Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:45])[C@@H:24]([NH:25][C:26](=[O:44])/[C:27](/[C:31]4[N:32]=[C:33]([NH:36]C(OC(C)(C)C)=O)[S:34][CH:35]=4)=[N:28]\[O:29][CH3:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:46][S:47][C:48]2[N:49]=[N:50][N:51](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:52]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(=O)([O-])O.[Na+:81]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O.C(OCC)(=O)C>[Na+:81].[NH2:36][C:33]1[S:34][CH:35]=[C:31](/[C:27](=[N:28]/[O:29][CH3:30])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:45])[N:22]3[C:17]([C:15]([O-:14])=[S:16])=[C:18]([CH2:46][S:47][C:48]4[N:49]=[N:50][NH:51][CH:52]=4)[CH2:19][S:20][C@H:21]23)=[O:44])[N:32]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CSc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nn3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C([O-])=S)=C(CSc3c[nH]nn3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-methoxyiminoacetyl]amino-3-(1-trityl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (570 mg: 0.55 mMol.) in a mixture of anisole (1.7 ml) and nitromethane (5 ml) at -30° C. is added e solution of aluminum chloride (0.51 g: 3.83 mMol.) in anisole (1.8 ml), and the mixture is stirred for 30 minutes. The reaction mixture is mixed with 1N-hydrochloric acid (4 ml) and ethyl acetate (10 ml), stirred at room temperature for 5 minutes, poured into a solution of sodium hydrogen carbonate (3.2 g) in water (100 ml), and stirred for several minutes. After filtering off the insoluble material, the reaction mixture is washed with ethyl acetate, concentrated in vacuum to remove the organic solvents. The resulting aqueous layer is purified by stylene-divinylbenzene copolymer chromatography (water: methanol=10:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl]amino-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid sodium salt as white foam (194 mg). Yield: 64%.
Reaction SMILES: IC1C(C)=CC=CC=1C(O)=O.[NH2:12][CH2:13][C@@H:14]1[C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:22].F[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[CH3:20][C@@H:19]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=2[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:35]=2)=[O:22])[C@@H:14]1[CH2:13][NH:12][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1
Reactant: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1-c1ncccn1
Reactant: Fc1ccc(C(F)(F)F)cn1
Agent: Cc1cccc(C(=O)O)c1I
Product: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1-c1ncccn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A230 using 2-iodo-3-methylbenzoic acid to make ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][OH:9].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>CCOC(C)=O>[OH:9][N:8]=[C:17]([NH2:18])[C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=1
Reactant: NO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: NC(=NO)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 86.88 %

Procedure:
Potassium carbonate and hydroxylamine hydrochloride were added to an ethanolic solution of 4-nitrobenzonitrile. The solution was refluxed at 80° C. for 5 hours. After completion of the reaction the solvent was evaporated and the crude so obtained was dissolved in EtOAc and washed with water, brine, then dried by sodium sulfate and concentrated to give a solid. It was the purified by column chromatography and further recrystallized from EtOAc: petroleum ether to obtain the title product in 86.88% yield. 1H NMR (DMSO-d6) δ: 6.071 (s, 2H, NH2) 8.24 (d, 2H, CH), 8.317 (d, 2H, CH), 10.138 (S, 1H, OH), ms (m/z) 180 (M−−H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.C(OCC)C>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][C:3]([C:5]3[CH:18]=[CH:17][C:8]([O:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
The product from step (i) above (2.00 g) in acetonitrile (10 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (1.04 g) and triethylamine (0.89 ml) in acetonitrile (15 ml) and the mixture stirred overnight. The precipitated solid was removed by filtration and the filtrate evaporated. Purification of the residue by flash chromatography on silica, eluting with 0 to 5% v/v methanol/dichloromethane, gave a yellow gum. Trituration of this gum with diethyl ether gave methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]phenoxy]isobutyrate, 170 mg, as a white solid: m.p. 88°-90° C.; NMR (d6DMSO) δ 8.15 (2H, d), 7.96 (2H, d), 6.82 (4H, m), 3.92 (2H, s), 3.70 (3H, s), 3.33 (4H, t), 2.63 (4H, t), 1.60 (6H, s); m/e 398 (M+H)+ ; calculated for C22H27N3O4.0.25H2O: C, 65.8; H, 6.8; N, 10.5. found: C, 65.8; H, 7.1; N, 10.4%.
