Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]([F:19])=[C:4]([F:20])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:22]>C1COCC1.CO>[CH3:22][O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[CH:3][C:4]([F:20])=[C:5]([F:19])[C:6]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=C(O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3.18 g, 8.77 mmol) in THF-MeOH (16 mL/5 mL) was added TMSCHN2 (5.30 mL, 10.6 mmol, 2 M solution in hexanes) at room temperature. The resulting mixture was stirred for 1 hour, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (3.31 g, 100%) that was used directly without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[C:11](B(O)O)[CH:10]=[N:9][CH:8]=1.[Br:16][C:17]1[CH:30]=[CH:29][C:28]2[O:27][C:26]3[C:21](=[CH:22][C:23](I)=[CH:24][CH:25]=3)[C:20]3([CH2:35][S:34][C:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:32]3)[C:19]=2[CH:18]=1.COCCOC>CCOC(C)=O.O>[Br:16][C:17]1[CH:30]=[CH:29][C:28]2[O:27][C:26]3[C:21](=[CH:22][C:23]([C:11]4[CH:12]=[N:7][CH:8]=[N:9][CH:10]=4)=[CH:24][CH:25]=3)[C:20]3([CH2:35][S:34][C:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:32]3)[C:19]=2[CH:18]=1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)NC1=NC2(CS1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a mixture of sodium carbonate (1.562 g, 14.74 mmol), palladium tetrakistriphenylphosphine (0.454 g, 0.393 mmol), pyrimidin-5-ylboronic acid (0.791 g, 6.39 mmol) and 2′-bromo-N-tert-butyl-7′-iodo-5H-spiro[thiazole-4,9′-xanthen]-2-amine (2.600 g, 4.91 mmol) in a resealable pressure tube, was added DME (15 mL) and water (5 mL) at RT. The tube was sealed and heated to 80° C. After 24 hrs, the mixture was cooled to RT, diluted with EtOAc, and washed with water and brine. The organic fraction was adsorbed onto silica gel and purified by silica gel chromatography using 40% hexanes:EtOAc to afford 2′-bromo-N-tert-butyl-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine MS: MH+=481.0/483.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14](P(OCC)(OCC)=O)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]1[C:30]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1)=O>C1COCC1>[CH2:3]([O:10][C:11]([NH:13]/[C:14](=[CH:27]\[C:29]1[C:30]([NH:41][C:42]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:48])=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1)/[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(-c2ccccc2)cnc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.3 %

Procedure:
To a slurry of 60% of sodium hydride (156 mg, 3.90 mmol) in THF (8 niL) at 0° C. was added 1A (1.2 g, 3.34 mmol) in several portions over 10 min. The reaction mixture was then brought to RT for 20 min, then cooled again at 0° C. A suspension of 1D (830 mg, 2.78 mmol) in THF (10 mL) was added over 10 min at 0° C., then the reaction was warmed up to RT. After stirring for 20 min, the reaction was quenched with water (30 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined organics were dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with CH2Cl2-hexanes to give the title compound (620 mg). The mother liquid was concentrated and the resulting residue was purified by silica gel (110 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give additional 130 mg of the title compound (total 750 mg, 54%) as an off-white solid. LC/MS (method A): retention time=3.40 min, (M+H)+=504.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH:7]([CH3:9])[O:6][C:5]1=[O:10])(=O)[CH3:2].[Na].[CH:12]1(C=O)[CH2:17][CH2:16]C[CH2:14][CH2:13]1>C(OC(OCC)CC)C>[CH:2]1([CH:1]=[C:4]2[CH2:8][CH:7]([CH3:9])[O:6][C:5]2=[O:10])[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1
Reactant: CC(=O)C1CC(C)OC1=O
Reactant: O=CC1CCCCC1
Agent: CCOC(CC)OCC
Agent: [Na]
Product: CC1CC(=CC2CCCCC2)C(=O)O1
Yield: 97.8 %

