Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([F:5])=[O:4].[F-:8].[K+].[CH2:10]=[C:11]([C:16](OS(F)(=O)=O)([F:18])[F:17])[C:12]([F:15])([F:14])[F:13]>COCCOCCOC>[F:17][C:16]([F:18])([O:4][C:3]([F:8])([F:5])[C:2]([F:7])([F:6])[F:1])[C:11]([C:12]([F:15])([F:14])[F:13])=[CH2:10]
Reactant: [F-]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Reactant: O=C(F)C(F)(F)F
Agent: [K+]
Solvent: COCCOCCOC
Product: C=C(C(F)(F)F)C(F)(F)OC(F)(F)C(F)(F)F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
Trifluoroacetyl fluoride (6 g, 0.051 mole) is bubbled into a mixture of KF (2.4 g, 0.041 mole) and dry diglyme (15 ml). The reaction mixture is stirred at 20° C. for 30 minutes and then CH2═C(CF3)CF2OSO2F (10 g, 0.041 mile) is added gradually. The resulting mixture is stirred at 20° C. for 1 hour. Hexafluoroisobutylene is distilled from the reaction mixture and the residue is poured into water. The organic layer. is separated, washed in turn with aqueous sodium bicarbonate solution and water, and then dried over MgSO4. Distillation gives 3,3-Difluoro-3-pentafluoroethoxy-2-trifluoromethylpropene (CH2═C(CF3)CF2OCF2CF3) (3.5 g, 31% yield, b.pt. 67° C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[CH:3]1.CS(C)=[O:16].[ClH:18]>>[ClH:18].[NH2:13][CH2:12][CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[O:16]
Reactant: Cn1cc(CCN)c2ccccc21
Reactant: CS(C)=O
Agent: Cl
Product: CN1C(=O)C(CCN)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-3-yl)ethanamine (2.5 g cude) in DMSO (1.33 g, 17.0 mmol) was added concentrated hydrochloric acid (1.2 mL) slowly. The resulting reaction mixture was stirred at room temperature in a sealed reactor for 16 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC to afford the title compound (1.5 g, 6.59 mmol, 45% yield over two steps) as a yellow solid. MS (ESI) m/z 191.1 [M+H]+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15][C:16]1[C:17](=O)[C:18]2[C:26](=[CH:27][CH:28]=1)[C:25]1[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:19]=2.C([O:32]CC)C>BrC(Br)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]1([OH:32])[C:18]2[CH:17]=[C:16]([Br:15])[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C1C(Br)=CC=C2C1=Cc1ccccc12
Reactant: CCOCC
Agent: CC(Br)Br
Agent: [Mg]
Product: OC1(c2ccccc2-c2ccccc2)c2ccccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 100 ml three neck distilling flask was charged with magnesium (1.26 g, 0.052 mol). Vacuum was formed in a system. The magnesium was heated to stir for 30 minutes to be activated. After cooling to room temperature, nitrogen gas stream was formed in the system. Then, 5 ml diethyl ether and a few drops of dibromoethane were added. And then, 2-bromobiphenyl (11.65 g, 0.050 mol) dissolved in 15 ml diethyl ether was slowly dropped. After dropping, the reaction was refluxed for 3 hours to be a Grignard reagent. A 200 ml three neck distilling flask was charged with 2-bromofluorenone (11.7 g, 0.045 mol) and 40 ml diethyl ether. The synthesized Grignard reagent was slowly dropped to the reacted solution. After the dropping, the solution was refluxed for 2 hours and stirred at room temperature overnight. After reaction, the reacted solution was washed with saturated ammonium chloride solution twice, and a water layer was extracted with ethyl acetate twice and washed with saturated salt solution twice with an organic layer. After drying with magnesium sulfite, the reacted solution was suctioned and filtrated, and condensed to give 18.76 g 9-(2-biphenylyl)-2-bromo-9-fluorenol in a solid state in a yield of 90%.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1)C.[OH-].[Na+]>CO.Cl.O>[CH3:25][S:22]([N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:26])=[O:3])[CH:11]=[CH:10][CH:9]=1)[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1cccc(CN(Cc2ccc(C)cc2)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(CN(Cc2cccc(CC(=O)O)c2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of (3-{[methanesulfonyl-(4-methyl-benzyl)amino]-methyl}-phenyl)-acetic acid ethyl ester (101.4 mg, 0.27 mmol) in MeOH (3 mL) was added aqueous NaOH (2N, 0.4 mL). The reaction was stirred at room temperature for 1 h and was diluted with a 1:1 mixture of 1 N HCl and water. The product was extracted into CH2Cl2 (3×) and the organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (87 mg). 1H NMR (400 MHz, CDCl3) δ 7.13-7.34 (m, 8H), 4.28 (d, 4H), 3.65 (s, 2H), 2.75 (s, 3H), 2.33 (s, 2H); MS 346 (M−1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=[O:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O>Cl.CCO.CC(O)=O.O.[Fe]>[NH2:1][C:4]1[C:5]([CH:14]=[O:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(C=O)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 770.4 %

