Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]([OH:45])[CH:41]=[C:42]([OH:44])[CH:43]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>C1COCC1.CN(C=O)C>[CH2:62]([O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:45][C:40]1[CH:39]=[C:38]([O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:43]=[C:42]([O:44][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:41]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: BrCCOCCOCCOCCOCCOCc1ccccc1
Reactant: Oc1cc(O)cc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(COCCOCCOCCOCCOCCOc2cc(OCCOCCOCCOCCOCCOCc3ccccc3)cc(OCCOCCOCCOCCOCCOC(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 118.7 %

Procedure:
To an ice-cooled mixed suspension of sodium hydride (350 mg, 8.8 mmol; 60% in mineral oil) in THF (4.5 ml) and DMF (1.5 ml), a mixed solution of Compound 45 (1.0 g, 1.7 mmol) in THF (4.5 ml) and DMF (1.5 ml) was gradually added, and this was followed by stirring for 30 minutes. A solution of Compound 20 (2.7 g, 6.8 mmol) in THF (4 ml) was added thereto, and this was followed by stirring for 20 minutes. After the ice bath was removed, stirring was further conducted at room temperature for 4 hours. After the product was again immersed in the ice bath, water was carefully added to stop the reaction, and this was followed by concentration under reduced pressure. Extraction from ethyl acetate was conducted, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. Filtration and concentration under reduced pressure were conducted, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate:methanol 19:1)) to yield Compound 46 (light-yellow oil 1.22 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[Cl:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[S:38])=[O:35]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]Br.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Br:10])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1F
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1F

Procedure:
A reaction vessel was charged with 128 g (1.016 mol) of 2-fluoroanisole and 250 ml of chloroform. To this mixture was added dropwise under agitation at room temperature 177 g (1.106 mol) of bromine over the period of at least 3 hours. The reaction liquid was poured into a diluted aqueous solution of NaOH, and the chloroform layer was separated, washed with a solution of edible salt and dried over Glauber's salt. The solvent was distilled off and the residue was distilled under reduced pressure to obtain 2-fluoro-4-bromoanisole.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>C(#N)C>[CH2:24]([N:12]1[CH2:13][CH2:14][CH:9]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)=[O:8])[CH2:10][CH2:11]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
(3 g, 12.3 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride was suspended in acetonitrile (60 mL) and triethylamine (4.29 mL, 3-1 mmol), benzylbromide (1.61 mL, 14 mmol) and sodium iodide (2.8 g, 18 mol) were added. The mixture was stirred at 80° C. overnight and after cooling the mixture was filtrated, water was added and the aqueous phase was extracted with 100 mL of dichloromethane. The combined organic phases were dried with magnesium sulfate, filtrated concentrated and purified with column chromatography on silica using dichloromethane/Methanol (95/0.5) to yield 3.6 g, (12 mmol, 99% yield) of the title compound as a brown solid. MS (m/e): 298.4 (M+H+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[C:16](=[O:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[CH:20]2[CH2:22][CH2:21]2)=[CH:6][CH:5]=1>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]([OH:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[CH:20]2[CH2:21][CH2:22]2)=[CH:8][CH:9]=1
Reactant: O=C1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Reaction time: 16 h
Yield: 39.2 %

Procedure:
Sodium borohydride (94 mg) was added to a stirred solution of Intermediate 29 (238 mg) in dichloromethane (3 ml) and methanol (3.00 ml). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under vacuum, partitioned between EtOAc (20 ml) and water (15 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (2×10 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a dichloromethane:methanol 0-25% gradient. The fractions were combined and concentrated under vacuum. The residue was purified by MDAP (Method B, UV detection only). The solvent was evaporated in vacuo to give the required product (94 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=1)O.S(Cl)([Cl:19])=O>>[Cl:19][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=1)[C:2]([CH3:16])([CH3:15])[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ncc(C(O)C(C)(C)C)cn1
Product: CC(C)(C)c1ncc(C(Cl)C(C)(C)C)cn1
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethyl-1-[2-(1,1-dimethylethyl)pyrimidin-5-yl]propan-1-ol (19.37 g) in thionyl chloride (125 cm3) was heated at the reflux temperature for 30 minutes. After cooling to the ambient temperature, the excess thionyl chloride was removed by evaporation under reduced pressure, and the residue dissolved in dichloromethane and washed with aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulphate, concentration of the organic solution by evaporation of the solvent under reduced pressure gave 1-chloro-2,2-dimethyl-1-[2-(1,1-dimethylethyl)pyrimidin-5-yl]propane (20.95 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[OH:18][C:19]1[C:20]([C:27](O)=[O:28])=[N:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[OH:18][C:19]1[C:20]([C:27]([NH:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:16][CH:15]=2)=[O:28])=[N:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccnc(C(=O)Nc2ccc(OCc3ccccc3)cc2)c1O
Reaction time: 8 h
Yield: 58.6 %

