Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[CH:18][N:17]([CH3:20])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[CH:18][N:17]([CH3:20])[N:16]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cn1cnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 110 °C
Yield: 81.5 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(1-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (32 mg, 0.078 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (21 mg, 0.095 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) and 2M aq. Na2CO3 (0.2 ml, 0.4 mmol). The reaction mixture is heated under Argon at 110° C. for 2 hours. The residue is diluted with EtOAc, washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-3% 7M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (27 mg, 82%) as an off-white solid. LCMS (ESMS): m/z 425.66 (M++1)
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1.[Li].[B:28](OC)([O:31]C)[O:29]C>C1COCC1>[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[C:17]=1[B:28]([OH:31])[OH:29]
Reactant: COc1ccc2c(c1)OC(C)(C)C2
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1B(O)O)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
s-BuLi (35 mL, 1.3M in cyclohexane) was added to TMEDA (6.6 mL) at −78° C. drop wise within 30 min, 20 mL of THF was added to keep stirring. After 20 min, 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran (5.4 g, 30.3 mmol) in THF (30 mL) was added into the lithium solution slowly. The solution was stirred at −78° C. for 1.5 h and trimethyl borate (18 mL) was added. The mixture was warmed to room temperature and stirred at room temperature overnight. The solution was acidified to pH=5-6 and extracted with ethyl acetate. The organic layer was concentrated and the resulted residue was purified on column chromatography (silica gel, dichloromethane/petroleum ether=3/1) to give the crude product, which was sonicated with petroleum ether. The white precipitate was filtered and dried to give 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-ylboronic acid (3.55 g, 53%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15](/[CH:16]=[C:17]3/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CN(C=O)C.Cl.[NH2:33][OH:34]>C1COCC1>[OH:34][N:33]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15](/[CH:16]=[C:17]2/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/2)=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=O)COc2ccc(/C=C3\SC(=O)NC3=O)cc2)c1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(C(COc2ccc(/C=C3\SC(=O)NC3=O)cc2)=NO)c1
Reaction time: 8 h

Procedure:
A stirring suspension of (5Z)-5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (1.42 g, 3.84 mmol; Supplier=Kalexsyn; Lot=1003-TTP-149) in THF (15 ml) was heated with a heat gun—no solution. Added DMF (5 ml) and heated—no solution. Added another 5 ml DMF and heated until all solids dissolved. The hydroxylamine hydrochloride was added portionwise. Added HONH2.HCl (100 mg) and allowed to sit at RT overnight. HPLC showed a ratio of ca. 2:1 SM:pdt. Added 100 mg HONH2.HCl. After 4 hours there was little change in HPLC. Added 100 mg HONH2.HCl and left to stir over the weekend. The reaction was complete. The reaction mixture was partitioned between EtOAc (30 ml) and 1M KHSO4 (30 ml). The aqueous phase was extracted with EtOAc (30 ml). The combined organic phases were washed with saturated NaHCO3 (30 ml), brine (30 ml), dried (Na2SO4), filtered and evaporated in vacuo to give 1.34 g yellow solid. 1H-NMR (DMSO-d6): δ 12.53(brs, 1H), 12.02(brs, 1H), 7.73(s, 1H), 7.54(d, J=8.9 Hz, 2H), 7.30(t, J=7.9 Hz, 1H), 7.20(m, 2H), 7.10(d, J=8.9 Hz, 2H), 6.95(dd, J=8.1, 2.5 Hz, 1H), 5.31(s, 2H), 3.74(s, 3H). HPLC: 3.690 min., 10 area %, and 3.788 min., 89 area % @ 210 nm; 3.690 min., 6 area %, and 3.789 min., 94 area % @ 254 nm. MS (ESI−) for C19H16N2O5S m/z 383.3 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].S(O)(O)(=O)=O.[CH3:23][O:24][C:25](=[NH:27])[NH2:26].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:27][C:25]([O:24][CH3:23])=[N:26][C:15]([CH3:16])=[C:10]2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C(=Cc1ccc(F)c(F)c1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)c(F)c1
Temperature: 70 °C
Yield: 35.2 %

Procedure:
A mixture of methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate (8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate (9.4 g, 55 mmol), and NaHCO3 (12.3 g, 0.146 mol) in DMF (30 mL) was stirred and heated at 70° C. for 16 hours. The mixture was cooled, diluted with EtOAc (300 mL) and washed with water (5×300 mL), brine (300 mL), and dried (MgSO4). Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10% through 20% EtOAc in hexane as the gradient eluent, to leave the product as an oil (3.82 g, 30.2%); 1H-NMR (CDCl3): δ2.32,2.39 (2 s, 3 H), 3.58, 3.64 (2 s, 3 H), 3.72, 3.85 (2 s, 3 H), 5.55 (s, 1H), 6.13-7.8 (m, 4 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:41][C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 0.908 ml benzyl bromoacetate and 3.571 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 200 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[C:9]1(=O)[CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:11]2[CH2:10]1>CO>[C:9]1(=[N:7][OH:8])[CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:11]2[CH2:10]1
Reactant: O=C1CC2c3ccccc3CC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CC2c3ccccc3CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (1.45 g, 17.7 mmol) and hydroxylamine hydrochloride (0.68 g, 9.75 mmol) were added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (1.4 g, 8.86 mmol) in MeOH (18 mL), and stirred overnight at room temperature. The reaction solution was concentrated via rotary evaporation. The residue was dissolved in CH2Cl2 (100 mL), washed with H2O (50 mL), dried over MgSO4, and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C11H11NO+H: 174, observed: 174.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH2:25][NH:24][C:23]3=[O:28])[CH2:18][CH2:17]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(OCC(O)CN2CCC(N3CCCNC3=O)CC2)cc1