Procedure:
8-nitroquinoline-7-carbaldehyde 204 (100 mg, 0.49 mmol), iron powder (0.02 ml, 4.95 mmol) and conc. HCl (2 drops) was suspended in a mixture of EtOH/AcOH/water (2:2:1) and the mixture was heated under reflux for 15 min and then stirred at room temperature for 25 min. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc and washed with sat. NaHCO3 solution until the pH remained neutral. The organic phase was purified by column chromatography with heptane/EtOAc (80:20) as the eluent to yield the title compound (650 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:22]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH3:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:22]=1
Reactant: COC(=O)c1ccc(C=Cc2nc3cc(C)c(C)cc3o2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2nc(C=Cc3ccc(C(=O)O)cc3)oc2cc1C
Yield: 89.8 %

Procedure:
A mixture of 3.0 g methyl 4-[(5,6-dimethyl-2-benzoxazolyl)vinyl]benzoate, 25 mL of acetic acid, 9.0 mL of concentrated sulfuric acid, and 7 mL of water is stirred and refluxed for three hours. The mixture is cooled and added to water. The product is collected by filtration, washed with water and air dried. The crude product is recrystallized from N,N-dimethylformamide to give 2.57 g of 4-[2-(5,6-dimethyl-2-benzoxazolyl)vinyl]benzoic acid, which melts at >300° C.
Reaction SMILES: C([N:18]([CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)[CH2:19][C:20]([OH:22])=[O:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH2:32][C@H:33]([C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])[CH:34]([CH3:36])[CH3:35].CN(C=O)C.N1CCCCC1>C(Cl)Cl>[CH:23]1([NH:18][CH2:19][C:20]([OH:22])=[O:21])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1.[NH2:32][C@H:33]([C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])[CH:34]([CH3:36])[CH3:35]
Reactant: O=C(O)CN(C(=O)OCC1c2ccccc2-c2ccccc21)C1CCc2ccccc21
Agent: C=CCOC(=O)[C@@H](N)C(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)CNC1CCc2ccccc21
Reaction time: 0.75 h

Procedure:
Fmoc-Indanylglycine-Val-OAllyl (0.758 g, 1.31 mmol) was solvated in CH2Cl2 (5 mL) and DMF (1.8 mL) followed by dropwise addition of piperidine (1.05 mL, 8.1 eq) over 30 seconds. After 45 min, the mixture was subjected to extraction CH2Cl2/brine (30/15 mL) and saturated NH4Cl (5 mL). The organic layer was dried over MgSO4, concentrates and purified by silica using a gradient of MeOH/CH2Cl2 (0 to 5%) to get 0.45 g of the desired compound.
Reaction SMILES: BrCC([O:5][CH2:6][CH3:7])=O.[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[NH:14]1[C:9]2[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:15][CH2:7][C:6]1=[O:5]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CNc2ccccc2N1