Reaction SMILES: [CH2:1]([OH:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>CCCCCC>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:12][CH2:1][C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1)=[O:22]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1ccc(CO)cc1OC
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(COC(=O)CCCCCCC(C)C)cc1OC
Temperature: 50 °C
Yield: 89.1 %

Procedure:
Veratryl alcohol (734 mg, 4.53 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give veratryl 8-methylnonanoate (1.25 g, yield 89.1%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[NH:28]C(=O)OCC[Si](C)(C)C)[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:28][C@@H:18]1[CH2:19][C@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:21][CH2:22][C@@H:17]1[N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:38]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A stirring solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexylcarbamate (272 mg, 0.5 mmol) in dichloromethane (3 mL) was charged with trifluoroacetic acid (2 mL). The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and washed with saturated NaHCO3 (15 ml). the aqueous layer was extracted with dichloromethane (4×30 ml). Combined all the dichloromethane layers and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-amino-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (190 mg, 94.5%). LC/MS found [M+H]+=403.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: ClCCN1CCCCC1
Reactant: COc1cc(O)ccc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCCCC2)ccc1C=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
In 2.0 mL of N,N-dimethylformamide were dissolved 304 mg (2.00 mmol) of 4-hydroxy-2-methoxybenzaldehyde, 0.55 g (4.0 mmol) of potassium carbonate, and 64 mg (0.20 mmol) of tetrabutylammonium bromide. To this solution was added 0.74 g (4.0 mmol) of 1-(2-chloroethyl)piperidine hydrochloride and the mixture was stirred at 100° C. overnight. The resulting reaction mixture was diluted with ethyl acetate (100 mL), washed with water and then with saturated brine (each in an amount of 20 mL), and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 to 90/10) to give 88.9 mg (16% yield) of the title compound as a brown viscous matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:26])[CH:3]=1.[C:27](=O)([O-])O.[Na+]>COS(OC)(=O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:27])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][C:17]=2[Cl:26])[CH:3]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)CN(C)c1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
The subtitle compound was prepared by using the product from example 15 step ii). (0.70 g) which was dissolved in dimethylsulphate (3 ml). Sodium hydrogen carbonate (0.355 g) was added and heated to 90 C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated under reduced pressure to give an oil. The residue was purified by chromatography on silica eluting with diethyl ether, yield 0.70 g.
Reaction SMILES: O[CH:2]1[CH:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][N:5]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:4]2[CH:27]=[CH:28][CH:29]=[CH:30][C:3]1=2.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II>C1(C)C=CC=CC=1.C(OCC)C>[S:17]([N:5]1[CH2:6][CH2:7][C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:2][C:3]2[CH:30]=[CH:29][CH:28]=[CH:27][C:4]1=2)([C:20]1[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=1)(=[O:18])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)C(O)c3ccccc32)cc1
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)=Cc3ccccc32)cc1
Temperature: 110 °C
Yield: 10.5 %

Procedure:
To a solution of tert-butyl 5-hydroxy-1-tosyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate (200 mg, 0.46 mmol) and imidazole (94 mg, 1.38 mmol) in toluene (10 mL), triphenylphosphine (242 mg, 262 mmol) and iodine (237 mg, 0.092 mol) were added. The reaction mixture was heated to 110° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with diethyl ether (50 mL). The precipitate that formed was filtered off and the filtrate washed with water followed by a saturated solution of sodium thiosulphate, a saturated solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under vacuo to give tert-butyl 1-tosyl-2,3-dihydro-1H-benzo[b]azepin-4-ylcarbamate (20 mg, 10.4%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](C(O)=O)=[C:5]2[CH3:15].BrC1C(C)=C2C(=CC=1)NC(C(O)=O)=C2C.CCOCC.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[C:5]2[CH3:15]
Reactant: Cc1cc2[nH]c(C(=O)O)c(C)c2cc1Br
Agent: [Cu]
Agent: Cc1c(Br)ccc2[nH]c(C(=O)O)c(C)c12
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: Cc1cc2[nH]cc(C)c2cc1Br
Temperature: 240 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A 1:1 mixture of 5-bromo-3,6-dimethyl-1H-indole-2-carboxylic acid and 5-bromo-3,4-dimethyl-1H-indole-2-carboxylic acid (4.39 g, 16.4 mmol) in quinoline (10 mL) with copper powder (250 mg) was stirred at 240° C. for 3 h to give the corresponding mixture of the decarboxylated products. Upon cooling, ether (200 mL) was added and the mixture acidified with 5N HCl. The layers were separated, the organics were washed with brine, dried and evaporated. Chromatography (silica, 15% CH2Cl2 in hexane) and crystallization from a CH2Cl2/hexane mixture afforded the title compound (1.35 g 37%). 1H NMR (300 MHz, CDCl3) 7.74 (s, 1H), 7.21 (is, 1H), 6.90 (s, 1H), 2.48 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)(C)C>[CH2:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)=[N:3][CH:4]=1)[CH3:9]
Reactant: CCc1cnc(Br)cn1
Reactant: OC1CCNCC1
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(O)CC2)cn1
Temperature: 150 °C

Procedure:
A mixture of 2-bromo-5-ethyl-pyrazine (1.66 g) and 4-hydroxy-piperidine (2.24 g) in isopropanol (15 mL) is heated in an autoclave to 150° C. over night. The solvent is evaporated in vacuo and the residue is mixed with water and dichloromethane. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound. LC (method 7): tR=0.66 min; Mass spectrum (ESI+): m/z=208 [M+H]+.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH:19]([C:25]([OH:27])=O)[C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.Cl.CNC.C1C=CC2N(O)N=NC=2C=1>C(N(CC)CC)C.C(#N)C>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH:19]([C:25]([N:3]([CH3:4])[CH3:2])=[O:27])[C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)O)C2
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)NC(=O)C(C(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
WSC (6.5 g) was added to an acetonitrile solution of 7-methoxy-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylic acid (3.74 g), dimethylamine hydrochloride (3.44 g), HOBt (2.85 g) and triethylamine (8.5 g). The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue was diluted with ethyl acetrate. The organic layer was washed with 1N aqueous hydrochloric acid solution, 10% aqueous potassium carbonate solution, and a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the entitled compound (1.63 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[CH2:45]([OH:52])[C:46]([NH2:51])([CH2:49][OH:50])[CH2:47][OH:48].NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:51][C:46]([CH2:49][OH:50])([CH2:47][OH:48])[CH2:45][OH:52])=[CH:33][CH:32]=3)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NC(CO)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCCNC(CO)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and tris(hydroxymethyl)aminomethane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Br)(=O)C.[CH2:10]([C:12]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH2:30][N:31]([CH2:33][CH3:34])[CH3:32])[CH:24]=3)[O:20][N:19]=2)[CH:15]=[C:14]([CH3:35])[C:13]=1[OH:36])C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:33]([N:31]([CH2:30][C:25]1[CH:24]=[C:23]([C:21]2[O:20][N:19]=[C:18]([C:16]3[CH:15]=[C:14]([CH3:35])[C:13]([O:36][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[C:12]([CH3:10])[CH:17]=3)[N:22]=2)[CH:28]=[C:27]([CH3:29])[CH:26]=1)[CH3:32])[CH3:34]
Reactant: CC(=O)OCCCCBr
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C)Cc1cc(C)cc(-c2nc(-c3cc(C)c(OCCCCO)c(C)c3)no2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-bromobutyl acetate (186 mg, 936 μmol) was added to a suspension of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (114 mg, 312 μmol) and K2CO3 (129 mg, 936 μmol) in acetonitrile (2 mL). The mixture was stirred at 70° C. for 2 h before it was filtered. The filtrate was diluted with 25% aq. ammonia (0.5 mL) and a 32% aq. NaOH solution (300 μL) and the bi-phasic mixture was stirred at 70° C. for 2 h. The aq. phase was separated and 1N aq. NaOH (0.4 mL) was added. The now homogenous mixture was separated by prep. HPLC (XBridge 30×75 mm, eluting with a gradient of MeCN in water containing 0.5% of sat. aq. ammonia) to give the title compound as a white lyophilisate (53 mg). LC-MS: tR=0.65 min; [M+1]+=438.25; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.61-1.69 (m, 2H), 1.78-1.86 (m, 2H), 2.15 (s, 3H), 2.34 (s, 3H), 2.41-2.48 (m, 5H), 2.71 (q, J=7.5 Hz, 2H), 3.47-3.53 (m, 2H), 3.55 (s, 2H), 3.81-3.86 (m, 2H), 4.47 (br s, 1H), 7.47 (s, 1H), 7.80 (s, 2H), 7.90 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Product: O=C1N(c2ccnc(C(F)(F)F)c2)CCN1c1cnccc1C1CC1
Yield: 33.4 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 70 mg, 0.344 mmol) was reacted with 4-bromo-2-(trifluoromethyl)pyridine (93.5 mg, 0.413 mmol) 1,4-dioxane (5 mL), copper iodide (6.5 mg, 0.034 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (4.8 mg, 0.034 mmol) and potassium phosphate (219 mg, 1.034 mmol) to afford the crude product. Purification by preparative HPLC afforded 40 mg of the product (33% yield).
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](NN)([CH3:9])[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:4]=1)[NH2:2].C(N(CC)CC)C.[C:25]([O:29][C:30](ON=C(C1C=CC=CC=1)C#N)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OC(C)C)(C)C>O1CCCC1>[C:25]([O:29][C:30]([NH:2][NH:1][C:3]1[N:4]=[N:5][C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH3:9])[N:8]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CC1(NN)NC(NN)=NN=C1c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: Cc1nc(NNC(=O)OC(C)(C)C)nnc1-c1ccccc1
Temperature: 63 °C
Reaction time: 61 h
Yield: 104.6 %

Procedure:
A mixture of 3-hydrazino-5-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (6.6 g), triethylamine (5.4 g), 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (9.76 g) in tetrahydrofuran (60 ml) was heated at 63° C. for 5.5 hours with stirring and then allowed to stand at room temperature for 61 hours. The mixture was treated with diisopropyl ether (40 ml), and the resultant precipitates were collected by filtration, washed successively with diisopropyl ether, methanol and diisopropyl ether, and dried to give 3-(2-t-butoxycarbonylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (8.92 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27](Br)[CH:28]=[CH2:29].O>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[CH2:29][CH:28]=[CH2:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
Sodium hydride (47 mg of 60% oil dispersion, 1.2 mmol) was added to a solution of 4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)piperidine (200 mg, 0.598 mmol) from Procedure 4, Step C and allyl bromide (0.251 mL, 351 mg, 2.9 mmol) in 2.0 mL of DMF, and the reaction was stirred overnight at rt. The reaction mixture was poured into 20 mL of water and extracted with 3×20 mL of ethyl ether. The combined organic layers were washed with 30 mL of brine, dried over sodium sulfate, and evaporated. The crude product was purified by FC on silica gel, eluting with 20% ethyl acetate in hexane, to give 246 mg of the title compound as a viscous oil.