Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[S:4]
Reactant: CN(C)C(=O)CCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C)C(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 92.4 %

Procedure:
Thiosemicarbazide (2.75 g, 30.2 mmol) was added to a solution of 4-oxo-N,N-dimethyl-4-phenyl-butyramide (3.80 g, 18.5 mmol), prepared in the previous step, in 65 ml of methanol plus 5 ml of 1 N HCl plus 5 ml of water and the reaction stirred at room temperature for 28 hours. The solid present was collected by filtration to give 4.76 g of a white solid. The solid was triturated with water and then dried to give the title compound (4.53 g, 88%) as a white solid, mp 173-175° C.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[O:13]1[C:17]2=[N:18][CH:19]=[C:20]([CH2:22][OH:23])[CH:21]=[C:16]2[CH:15]=[CH:14]1.O.C(OCC)C>CS(C)=O>[CH:22]([C:20]1[CH:21]=[C:16]2[CH:15]=[CH:14][O:13][C:17]2=[N:18][CH:19]=1)=[O:23]
Reactant: OCc1cnc2occc2c1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: O=Cc1cnc2occc2c1
Yield: 54.6 %

Procedure:
To o-iodoxybenzoic acid (1.036g, 3.7 mmol) in dimethyl sulfoxide (7.4 mL) was added furo[2,3-b]pyridine-5-methanol (500 mg, 3.36 mmol). Stirring was continued for 2.5 h before the addition of water, filtration, and extraction of the filtrate with ethyl ether (3×30 mL). The organic phase was washed with brine (10 mL), dried with magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexane) yielded 5-formyl-furo[2,3-b]pyridine (270 mg, 55%). This material (260 mg, 1.77 mmol) in toluene/tetra-hydrofuran (2 mL each) was added at -78° C. to a solution of methyltriphenyl-phosphorane (2.12 mmol) in toluene (15 mL). Stirring was continued at this temperature for 15 min, followed by warming to 20° C. over 1 h. Dilution with ethyl ether was followed by filtration through celite, and concentration. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexane) yielded 241.5 mg (94% yield) of the title compound as a colorless oil: 1H NMR (CDCl3) ∂8.32 (d,1H, J=2 Hz), 7.97 (d, 1H, J=2 Hz), 7.68 (d,1H, J=2 Hz), 6.80 (dd, 1H, J=18+12 Hz), 6.76 (d, 1H, J=2 Hz), 5.79 (d,1H, J=18 Hz), 5.32 (d, 1H, J=12 Hz).
Reaction SMILES: [NH2:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]1=[NH:17].[CH:18]([O-])([O-])OCC>>[CH2:12]([N:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[C:10](=[O:11])[N:2]2[N:1]=[CH:18][N:17]=[C:3]12)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCn1c(=N)n(N)c(=O)c2[nH]cnc21
Reactant: CCOC([O-])[O-]
Product: CCCCCn1c2nc[nH]c2c(=O)n2ncnc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
The mixture of 1-amino-2-imino-3-pentyl-1,2,3,7-tetrahydro-6H-purin-6-one (0.10 g, 0.4 mmol) and ethyl orthoformate (5 mL, 30 mmol) was stirred at 100° C. for 6 hours. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product (20 mg, 20%). LCMS calculated for C11H15N6O (M+H): 247.1. found: 247.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:15][CH2:14][CH2:13][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Cc2ccccc2N1CCCCl
Temperature: 25 °C
Yield: 39.3 %

