Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2cncc(C(F)(F)F)c2)c(F)c1
Product: CN1c2cc(OCc3cc(F)c(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and 7-chlo-ro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[Cs+]>COCCOC.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:10][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccccc2)cc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 4-bromo-2-fluorobenzonitrile (1.12 g, 5.6 mmol) in 1,2-dimethoxyethane (10 mL) were added Phenyl boronic acid (750 mg, 6.16 mmol), tetrakis(triphenylphosphine)palladium (0) (194 mg, 0.17 mmol) and Cesium fluoride (1.8 g, 12.3 mmol). The mixture of reaction was stirred at 100° C. under nitrogen for 3 h. Then, the mixture is cooled and filter through celite. Then added ethyl acetate and water and extracted (3×). The crude was purified by chromatography (silica gel, hexane-ethyl acetate 10:1) affordind 818 mg (74% yield)n of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:18][CH2:19][CH2:20]Cl)[C:9](=O)[O:10]C2C=CC=CC=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)C>[NH2:23][N:24]1[CH2:20][CH2:19][CH2:18][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:10]
Reactant: NN
Reactant: O=C(Oc1ccccc1)N(CCCCl)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: NN1CCCN(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C

Procedure:
Thionyl chloride (4.4 mL) was added to a solution of 3-(4-chlorophenylamino)propan-1-ol (2.17 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added, followed by extraction with ethyl acetate (200 mL). Heptane (100 mL) was added to the resulting extract to prepare a mixed solution. The solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=2:1) to obtain (4-chlorophenyl)-(3-chloropropyl)amine. (4-Chlorophenyl)-(3-chloropropyl)amine was dissolved in THF (45 mL). Triethylamine (4.9 mL) and phenyl chlorocarbonate (1.8 mL) were added at 0° C., and the reaction solution was stirred at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g). Phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g) was dissolved in ethanol (60 mL). Hydrazine monohydrate (5.65 mL) was added at room temperature, and the reaction solution was heated under reflux for 17 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 2.19 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([O-:21])=O)[NH:16][C:13]3=[N:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2C=[CH:34][CH:35]=[CH:36][C:31]=2N=N1.N1CCCCC1.C(N(CC)C(C)C)(C)C>>[N:28]1([C:19]([C:17]2[NH:16][C:13]3=[N:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=[C:12]3[CH:18]=2)=[O:21])[CH2:34][CH2:35][CH2:36][CH2:31][CH2:32]1
Reactant: O=C([O-])c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: O=C(c1cc2cc(OCCCN3CCCC3)cnc2[nH]1)N1CCCCC1
Yield: 32 %

Procedure:
The title compound was synthesized in analogy to example 1 from lithium 5-(3-pyrrolidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, piperidine and N,N-diisopropylethylamine to give the desired product as a light brown solid (32% G).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1COCCN1
Product: Brc1ccc(-c2nsc3cc(OCCCN4CCOCC4)ccc23)cc1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and morpholine were converted to yield 3-(4-Bromo-phenyl)-6-(3-morpholin-4-yl-propoxy)-benzo[d]isothiazole, MS: 434 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3([CH2:15][OH:16])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[Si:24](OS(C(F)(F)F)(=O)=O)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:24]([O:16][CH2:15][C:12]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:14][CH2:13]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cc1ccc2cccc(C3(CO)CC3)c2n1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(C3(CO[Si](C)(C)C(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of (1-(2-methylquinolin-8-yl)cyclopropyl)methanol (0.050 g, 0.234 mmol) and triethylamine (0.065 mL, 0.47 mmol) in DCM (5 mL) was added TBSOTf (0.065 mL, 0.28 mmol) at ambient temperature and the reaction was stirred at ambient temperature for 1 hour. Saturated sodium bicarbonate (10 mL) and DCM (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10:1 hexane/ethyl acetate) to give 8-(1-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)-2-methylquinoline (0.071 g, 92.5%) as an oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][O:17][C:18]2[C:19]([C:24]([NH2:26])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].I[CH2:32][C:33]1([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[OH:39][C:33]1([CH2:32][NH:26][C:24](=[O:25])[C:19]2[C:18]([O:17][CH2:16][C@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:9]([C@H:6]3[CH2:7][CH2:8][C@H:3]([C:2]([F:1])([F:27])[F:28])[CH2:4][CH2:5]3)=[O:10])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: OC1(CI)CCOCC1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(NCC1(O)CCOCC1)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide (105 mg, 0.263 mmol, EXAMPLE 75 Step 1) in 1-Methyl-2-pyrrolidone (5 mL) was added sodium hydride (60% oil dispersant, 16 mg, 0.394 mmol) at ambient temperature. After being stirred at room temperature for 1 h, 4-(iodomethyl)tetrahydro-2H-pyran-4-ol (76 mg, 0.315 mmol, EXAMPLE 77 Step 1) was added to the mixture. The mixture was heated at 70° C. and stirred for 3 days. After cooling to room temperature, aq. citric acid was added to the mixture. The mixture was extracted with ethyl acetate twice and washed successively with aq. sodium thiosulfate, aq. sodium bicarbonate, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford 72 mg of crude oil. The residual oil was purified by preparative HPLC purification.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:19][C:20]1([CH3:36])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([CH2:32][C:33](Cl)=[O:34])[CH:23]=[CH:22][C:21]1=2>>[OH:1][C:2]1[CH:17]=[C:16]([O:18][C:33](=[O:34])[CH2:32][C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:19])([CH3:36])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1O
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)Cl)ccc21
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)Oc3ccc(C(=O)OCc4ccccc4)c(O)c3)ccc21

