Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH2:19][C@H:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:25].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][C@H:2]([CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH2:19][C@H:20]([CH3:24])[CH:21]([CH3:22])[CH3:23])[CH:13]=2)(=[O:34])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:25]
Reactant: Cc1ccc(S(=O)c2ccc(C)c(C[C@H](C)C(C)C)c2)cc1C[C@H](C)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2ccc(C)c(C[C@H](C)C(C)C)c2)cc1C[C@H](C)C(C)C

Procedure:
(2S)-2,3-Dimethylbutyl-p-tolylsulfoxide (10) (52 mg, 0.2 mmol) was dissolved in 1.0 mL of anhydrous dichloromethane and 60 mg (0.3 mmol) of 3-chloroperoxybenzoic acid (80-85%, Sigma) added with stirring. The reaction mixture was stirred for 2 h and quenched with 10% sodium bicarbonate. More dichloromethane was added and the combined organic extracts were washed with aqueous sodium sulfite and brine and dried with MgSO4. The solvent was removed in vacuo and the crude sulfone was purified by silica gel flash chromatography using hexane ethyl acetate mixtures to afford sulfone (12) as a colorless oil. For analytical purposes this was also purified by HPLC (Zorbax Sil 9.4×25 cm column) using 10% ethyl acetate in hexane to give 42 mg of pure (2S)-sulfone (12): [α]D20 =+17 (c=3.5 in CHCl3); MS m/z (relative intensity) 240 (M+, 3), 197 (5), 157 (100), 92 (19), 91 (27), 85 (25), 84 (31), 43 (72); 1H NMR δ0.77 (3H, d, J=7 Hz), 0.82 (3H, d, J=7.0 Hz), 1.00 (3H, d, J=7.0 Hz), 1.66-1.98 (2H, m), 2.45 (3H, s, CH3 -Aryl), 2.86 (1H, dd, J=8, 11 Hz), 3.06 (1H, dd, j=4, 12 Hz), 7.35 (2H, d, J=7.0 Hz, H-aryl ortho), 7.75 (2H, d, J=8, H-aryl ortho). Anal. Calcd. for C13H20O2S: C, 64.96; H, 8.39; S, 13.34. Found C13H20O2S: C, 65.05; H, 8.37; S, 13.24
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)(=O)[O:41]C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1.BrBr.Cl>O1CCCC1.N1C=CC=CC=1.C(N(CC)CC)C>[O:1]([CH2:8][C:9]([NH:10][CH:11]1[C:12](=[O:33])[N:13]2[C:16]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])=[C:30]([OH:32])[CH2:31][S:15][C@H:14]12)=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: O=P(Cl)(Oc1ccccc1)c1ccccc1
Agent: BrBr
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (9.38 g.) in tetrahydrofuran (120 ml.) under a nitrogen atmosphere at 20° C. was added triethylamine (3.21 ml.) followed by phenyl phenylphosphonochloridate (5.82 g.) After stirring for 2 hours at 20° C., the reaction mixture was cooled to 0° C. and morpholine (4.01 ml.) added. After stirring for 2.5 hours at 0°-5° C., the mixture was cooled to -30° to -35° C. and pyridine (1.62 ml.) added followed by dropwise addition of bromine (1.00 ml.) over a period of 10 minutes. The reaction mixture was stirred at -30° to -35° C. for 20 minutes and 5% hydrochloric acid (144 ml.) added. After stirring at 20° C. overnight the mixture was extracted with dichloromethane and the extracts washed with water and saturated sodium chloride solution, dried with magnesium sulphate and evaporated to dryness. The residue was dissolved in glacial acetic acid (10 ml.) and the resulting solution stirred for approximately 10 minutes to crystallise the product. The crystallisation was completed by addition of isopropanol (120 ml.) over 0.5 hour. The crystals were isolated by filtration, washed with isopropanol and dried in vacuo at 40° C. overnight. The yield of p-nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate acetic acid solvate was 8.29 g. (76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5](O)=[O:6].B.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[CH2:5][OH:6]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: OCc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a solution of 3-fluoro-4-(trifluoromethyl)benzoic acid (10.5 g, 50.7 mmol) in tetrahydrofuran (30 ml) was added a 1M tetrahydrofuran solution of borane (63 ml, 63 mmol) and the mixture was stirred at room temperature for 8 hrs. 1N Hydrochloric acid (100 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 3-fluoro-4-(trifluoromethyl)benzyl alcohol (10.3 g, purity 90%, 94%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=2[F:12])[C:5]([CH2:15][CH2:16][OH:17])=[CH:4]1)C.F[C:19]1[CH:20]=[C:21]([CH2:33][CH2:34]C2C=CC=CC=2)[C:22](OC)=[C:23]2[C:27]=1NC=C2CCO>>[F:12][C:10]1[CH:9]=[C:8]([CH2:34][CH2:33][C:21]2[CH:22]=[CH:23][CH:27]=[CH:19][CH:20]=2)[C:7]([O:13][CH3:14])=[C:6]2[C:11]=1[N:3]([CH3:1])[CH:4]=[C:5]2[CH2:15][CH2:16][OH:17]
Reactant: CCn1cc(CCO)c2c(OC)ccc(F)c21
Reactant: COc1c(CCc2ccccc2)cc(F)c2[nH]cc(CCO)c12
Product: COc1c(CCc2ccccc2)cc(F)c2c1c(CCO)cn2C
Yield: 69 %

Procedure:
Following the procedure (step 2, scheme 20) used to prepare compound 20-3, compound 23-2 gave compound 23-3 in 69% yield as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm: 7.22-7.29 (m, 5H), 6.79 (s, 1H), 6.70 (d, J=12.9 Hz, 1H), 3.90 (d, J=1.92 Hz, 3H), 3.84-3.89 (m, 2H), 3.74 (s, 3H), 3.05 (d, J=6.0 Hz, 2H), 2.9-2.96 (m, 4H), 2.11 (t, J=5.8 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(Cl)CCl.[NH2:28][CH2:29][C:30]#[N:31]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:29]([CH2:30][NH:31][C:13]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:5]=2)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[CH:11]=1)=[O:15])#[N:28]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: N#CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NCC#N)c2nc(C3CC3)cnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To a solution of 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.59 mmol) in CH2Cl2 (5 mL) was added EDC (0.14 g, 0.72 mmol), 4-(dimethylamino)pyridine (0.088 g, 0.72 mmol), and aminoacetonitrile (0.041 g, 0.72 mmol). The reaction mixture was stirred at room temperature for 5 h then diluted with CH2Cl2 and washed with H2O and brine. The organics were dried over Na2SO4 and concentrated. The residue was purified by SiO2 chromatography (25% EtOAc/hexanes) to obtain 0.194 g (88%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyanomethyl-amide a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1C(C(O)=O)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=[CH:9]1>CN(C=O)C.C(Cl)Cl>[CH3:7][N:8]1[C:1]([C:2]([Cl:4])=[O:3])=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=[CH:9]1
Reactant: Cn1cnc(-c2ccccc2)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cnc(-c2ccccc2)c1C(=O)Cl
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.35 mL) followed by one drop of DMF was added to 1-methyl-4-phenyl-1H-imidazole-5-carboxylic acid (intermediate 3) (732 mg) suspended in anhydrous DCM (6 mL). After stirring for 1 hour under inert atmosphere the mixture was evaporated to dryness and used immediately without further purification (800 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:26](OC)=O)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].[Br-].[C:61]([C:63]1[CH:64]=[C:65]([CH:86]=[CH:87][CH:88]=1)[CH2:66][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:62].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCCCCC.C(O)C.O1CCCC1.C(OCC)(=O)C.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][C@H:25]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH:26]=[CH:66][C:65]3[CH:64]=[C:63]([CH:88]=[CH:87][CH:86]=3)[C:61]#[N:62])=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1)NC(=O)OC(C)(C)C
Reactant: N#Cc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Br-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C=Cc1cccc(C#N)c1)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reaction time: 0.17 h