Procedure:
A solution of ethyl bromoacetate (III, 13.3 ml) in THF (50 ml) is added over 2 hr to a stirred solution of 1,2-phenylenediamine (II, 10.0 g) and triethylamine (16.8 ml) in THF (22 ml) and methylene chloride (22 ml). The mixture is heated at 60° for 3 hr, and is concentrated. The resulting solids are suspended and shaken vigorously in hexane (250 ml) and water (150 ml). The hexane layer is decanted, and the process is repeated with two additional 250 ml portions of hexane. The solids are filtered, dried and recrystallized from methylene chloride/hexane to give the desired product as a solid. The concentrated filtrate is purified by flash chromatography eluting with ethyl acetate/methylene chloride (25/75) to give additional title compound, mp 135°-136°: NMR (CDCl3) 8.30, 6.85-6.95, 6.65-6.80, 4.00 and 3.86 δ.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=[O:22].N#N.[CH2:29]([N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1)C=C>CN(C=O)C>[CH3:43][C:40]1[CH:39]=[CH:38][C:37]2[N:36](/[CH:2]=[C:3](/[C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)\[CH3:4])[C:35]3[CH2:44][CH2:45][N:32]([CH:29]=[O:22])[CH2:33][C:34]=3[C:42]=2[CH:41]=1
Reactant: C=CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(=CBr)c1ccncc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C=O)CC2)c1ccncc1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
4-(2-Bromo-1-methyl-vinyl)-pyridine (2.5 g, 13 mmol) and potassium phosphate (4.2 g, 20 mmol) were stirred for 5 min. DMF (20 mL) was added and the contents stirred for 5 min. L-proline (230 mg, 2.0 mmol) and cuprous iodide (190 mg, 1.0 mmol) were added to the reaction mixture and N2 bubbled into the reaction mixture. 2-Allyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.0 g, 10 mmol) was added and the contents heated at 120° C. for 16 h. After completion of reaction (as monitored by TLC) the reaction mixture was concentrated under vacuum and diluted with water. The desired compound was extracted with EtOAc (4×100 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by column chromatography [Eluent: 2% MeOH in DCM]. 1H NMR (DMSO, free base) δ (ppm): 8.60 (d, 2H), 8.20 (s, 1H), 7.64 (d, 2H), 7.42 (s, 1H), 7.32 (s, 1H), 7.10 (d, 1H), 6.98 (s, 1H), 4.60 (d, 2H), 3.80 (m, 2H), 2.80 (m, 2H), 2.41 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([O-:6])=[O:5].[OH:12][CH2:13]CCCNC(=O)OC(C)(C)C.[CH3:25]O>>[OH:1][C:2]1[CH:10]=[C:9]([O:12][CH3:13])[CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([O:6][CH3:25])=[O:5]
Reactant: CO
Reactant: O=C([O-])c1c(O)cccc1O
Reactant: CC(C)(C)OC(=O)NCCCCO
Product: COC(=O)c1c(O)cc(OC)cc1O

Procedure:
The tilted compound was prepared according to the procedure described for Example 12A, substituting 2,4,6-trihydroxybenzoate for 2,6-dihydroxybenzoate and methanol for tert-butyl 4-hydroxybutylcarbamate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O-:11].[Na+].C1C2C(=CC=CC=2)C=CC=1O.[C:24](=[O:26])=[O:25].S(=O)(=O)(O)O>O>[OH:11][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C=O
Reactant: [O-]c1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Agent: Oc1ccc2ccccc2c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 40 °C

Procedure:
In a pressure reaction vessel were charged 166 g of sodium 2-naphtholate, 72 g of 2-naphthol and 498 g of hydrogenated triphenyl, and a reaction was allowed to proceed at 260° C. and at a carbon dioxide pressure of 5 kg/cm2 (G) for 3 hours, with stirring. The reaction mixture was charged into 800 ml of water, and the resulting mixture was adjusted to a pH 5.5 with sulfuric acid, followed by separation into the reaction medium layer and the water layer at 85° C. The 2-naphthol was recovered with an aqueous sodium hydroxide solution from the reaction medium layer. After recovery of 2-naphthol, the water layer was adjusted to a pH 2.0 with sulfuric acid at the same temperature, cooled to 40° C. and subjected to filtration to give 89.3 g of 2-hydroxynaphthalene-3-carboxylic acid. The product was found to contain only 0.1% of 2-hydroxynaphthalene-6-carboxylic acid, with no trace of 2-hydroxynaphthalene- 1-carboxylic acid. The yield based on sodium 2-naphtholate was 47.5%, with the selectivity being 99.3%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:11]OC(OC)N(C)C.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>>[CH3:1][O:2][CH2:3][C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:11][N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:29]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COCc1nn(-c2ccc(OC)cc2)cc1C(=O)OC
Yield: 50 %

Procedure:
Using methyl 4-methoxyacetoacetate (5.8 g), dimethylformamide dimethylacetal (5.4 mL) and 4-methoxyphenylhydrazine hydrochloride (7.0 g) and in the same manner as in Example 15(1), the title object compound (5.5 g, 50%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:23]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:23])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(Br)c1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NCC(=O)c1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To an ice-cooled mixture of the product from Step A (4.6 g, 23 mmol) and diisopropylethylamine (4.46 g, 34.5 mmol) in dichloromethane (50 mL) was added 2-bromo-4′-chloroacetophenone (5.48 g, 23 mmol). The reaction mixture was stirred at room temperature for 3 hours and then diluted with dichloromethane (100 mL). The mixture was washed with water and brine, dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, 20 to 40% ethyl acetate/hexanes) purification provided the 2-(1-(3-bromophenyl)ethylamino)-1-(4-chlorophenyl)ethanone (6.0 g, 74%): 1H NMR (CDCl3, 300 MHz) δ 7.80 (dd, J=6.7, 2.0 Hz, 2H), 7.52 (t, J=1.7 Hz, 1H), 7.43-7.37 (m, 3H), 7.29-7.17 (m, 2H), 3.93 (d, J=1.4 Hz, 2H), 3.80 (q, J=6.6 Hz, 1H), 1.42 (d, J=6.6 Hz, 3H). ESI MS m/z=352 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].N1C=CC=CC=1.[CH2:19]([O:21][C:22](Cl)=[O:23])[CH3:20]>CC(N(C)C)=O>[CH2:19]([O:21][C:22]([N:9]([C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:12])[NH2:10])=[O:23])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: NNC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCOC(=O)N(N)C(=O)c1cc(Cl)ccc1O
Temperature: 90 °C

Procedure:
37.2 g of 5-chloro-2-hydroxybenzoic acid hydrazide are dissolved in 200 ml of dimethylacetamide and 16 g of pyridine and 22 g of chloroformic acid ethyl ester are added simultaneously over the course of 30 minutes. The reaction mixture is subsequently heated to 90° C for 3 hours whilst stirring, cooled and poured onto 1 litre of ice water. The precipitate which has separated out slowly crystallises throughout. The N-(5-chloro-2-hydroxybenzoyl)-hydrazinecarboxylic acid ethyl ester thus obtained (Stabiliser No. 11) is isolated, washed with water and recrystallised from ethanol. Melting point 172° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].[Cl:17]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl.CO>[Cl:17][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:12][C:13]([F:14])([F:15])[F:16])[C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(OC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(Cl)c(O)c(OC(F)(F)F)c1
Temperature: 50 °C
Reaction time: 19 h
Yield: 112.4 %