Procedure:
In a manner similar to Example 1(d), by reaction of 2.44 g (10 mmol) of benzyl 2,4-dihydroxybenzoate with 2.6 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylacetyl chloride, 3.9 g (83% ) of the expected ester are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22](O)=[C:19]([O:20][CH3:21])[CH:18]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:8][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1)[CH:16]=[O:15]
Reactant: Cc1nn(-c2ccccn2)cc1CO
Reactant: COc1cc(C=O)ccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OCc1cn(-c2ccccn2)nc1C
Reaction time: 15 h
Yield: 77.5 %

Procedure:
To a mixture of (3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methanol (1.07 g), vanillin (0.85 g), tributylphosphine (1.70 g) and tetrahydrofuran (100 mL) as added 1,1′-(azodicarbonyl)dipiperidine (2.12 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.40 g, yield 77%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]([OH:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([O:23][CH2:24][CH3:25])=[CH2:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]1([CH:7]([NH:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]([O:11][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])[CH:9]=[CH2:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=COCC
Reactant: C=CC(O)C(NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(OC(C)OCC)C(NC(=O)c1ccccc1)c1ccccc1
Yield: 91 %

Procedure:
708 mg (2.65 mmol) of 1-phenyl-1-benzoylamino-2-hydroxybut-3-ene, syn form, 13.5 cm3 of dry methylene chloride, 2.53 cm3 (1.911 g, 26.5 mmol) of ethyl vinyl ether and 66.5 mg (0.265 mmol) of pyridinium p-toluenesulphonate (PPTS) are introduced successively into a 50 cm3 single-necked flask placed under an argon atmosphere and equipped with a magnetic stirring system. The resulting homogeneous reaction mixture is left to react for 4 hours at a temperature of about 20° C. When the reaction is complete, 1 drop of pyridine is added and the reaction mixture is then diluted in 20 cm3 of methylene chloride. The organic phase is washed once with 20 cm3 of water. The aqueous phase is extracted twice with 20 cm3 of methylene chloride. The combined organic phases are washed twice with 20 cm3 of water and once with 10 cm3 of a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulphate. After filtration, the solvents are driven off under reduced pressure on a rotary evaporator. The residue obtained (992 mg) is chromatographed on a column of silica gel. Elution with a hexane/ether mixture (6/4 by volume) gives 1-phenyl-1-benzoylamino-2-(1-ethoxyethoxy)but-3-ene, syn form, with a yield of 91% (818 mg, 2.41 mmol). The product obtained is in the form of an equimolar mixture of the two epimers (determination by the proton nuclear magnetic resonance spectrum).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)NC1CCC(O)c2ccccc21
Reaction time: 5 h
Yield: 11.8 %

Procedure:
To a stirred solution of 4.6 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea in 230 ml of ethanol 0.85 g of sodium borohydride is added. The reaction mixture is stirred for about 5 hours and after standing overnight 50 ml water is added while stirring. The mixture is then evaporated in vacuo to remove the solvent. Water (50 ml) is added, then glacial acetic acid is added, until the foaming caused by the acid ceases. The solution is evaporated to dryness in vacuo, alcohol is added and the whole evaporated to dryness in vacuo. Then 30 ml of ethanol is added to the residue and the mixture stirred and filtered. The collected insoluble solid is air dried. This solid is heated with 300 ml of acetone and filtered. The filtrate is concentrated in vacuo to afford 0.55 g of the title compound, melting point 170°-176° C. On further work-up of the acetone mother liquor, 0.2 g of the title compound, melting point 169°-174° C, is recovered.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]([O:17]C)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.O.[OH-].[Li+]>CO.O>[Br:1][C:2]1[S:3][C:4]([C:15]([OH:17])=[O:16])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:6]=1
Reactant: COC(=O)c1sc(Br)nc1-c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc(Br)sc2C(=O)O)cc1
Yield: 35.5 %