Procedure:
4-Benzyloxyaniline hydrochloride (0.21 g, 0.87 mmol), 0.15 g (0.73 mmol) of 3-hydroxy-4-methoxypicolinic acid hydrochloride, 0.15 g (1.10 mmol) of 1-hydroxybenzotriazole, and 0.16 g (1.10 mmol) of triethylamine were mixed into chloroform to prepare a suspension (2 ml). A chloroform solution (2 ml) of WSCI.HCl (0.21 g, 1.10 mmol) and 0.11 g (1.10 mmol) of triethylamine were added dropwise at −20° C. to this suspension, and a reaction was then allowed to proceed at room temperature overnight. The reaction mixture was concentrated under the reduced pressure. The concentrate was redissolved in chloroform. The solution was washed with saturated brine, and was then dried over anhydrous sodium sulfate. The dried solution was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to give 0.15 g (yield 59%) of title compound.
Reaction SMILES: CCN(CC)CC.[C:8]([C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:9].[SH2:21]>N1C=CC=CC=1>[C:8]([C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[S:21])[NH2:9]
Reactant: CCOC(=O)c1cccnc1C#N
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccnc1C(N)=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Et3N (10 ml) was added to a solution of ethyl 2-cyanonicotinate (1.9 g, 10.78 mmol) in 20 ml of pyridine. Hydrogen sulfide was passed through the reaction mixture at 5° C. for 20 minutes, then the mixture was stirred for 1 hour at room temperature. For work up the solution was purged with nitrogen for 30 minutes, evaporated to dryness, and the remaining solid dissolved in 200 ml of dichloromethane. The organic layer was washed successively with water and brine, dried, evaporated and treated with ethylacetate to give 2.15 g of a red oil which was reacted without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[OH2:22].[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:16][CH2:17][S:18](=[O:22])[CH2:19][CH2:20]1
Reactant: CN1CCN(C)C1=Nc1ccccc1N1CCSCC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCN(C)C1=Nc1ccccc1N1CCS(=O)CC1

Procedure:
Reaction of 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]thiamorpholine (1.5 g prepared as described in Example 144) in methanol (20 ml) and sodium metaperiodate (1.4 g) in water (4 ml) for 4 hours at 10° C. yielded 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]thiamorpholine-1-oxide monohydrate (m.p. 103°-105° C.) which was recrystallised from a 1:1 mixture of 1,2-dimethoxyethane and hexane.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:13][S:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:19]([OH:20])[C:18]1[CH:21]=[CH:22][C:15]([S:14][CH3:13])=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Reactant: CSc1ccc(C=O)cc1
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: CSc1ccc(C(O)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (32 mmol) and 4-(methylthio)benzaldehyde (30 mmol) using the procedure described for compound (96) (9.4 g, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[C:32]([O:34][CH2:35][CH3:36])[CH:31]=[CH:30][N:29]=3)[N:25]([C:37]3[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[N:24]=2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:35]([O:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([C:26]2[N:25]([C:37]3[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[N:24]=[C:23]([C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH3:13])[CH2:16][CH2:17]3)=[O:22])[CH:27]=2)[CH:33]=1)[CH3:36]
Reactant: CCOc1ccnc(-c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)nn2-c2ccc(OC)nc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccnc(-c2cc(C(=O)N3CCN(C)CC3)nn2-c2ccc(OC)nc2)c1
Reaction time: 0.5 h

