Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.C1COCC1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(OC)(C)C>[Si:18]([O:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1OCC[C@@H]1O
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](O[C@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a stirred solution of (S)-3-hydroxydihydrofuran-2(3H)-one (5.24 g, 51.4 mmol), imidazole (3.8 g, 56 mmol), and THF (70 mL) at 0° C., under N2, was added t-butyldiphenylsilyl chloride (11.8 g, 43 mmol) dropwise. The mixture was stirred at 0° C. for 6 hours. TBME (150 mL) was added and the solution was washed with water (2×100 mL), brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure to afford (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (13.9 g, 95%) as a slightly yellow oil. 1H-NMR (400 MHz, CDCl3) δ 7.84-0.82 (m, 2H), 7.73-7.71 (m, 2H), 7.50-7.40 (m, 6H), 4.41-4.31 (m, 2H), 4.06-4.00 (m, 1H), 2.29-2.19 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>ClCCl>[CH3:23][S:24]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Yield: 57.9 %

Procedure:
To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (3.8 g, 17.65 mmol, 1.00 equiv) and triethylamine (3.9 g, 38.54 mmol, 2.20 equiv) in dichloromethane (40 mL) was added methanesulfonyl chloride (2.43 g, 21.21 mmol, 1.21 equiv) dropwise with stirring at 0° C. The reaction mixture was stirred overnight at room temperature. Water (50 mL) was added to quench the reaction. The resulting mixture was extracted with 3×50 mL of dichloromethane. The combined organic layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.0 g (58%) of tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C[N:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=C([N+]([O-])=O)C1=O.N>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:10]=[CH:15][C:14]([N+:16]([O-:18])=[O:17])=[CH:13][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: ClC(Cl)Cl
Product: CC1CCc2ncc([N+](=O)[O-])cc2C1
Yield: 72.7 %

Procedure:
4-Methylcyclohexanone (170 mg, 1.52 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (300 mg, 1.51 mmol) in 1M methanolic ammonia (30 mL, 30 mmol). The solution was heated at gentle reflux for 3 h. Evaporation of the solvent gave an orange residue which was suspended in CHCl3 and flash chromatographed over silica gel (16 g) eluting with EtOAc/hexane (1:10) to afford a white solid (211 mg, 73% yield): mp 50-52° C.
Reaction SMILES: [C:1](=[O:15])([O:12][CH:13]=[CH2:14])[O:2][C:3]1[CH:8]=CC([N+]([O-])=O)=CC=1.OCC[O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22].CS(C)=O.[OH-].[Na+]>O>[C:1](=[O:15])([O:12][CH:13]=[CH2:14])[O:2][CH2:3][CH2:8][O:24][C:20](=[O:19])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)OCCO
Reactant: C=COC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=COC(=O)OCCOC(=O)C(=C)C

Procedure:
A solution of p-nitrophenyl vinyl carbonate, hydroxyethylmethacrylate, DMSO and sodium hydroxide is stirred at room temperature for a minimum of 12 hours. Reaction completion is monitored by G.C. The solution is drowned into water and the mixture extracted with ethyl acetate. The product solution is washed with water, dried with magnesium sulfate, then stripped to an oil under vacuum. The crude product is then purified.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:2][CH3:3].[Cl:13][CH:14]=[CH:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:13]/[CH:14]=[CH:15]/[CH2:16][N:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:1][CH2:2][CH3:3]
Reactant: CCCNCc1cccc(O)c1
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCN(C/C=C/Cl)Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 3.30 g (20 mmol) of N-propyl-3-hydroxybenzylamine in 20 ml of dimethyl sulfoxide were added 1.82 g (20 mmol) of 1,3-dichloropropene (E/Z=2/1) and 1.38 g (10 mmol) of ground potassium carbonate under ice cooling. The mixture was stirred for 1.5 hours at room temperature and for 3 hours at 50° C., poured into 70 ml of ethyl acetate, washed with 50 ml×2 of water and 50 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 2.29 g (yield: 48%) of the above identified compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1[OH:28].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:28][C:21]1[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=1[Cl:19]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Oc1ccccc1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)c(Cl)cc2Cl)c(Cl)c1Oc1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 28.4 gm of 2,3-dichloro-6-nitro-1-phenoxy-benzene, 21.6 gm of 2,4,5-trichloro-phenol, 10 ml of 10 N sodium hydroxide and 80 ml of dimethylsulfoxide was stirred for 6 hours at 100° C. Thereafter, the reaction mixture was admixed with 600 ml of 1 N sodium hydroxide, and the precipitated product was collected by suction filtration and recrystallized from 150 ml of ethanol. 31 gm (77.4% of theory) of the title compound, m.p. 112° C., were obtained. An additional amount of the product (about 6 gm) was obtained by evaporating the filtrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH2:17]([O:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[CH3:18]>C1CCCCC1.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:23])[CH3:18]
Reactant: CCOC(=O)C(C)(C)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine and 2,2-dimethyl-malonic acid monoethyl ester (Holmes et al., J. Amer. Chem. Soc. 1984, 106, 2353). Yield after flash-chromatography with cyclohexane/ethyl acetate 7:3: 79%. Colorless oil. MS: m/e=359 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N#CCC(=O)c1cccc(Br)c1
Reactant: N=CN(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A mixture of 2-(3-bromobenzoyl)acetonitrile (16.5 g, 73.6 mmol) and N,N-diphenylformamidine (14.5 g, 73.6 mmol) in xylene (100 ml) was heated at reflux under a nitrogen atmosphere. After 3 h, the reaction mixture was cooled to room temperature and diluted with ether to give 2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (17.9 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>ClCCl.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][C:14]=1[N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc(F)cc2)cc1N1CCN(C)CC1
Yield: 88.9 %

Procedure:
4-Fluorobenzoyl chloride (0.23 ml, 1.95 mmol) with 4-methoxy-3-(4-methyl-1-piperazinyl)phenylamine (400 mg, 1.95 mmol) in dry dichloromethane (40 ml) and triethylamine (1 ml) was stirred for 1 h. The solution was partitioned between dichloromethane (40 ml) and saturated aqueous potassium carbonate (40 ml), the organic solution dried (sodium sulphate) and evaporated to dryness under reduced pressure to afford an oil, which was purified by column chromatography (silica, chloroform,/methanol 5%) to afford the tide compound (595 mg, 89%) which was crystallised from methanol/diethyl ether as the oxalate salt.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([OH:32])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
23.8 ml of diisopropylamine were initially charged under argon in 250 ml of THF and cooled to 0° C., and 70 ml of n-butyllithium solution (2.5 M in toluene) were added. The mixture was stirred at 0° C. for 30 minutes, then cooled to −75° C., 16.2 ml of ethyl acetate were added slowly and the mixture was stirred for 30 minutes. Then, at −75° C., 30 g of p-benzyloxybenzaldehyde, dissolved in 250 ml of THF, were added dropwise (internal temp. max. −68° C.; 1 h). The mixture was stirred for a further 20 minutes and then the reaction mixture was quenched with 200 ml of sat. NH4Cl solution and 20 ml of 1 N HCl (internal temp. max. −50° C.). The mixture was allowed to thaw to room temperature, the phases were separated and the organic phase was washed three times with 100 ml each time of sat. NH4Cl solution and once with 100 ml of sat. NaCl solution. The solvent was removed under reduced pressure. The residue was extracted by stirring with n-heptane/2% THF and the precipitated solid was filtered off with suction and dried under reduced pressure at 40° C. This gave 41 g of ethyl 3-(4-benzyloxyphenyl)-3-hydroxypropionate as a colorless solid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([F:27])[C:25]=1[F:26])[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:21]=[C:20]2[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40]>O.O1CCOCC1.C(OCC)(=O)C.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>[F:26][C:25]1[C:24]([F:27])=[C:23]2[C:19]([C:20]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:21][N:22]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:18][C:17]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(Br)cc12
Reactant: OB(O)c1ccccc1
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(-c3ccccc3)cc12
Yield: 96.3 %

Procedure:
469 mg of phenylboronic acid, 760 mg of sodium carbonate in 30 cm3 of water and 379 mg of tetrakis(triphenylphosphine)palladium are added to 1.15 g of N-(5-bromo-6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl)butanamide, prepared in Example 104, in 150 cm3 of dioxane, and the mixture is refluxed for 4 hours. The reaction medium is diluted with 100 cm3 of ethyl acetate and 75 cm3 of water and filtered through a sinter funnel packed with Celite. The organic phase is separated out after settling of the phases has taken place, washed with 75 cm3 of water and with 75 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 2 g of crude product in the form of a black oil. The crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa, 45° C.); to give 1.1 g of N-[6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([CH:27]=1)[OH:26]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3].CO>[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([OH:26])[C:27]=1[CH3:1]
Reactant: Cc1cc(O)ccc1O
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [Cr+3]
Agent: Cc1c(O)ccc(O)c1C
Agent: [O-2]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.115 g of methylhydroquinone, 3.268 g of methanol and 4.6 mg of chromium oxide (manufactured by High Purity Chemicals). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 18 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 17% by mole, the selectivity of dimethylhydroquinone was 74% by mole and the selectivity of trimethylhydroquinone was 2% by mole. No tetramethylhydroquinone was produced.
Reaction SMILES: [N+:1]([O:4][CH2:5][C:6]([CH2:17][O:18][N+:19]([O-:21])=[O:20])([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:7][O:8]C(=O)C)([O-:3])=[O:2].[OH-].[Na+].C(O)C.Cl>CC(C)=O.O>[N+:1]([O:4][CH2:5][C:6]([CH2:7][OH:8])([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:17][O:18][N+:19]([O-:21])=[O:20])([O-:3])=[O:2]
Reactant: CC(=O)OCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])OCC(CO)(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 67.6 %

Procedure:
Pentaerythritol acetate trinitrate (2.0 grams, 0.006 mol) was dissolved in 20 ml of acetone and added to a solution of 332 mg of NaOH dissolved in 10 ml of water. To this mass was added 5 ml of ethanol to effect solution. The solution was stirred at room temperature for 30 minutes whereupon 1N HCl was added to bring the pH of the solution to approximately 7. The volatiles were removed under vacuum and the remaining liquid was extracted twice with ether. The combined ether extracts were washed with brine and concentrated. The mixture was purified by flash chromatography (1:1, ether:hexane) to isolate a product of Rf =0.5. About 1.1 gram of pentaerythritol trinitrate was isolated as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1.F[C:17]1C=C(C)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=1C.[Cl-].[Na+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:5]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=[C:18]([CH3:17])[C:3]=1[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[C:10]1=[O:15]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1F
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc[nH]c1=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 452 mg (4.03 mmol) of potassium tert-butoxide are added to 336 mg (2.69 mmol) of 3-methoxypyridinone in 10 ml of DMF, and the mixture is stirred at room temperature for 30 min. 500 mg (2.96 mmol) of 1-fluoro-2,5-dimethyl-4-nitrobenzene are added, and the mixture is stirred at 80° C. After 22 h, the mixture is heated at 120° C. and stirred for a further 20 h. The mixture is then cooled and added to 100 ml of water and 15 ml of saturated aqueous sodium chloride solution. The mixture is extracted three times with in each case 300 ml of ethyl acetate, and the combined organic phases are dried over sodium sulphate. After filtration, the solvents are removed under reduced pressure and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1). This gives 383 mg (52% of theory) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2ocnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ocnc2c1
Yield: 39.6 %

