Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: CC1(C)CCC(CNOCc2ccccc2)(C(=O)O)CC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a cold solution of formic acid (12.8 mL, 0.33 mol) in dichloromethane (50 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (4.8 mL, 51 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-4,4-dimethyl-cyclohexanecarboxylic acid from Preparation 30 (5.11 mmol theoretical) in dichloromethane (50 mL) was added. The reaction was stirred at room temperature for 18 h and was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with dichloromethane (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound (1.55 g, 95%). MH+320.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=C[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[Cl:18]N1C(=O)CCC1=O.Cl[CH2:27][Cl:28]>>[Cl:18][C:15]1[CH:16]=[C:11]([C:2]([F:1])([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4])[CH:12]=[C:27]([Cl:28])[C:14]=1[NH2:17]
Reactant: ClCCl
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Product: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (10 g, 38.30 mmol) (prepared according to EP 1,006,102) in dichloromethane (150 ml), at 20° C., was added N-chlorosuccinimide (“NCS”) (21.48 g, 160.8 mmol). The reaction mixture was stirred overnight at ambient temperature. The reaction was quenched by addition of aqueous sodium hydroxide (2N) and the phases were separated. The aqueous layer was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:4) to give 2,6-dichloro-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (7.6 g, 60.1% yield). 1H-NMR (CDCl3, 400 MHz): 7.41 (s, 2H), 4.77 (s, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=O)[O:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1.N1CCCN2CCCN=C12>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:6]=[C:5]([C:7]([N:12]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)=[O:22])[CH2:19][CH2:20]2)[CH3:11])=[O:9])[O:4][N:3]=1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: COC(=O)c1cc(O)no1
Agent: C1CN=C2NCCCN2C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1cc(O)no1

Procedure:
A solution comprising of methyl 3-hydroxyisoxazole-5-carboxylate (20.72 mg, 0.145 mmol), 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (step 3) (50 mg, 0.145 mmol) and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (20.16 mg, 0.145 mmol) in DMF (483 μl) was refluxed for 18 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[NH2:13])([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O.CCOCC>[N+:1]1([O-:2])[C:4]2[CH:12]=[C:11]3[C:7](=[CH:6][C:5]=2[N:13]=[C:15]([NH2:16])[N:14]=1)[CH2:8][CH2:9][CH2:10]3
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Temperature: 50 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of amine 2 (21.67 g, 121.6 mmol), cyanamide (20.45 g, 486 mmol) and Et2O (10 mL) were mixed together at 80° C., cooled to ca. 50° C., cHCl (20 mL) added dropwise, during which a vigorous reaction occurred, and the mixture was heated at 80° C. for 1 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 8 h. The mixture was cooled, diluted with water (500 mL), and the yellow/green precipitate filtered. The precipitate was washed with water (3×50 mL), washed with ether (3×30 mL) and dried to give crude material (20.93 g, 85%), which can be used without further purification. The material was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1-oxide 19 (16.72 g, 68%) as a yellow powder: mp (MeOH/DCM) 270-272° C.; 1H NMR [(CD3)2SO] δ 7.92 (s, 1H, H-9), 7.33 (s, 1 H, H-5), 7.11 (br s, 2H, NH2), 2.91-2.99 (m, 4H, H-6, H-8), 2.01-2.09 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 159.9, 154.0, 148.5, 142.5, 128.7, 119.8, 113.8, 32.4, 31.6, 25.2. Anal. calcd for C10H10N4O: C, 59.4; H, 5.0; N, 27.7. Found: C, 59.4; H, 5.1; N, 27.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH2:9][CH2:8]2)[NH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=O.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>C(O)(=O)C.CO>[CH3:10][O:11][C:12]([C:13]1[C:6]2[C:5]([CH:7]3[CH2:9][CH2:8]3)=[N:4][NH:3][C:2]=2[N:1]=[C:22]([C:21]2[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=2)[CH:15]=1)=[O:16]
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)C(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C3CC3)c12
Temperature: 75 °C
Reaction time: 14 h
Yield: 16.9 %

