Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.F[C:9](F)(F)C(O)=O.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:52]=[CH:51][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38][C:37]3=[O:44])=[O:33])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>CC(C)=O>[CH:2]([N:48]1[CH2:49][CH2:50][CH:45]([C:36]2([CH2:35][NH:34][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=[C:16]([CH3:15])[CH:25]=4)=[CH:52][CH:51]=3)[C:37](=[O:44])[NH:38][C:39](=[O:43])[NH:40][C:41]2=[O:42])[CH2:46][CH2:47]1)([CH3:3])[CH3:9]
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(C4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1cc(COc2ccc(C(=O)NCC3(C4CCN(C(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 32.8 %

Procedure:
Following the procedure analogous to that used in reaction (9), the compound from Example 29 was reacted with acetone for 5 days to provide the title compound (7 mg, 32.8%). MS found: (M+H)+=558.4.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]1)[CH2:27][CH3:28])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:52][CH2:53][OH:54].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][C@H:30]1[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][CH2:35]1)[CH2:27][CH3:28])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:52][CH2:53][OH:54])=[CH:12][N:13]=1
Reactant: OCCBr
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(O)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCO)cn2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethyl trans-(4-{[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-methyl}-cyclohexyl)-acetate (300 mg) is dissolved in N,N-dimethylformamide (4 ml), and thereto are added 2-bromoethanol (87 μl) and potassium carbonate (172 mg), and the mixture is stirred at 60° C. for 1 day. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=7:3% 1:1) to give ethyl trans-[4-({[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-hydroxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-methyl)-cyclohexyl]-acetate (138 mg). MS (m/z): 765 [M+H]+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([O-])=[O:29])=[C:26](CC)[CH:25]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:8][CH3:9].C(OCC)(=O)C.Cl>C1COCC1>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][C:24]3[CH:32]=[CH:31][C:27]([CH2:28][OH:29])=[CH:26][CH:25]=3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C(=O)[O-])c(CC)c3)CC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(CO)cc3)CC2)cc1

Procedure:
Under cooled condition with ice, 1.6 g of lithium aluminum hydride was added little by little to 100 ml of THF and stirred. A liquid mixture of 16.2 g of the 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)ethylbenzoate mentioned above in 200 ml of THF was added dropwise thereto. It was stirred as it was cooled with ice for 2 hours, and then 200 ml of ethyl acetate was added dropwise thereto. The reaction solution was added to 200 ml of dilute hydrochloric acid cooled with ice and extracted with 200 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 10.1 g of 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.O[NH:12][C:13](=[NH:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[C:14]([C:13]1[N:18]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[O:9][N:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)C(=N)NO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1noc(-c2ccc(Cl)nc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3.8 g (21.5 mmol) of 6-chloropyridine-3-carbonyl chloride in 100 mL of toluene, in Dean-stark apparatus, are added portionwise 2.5 g (21.5 mmol) N-hydroxy-2,2-dimethylpropanimidamide, and the reaction medium is stirred for 2 hours at room temperature and then heated for 2 hours. After cooling to room temperature, the medium is concentrated under reduced pressure and purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 10% EtOAc. 4.1 g of 5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-chloropyridine are obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45].[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid (519 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The crude product (492 mg) was used directly in the next step without further purification.
Reaction SMILES: [O:1]([CH2:19][CH:20]([CH3:51])[CH2:21][CH2:22][CH2:23][C:24]([CH3:50])([O:46][CH2:47][S:48][CH3:49])[C:25](=[O:45])[CH2:26][CH2:27][C:28]1([O:44][CH2:43][CH2:42][O:41]1)[CH2:29][O:30][S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[O:1]([CH2:19][CH:20]([CH3:51])[CH2:21][CH2:22][CH2:23][C:24]([CH3:50])([O:46][CH2:47][S:48][CH3:49])[CH:25]([OH:45])[CH2:26][CH2:27][C:28]1([O:44][CH2:43][CH2:42][O:41]1)[CH2:29][O:30][S:31]([C:34]1[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=1)(=[O:32])=[O:33])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CSCOC(C)(CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CCC1(COS(=O)(=O)c2ccc(C)cc2)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSCOC(C)(CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(O)CCC1(COS(=O)(=O)c2ccc(C)cc2)OCCO1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