Procedure:
A solution of 19.35 g of 1-(p-acetamido-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 10 ml of abs. ethanol is heated to 95° C. The reaction product crystallises out at boiling heat after about 5 minutes. The crystal broth is diluted with 10 ml of abs. ethanol and heated for a further 5 hours. When the reaction is terminated the batch is evaporated in vacuo and the residue is recrystallised from abs. ethanol/ether to yield the 1-[3-(p-acetamido-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 218°-221° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:11].[Na+].O>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][SH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [SH-]
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: SCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-phenylpropylbromide (1.08 g) in ethanol (8 ml) was added sodium hydrosulfide (0.871 g), and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, extracted with diethyl ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3-phenylpropanethiol. To a solution of the obtained 3-phenylpropanethiol in dioxane (15 ml) were added compound 227-1 (500 mg), diisopropylamine (0.327 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (27 mg) And tris(dibenzylideneacetone)palladium(0)-chloroform adduct (24 mg), and the mixture was stirred at 120° C. for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a mixture of (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester and a starting material (Compound 227-1). Again, 3-phenylpropanethiol in the same amount as the above was prepared, and the above-mentioned operation was repeated using the mixture of (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester and the starting material obtained above instead of compound 227-1 to give (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester as a pale-yellow oil. The pale-yellow oil was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, the residue was washed with diethyl ether to give a pale-yellow solid. The pale-yellow solid was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (90 mg) as a white powder.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].CC1(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]3)[CH:35]=2)OC1(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]4)[CH:35]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CC(F)(F)C2)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)cc2N(C(=O)OC2CC(F)(F)C2)C[C@@H]1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A 100-mL round-bottom flask was purged with nitrogen and then charged with 3,3-difluorocyclobutyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (300 mg, 0.70 mmol), tert-butyl 3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (487 mg, 1.39 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane complex (69 mg, 0.08 mmol), cesium carbonate (456 mg, 1.40 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixture stirred overnight at 90° C. in an oil bath. After cooling to room temperature, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 8:1 ethyl acetate/petroleum ether) to afford 3,3-difluorocyclobutyl (S)-4-acetyl-7-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (300 mg, 79%) as a yellow oil. MS (ESI, pos. ion) m/z 546 [M+H]+.
Reaction SMILES: [CH2:1]([C:6]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:21])[C:8]=2[CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].C(C1C=CC=CC=1)C(C)(C)C.C1(=O)OC(=[O:37])C2=CC=CC=C12>>[CH2:1]([C:6]1[CH:19]=[CH:18][C:17]([C:16]([C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:21])=[O:37])=[O:20])=[CH:8][CH:7]=1)[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(C)(C)Cc1ccccc1
Product: CC(C)(C)Cc1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
A process for the preparation of 2-neopentylanthraquinone, wherein neopentylbenzene is acylated with phthalic anhydride by a Friedel-Crafts reaction to give 2-(4-neopentylbenzoyl)-benzoic acid and the latter is cyclized in the presence of a strong anhydrous acid to give a composition consisting essentially of 2-neopentylanthraquinone without isomerization or degradation of the neopentyl group taking place.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[C:14](=[CH:15][N:16]([CH3:22])[C:17](=[O:21])[C:18]=2[CH3:20])[NH:13]C1=O.[Si]([O:31][CH2:32][CH2:33][C:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1)(C(C)(C)C)(C)C>CN(C=O)C.C1COCC1>[OH:31][CH2:32][CH2:33][C:34]1([S:37]([NH:13][C:14]2[C:19]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=3[F:3])=[C:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=2)(=[O:39])=[O:38])[CH2:36][CH2:35]1
Reactant: Cc1c(=O)n(C)cc2[nH]c(=O)n(-c3ccc(I)cc3F)c12
Reactant: CC(C)(C)[Si](C)(C)OCCC1(S(=O)(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCO)CC2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60% in mineral oil) (21.8 mg, 0.544 mmol) is added to a solution of 1-(2-fluoro-4-iodophenyl)-5,7-dimethyl-1H-imidazo[4,5-c]pyridine-2,6(3H,5H)-dione (100 mg, 0.251 mmol) in dry DMF (5 mL) at 0° C. The cooling bath is removed and the solution stirred at room temperature for 1 hour. The solution is re-cooled to −5° C. in a dry-ice/acetone bath, and 1-[2-(tert-butyldimethylsilanyloxy)ethyl]-cyclopropanesulfonyl chloride (300 mg, 1 mmol) in dry THF (2 mL) is added. The mixture is warmed to room temperature and stirred for an additional 16 hours. The mixture is concentrated to give an oily residue and purified via flash chromatography (SiO2, EtOAc:MeOH=9:1) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([NH:38][S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])=[O:27])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared by coupling 2e and benzene sulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (70%); 1H NMR (d6-DMSO) δ 12.25 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.66 (m, 3H), 7.42 (d, J=15.7 Hz, 1H), 7.34–7.14 (m, 10H), 6.88 (d, J=8.1 Hz, 2H), 6.72 (d, J=7.3 Hz, 1H), 6.48 (d, J=15.7 Hz, 1H), 2.79 (m, 2H), 2.28 (m, 2H), 2.09 (m, 2H); ESI m/z: 504 (M−H−, 100%).
Reaction SMILES: [CH2:1]([CH:4]([C:9]([O:11]C)=O)[C:5]([O:7]C)=O)[C:2]#[CH:3].Cl.[C:14]([NH2:17])(=[NH:16])[CH3:15]>CO>[CH3:15][C:14]1[N:17]=[C:5]([OH:7])[C:4]([CH2:1][C:2]#[CH:3])=[C:9]([OH:11])[N:16]=1
Reactant: CC(=N)N
Reactant: C#CCC(C(=O)OC)C(=O)OC
Agent: Cl
Solvent: CO
Product: C#CCc1c(O)nc(C)nc1O
Yield: 36.9 %

Procedure:
To a 250 mL flask was added 1 (3.96 g, 20 mmol), 2 (1.85 g, 20 mmol) and 50 mL anhydrous MeOH. After 800 mg (20 mmol) Na was added to the solution, yellow precipitate was observed. The resulting mixture was refluxed overnight. The yellow precipitate was collected by filtration and then dissolved in 10 mL H2O. The pH of the resulting solution was adjusted to 6.5 by adding 2 N HCl to afford a yellow precipitate, which was collected by filtration and dried over P2O5 to afford 1.21 g (37%) of 3: TLC Rf0.11 (CHCl3/MeOH 6:1); mp>300° C.; 1H NMR (DMSO-d6) δ 2.23 (s, 3 H), 3.05 (s, 2 H), 3.32 (s, 1 H), 11.92 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=[O:12].[CH:40]1([CH2:43][O:44][C:45]2[CH:50]=[C:49]([CH2:51]O)[CH:48]=[CH:47][C:46]=2[N:53]([S:61]([CH3:64])(=[O:63])=[O:62])C(=O)OC(C)(C)C)[CH2:42][CH2:41]1.Cl.O1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][CH2:51][C:49]1[CH:48]=[CH:47][C:46]([NH:53][S:61]([CH3:64])(=[O:63])=[O:62])=[C:45]([O:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)[CH:50]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(COC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared in an analogous manner as described in Scheme 3, Step 1) (0.150 g, 0.256 mmol) in DCM (10 ml), DMAP (0.0156 g, 0.128 mmol) was added followed by tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl(methylsulfonyl)carbamate (0.124 g, 0.333 mmol), and the resulting mixture was stirred at RT for 3 hours. HCl 4M in dioxane (3 ml, 12 mmol) was added and the reaction was stirred at RT for additional 5 hours. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.15). A further purification by flash chromatography on silica gel column (DCM:acetone=10:1) was required to obtain (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzyloxy)carbonyloxy)ethyl)pyridine 1-oxide as a white solid (0.073 g, 0.102 mmol, 39.7% yield, MS/ESI+ 716.93 [MH]+, [αD]=−11.84, c=0.495, DCM).
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH3:25])[C:7]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[C:8]([CH3:13])[CH:9]=2)[O:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[CH3:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:25])[C:7]=1[OH:14])[O:4][CH2:3][C@@H:2]([N:36]1[CH2:35][CH2:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)([OH:39])[CH2:38][CH2:37]1)[C@H:11]2[OH:12]
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: Cc1cc2c(=O)c(Br)coc2c(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc2c(c(C)c1O)OC[C@@H](N1CCC(O)(c3ccc(F)cc3)CC1)[C@H]2O
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-6,8-dimethyl-7-triisopropylsilyloxychromen-4-one (the compound of Example 19, 0.23 g, 0.54 mmol), 4-(4-fluorophenyl)-4-hydroxypiperidine (0.22 g, 1.12 mmol) and triethylamine (0.3 mL, 2.15 mmol) in acetonitrile (15 mL) was stirred over the weekend at ambient temperature. The precipitate which formed was collected and rinsed with water and ether. This solid was flash chromatographed on silica gel (1×4 inches packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (100 mL), nil; 25% ethyl acetate/hexane (200 mL), 0.065 g (22%) 6,8-dimethyl-7-triisopropylsilyloxy-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chromen-4-one which had: mp 226.5-227° C. Analysis calculated for C31H42FNO4Si: C, 68.98; H, 7.84; N, 2.59. Found: C, 69.00; H, 7.94; N, 2.37. This product was identical to the product isolated in the first step of example 19 and was converted to the title product following the procedure of example 19.