Procedure:
A mixture of 3-amino-5-cyclopropylpyrazole (8.95 g), pyruvic acid methyl ester (8.24 g) and 4-hydroxybenzaldehyde (8.87 g) in acetic acid/methanol (v/v=1/1, 120 mL) was stirred at 75° C. for 14 h. The methanol was removed in vacuo, and the remaining mixture was poured unto water, and extracted with ethyl acetate three times. The combined organic phases were washed with brine, dried over magnesium sulfate, filtrated and concentrated in vacuo. The residue was dissolved in 50 ml of acetic acid/methanol (v/v=1/1), heated to reflux for 1 h and cooled to r.t. The precipitated product was isolated by filtration and dried in vacuo at 60° C. 3.80 g (17%) of the title compound were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])SC.[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>C(O)C>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([CH2:11][NH:10][C:3]([NH:2][CH3:1])=[N:6][N+:7]([O-:9])=[O:8])=[CH:13][CH:14]=1
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: NCc1ccc(Cl)nc1
Solvent: CCO
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 34 %

Procedure:
A mixture of 0.45 g of 1,2-dimethyl-3-nitroisothiourea, 0.43 g of 5-(aminomethyl)-2-chloropyridine and 25 ml of ethanol was refluxed for 6 hours and concentrated. The residue was purified by a column chromatography [developing solvent: chloroform-ethanol (5:1)] to afford 0.25 g of 1-(6-chloro-3-pyridylmethyl)-3-methyl-2-nitroguanidine (Compound No. 5).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P(OCC)(OCC)OCC.C(O)(=O)C>C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][N+:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Reactant: c1ccncc1
Agent: CCOP(OCC)OCC
Solvent: CC(=O)O
Solvent: CC#N
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1
Temperature: 22.5 °C
Reaction time: 8 h

Procedure:
In 2 ml of acetonitrile was suspended 103 mg of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4 -carboxylic acid. To the suspension were added in sequence 0.10 ml of pyridine, 0.21 ml of triethyl phosphite and 0.2 ml of acetic acid. The mixture was stirred at 20 to 25° C. for 8 hours, followed by concentration under reduced pressure. To the concentrated solution was added 10 ml of tetrahydrofuran, then precipitating powdery product was collected by filtration, followed by concentration under reduced pressure to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(1 -pyridinio)methyl-3-cephem-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:24][C:23](=O)[O:22][C:20](=[O:21])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[N:9]=[C:23]([CH2:24][CH:18]([C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)[CH2:19][C:20]([OH:22])=[O:21])[NH:10][C:4]=2[CH:3]=1.[ClH:1]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1cc(F)c(Cl)cc1N
Product: Cl
Product: O=C(O)CC(Cc1nc2cc(F)c(Cl)cc2[nH]1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.4, starting from commercial 4-chloro-5-fluoro-1,2-phenylenediamine and 3-(4-chlorophenyl)glutaric anhydride, 4-(5-chloro-6-fluoro-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid•HCl was obtained as light greyish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OCl)(C)(C)C.[CH3:23][S:24][CH2:25][C:26]([NH2:28])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=1[CH:25]([S:24][CH3:23])[C:26]([NH2:28])=[O:27]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CSCC(N)=O
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC(C(N)=O)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (-70° C.) solution of 12.77 g (0.055 mole) of 2-amino-5-chlorobenzophenone in 300 mL of methylene chloride, under nitrogen atmosphere, was added 6.0 g (0.552 mole) of t-butylhypochlorite in 20 mL of methylene chloride. After the reaction was stirred for an additional 15 min, a suspension of 5.8 g (0.055 mole) of α-(methylthio)acetamide in 150 mL of methylene chloride was added. The mixture was stirred at -65° C. for 1 h. Triethylamine (5.6 g, 0.055 mole) was added and the solution was allowed to warm to room temperature. The reaction mixture was extracted with water and the organic layer dried over magnesium sulfate. The volume of the solution was reduced in vacuo to about 200 mL and the product crystallized as a yellow solid, m.p. 173.5°-174.5° C. Yield was 6.86 g (37.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:61][C:62]1[CH:63]=[CH:64][C:65]([O:72][CH3:73])=[C:66]([CH2:68][C:69](O)=[O:70])[CH:67]=1>CN(C)C(=O)C>[F:61][C:62]1[CH:63]=[CH:64][C:65]([O:72][CH3:73])=[C:66]([CH2:68][C:69]([NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[CH:9][C:10]2[N:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[O:70])[CH:67]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: COc1ccc(F)cc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1CC(=O)NC1=c2ccc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(F)cc1
Yield: 91 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.09 M and 0.25 M in N,N-dimethylacetamide, respectively, 450 μL, 0.2 mmol Example 23e and 0.6 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.14 M in N,N-dimethylacetamide, 450 μL, 0.3 mmol), and 2-(5-fluoro-2-methoxyphenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.24 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to give 0.0243 g (91%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6/D2O) δ 10.28 (s, 1H), 8.12 (d, J=2.44 Hz, 1H), 7.65 (s, 1H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.20 (d, J=8.54 Hz, 1H), 7.11 (m, 2H), 7.04 (s, 1H), 7.01 (m, 1H), 6.83 (m, 2H), 6.48 (m, 2H), 5.02 (d, J=15.56 Hz, 1H), 4.18 (d, J=15.87 Hz, 1H), 4.04 (s, 3H), 3.79 (s, 3H), 3.70 (s, 2H). MS (APCI+) m/z 527.1 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22].Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:19]2[NH:15][C:16]([CH2:20][C:21]#[N:22])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: N#CCc1ccc[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C

