Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:14][CH2:15][OH:16].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[C:9]([O:10][CH2:14][CH2:15][OH:16])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(O)c(F)c(C=O)c1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(F)c(OCCO)c1
Temperature: 100 °C
Reaction time: 4.25 h

Procedure:
Under nitrogen atmosphere, a mixture of 2-fluoro-3-hydroxy-5-methoxybenzaldehyde (17.01 g, 100 mmol), 2-chloroethanol (8.72 mL, 130 mmol), sodium iodide (19.49 g, 130 mmol), potassium carbonate (17.97 g, 130 mmol), and N,N-dimethylformamide (85 mL) was stirred at 100° C. for 4.25 hours, after which 2-chloroethanol (4.70 mL, 70 mmol), sodium iodide (10.49 g, 70 mmol), potassium carbonate (9.68 g, 70 mmol), and N,N-dimethylformamide (17 mL) were added thereto, and the resulting mixture was stirred at the same temperature for 4.25 hours. To the mixture, 2-chloroethanol (2.01 mL, 30 mmol), sodium iodide (4.50 g, 30 mmol), and potassium carbonate (4.15 g, 30 mmol) were added, and the resulting mixture was stirred at 100° C. for 7 hours, after which 2-chloroethanol (2.01 mL, 30 mmol) was added thereto, and the resulting mixture was stirred at the same temperature for 2.5 hours. After cooling the mixture, ethyl acetate and water were added to the reaction mixture, and the resulting mixture was extracted. The organic layer was washed with water and concentrated under reduced pressure to obtain a crude product containing the captioned compound (17.70 g) as a red-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C@H:18]1[CH2:23][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20][N:19]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([N:31]([CH3:32])[C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:22]4[CH2:21][CH2:20][N:19]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C@@H:18]([CH3:17])[CH2:23]4)=[CH:30][CH:29]=3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(-c2cccc(F)c2)nc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4cccc(F)c4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The acid chloride from step 1 was taken up in DCM and added drop-wise to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.1 g, 0.313 mmol) and triethylamine (0.065 mL, 0.47 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature under argon for ˜15 h, then diluted with water and DCM. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography. Elution with EtOAc/petroleum ether yielded the title compound as a yellow oil (0.127 g). δH (CDCl3, 400 MHz) 8.51 (1H, d), 7.75 (1H, dd), 7.67 (2H, m), 7.55 (1H, d), 7.40 (1H, m), 7.24 (2H, d), 7.08 (1H, m), 7.03 (2H, d), 4.15 (1H, br.s), 3.78 (1H, d), 3.53 (3H, s), 3.45 (1H, d), 3.32 (1H, d), 3.06 (1H, td), 2.69 (1H, d), 2.49 (1H, d), 2.09 (1H, dd), 1.98 (1H, m), 1.44 (9H, s), 1.16 (3H, d). MS (ES): MH+ 519.3.
Reaction SMILES: [F:1][C:2]1([F:17])[C:7](O)([OH:8])[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CCO>[F:17][C:2]1([F:1])[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(O)C(F)(F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)C(F)(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
tert-Butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (3.10 g, 12.2 mmol) was dissolved in 95% EtOH (50 mL) and the solution was treated with sodium borohydride (2.32 g, 61.2 mmol) and stirred at ambient temperature for 3 hours. The reaction was treated dropwise with 3N HCl until vigorous gas evolution ceased, then stirred at ambient temperature for 20 minutes (pH of the mixture was 3-4 at this point). The reaction was neutralized with saturated NaHCO3 and concentrated in vacuo. The residue was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the desired product as a white solid (1.39 g).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4]1>[Fe].C(O)C.O>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: Cn1ncc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1ncc2cc(N)ccc21
Yield: 71.1 %

