Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:10]2[C:5](=[CH:6][CH2:7][CH2:8][C@H:9]2[CH2:11][OH:12])[CH2:4][CH2:3][CH2:2]1.CN(C=O)C.N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>O>[C:23]([Si:27]([O:12][CH2:11][C@H:9]1[C@@H:10]2[C:5]([CH2:4][CH2:3][CH2:2][O:1]2)=[CH:6][CH2:7][CH2:8]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: OC[C@@H]1CCC=C2CCCO[C@@H]21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1CCC=C2CCCO[C@@H]21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 360 mg (8S,8aR)-3,4,6,7,8,8a-hexahydro-2H-chromen-8-ylmethanol added 2.2 mL DMF, then 224 mg imidazole followed by 0.66 mL tert-butyl(chloro)diphenylsilane. The reaction was stirred overnight at RT, then added to water and extracted with diethyl ether. The crude extract was dried over Na2SO4, filtered, concentrated, then purified on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ=1.05 (s, 9H), 1.37-1.46 (m, 1H), 1.54-1.58 (m, 1H), 1.63-1.73 (m, 2H), 1.86-2.09 (m, 3H), 2.16-2.24 (m, 1H), 2.25-2.31 (m, 1H), 3.53 (m, 1H), 3.60 (dd, J1=9.8 Hz, J2=7.7 Hz, 1H), 3.80 (d, J=5.1 Hz, 1H), 3.90 (dd, 10.0 Hz, J2=7.4 Hz, 1H), 3.94-3.98 (m, 1H), 4.49-5.52 (m, 1H), 7.35-7.42 (m, 6H), 7.67-7.72 (m, 4H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]([O:29]C)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of methyl 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate (1.91 g, 4 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added 1N sodium hydroxide (8 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-isopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.67 g, 90.3%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[C:9]([N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13]O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS([Cl:37])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[C:9]([N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13][Cl:37])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of (R)-tert-butyl(1-(benzyl(2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2.80 g, 8.0 mmol) in CH2Cl2 (20 mL) were added Et3N (1.60 g, 16 mmol) and MsCl (1.40 g, 12.0 mmol) dropwise at −10° C. under N2. The mixture was stirred at rt overnight. The mixture was quenched with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered, concentrated to afford (R)-tert-butyl(1-(benzyl(2-chloroethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3.0 g, 100% yield) as a yellow solid, which was used for the next step without further purification. LC-MS m/z 369.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.37-7.28 (m, 3H), 7.22-7.20 (m, 2H), 5.27-5.18 (m, 1H), 4.93-4.86 (m, 1H), 4.64-4.39 (m, 2H), 3.85-3.66 (m, 2H), 3.61-3.39 (m, 2H), 2.03-1.97 (m, 1H), 1.45 (s, 9H), 0.98 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C@@H:27]([CH2:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]1=[O:39])[CH2:20]2.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][N:2]1[C:6]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH2:40][C:41]2[CH:42]=[C:43]([F:48])[CH:44]=[C:45]([F:47])[CH:46]=2)[CH2:28][N:29]2[C:30](=[O:39])[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]2=[O:38])[CH2:20]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cc(F)cc(F)c1)N1Cc2cc(Br)ccc2C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cc(F)cc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.557 g, 2.68 mmol), bis(tri-t-butylphosphine)palladium (0.114 g, 0.223 mmol), 2-[(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1, 3(2H)-dione (1.05 g, 2.06 mmol) and N,N-diisopropylethylamine (1.16 mL, 6.69 mmol) in 1,4-dioxane (12 mL, 150 mmol) and water (0.60 mL, 33 mmol) was stirred under microwave at 110° C. for 15 minutes. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (30-100%) to give 0.72 g (68.4% yield) of the desired product. LCMS found: 513.1 (M+H)+.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[CH2:9]([C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2[C:23](O)=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].C(OCC)(=O)C>CC(C)=O>[CH2:9]([C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2[C:23]([O:4][CH3:1])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ccc(Cc2ncccc2O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCCc1ccc(Cc2ncccc2OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.2 %

Procedure:
Potassium carbonate (33.0 mg, 0.239 mmol) and methyl iodide (14.9 μl, 0.239 mmol) were added to a solution of the compound of Example B230 (19.2 mg, 0.0796 mmol) in acetone (1 ml), and this reaction mixture was stirred at room temperature for 3 hours. After ethyl acetate was added, the reaction mixture was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.47 mg).
Reaction SMILES: [N+:1]([C:4](O)=[O:5])([O-])=O.Cl.CN(C)CCCN=C=NCC.[OH2:19].[OH:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2N=N1>CN(C=O)C.ClCCl>[N+:21]([C:25]1[CH:24]=[CH:29][C:28]([C:4]([NH2:1])=[O:5])=[CH:27][CH:26]=1)([O-:20])=[O:19]
Reactant: On1nnc2ccccc21
Reactant: O
Reactant: O=C(O)[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of nitrocarboxylic acid (NB-2 or NB-3; 1.2 equivalents), amine (A13, A14 or A16; 1.1 equivalents), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 equivalents), and 1-hydroxybenzotriazole hydrate (1.2 equivalents) in DMF (0.79 M) was stirred at room temperature for 4 hours. The mixture was diluted with dichloromethane (100 mL) and washed with aqueous saturated sodium bicarbonate solution (50 mL). The aqueous layer was re-extracted with dichloromethane (2×50 mL) and the combined organic solution was dried (Na2SO4), filtered and evaporated under reduced pressure. The crude mixture was purified on silica gel column to provide the 4-nitrobenzamide (NB-2-A13, NB-2-A14 or NB-3-A16).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[C:18]([CH3:34])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22](C)([CH2:29]C(O)=O)[CH2:21][CH2:20]2.[F:35][C:36]1[CH:55]=[CH:54][C:39]([CH:40]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[CH:38][CH:37]=1.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:16][C:17]1[C:18]([CH3:34])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][CH:22]([CH3:29])[CH2:21][CH2:20]2.[C:17]([CH:50]1[CH2:49][N:48]([CH:40]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[C:39]2[CH:54]=[CH:55][C:36]([F:35])=[CH:37][CH:38]=2)[CH2:53][CH2:52][NH:51]1)(=[O:16])[CH3:26]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(=O)C1CN(C(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.3 %

Procedure:
A solution of dicyclohexyl carbodiimide (Aldrich, 3.55 g, 17.23 mmol) in methylene chloride (50 mL) was added dropwise to a slurry comprised of 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid (4.14 g, 15.66 mmol), 4,4'-difluorobenzhydryl piperazine (Schweizerhall, 4.51 g, 15.66 mmol), and 1-hydroxybenzotriazole hydrate (Aldrich, 2.33 g, 17.23 mmol) in methylene chloride (150 mL) which was cooled by an ice/water bath. After the addition was complete, the reaction mixture was allowed to come to ambient temperature and was stirred at ambient temperature for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed (flash, silica gel, 95:5 methylene chloride/methanol) to give an oil which crystallized from a mixture of ethyl acetate and hexane. The solid was crystallized from ethanol to give 3.67 g (43.8% yield) of the desired product as a white solid.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH:12]=[CH:13][C:14]=1[CH2:15]O.C([N:38](CC)CC)C.N>C1COCC1>[CH2:15]1[C:14]2[C:9](=[CH:10][C:11]([NH:17][C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:38]1
Reactant: CCN(CC)CC
Reactant: O=C(Nc1ccc(CO)c(CCO)c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (0.085 mL) was added to a 0° C. solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide (214 mg, 0.51 mmol) and triethylamine (0.18 mL) in THF (8.5 mL). TLC showed complete reaction after 30 min. The contents were cooled to -78° C., excess ammonia was added, and the contents were stirred for 18 hrs at 25° C. The solvents were removed under vacuum, methylene chloride (10 mL) and aqueous 1N HCl were added and the contents were stirred for 1 hr. The phases were separated and the aqueous phase was rendered alkaline with aqueous sodium hydroxide to a pH of 12. The organic phase was extracted with methylene chloride (4×10 mL), the solvent removed under vacuum to give a white solid (108 mg) which was chromatographed on silica eluting with 5% methanol/methylene chloride with 0.5% ammonium hydroxide. The product was obtained as a white solid (40 mg, 20%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:32](=[O:33])[CH2:31][C:28]1[CH:29]=[CH:30][N:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccn(-c2ccc(F)cc2)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccn(-c2ccc(F)cc2)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of (S)-(-)-4-benzyl-2-oxazolidinone (710 mg, 4 mmol) in dry THF (10 mL) at -78° C. was added n-butyllithium (2.5 mL of 1.6 M in hexanes). In a separate reaction vessel, to a solution of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid (920 mg, 4.2 mmol) and triethylamine (0.7 mL, 5 mmol) in dry THF (20 mL) at -78° C. was added dropwise pivaloyl chloride (0.5 mL, 4 mmol). After stirring at -78° to 0° C. over 1 hour, then recooling to -78° C., the above solution was added via cannula. The resultant mixture was allowed to warm to ambient temperature over 17 hours, then partitioned with EtOAc and aqueous NH4Cl. The separated aqueousueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to an oil, which was purified via flash column chromatography with 15-20% EtOAc/hex gradient eluant. The oily product crystallized from benzene to give 1.04 g (69%) of 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-ethanone as a solid, mp 106-8° C. 1H NMR: δ 7.36-7.25 (m, 5H), 7.17-7.07 (m, 4H), 7.04 (s, 1H), 6.98 (t, 1H, J=2.6 Hz), 6.35 (dd, 1H, J=1.8, 2.6 Hz), 4.72-4.67 (m, 1H), 4.28-4.14 (m, 4H), 3.28 (dd, 1H, J=3.3, 3.6 Hz), 2.79 (dd, 1H, J=9.4, 13.4 Hz). Anal. Calculated for C22H19N2O3F: C, 69.83; H, 5.06; N, 7.40. Found: C, 69.80; H, 5.07; N, 7.30.
Reaction SMILES: [CH:1]([Mg]Br)=[CH:2][CH2:3][CH3:4].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([CH2:14][CH2:15][CH:16]=[O:17])[CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH3:19][O:18][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][C:12]=1[CH2:14][CH2:15][CH:16]([OH:17])[CH2:1][CH:2]=[CH:3][CH3:4]
Reactant: CCC=C[Mg]Br
Reactant: COc1ccc(F)cc1CCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=CCC(O)CCc1cc(F)ccc1OC
Yield: 172.5 %

Procedure:
To a solution of 1-butenylmagnesium bromide (0.5 M in THF, 18 mL, 9.0 mmol) at 0° C. was added a solution of 3-(5′-fluoro-2′-methoxyphenyl)propionaldehyde (3.0 g, 16.5 mmol) in THF (30 mL) dropwise for 15 min. The reaction mixture was poured into a solution of saturated ammonium chloride (80 mL) in a separatory funnel. The organic function was extracted with ethyl acetate (3×80 mL) and the combined organic layers were washed with brine (80 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by a flash column chromatography (15% EtOAc in hexane, Rf=0.20) to give the product as an oil (3.7 g, 94%).
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@H](CO)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[OH:2][CH2:1][C@@H:32]1[CH2:31][CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@@H:33]1[C@H:34]1[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7α-Hydroxymethylandrostane-3,17-dione II-av was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7α-hydroxymethyl-androstane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (I-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.71 (2H, m), 3.30 (1H, t), 2.50-1.25 (21H, m), 1.12 (3H, s), 0.85 (3H, s).
Reaction SMILES: [CH2:1]=[C:2]1[C@H:6]([CH2:7][OH:8])[C@@H:5]([OH:9])[CH2:4][C@@H:3]1[N:10]1[C:14]2[N:15]=[C:16]([NH2:20])[NH:17][C:18](=[O:19])[C:13]=2[N:12]=[CH:11]1.C(O)(C(F)(F)F)=[O:22]>>[CH2:1]=[C:2]1[C@H:6]([CH2:7][OH:8])[C@@H:5]([OH:9])[CH2:4][C@@H:3]1[N:10]1[C:14]2[NH:15][C:16]([NH2:20])=[N:17][C:18](=[O:19])[C:13]=2[N:12]=[CH:11]1.[OH2:22]
Reactant: O=C(O)C(F)(F)F
Reactant: C=C1[C@H](CO)[C@@H](O)C[C@@H]1n1cnc2c(=O)[nH]c(N)nc21
Product: C=C1[C@H](CO)[C@@H](O)C[C@@H]1n1cnc2c(=O)nc(N)[nH]c21
Product: O

Procedure:
Finally, M6 (e.g., ethylidene protection) was converted to entecavir with high reactivity in the presence of aqueous TFA solution or other aqueous organic/inorganic acid solutions. After purification, the desired entecavir monohydrate was obtained with high quality in high yield. The use of crystalline intermediates within our synthetic process for entecavir allows the manufacture of high quality API since the quality can be controlled at the various intermediates. This reaction may be carried out at 70° C. for about 1 hour. Two steps, namely, neutralization (e.g., using TFA) and extraction, may be needed in making entecavir monohydrate from M6. The yield is relatively high (e.g., 70%). The purification of entecavir monohydrate may be conducted through crystallization from water and methanol. In contrast, in BMS′ process, three steps are needed to make entecavir monohydrate from BMS′s compound 57, which corresponds to M6 of the present application, and the yield is relatively low (32.4%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][N:14]([CH3:25])[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH2:41][CH:42]([O:45][CH3:46])[O:43][CH3:44])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]([CH2:41][CH:42]([O:45][CH3:46])[O:43][CH3:44])[C:1]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][N:14]([CH3:25])[CH3:13])=[CH:19][CH:20]=2)=[O:2])=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(CNc1ccc(OCc2ccccc2)cc1)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCOc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COC(CN(C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCc2ccccc2)cc1)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Carbonyldiimidazole (2.7 g) was added to a solution of 4-(2-dimethylaminoethoxy)phenylamine (3.01 g) in dimethylformamide (40 mL) cooled in ice. After 30 minutes, (4-benzyloxyphenyl)-(2,2-dimethoxyethyl)amine (4.8 g) was added, and the mixture was heated at 80° C. for 30 minutes. After cooling, volatiles were removed and the residue was purified by MPLC (eluent: heptane/ethyl acetate 9:1). The product with the molecular weight of 493.61 (C28H35N3O5); MS (ESI): 494 ([M+H]+), was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[Cl:21])([CH3:11])[C:9]#[N:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=2)([CH3:11])[C:9]#[N:10])=[C:13]([Cl:21])[CH:14]=1
Reactant: [H][H]
Reactant: CC(C#N)(c1ccc(Cl)c(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: CC(C#N)(c1ccc(Cl)c(C(F)(F)F)c1)c1ccc(N)cc1Cl

Procedure:
A mixture of 31.1 parts of 4-chloro-α-(2-chloro-4-nitrophenyl)-α-methyl-3-(trifluoromethyl)benzeneacetonitrile, 2 parts of a solution of thiophene in methanol 4% and 480 parts of methanol was hydrogenated in the Parr apparatus at 50° C. with 3 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off, washed with tetrahydrofuran and the filtrate was evaporated in vacuo. The residue was crystallized from 160 parts of 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 23.7 parts (82.4%) of (4-amino-2-chloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-α-methylbenzeneacetonitrile; mp. 180.4° C. (intermediate 26).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][N:9]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccn(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccn(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
To a solution of 1-benzyloxy-1H-pyrrole-3-carbaldehyde described in Preparation Example 63 (500 mg, 2.5 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (75 mg, 1.97 mmol), and the solution was stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction solution, which was then partitioned, silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification by silica gel column chromatography (hexane:ethyl acetate=2:1) was carried out, and the title compound (168 mg, 0.828 mmol, 33.1%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28]([O:30]CC)=O)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][NH2:34]>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[N:14][CH:13]=[C:12]([CH:11]=2)[C:16]([N:18]=[S:19]([CH2:27][C:28]([NH:34][CH3:33])=[O:30])(=[O:20])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Product: CNC(=O)CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 90.2 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (50 mg, 0.11 mmol) and methylamine (2.0 M solution in MeOH, 0.5 mL, 1.0 mmol) were reacted to give the title compound as colorless oil (43 mg, 90%).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([CH3:14])=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1>>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([CH3:14])=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)N=C(C)N2
Agent: Cl
Product: CC1=NS(=O)(=O)c2cc(O)ccc2N1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
HCl (20 g) is heated to 210° C. and 5 g of 7-methoxy-3-methyl-4H-1,2,4-benzothiadiazine-1, 1-dioxide are added. This mixture was kept at about 210° C. for about 11/2 hours. The mixture was then cooled slightly and about 60 ml of ice cold water was added with stirring. This mixture was filtered and the solid washed with 25 ml. of cold water and dried yielding 3.5 g of 7-hydroxy-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (A). An additional 0.63 g of A was recovered from the filtrate to allowing it to stand in the refrigerator for about one hour. Total yield of this product was 4.13 g (88%), m.p. 333°-336° C. (dec.). ##STR12##