:25](OC)=[O:26])[N:6]=1)=O.[BH4-].[Na+].Cl>O1CCOCC1.O>[OH:18][CH2:17][C:15]1[CH:16]=[C:11]([C:9]2[CH:10]=[C:5]([CH2:3][OH:2])[N:6]=[C:7]([CH2:25][OH:26])[CH:8]=2)[CH:12]=[C:13]([CH2:21][OH:22])[N:14]=1
Reactant: COC(=O)c1cc(-c2cc(C(=O)OC)nc(C(=O)OC)c2)cc(C(=O)OC)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc(-c2cc(CO)nc(CO)c2)cc(CO)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 g (128.77 mmol) of 2,2', 6,6'-tetra(methoxycarbonyl)-4,4'-bipyridine is dissolved in a mixture of 400 ml of dioxane/400 ml of water and, in portions, 48.71 g (1.28 mol) of sodium borohydride is added thereto. The mixture is stirred overnight at room temperature. The solution is acidified with 5N hydrochloric acid and evaporated to dryness. The residue is suspended in 1 liter of 1N sodium hydroxide solution and extracted three times with 250 ml of chloroform. The organic phases are dried over magnesium sulfate and evaporated under vacuum. The residue is recrystallized from ethanol/ether.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[OH-].[K+].[CH3:9][Si:10]([CH3:25])([CH3:24])[C:11]1[CH:12]=[C:13](C(=O)C)[CH:14]=[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=1.S(=O)(O)[O-].[Na+]>O>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:15]1[CH:14]=[C:13]([CH:12]=[C:11]([Si:10]([CH3:25])([CH3:24])[CH3:9])[CH:16]=1)[C:1]([OH:2])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc([Si](C)(C)C)cc([Si](C)(C)C)c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: C[Si](C)(C)c1cc(C(=O)O)cc([Si](C)(C)C)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A suspension of 2.0 g (14 mmol) of Ca(OCl)2, 1.38 g (10 mmol) of potassium carbonate and 0.40 g (7.12 mmol) of potassium hydroxide in 40 ml of water was stirred at 65° C. for 30 minutes and filtered. The filtrate was added to 0.53 g (2 mmol) of 3',5'-bis(trimethylsilyl)acetophenone and the mixture was refluxed for 7.5 hours with stirring. After cooling, 3 ml of aqueous sodium bisulfite solution was added to the reaction mixture. The aqueous solution was extracted with AcOEt. The extract was washed successively with water and sat.aq.NaCl, dried over anhyd.Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel [eluent: n-hexane-AcOEt (2:1-1:1)] to give 0.27 g of white powder, m.p. >300° C. (yield 51%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1C
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1C

Procedure:
A solution of 11.5 g. (0.07 mol.) of 3-methyl-4-methoxybenzoic acid and 10.7 g. (0.09 mol.) of thionyl chloride in 60 ml. of methylene chloride was refluxed on a steam bath for two hours. Concentration in vacuo and distillation of the residue gave 3-methyl-4-methoxybenzoic acid chloride, m.p. 37°-39°.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[S:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[S:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:28][CH:29]=1)(=[O:22])(=[O:23])[NH2:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccc(S(N)(=O)=O)cc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(4-sulfamoyl-phenyl)-ethyl-amine to afford the title compound. MS: m/e=441 (M+H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:7]=[N:6][CH:5]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:3][C:4]2[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:7]=[N:6][CH:5]=2)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)Cn1cncc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(O)nc(SCc2cncn2CC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 5-(chloromethyl)-1-(2-methylpropyl)-1H-imidazole hydrochloride (1.0 g, 4.89 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (0.546 g, 3.84 mmol), and potassium carbonate (0.677 g, 4.90 mmol) was added. The reaction mixture was stirred at room temperature overnight. Potassium carbonate was filtered, and the solvent was evaporated, affording the title compound as a white solid (1.09 g, 82% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.82 (d, J=6.6 Hz, 6H), 2.01 (m, 1H), 2.21 (s, 3H), 3.75 (d, J=7.6 Hz, 2H), 4.47 (s, 2H), 6.03 (bs, 1H), 6.88 (s, 1H), 7.58 (s, 1H); M+1 279.3.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3C(CON)=NN=[C:10]3[CH2:9][N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:24]=1.[H-].[Na+].CI>CN(C)C=O>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:24][C:6]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C1=CNc2ccccc2C=N1
Reaction time: 18 h

Procedure:
A stirred solution of 8-chloro-1-[(aminooxy)methyl]6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (0.02 mole) in dry dimethylformamide (50 ml.) is cooled in an ice bath under nitrogen and treated successively with a 57% mineral oil suspension of sodium hydride (0.84 g,. 0.02 mole) and methyliodide (0.02 mole). The mixture is allowed to come slowly to ambient temperature and stand for 18 hours. It is then concentrated in vacuo. The residue is chromatographed on silica gel with methanol to give 8-chloro-1-[[(methylamino)oxy]methyl]6-phenyl-4H-s-triazolo]4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 101 mg of 4-methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.69 (s, 3H), 6.68 (d, 2H, J=8.8 Hz), 7.36-7.47 (m, 4H), 7.46, 7.55-7.69 (m, 5H), 9.65 (s, 1H). MS: m/z 448.3 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11]
Reactant: Clc1cccc2[nH]ccc12
Reactant: Cc1c[nH]c2ccccc12
Product: Cn1ccc2c(Cl)cccc21
Yield: 100 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 4-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%) was obtained as an amber oil: MS (ES) m/e 166.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[CH:8]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:11][C:12](=[O:13])[CH:14]=[CH:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:10])=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccc(C=O)c(Cl)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=CC(=O)C=Cc2ccc(C)cc2Cl)c(Cl)c1

Procedure:
The starting material, 1,5-bis(3-chloro-p-tolyl)-1,4-pentadien-3-one is prepared by the reaction of two moles of 3-chloro-p-tolualdehyde [Wahl, Ann. Chim. [11] 5 (1936), pp. 5, 39] and one mole of acetone in ethanol solution in the presence of sodium hydroxide.