Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=O)[CH2:2]2.[NH:10]1[CH2:15][CH2:14][C:13]2([O:20][C:19](=[O:21])[NH:18][C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=3)[CH2:12][CH2:11]1.[BH4-].[Na+].[OH-].[Na+]>CO.CS(C)=O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].ClCCl.C(COC)OC>[CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([N:10]1[CH2:11][CH2:12][C:13]3([O:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]3=4)[CH2:14][CH2:15]1)[CH2:2]2
Reactant: O=C1CC2CCC(C1)C2
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: O=C1Nc2ccccc2C2(CCN(C3CC4CCC(C4)C3)CC2)O1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A scintillation vial was charged with bicyclo-[3.2.1]octan-3-one (iia) (31 mg, 0.25 mmol), spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (44 mg, 0.20 mmol), and anhydrous dimethoxyethane:dichloromethane (1.0 mL, 1:1 v/v). The mixture was treated with titanium tetraisopropoxide (171 mg, 0.60 mmol). The vial was flushed with nitrogen and stirred at room temperature for 60 hours. The reaction was then cooled in an ice water bath, quenched with methanol (1.0 mL) and treated with sodium borohydride (15 mg, 0.40 mmol). The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, treated with 1.0 N NaOH (1.0 mL), diluted with methanol (2.0 mL), and stirred at room temperature for 15 min. The suspension obtained was centrifuged (3K rpm, 10 min), and the supernatant was filtered (Whatman 0.2 μm PTFE). The filtrate was concentrated under reduced pressure and the residue obtained dissolved in DMSO:methanol (1.5 mL, 1:1 v/v), filtered and subjected to reverse-phase HPLC purification [2-99% CH3CN gradient over 13 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected] to provide 1′-(bicyclo[3.2.1]octan-3-yl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 67) as a TFA salt. LC/MS m/z 327.2 [M+H]+, retention time 1.80 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: [C:1]([C:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:3])[NH2:2].[CH2:24](Br)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7]1)(=[O:3])[NH2:2]
Reactant: BrCCc1ccccc1
Reactant: NC(=O)C(CC1CCNCC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(CC1CCN(CCc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A mixture of 4-(2-carbamoyl-2,2-diphenylethyl)piperidine (300 mg, 0.97 mmol) (Preparation 3), phenethyl bromide (198 mg, 1.07 mmol) and potassium carbonate (400 mg) in acetonitrile (10 ml) was heated under reflux for 6 hours, allowed to cool to room temperature and evaporated. The residue was partitioned between dichloromethane and 10% aqueous potassium carbonate solution and the aqueous layer was extracted twice into dichloromethane. The combined organic layers were dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (195 mg, 49%) as a colourless foam, which was characterised as a hydrate.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH:30]=O)[CH:23]=1.Cl>COCCOC>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH:30]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:23]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C=O
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C=C1C(=O)C(C)(C)OC1(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (1.15 g, 0.0081 mol) in 1,2-dimethoxyethane (2 ml) is added sodium methoxide (0.481 g, 0.0089 mol) in one portion. The reaction mixture is then stirred for 5 minutes at this temperature, followed by the addition of a second solution of 2′,4′-dichloro-4-ethylbiphenyl-3-carbaldehyde (2.02 g, 0.0072 mol) in 1,2-dimethoxyethane (2.7 ml). After stirring for an additional 2 hours at 0° C. the reaction mixture is allowed to stand at room temperature overnight. The crude solution is poured into 2M hydrochloric acid and extracted with ether (×3). The organics are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash column chromatography (5% ethyl acetate in isohexane to 25% ethyl acetate in isohexane) to afford 4-[1-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one as a yellow gum.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1)#[N:20]>>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][CH:25]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: N#Cc1ccc(-c2ncc[nH]2)cc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(C#N)cc3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 26, with Intermediate C instead of Intermediate B and with 2-(4-cyanophenyl)-1H-imidazole instead of 2-phenyl-1H-imidazole. LCMS: 402.2 m/z (M+H)+; ret. Time: 6.26 min (Analytical Method C).