Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.[OH-].[Na+].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>O1CCCC1.CN(C)C=O>[O:19]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=2)[N:15]1[CH2:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C=CC(=O)OCC
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CCN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 4 h
Yield: 58 %

Procedure:
To a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one, prepared as described above (90 mg, 0.31 mmol) in anhydrous tetrahydrofuran (3 mL) was added at room temperature 20-40 mesh beads of sodium hydroxide (48 mg, 1.20 mmol) and ethyl acrylate (1.200 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 4 hours under an atmosphere of dry N2, followed by addition of a second portion of sodium hydroxide (96 mg, 2.40 mmol). The reaction was followed by LCMS and stirring was continued until all of the starting material had disappeared. Solvent was removed from the reaction mixture under reduced pressure, diluted with ethyl acetate (20 mL), and aqueous Na2SO3 (10 mL) added. The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase successively washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent gave a crude mixture that was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford ethyl 3-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate (65 mg, 0.18 mmol, 58%). LCMS mz 364.0 (M+H), 386.0 (M+Na), anal HPLC>99% in purity. 1H NMR (400 MHz; CD3CN) δ7.87 (d, J=8.2 Hz, 2H); 7.81 (d, J=8.6 Hz, 2H); 7.66 (d, J=2.3 Hz, 1H); 7.63 (m, 1H); 7.26 (d, J=8.6 Hz, 1H); 4.25 (m, 2H); 3.02 (m, 2H); 2.67 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: ClCCCOC1CCCCO1
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCCOC1CCCCO1)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H, 2.98 g, 0.017 mole), 2-(3-chloro-propoxy)-tetrahydro-pyran (Compound 18a) (6.0 g, 0.034 mole), and potassium carbonate (10.0 g, 0.0725 mole) were stirred in 50 mL of DMF at 80° C. overnight under Argon. The reaction mixture was then diluted with 200 mL of ethyl acetate and washed 3 times with water. After drying over sodium sulfate, the solvent was removed in vacuo. The crude material solidified on standing to yield the title compound, 6-Methoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one. MS m/z 309 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([CH2:8][CH3:9])[CH2:6][OH:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([CH2:8][CH3:9])[CH2:6][O:7][S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CC[C@H](CO)Cc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](COS(C)(=O)=O)Cc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
A flask was charged with 7.2 g (36 mmol) of (S)-2-(2,4-difluoro-benzyl)-butan-1-ol and 30 mL of dichloromethane, and the solution was cooled to 0° C. To this solution was added 7.53 mL (54 mmol) of triethylamine, and the mixture was stirred cold for 5 minutes. Then 3.1 mL (39.6 mmol) of methane sulfonyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The dichloromethane was removed under reduced pressure, and the residue was partitioned between 1 N HCl aq. and diethyl ether. The ether layer was collected and washed with sat. aq. sodium bicarbonate, water, and brine. The ether layer was dried over sodium sulfate, filtered, and the ether was removed under reduced pressure. This procedure gave 9.54 g (95% yield) of (2S)-methanesulfonic acid 2-(2,4-difluoro-benzyl)-butyl ester as an orange oil. This material was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[F:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([OH:30])[CH2:27][N:26]3C(OC(C)(C)C)=O)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([OH:30])[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:38]=[CH:39][C:11]([F:10])=[CH:12][CH:13]=3)=[CH:21][CH:20]=2)=[O:24])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)Cn1cncn1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](O)CN1C(=O)Cn1cncn1

Procedure:
Proceeding as in Reference 11, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid and (2S,4R)-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate, gave (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH3:7]
Reactant: C1COCCN1
Reactant: CCOC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCOC(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N1CCOCC1

Procedure:
The compound was synthesized as in Example 17 from Intermediate 11 (4.0 g, 10.8 mmol) and morpholine (2.1 g, 24 mmol). This gave 0.91 g (22%) of pure product.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:11]=[C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[O:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:21]([CH:23]1[O:25][CH2:24]1)Br>>[C:3]([C:7]1[CH:11]=[C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:23]2[O:25][CH2:24]2)[O:9][N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCC1CO1
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2O)on1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cc(C=Cc2ccccc2OCC2CO2)on1

Procedure:
This is prepared, using the method described in Example VI, from 3.8 g of 55% strength sodium hydride (0.086 mole), 21 g (0.086 mole) of 3-tert.-butyl-5-(2-hydroxystyryl)-isoxazole and 11.8 g (0.086 mole) of epibromohydrin. 25.0 g (97% of theory) of a colorless oil are obtained.
Reaction SMILES: COC(=O)C(N1C(=O)CCN(C(=O)/C=C/C2C=CC=C([Cl:26])C=2)CC1)CC(O)=O.CCN(CC)CC.[CH2:36]1[C:38]2([CH2:43][CH2:42][NH:41][CH2:40][C@H:39]2[OH:44])[CH2:37]1>>[ClH:26].[CH2:37]1[C:38]2([CH2:43][CH2:42][NH:41][CH2:40][C@H:39]2[OH:44])[CH2:36]1
Reactant: COC(=O)C(CC(=O)O)N1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Agent: O[C@@H]1CNCCC12CC2
Solvent: CCN(CC)CC
Product: Cl

Procedure:
In analogy to the procedure described in example 6A, 2-{4-[(E)-3-(3-chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-succinic acid 1-methyl ester (intermediate 8) with 1.1 eq. of Et3N (added before cooling) and 1.05 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave, after purification on a SiO2-column (dichloromethane/MeOH 98:2-95:5), the titled compound in 76% yield as white foam. MS: 518.3 (MH+, 1Cl).
Reaction SMILES: Br.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Br:13])=[CH:5][C:4]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+]>C1COCC1>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Br:13])=[CH:5][C:4]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cc(Br)c2ccccc2c1N
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1c(C(=O)O)cc(Br)c2ccccc12
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 1-amino-4-bromo-2-naphthoate hydrobromide (2.00 g, 5.54 mmol) in 20 mL of THF was added sodium hydroxide (11.1 mL, 20% aqueous, 55.4 mmol). The mixture was stirred at 50° C. for 20 h, then heated at 90° C. for 2 h. The solvent was removed in vacuo and hydrochloric acid (1 N aqueous) was added until pH ˜2. The beige solid was collected via filtration, washed twice with water, and dried to provide 1-amino-4-bromo-2-naphthoic acid that gave a mass ion (ES+) of 266.0 (79Br) for [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[C:23]=[O:24]>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:23]([NH:22][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[CH3:33])=[O:24])[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: COc1ccc(N=C=O)c(C)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)NC2N=C(c3ccccc3)c3cc(Cl)ccc3N(C)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-7-chloro-5-phenyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 1) (0.299 g, 1 mmol) in dichloromethane (15 ml) was added 1-isocyanato-4-methoxy-2-methyl-benzene (0.163 g, 1 mmol). The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0.197 g, 42%). 1H-NMR (CDCl3): δ 7.57-7.48 (m, 3H), 7.47-7.44 (m, 1H), 7.39-7.38 (m, 3H), 7.36-7.29 (m, 2H), 6.77-6.73 (m, 2H), 6.71 (d, J=2.8 Hz, 1H), 6.61 (s, 1H), 5.51 (d, J=8.4 Hz, 1H), 3.78 (s, 3H), 3.39 (s, 3H) and 2.29 (s, 3H). MS (ESI) (M+H)+=463.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH2:7]1)=[O:5])C.[ClH:26]>C(O)(=O)C>[ClH:26].[ClH:26].[NH2:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCON2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Solvent: CC(=O)O
Product: NOCCN1CCC[C@@H](C(=O)O)C1
Temperature: 80 °C

Procedure:
A mixture of the above ester (3.3 g, 10 mmol), acetic acid (7 ml) and concentrated hydrochloric acid (4.2 ml) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to 5° C., filtered and the filterpad washed with cold acetic acid (2×2 ml). The solvent was evaporated from the filtrate in vacuo and the residue was dissolved in warm absolute ethanol (10 ml) and left for crystallisation. The precipitate was collected and dried in vacuo to give 1.1 g of (R)-1-(2-((amino)oxy)ethyl)-3-piperidinecarboxylic acid dihydrochloride.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([S:43][CH:44]([CH2:73][N:74]1[CH2:79][CH2:78][S:77](=[O:81])(=[O:80])[CH2:76][CH2:75]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=2[NH:63][S:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=1)(=[O:66])=[O:65])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.O>[O:80]=[S:77]1(=[O:81])[CH2:76][CH2:75][N:74]([CH2:73][CH:44]2[S:43][C:47]([C:49]3[NH:50][C:51]4[C:56]([CH:57]=3)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=4[NH:63][S:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=3)(=[O:66])=[O:65])=[N:46][CH2:45]2)[CH2:79][CH2:78]1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCS(=O)(=O)CC3)SCc3ccccc3)cc2c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CSc1ccccc1
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)(=O)CC4)S3)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.2 %

Procedure:
A mixture of trifluoromethanesulfonic anhydride (100 mg), triphenylphosphine oxide (95 mg) and dichloromethane (5 mL) was stirred at 0° C. for 10 min. A solution of N-[2-(benzylthio)-3-(1,1-dioxidothiomorpholino)propyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (210 mg) and thioanisole (80 mg) in dichloromethane (40 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred for 2 hr under ice-cooling. The reaction mixture was added dropwise to a mixture of trifluoromethanesulfonic anhydride (100 mg), triphenylphosphine oxide (95 mg) and dichloromethane (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:3-5:95, volume ratio) to give the title compound (80 mg, yield 44%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 218-219° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[N:16]([CH3:21])[N:17]=[C:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[CH3:21][N:16]1[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:27]=[N:26][C:25]([CH3:24])=[CH:30][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])=[CH:19][C:18]([CH3:20])=[N:17]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Cc1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)n(C)n1
Product: Cc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cc(C)nn2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate C, 50 mg, 0.135 mmol) and 2-methylpyridine-5-boronic acid (Frontier Scientific, Logan, USA, 28 mg, 0.181 mmol) to give the title compound as a red solid. (HPLC: tR 2.20 min (Method A); M+H=385 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.02 (s, 1H), 8.62-8.52 (m, 1H), 8.17-8.08 (m, 1H), 8.00-7.91 (m, 1H), 7.81-7.73 (m, 1H), 7.39-7.32 (m, 1H), 7.13 (s, 1H), 6.52 (s, 1H), 3.62 (s, 3H), 3.51 (s, 3H), 2.55-2.45 (3H), 2.29 (s, 3H))
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.Cl.CO.[CH3:18]COC(C)=O>COC(OC)(C)C>[CH3:18][O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cl
Solvent: CO
Solvent: COC(C)(C)OC
Product: COC(=O)c1ccc2cc(O)ccc2c1
Reaction time: 16 h

Procedure:
Treat a mixture of 6-hydroxy-2-naphthoic acid (4.45 g, 23.6 mmol) in 2,2-dimethoxypropane (235 mL) with conc. HCl (24 mL) and then MeOH (60 mL). Stir the reaction at RT for 16 h and then at 55° C. for 16 h. Pour the reaction mixture into EtOAc (250 mL) and wash with brine (3×100 mL). Dry the organic layer over Na2SO4, concentrate the filtrate, and chromatograph the concentrated filtrate (0.5 kg silica gel, 5:95 to 15:85 EtOAc:hex) to give the title compound (4.77 g, quant). MS (ES) m/e 203 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][C:19]([C:12]1[N:13]([CH3:18])[C:14]2[C:10]([CH:11]=1)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=2)=[O:21])[CH3:23]
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: CCN
Product: CCNC(=O)c1cc2c(O)cccc2n1C

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and ethylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=219.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:25])[O:24][CH2:23][CH2:22][CH2:21]1>>[OH:25][CH2:20][CH2:21][CH2:22][C:23]([NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:24]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCCO
Temperature: 150 °C
Reaction time: 2 h

Procedure:
In a glass reaction vessel, 13.5 grams of octadecylamine were admixed with 4.3 grams of butyrolactone. The mixture was then heated to 150° C. by means of an oil bath until the reaction was complete in a period of 2 hours. A conversion of greater than 95% based on butyrolactone was achieved. Upon cooling to room temperature, the product formed a white to pale yellow, hard, waxy solid. Substantially all of the butyrolactone was reacted indicating greater than 95% conversion.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:23]1[CH2:27][CH2:26][N:25]([N:28]=CC3C=CC=CC=3)[C:24]1=[O:36])([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.[N+](C1C=C([N+]([O-])=O)C=CC=1NN)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].[Cl-].[Na+]>O.CO.C(Cl)Cl>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:23]1[CH2:27][CH2:26][N:25]([NH2:28])[C:24]1=[O:36])([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:11])[CH2:6]2
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N)C3=O)S[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
In a mixed solvent consisting of 200 ml of methylene chloride and 70 ml of methanol was dissolved 13.2 g of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. Thereto were added 10.3 g of 2,4-dinitrophenylhydrazine and 9.83 g of p-toluenesulfonic acid monohydrate in this order. The mixture was stirred at room temperature for 1.5 hours. The insolubles were removed by filtration. The insolubles were washed with a mixed solvent consisting of 60 ml of methylene chloride and 20 ml of methanol. The washings and the filtrate obtained previously were combined, and mixed with 50 ml of water. The aqueous layer was separated. The organic layer was mixed with 30 ml of water and adjusted to pH 1.2 with 6N hydrochloric acid. The aqueous layer was separated. This aqueous layer and the aqueous layer obtained previously were combined and adjusted to pH 7 with sodium hydrogencarbonate. Thereto was added sodium chloride to saturation. Then, the aqueous layer was extracted with 150 ml of methylene chloride. The aqueous layer was further extracted 7 times each with 50 ml of methylene chloride. The extracts were combined with the organic layer obtained previously, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=50/1 to 15/1) to obtain 8.93 g (yield: 81.8%) of (3R, 5R,6R)-6-amino-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=2)[C:12](=[O:28])[C:11]([CH3:30])([CH3:29])[CH2:10]1>N1C=CC=CC=1>[CH3:29][C:11]1([CH3:30])[C:12](=[O:28])[C:13]2[C:18](=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:9]([N:8]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH2:10]1
Reactant: CC1(C)CN(N)c2cc(S(=O)(=O)c3ccccc3)ccc2C1=O
Reactant: O=C(Cl)CCCCl
Solvent: c1ccncc1
Product: CC1(C)CN(N2CCCC2=O)c2cc(S(=O)(=O)c3ccccc3)ccc2C1=O
Temperature: 0 °C
Yield: 41 %

Procedure:
While stirring under chilling with ice water, 220 μl of chlorobutyryl chloride were added to a solution of 550 mg of 1-amino-2,3-dihydro-3,3-dimethyl-7-phenylsulfonyl-4(1H)-quinolinone in pyridine. After stirring overnight at room temperature, the liquid reaction mixture was extracted with chloroform with the system acidified with hydrochloric acid. After the extract was dried over magnesium sulfate, chloroform was distilled off. The residue was dissolved in dimethylformamide, and 91 mg of sodium hydride were added to the solution under chilling with ice water to stir the resultant mixture at room temperature for 30 minutes. After completion of the reaction, ice water was added to the liquid reaction mixture, which was then extracted with diethyl ether. After the extract was dried over magnesium sulfate, diethyl ether was distilled off, and the residue was purified by column chromatography on silica gel to obtain 249 mg (yield: 41%) of the title compound as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](O)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].CCCP(=O)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:19]([C:15]2[C:16]3[C:11](=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[O:20])=[CH:32][C:31]=1[C:37]([F:38])([F:39])[F:40]
Reactant: Nc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reaction time: 1 h

Procedure:
To a suspension of 2.58 g (9.2 mMol) 6-(2-amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid in 50 ml DMF, 12.8 ml (92 mMol) Et3N, 490 mg (4.0 mMol) DMAP, 1.41 ml (11 mMol) 4-fluoro-3-trifluoromethyl-aniline and finally 11 ml propylphosphonic anhydride (50% in DMF; 19 mMol) are added. The mixture is stirred for 1 h and then concentrated in vacuo. The residue is diluted with water and EtOAc, the aq. phase is separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/EtOAc 2:1→1:1→1:2) and re-crystallization from CH3CN gives the title compound: m.p.: 205° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]=1[O:24]S(C(F)(F)F)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C)ccc2c1O
Reaction time: 1 h

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(3,6-dimethyl-1-(trifluoromethyl-sulfonyloxy) naphthalen-2-yl)acetate (1.8 g, 3.9 mmol) in THF (18.2 mL) pre-cooled to −10° C. was treated dropwise with tetrabutylammonium fluoride (1M in THF, 7.8 mL, 7.8 mmol). After 1 hour, saturated NaHCO3 was added and the mixture stirred for 20 minutes. Following extraction of the aqueous layer with EtOAc, the combined organics were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification via Yamazen silica gel column chromatography afforded (S)-ethyl 2-tert-butoxy-2-(1-hydroxy-3,6-dimethylnaphthalen-2-yl)acetate. LCMS-ESI− (m/z): [M−H]− calcd for C20H25O4: 329.4. found: 329.1.