Procedure:
Reflux together oxindole (2.66 g, 20.0 mmol), 1-bromo-3-chloropropane (2.56 mL, 26.0 mmol) and potassium carbonate (5.52 g, 40.0 mmol) in acetonitrile (300 mL) under nitrogen for 16 h. Cool the suspension to room temperature and filter off the precipitate. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 3:2 gradient over 40 min) to give the title compound as an orange oil (1.65 g, 39%). MS (ES+) m/z: 210 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.Cl[CH2:19][CH2:20][CH2:21][C:22]1([C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30][CH3:31])=[O:29])[CH2:23]1>O1CCCC1>[C:24]12([C:28]([O:30][CH3:31])=[O:29])[CH2:23][C:22]([C:32]([O:34][CH3:35])=[O:33])([CH2:27][CH2:26][CH2:25]1)[CH2:21][CH2:20][CH2:19]2
Reactant: COC(=O)C1CCCC(CCCCl)(C(=O)OC)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C12CCCC(C(=O)OC)(CCC1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a pre-cooled (−78° C.) solution of lithium diisopropylamide (86 mL, 172 mmol) in tetrahydrofuran (400 mL) was added DMPU (70.4 g, 550 mol) dropwise, followed by an addition of dimethyl 1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate (30 g, 114.5 mmol) in anhydrous THF (50 mL) within 20 min. After stirring at −78° C. for 30 min, the reaction was allowed to warm up to room temperature over a period of 1.5 h, and then quenched with saturated NH4Cl (100 mL). The mixture was concentrated under reduced pressure and then diluted with water (300 mL). The resulting aqueous mixture was extracted with DCM (4×100 mL) and the combined organic layer was washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30/1) to afford 15.5 g (60%) of the title compound, dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate as a light yellow oil. ESI-MS m/z: 227 (M+H)+.
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.O[CH2:28][CH2:29][CH2:30][C:31]1[S:35][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:33][CH:32]=1>C(Cl)Cl>[I:1][CH2:28][CH2:29][CH2:30][C:31]1[S:35][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:33][CH:32]=1
Reactant: II
Reactant: COC(=O)c1ccc(CCCO)s1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCI)s1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Iodine (187 mg, 0.74 mmol) was added to a solution of triphenylphosphine (194 mg, 0.74 mmol) and imidazole (49 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) at 23° C. After 0.5 h a solution of methyl 5-(3-hydroxypropyl)thiophene-2-carboxylate 7 (123 mg, 0.62 mmol) in CH2Cl2 (0.5 mL) was added. After stirring for 2 h the reaction was concentrated in vacuo and the residue was purified by FCC (silica gel, 7:3 hex/EtOAc) to provide 170 mg (89%) of the iodide 108.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](F)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC([O:24]C(Cl)=O)C.CO>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([OH:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: FC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CO
Product: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 55 %

Procedure:
To 1-benzyl-4-fluoro-4-phenyl-piperidine (0.22 g) in dry DCM (5 mL) was added 1-chloroethylchloroformate (1 mmol). The mixture was stirred for 1 hour and then methanol (5 mL) was added and the mixture stirred overnight. The solvent was removed under vacuum, and the resulting solid triturated from diethyl ether to give the title compound as a white solid (0.12 g). LCMS m/z 180.1 [M+H]+. R.T.=2.27 min (Analytical Method 4).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:5])[CH3:4]>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)c1nc(O)sc1C(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(O)sc1C(=O)CBr
Yield: 94.7 %

Procedure:
A solution of bromine (10.8 g) in methylene chloride (5 ml) was dropwise added to a solution of ethyl 5-acetyl-2-hydroxy-4-thiazolecarboxylate (12.9 g) in a mixture of methylene chloride (150 ml) and acetic acid (10 ml) at 30° C. to 35° C. with stirring and the mixture was stirred at the same temperature for 30 minutes. An insoluble material was filtered off. The filtrate was washed brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give ethyl 5-(2-bromoacetyl)-2-hydroxy-4-thiazolecarboxylate (16.7 g). mp 105°-108° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[NH2:9][CH2:10][CH2:11][CH2:12][OH:13].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[OH:13][CH2:12][CH2:11][CH2:10][NH:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: [O-][n+]1ccccc1Cl
Reactant: NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: [O-][n+]1ccccc1NCCCO
Temperature: 67 °C
Reaction time: 23 h
Yield: 80.3 %

Procedure:
A mixture of 2-chloropyridine-N-oxide (16.6 g, 100 mmoles), 3-amino-1-propanol (15.3 ml, 200 mmoles), NaHCO3 (42 g, 0.5 mole), and tert-amyl alcohol (100 ml) was heated to reflux. After 23 hours, the reaction was cooled, diluted with CH2Cl2 (300 ml), and filtered to remove insoluble materials. The filtrate was concentrated to afford a brown oil. The oil was dried under vacuum overnight. Ether (100 ml) was added to give a brown solid. The ether was decanted and the solid was washed further with ether/acetonitrile (3/1). The resulting solid was heated at 67° C. under vacuum to give the desired product (13.5 g). 1H NMR was consistent with the proposed structure.
Reaction SMILES: O.S(=O)(=O)(O)O.[Si:7]([O:17]CC)([O:14]CC)([O:11]CC)[O:8][CH2:9][CH3:10].[CH3:20][Si:21]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>C(O)C.C(O)(C)C>[Si:7]([O-:17])([O-:14])([O-:11])[O:8][CH2:9][CH3:10].[CH3:20][Si:21]([O:22][CH2:23][CH3:24])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CCO[Si](C)(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: CCO[Si]([O-])([O-])[O-]
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A sample of 90% hydrolyzed ethyl silicate/methyltriethoxy silane co-condensate was prepared by adding water (11 grams) containing a trace of sulfuric acid to a solution of tetraethyl orthosilicate (37.5 grams) and methyl triethoxy silane (37.5 grams) in anhydrous ethanol (75 grams). Ethocel (4.5 grams) was added to thicken the solution. To a portion (11.5 grams) of the solution was added a 60% total solids TiO2 dispersion in isopropanol (40.3 grams) and a dispersing aid, Nuosperse 657 (3.5 grams). A 2 mil dry coating was prepared on a three by six inch steel Q panel and conditioned for 15 minutes at 200° C. The coated panel was then placed in a muffle furnace at 510° C. and its condition checked after 1, 2, 3, and 4 hours. At all times, the coating remained white, uncracked and adhered to the substrate. In comparison with the results contained in Control B and Examples 1-9, this demonstrates the usefulness of the highly filled co-condensate in this elevated temperature application.
Reaction SMILES: [CH2:1]([C:3]([OH:18])([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(C(C)=O)C(C)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:3]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:8][CH:9]=2)([OH:18])[CH2:1][CH3:2])[CH:16]=[CH:15][CH:14]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1cccc(Cl)c1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCC(O)(c1ccc(OCCCN2CCCCC2)cc1)c1cccc(Cl)c1

Procedure:
7.9 g. of α-ethyl-α-(3-chlorphenyl)-4-hydroxybenzyl alcohol, 14 g. of anhydrous potassium carbonate and 6.6 g. of N-(3-chloropropyl)-piperidine hydrochloride in 80 ml. of methyl isobutyl ketone are boiled under moderate reflux for three hours. The solvent is distilled off under reduced pressure, to the residue water is added and it is extracted with benzene. The benzene phase is washed with an aqueous potassium hydroxide solution and subsequently with water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. Crystallization of the residue from n-hexane yields 8.6 g. of the title compound, melting at 80° to 81° C.
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:43])[N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]3)[CH3:31])[CH:23]=2)=[CH:19][CH:18]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1>C(O)C>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]([CH3:31])[C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]4[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=4)=[S:58])=[CH:45][CH:44]=3)[CH:27]=[CH:26][N:25]=2)=[O:43])[CH2:33][CH2:34]1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (119 mg) to a solution of 3-[4-(4-aminophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (121 mg) in ethanol (2.0 ml), the mixture was stirred for 10 minutes at room temperature. Next, 2-(4-fluorophenyl)acetyl isothiocyanate (2.34 ml, 0.25 M solution in toluene) was added thereto and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were combined and concentrated. The residue was purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were concentrated, and saturated aqueous sodium hydrogencarbonate was added to the resultant residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated to provide the title compound (26.3 mg, 14.8%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:8][CH:9]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CCO)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCOS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 300 mg (1.61 mmol) 5-(2-hydroxy-ethyl)-thiophene-2-carboxylic acid methyl ester in 10 mL DCM is added 0.90 mL triethylamine (6.44 mmol) and subsequently 312 μL (4.03 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and is diluted with 50 mL DCM. The organic phase is separated, washed three times with water and is dried over MgSO4. After filtration and evaporation of the solvent, the product is afforded.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[C:4]([I:13])[CH:3]=1.[H-].[Na+].I[CH3:17]>CN(C=O)C>[CH3:17][N:8]1[C:9]2[C:5](=[C:4]([I:13])[CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1
Reactant: CI
Reactant: Cc1cc(I)c2c(C=O)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(I)c2c(C=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold solution (0° C.) of 6-methyl-4-iodo-indole-3-carboxaldehyde (265 mg, 0.92 mmol) in dry DMF (2 mL) was added NaH (60% dispersion in mineral oil, 50 mg, 1.25 mmol). The resulting mixture was stirred at 0° C. for 20 min. Iodomethane (0.5 mL, excess) was added to the reaction mixture in a drop wise fashion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was quenched with water and was extracted repeatedly from EtOAc. Combined organic was washed with water (twice) and brine. After drying over magnesium sulfate, solvent was removed. The product, 1,6-dimethyl-4-iodo-indole-3-carboxaldehyde was obtained as a solid was which was suspended in hexane, stirred for few minutes and was filtered. The product was further washed with more hexane and was dried to yield 213 mg (77%) of the desired product. MS: 300 (M+H), 322 (M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([N+:25]([O-:27])=[O:26])[CH:3]=1.[CH3:28][O:29][C:30]1[C:35]([CH3:36])=[C:34](B(O)O)[C:33]([CH3:40])=[CH:32][N:31]=1.C(OCC)(=O)C.O>O1CCOCC1>[O:18]1[CH2:19][CH:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[C:33]([CH3:40])=[CH:32][N:31]=[C:30]([O:29][CH3:28])[C:35]=4[CH3:36])=[CH:3][C:4]=3[N+:25]([O-:27])=[O:26])=[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=[N:11]2)[CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(Br)cc1[N+](=O)[O-]
Reactant: COc1ncc(C)c(B(O)O)c1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(-c2c(C)cnc(OC)c2C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 6.75 h
Yield: 155.5 %

Procedure:
Water (0.2 mL), (2-methoxy-3,5-dimethylpyridin-4-yl)boronic acid (39.5 mg) obtained in Preparation Example 29, Pd(PPh3)4 (10.5 mg) and cesium carbonate (178 mg) were added to a solution of ethyl 5-(4-bromo-2-nitrophenyl)-1-(1,4-dioxepan-6-yl)-1H-pyrazole-4-carboxylate (80 mg) obtained in Preparation Example 9-(2) in 1,4-dioxane (1.3 mL), and the reaction mixture was stirred at 100° C. for 6.75 hours. (2-methoxy-3,5-dimethylpyridin-4-yl)boronic acid (15 mg) was added to the reaction mixture and the reaction mixture was stirred at 100° C. for 2.5 hours. After the reaction mixture was returned to mom temperature, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, ethyl acetate/n-heptane, 20 to 33%) to give the title compound (64 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1.CCCCC>C(O)C.C(O)(=O)C>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:19]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1ccc(NN)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCCCC
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
4,4-Dimethyl-3-oxo-pentanenitrile (14.28 g, 114 mmol) and 4-methoxyphenyl hydrazine (19.89 g, 114 mmol) were dissolved in a mixture of absolute ethanol (170 mL) and glacial acetic acid (5.0 mL) then heated to reflux for 3 h, before allowing to standing overnight at RT. The resulting red/brown solid was filtered off, and the filtrate was then diluted with water (500 mL), and basified with 880 ammonia solution until the pH=5. This aqueous solution was extracted into diethyl ether (3×). The combined organics were dried (MgSO4) and evaporated in vacuo to a brown oil. Trituration (pentane) gave the title compound as a light purple/brown solid (23.07 g, 94.1 mmol, 82%). LCMS (method 1): Rt 2.87 min, m/z 246/247 [MH+].
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:22])[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:22])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Yield: 63.3 %

Procedure:
Hydrogenolysis of 500 mg of the 5-[(1,1′-biphenyl)-4-yl]-3-phenylmethoxy-4-hydroxy-5-methyl-2(5H)-furanone was performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 240 mg (63% yield) of 5-[(1,1′-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone as a white powder: mp 206-212° C. dec. (MeOH/H2O), 1H NMR (acetone-d6) δ 7.69-7.33 (m, 9H), 1.88 (s, 3H). 13C NMR (acetone-d6) δ 169.5, 157.1, 141.6, 141.0, 139.8, 129.6, 128.3, 127.6. 127.6, 126.6, 117.9, 81.2, 24.5. Anal Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.07; H, 5.14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2cc(Br)ccc2NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1Cc2cc(Br)ccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A stirring mixture of 87E (0.60 g, 1.76 mmol), K2CO3 (0.49 g, 3.52 mmol), and benzyl bromide (0.36 g, 2.11 mmol) in acetone (15 mL) was heated to reflux under argon for 16 h. The mixture was then cooled to RT and the solvent was evaporated under vacuum. The resulting residue was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried (Na2SO4), and evaporated. The resulting crude product was chromatographed on silica gel eluted with 10-20% EtOAc in hexane (step-wise gradient) to obtain the title compound (0.72 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[N:10]=1)[C:5]([OH:7])=O.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH2:21][CH2:20]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:4]([C:5]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=3)[CH2:20][CH2:21]2)=[O:7])[CH:3]=1
Reactant: CS(=O)(=O)Nc1cc(C(=O)O)cc(Cl)n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.28 g (1.1 mmol) 2-chloro-6-methanesulphonylamino-isonicotinic acid, 0.16 g (1.1 mmol) 5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEA in 4.0 mL DMF were mixed with 0.39 g (1.2 mmol) TBTU and stirred for 2 h at RT. The reaction mixture was purified by HPLC. The product fractions were combined and evaporated down.