Procedure:
Methyl 4-hydroxy-3-trifluoromethoxybenzoate (2.05 g) was dissolved in chloroform (20 mL) and methanol (3 mL), and N-chlorosuccinimide (1.39 g) and trifluoromethanesulfonic acid (0.05 mL) were added to the solution, and then the mixture was stirred at 50° C. for 19 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.64 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Cl[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[O:18][N:17]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[O:18][N:17]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: Cc1noc(C)c1-c1nc(Cn2c(C)cc3c(Cl)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 5.81 (s, 2 H), 3.30 (s, 3H), 2.66 (s, 3H), 2.39 (s, 3H); MS (ES) m/z 368 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][N:14]=[CH:13]1.C(N(CC)CC)C>COCCOC>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NCCCn1ccnc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1cc(NCCCn2ccnc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
A mixture of 31.2 g (0.2 mol) of 4-fluoro-2-methyl-1-nitrobenzene, 37.5 g (0.3 mol) of 3-imidazol-1-ylpropylamine and 34.8 ml (0.25 mol) of triethylamine in 30 ml of 1,2-dimethoxyethane was heated with stirring for 3 hours on a boiling water bath.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Br[CH2:31][CH2:32][N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:31][CH2:32][N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(OCCN2C(=O)c3ccccc3C2=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.90 g (5.0 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (product of Description 1) were dissolved in 20 ml of THF. 3.80 g (14.9 mmol) of N-(2-bromoethyl)phthalimide dissolved in 15 ml of THF, 2.00 g (14.5 mmol) of K2CO3 and 0.25 g of KI were added and the suspension was stirred at room temperature for 2.5 hours and then refluxed for 2 hours. Additional 1.90 g (7.4 mmol) of N-(2-bromoethyl)phthalimide and a catalytic amount of KI were added and the reaction refluxed for 3.5 hours; additional 0.50 g (2.0 mmol) of N-(2-bromoethyl)phthalimide and a catalytic amount of KI were added and the reaction refluxed for 5 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15].C[Si](C)(C)[O:18][C:19]([CH:21]=[CH2:22])=[CH2:20].C1(C)C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:15][O:14][C:4]1[CH:5]=[C:6]([CH:9]2[CH:10]([N+:11]([O-:13])=[O:12])[CH2:22][CH2:21][C:19](=[O:18])[CH2:20]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Temperature: 140 °C
Reaction time: 48 h

Procedure:
90.0 g of 3,4-dimethoxy-w-nitrostyrene (compound G2), 90 ml of 2-trimethylsilyloxy-1,3-butadiene and 180 ml of abs. Toluene are put in an autoclave, where the mixture is stirred at 140° C. for 2 days and then cooled. After addition of 1000 ml of ethyl acetate, 300 ml of a 2 N solution of hydrochloric acid are dropped under stirring. The phases are separated and the aqueous layer is extracted three times with dichloromethane. The combined organic extracts are washed with saturated sodium hydrogen-carbonate solution, dried over magnesium sulfate and the solvents are removed under reduced pressure to give 150 g of the crude title compound. Further purification is carried out by chromatography on silica gel using petroleum ether/ethyl acetate in the ratio 1/1 as eluent to give 81.5 g (67% of theory) of the pure title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])=[O:3].CI.[C:14](=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[O:11][CH3:14])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(F)cc1O
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
A solution of 4-fluoro-2-hydroxyacetophenone (1 g, 6.5 mmol), methyl iodide (0.4 ml), potassium carbonate (1.34 g, 9.7 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir at room temperature for 2 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to afford 1.1 g (100%) of product as a light yellow solid: mp 50-51.5° C.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17]>C1COCC1.C(O)(=O)C.O>[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](=[O:17])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COC(=O)c1ccccc1C
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)c1ccccc1C)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
n-Butyl lithium (1.58N, 52.5 ml, 83 mmol) was added dropwise to a stirred solution of dimethyl methylphosphonate (10.3 g, 83 mmol) in 100 ml of anhydrous THF at -78° C. under argon atmosphere. After 30 minutes, methyl o-methylbenzoate (5.0 g, 33 mmol) in 10 ml of anhydrous THF was added dropwise. After being stirred for 30 minutes, this reaction mixture was allowed to warm to 0° C., diluted with 5 ml of acetic acid and 10 ml of water, and concentrated. 20 ml of water was added and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give an oil of dimethyl 2-o-methylphenyl-2-oxoethylphosphonate (68 g, 28.1 mmol, yield 85.1%, b.p. 134°-136° C./0.21 mmHg), which was assigned the structure by the following data: