Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([NH:22][C:23]([CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[C:38]([O:45][C@@H:46]3[O:72][C@H:71]([CH2:73][O:74][C:75](=[O:80])[C:76]([CH3:79])([CH3:78])[CH3:77])[C@@H:63]([O:64][C:65](=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67])[C@H:55]([O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C@H:47]3[O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])=[N:39][NH:40]4)=[CH:30][CH:29]=2)=[O:24])([CH3:21])[CH3:20])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:82][C:83]([NH2:85])=[O:84].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([NH:22][C:23]([CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[C:38]([O:45][C@@H:46]3[O:72][C@H:71]([CH2:73][O:74][C:75](=[O:80])[C:76]([CH3:79])([CH3:78])[CH3:77])[C@@H:63]([O:64][C:65](=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67])[C@H:55]([O:56][C:57](=[O:62])[C:58]([CH3:59])([CH3:60])[CH3:61])[C@H:47]3[O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])=[N:39][N:40]4[CH2:82][C:83](=[O:84])[NH2:85])=[CH:32][CH:33]=2)=[O:24])([CH3:20])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(C#Cc4ccc(/C=C/CC(=O)NC(C)(C)C(=O)N5CCN(C(=O)OCc6ccccc6)CC5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2nn(CC(N)=O)c3cccc(C#Cc4ccc(/C=C/CC(=O)NC(C)(C)C(=O)N5CCN(C(=O)OCc6ccccc6)CC5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Yield: 70.3 %

Procedure:
To a solution of 4-[2-(4-{(E)-3-[1-{[4-(benzyloxy-carbonyl)piperazin-1-yl]carbonyl}-1-(methyl)ethyl-carbamoyl]prop-1-enyl}phenyl)ethynyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (73 mg) in acetone (4 mL) were added 2-bromoacetoamide (18 mg), cesium carbonate (54 mg) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=40/1-30/1) to give 4-[2-(4-{(E)-3-[1-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]prop-1-enyl}-phenyl)ethynyl]-1-carbamoylmethyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (54 mg). The title compound (10 mg) was prepared in a similar manner to that described in Example 109 using this material as the starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[NH4+].[Cl-].[N-:27]=[N+]=[N-].[Na+]>CO>[NH2:27][C:16]1[C:17](=[O:18])[C:10]2[O:9][C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=3)=[C:12]([CH3:13])[C:11]=2[C:14](=[O:22])[C:15]=1[CH2:19][CH2:20][CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC1=CC(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC1=C(N)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O

Procedure:
To a solution of 2-(4-methoxybenzyl)-3-methyl-5-propyl-4,7-benzofurandione (from Preparation 28) (295 mg, 0.91 mmol) in MeOH (3 mL) were added NH4Cl (109 mg) and NaN3 (130 mg). The mixture was heated to reflux for 4 hours and the solvent was then removed in vacuo. Water was added and the product was extracted into CH2Cl2 and chromatographed on silica gel (15% EtOAc/hexane) to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3](=[O:10])[CH2:2][S:15][C:12]([CH3:14])([CH3:13])[CH3:11])[CH3:9]
Reactant: CC(C)(C)S
Reactant: CCOC(=O)CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CSC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-chloroacetoacetate (7.5 mL, 51.9 mmol), 2-methyl-2-propanethiol (5.6 mL, 49.7 mmol), triethylamine (10.8 mL, 77.4 mmol), and catalytic tetrabutylammonium bromide were dissolved in THF (250 mL) and stirred at room temperature overnight. Silica gel was added, and the mixture was concentrated and filtered over a plug of silica gel to obtain the desired product (B-1), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:9][C:8]2=[O:25])=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>C(O)C>[CH3:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:9][C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1cc(=O)n(Cc2ccc(C)cc2)c2ccc(C)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)O)c3cc(C)ccc32)cc1

Procedure:
A solution of ethyl α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionate (0.1 g.) in ethanol (2.0 ml.), containing potassium hydroxide (0.07 g.) and water (0.2 ml.), was heated under reflux for 2 hours. The ethanol was then removed in vacuo and the residue was dissolved in water (10 ml.). The solution obtained was acidified, by addition of 5N-hydrochloric acid, to give a creamy solid, which was separated by filtration, washed with water and air dried to give α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionic acid, 0.08 g., m.p. 188°-190° C., (m.p. 193°-194° C., after recrystallisation from ethanol).
Reaction SMILES: C[O-].[K+].CO.CO.[NH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].[CH2:14](Cl)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>COCCOCCOC>[CH2:14]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCCN1
Reactant: CCCCCCCCCl
Agent: C[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOCCOC
Product: CCCCCCCCN1CCCC1=O
Reaction time: 6 h

Procedure:
230 g of a 31.98 wt. % strength potassium methoxide-methanol solution (1.05 mol) is added dropwise at about 155° C., while distilling methanol to a solution of 85.2 g of 2-pyrrolidone (butyrolactam, 1.0 mol) in 500 ml of diethylene glycol dimethyl ether. For complete removal of all the methanol, the clear solution is evacuated for a short period until reaching 500 mbar. 156 g of n-octyl chloride (1.05 mol) is then metered in likewise at 155° C. over a period of 20 minutes, and the reaction is brought to completion over a period of another 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[O:4].C(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1CCCC1=O
Reactant: OCc1ccccc1
Product: O=C1CCCC1C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 50 g. of methyl-2-oxocylopentanecarboxylate and 50 g. of redistilled benzyl alcohol was heated at 160° C. under a stream of nitrogen in a 500 ml. flask for 20 hours. Methanol distilled off as it was formed. The reaction mixture was subsequently cooled and the mixture distilled on the kugelrohr apparatus. The benzyl alcohol was removed by heating to 120° C. at 2 mm and the benzyl ester collected at 130° C. Yield was 45 g. (59%).
Reaction SMILES: [C:1]([CH2:4][C@H:5]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(O)=[O:2].C1C=CC2N(O)N=[N:34][C:32]=2C=1.C(Cl)CCl.CCN(CC)CC.CN.C1COCC1>CN(C=O)C.O>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:7]([NH:6][C@@H:5]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])[CH2:4][C:1](=[O:2])[NH:34][CH3:32])=[O:18]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C(=O)N[C@H](CC(=O)O)c2cccc(C(=O)O)c2)cc1OC
Agent: CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)C[C@@H](NC(=O)c1ccc(OC)c(OC)c1)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 158.4 %

Procedure:
To a solution of 3-[(R)-2-carboxy-1-(3,4-dimethoxy-benzoylamino)-ethyl]benzoic acid (100 mg, 0.268 mmol), HOBt (42 mg, 0.295 mmol), and EDC (58 mg, 0.295 mmol) in DMF (2 mL) add Et3N (0.149 mL, 1.072 mmol). Stir this at room temperature for 2 h, then add 2 M methylamine in THF solution (1.34 mL, 2.68 mmol) and stir the solution at room temperature for 24 h. Dilute the reaction with water (1 mL) and quench with conc. HCl (a few drops). Extract with EtOAc (3×50 mL), wash the organics with water (50 mL) and brine (50 mL) and dry (Na2SO4) and concentrate to a residue in vacuo then dry under P2O5. Triturate the solid in MeOH/EtOAc and filter off the inorganic salts. Concentrate the filtrate and dry in vacuo to a residue. Triturate this in EtOAc/hexane to give 164 mg of 3-[(R)-1-(3,4-dimethoxy-benzoylamino)-2-methylcarbamoyl-ethyl]-benzoic acid as a hydroscopic solid.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[CH:14])[N:8]=1.[CH3:15][C:16]([CH3:18])=[O:17]>O1CCCC1>[Br:6][C:7]1[N:8]=[C:9]([C:13]#[C:14][C:16]([CH3:18])([OH:17])[CH3:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)=O
Reactant: C#Cc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.6 mL of 1.6M in hexanes, 0.96 mmol) was added to a cooled (−78° C.) solution of 2-bromo-6-ethynylpyridine (150 mg, 0.82 mmol) in tetrahydrofuran (4.1 mL). A tan slurry formed. The mixture was stirred for 30 minutes while warming to −30° C. at which time acetone (0.3 mL, 4.1 mmol) was added. The slurry dissolved to form a light orange solution. The reaction was stirred for an additional 2 hours while warming to 0° C. The reaction was quenched via the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo and purified via flash chromatography (0-50% ethyl acetate/hexanes) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]12[CH:17]([CH3:18])[CH:15]3[NH:16][C:12]4=[C:13]([CH2:14]3)[C:8](=[C:9]1[CH2:10][CH2:11]4)[CH:7]=[CH:6][CH2:5][N:4]=[CH:3]2.CN(C)C=O.C(N(C(C)C)CC)(C)C.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>C(OCC)(=O)C.O>[CH:33]1([CH2:36][N:16]2[C:12]3[CH2:11][CH2:10][C:9]4[C:2]5([CH3:1])[CH:17]([CH3:18])[CH:15]2[CH2:14][C:13]=3[C:8]=4[CH:7]=[CH:6][CH2:5][N:4]=[CH:3]5)[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of 3.22 g of 1,2,3,4,5,6-hexahydro-6,12-dimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 58 ml of dimethylformamide was added 4.70 ml of diisopropylethyl amine and then 1.56 ml of cyclopropylmethyl bromide, under nitrogen. The reaction mixture was warmed in an oil bath at 70°-80° C. for 1.5 hr and stirred at room temperature overnight. The reaction mixture was poured into water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/0-10% methanol/ethyl acetate) gave 2.48 g (63%) of product. Sublimation (173°-175° C., ~0.3 mm) gave the analytical sample, mp 187°-190° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1
Reactant: O=C1CCCN1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Nc1cc(N2CCCC2=O)cc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
Into a 16 by 100 mm vial sparged with argon was added 3-amino-5-bromobenzotrifluoride (1 g, 4.16 mmol), 2-pyrrolidinone (425 mg, 5 mmol), N,N′-dimethylethylenediamine (37 mg, 0.416 mmol), potassium carbonate (1.15 g, 8.33 mmol), copper(1)iodide (80 mg, 0.416 mmol), and toluene (1 mL). Vial capped, heated with stirring at 85° C. for 24 h. Reaction cooled to RT, solvent removed under reduced pressure, reconstituted in DCM and filtered through silica. Affords a gray solid. MS m/z=245 [M+H]+. Calc'd for C11H11F3N2O: 244.2
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1cccc(F)c1Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cccc(F)c1Cl

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (5.32 mL, 30.9 mmol), pyridine (3.33 mL, 41.2 mmol) and 2-chloro-3-fluoroaniline (3.00 g, 20.61 mmol) over 7 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2-chloro-3-fluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=274.0 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[C:23](OCC)(=[O:25])[CH3:24].C(OC(=O)C)(=O)C>C1CCCCC1>[C:23]([NH:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:25])[CH3:24]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: C1CCCCC1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 27.5 °C
Reaction time: 6 h

Procedure:
To a solution of (2R)-2-Amino-N-benzyl-3-methoxypropanamide (60.0 gms) and triethylamine (7.29 gms) in cyclohexane (600 ml) charged ethyl acetate (540 ml) and added acetic anhydride (35.29 gms) slowly maintaining the temperature at 25-30° C. in 15-20 minutes. Raised the temperature of the reaction mass to 35-40° C. and maintained for 4 hours. After completion of the reaction the reaction mass was cooled to 0 to 5° C. within 1 hour and maintained for 1.5 hours. Filtered the reaction mass at 0-5° C. and washed with cooled 1:1 mixture of ethyl acetate: cyclohexane (2×120 ml). The wet solid was taken in diethyl ether (612 ml) and stirred for 6 hours at 20-25° C. Filtered the product (2R)-2-acetamido-N-benzyl-3-methoxypropanamide and washed with diethyl ether and dried at 50-55° C. till constant weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]([O:22]C)(=[O:21])[C:18]([CH3:20])=[O:19]>ClC1C=CC=CC=1Cl>[OH:19][C:18]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)([CH3:20])[C:17]([OH:22])=[O:21]
Reactant: COc1ccc2ccccc2c1
Reactant: COC(=O)C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: COc1ccc2cc(C(C)(O)C(=O)O)ccc2c1
Yield: 32.5 %

Procedure:
In 20 ml of o-dichlorobenzene were placed 1.58 g of 2-methoxynaphthalene and 2.93 g of anhydrous aluminum chloride. By dissolving 2.04 g of methyl pyruvate in 5 ml of o-dichlorobenzene, the solution was added dropwise to the above mixture at 7° to 11° C. over 13 minutes while stirring. After stirring the mixture for further 30 minutes, ice-cold water was added thereto and the o-dichlorobenzene layer was separated. After washing with water, the o-dichlorobenzene layer was dried over anhydrous magnesium sulfate. By removing o-dichlorobenzene under reduced pressure, the residue was subjected to the same procedure as in Example 3 to give 0.80 g of 2-hydroxy-2-(6-methoxy-2-naphthyl)propionic acid. Yield: 33%.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C([O-])(O)=O.[Na+]>[CH3:16][C:3]1([CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:26][CH2:27]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1ccc(CCC2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CCc3ccccc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 42.5 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.5 g), 4-(2-phenylethyl)piperidine (2.0 g), and triethylamine (5.3 g) was stirred under argon gas at 180° C. for 15 hours. After cooling, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1) and recrystallized from diisopropyl ether to provide 0.88 g of the title compound. Yield 42%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]=[CH:10][CH2:11][NH2:12]>>[CH3:8][CH:9]=[CH:10][CH2:11][NH:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: CC=CCN
Product: CC=CCNc1ccncc1
Temperature: 130 °C
Yield: 74.9 %

Procedure:
Silane 1a was prepared by first preparing and then hydrosilating 4-(N-methylallylamino)pyridine with diethoxy(methyl)silane, (EtO)2MeSiH. The 4-(N-methylallylamino)pyridine was first obtained by reaction of 4-chloropyridine and N-methylallylamine. Thus, 4-chloropyridine (11.4 g; 0.1 mol) and N-methylallylamine (7.1 g; 0.1 mol) were combined in a glass ampoule or steel container, after which the mixture was degassed under vacuum and the vessel was sealed. The vessel was heated for three days at 130° C. The vessel was thereafter opened and the contents were dissolved in water and then neutralized with 10% aqueous NaOH. The aqueous solution was extracted with several portions of diethyl ether. The ether extract was filtered and evaporated. The residue was distilled under vacuum to give 4-(N-methylallylamino)pyridine (11.1 g; 75%; b.p. 70° C. @ 0.1 torr). 4-(N-Methylallylamino)pyridine (4.45 g; 0.030 mol), MeSiH(OR)2 (6.7 g; 0.050 mol) and H2PtCl6 (60 μL; 0.080 mol/L in i-PrOH; 4.6×10-6 mol) were combined and heated under vacuum in a sealed vessel for 10 hours at 130° C. Distillation of the products gave Silane 1a, N-(3-(diethoxy(methyl)silyl)propyl)-N-methyl-4-aminopyridine, as a colorless liquid (6.3 g; 74%; b.p. 122-127° C. @ 0.05 torr). The product was characterized by elemental analysis, infrared, 1H and 13C--NMR spectroscopy, and gas chromatography-mass spectrometry.
Reaction SMILES: O1CCCCC1C[C:8](=[O:37])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][CH:10]1[CH:30]([C:34]([OH:36])=[O:35])[C:31]([OH:33])=[O:32].[C:38](OC(=O)C)(=[O:40])C>>[OH:28][C@H:24]1[CH2:25][C@@:26]2([CH3:27])[C@@H:12]([CH2:11][CH:10]([CH:30]([C:34]([OH:36])=[O:35])[C:31]([OH:33])=[O:32])[C@@H:9]2[C:8](=[O:37])[CH2:38][OH:40])[C@H:13]2[C@H:23]1[C@:21]1([CH3:22])[C:16]([CH2:15][CH2:14]2)=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]1
Reactant: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC(C(C(=O)O)C(=O)O)[C@@H]2C(=O)CC1CCCCO1
Reactant: CC(=O)OC(C)=O
Product: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC(C(C(=O)O)C(=O)O)[C@@H]2C(=O)CO

Procedure:
The process of claim 12 which additionally comprises reacting (IX) with acetic anhydride to produce (X) 21-acetoxy-16α-methoxycarbonyl-11β-hydroxy-3,20-dioxo-1,4-pregnadiene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:30]2
Reactant: Nc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 20 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 5-aminoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 47 mg of the target compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:15]1[CH2:16][CH2:17][CH:13]([OH:12])[CH2:14]1
Reactant: OC1CCNC1
Reactant: FC(F)(F)c1ccccc1Br
Product: OC1CCN(c2ccccc2C(F)(F)F)C1
Yield: 67 %

Procedure:
The title compound (3.72 g, yield 67%) was obtained from 2-(trifluoromethyl)phenyl bromide and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]([CH:9]([N:17]1[CH2:20][CH:19]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:8].[Br:32]Br.C(OCC)(=O)C>O1CCOCC1>[CH3:5][O:6][C:7]([CH:9]([N:17]1[CH2:20][CH:19]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([Br:32])[CH:15]=1)=[O:8]
Reactant: BrBr
Reactant: COC(=O)C(c1ccc(O)cc1)N1CC(NC(=O)Cc2ccccc2)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(c1ccc(O)c(Br)c1)N1CC(NC(=O)Cc2ccccc2)C1=O
Yield: 8.1 %

Procedure:
Chloroform (1.5 ml.) was added to a solution of 1-(α-methoxycarbonyl-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone (184 mg.) dissolved in dioxane (2 ml.), and a chloroform (0.5 ml.) solution containing bromine (184 mg.) was added dropwise to said mixture in 5 minutes under ice-cooling. After addition of ethyl acetate (80 ml.) to said reaction mixture, the ethyl acetate layer was separated out, washed with water and dried over anhydrous magnesium sulfate. This solution was concentrated, and the residue was dissolved in a small amount of acetone. The solution was subjected to preparative thin layer chromatography using silica.gel [developing solvent; a mixture of chloroform and methanol (5:0.3)] for isolation and purification. The product thus obtained was recrystallized from a mixture of ethyl acetate and acetone to give 1-(α-methoxycarbonyl-3-bromo-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone (18 mg.). Mp 151° to 153° C. (dec.).