Procedure:
To a chilled suspension of 26.80 g. (0.2 mole) of aluminum chloride in 110 ml. of methylene chloride is added dropwise 35 g. (0.2 mole) of p-chlorobenzoyl chloride. The mixture is added dropwise to a solution of 21.22 g. (0.2 mole) of pyrrole-2-acetonitrile in 125 ml. methylene chloride which is cooled externally with an ammonium chloride ice bath. After addition is complete, the reaction mixture is stirred for ten minutes at 0° C. and then poured into ice acidified with dilute hydrochloric acid. A solid precipitate, 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile, which is filtered off, washed with hot methanol and dried, m.p. 203-205° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]([N:21]=[C:22]=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:22](=[O:23])[NH:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCCCCCN=C=O
Reactant: CN1CCCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2C
Reaction time: 0.33 h

Procedure:
A solution of 1-methyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.244 g., 1 mmol) in dry tetrahydrofuran (5 ml) was added to a stirred suspension of sodium hydride (0.024 g., 1 mmol) in dry tetrahydrofuran (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then hexyl isocyanate (0.26 g., 1 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20.80) as eluant to give 2m; yield: 0.25 g. (57.9%), m.p. 50° C., C17H26N2O2; 1H NMR δ ppm (CDCl3): 0.88 (bs, 3H), 1.26-1.54 (m, 8H), 1.96-1.99 (m, 2H), 2.71 (t, 2H), 2.85 (s, 3H), 3.14-3.25 (m, 4H), 4.90 (bs, 1H), 6.54 (d, 1H), 6.71-6.87 (m, 2H); IR vmax (KBr) (cm−1): 656, 757, 895, 1160, 1226, 1319, 1387, 1502, 1721, 2932, 1914, 2370, 2863, 3339, 3773; MS: m/z: 391 (M+).
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:19]1([C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:12][CH2:11][C@H:9]2[O:10][C@@H:2]([S:1][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]2[OH:8])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O[C@@H]1[C@@H](O)[C@H](Sc2ccccc2)O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1O
Yield: 98.7 %

