Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH2:16](I)[CH2:17][CH3:18]>CS(C)=O>[CH2:16]([O:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:17][CH3:18]
Reactant: Cc1cnc(CCCC#N)c(O)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCOc1cc(C)cnc1CCCC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-hydroxy-2-(3-cyanopropyl)-5-methylpyridine from Example 3(a) (1.5 g), in dimethyl sulphoxide (11 ml) was first treated with sodium hydride (0.2 g) and then with n-propyl iodide in dimethyl sulphoxide (3 ml) at 17°-20° C. After stirring for four hours at room temperature, the solvent was removed in vacuo and the residue partitioned between chloroform and water, the chloroform extract was evaporated to dryness to give 3-n-propyloxy-2-(3-cyanopropyl)-5-methylpyridine (1.79 g) N.M.R. (CDCl3), assignment, δ(p.p.m.), multiplicity; O(CH2)2CH3, 1.07; t; OCH2CH2CH3, 1.86; m; CH2CH2CN, 2.12, m; CH2CN, 2.40, m; 5-CH3, 2.30, s; CH2 (CH2)2CN, 3.94, m; OCH2, 3.91, t; 4-H pyridyl, 6.96, m; 6-H pyridyl, 7.91, m;
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:11]([O:10][C:8](=[O:9])[C:7](=[N+:22]=[N-:23])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=[N+]=[N-])c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl phenylacetate (3.28 g) in acetonitrile (60 mL) is added para-toluenesulfonylazide (4.53 g). The reaction mixture is cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 mL) is added dropwise. The reaction mixture is kept at 5° C. overnight. Solvent is removed to dryness and the residue is purified by chromatography (gradient petroleum ether/dichloromethane from 90/10 to 80/20) to give diazophenylacetic acid ethyl ester;
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C.O.C(OCC)(=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1])[CH3:24]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-trifluoromethylphenol (1.62 g) in anhydrous acetonitrile was treated with cesium carbonate (3.25 g) and ethyl bromoacetate (1.75 g) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with water and ethyl acetate and the organic layer washed with water and dried with brine and over sodium sulfate. Evaporation of ethyl acetate gave the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.I[CH3:32].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7]([S:9][CH3:32])=[N:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=S)[nH]c3cc(Cl)ccc32)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1nc2cc(Cl)ccc2n1C1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.21 parts of 1-{3-[4-(5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, 0.71 parts of iodomethane, 0.28 parts of sodium methanolate and 40 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated. The residue is stirred with water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1.1 parts of 1-[3-{4-[5-chloro-2-(methylthio)-1H-benzimidazol-1yl]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 196.1° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]([OH:14])=[O:13].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1.Br>C(#N)C>[Br-:10].[C:12]([CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:4]1)([OH:14])=[O:13]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C(O)CBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)Cn1c[n+](Cc2ccc3ccccc3c2)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 2-bromoacetic acid (2.15 g, 15.46 mmol) was added to the solution and refluxed for 2.5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 2-(bromomethyl)naphthalene (1.63 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting white precipitate was collected and analyzed. 1H NMR (300 MHz, DMSO-d6): δ 4.71, 5.75, 7.59, 8.02, 9.81, 12.71.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[CH2:13])[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16].[N+](=[CH2:20])=[N-].C(OCC)(=O)C>C(OCC)C.CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]3[CH2:20][CH2:13]3)[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16]
Reactant: C=[N+]=[N-]
Reactant: C=Cc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(C)CC(C)(C)c2cc(Br)cc(C3CC3)c2O1
Temperature: 25 °C

Procedure:
A stirred, cooled (−30° C.) solution of 6-bromo-8-vinyl-2,2,4,4-tetramethyl chroman (Intermediate 31, 0.37 g, 1.26 mmol) in diethyl ether was treated with a solution of diazomethane in diethyl ether and catalytic amount of palladium (II)acetate (˜30 mg). The reaction mixture was allowed to warm to ambient temperature and subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the title compound as a clear, pale yellow oil (0.376 g, 97%).
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[C:20]([C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([CH3:25])[S:22][C:23]=3[CH3:24])=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10]1.O>CO>[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[C:20]([CH:26]([OH:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([CH3:25])[S:22][C:23]=3[CH3:24])=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C(=O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Reaction time: 1 h