11-t-Butyldiphenylsiloxy-6,10-dimethyl-2,2-ethylenedioxy-6-methylthiomethoxy-5-oxo-1-tosyloxyundecane (0.493 g) in methanol (30 ml) is cooled to 0° C.; sodium borohydride (0.438 g) is added and the resulting solution is stirred for 2 hours. The solvent is removed in vacuo and the residue is neutralized to pH 7 with aqueous hydrochloric acid and extracted with ether. The ether extract is washed with brine and dried over sodium sulfate. The solvent is removed in vacuo to give 11-t-butyldipheylsiloxy-6,10-dimethyl-2,2-ethylenedioxy-5-hydroxy-6-methylthiomethoxy-1-tosyloxyundecane (0.481 g) as an epimeric mixture of alcohols. The alcohols are separated by chromatography on silica employing ethyl acetate:hexane as the eluting solvent. The epimers have the following nmr spectra:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].O>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:16](=[O:17])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(OCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Methylphenol (5.4g; 0.05 m) and potassium carbonate (6.9g; excess) were mixed in dry acetone (40 ml.) phenacyl bromide (9.95 g.; 0.05 m) was added and the mixture was boiled under reflux with vigorous stirring for 4 hours. The mixture was cooled to room temperature, poured into iced water extracted with ether, washed with dilute sodium hydroxide solution water, dried and evaporated. The crude product was recrystallised from ethanol to give the title compound, m.p. 65° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[S:21](Cl)(=[O:23])=[O:22])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:21]([C:17]1[S:18][CH:19]=[CH:20][C:16]=1[S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:23])=[O:22]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1Sc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2sccc2Sc2ccccc2)c1Br
Yield: 83 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-(phenylthio)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 using 5-amino-4-bromo-3-methylisoxazole (192 mg, 1.1 mmol) and 3-phenylthiothiophene-2-sulfonyl chloride (300 mg, 1.0 mmol). Purification by column chromatography using 10% MeOH/CHCl3 yielded 358 mg (83%) of the pure sulfonamide as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:10].[H-].[Na+]>N1C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:22])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:10]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: Clc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)CSc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-bromo chlorobenzene (1.92 g, 10 mmol), (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), sodium hydride (460 mg, 10 mmol) and copper(u) chloride (500 mg) was refluxed in anhydrous pyridine (50 ml) for 12 hrs. The reaction mixture was carefilfly quenched with ice cold water and acidified with concentrated HCl. The product was extracted with choroform, washed well with water; dried and concentrated The product was purified by silica gel column chromatography by eluting with 30% ethyl acetate:hexane. Yield 2.5 g (77%); Colorless low melting solid; MS: 323 (M+H)+. Alternatively the title compound may be prepared from 4-(4-chloro-phenoxy)-benzenethiol and bromo ethyl acetate as described in example 83.
Reaction SMILES: ClC1C=C(C=CC=1Cl)C([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=O.[CH3:30][O:31][C:32]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:30][O:31][C:32]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:33]=1[C:34]([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:9]1)=[O:36]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 3′ (40 mg), 2-methoxy-4-nitro-benzoic acid (47 mg), triethylamine (0.07 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg) in dry tetrahydrofuran (3 ml) was stirred at 20° C. for 18 h under a nitrogen atmosphere. The mixture was then partitioned between potassium carbonate solution and dichloromethane. The organic phase was passed through a hydrophobic frit and evaporated. The residue was purified on a silica gel SPE cartridge. Elution with dichloromethane, then with dichloromethane:ethanol: 0.880 ammonia; 400 then 200:8:1 gave an oil which was triturated with diethyl ether giving the title compound as a colourless solid (51 mg).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([CH2:16][CH3:17])[C@H:13]([NH:18]C(OC(C)(C)C)=O)[CH2:12]1)=O)C1C=CC=CC=1.F[C:27]1[C:36](C)=[C:35]2[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]2[C@@H:38]2[CH2:40][C@@H:39]2[F:41])=[CH:29][CH:28]=1.C(N(CC)CC)C>[C].[Pd].CO>[NH2:18][C@H:13]1[C@@H:14]([CH2:16][CH3:17])[CH2:15][N:11]([C:9]2[C:36]([CH3:27])=[C:35]3[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]3[C@@H:38]3[CH2:40][C@@H:39]3[F:41])=[CH:29][CH:28]=2)[CH2:12]1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(c2ccc3c(=O)c(C(=O)O)cn([C@@H]4C[C@@H]4F)c3c2C)C[C@H]1N
Temperature: 65 °C
Reaction time: 192 h
Yield: 50.1 %

Procedure:
A 10% palladium carbon catalyst (27 mg) was added to a solution of (3S,4S)-1-(benzyloxycarbonyl)-3-(tert-butoxycarbonylamino)-4-ethylpyrrolidine (270 mg, 775 μmol) in methanol (7.75 mL), and the resultant mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dimethyl sulfoxide (3 mL), and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (216 mg, 775 μmol) and triethylamine (130 μL, 930 μmol) were added to the solution, followed by stirring in an oil bath at 65° C. for 8 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The solution was washed sequentially with a 10% aqueous citric acid solution (30 mL), water (30 mL×2), and saturated brine (30 mL), followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Subsequently, concentrated hydrochloric acid (2 mL) was added to the obtained residue at room temperature, and the resultant mixture was transferred to a separatory funnel with water (20 mL), followed by washing by chloroform (30 mL×2). The pH of the obtained aqueous layer was adjusted to 12.0 with a 10 mol/L aqueous sodium hydroxide solution under cooling with ice. The pH was adjusted again to 7.4, and the resultant mixture was extracted with chloroform (100 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized from hot ethanol, and dried under reduced pressure, to thereby yield the title compound as pale yellow crystals (145 mg, 50.1%).