Procedure:
3.87 g (7.70 mmol) of methyl (2S)-3-[4-[1-(benzyloxycarbonyl)-4-piperidyloxy]phenyl]-2-(t-butoxycarbonylamino)propionate was dissolved in 77 ml of toluene. 19.3 ml (19.3 mmol) of 1.0 M solution of diisobutylaluminum hydride in hexane was added to the obtained solution at −78° C., and they were stirred for 10 minutes. 10 ml of methanol and 20 ml of saturated aqueous solution of potassium sodium tartrate were added to the resultant mixture, and they were stirred at room temperature for additional one hour. After the treatment with ethyl acetate as the extractant in an ordinary manner, the obtained oily residue was dissolved in a mixed solvent of 30 ml of ethanol and 30 ml of tetrahydrofuran. After the addition of 3.53 g (7.70 mmol) of (3-cyanobenzyl)triphenylphosphonium bromide and 1.15 ml (7.70 mmol) of DBU at room temperature, the resultant mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the residue was purified by the silica gel column chromatography to obtain the title compound in the form of a mixture of geometrical isomers (E:Z=2:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(C)(=O)=O)cc3CO1)CO2
Yield: 42.6 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (150 mg, 0.482 mmol) and methanesulfonyl chloride (61 mg, 0.53 mmol) according to the procedure described for Example 27. Obtained the title compound as a white solid (80 mg, 43%), MS (ISP) m/e=390.1 [(M+H)+].
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8](O)[C:7]([C:11]#[N:12])=[CH:6][N:5]=1)[CH3:2].[Cl-].[Cl:14]C=[N+](C)C>O1CCOCC1>[CH2:1]([S:3][C:4]1[N:9]=[C:8]([Cl:14])[C:7]([C:11]#[N:12])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCSc1ncc(C#N)c(O)n1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCSc1ncc(C#N)c(Cl)n1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
To a solution of 2-ethylthio-4-hydroxy-5-cyanopyrimidine (196 mg, 1.08 mmol) in 1,4-dioxane (5 mL) was added (chloro-methylene)dimethylammonium chloride (550 mg, 4.32 mmol). The mixture was heated at 100° C. for 4 h, cooled, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography using 1:20 acetone:hexane system to yield 130 mg of the title compound. Mass spectrum 199.3 (EI, M+).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[BH4-].[Na+].O.Cl>CO.O1CCCC1>[OH:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([CH:2]([OH:1])[CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=1
Reactant: CCCC(O)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(CO)cc1
Yield: 94.7 %

Procedure:
4-(1-Hydroxybutyl)benzaldehyde (4.51 g, 25.3 mmol) was dissolved in a mixture of methanol (10 mL) and tetrahydrofuran (20 mL), and sodium borohydride (0.479 g, 12.7 mmol) was added with stirring under ice-cooling. The mixture was stirred at the same temperature for 1.5 hr. Water and 1N hydrochloric acid were added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-80:20) to give the title compound (4.32 g, yield 95%) as a colorless oil.
Reaction SMILES: C(OC([NH:11]/[C:12](=[N:20]\C(=O)OCC1C=CC=CC=1)/[NH:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.[H][H]>CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[CH3:19][N:18]1[C:14]([NH:13][C:12]([NH2:20])=[NH:11])=[CH:15][CH:16]=[N:17]1
Reactant: Cn1nccc1N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1nccc1NC(=N)N
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a stirred solution of 180 (1.00 g, 2.45 mmol) in EtOH/THF (1:1, 35 mL) at RT was added Pearlman's Catalyst (0.172 g, 0.245 mmol). The mixture subjected to a vacuum/purge cycle three times with hydrogen gas and then maintained under 1 atmosphere balloon of hydrogen pressure. After stirring overnight and the reaction was filtered through GF/F filter paper with EtOH and the filtrate was concentrated to afford 0.31 g (90%) of 1-(1-methyl-1H-pyrazol-5-yl)guanidine (182) as a clear glass which was used without further purification: MS m/z (APCI-pos) M+1=140.0.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[NH:8][C:9]1[NH:10][C:11](=[O:20])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>C(O)(=O)C>[CH2:1]([O:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[NH:8][C:9]1[NH:10][C:11](=[O:20])[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1ccccc1Nc1ncc(C(=O)O)c(=O)[nH]1
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Ethyl 1,6-dihydro-2-(2-butoxyanilino)-6-oxo-5-pyrimidinecarboxylate (12 g) and sodium hydroxide (3 g) are added to water (150 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate thus obtained is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2-butoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (8 g). M.p. 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH2:19][CH3:20])=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:21]=1.Cl.[C:23](=N)(OC)[CH3:24].C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH2:18][CH2:19][CH3:20])[C:23]([CH3:24])=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:21]=1
Reactant: CCCNc1ccc(-c2nc3cc(Cl)ccc3o2)cc1N
Reactant: COC(C)=N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCn1c(C)nc2cc(-c3nc4cc(Cl)ccc4o3)ccc21
Yield: 71.8 %

Procedure:
To a solution of 5-(5-chlorobenzoxazol-2-yl)-2-n-propylaminoaniline (see Working Example 135-1) (200 mg, 0.663 mmol) in ethanol (5 mL) was added methyl acetimidate hydrochloride (123 mg, 0.995 mmol), and this was heated to reflux for 5 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, filtered, and concentrated to give crude crystals that were washed with diethyl ether to yield the title compound (155 mg, 72% yield) as green crystals.
Reaction SMILES: [OH:1]CC(C)(C)C=O.[CH3:8][O:9][CH2:10][C:11]([CH3:18])([CH3:17])[CH:12](Br)[C:13]([OH:15])=[O:14]>>[CH3:8][O:9][CH2:10][C:11]([CH3:18])([CH3:17])[CH:12]([OH:1])[C:13]([OH:15])=[O:14]
Reactant: COCC(C)(C)C(Br)C(=O)O
Reactant: CC(C)(C=O)CO
Product: COCC(C)(C)C(O)C(=O)O

Procedure:
4-methoxy-3,3-dimethyl-2-hydroxy butyric acid is prepared by conventional methods from 3-hydroxy-2,2-dimethyl-propionaldehyde and from that compound the ethyl ester of 4-methoxy-3,3-dimethyl-2-bromo-butyric acid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].O>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2cnnn2)cc1C(=O)O
Reaction time: 4 h

Procedure:
Combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (2.86 g, 12.2 mmol) and a 1M aqueous solution of sodium hydroxide (13.43 mL, 13.43 mmol) in methanol/water (100 mL, 5:1 vol./vol.). Heat to reflux. After 4 hours, concentrate in vacuo to remove most of the methanol, add water (50 mL), and adjust the pH to about 4 using a 1M aqueous hydrochloric acid solution. Evaporate in vacuo to give a solid, slurry the solid with water, filter, and dry to give 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.
Reaction SMILES: [CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[CH2:21][C@@H:20](/[CH:25]=[CH:26]/[CH2:27][CH2:28][S:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:19][C:18](=[O:49])[CH2:17][NH:16][C:15](=[O:50])[C@@H:14]([CH:51]([CH3:53])[CH3:52])[NH:13][C:12](=[O:54])[C@@H:11]([CH2:55][S:56]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:10][C:9]1=[O:76])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO>[CH2:1]([C@@H:8]1[C:9](=[O:76])[NH:10][C@@H:11]2[CH2:55][S:56][S:29][CH2:28][CH2:27][CH:26]=[CH:25][C@@H:20]([O:19][C:18](=[O:49])[CH2:17][NH:16][C:15](=[O:50])[C@@H:14]([CH:51]([CH3:53])[CH3:52])[NH:13][C:12]2=[O:54])[CH2:21][C:22](=[O:24])[NH:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](CC(=O)N[C@H](Cc3ccccc3)C(=O)N2)OC(=O)CNC1=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](CC(=O)N[C@H](Cc3ccccc3)C(=O)N2)OC(=O)CNC1=O

Procedure:
To a vigorously stirred solution of 12 (254 mg, 1.0 mmol) in CH2Cl2/MeOH (9:1, 230 mL) was added dropwise a solution of bis-trityl 8B (105 mg, 0.10 mmol) over 30 minutes. After a further 30 min the reaction was quenched by the addition of sodium thiosulfate (0.05M, 100 mL) followed by brine (10 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give a white solid. Purification by column chromatography on silica gel (1-3.5% MeOH/CH2Cl2) gave bicyclic depsipeptide 9B (43 mg, 0.08 mmol, 75%) as a white solid: [α]25D −98 (c 0.05, 1:1 MeOH/CHCl3); IR νmax 3280, 1732, 1627, 1538, 1445 cm−1; 1H-NMR (400 MHz, 19:1 CD3OD/CDCl3) δ 7.35-7.18 (m, 5H), 5.86-5.76 (m, 1H), 5.74-5.66 (m, 2H), 4.62 (dd, J=11.3, 4.0 Hz, 1H), 4.45 (dd, J=9.3, 5.3 Hz, 1H), 4.28 (d, J=17.6 Hz, 1H), 3.77 (d, J=17.6 Hz, 1H), 3.39 (d, J=10.5 Hz, 1H), 3.27-3.17 (m, 2H), 3.11-2.99 (m, 3H), 2.97-2.83 (m, 2H), 2.81 (dd, J=13.6, 2.0 Hz, 1H), 2.70-2.53 (m, 3H), 0.96 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H); 13C-NMR (100 MHz, 19:1 CD3OD/CDCl3) δ 173.8 (C), 173.2 (C), 172.9 (C), 171.3 (C), 169.4 (C), 137.7 (CH), 131.3 (CH), 131.3 (CH), 129.7 (CH), 129.6 (CH), 128.0 (CH), 71.9 (CH), 65.9 (CH), 58.3 (CH), 58.1 (CH), 42.6 (CH2), 39.3 (2×CH2), 36.9 (CH2), 36.8 (CH2), 31.8 (CH2), 28.1 (CH), 20.6 (CH3), 20.5 (CH3); LRMS (ES+) m/z 580 (50%, [2M+Na]+), 563 (100%, [M+NH4]+), 563 (10% [M+H]+).
Reaction SMILES: C1(C)C=CC=CC=1.[OH-].[Na+].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([CH:15]=[C:16]2[CH2:20][CH2:19][C:18]([CH:25]([CH3:27])[CH3:26])(C(OC)=O)[C:17]2=[O:28])=[CH:13][CH:12]=1.Cl>O.C(O)(C)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[C:16]2[CH2:20][CH2:19][CH:18]([CH:25]([CH3:27])[CH3:26])[C:17]2=[O:28])=[CH:29][CH:30]=1
Reactant: COC(=O)C1(C(C)C)CCC(=Cc2ccc(Cl)cc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C1CCC(=Cc2ccc(Cl)cc2)C1=O
Reaction time: 4 h

Procedure:
To a mixed solution of 150 ml of toluene, 50 ml of isopropanol, and 100 ml of water were added 58.6 g of sodium hydroxide and 50 g of methyl 3-(4-chlorobenzylidene)-1-isopropyl-2-oxocylopentanecarboxylate (prepared in Example 2). The mixture was stirred for 4 hours at 70°-80° C. The reaction mixture was poured into 2000 ml of 10% aqueous solution of hydrochloric acid and extracted with 300 ml of ethyl acetate. The organic layer was washed with water and dried, followed by evaporation of the solvent to obtain the target compound.
Reaction SMILES: [C:1](Cl)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]([NH2:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)O.Cl>>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]1[O:9][C:18]2[CH:17]=[CH:16][CH:15]=[CH:13][C:12]=2[C:11](=[O:19])[N:20]=1
Reactant: O=C(Cl)c1ccccc1O
Reactant: NC(=O)c1ccccc1O
Agent: Cl
Product: O=c1nc(-c2ccccc2O)oc2ccccc12

Procedure:
106.0 g of salicyloyl chloride and 93.0 g of salicylamide are mixed and heated at 170° C. for 30 min until hydrogen chloride no longer escapes. The mixture is cooled and the residue is crystallized from ethanol. After drying, 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one is obtained as slightly yellow crystals of m.p. 206-208° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:33][N:34]([CH2:35][CH2:36][CH2:37][NH:38][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:3]2[C:2](=[O:1])[C:6]3[N:7]=[N:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]=3[NH:4]2)=[CH:16][CH:17]=1)[CH3:39]
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CN(C)CCCNC(=O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)benzoic acid (25 mg, 0.08 mmol) was mixed with DMF (1 ml). Diisopropylethylamine (21 mg, 28 μl, 0.16 mmol) and 3-dimethylaminopropylamine (8.2 mg, 10.0 μl, 0.09 mmol) were added followed by HBTU (30.3 mg, 0.08 mmol). The mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC. The title compound was isolated as a red solid (12.6 mg, 0.032 mmol, 40%). LCMS: m/z 391 [M+H]+.