Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:6][C:7](=[O:42])[C:8]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][N:11]=[C:10]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[Cl:41])(=[O:33])=[O:32])[CH:9]=1)CCCC.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:41][C:35]1[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=1[S:31]([NH:30][C:10]1[CH:9]=[C:8]([C:13]([S:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:12][N:11]=1)[C:7]([OH:42])=[O:6])(=[O:33])=[O:32]
Reactant: CCCCCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 89.7 %

Procedure:
A solution of 2-(2,4-dichloro-benzenesulfonylamino)-5-[4-(piperidine-1-sulfonyl) -phenylsulfanyl]-isonicotinic acid pentyl ester (217 mg, 0.32 mmol) and lithium hydroxide monohydrate (54 mg, 1.3 mmol) in THF (15 ml) and water (15 ml) was stirred at 30° C. overnight. The reaction was diluted with water (25 ml), acidified to pH 1 with 1N HCl and extracted with ethyl acetate (2×30 ml). The combined extracts were dried (MgSO4) and concentrated under reduced pressure to give 2-(2,4-dichloro-benzenesulfonylamino)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid as a yellow solid (173 mg, 90%). 1H NMR (CDCl3): 8.06 (1H, d, Ar); 7.96 (1H, s, Ar); 7.82 (1H, s, py); 7.67 (3H, m, py and Ar); 7.39 (3H, m, Ar); 2.94 (4H, m, 2×CH2N pip); 1.56 (4H, m, 2×CH2 pip); 1.39 (2H, m, CH2 pip).
Reaction SMILES: O=C1C(C2C=CC=CC=2)(C2C=CC=CC=2)CCN1CC(O)=O.F[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:40]3[CH:45]=[CH:44][C:43](F)=[CH:42][CH:41]=3)[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=O)[C:31]2=[O:39])=[CH:26][CH:25]=1.[C:47]([C:51]1[CH:61]=[CH:60][C:54](/[C:55](=[N:58]/[H])/[NH:56]O)=[CH:53][CH:52]=1)([CH3:50])([CH3:49])[CH3:48].ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:47]([C:51]1[CH:61]=[CH:60][C:54]([C:55]2[N:56]=[C:36]([CH2:35][N:32]3[CH2:33][CH2:34][C:30]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:27]4[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=4)[C:31]3=[O:39])[O:38][N:58]=2)=[CH:53][CH:52]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: CC(C)(C)c1ccc(-c2noc(CN3CCC(c4ccccc4)(c4ccccc4)C3=O)n2)cc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-4-tert-butyl-N-hydroxybenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 7.99-7.91 (m, 2H), 7.51-7.46 (m, 2H), 7.42-7.27 (m, 9H), 6.95-6.89 (m, 1H), 4.89 (s, 2H), 3.55 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H), 1.36 (s, 9H); MS (DCI) m/z 452.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[OH:7].[C:8]([C:12]1[CH:17]=[C:16](I)[CH:15]=[C:14]([I:19])[C:13]=1[O:20][CH3:21])([CH3:11])([CH3:10])[CH3:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[C:8]([C:12]1[CH:17]=[C:16]([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])[CH:15]=[C:14]([I:19])[C:13]=1[O:20][CH3:21])([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1c(I)cc(I)cc1C(C)(C)C
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1c(I)cc(-n2ccccc2=O)cc1C(C)(C)C
Temperature: 110 °C

