Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH:3]=[O:4].[C:7]([O:11]C(=O)CC)(=[O:10])[CH2:8][CH3:9].Cl(O)(=O)(=O)=O>>[C:7]([O:4][CH:3]([O:11][C:7](=[O:10])[CH2:8][CH3:9])[C:2]([Cl:6])([Cl:5])[Cl:1])(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=CC(Cl)(Cl)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCC(=O)OC(OC(=O)CC)C(Cl)(Cl)Cl

Procedure:
Trichloroacetaldehyde (0.2 mol) and propionic anhydride (0.2 mol) were reacted in the presence of 0.2 ml. 70% perchloric acid by the procedure of Example 4. The resulting 2,2,2-trichloroethylidene bispropionate product (13 g.) distilled at 65°-66° C. (0.1 mm/Hg). Elemental analysis for C8H11Cl3O4 showed:
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]([OH:40])[CH2:14][CH2:15][CH:16]([NH:27][CH:28]([C:37]([OH:39])=[O:38])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH2:12][CH:13]([OH:40])[CH2:14][CH2:15][CH:16]([NH:27][CH:28]([C:37]([OH:39])=[O:38])[CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18]
Reactant: O=C(NCC(O)CCC(NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCC(O)CCC(NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Compound VII in ethanol was hydrogenated at 40 psi at room temperature for 24 hours using 10% Pd/C. Filtration, purification over LH-20 and freeze drying gave VIII.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([C:24]#[N:25])=[CH:21][NH:22][CH:23]=1.[H-].[Na+]>CN(C=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:22]2[CH:23]=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])[C:20]([C:24]#[N:25])=[CH:21]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: N#Cc1c[nH]cc1-c1ccccc1Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cn(-c2ccc([N+](=O)[O-])c(N)c2)cc1-c1ccccc1Cl

Procedure:
The title compound was prepared from 5-chloro-2nitroaniline, 4-(o-Chlorophenyl)-pyrrole-3-carbonitrile [CAS-No. 74738-15-1] and NaH in DMF at 150° C. for 3 h according to the general procedure E (method b). Obtained as a yellow-brown solid (218 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[Si:35]([O:42][C:43]([C@@H:46]1[CH2:51][CH2:50][C@H:49](O)[CH2:48][CH2:47]1)([CH3:45])[CH3:44])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[Si:35]([O:42][C:43]([C@H:46]1[CH2:47][CH2:48][C@H:49]([O:34][C:31]2[CH:32]=[CH:33][C:28]([N:4]3[C:5](=[O:27])[C:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]3[CH2:1][CH3:2])=[CH:29][CH:30]=2)[CH2:50][CH2:51]1)([CH3:45])[CH3:44])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(O[C@H]3CC[C@H](C(C)(C)O[Si](C)(C)C(C)(C)C)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.58 g), cis-4-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)cyclohexanol (1.05 g) and triphenylphosphine (1.01 g) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (2.0 mL, 1.9 M toluene solution), and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[C:20]([CH:29]=O)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:29][C:20]3[CH:19]=[C:18]([CH3:17])[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Product: Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)nn1-c1ccccc1
Yield: 65.4 %

Procedure:
Compound 74 was prepared using the same method as Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 101.6 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0094 mL (0.072 mMol) 2-methylbenzoyl chloride, 0.023 gm (100%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CC1CCc2cc(O)ccc21
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-(5-methoxy-2,3-dihydro-1H-inden-1-yl)acetate (200 mg, 0.85 mmol, 1.00 equiv), dichloromethane (5 mL). This was followed by the addition of BBr3 (1 mL) at −78° C. The resulting solution was stirred for 15 min at 30° C. The reaction was then quenched by the addition of 5 mL of water/ice. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30:70). This resulted in 150 mg (74%) of ethyl 2-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)acetate as colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:13]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:14]1)[CH:7]=[CH:6]2>Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:13]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:14]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(-n3nc(OCCN4CCOCC4)cc3C)ccc2c1
Agent: Cl
Product: Cc1cc(OCCN2CCOCC2)nn1-c1ccc2cc(O)ccc2c1
Yield: 87 %