Procedure:
At 0° C., sodium tetraborohydride (10 mg, 0.26 mmol) was added to a solution of ethyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethyl thiophen-3-yl]-2-oxoacetate (17d) (90 mg, 0.26 mmol) in methanol (5 mL). After 1 hour, water (5 mL) was added, the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired alcohol (17e) as a white solid without further purification (88 mg, 0.25 mmol, 98%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.B([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([OH:43])=[O:42])(O)O.O1CCOCC1>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.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:38]4[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=4)[C:41]([OH:43])=[O:42])=[CH:32][C:17]=3[C:18]=2[C:28](=[O:31])[NH:29][CH3:30])=[CH:22][CH:23]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: O=C(O)c1cccc(B(O)O)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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (3.5 g, 10.7 mmol) was added to Pd(Ph3P)4 (108 mg, 0.093 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (3.0 g, 7.19 mmol), 3-boronobenzoic acid (1.97 g, 11.86 mmol). Dioxane (60 ml) and water (12 ml) was added at rt. The reaction was degassed 3× and then heated to 95° C. and allowed to stir overnight. It was allowed to cool to rt. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The precipitate that formed was filtered and dried overnight at 55° C. under vacuum. The remaining organic phase was concentrated and triturated with DCM, followed by hot DCE and finally hot MeOH to afford the titled compound which was combined with the previously collected precipitate (2.4 g, 87%). LC-MS retention time: 1.19 min; m/z (MH+): 390. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]2[C:14](=[O:15])[CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]>C(O)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]2[CH2:11][O:12][CH2:13][C:14](=[O:15])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C2COCC(=O)N2CC1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN2C(=O)COCC12
Reaction time: 18 h
Yield: 102.2 %

Procedure:
A solution of 68 (1.056 g, 5.0 mmol) in 25 ml of acetic acid is hydrogenated over 1.056 g of platinum dioxide at RT and normal pressure for 18 hours. The black suspension is diluted with 20 ml of DCM and filtered through a pad of celite. The filtrate is evaporated to give 1.09 g of a yellow oil which is purified by chromatography (Silica gel 60, 0.063-0.2 mesh, ethyl acetate/ethanol 9:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=1.BrC[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:28]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[N:27]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[CH:6]=1)[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[N:28]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[N:27]=1
Reactant: COc1ccc(-n2nc(CCBr)cc2-c2ccc(C)cc2)cc1
Reactant: COC(=O)Cc1cn(COCC[Si](C)(C)C)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cc(-c2ccc(C)cc2)n(-c2ccc(OC)cc2)n1)c1cn(COCC[Si](C)(C)C)c2ccccc12
Yield: 83.9 %

Procedure:
The title compound was synthesized via Method 2 from [1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3yl]-acetic acid methyl ester (Step A, 0.17 g, 0.56 mmol), 3-bromoethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole (Method 1 pyrazole bromide, 0.10 g, 0.28 mmol), sodium hydride (22 mg, 0.56 mmol) and DMF (4.0 mL), yielding 140 mg (84%) of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid methyl ester. HPLC: Rt=3.91 (Method B). MS (ES+): mass calculated for C35H41N3O4Si, 595.29; m/z found 596.27 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.76 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.61 (s, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.27-7.19 (m, 5H), 7.15 (d, J=8.1 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.44 (s, 1H), 5.64 (s, 2H), 4.47 (t, J=7.6 Hz, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.62-3.52 (m, 3H), 3.25 (dd, J=6.6, 14.9 Hz ,1H), 2.40 (s, 3H), 0.87 (t, J=8.0 Hz, 2H), 0.0 (s, 9H).
Reaction SMILES: CO.[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].C1(C(C2C=CC=CC=2)[N:16]2[CH2:19][C@@H:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C@@H:17]2[CH3:31])C=CC=CC=1.[OH-].[NH4+]>O>[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[CH3:31][C@H:17]1[C@H:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=2)[CH2:19][NH:16]1
Reactant: C[C@H]1[C@H](Oc2cccc(C(F)(F)F)c2)CN1C(c1ccccc1)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Reaction time: 12 h
Yield: 122.4 %

Procedure:
A methanol-warm water solution of 33 g (0.068 mole) of trans-1-diphenylmethyl-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was treated with ammonium hydroxide until basic, then extracted with 4×150 ml of methylene chloride. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate, and concentrated in vacuo to a pale yellow oil. This oil was dissolved in 200 ml of 190 ethanol plus 5 ml of triethylamine and hydrogenated on a Parr apparatus with 3.3 g of 5% palladium-on-charcoal catalyst with a 40 psi atmosphere of hydrogen at 70° C. for 12 hr. After the calculated amount of hydrogen had been absorbed, the catalyst was removed by filtration and the filtrate concentrated in vacuo to yield 26.73 g of crude product. An 8 g portion was converted to the oxalate salt in isopropyl alcohol yielding 6.1 g of fine white powder; m.p. 155°-156° C. Total yield extrapolated from the aliquot converted to the oxalate salt was 84% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[CH:14]=[N:15]O.P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[C:14]#[N:15]
Reactant: CCn1c(Cl)c(C=NO)c(=O)n(CC)c1=O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1c(Cl)c(C#N)c(=O)n(CC)c1=O