Procedure:
To a solution of 2-bromo-4-[(4-methoxy)phenyl]-5-(methoxycarbonyl)thiazole (6.24 g, 19.74 mmol) in 20 mL of methanol and 20 mL of water was added lithium hydroxide monohydrate (0.91 g, 21.7 mmol). The mixture was stirred at ambient temperature for 1 h, whereupon aditional lithium hydroxide monohydrate (0.91 g, 21.7 mmol) was added. After stirring an additional hour, the volatiles were removed in vacuo and the residue was quenched with 10% aq HCl. The mixture was extracted with ethyl acetate and the organics were washed with brine, dried (MgSO4) and concentrated. The residue was recrystallized from chloroform/hexane to afford 2.2 g (37%) of the title compound as a white solid. LRMS (ES−): 303 (M−H)−.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CO>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(SCc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
10 ml of methanol solution containing 2.8 g of 4-mercaptophenol was dropped with ice cooling into 20 ml of methanol solution containing 1.4 g of potassium hydroxide, followed by further stirring for 30 minutes. To this reaction mixture, 10 ml of methanol solution containing 5.0 g of 4-trifluoromethyl benzyl bromide was added with ice cooling, followed by stirring for 18 hours at room temperature. After concentrating the reaction mixture, ethyl acetate and water were added, followed by fractionating an organic layer. After the organic layer was dried with anhydrous magnesium sulfate, it was concentrated. The concentrate was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate/gradation) to produce 2.23 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[O:8])([O-:3])=[O:2].[F:23][C:24]([F:51])([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][C:47]([F:50])([F:49])[F:48])=[CH:39][CH:38]=1)[O:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](O)=[O:35])=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]1[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:51])[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][C:47]([F:50])([F:49])[F:48])=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(OCCCCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
3.68 g (11.8 mmol) of 6-hydroxyhexyl 3,5-dinitrobenzoate, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) is added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yielded 6.85 g of 6-[((2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:27][NH:26][C:10](=[O:11])[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1
Reactant: CC1(O)OC(=O)C(c2c(F)cc(F)cc2F)=C1c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
17.03 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2,4,6-trifluorophenyl)-2(5H)-furanone, 2.64 g of hydrazine monohydrate and 240 ml of 1-butanol were mixed, and stirred at 90° C. for 3 hours. Then, the reaction mixture was cooled to 0° C. The resulting solid was collected by filtration. The collected solid was washed using hexane and t-butyl methyl ether, and dried under reduced pressure to obtain 6.99 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:26])C(=O)C1>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:26])[N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Temperature: 25 °C
Reaction time: 22 h
Yield: 63.9 %

Procedure:
To a solution of 3-butyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.34 g, 13.4 mmol) in anhydrous DMF (19 ml) was added NCS (1.97 g, 14.8 mmol) and left to stir at rt under nitrogen for 22 hours. The mixture was concentrated in vacuo to give a yellow solid which was filtered and washed with methanol. The filtrate was concentrated and the process repeated. On the final wash the filtrate was purified by SPE (Si, 20 g) cartridge eluting with 1:1; EtOAc:cyclohexane. The combined solids were dried under vacuum to afford the title compound (2.42 g, 64%); m/z 283.3 [MH+]
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C[Si](C)(C)[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]>C1(C)C=CC=CC=1>[O:4]([C:2]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[Si](C)(C)N1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of phenyl chloroformate (3.13 g, 20.0 mmol) in anhydrous toluene (10 ml) was added a solution of 1-trimethylsilyl-2-pyrrolidinone (3.46 g, 22.0 mmol) in anhydrous toluene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. Recrystallization from ethanol afforded 2.37 g of colorless prisms. Yield 57.7%.
Reaction SMILES: C([O:3][C:4](=[O:32])/[C:5](/[O:29][CH2:30][CH3:31])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])C.[OH-].[Na+]>C1COCC1.CO>[CH2:30]([O:29]/[C:5](=[CH:6]\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])/[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCO/C(=C\c1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of (Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-acrylic acid ethyl ester (6.8 g, 15.6 mmol) in THF/methanol 2/1 (102 ml) was added a 3 M aqueous NaOH solution (26 ml, 78 mmol). The reaction mixture was stirred for 3 h at ambient temperature, concentrated under reduced pressure, diluted with ice water and acidified with with 1 M aqueous HCl solution. Twofold extraction with ethyl acetate was followed by washing of the combined extracts with ice water/brine 1/1 (three times) and drying of the organic layer over sodium sulfate. The solvent was removed under reduced pressure and the crude product crystallized from dichloromethane/n-heptane to give the title compound (6.3 g, 15.5 mmol, 99%) as colorless crystals.