Procedure:
Iron (3.62 g, 64.7 mmol) and concentrated hydrochloric acid (0.1 mL) were added to ethanol/water (20 mL/20 mL), and refluxed for 1 hour. The mixed reaction solution was added with 1-methyl-5-nitro-1H-indazole (2.29 g, 12.9 mmol) obtained in <Step 1> above, and further refluxed for 3 hours or more. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with chloroform/2-propanol=4/1(v/v). The filtrate obtained was distilled under reduced pressure, and dissolved in chloroform/2-propanol=4/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.35 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:21]([O:22][CH3:23])=[CH:20][C:5]2[CH:6]([C:11]3[C:19]4[O:18][CH2:17][CH2:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.CN(C)C=O.Cl.[CH3:30][N:31]([CH3:44])[CH2:32][CH2:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[C:21]([O:22][CH3:23])=[CH:20][C:5]2[CH:6]([C:11]3[C:19]4[O:18][CH2:17][CH2:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)[CH2:7][N:8]([C:39]([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:31]([CH3:44])[CH3:30])=[CH:43][CH:42]=3)=[O:40])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Reactant: COc1cc2c(cc1Cl)CCNCC2c1cccc2c1OCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)CCN(C(=O)c1ccc(OCCN(C)C)cc1)CC2c1cccc2c1OCC2

Procedure:
Similarly as described in example 22 using a solution of 7-chloro-1-(2,3-dihydrobenzofuran-7-yl)-8-methoxy-1,2,4,5-tetrahydrobenzo[d]azepine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 pi), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[C:12]([CH3:25])[CH:13]=[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:24])[C:9]2=[N:8][C:7]=1[CH3:26])(OCC)=[O:2].COCCO[AlH2-]OCCOC.[Na+].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].O>C1(C)C=CC=CC=1>[CH3:26][C:7]1[N:8]=[C:9]2[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:24])=[CH:13][C:12]([CH3:25])=[CH:11][N:10]2[C:6]=1[CH2:1][OH:2]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3C)cc(C)cn12
Agent: COCCO[AlH2-]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(NCc2c(C)cccc2C)c2nc(C)c(CO)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 3-carboethoxy-2,6-dimethyl-8-(2,6-dimethylbenzylamino)imidazo[1,2-a]pyridine (0.4 g, 1.1 mmol) in 10 ml toluene was cold with ice- water, Red-AL 65% in to toluene (2.1 g, 6.6 mmol) was added after 30 min. The solution was stirred for 2 h at room temperature. 10 ml of Rochelle-salt solution (sodium potassium tartrate tetrahydrate, 35 g/250 ml water) was added dropwise, 10 ml toluene was added, the organic layer was separated and washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluent dichloromethane:methanol 9:1, to give 0.21 g, (62%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][CH2:15][C:16]2[CH:29]=[CH:28][C:19]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:28][CH:29]=2)=[CH:11][CH:10]=1)[CH2:45][C:41]1[NH:40][CH:44]=[CH:43][N:42]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)Cc1ccc(COCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(COCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The compound (136 mg) obtained in Example 80-4 was dissolved in anhydrous methanol (3.0 ml) and then added with sodium cyanoborohydride (40.6 mg), acetic acid (1.00 ml), and 2-imidazole carboxaldehyde (46.6 mg), followed by stirring under a nitrogen atmosphere at 60° C. overnight. After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (109 mg) of the subject compound as a white solid.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH2:11])[C:5]=2[N:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][CH2:25][CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: NC1CCCc2nccnc21
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2nccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 5,6,7,8-tetrahydroquinoxalin-5-ylamine (313 mg, 2.09 mmol) in CH2Cl2 (20 mL) at room temperature under inert atmosphere was added 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (227.8 mg, 1.05 mmol) followed by sodium triacetoxyborohydride (444 mg, 2.10 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resultant material was purified by column chromatography on silica gel (10:1:0.5 CH2Cl2: MeOH: NH4OH) to provide the product as a clear oil (298 mg, 81%): 1H NMR (CDCl3): δ 1.56-1.66 (m, 2H), 1.70-1.95 (m, 4H), 2.04-2.22 (m, 4H), 2.71-2.85 (m, 2H), 2.87-3.05 (m, 2H), 7.69-7.73 (m, 2H), 7.80-7.85 (m, 2H), 8.34 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Yield: 65 %

