Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3([C:14](=[O:15])[C:13]([CH2:17][O:18][CH3:19])([CH3:16])[O:12][C:11]3([CH3:21])[CH3:20])[O:9]2)=[C:4]([CH2:22][CH3:23])[CH:3]=1.BrC1C=CC(C2C3(C(=O)C(C)(C)OC3(COC)C)O2)=C(CC)C=1.S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10](=[O:9])[C:11]([CH3:21])([CH3:20])[O:12][C:13]([CH2:17][O:18][CH3:19])([CH3:16])[C:14]2=[O:15])=[C:4]([CH2:22][CH3:23])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C1OC12C(=O)C(C)(COC)OC2(C)C
Agent: CCc1cc(Br)ccc1C1OC12C(=O)C(C)(C)OC2(C)COC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC(C)(COC)C1=O
Temperature: 7.5 °C
Reaction time: 0.92 h

Procedure:
To an ice cold solution of a mixture of 2-(4-bromo-2-ethylphenyl)-6-methoxymethyl-4,4,6-trimethyl-1,5-dioxaspiro[2.4]heptan-7-one and 2-(4-bromo-2-ethylphenyl)-4-methoxymethyl-4,6,6-trimethyl-1,5-dioxaspiro[2.4]heptan-7-one (5 g, 0.013 mol) in dichloromethane (2.5 ml) is added concentrated sulphuric acid (15 ml), dropwise over 50-60 minutes, maintaining the temperature of the reaction mixture at 5-10° C. The reaction mixture is maintained at 5-10° C. for 10-15 minutes, quenched into crushed ice (75 g) and extracted with dichloromethane (3×50 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2-methoxymethyl-2,6,6-trimethylpyran-3,5-dione (1.82 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[O:5])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1(C(=O)OCC)c2cc(OC)ccc2NC1C=CC(=O)OC
Product: CCOC(=O)C1(C(=O)OCC)c2cc(OC)ccc2N(C(C)=O)C1C=CC(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude indoline 9 was dissolved in acetic anhydride (35 ml). This solution was stirred for 1 h at room temperature. Thereupon the acetic anhydride was removed in vacuo. The residue (~27 g) was sufficiently pure for further conversions. A sample of this residue was purified by flash column chromatography (SiO2, CH2Cl2 /acetone 95/5). A pale yellow oily product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[C:5](=[O:15])[C:6](=[O:14])[NH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[C:5](=[O:15])[C:6](=[O:14])[N:7]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]
Reactant: COCCOCCBr
Reactant: COc1ccc(OC)c2c1NC(=O)C2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOCCN1C(=O)C(=O)c2c(OC)ccc(OC)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 4,7-dimethoxy-1H-indole-2,3-dione (1.8 g, 8.7 mmol) in anhydroud N,N-dimethylformamide (20 mL) and anhydrous tetrahydrofuran (120 mL) at ambient temperature was added cesium carbonate (11.4 g, 35.0 mmol), The mixture was stirred at ambient temperature for 30 min and 1-bromo-2-(2-methoxyethoxy)ethane (2.35 mL, 17.4 mmol) was added in one portion. The mixture was stirred at ambient temperature for 16 h, concentrated in vacuo to a small volume and poured into ice water (300 mL). The mixture was extracted with ethyl acetate and the combined organic extracts were filtered through a pad of diatomaceous earth. The filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Trituration of the residue in hexanes afforded 4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1H-indole-2,3-dione (2.2 g, 82%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)=O>CO.[Pd]>[N:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O=CO
Product: CS(=O)(=O)Nc1ccccc1N1CCNCC1
Yield: 57.1 %

Procedure:
A solution of the product of N-[2-(4-benzylpiperazin-1-yl)phenyl]methanesulfonamide (2.83 g, 8.2 mmol) in methanol (40 mL) was purged with nitrogen (0.25 hour). Ammonium formate (1.55 g, 24.6 mmol), formic acid (0.31 mL, 8.21 mmol) and palladium on activated charcoal (0.5 g) were added. The mixture was heated at reflux for 2 h., cooled, filtered, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with aqueous potassium carbonate (saturated, 3×). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow crystalline solid (1.196 g, 57%), δH (250 MHz, CDCl3) 7.52 (1H, dd, J 1.6, 8.0 Hz), 7.23-7.05 (4H, m), 3.06 (3H, s), 3.06-3.02 (4H, m), 2.85-2.78 (4H, m), and 1.80 (1H, br s).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:41])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH2:36][CH3:37])([CH2:34]C)[CH2:32][CH3:33])[NH:17][CH:16]2[C:38](O)=[O:39])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:47][C@@H:46]([CH2:48][CH2:49][NH2:50])[CH2:45][O:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:47][C@H:46]([CH2:45][OH:44])[CH2:48][CH2:49][NH:50][C:38]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:41])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH2:32][CH3:33])([CH3:34])[CH2:36][CH3:37])[NH:17]1)=[O:39]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CCC(CC)(CC)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(CC)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 51.5 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 106c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.43 g, 3 mmol), HATU (0.67 g, 1.8 mmol) and iPr2NEt (0.86 mL, 4.9 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 53%).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.57 g, 2.9 mmol) and sodium methoxide (0.18 g, 2.9 mmol) were added. The mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue thus obtained was extracted with dichloromethane (50 ml×3). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was crystallized from dichloromethane-diethyl ether to give the title compound (0.37 g, 1.6 mmol, yield: 61%) as colorless needles.
Reaction SMILES: [NH2:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[S:15][CH:14]=[N:13][C:12]=3[CH3:16])[CH2:7][S:8][C@H:3]12.[C:31]([NH:50][C:51]1[S:52][CH:53]=[C:54]([C:56](=[N:60][O:61][CH3:62])[C:57](O)=[O:58])[N:55]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:17]([C:5]2[N:4]3[C:29](=[O:30])[CH:2]([NH:1][C:57](=[O:58])[C:56](=[N:60][O:61][CH3:62])[C:54]4[N:55]=[C:51]([NH:50][C:31]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[S:52][CH:53]=4)[C@H:3]3[S:8][CH2:7][C:6]=2[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[N:13][C:12]=2[CH3:16])=[O:18])=[CH:26][CH:25]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3scnc3C)CS[C@@H]3C(N)C(=O)N23)cc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 72 %

Procedure:
p-Methoxybenzyl 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylate (trans-isomer) as prepared by the method of Reference Example 2 as above and 2-(tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid (syn-isomer) were reacted with each other and the reaction product was processed in the same manner as in Example 1 to give the titled compound in a yield of 72%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH2:8][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN2CCNCC2)cc(C(C)(C)C)c1

Procedure:
Synthesized according to General Procedure A: 3,5-di-tert-butylbenzyl bromide (4{22}, 5 g, 17.7 mmol, 1 equiv.), piperazine (9.1 g, 105.9 mmol, 6 equiv.), THF (38.7 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{22} (4.15 g, 82%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.31 (t, 1H, J=2.0 Hz), 7.15 (d, 2H, J=2.0 Hz), 3.51 (s, 2H), 2.89 (t, 4H, J=5.0 Hz), 2.42 (br s, 4H), 1.73 (br s, 1H), 1.33 (s, 18H). 13C-NMR (125 MHz, CDCl3): δ 150.3, 136.8, 123.3, 120.7, 64.1, 54.3, 46.1, 34.7, 31.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:42])([F:41])[C:22]1[CH:23]=[C:24]([C@@H:32](OC(=N)C(Cl)(Cl)Cl)[CH3:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>C(Cl)Cl>[F:20][C:21]([F:41])([F:42])[C:22]1[CH:23]=[C:24]([C@H:32]([O:19][C@@H:10]2[C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH3:33])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](O)C1
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g (3.8 mmol) (3R,4S) tert-butyl-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (Step B) and 3 g (7.6 mmol, 2 equiv) (S)-trichloroacetimidate (step C) in 40 mL dry heptanes and 10 mL dry methylene chloride under nitrogen atmosphere at 0° C. was added dropwise 0.092 mL (0.8 mmol, 0.2 equiv) HBF4-dimethyl ether complex. The resulting reaction mixture was stirred at 0° C. for 24 hr. The volatiles were removed under vacuum and the residue dissolved in 10 mL methylene chloride and purified by column chromatography on silica gel eluting with hexanes/EtOAc (8/2) to afford a mixture of two products. This mixture was further purified by preparative HPLC on ChiralPak OD column eluting with heptanes/ethanol (98/2) to obtain the minor isomer (epimeric at the benzylic methyl position) and the title compound. 1H-NMR (CDCl3): (rotamers): δ: 1.43-45 (2d, 3H, 6.5 Hz), 1.49-1.52 (2s, 9H), 3.3-3.5 (m, 3H), 3.73-3.97 (m, 3H), 4.53 (q, 1H, 6.5 Hz), 7.06-7.09 (m, 2H), 7.20-7.25 (m, 3H), 7.55 (m, 2H), 7.74 (s, 1H), 7.75 (s, 2H)ppm. MS: 447.9 (M-t-Bu)+ observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]3[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1.[Br:21]Br>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Br:21][C:12]1[N:7]2[C:8]([S:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=32)=[N:10][C:11]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)sc1nc(-c3ccccc3)c(Br)n12
Yield: 78 %

Procedure:
While stirring vigorously a mixture of a solution of 2.0 g of 7-methoxy-2-phenylimidazo[2,1-b]benzothiazole in 50 ml of chloroform and 30 ml of a saturated aqueous sodium hydrogencarbonate solution, a solution of 1.2 g of bromine in 5 ml of chloroform was gradually added dropwise to the mixture at room temperature. Thereafter, the chloroform layer was recovered, dried by anhydrous magnesium sulfate, and concentrated under reduced pressure to form a solid material. The solid product was recrystallized from a mixture of toluene and n-hexane to provide 2.0 g of 3-bromo-7-methoxy-2-phenylimidazo[2,1-b]benzothiazole.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:15])=[C:6]([CH:13]=O)[C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:4]1[C:5]([OH:15])=[C:6]([CH2:13][N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)[C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(c(C=O)c1O)OCO2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(CN3CCN(C(=O)OC(C)(C)C)CC3)c1O)OCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of 6-acetyl-5-hydroxybenzo[d][1,3]dioxole-4-carboxaldehyde (0.14 g, 0.67 mmol) in methylene chloride (5.0 mL) was added with N-Boc-piperazine (0.13 g, 0.67 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.14 g, 0.67 mmol). After completion of the addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with methylene chloride, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (2:1→3:7)) to obtain tert-butyl 4-[(6-acetyl-5-hydroxybenzo[d][1,3]dioxol-4-yl)methyl]piperazine-1-carboxylate (0.18 g, 71%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(N(CC)CC)C.[CH3:28][CH:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1>[CH3:28][CH:29]([N:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CC(c1ccccc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(c1ccccc1)N1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
5.8 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 3 ml of triethylamine and 4.2 gm of 1-(α-methyl benzyl)-piperazine (R1 = ##STR10## were stirred in 40 ml of dioxane for 2 hours at 80° C. The dark solution was then evaporated in vacuo, and the residue was taken up in chloroform/water and shaken. The organic phase was then clarified with activated charcoal, dried with sodium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH:26]1([CH2:25][CH2:24][C:23]([NH:22][C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[N:4]4)=[O:13])[CH:16]=2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: Cc1ccc(NC(=O)CCC2CCCCC2)cc1N
Product: Cc1ccc(NC(=O)CCC2CCCCC2)cc1NC(=O)c1ccc2nccnc2c1

Procedure:
Using an analogous procedure to that described in Example 5, quinoxaline-6-carboxylic acid was reacted with N-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide to give the title compound; NMR Spectrum: (DMSOd6) 0.76-0.97 (m, 2H), 1.04-1.24 (m, 3H), 1.40-1.78 (m. 8H), 2.2 (s, 3H), 2.28 (t, 2H), 7.17 (d, 1H), 7.39 (d, 1H), 7.69 (s, 1H), 8.22 (d, 1H), 8.44 (d, 1H), 8.74 (s, 1H), 9.05 (m, 2H), 9.84 (s, 1H), 10.25 (s, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[C:20]1([S:26]([O-:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:20]1([S:26]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: O=S([O-])c1ccccc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 43.7 %

Procedure:
Trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (13.0 g, 0.044 mole), sodium benzenesulfinate (7.25 g, 0.044 mole), 4,5-bis(diphenylphosphino-9,9-dimethyl Xanthos (1.1 g, 0.004 mole), tris(dibenzylideneacetone) dipalladium(0) (1.0 g, 0.004 mole), cesium carbonate (5.0 g) and tetrabutylammonium fluoride (5 mL of 1M in THF) were all added to 100 mL toluene, and the reaction mixture was refluxed for four hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, and solvent was removed under reduced pressure. The resulting residue was purified by medium pressure chromatography eluting with methylene chloride to yield 5.5 g of 6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one. Mp: 121° C. MS: 287 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C([O-])(O)=O.[Na+]>C1COCC1>[CH:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:16])([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(C)N1C(=O)NC(C)(c2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)N(C(C)C)C(=O)C1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (t)-3-isopropyl-5-methyl-5-phenyl imidazoline-2,4-dione from Step A (1.0 g, 4.3 mmol) in THF (50 mL) at 0° C. was added NaH (220 mg of a 60% dispersion in oil, 5.6 mmol). After 5 min, methyl bromoacetate (0.69 g, 4.52 mmol) was added and the mixture was stirred for 1 h. The reaction mixture was warmed to ambient temperature and then poured into saturated aqueous NaHCO3 (200 mL) and extracted with EtOAc (2×250 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 50:50, to give racemic title compound. The enantiomers were resolved by HPLC, utilizing a ChiralPak OD column and eluting with hexane:EtOH 60:40. The first major peak to elute was methyl (3-isopropyl-5-methyl-2,4-dioxo-5-phenylimidazolin-1-yl)acetate, isomer A, and the second major peak to elute was methyl (3-isopropyl-5-methyl-2,4-dioxo-5-phenylimidazolin-1-yl)acetate, isomer B, the title compound. MS: m/z=305 (M+1).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:34][O:35][C:36](=O)[O-:37]>C(Cl)Cl>[CH3:34][O:35][C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([NH:9][C:10]2([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:2][CH2:3]1)=[O:37]
Reactant: O=C([O-])OCCl
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
Subsequently, 0.98 ml (2.83 mmol) of the phenylmethyl 1-[N-(piperazine-1-carbonyl)amino]cyclohexanecarboxylate and 0.39 ml (2.83 mmol) of triethylamine were dissolved in 20 ml of anhydrous methylenechloride and then 0.21 ml (2.83 mmol) of chloromethylcarbonate was added to the above prepared mixture and stirred for 12 hours at the room temperature. The reaction solution was successively washed with 1N hydrochloric acid, saturated sodium hydrogen-carbonate solution and saturated brine, and dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 1.12 g of phenylmethyl 1-[N-[4-(methoxycarbonyl)piperazine-1-carbonyl]amino]cyclohexanecarboxylate was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Reactant: OCCN1CCCC1
Solvent: O=S(Cl)Cl
Product: O=C(OCCN1CCCC1)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1

Procedure:
Treatment of 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1 g, Example 33b) with thionyl chloride (10 ml) followed by 1-(2-hydroxyethyl) pyrrolidine (0.43 ml) as described in Example 33c, gave 2-(1-pyrrolidinyl)ethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.7 g). δ (360 MHz, DMSOd6) 1.70 (4H, bs, pyrrolidine-3,4-H), 2.60 (4H, bs, pyrrolidine-2.5-H), 2.88 (2H, t, CH2N), 4.48 (2H, t, CO2CH2), 5.50 (2H, s, OCH2), 7.38 (3H, m, m,p-ArH), 7.58 (2H, d, o-ArH), 7.71 (1H, s, 3-H), 7.86 (1H, d, 6-H) and 8.13 (1H, d, 8-H).