Procedure:
Phenyl 1-thio-β-D-glucopyranoside (5) (7.01 g, 25.8 mmol) and triphenylmethyl chloride (9.33 g, 33.5 mmol) were suspended in pyridine (20 ml), and the mixture was refluxed for 5 hr. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; dichloromethane:ethyl acetate=1:1) to give phenyl 6-O-triphenylmethyl-1-thio-β-D-glucopyranoside (6) (13.1 g, yield 99%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([C:16]#[N:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].O.C([O-])([O-])=[O:23].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([C:16]([NH2:17])=[O:23])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(3,4-difluorophenyl)methyl]-3-nitro-2-pyridinecarbonitrile (3.39 g, 12.32 mmol) in acetone (60 ml), was added water (23 ml), urea-hydrogen peroxide complex (19.69 g, 209 mmol), and K2CO3 (2.04 g, 14.78 mmol). The reaction mixture was stirred at room temperature for 30 minutes and the acetone was evaporated without using heat. The resulting precipitate was collected by filtration and thoroughly washed with water to afford a yellow solid. 1H NMR (d6-DMSO) δ 8.79 (1H, s), 8.33 (1H, s), 8.21 (1H, br s), 7.87 (1H, s), 7.49-7.40 (1H, m), 7.38-7.33 (1H, m), 7.19-7.16 (1H, m), 4.12 (2H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]1([CH2:17][CH:18]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:18]/[CH2:17][C:11]1([CH3:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC1(CC=O)CCCCC1
Solvent: ClCCl
Product: CC1(C/C=N/CC(=O)OC(C)(C)C)CCCCC1
Yield: 93.8 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.87 g, 14.3 mmol) was reacted with (1-methyl-cyclohexyl)-acetaldehyde (2.9 g, 14.3 mmol) in CH2Cl2 at room temperature for 18 h to give [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (3.4 g, 95%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[OH:3][CH2:2][C:1]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2)=[O:5]
Reactant: Cc1cc(Nc2ncnc3cccc(OCCN)c23)ccc1O
Reactant: O=C(O)CO
Product: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1O
Yield: 58 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-{[5-(2-aminoethoxy)quinazolin-4-yl]amino}-2-methylphenol to give 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]acetamide as a light brown solid in 58% yield; NMR spectrum (DMSO-d6) 2.16 (s, 3H), 3.69 (q, 2H), 3.76 (d, 2H), 4.43 (t, 2H), 6.82 (d, 1H), 7.30 (m, 4H), 7.90 (t, 1H), 8.20 (t, 1H), 8.66 (s, 1H), 9.42 (s, 1H), 10.55 (s, 1H); Mass spectrum MH+ 369.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[C:11](=[O:12])[NH:10][C:9](=[O:13])[O:8]2)=[CH:4][CH:3]=1.C([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]=O)[CH:31]=2)=[C:25]([CH3:38])[CH:24]=1)(=O)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:56]>O.C1COCC1>[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][NH:1][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][N:7]4[C:11](=[O:12])[N-:10][C:9](=[O:13])[O:8]4)=[CH:4][CH:3]=3)[CH:31]=2)=[C:25]([CH3:38])[CH:24]=1.[Na+:56]
Reactant: CC(=O)OCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Reactant: Nc1ccc(Cn2oc(=O)[nH]c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCO)cc(C)c1-c1cccc(CNc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 26.5 %

Procedure:
A mixture of 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (365 mg), 2-[(3′-formyl-2,6-dimethylbiphenyl-4-yl)oxy]ethyl acetate (660 mg), acetic acid (0.3 ml), THF (20 ml) and Molecular Sieves 4A (1 g) was stirred at room temperature for 22 hours. Sodium triacetoxyborohydride (560 mg) was added to the reaction mixture, followed by stirring at room temperature for 22 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, toluene was added to the residue, the solvent was again evaporated under a reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate). Methanol (10 ml) and sodium methoxide (52 mg) were added to the resulting pale yellow foamy substance (406 mg), followed by stirring for 2 hours while heating at 60° C. The solvent was evaporated under a reduced pressure, and chloroform was added to the residue, followed by washing with water and a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and THF (5 ml), methanol (5 ml) and a 1 M sodium hydroxide aqueous solution (0.81 ml) were added to the resulting pale yellow foamy substance (373 mg), followed by stirring at room temperature for 5 minutes. The solvent was evaporated under a reduced pressure, the residue was purified by an ODS column chromatography (water-acetonitrile), the resulting pale yellow foamy substance was made into a solid by adding diethyl ether. The solid was collected by filtration and then dried by heating under a reduced pressure to obtain sodium 2-[4-({[4′-(2-hydroxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)benzyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (226 mg) as a pale yellow solid.