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(OC(O[CH:17]1[CH2:29][CH2:28][C:27]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH:26]([OH:37])[CH:25]=[CH:24][CH:23]([CH3:38])[CH:22](/[C:39](/[CH3:60])=[CH:40]/[CH:41]=[CH:42]/[CH:43]([CH3:59])[CH2:44][CH:45]2[O:58][CH:46]2[CH:47]([CH3:57])[CH:48]([O:51][CH:52]([O:54][CH2:55][CH3:56])[CH3:53])[CH2:49][CH3:50])[O:21][C:19](=[O:20])[CH2:18]1)C)C.Cl.C(Cl)(=O)C1C=CC=NC=1.C(OCC)(=O)C>O1CCCC1.O1CC(CCN)C(CCN)C1CCN.O>[CH2:35]([O:34][CH:32]([O:31][C:27]1([CH3:30])[CH:26]([OH:37])[CH:25]=[CH:24][CH:23]([CH3:38])[CH:22](/[C:39](/[CH3:60])=[CH:40]/[CH:41]=[CH:42]/[CH:43]([CH3:59])[CH2:44][CH:45]2[O:58][CH:46]2[CH:47]([CH3:57])[CH:48]([O:51][CH:52]([O:54][CH2:55][CH3:56])[CH3:53])[CH2:49][CH3:50])[O:21][C:19](=[O:20])[CH:18]=[CH:17][CH2:29][CH2:28]1)[CH3:33])[CH3:36]
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)/C=C\CCC(C)(OC(C)OCC)C(O)/C=C/C1C
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(C)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)C=CCCC(C)(OC(C)OCC)C(O)C=CC1C
Reaction time: 0.33 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M tetrahydrofuran solution, 50 μL, 50 μmol) was added dropwise to a solution of (8E,12E,14E)-3,6,21-tri(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (10.8 mg, 15.2 μmol) in tetrahydrofuran (2 mL) at −40° C. under nitrogen atmosphere, followed by stirring at the same temperature for 20 min. Then, a solution of nicotinoyl chloride hydrochloride (5.7 mg, 30.4 μmol) in tetrahydrofuran-triethylamine (tetrahydrofuran: 0.5 mL and triethyamine: 1 drop) was added dropwise thereinto, followed by stirring at 0° C. for 30 min. Ethyl Acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane=1:4) to obtain the title compound (6.3 mg, 67%) as a colorless oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([C:35]([NH:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([N:48]3[CH:52]=[C:51]([CH3:53])[N:50]=[CH:49]3)[CH:39]=1)=[O:36])=[CH:30][CH:29]=[CH:28]2)(C)C>O1CCCC1>[OH:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([C:35]([NH:37][C:38]1[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=[C:40]([N:48]3[CH:52]=[C:51]([CH3:53])[N:50]=[CH:49]3)[CH:39]=1)=[O:36])=[CH:30][CH:29]=[CH:28]2
Reactant: Cc1cn(-c2cc(NC(=O)c3cccc4cc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)ccc34)cc(C(F)(F)F)c2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(NC(=O)c3cccc4cc(O)ccc34)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tetrabutylammonium fluoride (3.5 mL of 1 M) in tetrahydrofuran is added to a stirred solution of 6[[(1,1-dimethylethyl)diphenylsilyl]oxy]-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-1-naphthalenecarboxamide (1.91 g, 2.94 mmol) in tetrahydrofuran (50 mL) and the mixture is stirred at room temperature for 60 min. The solvent is evaporated off under reduced pressure and the residue is purified by column chromatography (SiO2; ethyl acetate) to afford the title compound as a cream solid m.p.: 169-172° C.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[C:19]1([C@H:25]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[OH-].[K+]>ClCCl.CN(C)C=O>[Br:12][C:8]1[CH:7]=[C:6]([CH:2]2[C:3](=[O:5])[N:27]([C@@H:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:26])[CH2:28][CH2:29][CH2:30][O:31]2)[CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H](NCCCO)c1ccccc1
Reactant: O=C(O)C(Br)c1cccc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1CCCOC(c2cccc(Br)c2)C1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of bromo-(3-bromo-phenyl)-acetic acid (27.8 g, 94.6 mmol) in dichloromethane (200 ml) was added oxalylchloride (19.8 g, 156 mmol) and a few drops of N,N-dimethylformamide at room temperature. After the mixture was stirred at 40° C. for one hour, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (30 ml) and the solution was added to a solution of (R)-3-(1-phenylethyl amino)propan-1-ol (18.6 g, 104 mmol) and triethylamine (11.6 g, 114 mmol) in dichloromethane (312 ml) at 0° C. The mixture was stirred for 1.5 hours at 0° C. and partitioned between 0.5 N hydrochloric acid and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved into 2-propanol (312 ml) and then potassium hydroxide (11.7 g, 208 mmol) was added at 0° C. The mixture was stirred at 0° C. for 3 hours and partitioned between saturated ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude mixture was triturated with ether. The resulting solid materials were collected by filtration and dried under reduced pressure to afford diastereomerically pure 2-(3-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer 1) as white solid (9.71 g, 25%).