Procedure:
A solution of 4-{2-[1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine (448 mg, 1.22 mmol) in HCl conc. (5 ml) was heated to reflux during 7 hrs, it was cooled and evaporated to dryness in a rotavapor. 375 mg of 4-{2-[1-(6-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine chlorhydrate were obtained in amorphous solid form that was highly hygroscopic (yield: 79%)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[C:3]=1[Cl:12].[Sn](Cl)Cl.O.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Br)c(Cl)c1N
Temperature: 25 °C
Yield: 78.9 %

Procedure:
4-Bromo-3-chloro-2-nitroaniline (4.78 g, 19.01 mmol) was dissolved in ethanol (112 mL). Tin (II) chloride (14.42 g, 76 mmol) was added, and the resulting mixture was stirred at reflux for 12 hours. The mixture was cooled to room temperature, poured into water, and adjusted to pH 5 with saturated sodium bicarbonate solution. The resulting solid was filtered and rinsed well with ethyl acetate. The filtrate was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-50% EtOAc in hexane to give the title compound (3.32 g, 79%). 1H NMR (400 MHz, CDCl3) δ ppm 6.94 (d, 1H), 6.51 (d, J=7.0, 1H), 3.87 (br s, 2H), 3.46 (br s, 2H).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[CH3:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]([CH3:35])[C:32](=[O:36])[N:31]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[C:38]=1[CH3:52])[C:30]2=[O:53].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C(Cl)Cl.CO>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([N:31]2[C:30](=[O:53])[C:29]4[C:34](=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][CH:28]=4)[N:33]([CH3:35])[C:32]2=[O:36])[C:38]=1[CH3:52])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: COc1cccc2c(=O)n(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3C)c(=O)n(C)c12
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc2c(=O)n(-c3cccc(-c4c(Cl)cc(C(N)=O)c5[nH]c6cc(C(C)(C)O)ccc6c45)c3C)c(=O)n(C)c12
Temperature: 60 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3](200 mg, 0.524 mmol), 8-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 12] (221 mg, 0.524 mmol), Cs2CO3 (512 mg, 1.57 mmol) PdCl2(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water (0.50 mL) in a pressure reaction vial was heated at 60° C. overnight, then at 90° C. for 4 hours. The cooled mixture was diluted with DCM and MeOH, and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 20-55%), to give a mixture of four atropisomers of 3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(8-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (136 mg, 41% yield). This material was separated by chiral super-critical fluid chromatography as follows: column. CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO2-IPA (55:45) at 85 mL/min; sample preparation: 17 mg/mL in MeOH; injection: 1.0 mL. The fourth peak eluting from the column provided a single atropisomer of 3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(8-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (26 mg, 20% yield). The chiral purity was determined to be greater than 99%. Mass spectrum m/z 579 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.42 (s, 1H), 7.90 (dd, J=7.2, 2.3 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.55-7.49 (m, 1H), 7.40-7.36 (m, 1H), 7.35-7.31 (m, 1H), 7.25-7.19 (m, 3H), 6.97 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 1.85 (s, 3H), 1.63 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH3:2].O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:17][CH2:18][C:19]([O:21][N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30])=[O:20])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CCOC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](CCC(=O)ON1C(=O)CCC1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-CBZ-L-glutamic acid-α-ethyl ester (0.096 mole, 29.6 g.) and N-hydroxysuccinimide (0.1 mole, 11.5 g.) in 200 ml. of dioxane was added with stirring at room temperature (0.1 mole, 21 g.) of dicyclohexylcarbodimide. After stirring 24 hours at room temperature, the mixture was filtered to remove dicyclohexylurea. The filtrate was concentrated in vacuo to give an oil. This oil failed to crystallize and was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCOCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: BrCCCCCCOCCOCc1ccccc1
Reaction time: 18 h

Procedure:
A solution of 2-(benzyloxy)ethanol (2.00 g) and tetrabutylammonium bromide (84 mg) in 1,6-dibromohexane (6.06 ml) was treated with 50% w/v sodium hydroxide solution (5.0 ml) and the mixture was vigorously stirred for 18 h at 20°. Water (50 ml) was added and the mixture was extracted with dichloromethane (40 ml). The organic extract was dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by flash chromatography on silica gel. Elution with EtOAc-PE (1:9) gave the title compound (2.87 g). LCMS RT=3.94 min, ES+ve 337 (MNa)+, 339 (MNa)+
Reaction SMILES: C([Li])CCC.N1CCOCC1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.C([Li])(CC)C.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].Cl>CCCCCC.O1CCCC1.C1CCCCC1>[Si:24]([C:16]1[O:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1COCCN1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)c1cc(C=O)co1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (a 2.5M solution) in hexane; 8.3 ml, 20.8 mmol) was added to a solution of morpholine (1.81 ml, 20 mmol) in tetrahydrofuran (100 ml) at -78° C. under argon. After 20 minutes 3-furaldehyde (1.8 ml, 20.8 mmol) was added. After another 15 minutes, sec-butyl lithium (a 1.3M solution in cyclohexane; 16.8 ml, 21.9 mmol) was added dropwise and stirring continued at -78° C. for 1 hour before a solution of t-butyldimethylsilyl chloride (9.4 g, 62.4 mmol) in tetrahydrofuran (10 ml) was added. Stirring was continued overnight (16 hours) while the cooling bath was allowed to attain room temperature. The solution was poured into ice cold 10% (v/v) hydrochloric acid (40 ml) and after stirring at 0° for 10 minutes, the layers were separated. The aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (magnesium sulfate) and evaporated to dryness to give a brown oil, which was distilled under high vacuum to give the title aldehyde, boiling point 80°-5°/0.5 torr., m.p. 37-8.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[F:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][CH:33]=1)[CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([CH:29]=O)[CH:15]=2>N1C=CC=CC=1.CCOC(C)=O>[F:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][CH:33]=1)[CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([CH:29]=[N:4][O:3][CH3:2])[CH:15]=2
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C=O)ccc3n2Cc2cccc(F)c2)C1
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.1 %

Procedure:
Add methoxyamine hydrochloride (613 mg, 7.34 mmol) to a solution of (R)-N-[9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 200) (2.40 g, 6.11 mmol) in pyridine (40 mL). Stir the reaction mixture at room temperature for 18 h. Concentrate the reaction in-vacuo and dilute with EtOAc (175 mL). Wash the organics with water (3×75 mL), dry (MgSO4), filter, and concentrate to give the crude product (2.22 g) as a brown foam. Purify the crude product on 40 g silica gel (15-80% EtOAc/hexanes) to give 261 mg (10%) of the title compound as a yellow flaky solid. Re-purify the impure fractions on 40 g silica gel (50-80% (1% (2M NH3/MeOH)/CH2Cl2)/hexanes) and combine the purified materials to give 673 mg (26%) of the title compound as a yellow flaky solid. MS (ES): m/z 422 (M+1), 420 (M−1); HPLC (Method B): Rt=7.98 min (99%).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]([C:31](OC4C=CC=CC=4)=[O:32])C(=O)OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:31]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:32])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCOCC4)c3)ccc21
Temperature: 25 °C
Reaction time: 9 h
Yield: 68.5 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (20 g, 38 mmol) synthesized in Production example 5-2 was dissolved in N,N-dimethylformamide (190 ml); morpholine (13.3 mg, 153 mmol) was added thereto; and the reaction system was stirred at room temperature for 9 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate and a small amount of tetrahydrofuran; this suspension was filtrated with silica gel; and ethyl acetate and three different ratio of solvent mixtures of ethyl acetate:methanol=20:1, 10:1, and 5:1 were eluted through the gel. The filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (40 ml); hexane (200 ml) was added thereto; and precipitated insoluble syrupy portion was removed from the solution; and the resultant solution was concentrated again under reduced pressure. The residue was dissolved in ethyl acetate (300 ml) and was allowed to stand at room temperature. After the crystals were precipitated, the crystals were filtered off, washed with ethyl acetate, and dried to yield the crude crystals of the title compound (10.3 g). 9 g of this crude crystals was suspended in a mixture of tetrahydrofuran (3 ml) and N,N-dimethylformamide (3 ml each); this suspension was diluted with ethanol (60 ml); and the crystals were filtered off, washed with ethanol and dried to yield the title compound as colorless crystals (7.70 g, 19 mmol).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[N-:30]=[N+:31]=[N-:32].[Na+].CC(C)=O>O>[N:30]([C:3]1([CH3:2])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:13])[Cl:14])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:5]2[S:4][CH2:29]1)=[N+:31]=[N-:32]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(N=[N+]=[N-])CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After acetone was distilled off under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with saturated sodium bicarbonate aqueous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small quantity of ether was added to the residue to give colorless crystals of 2,2, 2-trichloroethyl 3-azido-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (170 mg). This substance was recrystallized from carbon tetrachloride to give crystals melting at 136° to 140°C.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:4]=2[N:3]=1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH2:21]([O:20][C:18]1[CH:17]=[CH:16][C:5]2[C:6]3[C:7]4[CH:8]=[CH:9][N:10]=[CH:11][C:12]=4[C:13](=[O:15])[C:14]=3[C:2]([Cl:1])=[N:3][C:4]=2[CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1c2cnccc2-c2c1c(Cl)nc1cc(O)ccc21
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1c2cnccc2-c2c1c(Cl)nc1cc(OCc3ccccc3)ccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6-Chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34a) (27 mg) was dissolved in DMF (2 ml). To the solution were added benzyl chloride (0.016 ml) and potassium carbonate (29 mg). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was dissolved in dichloromethane and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane and dichloromethane-MeOH=50:1. The desired product (12 mg) was obtained as a light yellow solid. EI−MS: m/z 372 (M+); 1H-NMR (CDCl3): δ5.25 (2H, s), 7.30-7.55 (7H, m), 8.00 (1H, dd, J=5 Hz, 1 Hz), 8.36 (1H, d, J=9Hz), 8.95 (1H, d, 5 Hz), 9.03 (1H, d, J=1 Hz).
Reaction SMILES: [BrH:1].C([C:6]([NH:21]C(OC(C)(C)C)=O)([CH2:10][S:11](=[O:20])(=[O:19])[CH2:12][CH2:13][NH:14][C:15](=[NH:18])[CH2:16][F:17])[C:7]([OH:9])=[O:8])(C)(C)C.Br>C(O)(=O)C>[BrH:1].[BrH:1].[NH2:21][CH:6]([CH2:10][S:11](=[O:20])(=[O:19])[CH2:12][CH2:13][NH:14][C:15](=[NH:18])[CH2:16][F:17])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)NC(CS(=O)(=O)CCNC(=N)CF)(C(=O)O)C(C)(C)C
Agent: Br
Solvent: CC(=O)O
Product: N=C(CF)NCCS(=O)(=O)CC(N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 173.1 %

Procedure:
t-Butyl-2-t-butoxycarbonylamino-6-(1-imino-2-fluoroethylamino)-4,4-dioxo-4-thiahexanoic acid hydrobromide (300 mg) was dissolved in glacial acetic acid (4.5 ml), and cooled whilst HBr in acetic acid (45% w/v, 1.5 ml) was added. The mixture was then stirred at room temperature for 2 h. The volatile materials were evaporated in vacuo and the residue dissolved in water. The solution was evaporated to dryness in vacuo, and this process repeated twice more. Ethanol was added to the residue and the mixture concentrated in vacuo to an off-white foam. The material could be further purified by dissolving in a minimum of warm ethanol and precipitating the product with ether to yield a white hygroscopic solid (220 mg) as the dihydrate.