Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:24])=[CH:5][CH:4]=1.Cl>>[NH2:24][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[C:15]=1[N:16]=[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[N:9]2[C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[N:8][CH:7]=1
Reactant: COc1ccc(-n2c(-c3ccccn3)nc3c(N)ncnc32)cn1
Agent: Cl
Product: Nc1ncnc2c1nc(-c1ccccn1)n2-c1ccc(O)nc1
Temperature: 105 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
A mixture of 350 mg of 9-(6-methoxy-3-pyridyl)-8-(2-pyridyl)-9H-6-purineamine and 6 mL conc. aqueous hydrochloric acid was stirred at 105° C. for 1 hour and 45 minutes. From the resulting yellowish brown oily material, the solvent was evaporated, whereby yellowish brown crystals were obtained. The resulting crystals were collected by filtration with ethanol, to give 77 mg of the title compound as brown crystals (23% y.).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1([CH3:28])[C:24]2[C:16](=[CH:17][C:18]3[CH2:19][C:20]([CH3:25])=[CH:21][C:22]=3[CH:23]=2)[C:15]([CH3:27])([CH3:26])[CH2:14]1.[Si:29]([CH3:33])([CH3:32])(Cl)[Cl:30]>CCOCC>[Cl:30][Si:29]([CH:21]1[C:20]([CH3:25])=[CH:19][C:18]2[CH:17]=[C:16]3[C:24]([C:13]([CH3:28])([CH3:12])[CH2:14][C:15]3([CH3:27])[CH3:26])=[CH:23][C:22]1=2)([CH3:33])[CH3:32]
Reactant: CC1=Cc2cc3c(cc2C1)C(C)(C)CC3(C)C
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)C(C)(C)CC3(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A 2.5 M n-BuLi solution in hexane (3.8 mL, 9.50 mmol, n-BuLi:indacene=1:1) was added dropwise at 0° C. to a solution of 2.16 g of 1,1,3,3,6-pentamethyl-1,2,3,5-tetrahydro-s-indacene (9.54 mmol) in 40 mL of Et2O. At the end of the addition, the resulting light yellow solution was allowed to warm up to room temperature and stirred for 1 h with final formation of a white suspension. An aliquot of this suspension was quenched with CD3OD and dried: the related 1H NMR analysis in CDCl3 showed complete conversion of the starting indacene to the corresponding lithium salt. The latter was then cooled again to 0° C. and added to a solution of Me2SiCl2 (98%, 1.27 g, d=1.064, 9.64 mmol) in 10 mL of Et2O, previously cooled to 0° C. too. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h with final formation of a white suspension. After 40 min stirring at r.t. the conversion was ca. 80% by 1H NMR analysis. The solvents were removed in vacuo and the residue extracted with 70 mL of toluene to remove the LiCl. The filtrate was brought to dryness in vacuo at 40° C. to give a thick yellow oil as product (3.03 g), which tended to crystallize by standing at room temperature. Isolated yield=97.9% (purity 97.9% wt. by 1 H NMR analysis). Starting indacene was still present in 2.1% wt.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22].CCN(C(C)C)C(C)C>C(O)C>[OH:22][CH2:21][C@H:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[NH:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N[C@H]1CCC[C@H]1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@@H]1CO
Temperature: 60 °C
Yield: 95.6 %

Procedure:
To a stirred solution of ethyl 4-chloro-2-(methylthio)-pyrimidine-5-carboxylate (5.00 g, 21.49 mmol) and cis-(2-aminocyclopentyl)-methanol (2.60 g, 22.56 mmol) in ethanol (85 mL) was added DIEA (5.61 mL, 32.2 mmol) and heated to 60° C. for 2.5 h. Upon completion of reaction, as indicated by LCMS and TLC, the reaction was removed from heat and concentrated, then purified by silica gel chromatography (0-80% ethyl acetate/hexane). The desired product fractions were combined and concentrated to afford ethyl 4-(cis-2-(hydroxymethyl)cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (6.4 g, 96% yield) as a white solid. MS (ESI) m/z 312.4 [M+1]+.
Reaction SMILES: [F:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(F)(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.6 %

Procedure:
To a 0° C. solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (2.60 g, 11.1 mmol) and triethylamine (2.33 mL, 16.7 mmol) in 55 mL dichloromethane was added neat methanesulfonyl chloride (0.949 mL, 12.3 mmol) dropwise by syringe. The reaction mixture was slowly warmed to ambient temperature and stirred at ambient temperature for 17 hours. Saturated NaHCO3 was added, the mixture was extracted with dichloromethane, and combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (4:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to give the title compound (3.2 g, 92.2% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(Cl)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of ethyl 2-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.37 mmol) in 85% hydrazine monohydrate (4 ml) and methanol (6 ml) was stirred at room temperature for 2 h. The mixture was filtered and washed with water to give the title compound (89 mg, yield: 65%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.44 (s, 3H), 4.69 (d, J=10.8 Hz, 1H), 4.96 (d, J=10.8 Hz, 1H), 6.76 (s, 1H), 6.93 (d, 1H), 7.16 (d, J=8 Hz, 1H), 7.33-7.44 (m, 6H), 7.56-7.60 (m, 1H), 12.19 (d, 1H); LC-MS (ESI) m/z: 378 (M+1)+.
Reaction SMILES: [C:1]([O:11][CH:12]([C:14]([O:17][CH2:18][CH2:19][OH:20])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:35])([F:34])[C:29]([F:33])=[C:30]([F:32])[F:31]>C(#N)C>[C:1]([O:11][CH:12]([C:14]([O:17][CH2:18][CH2:19][O:20][C:30]([CH:29]([C:28]([F:35])([F:34])[F:27])[F:33])([F:32])[F:31])([F:16])[F:15])[F:13])([C:4]([C:7]([F:9])([F:8])[F:10])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: OCCOC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)OCCOC(F)(F)C(F)C(F)(F)F
Temperature: 30 °C
Reaction time: 0.67 h
Yield: 86.3 %

Procedure:
Perfluoropropylvinyl ether (139.0 g, 0.52 mole), potassium carbonate (19.3 g, 0.14 mole), ethylene glycol (155.5 g, 2.5 mole) and acetonitrile (200 mL) were combined in a 600 mL Parr reactor. The reactor was sealed and heated to 30° C. for 2.75 hours. The reaction mixture was filtered and then water washed four times to give 146.4 g of C3F7OCFHCF2OC2H4OH (54.2%) and (C3F7OCFHCF2OCH2)2 (43.4%). This material was combined with 179 g from a previous run consisting of 21.6% C3F7OCFHCF2OC2H4OH and 76.1% (C3F7OCFHCF2OCH2)2 and fractionated to give a 106.3 g fractionation cut boiling from 167-173° C. of C3F7OCFHCF2OC2H4OH (80.8% pure). This material along with potassium carbonate (7.3 g, 0.052 mole) and acetonitrile (200 mL) were added to a 600 mL Parr reactor. The reactor was sealed and heated to 30° C. Hexafluoropropene (48.5 g, 0.32 mole) was added to the reactor over a 30 minute period and the reactor contents were held at 30° C. an additional 40 minutes. The reactor was cooled and the contents filtered into a 1-L separatory funnel and water washed four times, dried with anhydrous sodium sulfate and filtered. The material was shaken with anhydrous HF, water washed, dried with anhydrous sodium sulfate and filtered to give 125.6 g of C3F7OCHFCF2OC2H4OCF2CFHCF3 (86.3% pure). The material was fractionated in the concentric tube unit to give 72.3 g of C3F7OCHFCF2OC2H4OCF2CFHCF3 (95.3% purity) boiling at 194° C. Structure was confirmed by gc-ms. The viscosity was 48 centistokes (48×10−6 m2/s) at −50° C. measured using a Cannon-Fenske viscometer and a Wescan Model 221 viscosity timer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:24]3C(=O)C4=CC=CC=C4C3=O)=[N:21][N:20]=[C:19]2[CH2:35][N:36]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=O.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[C:22]([CH2:23][NH2:24])=[N:21][N:20]=[C:19]3[CH2:35][N:36]=[C:7]([C:9]3[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=3[F:16])[C:6]=2[CH:17]=1
Reactant: O=C(c1cc(Cl)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 22, 5-chloro-2',6'-difluoro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-chloro-1-(aminomethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH:14]1([O:20][C:21](N2C=CC=CC2=O)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O.C1COCC1>[CH:14]1([O:20][C:21]([NH:1][C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: O=C(OC1CCCCC1)n1ccccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](NC(=O)OC1CCCCC1)C(=O)O
Yield: 97.9 %

Procedure:
To a stirred mixture of D-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing cyclohexyl-2-pyridyl-carbonate and cyclohexyl-2-oxopyridine 1-carboxylate (0.418 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.3 g, 97%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 246 [M−H]+; (ESI) m/z: 244 [M−H]−. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.2 Hz, 3H), 1.16-1.43 (m, 5H), 1.49 (s, 1H), 1.69 (s, 2H), 1.80 (s, 2H), 3.93 (dd, J=2.9, 8.8 Hz, 1H), 3.99-4.12 (m, 1H), 4.44-4.61 (m, 1H), 6.59 (d, J=8.9 Hz, 1H), 12.32 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CC(C)=O.CO>[CH2:20]([O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O)cc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 32.9 %

Procedure:
To a solution of 2.0 g (9.3 mmol) of 4,4'-dihydroxybenzophenon in 50 ml dry acetone was added 27.5 ml of 0.34M NaOMe in MeOH. After the reaction mixture had been stirred for 20 min, 1.6 g (9.3 mmol) of benzylbromide was added. The reaction was stirred at room temperature for 15 h. 250 ml EtOAc was added and then extracted with 2150 ml 0.5M HCl, 2150 ml H2O and 50 ml saturated NaCl(aq). Drying (MgSO4), evaporation of the EtOAc and purification on silica gave 0.93 g (33%) of 4'-benzyloxy-4-hydroxy benzophenon.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.00 g) was dissolved in dichloromethane (25 ml). Triethylamine (0.42 ml) was added, and a solution of benzoyl chloride (0.32 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 14 hr, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.35 g of 4-amino-N-(1-(6-benzoylaminohexyl)-piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([C:9]1([CH:26]=O)[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[S:11][CH2:10]1)[CH3:8].[NH4+].[Cl-]>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:7]([C:9]1([CH:26]=[CH2:1])[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[S:11][CH2:10]1)[CH3:8]
Reactant: CCC1(C=O)CSc2ccccc2C(c2ccccc2)=N1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC1(CC)CSc2ccccc2C(c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.0M solution of potassium t-butoxide in THF (82 ml, Aldrich) was added to a suspension of methyl triphenylphosphonium bromide (29.0 g, Aldrich) in 250 ml of THF. After complete addition, the reaction mixture was refluxed for one hour, cooled with an ice bath and the product from step (e) (12.0 g) in 70 ml of THF was added. The reaction was stirred for 1 hr at room temperature, refluxed for 2.5 hr and then stirred at room temperature for 17 hr. Saturated NH4Cl(200 ml) was added, the organic layer was separated, dried and concentrated to give a red-orange oil. Chromatography on silica using hexanes/EtOAc (9:1) as eluant afforded the title product as a light orange oil (11.0 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([CH:24]=2)[C:20]([O:22]C)=[O:21])[N:10]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([CH:24]=2)[C:20]([OH:22])=[O:21])[N:10]=1
Reactant: COC(=O)c1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Yield: 0 %

Procedure:
The title compound was prepared according to the procedure described in step-3 of Intermediate-9 by using of methyl 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoate (1.5 g, 3.97 mol) and sodium hydroxide (0.320 g, 7.95 mmol) to afford 0.700 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.84 (s, 3H), 7.24 (t, J=9.3 Hz, 1H), 7.48 (t, J=8.7 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.65-7.72 (m, 1H), 8.00 (d, J=8.7 Hz, 1H), 8.17 (s, 1H), 12.60 (s, 1H), 12.85 (br s, 1H).
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH:13]=[CH:12][N:11]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:10]3[C:9]=2[N:8]([C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)(=O)C.[Mn]([O-])(=O)(=O)=[O:30].[K+].S([O-])(O)=O.[Na+]>CC(C)=O.O>[C:20]([N:8]1[C:9]2[C:10]3=[N:17][C:16]([CH3:18])=[C:15]([CH3:19])[N:11]3[CH:12]=[CH:13][C:14]=2[C:5](=[O:4])[C@H:6]([OH:30])[C@H:7]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:21]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)OC1=C[C@@H](c2ccccc2)N(C(C)=O)c2c1ccn1c(C)c(C)nc21
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C(=O)[C@H](O)[C@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
2.0 g (5.4 mmol) of (9S)-7-acetoxy-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2h][1,7]-naphthyridine are dissolved in 30 ml of acetone and 6 ml of water. 1.0 g (6.4 mmol) of potassium permanganate is then introduced in portions at 0° C. After 30 min, the brown suspension is admixed with 1 ml of saturated sodium hydrogensulphite solution, filtered through Celite and washed with methanol and dichloromethane. The filtrate is concentrated and the residue crystallized using ethanol. 0.3 g (16%) of the title compound is isolated as a yellow solid (m.p. 192° C.).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:31][O:32][CH3:33])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[N:17]([S:26]([O-:29])(=[O:28])=[O:27])[C:16]2=[O:30])=[O:13])[N:10]=1)=O.[Na+:34].C(=S)(SC)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:31][O:32][CH3:33])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[N:17]([S:26]([O-:29])(=[O:28])=[O:27])[C:16]2=[O:30])=[O:13])[N:10]=1.[Na+:34]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1Sc1nnnn1C)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1Sc1nnnn1C)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a solution of 0.300 g of the above sodium (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazol-5-yl)thio-2-oxoazetidine-1-sulfonate in 4 ml of water and 4 ml of a buffer (pH 6.56) is added under ice-cooling 0.0689 g of sodium monomethyl dithiocarbamate, and the mixture is stirred at room temperature for 2 hours. The same procedure as Example 3B yields 0.106 g of sodium (3R,4S)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazol-5-yl)thio-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[ClH:38]>C(OCC)C>[ClH:38].[F:37][C:2]([F:1])([F:36])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17]2[CH2:23][CH:24]4[NH:28][CH:27]([C:16]3=2)[CH2:26][CH2:25]4)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(OC(F)(F)F)c4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4cccc(OC(F)(F)F)c4)ccc31)C1CCC(C2)N1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 90:9.9:0.1 dichloromethane/methanol/ammonium hydroxide). The free base was treated with 1.25 M HCl in methanol (1 mL) and the solution concentrated in vacuo to give 2-(3-trifluoromethoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (30 mg, 34%, AUC HPLC >99%) as an off-white solid: mp 193-196° C.; 1H NMR (CD3OD, 300 MHz): δ 8.31 (m, 1H), 7.91-7.99 (m, 1H), 7.79-7.85 (m, 1H), 7.71-7.78 (m, 1H), 7.58-7.70 (m, 2H), 7.48-7.57 (m, 1H), 5.26-5.34 (m, 1H), 4.50-4.60 (m, 1H), 3.72 (s, 3H), 3.49 (dd, J=17.4, J=4.2 Hz, 1H), 3.07 (d, J=17.7 Hz, 1H), 2.20-2.52 (m, 3H), 1.91-2.03 (m, 1H). ESI MS m/z 437 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:21](=[O:28])[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:21](=[O:28])[CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: CON(C)C(=O)Cc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)c1ccc(C2OCCO2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A 25 ml RB flask with a stirring bar was charged with 1-bromo-4-(1,3-dioxolan-2-yl)benzene (243 mg, 1.0 mmol), followed by anhydrous THF (5 mL). The mixture was cooled to −78° C. and n-butyllithium (687 μL of 1.6 M solution in hexanes) was added dropwise over 2 min. After stirring for 15 min. at −78° C., N-methoxy-N-methyl-2-(2-thienyl)acetamide (1-1) (185 mg, 1 mmol) was added in one portion. After another 30 min at −78° C., the mixture was quenched with sat. ammonium chloride (20 mL), extracted twice with ethyl acetate (10 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified via column chromatography over silica gel (0-50% ethyl acetate/hexanes) to give 1-[4-(1,3-dioxolan-2-yl)phenyl]-2-92-thienyl)ethanone (1-2). 1H NMR (CDCl3, ppm) δ: 7.98 (d, J=8.25 Hz, 2H), 7.45 (d, J=8.25 Hz, 2H), 7.15 (d, J=5.15 Hz, 1H), 6.86 (m, 1H), 6.83 (m, 1H), 5.77 (s, 1H), 4.38 (s, 2H), 4.01 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=O)[CH3:2].C(O)(=O)C.O.[NH2:30][NH2:31].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[NH:31][N:30]=1)=[O:24])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]n1
Yield: 63.8 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-ethanone (10 g, 0.0735 mole) in DMF (50 mL) was added K2CO3 (20.2 g, 0.147 mole) at ambient temperature. Benzyl bromide (13.83 g, 0.0808 mole) was then added and the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then quenched with iced water. The resulting precipitate was isolated by filtration and dried to afford 16.2 g (98%) of 1-(4-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 98.38%. A mixture of THF (130 mL) and NaH (60% w/w dispersion in oil) (5.28 g, 0.132 mole) was cooled to 0° C. with stirring for 5 minutes. Diethyl oxalate (12.87 g, 0.0886 mole) was added and the mixture was heated to reflux for 15 minutes. after cooling to ambient temperature 1-(4-benzyloxy-phenyl)-ethanone (10 g, 0.0442 mole) in THF (50 mL) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 70° C. for 1 hour. The reaction mixture was then quenched with cold aqueous NH4Cl solution. The resulting precipitate was isolated by filtration and dried to afford 21.2 g of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 36.5%. A solution of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (10 g, 0.03064 mole), acetic acid (20 mL) and hydrazine hydrate (1.685 g, 0.0337 mole) was heated to reflux for 8 hours. The reaction mixture was then poured into iced water and basified with saturated aqueous NaHCO3 solution. The product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 6.3 g (64%) of 5-(4-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 95.10%.