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:35][C:36](=[O:42])[NH:37][CH2:38][C:39](Cl)=[O:40])=[NH:34])=[CH:28][CH:27]=1>CN(C)C=O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:35][C:36](=[O:42])[NH:37][CH2:38][C:39]([NH:1][CH:2]2[C:15](=[O:16])[N:4]3[CH:5]([C:10]4[NH:11][N:12]=[N:13][N:14]=4)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]23)=[O:40])=[NH:34])=[CH:30][CH:31]=1
Reactant: N=C(Cc1ccc(Cl)cc1)NC(=O)NCC(=O)Cl
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)CNC(=O)NC(=N)Cc3ccc(Cl)cc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 1 h

Procedure:
To a stirred solution of 480 mg. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 404 mg. of triethylamine, in 6 ml. of N,N-dimethylformamide, is added 650 mg. of 2-(3-[2-(p-chlorophenyl)acetimidoyl]ureido)acetyl chloride hydrochloride. Stirring is continued for 1 hour, and then the reaction mixture is filtered. The filtrate is added to 300 ml. of ether, and the solid which precipitates is filtered off. The solid is washed thoroughly with methylene chloride, and dried, giving 585 mg. of the title compound, m.p. 150°-162° C. IR spectrum (Nujol mull): 1780 cm-1 (β-lactam). NMR spectrum (DMSO-d6): 8.90 ppm (d, 1H), 8.00-7.20 ppm (m, 8H), 5.80-5.20 ppm (m, 3H), 4.10-3.60 ppm (m, 4H), 1.65 ppm (s, 3H), 1.10 ppm (s, 3H).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25](O)=[O:26])=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:43]([O:42][C:40]([N:47]1[CH2:48][CH2:49][N:50]([C:25]([C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[N:23][C:24]=3[C:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:16]3[C:30](=[O:31])[N:29]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)[CH2:28][C:17]=23)=[O:26])[CH2:51][CH2:52]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
Carboxylic acid 213 (0.015 g, 0.029 mmol) was dissolved in 0.8 mL of dimethylformamide. To this was added BOC-piperazine (0.0116 g, 0.058 mmol), triethylamine (0.012 mL, 0.087 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.011 g, 0.058 mmol), 1-Hydroxybenzotriazole hydrate (0.0059 g, 0.0435 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Dilute with dichloromethane, washed with 1M HCl solution, saturated brine solution, dried (Na2SO4), concentrated to give crude product. Chromatographed (10 to 50% ethyl acetate/hexanes) to give 4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester 229 (0.009 g, 0.013 mmol, 45%.) 1H NMR (CDCl3) 9.075 (s, 1H), 8.15 (s, 1H), 8.03 (d, 1H), 7.74 (dd, 4H), 7.53 (dd, 1H), 7.27 (m, 8H), 7.04 (dd, 2H), 4.91 (d, J=17 Hz, 1H), 4.69 (d, J=17 Hz, 1H), 4.41 (d, J=17 Hz, 1H), 4.055 (d, J=17 Hz, 1H), 3.55-2.96 (br m, 8H), 1.44 (s, 9H.) MS: 687 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=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:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:23][CH3:24])[CH:20]([CH3:21])[CH3:22]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: CCC(NC(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure I' above and using 4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' 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:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)#[N:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:26][CH:27]=1)#[N:2]
Reactant: COC(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Methyl 4-[5-(4-cyanophenoxy)-pentoxy]-3-methoxybenzoate (3600 g, 9.74 mol) is dissolved in tetrahydrofuran (36 L) with warming to 30° C. The solution is then cooled to 20° C. and a solution of tetrabutylammonium hydroxide (40% in water, 7.1 L, 1.64 m) is added over 20 minutes. The reaction mixture is then stirred at an internal temperature of 25° C. for 7 hours and overnight at room temperature (23° C.). After cooling to 10° C. with an ice bath, hydrochloric acid (1.0N, 14.4 L) is added over 1 hour. After stirring and cooling to 10° C. for three hours, the product is filtered, washed with water (24 L) and dried in vacuo (76° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid, mp 159°-161° C. HPLC indicates 99.1% purity. A second crop of acid is obtained from the filtrates after diluting further with water (20 L). The product is filtered, washed with water (4×3 L) and dried in vacuo to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid, mp 158°-160° C., (HPLC indicates 98.3% purity).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:27]=[C:25]([C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[O:26][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: COc1ccc(C(N)=O)cc1
Product: COc1ccc(-c2nc(-c3cc(Br)ccc3OCC(=O)O)co2)cc1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 4-methoxybenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.61 min, m/z 404 [M+H]+.