Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C)[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[CH2:17]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:17]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[O:16][C:3]1[C:2]([Br:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:15])[NH:8]2)[CH:18]=[CH2:19]
Reactant: C=CCn1c(Br)nc2ccccc21
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCn1c(Oc2c(Br)ccc3c2CC[C@H](C)N3)nc2ccccc21
Temperature: 200 °C
Yield: 40.7 %

Procedure:
A mixture of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.200 g, 0.71 mmol), 1-allyl-2-bromo-1H-benzo[d]imidazole (0.340 g, 1.44 mmol), and potassium carbonate (0.293 g, 2.12 mmol) in N,N-dimethylacetamide (10 mL) was heated in the microwave for 2 h at 200° C. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 20% ethyl acetate/petroleum ether) to afford (S)-5-(1-allyl-1H-benzo[d]imidazol-2-yloxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinoline (0.115 g, 41%) of as a light yellow solid. MS (ESI, pos. ion) m/z 398, 400 [M+H]+.
Reaction SMILES: C(OC[C@@H](N1C(C)=CC=C1C)C)(=O)C.[C:15]([O:18][CH2:19][CH:20]([N:22]1[C:26]([CH3:27])=[CH:25][C:24]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]1[CH3:36])[CH3:21])(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:19][C@@H:20]([N:22]1[C:26]([CH3:27])=[CH:25][C:24]([C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:23]1[CH3:36])[CH3:21])(=[O:17])[CH3:16]
Reactant: CC(=O)OCC(C)n1c(C)cc(C(=O)c2ccccc2)c1C
Agent: CC(=O)OC[C@H](C)n1c(C)ccc1C
Product: CC(=O)OC[C@H](C)n1c(C)cc(C(=O)c2ccccc2)c1C
Yield: 42.8 %

Procedure:
Compound (316) was prepared in a yield of 42.8% using (2S)-2-(2,5-dimethylpyrrol-1-yl)-2 methylethyl acetate ([α]D21 =-5.17°, c=0.027, C2H5OH) as a starting material in the same way as in Example 28. The IR, NMR and mass spectra of this product were identical with those of the product (306) of Example 28.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.C(O)=[O:20]>[Ni]>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:20])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCOc2ccc(C#N)cc2)n1
Reactant: O=CO
Agent: [Ni]
Product: Cc1cccc(CCOc2ccc(C=O)cc2)n1

Procedure:
A mixture of 4-[2-(6-methyl-2-pyridyl)ethoxy]benzonitrile (9.62 g), Raney nickel alloy (10.0 g) and 75% formic acid (150 ml) was heated under reflux for 1 hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water, alkalinized with 4N-KOH, and extracted with ethyl ether. The ethyl ether layer was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was recrystallized from ethyl etherhexane to give 4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([C:18]([CH2:20][N-:21][CH3:22])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:23]>C(O)C.[C].[Pd]>[ClH:23].[NH:14]1[CH2:17][CH:16]([C:18]([CH2:20][N-:21][CH3:22])=[O:19])[CH2:15]1
Reactant: C[N-]CC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[N-]CC(=O)C1CNC1
Reaction time: 16 h

Procedure:
1-Benzhydrylazetidine-3-carbonyldimethylamide (I-144) (0.24 g, 0.82 mmol) was dissolved in ethanol (10 ml), then 1 N hydrochloric acid (0.90 m, 0.90 mmol) and 10% palladium-carbon (containing about 50% water, 0.10 g) were added, followed by stirring under hydrogen atmosphere for 16 hours. The catalyst was removed by filtration, the solvent was evaporated away under reduced pressure to obtain a mixture containing the entitled compound (0.25 g). This was used in the next reaction as it was.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)O1.[C:23]1([S:29]([C:32]([C:35]2[CH:40]=[C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:38]=[C:37](Cl)[N:36]=2)([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[C:23]1([S:29]([C:32]([C:35]2[CH:40]=[C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:38]=[C:37]([C:15]3[CH:16]=[CH:17][C:18]([NH2:19])=[CH:20][CH:21]=3)[N:36]=2)([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccc2)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccc2)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Sodium carbonate (2M aqueous solution) (3.21 mL, 6.43 mmol) was added to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (391 mg, 1.79 mmol) and 4-[2-(benzenesulfonyl)propan-2-yl]-2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (707 mg, 1.79 mmol) in a mixture of DME (8.0 mL), ethanol (4.0 mL), DMF (4.0 mL) and water (4.0 mL) under nitrogen. The mixture was degassed and purged with nitrogen three times. Bis(triphenylphosphine)palladium(II) chloride (63 mg, 0.09 mmol) was added and the mixture was degassed and purged with nitrogen a further three times. The resulting suspension was stirred at 80° C. for 30 minutes. The reaction mixture was concentrated and diluted with ethyl acetate (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2% methanol in DCM, to give the desired material as a beige solid (578 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([O:21]C)=[O:20])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: COC(=O)c1nc(-c2ccc(F)cc2)c(C(F)(F)F)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 3-amino-6-(4-fluorophenyl)-5-(trifluoromethyl)picolinate (step 1) (6.00 mmol) in EtOH (5 ml) was added 2M NaOH (3 ml, 6.00 mmol) and the solution was stirred at RT for 15 minutes. The resulting mixture was diluted with water (10 ml) and the pH was adjusted to pH 6 using 1M HCl. The mixture was extracted with DCM (2×10 ml) and the phases were separated using a phase separating cartridge. The combined organic extracts were concentrated in vacuo and used in the next step without further purification;
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:27]1([C:38](O)=[O:39])[CH:28]=[CH:29][CH:30]=[C:31]2[CH2:37][CH2:36][CH2:35][CH:34]=[CH:33][C:32]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[CH2:37][CH2:36][CH2:35][CH:34]=[CH:33][C:32]=23)=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: Cc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1OC(F)(F)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: Cc1ccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2ccc(F)cc2)cc1OC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (300 mg, 0.80 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (150 mg, 0.80 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg, 1.20 mmol) and 1-hydroxy-1H-benzotriazole (123 mg, 0.80 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (363 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([CH:29]=[O:30])[CH2:7][CH2:6]2.C1(C=CC=C(O)C=1)[OH:32].C1COCC1.Cl([O-])=O.[Na+]>O.C(O)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[C:8]([C:29]([OH:32])=[O:30])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C=O)=C2Oc1ccc(OCCN2CCCCC2)cc1
Reactant: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(C(=O)O)=C2Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
To a round bottom flask, add 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)-3,4-dihydronaphthalene-2-carbaldehyde (3.0 g, 4.34 mmol), resorcinol (531 mg, 4.8 mmol), THF (8 mL), ethanol (8 mL) and acetic acid (0.9 mL). Stir the mixture at 25° C. for 5 min. Add slowly sodium chlorite (1.3 g, 11.2 mmol) in water (8 mL) to the reaction mixture. Stir the mixture at 80° C. for 2 hours. Quench the reaction mixture with ice-water. Add ethyl acetate to the vessel with stirring. Wash the mixture with dilute NaOH three times and discard the organic phase. To the aqueous layer, add water so the pH was adjusted to 5-6. Extract the aqueous layer with ethyl acetate five times and discard the aqueous phase. Dry the organic layer over MgSO4, filter, and concentrate to dryness, which was further purified to give 400 mg of 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)-3,4-dihydronaphthalene-2-carboxylic acid. 1HNMR (d-DMSO, 300 MHZ): 9.97 (1H, s) 7.12 (1H, m), 6.86 (5H, m), 6.71 (1H, m), 4.27 (2H, m), 3.73 (3H, s), 4.26 (2H, s), 3.41 (3H, m), 2.82 (2H, m), 2.59 (2H, m), 1.70 (6H, m).
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:20])=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:21])[C:7]([C:22]([O:24]CC)=[O:23])=[CH:6]1)(C)(C)C.Cl.O1CCOCC1>O>[Cl:20][C:11]1[CH:10]=[C:9]2[C:14](=[N:13][C:12]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[NH:5][CH:6]=[C:7]([C:22]([OH:24])=[O:23])[C:8]2=[O:21]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)c(Cl)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c[nH]c2nc(N3CCCC3)c(Cl)cc2c1=O

Procedure:
A solution of EXAMPLE 80A (160 mg) in 1:1 9M HCl/1,4-dioxane (15 mL) was heated in a sealed tube at 115° C. for 15 minutes and at 95° C. for 24 hours then cooled, diluted with water (20 mL), and filtered. NMR (300 MHz, DMSO-d6) δ 15.25 (s, 1H), 13.11 (br s, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 3.84-3.80 (m, 4H), 1.96-1.91 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=1[Cl:25].[CH3:26][Al](C)C.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1(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)C=CC=CC=1>[Cl:25][C:14]1[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=1[CH2:12][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][C:9]([NH2:11])=[N:10][C:2]=2[CH3:26]
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Cl)c(OC)c1OC
Reactant: C[Al](C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(Cn2cnc3c(C)nc(N)nc32)c(Cl)c(OC)c1OC
Temperature: 25 °C

Procedure:
A suspension of 6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine, see example 97) (0.2 mmol) and tetrakis(triphenylphosphino)-palladium (0.02 mmol) in dry THF (3 mL) was treated with trimethylaluminum (2M in toluene, 0.45 mmol) under nitrogen and heated to reflux for 3 h. The reaction mixture was cooled to r.t., diluted with toluene (5 mL) and quenched with methanol (0.5 mL) followed by ammonium chloride (1 mmol). The mixture was heated to reflux for 2 h and filtered, while hot, on Celite. See J. Med. Chem. 1999, 42, 2064–2086. TLC (100% EtOAc) Rf was 0.2. HPLC Rt: 4.800 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].S(Cl)([Cl:17])=O>C(CC(C)(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:17])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: CC(C)CC(C)(C)C
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A stirred suspension of 1.0 g of 3-methoxy-4-nitrobenzoic acid and 1.40 ml of thionyl chloride is heated to reflux for 2 hours. The mixture is cooled to room temperature, 2 ml of iso-octane added and the mixture evaporated in vacuo to a solid residue. The residue is washed with iso-octane (2×2 ml), dried in vacuo to give 1.08 g of cream colored solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[S:4].Cl[CH:9]([CH:15]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]1[S:4][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][N:5]=1
Reactant: NC(=S)C(F)(F)F
Reactant: CCOC(=O)C(Cl)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(C(F)(F)F)s1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
A mixture of 11.22 g of 2,2,2,-trifluorothioacetamide and 10.14 g of ethyl 2-chloro-2-formylacetate was stirred for 30 minutes in an oil bath of 70° C. and then for 1.5 hours in an oil bath of 100° C., to which 100 ml of dichloromethane were added. After removing an insoluble substance, the mixture was concentrated and the residue was subjected to a column chromatography [developing solvent: hexane-ethyl acetate (10:1)], to obtain 3.74 g of ethyl 2-(trifluoromethyl)-5-thiazolecarboxylate as yellow liquid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]1[O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1[OH:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[O:21][C@H:13]1[C@H:14]2[O:19][CH2:18][C@@H:17]([OH:20])[C@H:15]2[O:16][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C

Procedure:
2.2 ml (20.0 mmol) 2,4-difluoro-1-nitro-benzene and 2.9 g (20.0 mmol) 1,4:3,6-dianhydro-D-mannitol in 70 ml THF are cooled to −5° C. 20 ml (20.0 mml) 1M LiHMDS in THF are added dropwise and the reaction mixture is allowed to warm to RT and stirred over night. 1M HCl is added and the mixture is extracted with EtOAc. The organic phases are pooled and washed with water, dried and evaporated. The residue is purified by FC.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:10]([C:11]([F:14])([F:12])[F:13])/[CH:9]=[CH:8]/[C:6]2[CH:7]=[CH:2][C:3]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[CH:4][CH:5]=2)[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in CH2Cl2 (10 mL) was added acetic anhydride (0.12 mL, 1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% ethyl acetate in hexane) afforded the title compound as an off-white solid (0.2 g, 60%) mp 107-109° C.; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4]Br.[CH3:11][NH:12][CH3:13]>CO>[CH3:11][N:12]([CH2:4][C:3]1[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][C:2]=1[F:1])[CH3:13]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CNC
Solvent: CO
Product: CN(C)Cc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (1.264 g, 4.72 mmol) was dissolved in methanol (10 ml). Dimethylamine (8 M in H2O, 1.77 ml, 14.2 mmol) was added as a solution in methanol (5 ml), and the resulting mixture was stirred at ambient temperature for about two hours. The progress of the reaction was monitored by thin layer chromatography. The methanol was removed by evaporation. The residue was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed with brine (7×) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification.
Reaction SMILES: C[O-].[Na+].C(O)C.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][SH:14])=[CH:9][CH:8]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(OCC)C>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:9][CH:8]=1
Reactant: SCc1ccncc1
Reactant: O=C(CBr)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CSCc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (0.81 g., 15 mmoles) was dissoled in 17.9 ml. of stirring absolute ethanol, and cooled in an ice bath. 4-Picolyl mercaptan (1.88 g., 15 mmoles) in 3 ml. of absolute ethanol was added dropwise over approximately 5 minutes, followed by alpha-bromoacetophenone (3.05 g., 15 mmoles) in 10 ml. of warm absolute ethanol added over approximately 10 minutes. The stirring reaction mixture was warmed to room temperature and left to stir for 17 hours. Salts were removed by filtration through diatomaceous earth, and the solids repulped for 0.5 hour with additional ethanol and refiltered. The ethanol filtrates were combined and concentrated to yield a waxy solid. The waxy solid was taken up in approximately 11 volumes of diethyl ether, treated with activated carbon, filtered and the mother liquor concentrated to a solid (1.90 g.). Recrystallization from diethyl ether/hexane gave purified alpha-(4-picolylthio)acetophenone (1.25 g. in two crops, m.p. 55°-59° C., ir (KBr): 5.92, 6.18, 7.00, 7.76, 9.78, 12.38, 13.70μ).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][O:36][Si](C(C)(C)C)(C)C)[O:13][CH2:14][C:15]1[CH:16]=[C:17](/[C:21](/[CH3:31])=[CH:22]/[CH:23]=[CH:24]/[C:25]([CH2:29][CH3:30])([OH:28])[CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][OH:36])[O:13][CH2:14][C:15]1[CH:16]=[C:17](/[C:21](/[CH3:31])=[CH:22]/[CH:23]=[CH:24]/[C:25]([CH2:26][CH3:27])([OH:28])[CH2:29][CH3:30])[CH:18]=[CH:19][CH:20]=1
Reactant: CCC(O)(/C=C/C=C(\C)c1cccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCC(O)(/C=C/C=C(\C)c1cccc(COc2ccc(CO)c(CO)c2)c1)CC

Procedure:
In a manner similar to Example 57(c) by reacting 520 mg (0.83 mmol) of (4E,6E)-7-{3-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-phenyl}-3-ethylocta-4,6-dien-3-ol with 2.5 ml of a tetrabutylammonium fluoride solution (1N in THF), a colourless oil is obtained (m=164 mg; Y=50%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].[F:10][C:11]1[C:18]([CH3:19])=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:17]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:10])[C:18]=2[CH3:19])[C@H:4]1[CH3:8])[CH3:2]
Reactant: CC[C@]1(O)CCN[C@H]1C
Reactant: Cc1c(F)ccc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(F)c2C)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 2,4-difluoro-3-methylbenzonitrile (340 mg) and lithium carbonate (218 mg), the title compound was obtained as colorless oil (yield: 184 mg, yield: 47%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O-:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc([O-])c(C#N)cc34)cc2)cc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CCOCC5)c(C#N)cc34)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
The sodium 6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate (100 mg) synthesized in Example 87 was dissolved in dimethylformamide (2.5 ml), and then potassium carbonate (65 mg, 0.4690 mmol) and 1-chloro-3-(morpholin-4-yl)propane (38 mg, 0.2345 mmol, J. Am. Chem. Soc. 67, 736 (1945)) were added and the mixture was heated and stirred at 80° C. for 2 hours. After allowing the mixture to stand and adding saturated brine, it was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in ethyl acetate, the suspension was diluted with diethyl ether, and the crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (120 mg) as light yellow crystals.