Procedure:
At room temperature, trifluoroacetic acid (1.4 mL) was added to a solution of the above-obtained 4-[5-(4-ethoxy-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (0.135 g) in methylene chloride (2.7 mL), and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in ethanol (2.7 mL). To the mixture were added 35% aqueous formalin solution (0.114 g), acetic acid (0.076 mL) and sodium cyanoborohydride (50.0 mg). The resultant mixture was stirred for 100 minutes at room temperature. Sodium cyanoborohydride (33.3 mg) was further added thereto, and the mixture was stirred for 50 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol). Subsequently, the residue was purified through silica gel thin-layer chromatography (chloroform-methanol), to thereby give the title compound as an oily product (86.9 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]#[N:6].[CH3:17][O:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:18][C:19]1[C:24]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]#[N:6])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COc1ncccc1B(O)O
Reactant: N#Cc1ccc(Oc2ccccc2)c(Br)c1
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: O
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1ccccc1
Temperature: 100 °C
Yield: 108.7 %

Procedure:
A mixture of 3-bromo-4-phenoxybenzonitrile (Preparation 21, 0.21 g, 0.7 mmol), (2-methoxypyridin-3-yl)boronic acid (0.2 g, 1.1 mmol) and sodium hydrogen carbonate (0.19 g, 2.1 mmol) was suspended in dioxane (10 mL) and water (3 mL). The reaction mixture was degassed for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.050 g, 0.07 mmol) was added and the mixture heated at 100° C. for 1 hour. After the reaction was allowed to cool to room temperature, the reaction was partitioned between EtOAc (50 mL) and water (15 mL). The organic layer was filtered through a pad of celite and the solvent removed in vacuo to provide a crude brown solid. The crude material was purified by silica gel chromatography eluting with 30% EtOAc in Heptane to afford the title compound as a yellow solid (0.23 g).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](/[Cl:25])\[C:18]([O:20]C(C)(C)C)=[O:19])=[C:13]([O:26][CH3:27])[C:12]([CH3:28])=[C:11]2[C:7]=1[C:8](=[O:29])[O:9][CH2:10]2)(=[O:4])=[O:3]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](/[Cl:25])\[C:18]([OH:20])=[O:19])=[C:13]([O:26][CH3:27])[C:12]([CH3:28])=[C:11]2[C:7]=1[C:8](=[O:29])[O:9][CH2:10]2)(=[O:3])=[O:4]
Reactant: COc1c(C)c2c(c(OS(C)(=O)=O)c1C/C=C(/Cl)C(=O)OC(C)(C)C)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)c2c(c(OS(C)(=O)=O)c1C/C=C(/Cl)C(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
t-Butyl (E)-4-(1,3-dihydro-4-methanesulfonyloxy-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2-chlorobut-2-enoate (2.7 g) was dissolved in freshly distilled trifluoroacetic acid (25 ml) and stirred at room temperature for 90 minutes. The mixture was diluted with CH2Cl2 (25 ml) and evaporated to dryness and repeated until a cream solid was obtained. The solid was recrystallized from a 4:1 mixture of hexanes-CH2CH2 (25 ml) affording 2.11 g of (E)-4-(1,3-dihydro-4-methanesulfonyloxy-6-methoxy -7-methyl-3-oxoisobenzofuran-5-yl)-2-chlorobut-2-enoic acid as white crystals, mp 200°-203° (d).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1>CC(N(C)C)=O>[CH3:18][O:19][C:20]([C:21]1[CH:26]=[CH:25][C:24]2[N:27]=[C:4]([C:3]3[CH:6]=[C:7]([C:10]4[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=4)[CH:8]=[CH:9][C:2]=3[OH:1])[NH:28][C:23]=2[CH:22]=1)=[O:29]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
To an ice-cold flask with a rubber stopper were added 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (2.29 g, 10 mol) and 3,4-diamino-benzoic acid methyl ester (1.83 g, 11 mmol) and the solid mixture was stirred at 0° C. for 15 min. Then DMA (10 mL) was added into the mixture via a syringe and the resulting solution was stirred at 0° C. for 1.5 h, and at the room temperature for 1.5 h. The rubber stopper was removed and the reaction mixture was stirred at 110° C. for 14 h open to the air. The DMA was removed under reduced pressure and the residue was mixed with 50 mL MeOH, and sonicated for 15 min. The mixture was filtered to get the solid precipitate, which was re-crystallized in 300 mL MeOH to afford the title compound (1.6 g, 42%). 1H NMR (DMSO-d6) δ 3.90 (s, 3H), 3.93 (s, 3H), 7.12-7.17 (2H), 7.65 (d, J=9 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 8.20 (d, J=6 Hz, 1H), 8.26 (s, 1H), 8.29 (s, 1H). ESI-MS m/z 376.3 (MH+).
Reaction SMILES: C([Mg:4][Br:5])(C)C.Br[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].[CH2:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>>[F:13][C:12]1[C:7]([Mg:4][Br:5])=[C:8]([F:17])[C:9]([F:16])=[C:10]([F:15])[C:11]=1[F:14].[CH2:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: CC(C)[Mg]Br
Solvent: CCCCOCCCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 35 °C
Reaction time: 2 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 90 ml of a dibutyl ether (chain ether solvent) solution containing 0.188 mol of isopropyl magnesium bromide as the hydrocarbon magnesium halide (2) was charged to the reaction vessel. Meanwhile, 0.182 mol of bromopentafluorobenzene and 50 ml of dibutyl ether (chain ether solvent) were charged to the dropping funnel. Then, the dibutyl ether solution of bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 2 hours at room temperature, and the reaction solution was stirred for 2 hours at 35° C. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a light-yellow dibutyl ether solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 97.5 mol % based on bromopentafluorobenzene.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=O.[Cl-].[OH:27][NH3+:28].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=[N:28][OH:27]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 25.2 %

