Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].[F:25][C:26]1[CH:27]=[C:28]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:29]=[C:30]([F:34])[C:31]=1[CH2:32]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:32][C:31]3[C:26]([F:25])=[CH:27][C:28]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:29][C:30]=3[F:34])[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: N#Cc1ccccc1-c1cc(F)c(CO)c(F)c1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 3′,5′-difluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile (1.6 g), 1,1′-(azodicarbonyl)dipiperidine (2.2 g), tributylphosphine (2.2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (1.5 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:29]([O-])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:33][CH:34]([CH3:37])[CH2:35][OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:29]([NH:33][CH:34]([CH3:37])[CH2:35][OH:36])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCCN(C)C(=O)Cn1c(=O)c(C(=O)[O-])c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CC(N)CO
Product: COCCN(C)C(=O)Cn1c(=O)c(C(=O)NC(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-{methyl[2-(methyloxy)ethyl]amino}-2-oxoethyl)-2-oxo-1,2-dihydro-1,5naphthyridine-3-carboxylate and (±)-2-amino-1-propanol employing methods similar to those described in Example 5, Step 4 and was obtained as an off-white solid: 1H NMR (CDCl3) mixture of rotamers δ 10.21 and 10.19 (1H, br d), 8.55 and 8.49 (1H, s), 7.33 and 7.10 (1H, s), 7.12-6.97 (4H, m), 5.21 and 4.97 (2H, m), 4.27 (1H, m), 4.09 (2H, s), 3.80-3.50 (6H, m), 3.34 and 3.32 (3H, s), 3.17 and 2.97 (3H, s), 1.30 and 1.29 (3H, d, J=7 Hz); HRMS calcd for C25H29FN4O6+H+: 501.2149. Found: 501.2160.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][CH:15]([CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:23][CH3:24])[CH:20]([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.COCN[C:15]([C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16].[Cl-].[Na+]>O1CCCC1.O>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:15]([C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: c1cscn1
Reactant: COCNC(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)c2nccs2)C1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
136.6 g (0.32 mol) of n-butyllithium (15% in n-hexane) were added dropwise at −68° C. to a solution of 25 g (0.291 mol) of thiazole in 1 l of tetrahydrofuran. The mixture was warmed to 0° C. and subsequently cooled to −40° C. This mixture was then added dropwise to a solution of 79.2 g (0.291 mol) of tert-butyl (S)-3-(methoxymethylcarbamoyl)piperidine-1-carboxylate in 1.4 l of tetrahydrofuran at −50° C. The reaction mixture was then slowly warmed to 0° C., and 2 l of ice-water were added. After addition of 2 l of water and 2 l of saturated sodium chloride solution, the crude mixture was extracted with a total of 4 l of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The crude product (87 g) was chromatographed over a silica-gel column, giving 76.4 g of tert-butyl (S)-3-(thiazole-2-carbonyl)piperidine-1-carboxylate as brown resin; rotation value in methanol [α]20D=+27.4°; 1H NMR (500 MHz, DMSO) δ 8.22 (d, J=3.0, 1H), 8.17 (d, J=3.0, 1H), 4.22-3.86 (m, 1H), 3.84-3.69 (m, 2H), 3.60-3.52 (m, 1H), 3.20-3.05 (m, 1H), 2.08-1.92 (m, 2H), 1.89-1.60 (m, 2H), 1.35 (s, 9H).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:26])[CH2:22][CH:23]([OH:25])[CH3:24])=[CH:17][C:16]=1[F:27]>C(Cl)Cl>[Si:10]([O:25][CH:23]([CH3:24])[CH2:22][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([F:27])[CH:17]=1)[OH:26])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CC(O)CC(O)c1ccc(Cl)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(CC(O)c1ccc(Cl)c(F)c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
Imidazole (96.0 mg, 1.42 mmol) and tert-butylchlorodimethylsilane (107 mg, 0.710 mmol) were added to a solution of 1-(4-chloro-3-fluorophenyl)butane-1,3-diol (130 mg, 0.590 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (15 mL), washed with brine and water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford 3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butan-1-ol (130 mg, 66% yield) as oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](I)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C([O-])([O-])=O.[K+].[K+].C(N1C2C(=CC=CC=2)C=C1C1C=COC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cn(Cc2ccccc2)c2ccccc12