Procedure:
In a 20 mL microwave tube were added pyridin-2-ol (190 mg, 2 mmol), copper(I) iodide (76 mg, 0.400 mmol), 1-tert-butyl-3,5-diiodo-2-methoxybenzene (998 mg, 2.400 mmol), potassium phosphate (849 mg, 4.00 mmol) and N,N′-dimethylethylenediamine (0.086 mL, 0.800 mmol) in dioxane (10 mL). The tube was sealed and the mixture was sparged with N2 for 10 minutes and heated in an oil bath at 110° C. for 16 hours. The mixture was cooled and partitioned into ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried (Na2SO4), filtered and the filtrate was treated with 3-mercaptopropyl functionalized silica gel, filtered through diatomaceous earth and concentrated in vacuo to give crude product which was purified on an Isco 12 g silica cartridge eluting with 3:2 hexane/ethyl acetate to give the title compound.
Reaction SMILES: [Na].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][C:7]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:6]=2[CH:5]=1.O>C(O)C>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:6]2[CH2:5]1
Reactant: C[n+]1ccc2c(c1)-c1ccccc1Cc1ccccc1-2
Agent: [I-]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CN1CCC2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g Sodium is added with stirring and under a nitrogen atmosphere to a suspension of 0.5 g 2-methyl-9H-dibenzo[1,2;5,6]cyclohepta[3,4-c]pyridinium iodide (formula IV, melting point>300° C.) in 50 ml ethanol, after which the mixture is refluxed for 1 hour. The reaction mixture is then poured out into H2O and extracted with methylene chloride. The organic phase is washed with H2O, dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:27])[C:20](=[O:26])[NH:21]2>O1CCCC1>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([OH:27])([C:7]1[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=1)[C:20](=[O:26])[NH:21]2
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (4.86 g, 22.0 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise a solution of isopropyl magnesium chloride (49.6 mmol, 24.8 mL, 2.0 M solution in tetrahydrofuran) at 0° C. for 10 min. The reaction mixture was stirred for 30 min upon which time 4-chloroisatin (4.00 g, 22.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 2 h and quenched by the addition of 10% aqueous hydrochloric acid (25.0 mL) and the mixture was concentrated in vacuo to dryness. The residue was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride (3×30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with hot diethyl ether to afford 4-chloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (6.70 g, 95%) as a beige solid: mp 250-253° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.30, (s, 1H), 9.04 (s, 1H), 7.20 (s, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.45 (s, 1H), 6.17 (s, 1H), 5.88 (d, J=6.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.1, 148.6, 147.0, 145.6, 139.6, 130.6, 130.1, 129.6, 122.3, 118.6, 108.9, 108.4, 101.1, 97.4, 75.8; MS (ES−) m/z 304.2 (M−17), 302.2 (M−17).
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[F:12])=O.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][CH2:2]/[C:3](=[N:19]/[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[F:12]
Reactant: Cc1cccc(C(=O)CF)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(/C(CF)=N\[S@](=O)C(C)(C)C)c1F
Yield: 58.2 %

Procedure:
To a solution of 2-fluoro-1-(2-fluoro-3-methylphenyl)ethanone (5.03 g, 29.6 mmol) in THF (70 mL) were added (R)-2-methylpropane-2-sulfinamide (7.17 g, 59.1 mmol) and titanium (iv) ethoxide (15.30 ml, 73.9 mmol) and the resulting mixture was heated to reflux for 1.5 h. The reaction went to completion, brought to rt, and brine was added. The suspension was filtered, the filtrate was washed with brine, the organics extracts were combined, dried over Na2SO4, concentrated and chromatographed on silica gel using 0-30% EtOAc/hexanes to afford a light yellow oil as (R,E)-N-(2-fluoro-1-(2-fluoro-3-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (4.71 g, 17.23 mmol, 58.3% yield). MS m/z=274 [M+H]+. Calculated for C13H17F2NOS: 273.10.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([CH3:11])[N:4]=1)[NH2:2].[C:12](OCC)(OCC)(OCC)[CH3:13]>>[CH3:12][C:13]1[N:4]2[C:5]([CH3:11])=[N:6][C:7]([S:9][CH3:10])=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CSc1cc(NN)nc(C)n1
Product: CSc1cc2nnc(C)n2c(C)n1

Procedure:
A mixture of 2.5 g (0.015 mole) of 4-hydrazino-2-methyl-6-methylthiopyrimidine and 50 ml of triethyl orthoacetate was heated at its reflux temperature for five days, and was then cooled. The solid was separated by filtration and recrystallized with treatment with decolorizing charcoal from first an ethyl acetate-hexane mixture, and then a benzene-hexane mixture to provide 3,5-dimethyl-7-methylthio-1,2,4-triazolo[4,3-c]pyrimidine, m.p. 201°-203° C.
Reaction SMILES: C(OC(=O)[N:7]([C:20]1[C:21]2[N:22]([N:34]=[CH:35][N:36]=2)[C:23]([C:26]2[O:27][CH:28]=[C:29]([C:31](=[O:33])[NH2:32])[CH:30]=2)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:20]3[C:21]4[N:22]([N:34]=[CH:35][N:36]=4)[C:23]([C:26]4[O:27][CH:28]=[C:29]([C:31]([NH2:32])=[O:33])[CH:30]=4)=[CH:24][N:25]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2cc(C(N)=O)co2)n2ncnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1coc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3ncnn23)c1

Procedure:
A solution of [5-(4-carbamoyl-furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (33 mg, 0.065 mmol) in a mixture 1:1 DCM:TFA (2 mL) (2 drops of water) is stirred at room temperature for 2 hours. After addition of sat. Na2CO3, a precipitate is formed, collected by filtration and washed with water, diethyl ether and petroleum ether. After drying under vacuum, the title compound is isolated (20 mg, 76%). Conversion into the mesylate salt using 0.1M methanesulfonic acid in MeOH (0.444 mL) yields the title compound (19 mg, 100%). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 2.36 (3H, s, MsOH), 3.22 (4H, m), 3.82-3.89 (4H, m), 7.13 (2H, d), 7.36 (1H, br s), 7.86 (1H, s), 7.95 (3H, m), 8.17 (1H, s), 8.40 (1H, s), 8.84 (1H, s), 10.17 (1H, s). LCMS: Rt 2.60 min (96.9%), m/z (APCI) 406 (M+H)+.
Reaction SMILES: [NH:1]([CH3:3])[CH3:2].[O-:4][N+:5]1[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[N:8]=[C:7]([CH2:18][CH2:19][CH:20]=O)[N:6]=1)[CH2:15][CH2:14][CH2:13]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:2][N:1]([CH3:3])[CH2:20][CH2:19][CH2:18][C:7]1[N:6]=[N+:5]([O-:4])[C:10]2[CH:11]=[C:12]3[C:16]([CH2:15][CH2:14][CH2:13]3)=[CH:17][C:9]=2[N:8]=1
Reactant: CNC
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reaction time: 0.33 h
Yield: 55.1 %

Procedure:
A solution of anhydrous Me2NH (2.4 g, 52 mmol) in MeOH (50 mL) was added to a solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (50 ml) at 0° C. and the solution stirred for 20 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred for 30 min, then HOAc (2 ml) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 ml), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 78 (930 mg, 55%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.17 (s, 1H, H-9), 7.81 (s, 1H, H-5), 3.06-3.12 (m, 4H, H-6, H-8), 2.94-3.03 (m, 4H, 2×CH2), 2.66 [s, 6H, N(CH3)2], 2.07-2.18 (m, 4H, H-7, CH2); 13C NMR δ 164.1, 155.0, 149.2, 146.8, 131.9, 122.4, 113.7, 56.6, 43.0 (2), 33.3, 32.7, 32.4, 25.4, 22.7; HRMS (FAB+) calcd for C15H21N4O (MH+) m/z 273.1715, found 273.1714.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:20](Cl)[N:21]=[CH:22][C:15]=2[N:14]([CH3:32])[C:13]1=[O:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:34][C:35]([F:47])([F:46])[O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:20]([C:39]3[CH:40]=[CH:41][CH:42]=[C:37]([O:36][C:35]([F:34])([F:46])[F:47])[CH:38]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:32])[C:13]1=[O:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccccc3)c(Cl)ncc21
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-(hydroxy(phenyl)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (400 mg, 0.817 mmol), 3-(trifluoromethoxy)phenylboronic acid (336.9 mg, 1.635 mmol), aq. 2M K3PO4 (2 ml, 4.085 mmol) in dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl2 (21 mg, 0.0288 mmol). The reaction was degassed with nitrogen (3×), heated at 120° C. (MW) for 2 h, cooled to RT, diluted with EA (20 mL) and water (8 mL) and filtered through Celite. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-5-(hydroxyl(phenyl)methyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (220 mg, 44% yield) as colorless oil. LCMS: MH+ 616 and TR=2.334 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C>O1CCCC1>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Clc1ccnc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccnc1Br
Temperature: -70 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2-bromo-4-chloropyridine (1.6 g, 8.0 mmol) in anhydrous tetrahydrofuran (40 mL) cooled at −70° C. was added the solution of lithium diisopropyl-amide (5.0 mL, 10.0 mmol, 2.0 M) over a period of 5 minutes and stirred at −70° C. for another 1 h. Anhydrous DMF (1.3 g) was introduced over a period of 3 minutes and the mixture was stirred for another 30 minutes. It was then quenched with saturated NH4Cl (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous Mg2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (20:1) to afford 114a as a yellow solid (900 mg, 48%). 1H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 7.79 (d, J=5.0 Hz, 1H).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:26])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[F:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[NH:11][C:10](=[O:26])[N:9]([OH:8])[C:18]2=[O:19]
Reactant: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1O
Yield: 113.1 %

Procedure:
Twenty percent Pd/C (50 mg) was added to a solution of 3-benzyloxy-6-fluoro-7-pyrrolidinyl-1H-quinazoline-2,4-dione (Example 1, 0.21 g, 0.6 mmol) in 100 mL of THF and 100 mL of methanol. The mixture was shaken under 50 PSI of hydrogen for 4.5 hours, filtered, and concentrated to afford 0.18 g of the title compound as a solid, mp >250° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](=[NH:19])OCC.C(N(CC)CC)C.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:41]3[C@H:37]([CH2:38][NH:39][CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:43]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:41]3[C@H:37]([CH2:38][N:39]([C:15](=[NH:19])[CH2:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[O:7][CH3:6])[CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCOC(=N)Cc1ccccc1OC
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=N)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Yield: 57 %

Procedure:
A solution of 1.56 g of ethyl (2-methoxyphenyl)acetimidate tetrafluoroborate and 0.96 cm3 of triethylamine in 20 cm3 of dry dichloromethane is added to a solution of 2 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol in 30 cm3 of dry dichloromethane, and then the reaction mixture is refluxed for 2 hours. 10 cm3 of a 10% aqueous solution of potassium carbonate are then added, decanted and then the organic phase is washed with 20 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on an alumina column (diameter 3.6 cm, height 31 cm), eluting under a nitrogen pressure of 0.1 bar with a dichloromethane and methanol mixture (95/5 by volume) and collecting fractions of 50 cm3. Fractions 5 to 30 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with isopropyl oxide, drained and dried. 1.4 g of (3aR,4S,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl]-4-perhydroisoindolol are obtained in the form of white crystals; melting point 105° C., with decomposition.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)=[C:27]([F:44])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([F:44])[C:28]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=5)=[C:29]([F:31])[CH:30]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCc3ccc(C(F)(F)F)cc3)c(F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCc4ccc(C(F)(F)F)cc4)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (33 mg, 0.184 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-[4-(trifluoromethyl)benzyloxy)phenyl]-1,3-thiazol-2-yl}acetamide (112 mg, 0.221 mmol) in the presence of NaH (11 mg, 0.276 mmol) in dry DMF (3.0 mL) to give 25 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.17 (s, 3H), 3.39 (s, 3H), 5.32 (br s, 4H), 6.22 (s, 1H), 7.35 (s, 1H), 7.70-7.72 (m, 4H), 7.78-7.80 (m, 3H), 12.68 (br s, 1H); ESI-MS (m/z) 606.15 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:27])(CC=C)[CH:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]>CO.O1CCCC1.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:5][CH:4]([OH:3])[CH2:9][OH:10])[C:21]([OH:27])=[C:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C=CCC1(O)C=CC(c2csc(-c3ccc(OCC)c(OCC)c3)n2)=CC1C(=O)OC
Agent: O=[Os](=O)(=O)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3cc(CC(O)CO)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 160.4 %

Procedure:
To a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-4-allylphenyl)thiazole in 20 ml of methanol and 20 ml of tetrahydrofuran were added 0.5 ml of osmium tetroxide (a 4% aqueous solution) and 1.22 g of4-methylmorpholine N-oxide. The mixture was stirred at room temperature for 4 hours. The solvent was removed by distillation. The residue was mixed with 50 ml of dichloromethane and 25 ml of water for phase separation. The organic layer was washed with 25 ml of a saturated aqueous sodium chloride solution and dried. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=199/1) to obtain 860 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-(2,3-dihydroxypropyl)phenyl]thiazole.
Reaction SMILES: [Na].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].ClC1C([O:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=C(Cl)C(Cl)=C(Cl)C=1Cl>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[O:15])=[CH:18][CH:19]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
7.0 g. of the sodium salt of 2-pyrrolidinone (prepared using sodium hydride) suspended in 120 ml. of dimethylformamide are added at -10° C. to a solution of 20.0 g. of p-methoxybenzoic acid pentachlorophenyl ester in 100 ml. of dimethylformamide. Subsequently, the mixture is stirred at room temperature for 1 hour and at 55° C. for 8 hours. The solvent is evaporated, the residue is treated with cold aqueous acetic acid solution and the mixture is extracted with ethyl acetate. The organic phase is washed with cold sodium bicarbonate solution and water, dried over sodium sulfate, filtered and evaporated. The residue is taken up in ethanol and stirred in an ice bath. The separated crystals are filtered off and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119°-120° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=O>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: COc1ccccc1-c1csc(-c2ccc(-c3ccccc3[N+](=O)[O-])c(C(=O)O)c2)n1
Yield: 67 %

Procedure:
4-[4-(2-Methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (183 mg, 67%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-2′-methoxyacetophenone (available from ASDI Incorporated) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.13-8.31 (m, 4H), 7.63-7.81 (m, 2H), 7.35-7.47 (m, 3H), 7.18 (d, J=8.3 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H).