Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[O:35]([CH2:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:43](=[O:44])[CH2:42][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)COc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a cooled (0° C.) mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.7 ml (19 mmol) of triethylamine in 15 ml of CH2Cl2 was added 1.58 g (11.4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered. The filtrate was washed with H2O, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed to give 2.4 g of crude methyl 2-{(4-methoxybenzenesulfonyl)-[2-(phenoxyacetylamino)benzyl]amino}acrylate as an oil. Anal. for C26H26N2O7S: Calc'd: C, 61.2; H, 5.1; N, 5.5; Found: C, 62.6; H, 5.1; N, 4.0.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.CN(C)[CH:22]=[O:23]>C1COCC1>[F:13][C:14]1[N:15]=[CH:16][CH:17]=[CH:18][C:19]=1[CH:22]=[O:23]
Reactant: Fc1ccccn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cccnc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 45.9 %

Procedure:
A solution of n-butyllithium (77 mL, 2.5 M in hexane, 0.19 mol) was added to a solution of N,N-diisopropylamine (27 mL, 0.19 mol) in dry THF (400 mL) under an atmosphere of nitrogen at −78° C. After the addition, the mixture was warmed to 0° C. for 15 minutes and then cooled again to −78° C. 2-Fluoropyridine (15.0 mL, 0.174 mol) was added dropwise to the mixture and stirred at −78° C. After 45 minutes, a pale yellow precipitate formed. N,N-Dimethylformamide (27 mL, 0.35 mol) was added slowly via syringe maintaining temperature below −55° C. After ten minutes, the cooling bath was removed and the mixture slowly warmed to room temperature. The reaction was quenched with NH4Cl/H2O and then 4 M HCl to adjust the pH ˜7. NaHCO3/H2O was then added to adjust the pH 9-10, and then extracted three times with Et2O. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to a yellow oil. The residue was purified by chromatography on silica gel, eluting with 25% EtOAc/hexane to provide 2-fluoronicotinaldehyde as a pale yellow oil (10.0 g, 45%). 1H NMR (CDCl3) δ 10.33 (s, 1H), 8.49 (m, 1H), 8.32 (m, 1H), 7.40 (m, 1H). LC/MS: 126 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[F:13][C:14]([F:27])([F:26])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.S(=O)(=O)(O)O>C(O)C(F)(F)F.O.C([O-])(O)=O.[Na+]>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([N:1]2[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][C:15]([C:14]([F:13])([F:26])[F:27])=[N:2]2)=[N:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)nc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a mixture of the 2-hydrazino-5-(methylsulfonyl)pyridine (456 mg, 2.04 mmol) and 4,4,4-trifluoro-1-phenyl-1,3-butanedione (441 mg, 2.04 mmol) in dry trifluoroethanol (30 ml) was added a catalytic amount of concentrated sulfuric acid (-0.5 ml) and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and diluted with water 50 ml and neutralized with saturated NaHCO3 to PH˜7 and then extracted with EtOAc (50 ml×3). The organic layer was washed with brine (25 ml), dried (MgSO4) and concentrated to give the crude solid. The crude solid was recrystallized in ethanol to provide a desired product as a crystalline white solid (337 mg, 45% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (3.0 g, 19.7 mmole), potassium carbonate (2.8 g, 20.2 mole) and N,N-dimethylformamide (40 mL) was stirred at 70° C. for 2 hours. Benzyl bromide (2.38 mL, 20 mmole) was added and the reaction was maintained for an additional 18 hours. The mixture was cooled to ambient temperature and dissolved into water (400 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated to provide 4.5 g of methyl 4-benzyloxybenzoate as a white powder, m.p. 96°-97° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH2:35][CH2:36][S:37]([CH3:39])=[O:38])=[CH:23][N:22]=3)[C:5]=2[CH3:40])[CH2:3][CH2:2]1.OO.N(C(OCC)=O)=NC(OCC)=[O:46]>O1CCCC1>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH2:35][CH2:36][S:37]([CH3:39])(=[O:46])=[O:38])=[CH:23][N:22]=3)[C:5]=2[CH3:40])[CH2:3][CH2:2]1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Agent: OO
Solvent: C1CCOC1
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)(=O)=O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
100 mg of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-(methylsulfinyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (2-8-1, 0.176 mmol, 1.0 eq.) were suspended in 0.93 mL dry tetrahydrofuran under a nitrogen atmosphere. 90 μL hydrogen peroxide (30%, 0.879 mmol, 5.0 eq.) and 33 μL diethyl azodicarboxylate (0.211 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 50° C. for 2 hours and concentrated in vacuo. The crude product was purified by flashcromatography to provide 31.9 mg (0.05 mmol, 31%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10]2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[CH2:29][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]2([CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:18])[F:19])[CH2:5][CH2:6]2)[CH2:10]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)CN1CCC2(CC1)CNc1ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC2(CCN(CC(F)(F)F)CC2)c2ccccc21