Procedure:
1-[5-(3,5-Dimethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.122 mmol, 29.9 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.122 mmol, 25.9 mg) were stirred with dimethylformamide (2 mL) and two drops of concentrated hydrochloric acid at room temperature for 24 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (34.7 mg, yield 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[O:9]=[C:10]1[NH:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.ClCCl.O1CCOCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:14]2[C:10](=[O:9])[CH2:11][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC(=O)N(c2ccc(Br)cc2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
1,4-Dioxane (8 ml) was added to 1,4-dibromobenzene (176 mg), t-butyl N-[(3R)-5-oxopyrrolidin-3-yl]carbamate (100 mg), tris(dibenzylideneacetone)dipalladium(0) (23 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (29 mg), and cesium carbonate (244 mg), and the mixture was stirred at 90° C. for 1 hour under an argon atmosphere and then further heated to reflux for 1 hour. Dichloromethane and water were added to the reaction solution to separate the aqueous and organic layers. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (24 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C.[N:23]1[NH:24][N:25]=[N:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:52]=[CH:51][C:37]2[N:38]([CH:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:42](O)=[O:43])[CH:39]=[N:40][C:36]=2[CH:35]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[O:43]=[C:42]([NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:41]([N:38]1[C:37]2[CH:51]=[CH:52][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[N:23]=[N:24][NH:25][N:26]=3)=[CH:35][C:36]=2[N:40]=[CH:39]1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C(=O)N[C@@H](Cc1ccccc1)C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21

Procedure:
L-Phenylalanine hydrochloride (1.75 mmoles, 380 mg), diisopropylethylamine (1.93 mmoles, 0.34 ml), 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.24 mmoles, 0.50 g), hydroxybenzotriazole (1.36 mmoles 184 mg) and dicyclohexylcarbodiimide (1.36 mmoles, 280 mg) were reacted as in Example 37. The stereoisomers were separated by chromatography over silica gel eluted with 2% methanol in chloroform. The isomers were hydrolyzed as in Example 37 to yield N-[1-oxo-2-[5-[2-(2H-tetrazole-5-yl]phenyl]-1H-benz imidazol-1-yl]octyl]-L-phenylalanine.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[C:6]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[H][H]>CO.[C].[Pd]>[CH3:26][Si:23]([CH3:24])([CH3:25])[C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:28])([CH3:27])[CH3:1])[CH:22]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)=[O:7]
Reactant: [H][H]
Reactant: C[Si](C)(C)c1cc(C(=O)Nc2ccc(C=CC(=O)O)cc2)cc([Si](C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)c1cc(C(=O)Nc2ccc(CCC(=O)O)cc2)cc([Si](C)(C)C)c1
Yield: 79.6 %

Procedure:
Compound 3 (10 mg) was dissolved in methanol (1 ml), and a catalytic amount of palladium carbon was added thereto. The obtained mixture was stirred in a hydrogen atmosphere at room temperature for 5 hours. After the reaction was over, the reaction mixture was filtered through Celite, and the filtrate was purified by silica gel column chromatography to obtain Compound 4 (8 mg, 80%) as a white solid.
Reaction SMILES: [C:1](N1CCNCC1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N[CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)=O>>[C:1]([C:23]1[NH:22][O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:21][C:20]=2[CH:24]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=CNC1CCNC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: O=C(OCc1ccccc1)C1=Cc2ccccc2ON1

Procedure:
In the described fashion as Example 2(b)-2(e), replacing the N-carbobenzoxypiperazine in Example 2(e) with 3-formamidopyrrolidine, one can obtain compound (F) (R8 =CH3, R9 =C2H5, R10 =C6H5, ##STR20##
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[O:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[O:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]3=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]3[CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 20.4 g) in THF (dry) (250 mL) was added 2-chloroethanesulfonyl chloride (32.2 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-phenoxyphenyl)pyridin-2-amine (29.09 g) in THF (dry) (150 ml) was dropwised at 0° C. and the mixture was stirred at room temperature under N2 for 2 days. The mixture was quenched with THF/water (v/v=5/1) at 0° C. under N2 carefully. Water (500 mL) and EtOAc (400 mL) were added to form precipitates (stirred for 30 min) which were washed with water and EtOAc, collected and crystallized from DMSO/EtOH (500 mL/1000 ml, at 90° C.) to give the title compound (36.0 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:19]
Reactant: CN1CC(=O)N=C1N
Reactant: COc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N=C2NC(=O)CN2C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-methoxyphenylisocyanate (14.91 g, 0.100 mole) is added dropwise over a period of about 15 minutes with cooling. After stirring for 8 hours, the mixture is poured into about 500 ml of ice water to yield white crystals of product which are filtered off, washed with water and purified by recrystallization (twice) from tetrahydrofuran-methanol. The crystalline product is reduced to finer size by adding a solution of the product in minimal DMF to vigorously stirred water (about 1.1 liters) and filtering off the resultant crystals which are then dried at room temperature in vacuo for 24 hours; m.p. 193°-5° C. dec.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:19]O>C(O)(=O)C>[CH:1]1([CH2:7][S:8]([C:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])([CH3:17])[CH2:11][C:10]=2[OH:18])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)CC(=O)C(SCC2CCCCC2)=C(O)C1
Reactant: OO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(S(=O)CC2CCCCC2)=C(O)C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(cyclohexylmethylthio)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one (8.0 g., 0.029 mole), 50 ml. of glacial acetic acid and 30 percent hydrogen peroxide (3.26 g., 0.029 mole) was allowed to stand at room temperature for 24 hours. The solution was then poured into ice-water, and the precipitated pink crystals were filtered and dried (7.7 g., m.p. 77°-79.5°C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[OH:12])=[O:10])=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:11]([OH:12])[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[OH:10])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(O)C(O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Yield: 75.4 %

Procedure:
In 3 liters of dry ethanol, 75 g of 4,4'-bismethoxybenzoin and 21 g of sodium borohydride were refluxed for 2 hours. After adding 250 ml of concentrated hydrochloric acid to the reaction mixture, the resulting mixture was poured into 1300 ml of ice water, followed by filtration of deposited crystals. After recrystallized from 95% ethanol, there was obtained 57 g of 1,2-di(p-methoxyphenyl)ethane-1,2-diol, which was then added to 570 ml of 80% acetic acid and stirred at 90° C. for 50 minutes. Then, the reaction mixture was poured into 4 liters of ice water and deposited crystals were filtered. After drying, the crystals were recrystallized from isopropyl ether to give 40 g of Compound (e) in 69% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]=C)=[N:14]1.I([O-])(=O)(=O)=[O:24].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]=[O:24])=[N:14]1
Reactant: C#CCOc1cc(-n2nc(CCC=C)[nH]c2=O)c(Cl)cc1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOc1cc(-n2nc(CCC=O)[nH]c2=O)c(Cl)cc1Cl
Yield: 92.2 %

Procedure:
To a solution of 500 mg (1.48 mmol) of 2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-2,4-dihydro-5-(3-butenyl)-3H-1,2,4-triazol-3-one in a mixture of 10 mL of tetrahydrofuran and 10 mL of water was added 696 mg (3.25 mmol) of sodium periodate and 167 mL of 0.18M aqueous solution of osmium tetroxide at room temperature. The mixture was stirred at the room temperature for 2h, and then diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel, eluting with a 96:4 v:v mixture of dichloromethane and methanol to give 464 mg of the title product of Step 1 as a white foam. 1H NMR (CDCI3, 400 MHz) δ 11.5 (broad s,1H), 9.8 (s,1H), 7.55 (s,1H), 7.2 (s,1H), 4.8 (s,2H), 2.9 (m,4H).