Procedure:
32 g (89.3 mmol) of 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone are dissolved in 200 ml of ethanol. To the solution are added 7.4 g (107 mmol) of hydroxylammonium chloride and 21.2 g (268 mmol) of pyridine. The reaction mixture is refluxed for 1.5 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, and extracted with ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from hexane/toluene, yielding 8.4 g of 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone oxime as a white solid with a melting point of 70-72° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.89 (t, 3H), 1.20-1.40 (m, 16H), 1.40-1.50 (m, 2H), 1.79 (m, 2H), 3.86-4.03 (m, 2H), 6.93(E)/6.97(Z) (d, 2H), 7.44(E)/7.53(Z) (d, 2H), 8.59(Z)/8.61 (E) (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates that the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=1:4.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=[C:4]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:11]1[CH2:10][CH2:9][O:8][C:7]2[C:2]([F:1])=[CH:3][C:4]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:5][C:6]1=2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CC1(C)OB(c2cc(F)c3c(c2)NCCO3)OC1(C)C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCOc2c(F)cc(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 70 °C
Yield: 76.9 %

Procedure:
A solution of 8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.507 g, 1.613 mmol, Ref. WO20100130034) and K2CO3 (0.512 g, 3.70 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, then treated with allyl bromide (0.8 mL, 9.17 mmol). The reaction tube was sealed and then heated (70° C.) for 22 h. The reaction was cooled then diluted with water (50 mL) and extracted into EtOAc (50 mL). The organic layer was then washed with water, brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by biotage column chromatography (12 g SiO2, 0% (3 CV); 0-40% (15 CV), 40% (2 CV), EtOAc in hexanes) to afford the desired product (0.396 g, 1.241 mmol, 77% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.96-7.01 (m, 2H), 5.84-5.95 (m, 1H), 5.21-5.32 (m, 2H), 4.32-4.38 (m, 2H), 3.94 (d, J=5.8 Hz, 2H), 3.30-3.37 (m, 2H), 1.32 (s, 12H). LCMS (M+H)=320.3.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:17][NH2:18]>>[OH:1][C:2]1[C:3]([CH3:15])=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:17][N:18]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(O)cccc1C(=O)CCC(=O)O
Reactant: NN
Solvent: O
Product: Cc1c(O)cccc1C1=NNC(=O)CC1

Procedure:
3-(3-hydroxy-2-methylbenzoyl)propionic acid was cydised with hydrazine hydrate in a similar manner to that described in Example 3 (i) to give 6-(3-hydroxy-2-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone.