Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.Cl[C:54]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:57]([N:64]2[CH2:69][CH2:68][N:67]([C:70]([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)=[O:71])[CH2:66][C@H:65]2[CH3:78])=[N:56][N:55]=1.[NH:79]1[CH2:84][CH2:83][O:82][CH2:81][CH2:80]1>ClCCl.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]>[CH3:78][C@H:65]1[N:64]([C:57]2[C:58]3[C:63](=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:54]([N:79]3[CH2:84][CH2:83][O:82][CH2:81][CH2:80]3)=[N:55][N:56]=2)[CH2:69][CH2:68][N:67]([C:70]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)=[O:71])[CH2:66]1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ccccc12
Reactant: C1COCCN1
Agent: [Pd]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(N2CCOCC2)c2ccccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Compound 66 was prepared as described in general method E. Sodium t-butoxide (0.0550 g, 0.572 mmol), rac-2,2-bis(diphenylphosphino)-1,1-binaphthalene (0.0102 g, 0.0164 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.00749 g, 0.00818 mmol), and (R)-(4-(4-chlorophthalazin-1-yl)-3-methylpiperazin-1-yl)(phenyl)methanone JK-5 (0.150 g, 0.409 mmol) were combined in a screw cap vial, purged to argon, and solvated with degassed morpholine (0.142 mL, 1.64 mmol). The reaction vial was sealed and stirred at 80° C. After 16 h, the reaction was taken up in dichloromethane and directly loaded onto silica gel. Purification by column chromatography (gradient elution 40 to 100% ethyl acetate in hexanes) afforded 66. MS (M+H)+=418.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:10])[CH:7]=[N:8][CH:9]=1)=[O:4].[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]([F:26])([F:25])[F:24])[CH:20]([C:27](O)=[O:28])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:10][C:27]([CH:20]2[CH:21]([C:23]([F:25])([F:24])[F:26])[CH2:22][N:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19]2)=[O:28])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1N
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cncn1NC(=O)C1CN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of compound 2 (2.0 g, 14.1 mmol), 1-Benzyl-4-trifluoromethyl-pyrrolidine-3-carboxylic acid (4.06 g, 14.9 mmol) and DIEA (10 mL, 42.5 mmol) in DMF (30 mL) was added HATU (8.1 g, 21.2 mmol). The resulting reaction mixture was stirred at r.t. overnight. The reaction was monitored by LC-MS. The reaction was quenched with water (100 mL) when it was complete. The aqueous solution was extracted with EtOAc (80 mL×3). The combined organic phase was washed with brine and concentrated to afford the crude product. The residue was purified by silica gel column (eluted with PE/EA=5:1 to 1:2) to afford compound 13 (4.8 g, 85.6% yield) as white oil. LC-MS: m/z 397 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 8.00 (br. s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.34˜7.28 (m, 5H), 3.81 (s, 3H), 3.78˜3.72 (m, 2H), 3.41˜3.38 (m, 1H), 3.30˜3.24 (m, 2H), 3.14˜3.12 (m, 1H), 2.71˜2.67 (m, 1H), 2.58˜2.53 (m, 1H).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:4]1[C:16]([O:18]C)=[O:17])=[O:2].[Li+:20].[OH-]>O1CCOCC1.O>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH:4]([C:16]([O-:18])=[O:17])[CH2:5]1)=[O:10])([CH3:15])([CH3:13])[CH3:14].[Li+:20]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C=O)C(C(=O)[O-])C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 28 g of the compound obtained in Step A (103 mmol) in 515 mL of dioxane there are added 4.8 g of LiOH (113 mmol) in solution in 100 mL of H2O. The whole is stirred at ambient temperature for 4 hours. The reaction mixture is subsequently concentrated to dryness and then co-evaporated several times with ethyl acetate. The title product is obtained in the form of a solid and is used directly for the following cyclisation step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]#[N:27])[CH:20]=2)[CH:5]=[CH:6][C:7]=1F.BrC1C=C(C(OCC)=O)OC=1C1C=CC=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]#[N:27])[CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2ccc(F)c(Cl)c2)o1
Agent: CCOC(=O)c1cc(Br)c(-c2cccc(Cl)c2)o1
Product: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2cccc(Cl)c2)o1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 15A starting with the compound from Example 5A. 111 mg (52% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][NH:10][C:11]2[CH:17]=[CH:16][N:15]=[CH:14][C:12]=2[N:13]=1.[C:18]([Cl:27])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21]>>[ClH:27].[C:18]([N:10]1[C:11]2[CH:17]=[CH:16][N:15]=[CH:14][C:12]=2[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[NH:9]1)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21]
Reactant: O=C(Cl)c1ccccc1O
Reactant: c1ccc(C2=Nc3cnccc3NN2)nc1
Agent: Cl
Product: O=C(c1ccccc1O)N1NC(c2ccccn2)=Nc2cnccc21
Yield: 78 %

Procedure:
2.46 g (0.01 moles) of 3-(2-pyridyl)-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with salicyloyl chloride as described in Example 2 to obtain 1-salicyloyl-3-(2-pyridyl)-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 78%; m.p.: 219°-220° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:15](O)([CH3:17])[CH3:16]>>[C:15]([C:17]1[CH:11]=[C:6]([NH:5][C:2]2[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:7]=[CH:8][CH:9]=1)#[CH:16]
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Reactant: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 4-chloro-7-nitroquinazoline (2.0 g, 9.54 mmol), isopropanol (30 mL), and 3-thynylbenzenamine (1.2 g, 10.00 mmol) was refluxed for 5 h. The resulting mixture was cooled to room temperature and refrigerated. The precipitate was filtered out, washed with cold isopropanol several times, and dried in vacuo to give 2.6 g (94%) of N-(3-ethynylphenyl)-7-nitroquinazolin-4-amine as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Nc1cncc(Cl)c1
Product: Cc1ccc(Nc2cncc(Cl)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 3-Amino-5-chloropyridine instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=343.0, 345.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N+:10]([O-])=[CH:9][C:8]2[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]3[N:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:5]=3[C:4]=2[CH:3]=1.BrC1[N+]([O-])=CC2N(COCC[Si](C)(C)C)C3N=C(Cl)C=CC=3C=2C=1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[C:6]3[N:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(Br)cc2c2c(Cl)ccnc21
Agent: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(Br)cc2c2ccc(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c2cnc(Br)cc2c2c(Cl)ccnc21

Procedure:
A solution of 6-bromo-4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-7-oxide with 6-bromo-2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-7-oxide (4:1, 90 mg, 0.2 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.5 mg, 0.012 mmol), and triethylamine (0.1 mL, 0.7 mmol) in acetonitrile (1.2 mL) was heated under microwave irradiation at 130° C. for 10 minutes. The cooled reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 40 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as a 4:1 mixture of the title compound with 6-bromo-2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole as an off-white solid (60 mg, 70%). The mixture was used in subsequent steps without any further purification.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[C:24]([CH3:31])[C:23]=2[CH:32]=1>CC#N>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([S:27]([NH:7][C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])(=[O:29])=[O:28])=[C:24]([CH3:31])[C:23]=2[CH:32]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COC(=O)c1cccc(N)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
Pyridine (200 μL, 2.48 mmol) was added to a solution of methyl 3-aminobenzoate (188 mg, 1.24 mmol) and 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (349 mg, 1.24 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature over night. After removal of the solvents, the residue was dissolved in EtOAc and water. The phases were separated, and the organic solution was washed with 1M HCl twice, water twice and brine then dried (MgSO4). The crude product, obtained after evaporation of the solvents, was crystallized from MeOH (ca 5 mL). The solid product was triturated using heptane, giving the intermediate methyl 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate as an off-white solid (432 mg, 88%). 1H NMR (500 MHz, CDCl3) δ ppm 2.46 (s, 3 H) 2.45 (s, 3 H) 6.91 (s, 1 H) 7.37 (t, J=7.81 Hz, 1 H) 7.43-7.47 (m, 2 H) 7.72 (d, J=1.96 Hz, 1 H) 7.72 (d, J=8.76 Hz, 1 H) 7.76 (t, J=1.83 Hz, 1 H) 7.85 (dt, J=7.81, 1.34 Hz, 1 H). MS (ESI+) 396 m/z [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]3[N:15]([CH3:24])[C:16](=[O:23])[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]3=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl[C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27].C(N(C(C)C)CC)(C)C>C1COCC1.CO>[CH3:22][C:19]([CH3:21])([CH3:20])[CH2:18][N:17]1[C:12]2[C:13](=[N:14][C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][C:26](=[O:27])[O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:10][CH:11]=2)[N:15]([CH3:24])[C:16]1=[O:23]
Reactant: CC(C)COC(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(CN)c3)nc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)COC(=O)NCc1cccc(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a microwave vial, 5-[3-(aminomethyl)phenyl]-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (23-1) (15 mg, 0.05 mmol) was added under nitrogen and dissolved in THF (0.25 ml). Isobutyl chloroformate (4.4 mg, 0.055 mmol) was added followed by diisopropyl ethyl amine 9 mg, 0.07 mmol). The reaction was allowed to stir for 2 hours at room temperature. The reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-methylpropyl {3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]benzyl}carbamate (23-2). HRMS (M+H)+: observed=425.2549, calculated=425.2547.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:38])[C:19]([C:32]3[N:33]=[C:34]([NH2:37])[S:35][CH:36]=3)=[N:20][O:21][CH2:22][CH2:23][S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH2:31])[C:15](=[O:39])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:44]>CO.C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:38])[C:19]([C:32]3[N:33]=[C:34]([NH2:37])[S:35][CH:36]=3)=[N:20][O:21][CH2:22][CH2:23][S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH2:31])[C:15](=[O:39])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:44]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCSc3ccccc3N)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCCSc3ccccc3N)c3csc(N)n3)[C@H]2SC1

Procedure:
1 ml of methanol was added to a mixture of the product of Example 23 and 1.5 ml of molar sodium acetate in methanol and the mixture was diluted with 6 ml of ethanol and was vacuum filtered. The recovered product was washed with ethanol and empasted with ether to obtain 235 mg of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-{2-(2-aminophenylthio)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([N:6]1[CH2:34][CH2:33][CH2:32][C@H:7]1[C:8]([NH:10][C@H:11]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:21])[NH:17][N+:18]([O-:20])=[O:19])=[O:9])=[O:5])[CH3:3].Cl.CCOC(C)=O.[NH:49]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C@H:50]([C:55]([OH:57])=O)[CH2:51][C:52](=[O:54])[NH2:53].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:49]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C@H:50]([C:55]([NH:1][C@H:2]([C:4]([N:6]1[CH2:34][CH2:33][CH2:32][C@H:7]1[C:8]([NH:10][C@H:11]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:21])[NH:17][N+:18]([O-:20])=[O:19])=[O:9])=[O:5])[CH3:3])=[O:57])[CH2:51][C:52](=[O:54])[NH2:53]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared from 2.9 g of Boc-Ala-Pro-Arg(NO2)-OBzl, 15 ml of 4 N HCl-AcOEt, 1.4 g of Z-Asn-OH, 1.0 g of HOBt and 1.1 g of DCC in the same manner as in Example 7- (3 ) .
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][C:10]=1[NH2:11].Cl.[C:26](=N)(OC)[CH3:27].C(=O)([O-])O.[Na+]>CO>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:9]2[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:26]([CH3:27])=[N:11][C:10]=2[CH:12]=1
Reactant: COC(C)=N
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1Cc1ccccn1
Yield: 93 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(2-picolyl)aminoanilin-5-yl)benzoxazole (see Working Example 79-1) (250 mg, 0.79 mmol) was added methyl acetimidate hydrochloride (100 mg, 0.87 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, after which it was filtered and concentrated to yield the title compound (250 mg, 93% yield) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+].[SiH3][O-].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Agent: [O-][SiH3]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C(=O)O)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A solution of 4-[2-(3-Chloro-4-methoxycarbonyl-phenoxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E41c.1 (4.5 g, 10.8 mmol) in THF at 0° C. was treated with potassium trimethylsilanolate (1.6 g, 10.9 mmol), and the mixture stirred at room temperature for 18 h. A further 1.6 g (10.9 mmol) potassium silanolate was added, and stirring continued at room temperature for 2 h. A further 1.6 g (10.9 mmol) potassium silanolate was added, and the mixture was stirred at 45° C. for 2 h. The mixture was then diluted with water and THF was removed in vacuo. The residue was washed with ether, cooled in an ice-bath and adjusted to pH5 with solid KHSO4 whereupon it was extracted with CHCl3 and CHCl3/isopropanol (90:10 v/v). The combined organics were dried and solvents were removed in vacuo to yield the title compound (3.7 g, 85%).
Reaction SMILES: CS(O[C@@H:6]1[C@H:13]2[C@H:9]([CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[CH2:8][CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[N:21]([C@H:6]1[C@H:13]2[C@H:9]([CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[CH2:8][CH2:7]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 90 °C

Procedure:
(3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (1.686 g, 5.71 mmol) from Step C and sodium azide (0.557 g, 8.56 mmol) were combined in N,N-dimethylacetamide (10 mL). The reaction was heated at 90° C. for 15 hours. The reaction was cooled and diluted with 200 mL of ethyl acetate and then quenched with 30 mL water. The organic layer was removed and washed with 2×20 mL of water, then 20 mL of brine. The solvent was removed in vacuo to give (3aS,4R,6aR)-4-azido-2-benzyloctahydrocyclopenta[c]pyrrole: 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.27 (m, 4H), 7.22 (dd, J=2.9, 5.8, 1H), 3.72-3.61 (m, 1H), 3.54 (s, 2H), 2.76-2.60 (m, 1H), 2.55-2.40 (m, 4H), 2.35 (dd, J=3.5, 9.1, 1H), 2.07-1.86 (m, 2H), 1.72-1.60 (m, 1H), 1.49-1.38 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[C:8](=[CH:13][C:14]=1[N+:15]([O-])=O)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].CO.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>[Pt].C1(C)C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[CH3:2][C:1]1[NH:15][C:14]2[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][C:5]=2[N:4]=1
Reactant: COC(=O)c1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2nc(C)[nH]c2cc1C(=O)OC
Reaction time: 2 h

Procedure:
A mixture of dimethyl 4-acetamido-5-nitrophthalate, methanol and 5% platinum on carbon is hydrogenated in a Parr hydrogenator. The reaction mixture is filtered through diatomaceous earth and the filtrate is concentrated in vacuo. The thus-obtained crude diamine intermediate (48.09, 0.180 mol) is mixed with p-toluenesulfonic acid (51.4 g, 0.270 mol) and toluene (400 mL), and stirred for 2 hours at reflux temperatures with azeotropic removal of water, cooled and concentrated in vacuo. The resultant residue is recrystallized from methanol to afford the p-toluene sulfonate salt of the title product. The salt is dissolved in hot water, made basic with sodium bicarbonate and extracted with methylene chloride. The combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to give a red solid. Recrystallization of a portion of the red solid affords the title product as white crystals, mp 151°-152° C.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[NH:13]([C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: CSc1ncnc2ccncc12
Solvent: CCO
Product: c1ccc(Nc2ncnc3ccncc23)cc1
Temperature: 0 °C
Yield: 16 %

Procedure:
A mixture of 4-methylthiopyrido[4,3-d]pyrimidine (174 mg, 0.97 mmol), and aniline (186.2 mg, 1.99 mmol) in EtOH (2 mL) is refluxed under N2 for 12 h. Cooling to 0° C. forms a solid which is filtered to yield 4-anilinopyrido-[4,3-d]pyrimidine (34.5 mg, 16%). 1H NMR (DMSO) δ 10.29 (1H, brs), 9.86 (1H, s), 8.82 (1H, d, J=5.8 Hz), 8.72 (1H, s), 7.85 (2H, d, J=7.5 Hz), 7.66 (1H, d, J=5.5 Hz), 7.45 (2H, t, J=8.0 Hz), 7.23 (1H, t, J=7.3 Hz).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34]O)[C:24]=1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:24]=1[OH:25]
Reactant: Oc1cccc2ccccc12
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Product: O=C1OC(CCOc2cccc3ccccc23)C(O)=C1O
Yield: 26.2 %

Procedure:
Mitsunoble coupling of 0.17 g (1.2 mmol) of 1-naphthol with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 75 mg (26% yield) of 3,4-dihydroxy-5-[2-(1-naphthoxy)ethyl]-2(5H)-furanone as colorless cubes: mp 163-164° C. (ether/hexanes) 1H NMR (acetone-d6) δ 8.38-8.25 (m, 1H), 7.92-7.79 (m, 1H), 7.60-7.34 (m, 4H), 7.05-6.93 (m, 1H), 5.11 (dd, J=5.3, 8.7 Hz, 1H), 4.39 (dd, J=2.6, 4.7 Hz, 2H), 2.75-2.52 (m, 1H), 2.25-2.05 (m, 1H). 13C NMR (acetone-d6) δ 169.62, 154.92, 153.61, 135.13, 127.83, 126.78, 126.50, 125.92, 125.05, 122.41, 120.66, 118.53, 105.28, 72.85, 63.93, 32.58. Anal Calcd for C16H14O5 : C, 67.11; H, 4.89. Found: C, 66.70; H, 4.88.