Reaction SMILES: [CH2:1]([N:8]([C:25](=[O:35])[C:26](NC1C=CC=CC=1)=[O:27])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2C=CC=C[CH:18]=2)[CH:12]=[C:11](C)[C:10]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].C(I)C=C>C(O)C>[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:10]([CH3:24])=[C:9]2[C:14]=1[C:26](=[O:27])[C:25](=[O:35])[N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:17]=[CH2:18]
Reactant: Cc1cc(OCc2ccccc2)cc(N(Cc2ccccc2)C(=O)C(=O)Nc2ccccc2)c1C
Agent: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCOc1ccc(C)c2c1C(=O)C(=O)N2Cc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
149.98 g (0.386 mol) of N-benzyl-5'-benzyloxy-2'-methylmethyloxalanilide was dissolve in 900 ml of 90% ethanol aqueous solution. After the addition of 44.0 g (0.786 mol) of potassium hydroxide, the mixture was stirred for 2 hours at 50° C. The reaction mixture was concentrated under reduced pressure, and to the residue were slowly added 400 ml of trifluoroacetic acid and then 400 ml of trifluoroacetic anhydride under cooling with ice. The temperature was raised to 50° C and the mixture was stirred for 1 hour, and for a further 35 hours at 60° C. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. The organic layer was partitioned by 1N aqueous solution of sodium hydroxide. Hydrochloric acid was added to the basic water layer to adjust pH to about 4, and this layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 200 ml of N,N-dimethylformamide, and 100 g (0.725 mol) of potassium carbonate and 50.0 g (0.298 mol) of allyl iodide were added to the solution, followed by stirring for 90 minutes at 60° C. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was recrystallized from benzene to obtain reddish brown crude crystals. The crystals were recrystallized from ethyl acetate-ether-n-hexane to obtain 17.3 g (three steps, 14.2%) of a reddish brown powder of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Cl)[CH3:27]>>[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:7])=[CH:24][CH:25]=1)[CH3:27]
Reactant: CCN(CC)CCCCl
Reactant: Cc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxybenzoyl)-2-(4-tolyl)benzofuran with 3-diethylaminopropyl chloride by the procedure described in Example 1 gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[C:3]=1[CH:13]=O>CC(C)=O>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[C:3]=1[CH:13]=[CH:4][C:5](=[O:6])[CH3:9]
Reactant: Cc1c(C)c(C=O)c2c(c1C)OCC2
Solvent: CC(C)=O
Product: CC(=O)C=Cc1c(C)c(C)c(C)c2c1CCO2

Procedure:
1-(2,3-Dihydro-5,6,7-trimethylbenzo[b]furan-4-yl)but-1-en-3-one was prepared from 2,3-dihydro-5,6,7-trimethylbenzo[b]furan-4-carboxaldehyde and acetone following essentially the same procedure as that described in Example 1 part (i), and was obtained as a brown oil.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]2
Reactant: CCOC1=CCc2cccc(N)c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cccc2c1CC(=O)CC2
Temperature: 40 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of (7-ethoxy-5,8-dihydronaphthalen-1-yl)amine (1.07 g, 5.65 mmol) in tetrahydrofuran (30 ml) was added solution of aqueous 2N HCl (10 mL), and stirred at 40° C. for 1 hour. The mixture was neutralized with addition of sodium bicarbonate, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 8-amino-3,4-dihydronaphthalen-2(1H)-one (0.71 g, 78% yield).