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(Cn2cc(-c3cccs3)c3ccccc32)cc1
Yield: 28 %

Procedure:
N-Benzyl-3-iodoindole (2), 2-thiopheneboronic acid, Pd(PPh3)4 and K2CO3 in toluene are allowed to react in the same manner as described in the preparation of compound 3 to give 0.054 g (28%) of 4: 1H NMR (CDCl3): δ7.90–7.94 (m, 1H), 7.02–7.27 (m, 12H), 5.24 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[H-].[Na+].Cl[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27]>O1CCCC1>[CH2:29]([O:28][C:26]([N:8]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]2[C:5](=[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[C:2]2=[O:1])[C:9]1=[O:10])=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: O=c1nc(-c2ccccc2)c2c(=O)nc(-c3ccccc3)c1=2
Reactant: CCCCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1C(=O)C2=C(c3ccccc3)N(C(=O)OCCCC)C(=O)C2=C1c1ccccc1
Reaction time: 24 h
Yield: 72.5 %

Procedure:
To a suspension of 0.5 g (0.00175 mol) of 1,4-diketo-3,6-diphenylpyrrolo[3,4-c]pyrrole in 17 ml of tetrahydrofuran are added, under argon, 0.28 g (0.007 mol) of solid sodium hydride. After stirring for 24 hours, 0.67 ml (0.007 mol) of n-butyl chloroformate are added and the suspension is stirred overnight. The mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in water/diethyl ether, the organic phase is dried over MgSO4 and then concentrated under vacuum. The residue is taken up in n-hexane and the precipitated yellow powder is collected by filtration and washed with a minor amount of n-hexane, giving 0.62 g (73% of theory) of N,N'-bis(n-butoxycarbonyl)-1,4-diketo-3,6-diphenylpyrrolo[3,4-c]pyrrole as a yellow fluorescent powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].C([Li])CCC.[Br:16][C:17]1[CH:18]=[C:19](/[C:24](=[N:26]/[S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])/[CH3:25])[C:20]([F:23])=[N:21][CH:22]=1.C[Al](C)C>C1COCC1.C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:18]=[C:19]([C@:24]([NH:26][S:27]([C:29]([CH3:30])([CH3:32])[CH3:31])=[O:28])([CH3:25])[CH2:1][S:2]([C:5]2([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]2)(=[O:4])=[O:3])[C:20]([F:23])=[N:21][CH:22]=1
Reactant: CS(=O)(=O)C1(C#N)CCC1
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)cnc1F
Agent: C[Al](C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N[C@@](C)(CS(=O)(=O)C1(C#N)CCC1)c1cc(Br)cnc1F
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
A solution of 1-(methylsulfonyl)cyclobutanecarbonitrile (8 g, 50.4 mmol) in THF (50 mL) was brought to −78° C. followed by the dropwise addition of butyllithium solution, 2.5M in hexanes (20.17 mL, 50.4 mmol). The resulting mixture was stirred at this temperature for 20 min. A solution of (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (9.0 g, 28.02 mmol) in toluene (40 mL) at −78° C. was treated with trimethylaluminum solution, 2.0 M in toluene (14 ml, 28.02 mmol) for 10 min. This solution was added dropwise to the previous mixture containing the nitrile and the resulting mixture was stirred at −78° C. for 1 h. The mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-100% EtOAc/hexanes to afford an off-white solid as N—((R)-2-(5-bromo-2-fluoropyridin-3-yl)-1-((1-cyanocyclobutyl)sulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (7.07 g, 14.72 mmol, 59.1% yield). LC/MS (ESI+) m/z=479.8 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]3[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:25]=1.C(=O)([O-])[OH:27].[Na+]>O1CCOCC1.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:25]=[C:3]([CH2:2][OH:27])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:8]=2[CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nc(CCl)cn1-2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nc(CO)cn1-2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 50.7 %

Procedure:
A solution of 5.1 g of 2-chloromethyl-8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine in 70 ml of dioxan was treated with a solution of 1.54 g of sodium hydrogen carbonate in 30 ml of water and the mixture was stirred at 80° C. for 2.5 h. The mixture was filtered and the filtrate was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloric acid. The filtrate was evaporated in a vacuum and the residue was taken up in chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and evaporated in a vacuum. The crystalline residue (3.2 g) was dissolved in chloroform and chromatographed over 130 g of silica gel. With chloroform and with chloroform/ethanol 98:2 there were eluted small amounts of various impurities, with chloroform/ethanol 97:3 and 96:4 there was eluted 8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. After recrystallization from ethanol there were obtained 2.45 g of pure 8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 250-251° C. which was converted into the hydrochloride (m.p. 295-297° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](OCC)=[O:11])=[CH:4][C:3]=1[O:15][CH3:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCOC(=O)CCc1ccc(F)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCCO)ccc1F
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Ethyl 3-(4-fluoro-3-methoxyphenyl)propanoate (1.019 g, 4.50 mmol) was dissolved in THF (22.52 ml) under nitrogen. A solution of lithium aluminum hydride (4.50 ml, 9.01 mmol) was added slowly. TLC shows reaction done after about 10 min. Water (0.35 mL) was slowed added and then the mixture was stirred for 30 min. 1 N NaOH (1.05 mL) was added and the reaction was stirred for 30 min. Additional water was added (0.35 mL) and the solution was stirred and then filtered. The cake was washed with ether and then rotovapped. Ether was added. The solution was dried over magnesium sulfate and then filtered and rotovapped. The solution was passed through silica gel with methylene chloride then ethyl acetate then rotovapped to give 3-(4-fluoro-3-methoxyphenyl)propan-1-ol (0.753 g, 4.09 mmol, 91% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3). δ ppm 6.98 (dd, 1H), 6.80 (dd, 1H), 6.71 (ddd, 1H), 3.89 (s, 3H), 3.68 (t, 2H), 2.68 (t, 2H), 1.94-1.82 (m, 2H), 1.33 (s, 1H)
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]([OH:14])=O)=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:19]([NH:21][CH:22]1[CH2:24][CH2:23]1)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:22]1([NH:21][C:19]([C:18]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([NH:15][C:12]([C:7]3[CH:8]=[CH:9][C:10](=[O:11])[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=3)=[O:14])[CH:17]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: CC(C)(C)n1cc(C(=O)O)ccc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(=O)n(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a solution of 1-tert-butyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (30 mg) in DMF (0.6 mL) were added 3-amino-N-cyclopropyl-4-methylbenzamide (44 mg), HATU (88 mg) and iPr2NEt (89 mg), and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hr. The reaction mixture was diluted with EtOAc (3 mL) and the resulting mixture was washed with 1 M HCl (3 mL×2), water (3 mL), saturated aqueous NaHCO3 (3 mL) and brine successively, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with 10% MeOH in CH2Cl2 to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-tert-butyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (27 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>C(#N)C>[CH2:28]([O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CBr
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCC(C)C
Temperature: 80 °C
Yield: 31.4 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and isobutyl bromide (115 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 31.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:28]O>C(O)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)(=[O:28])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1ccc2cc(OCCCCS(=O)c3ccc([N+](=O)[O-])cc3)ccc2[nH]1
Reactant: OO
Solvent: O=CO
Product: O=c1ccc2cc(OCCCCS(=O)(=O)c3ccc([N+](=O)[O-])cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 124 from 6-[4-(4-nitro-phenyl-sulfinyl)-butoxy]-carbostyril and hydrogen peroxide in formic acid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.[OH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[OH:24])[C:16]([CH2:18][C:19]#[N:20])=[O:17].NCCC(O)=O.O>C(O)C>[OH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[OH:24])[C:16]([C:18](=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[C:19]#[N:20])=[O:17]
Reactant: N#CCC(=O)c1ccc(O)c(O)c1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: NCCC(=O)O
Solvent: O
Solvent: CCO
Product: N#CC(=Cc1ccc2[nH]ccc2c1)C(=O)c1ccc(O)c(O)c1
Yield: 28.3 %

Procedure:
5-Formyl indole (145 mg, 1 mmole), 3,4-dihydroxybenzoylacetonitrile (177 mg, 1 mmole) and β-alanine (30 mg) in 30 ml ethanol were refluxed for 3 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was concentrated and the resulting oily residue was purified by chromatography on silica gel to give 86 mg (31%) of the title compound as an orange solid, m.p. 185° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)[N:23]=2)[NH:18][CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.Cl>O1CCOCC1>[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)[N:23]=2)[NH:18][CH:17]=1)=[O:15])([CH3:11])[CH3:12]
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)n[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO)c4n3)n[nH]c2c1
Reaction time: 2 h
Yield: 25.7 %

Procedure:
N-(1-(tert-Butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75 mg, 0.16 mmol) was added to a saturated solution of HCl (g) in dioxane (15 mL) at room temperature and stirred for 2 hours. The reaction mixture was filtered, the filter cake washed with 2 mL of methanol, then dried at 40° C. under reduced pressure to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 26.4%) as a yellow solid. MS: (M+H)+=365; 1H NMR (300 MHz, DMSO): δ 13.34 (s, 1H), 12.76 (s, 1H), 9.14 (s, 1H), 8.46 (d, 1H, J=7.8 Hz), 8.35 (s, 1H), 7.95 (s, 1H), 7.41 (s, 1H), 7.09 (d, 1H, J=8.4 Hz), 5.05 (t, 1H, J=5.7 Hz), 3.65 (d, 1H, J=5.7 Hz), 2.50 (s, 3H), 1.46 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][CH2:10][C:11]2[CH2:12][S:13][C@@H:14]3[C@H:34]([NH:35][C:36](=[O:84])/[C:37](/[C:59]4[N:60]=[C:61]([NH:64]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:62][CH:63]=4)=[N:38]\[O:39]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:33](=[O:85])[N:15]3[C:16]=2[C:17]([O:19]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:18])[CH:3]=1.Cl.O.[K+].[Br-]>C(O)=O>[NH2:64][C:61]1[S:62][CH:63]=[C:59](/[C:37](=[N:38]/[OH:39])/[C:36]([NH:35][C@@H:34]2[C:33](=[O:85])[N:15]3[C:16]([C:17]([OH:19])=[O:18])=[C:11]([CH2:10][S:9][C:4]4[CH:3]=[C:2]([CH3:1])[O:7][C:6](=[O:8])[CH:5]=4)[CH2:12][S:13][C@H:14]23)=[O:84])[N:60]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)cc(=O)o1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)cc(=O)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diphenylmethyl 3-(6-methyl-2-oxo-2H-pyran-4-ylthiomethyl)-7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetamido]ceph-3-em-4-carboxylate (969 mg) was dissolved in 100% formic acid (14.9 ml) and 1N hydrochloric acid (0.825 ml) and water (0.825 ml) were added. The mixture was stirred at room temperature for 0.5 h and then concentrated hydrochloric acid (0.66 ml) was added. The mixture was stirred for 1 h and then the solid was filtered off and washed with 90% formic acid. The combined filtrates were evaporated and a 1:1 mixture of toluene and tetrahydrofuran was evaporated from the residue twice. The residue was triturated with ether and the solid filtered off and washed with ether. The solid was suspended in water and the pH adjusted to 2.6 with 0.1N sodium hydroxide solution. The resulting solid was filtered off, washed with water and dried under vacuum to give the product. υmax (KBr) 1773, 1675 and 1624cm-1 ; δ[(CD3)2SO] 2.16 (3H, s), 3.47 (1H, d, J 17.9Hz), 3.70 (1H, d, J 18.0Hz), 4.11 (1H, d, J 12.9Hz), 4.19 (1H, d, J 13.1Hz), 5.18 (1H, d, J 4.8Hz), 5.79 (1H, dd, J 4.8 and 8.2Hz), 6.00 (1H, s), 6.21 (1H, s), 6.66 (1H, s), 7.17 (2H, s), 9.48 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:23])[N:9]3[C:16]4[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]=4[NH:14][C:10]3=[N:11]2)=[CH:6][CH:5]=1)[CH3:2].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:23])[N:9]3[C:16]4[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]=4[N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:10]3=[N:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)CBr
Reactant: CCOc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(C)c(C)cc13
Product: CCOc1ccc2c(=O)n3c4cc(C)c(C)cc4n(CC(C)C)c3nc2c1

Procedure:
3-Ethoxy-6-isobutyl-8,9-dimethylbenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-ethoxy-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and isobutyl bromide.