Procedure:
A mixture of 5-methylbenzoxazole (200 mg, 1.50 mmol), N-bromosuccinimide (321 mg, 1.80 mmol), and 2,2′-azobisisobutyronitrile (37 mg, 0.23 mmol) in CCl4 (3 mL) was heated at reflux for 22 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the crude material on silica gel (5% EtOAc/hexanes) gave the title compound as a colourless crystals (126 mg, 39%). 1H NMR (CDCl3) δ 4.64 (s, 2H), 7.46 (dd, 1H, J=8.6, 1.7 Hz), 7.57 (d, 1H, J=8.4 Hz), 7.83 (d, 1H, J=1.2 Hz), 8.12 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([F:9])[CH:5]=[C:6](C)[CH:7]=1.C=O.[BrH:12].[C:13](O)(=O)[CH3:14]>O>[CH3:1][C:2]1[CH:3]=[C:4]([F:9])[CH:5]=[C:13]([CH3:14])[C:7]=1[CH2:6][Br:12]
Reactant: Br
Reactant: Cc1cc(C)cc(F)c1
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Product: Cc1cc(F)cc(C)c1CBr
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 3,5-dimethyl-fluorobenzene (5 g, 0.04 mol), paraformaldehyde (15 g), hydrobromic acid (70 ml) (30% in acetic acid) and acetic acid (25 ml) was stirred at ambient temperature for 4.5 h. To the mixture were water and petroleum ether added and the organic layer was separated dried over anhydrous sodium sulfate and evaporated carefully under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether as eluent to give the desired product. (3.7 g, 43%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](F)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.N1CCNCC1.S(F)(F)(=O)=O>C(OCC)(=O)C>[CH2:24]([O:23][C:21]([N:15]1[CH2:16][CH2:17][N:18]([S:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=2)(=[O:13])=[O:12])[CH2:19][CH2:20]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)F)ccc1Cl
Agent: C1CNCCN1
Agent: O=S(=O)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)CC1
Reaction time: 14 h
Yield: 80.8 %

Procedure:
2-Chloro-5-fluorosulfonylbenzoic acid (Acros Organics, 105 mg, 440 μmol, 1.0 eq) was placed in a vial and the vial was flushed with nitrogen and a positive pressure was maintained. Anhydrous dichloromethane (1.4 mL) was added, followed by ethyl 1-piperazine carboxylate (80 μL, 528 μmol, 1.2 eq) and ethyldiisopropylamine (redistilled, 80 μL, 440 μmol, 1.0 eq). The miXture was stirred for 1.5 h after which time additional piperazine was added (60 μL, 352 μmol, 0.8 eq). After 14 h the mixture was analyzed by reverse-phase HPLC-MS in negative ionization mode. The sulfonyl fluoride starting material was present, as well as a less polar compound showing (M-1) ion in about 35:65 ratio. An additional 0.35 eq of piperazine and ethyldiisopropylamine each (154 μmol, 30 μl) were added and the mixture was stirred for 4 h. HPLC-MS at this time indicated little progress and an additional 0.25 eq of piperazine (100 μmol, 20 μl) was added. After stirring for 14 h HPLC-MS indicated the reaction was complete. The reaction mixture was diluted with 2 mL of ethyl acetate, washed with 1M HCl solution (2×1 mL) and dried over anhydrous sodium sulfate. The solution was filtered, the solvents removed on a rotary evaporator and vacuum pump to afford 134 mg of a white solid, 81%. NOTE: Addition of excess nucleophilic amine at the beginning of the reaction results in significant bis addition, giving sulfonamide and carboxamide product. Stepwise addition of nucleophilic amine as needed suppresses formation of this side product.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-:20])=[O:19])=[C:13](F)[C:12]=1[F:22]>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([I:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[C:14]([N+:18]([O-:20])=[O:19])=[C:15]([F:17])[CH:16]=[C:11]([F:10])[C:12]=1[F:22]
Reactant: Nc1ccc(I)cc1F
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A solution of 4-iodo-2-fluoro aniline (3.64 g, 15.37 mmol) in dry THF (100 mL) was cooled to −78° C. in a dry ice-acetone bath under a nitrogen atmosphere. To this solution was added dropwise via syringe a 1 M solution of LHDMS in THF (15.4 mL). During the addition the solution turns green and the mixture was stirred at that temperature for an additional 1 h. The mixture was cooled and to it was then added dropwise a solution of 1,2,3,5-tetrafluoro-4-nitrobenzene (3 g, 15.37 mmol) in dry THF (10.0 mL) via syringe. During the addition the color of the mixture changes to dark purple. The mixture was then allowed to stir at −78° C. for 1 h and then warmed to room temperature and stirred overnight (12 h). The mixture was then concentrated under vacuo to remove ⅔ of the THF, diluted with ethyl acetate (100 mL), washed with water (2×50 mL), and finally with brine. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by careful flash column chromatography over silica gel using a 1-5% ethyl acetate/hexanes gradient to afford the desired product as a yellow solid (4.4 g, 70%). 1H NMR (400 MHz, DMSO-d6): 6.85 (t, 1H), 7.35 (d, 1H), 7.60-7.65 (m, 2H), 8.78 (s, 1H).