Procedure:
A solution of 1′-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine] from Step A (64.0 mg, 0.237 mmol), potassium carbonate (49.0 mg, 0.355 mmol), potassium iodide (59.0 mg, 0.355 mmol), and tert-butyl bromoacetate (0.042 mL, 0.284 mmol) in DMF (2 mL) was stirred at 50° C. for 1 h. The reaction mixture was quenched with H2O. The aqueous layer was extracted with CH2Cl2 (3×20 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=385 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1>CN1C(=O)CCC1.O>[Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ncccc2Br)cc1
Reactant: Cc1ccc(F)nc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(Nc2ccc(Oc3ncccc3Br)cc2)nc1
Temperature: 170 °C

Procedure:
To a pressure vessel was added 4-(3-bromopyridin-2-yloxy)aniline (7.23 g, 27.3 mmol) and 2-fluoro-5-methylpyridine (3.03 mL, 27.2 mmol) in NMP (13.61 mL) to stir at 170° C. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-bromopyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].O.[OH:17][C:18]1[CH:28]=[CH:27][C:21]([CH:22](O)[C:23](O)=[O:24])=[CH:20][CH:19]=1>C(O)(=O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:23](=[O:24])[CH:22]([C:21]3[CH:27]=[CH:28][C:18]([OH:17])=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(O)cc1
Yield: 56.7 %

Procedure:
A mixture of 103.2 g (0.50 mol) of 2,4-di-tert-butylphenol and 102.4 g (0.55 mol) of 4-hydroxymandelic acid monohydrate in 100 ml of acetic acid is refluxed for 24 hours under a nitrogen atmosphere. The reaction mixture is then diluted with 140 ml of 50% aqueous acetic acid, cooled, and the precipitate formed is filtered off. The residue is washed with another 200 ml of 50% aqueous acetic acid and then dried, giving 95.9 g (57%) of 5,7-di-tert-butyl-3-(4-hydroxyphenyl)benzofuran-2-one, melting point 187°-190° C. (compound (101), Table 1).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:1]([C:5]1[N:6]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25](=[O:27])(=[O:26])[NH:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:35][CH:36]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)[nH]1
Product: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 74 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2,4-dihydro-2-(3-nitrophenyl)-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-1.0% MeOH in CH2Cl2) gave a 74% yield of the title compound as an off-white solid, mp 164°-165° C., homogeneous by TLC (19:1 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 564 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[C:23]1([C:20]2[S:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:15]=[CH:14][C:5]4[CH:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[N:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CC1COc2cc(O)ccc21
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1COc2cc(OCc3csc(-c4ccccc4)n3)ccc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
Methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (200 mg, 0.961 mmol) and 4-(chloromethyl)-2-phenyl-1,3-thiazole (240 mg, 1.14 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (160 mg, 1.16 mmol) was added, and the mixture was stirred at 60-70° C. for 3 hr. Water was added to the reaction mixture, and the mixture was neutralized with 2 M hydrochloric acid. The precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (270 mg, yield 74%) as colorless prism crystals.
Reaction SMILES: [OH:1][C:2]([CH3:17])([C:6]([NH:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:7])[C:3]([OH:5])=O.[NH2:18][C@@H:19]1[C:25](=[O:26])[NH:24][C:23]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=2[O:21][C@@H:20]1[CH:32]1[CH2:34][CH2:33]1>>[CH:32]1([C@@H:20]2[C@H:19]([NH:18][C:3](=[O:5])[C:2]([OH:1])([CH3:17])[C:6]([NH:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:7])[C:25](=[O:26])[NH:24][C:23]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=3[O:21]2)[CH2:34][CH2:33]1
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2cc(F)ccc2O[C@@H]1C1CC1
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2cc(F)ccc2O[C@@H]1C1CC1

Procedure:
N-((6R,7S)-6-Cyclopropyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide was obtained as mixture of epimers according to the procedures described for example 2b using racemic 2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid and (6R,7S)-7-amino-6-cyclopropyl-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one. The epimers were separated by chromatography on Chiralpak AD using isopropanol/heptane 15:85 to yield (−)-N-((6R,7S)-6-cyclopropyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, entity A, MS m/e (%): 484.5 (M+H+, 100), as first eluting fraction, and (−)-N-((6R,7S)-6-cyclopropyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, entity B, as second eluting fraction, MS m/e (%): 484.5 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:19][C@@H:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N[C@H]2CCc3ccccc32)nc(Cl)n1
Yield: 4.8 %

Procedure:
2,4-Dichloro-6-methylpyrimidine (2.54 g, 0.156 mol) was dissolved in ethanol (100 mL) and N,N-Diisopropylethylamine (4.07 mL, 0.23 mol) was added followed by (S)-1-Aminoindan (2.00 mL, 0.156 mol). The solution was heated to reflux for 2 hours, TLC indicated complete conversion. The solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 0 to 50% ethyl acetate in hexane to afford the title compound (1.95 g, 46%). LC/MS: Rt=1.90 min, ES+ 260 (AA standard).
Reaction SMILES: [CH2:1]([CH:4]1[C@@:9]([CH2:20][F:21])([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[F:19])[N:8]=[C:7]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]([CH3:38])([CH3:37])[S:5]1(=[O:40])=[O:39])[CH:2]=[CH2:3].C(=O)(O)[O-:42].[Na+].O=O.[BH4-].[Na+]>C(Cl)Cl.CO>[C:25]([O:24][C:23]([N:22]([C:7]1[C:6]([CH3:38])([CH3:37])[S:5](=[O:39])(=[O:40])[CH:4]([CH2:1][CH2:2][CH2:3][OH:42])[C@@:9]([CH2:20][F:21])([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[F:19])[N:8]=1)[C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CCC1[C@@](CF)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reactant: O=C([O-])O
Agent: O=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)C(CCCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl N-[(3S)-2-allyl-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (1.95 g, 3.33 mmol) in DCM (60 mL) and MeOH (20 mL) was added sodium bicarbonate (0.56 g, 6.65 mmol). The reaction mixture was cooled to −78° C. and ozonolized for about 15 min or until analysis showed no starting material present. A stream of oxygen was passed through the solution for 5 min, and then solid sodium borohydride (252 mg, 6.65 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach RT and stirred for 1 h. The reaction was quenched with satd. aqueous NH4Cl, diluted with water to dissolve solids, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-2-(3-hydroxypropyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate which was taken to next step without further purification. LC/MS (ESI+) m/z=614 (M+Na).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=3[F:19])[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:24][B:23](B2OC(C)(C)C(C)(C)O2)[O:22]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:19][C:12]1[C:13]([F:18])=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[C:3]2[CH:10]=[N:9]1
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)c(F)c1F
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle under N2 was added Intermediate 70A (169.2 mg, 0.451 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (217 mg, 0.855 mmol), potassium acetate (206 mg, 2.099 mmol) and anhydrous DMSO (4.5 mL). The reaction mixture was flushed with argon, then treated with PdCl2(dppf).CH2Cl2 (28.3 mg, 0.039 mmol). The reaction mixture was again flushed with argon, securely capped and heated at 85° C. for 1 h to give complete conversion to the desired product. LC/MS (Condition B): ret. T=3.3 min, (M+H)+ 294.03.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)[C@@H:10]([OH:29])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:45]([Si:49]([CH3:52])([CH3:51])Cl)([CH3:48])([CH3:47])[CH3:46].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:36]=1)[C@@H:10]([O:29][Si:49]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:52])[CH3:51])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.19 g (5.4 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(4-biphenylyl)methyl]hexanoic acid in 55 ml of DMF are silylated, at RT for 20 h and under a protective gas, with 3.71 g (24.6 mmol) of tert-butyldimethylchlorosilane and 3.0 g (44 mmol) of imidazole. The reaction mixture is evaporated and the residue is taken up in ethyl acetate; this solution is then washed with sat. NaHCO3 solution, water and saline. The aqueous phases are extracted 2× with ethyl acetate and the organic phases are dried with Na2SO4 and evaporated. The residue is dissolved in 64 ml of methanol and 15 ml of THF, and this solution is treated with 4.5 g of potassium carbonate and 15 ml of water and stirred at RT for 1 h. Working up in analogy with Example 88c), and medium pressure chromatography (gradient: 0-10% methanol in methylene chloride), results in the title compound: TLC Rf (B)=0.7; tRet (II)=22.7 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]2[C:14]3[NH:13][C:12](=[O:15])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2Br)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)c(Br)c2)S1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356/1998) and 5-[3-bromo-4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 58) according to the procedure of Example 63 as an olive green solid; 1H NMR (300 MHz, DMSO-d6) δ 1.66-1.77 (m, 4H), 2.10-2.19 (m, 4H), 2.68-2.76 (m, 2H), 3.07-3.14 (m, 3H), 3.99-4.09 (m, 2H), 5.62 (brs, 1H), 6.58-6.66 (m, 2H), 6.88 (t, J=8.1 Hz, 1H), 7.20-7.25 (m, 3H), 7.50 (dd, J=8.5, 2.0 Hz, 25 1H), 7.75 (d, J=2.0 Hz, 1H), 10.55 (s, 1H), 10.65 (s, 1H); MS (ES) m/z: 589.9 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=[O:7])#[N:2].[C:13](Cl)(=O)C>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([F:12])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: CC(=O)Cl
Reactant: N#Cc1cc(C(=O)O)ccc1F
Solvent: CO
Product: COC(=O)c1ccc(F)c(C#N)c1
Yield: 78.1 %

Procedure:
To a stirred suspension of 16.0 g (96.9 mmol) 2a and 161 ml methanol were added 30.4 g (387.6 mmol) acetyl chloride drop wisely at 0° C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane:ethylacetate). The desired product 2b was obtained in 78.1% yield (13.5 g; 75.7 mmol)