Procedure:
Example I was repeated using propionaldehyde diethyl acetal as the azeotropic solvent for the reaction to produce the -alkylidene lactone. For this experiment 100 ml propionaldehyde diethyl acetal was charged to the reactor with 14.9 g (0.10 mole) 3-acetyl-5-methyldihydro-2(3H)-furanone. The mixture was stirred and 4 g (0.10 mole) powdered sodium hydroxyde added. The mixture was allowed to stir for 10 minutes and then heated to reflux for 51/2 hours after which time 14.0 g (0.125 mole) cyclohexanecarboxaldehyde was added over a one-hour period. The mixture was heated under reflux for an additional twelve hours, cooled and worked up to recover 19 g crude 3-cyclohexylmethylene-5-methyldihydro-2(3H)-furanone (59% yield). The structure of the product was confirmed by proton and carbon nuclear magnetic resonance spectroscopy.
Reaction SMILES: CN1CCCC1=O.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Sn](C)(C)[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:39][CH:38]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:37][N:36]=2)=[CH:31][CH:30]=1.[CH3:47][C:48]([O:51][C:52]([N:54]1[CH2:59][CH:58]=[C:57](OS(C(F)(F)F)(=O)=O)[CH2:56][CH2:55]1)=[O:53])([CH3:50])[CH3:49]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:42]([NH:41][CH2:40][CH:38]1[O:37][N:36]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([C:57]3[CH2:58][CH2:59][N:54]([C:52]([O:51][C:48]([CH3:50])([CH3:49])[CH3:47])=[O:53])[CH2:55][CH:56]=3)=[CH:30][CH:31]=2)[CH2:39]1)(=[O:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC(=O)NCC1CC(c2ccc([Sn](C)(C)C)cc2)=NO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)NCC1CC(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)=NO1
Reaction time: 12 h

Procedure:
To a flame dried flask containing a pre-stirred slurry of 1-methyl-2-pyrrolidinone (15 mL), tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol), triphenylarsine (4 mg, 0.12 mmol) under an inert atmosphere is added N-[[4,5-dihydro-3-[4-(trimethylstannyl)phenyl]-5-isoxazolyl]methyl]acetamide (580 mg, 1.52 mmol) and 3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (450 mg, 1.37 mmol) and stirred for 12 hours. The reaction is diluted with ethyl acetate (100 mL) and water (50 mL). The organic phase is separated, extracted with water (5×50 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with methylene chloride/methanol (99/1). The appropriate fractions are combined (Rf =0.28, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 117-120° C.
Reaction SMILES: [CH2:1]([CH:3]([CH:9]([N+:11]([O-:13])=[O:12])[CH3:10])[CH2:4][CH:5]([OH:8])[C:6]#[N:7])[CH3:2].S(=O)(=O)(O)[OH:15].[C:19](O)([CH3:22])([CH3:21])[CH3:20]>O>[C:19]([NH:7][C:6](=[O:15])[C:5](=[O:8])[CH2:4][CH:3]([CH2:1][CH3:2])[CH:9]([N+:11]([O-:13])=[O:12])[CH3:10])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)O
Reactant: CCC(CC(O)C#N)C(C)[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCC(CC(=O)C(=O)NC(C)(C)C)C(C)[N+](=O)[O-]
Temperature: 75 °C

Procedure:
To a solution of 4-ethyl-2-hydroxy-5-nitrohexane nitrile (1.7 g) in t-butanol (6.8 ml) was added conc. sulfuric acid (0.8 ml) at 0° C. with stirring. After stirring for an hour at room temperature, the mixture was heated at 75° C. for an hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and then evaporated to dryness in vacuo. The resulting oil was dissolved in acetic acid (9 ml) and chromium trioxide (0.82 g) was added thereto. The resulting mixture was heated at 100° C. for 1.5 hours, with stirring, concentrated, diluted with water, and then extracted with ethyl acetate. The extract was washed successively with water and brine, and then dried over magnesium sulfate. Removal of the solvent gave an oil which was purified by a preparative thin layer chromatography (solvent: chloroform) to give N-t-butyl-4-ethyl-5-nitro-2-oxo-hexanamide (0.46 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][NH2:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:10][C:11]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:27])[Cl:28])[CH:20]=[C:19]([Cl:29])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][N:18]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCON=Cc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a mixture of 0.15 g of benzaldehyde and 10 ml of pyridine was added 0.56 g of O-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.50 g (yield, 79.4%) of benzaldehyde O-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)oxime, nD22.5 1.5797.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.Cl.[NH2:18][C@H:19]([CH3:23])[C:20]([NH2:22])=[O:21].C(N(CC)CC)C>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:18]([C@H:19]([CH3:23])[C:20]([NH2:22])=[O:21])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 52 °C
Reaction time: 3 h

Procedure:
To a solution of 5-nitro-isochromen-1-one (2 g, 0.01 mol) in methanol (40 mL, 1 mol) was added (R)-2-aminopropanamide hydrochloride (2.0 g, 0.016 mol) and triethylamine (2.6 mL, 0.019 mol) and stirred at 52° C. for 3 hr. The product (yellow solid) precipitated out and was filtered and carried on to the next reaction. MS m/z=262.1 (M+1).
Reaction SMILES: [Cl-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]=[N:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[OH:21])[CH:4]=1.[S:22]([O:27]C)([O:25][CH3:26])(=[O:24])=[O:23]>>[CH3:26][O:25][S:22]([O-:27])(=[O:24])=[O:23].[OH:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[N:10]=[N:9][C:5]1[CH:4]=[N+:3]([CH3:26])[CH:8]=[CH:7][CH:6]=1
Reactant: Oc1ccc2ccccc2c1N=Nc1cccnc1
Reactant: COS(=O)(=O)OC
Agent: [Cl-]
Agent: [Na+]
Product: COS(=O)(=O)[O-]
Product: C[n+]1cccc(N=Nc2c(O)ccc3ccccc23)c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 50.25 pounds of sodium chloride and 37 pounds (67.5 moles) or 1-(3-pyridylazo)-2-naphthol was blended in a 4.6 ft.3Littleford-Lodige precision blender and 18.75 pounds (67.5 moles) of dimethyl sulfate added thereto over a period of about 60 minutes in nine portions. The temperature of the reaction was maintained at about 35° C and the mixture blended for about 1 hour after addition of the dimethyl sulfate was complete. The crude product weighed 100 pounds (95% yield) and contained less than 0.1% of the substrate base and less than 0.01% dimethyl sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.N(CCO)CCO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccc(Cl)cc1Cl
Temperature: -25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 2′,4′-dichloroacetophenone (10.9 g, 77.0 mmol) in anhydrous THF (80 mL) at −78° C. under nitrogen was slowly added a solution of (+)-B-chlorodiisopinocampheylborane ((+)-Ipc2BCl, 27.2, 85.0 mmol) in THF (15 mL). After the addition is complete, the reaction mixture was slowly warmed to −25° C. and stirred at this temperature for 2 h. The reaction mixture was then quenched with diethanolamine (17.9 g, 170 mmol), and stirred for 10 min. During this time, a solid formed and it was filtered off. The filtrate was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified flash chromatography (SiO2, 0-20% ethyl acetate in hexanes) to give (R)-1-(2,4-dichlorophenyl)ethanol (12.0 g, 63.3 mmol, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[I:12].C([O-])([O-])=O.[K+].[K+].I[CH2:20][CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:10]=[C:4]2[C:3]=1[I:12]
Reactant: CC(C)CI
Reactant: O=c1[nH]nc2c(I)c(Br)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a stirring solution of 7-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (2.0 g, 5.9 mmol) in 20 mL DMF at 20° C. was added K2CO3 (1.6 g, 11.8 mmol), followed by addition of 1-iodo-2-methylpropane (2.2 g, 11.8 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. Analysis by HPLC/MS indicated that starting material had been entirely consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted with diethyl ether and EtOAc. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure to obtain the title compound (2.1 g, 5.3 mmol) as a light tan solid. MS: [M+H]+=396. 1H NMR (CDCl3): δ 7.65 (d, J=1.9 Hz, 1H), 6.68 (d, J=1.8 Hz, 1H), 3.82 (d, J=1.8, 2H), 2.33-2.30 (m, 1H), 0.96 (d, J=1.7 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCC(=O)NCCCCn1c(C)nc2c(N)nc3ccccc3c21
Yield: 51.8 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with butyryl chloride (0.43 mL, 4.1 mmol) to provide 0.65 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]butanamide as an off white solid, m.p. 169.4-170.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[NH2:2].NC1C=C(C(F)=CC=1[F:36])C(N)=O.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[C:9]([F:10])=[CH:8][C:7]([F:36])=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc(N)c(F)cc1F
Reactant: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2cc(C(N)=O)c(F)cc2F)C(=O)O)cc1OC
Yield: 80 %

Procedure:
23A was prepared in a procedure similar to that of 13A using 3-amino-4,6-difluorobenzamide, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 80%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.73-3.87 (m, 6H) 5.07 (s, 1H) 6.92 (t, J=7.69 Hz, 1H) 6.96-7.13 (m, 4H), LCMS: 367 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([S:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:4]=[CH:5][C:6]=1[O:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(S)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Sc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl

Procedure:
A mixture of 2,3-dichloro-4-methoxybenzenethiol (6.0 g., 0.024 mole), p-fluoronitrobenzene (3.04 ml., 0.029 mole) and anhydrous potassium carbonate (5.15 g., 0.038 mole) in 60 ml. of DMF was stirred at room temperature for 2 hours and then poured into water. The resulting solid product was filtered and washed well with ethanol to give 9.1 g. (96%), m.p. 236°-237°.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([C@@:1]2([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cn([C@@]2(C(=O)c3ccc([N+](=O)[O-])cc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 58 %

Procedure:
Thymidine (2.42 g; 10 mmol) is dried by coevaporation in pyridine, then taken up in 200 ml of anhydrous pyridine and cooled to 4° C. p-Nitrobenzoyl chloride (2.04 g; 11 mmol) is added. The temperature is allowed to rise and the reaction is left overnight at room temperature. The reaction is stopped with 5 ml of saturated sodium bicarbonate. The reaction mixture is concentrated and then taken up in 500 ml of chloroform. The organic solution obtained is washed with 2×500 ml of 0.5M NaHCO3 and then with 250 ml of saturated NaCl. The aqueous phases are counter-extracted with 100 ml of CHCl3. The organic phases are evaporated. The pure product is obtained by column chromatography on silica. It is eluted with 5% of methanol in chloroform. Yield=58%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[Cl:18]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CNC(Cc1cc(Cl)ccc1N)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A stirred solution of 8 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 40 ml of N,N-dimethylformamide was treated with a solution of 6.41 g of N-chlorosuccinimide in 40 ml of N,N-dimethylformamide and then stirred at room temperature for 8 hours. Evaporation of the volatiles afforded an oil which was decanted into 100 ml of water, basified with 30 ml of 10% aqueous sodium hydroxide and extracted with dichloromethane (2×100 ml). The extract was washed with water (2×100 ml), dried over anhydrous sodium sulfate and concentrated. Thin layer chromatography of the resultant oil indicated a multicomponent mixture. Purification of the mixture was accomplished by successive HPLC separations (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the appropriate fractions afforded a residue which was dissolved in diethyl ether, filtered free of insolubles and concentrated. The resultant oil crystallized upon standing to yield 1.05 g of 2-amino-5-chloro-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 59°-61° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1)C.[OH-].[Na+].O>CO>[O:32]=[C:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][CH:7]=1)[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Yield: 84.3 %

Procedure:
To 1.44 g (3.17 mmol) of alpha-oxo-4-[(12-phenoxydodecyl)oxy]benzeneacetic acid ethyl ester in 100 ml of hot methanol was added 3.5 ml (3.5 mmol) of 1N NaOH. The mixture was heated on a steam bath for 5 minutes, water (20 ml) was added and the solvents were removed at reduced pressure. Water (100 ml) and 7.0 ml of 1.0N HCl were added to the residue and the product was extracted with methylene chloride-THF (4:1). The dried extract was concentrated at reduced pressure to a solid which was recrystallized from acetone-hexane to give 1.14 g (84% yield, mp 98°-100°) of alpha-oxo-4-[(12-phenoxydodecyl)oxy]benzeneacetic acid
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.O>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([O:18][CH2:31][C:32]([F:35])([F:34])[F:33])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate (i.e. product of Step A) (0.8 g, 3 mmol) stirred in dry acetonitrile (15 mL) at −5° C. was added potassium carbonate (0.85 g, 6.15 mmol). The suspension was stirred for 15 minutes at 20° C. The stirred suspension was then cooled to 5° C., and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.8 g, 3.45 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then heated to reflux, at which time thin layer chromatography showed the reaction to be complete. Water (25 mL) was added to the reaction mixture, which was then extracted with ethyl ether. The ether extract was dried over magnesium sulfate and concentrated to yield the title product compound (1.05 g) as a pale yellow oil.