Reaction SMILES: [C:1]([CH2:4][C:5]1[O:6][C:7]([SH:10])=[N:8][N:9]=1)([OH:3])=[O:2].CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH2:15][S:10][C:7]3[O:6][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[N:9][N:8]=3)[CH2:25][S:24][C@H:19]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)Cc1nnc(S)o1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Reaction time: 3 h

Procedure:
A solution of 9.61 g (0.06 mol) of 2-carboxymethyl-1,3,4-oxadiazole-5-thiol in 120 ml of acetone is added to a warm (45°) solution of 10.9 g (0.04 mol) of 7-aminocephalosporanic acid in a mixture of 220 ml of water, 50 ml of acetone and 13.44 g (0.16 mol) of sodium bicarbonate. The temperature is raised to 65° and the pH maintained at 7.4-7.6 by addition of aqueous sodium carbonate solution. After 3 hours, the acetone is removed in vacuo and the reaction mixture is cooled to 10° and adjusted to pH 3.5 by addition of dilute hydrochloric acid. The product is collected, washed with water and then acetone to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@:4]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:6])[NH2:5].[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[O:35][C:36](Cl)=[O:37])[CH2:32]2.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@:4]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:6])[NH:5][C:36]([O:35][CH:26]1[CH:25]2[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]1[CH2:28]3)[CH2:32]2)=[O:37]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)[C@](C)(N)c1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@](C)(NC(=O)OC1C2CC3CC(C2)CC1C3)c1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-[9-(methylsulfonyl)-β-carbolin-3-yl]-alanine methylester (0.5 g, 1.4 mmol) in THF (10 mL) was added 2-adamantyloxycarbonyl chloride (345 rag, 1.7 mmol) and the solution was treated with diisopropyl ethylamine (219 mg, 1.7 mmol) in THF (5 mL). The reaction mixture was stirred for 4 hours at room temperature, evaporated in vacuum and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was separated,washed successively with 7.5% citric acid solution (50 mL), 8% NaHCO3 solution (50 mL) and then dried over Na2SO4. The solvent was evaporated in vacuum and N-(2-adamantyloxy-carbonyl)-2-[9-(methylsulfonyl)-β-carbolin-3-yl]-alanine methylester was isolated as a yellow oil which solidified upon drying(0.73 g, 97.7%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C([O-])=O.[C:52]([C:55]1[CH:56]=[CH:57][C:58]2[C:59]([CH:75]3[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]3)=[C:60]3[C:67]4[CH:68]=[CH:69][C:70]([F:72])=[CH:71][C:66]=4[CH2:65][NH2+:64][CH2:63][CH2:62][N:61]3[C:73]=2[CH:74]=1)([OH:54])=[O:53]>C(Cl)Cl.CN(C=O)C>[CH:75]1([C:59]2[C:58]3[CH:57]=[CH:56][C:55]([C:52]([OH:54])=[O:53])=[CH:74][C:73]=3[N:61]3[CH2:62][CH2:63][N:64]([C:9](=[O:11])[CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH2:65][C:66]4[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:67]=4[C:60]=23)[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC[NH2+]Cc1cc(F)ccc1-3
Reactant: CN1CCN(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(CC(=O)N2CCn3c(c(C4CCCCC4)c4ccc(C(=O)O)cc43)-c3ccc(F)cc3C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 3 eq of (4-methylpiperazin-1-yl)acetic acid in DCM (0.2 M), 4 eq of DIPEA and 2 eq of HATU were added and the mixture stirred at RT for 1 h. Then a solution of 1 eq of 11-carboxy-14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-6-ium trifluoroacetate in DMF (0.06 M) and 1 eq of DIPEA was added and the mixture stirred at RT overnight. Volatiles were removed in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters SYMMETRY prep. C18, 7 μm, 19×300 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (51%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[C:29]1[NH:30][C:31]2[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=2[N:33]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:38][C:36]4[CH:35]=[CH:34][C:32]5[N:33]=[C:29]([C:28]([F:40])([F:39])[F:27])[NH:30][C:31]=5[CH:37]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5nc(C(F)(F)F)[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (103 mg, 0.262 mmol) was coupled with 2-trifluoromethyl-3H-benzimidazol-5-ylamine (91 mg, 0.45 mmol) at 105° C. for 132 h to afford the title compound. Yield of TFA salt: 15 mg (26%) of brown powder; LC/MS: 529 (M+H); HPLC: 97% pure, RT=2.16 min; 1H NMR: (DMSO, δ) 9.68 (s, 1H), 9.07 (s, 1H), 8.53 (m, 2H), 8.02 (s, 1H), 7.86 (d, J=8.0, 1H), 7.83 (dd, J=9.1, 1.8, 1H), 7.75 (m, 3H), 7.25 (d, J=4.7, 1H), 7.03 (d, J=4.7, 1H), 1.12 (s, 9H)-benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]2[N:8]3[CH2:14][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@H:12]([C:23]4[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=4[F:31])[CH2:11][C:9]3=[N:10][C:6]=2[CH:5]=1)([O-])=O>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:33]=[CH:32][C:7]2[N:8]3[CH2:14][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@H:12]([C:23]4[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=4[F:31])[CH2:11][C:9]3=[N:10][C:6]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc([N+](=O)[O-])ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(N)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 2 h

Procedure:
To 54 mg (0.12 mmol) of the product from Step A in 4 mL of methanol was added 10 mg of 20% palladium hydroxide on carbon. The reaction mixture was purged with hydrogen gas and held under 1 atmosphere of hydrogen for 2 h. The mixture was filtered through a pad of Celite, and the filter cake was successively washed with three portions of methanol. The combined filtrate and washings were concentrated and used without further purification. LC/MS 433.1 (M+1).