Procedure:
To a stirred solution of the oxime (16 g) in tetrahydrofuran (320 ml)was added dropwise phosphorus oxychloride (30 g) with stirring. The reaction mixture was concentrated under reduced pressure. To the concentrate was added diisopropylether(200 ml), whereupon 6-chloro-5-cyano-1,3-diethylpyrimidine-2,4(1H,3H)-dione precipitated out as pale yellow prisms(12.4 g), m.p. 92°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:25][CH3:26])(C3C=CC(O)=C(CC)C=3)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:27]=1)=[O:4].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].[C:36]([O-:39])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([CH:25]([C:5]3[CH:6]=[CH:7][C:36]([O:39][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:9]([CH2:10][CH3:11])[CH:27]=3)[CH3:26])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:27]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCc1cc(C(CC)(CC)c2cc3cc(C(=O)OC)ccc3o2)ccc1O
Agent: [K+]
Product: CCc1cc(C(C)C(CC)c2cc3cc(C(=O)OC)ccc3o2)ccc1OCC(=O)C(C)(C)C
Yield: 198.9 %

Procedure:
2-[1-Ethyl-1-(4-hydroxy-3-ethyl-phenyl)-propyl]-benzofuran-5-carboxylic acid methyl ester (1.30 g, 3.55 mmol) and 1-bromopinacolone (0.953 g, 5.33 mmol) and K2CO3 (0.98 g, 7.10 mmol) are reacted analogous to Example 1E to give the title compound (1.64 g, 99%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.Cl.O>N1C=CC=CC=1>[C:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Yield: 94 %

Procedure:
128 ml benzoyl chloride is dripped into a solution of 170 g 4-hydroxybiphenyl in 500 ml pyridine, at 20° C.; subsequently, the reaction mixture is heated under reflux for 30 min. After cooling, the reaction mixture is mixed with a solution of 500 ml concentrated hydrochloric acid and 750 ml water. The remaining precipitate is filtered off, washed neutral with water, dried and recrystallized from n-butanol (melting point: 150° C.); yield: 94%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([O:11][S:12](=[O:18])(=[O:17])[O:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH3:10]>C1(C)C=CC=CC=1>[CH2:8]([O:11][S:12]([O-:18])(=[O:17])=[O:13])[CH2:9][CH3:10].[CH3:1][NH+:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:14][CH2:15][CH3:16])[CH2:3]1
Reactant: CCCOS(=O)(=O)OCCC
Reactant: CN1CCCCC1
Solvent: Cc1ccccc1
Product: CCCC1CCC[NH+](C)C1
Product: CCCOS(=O)(=O)[O-]
Temperature: 50 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
To a 50 ml four necked flask equipped with a stirrer, a dropping funnel, a cooling tube and a thermometer, 4.96 g (0.05 mol) of 1-methyl piperidine and 5 ml of toluene were charged, after heating to 50° C., 10.02 g (0.055 mol) of dipropyl sulfuric acid was dropped slowly taking one hour or more. After reacting for 10 hours, 13.37 g of 1-methyl-3-propyl piperidinium propyl sulfate was obtained by drying under a reduced pressure. Then, 13.37 g of the obtained 1-methyl-3-propyl piperidinium propyl sulfate was dissolved in 8 ml of water, and a solution in which 10.5 g of potassium bis(fluorosulfonyl)imide was dissolved in 8 ml of water was added thereto at a room temperature and stirred. From separated two layers, the lower layer was fractionated and by-products were removed by adding 40 wt % of purified water and water washing five times, and vacuum drying was applied to obtain 15.31 g of 1-methyl-3-propyl pyrrolinium bis(fluorosulfonyl) imide. As a result of ICP analysis, the total alkali metals was 1.8 ppm, chloride ion was 0.5 ppm, and each of iodide and bromide ions was 0.1 ppm or less (lower than ICP detection limit).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([OH:19])[CH2:16][CH:17]=[CH2:18]>CC([O-])=O.CC([O-])=O.[Pd+2].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.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:18]=[CH:17][CH2:16][CH2:15][OH:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCO
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1C=CCCO
Temperature: 120 °C

Procedure:
A mix of 1-(tert-butyl)-2-bromo-4-nitrobenzene (3.652 g), TEA (5.92 ml), 3-buten-1-ol (5.48 ml), Pd(OAc)2 (32 mg), Pd(PPh3)4 (327 mg) and toluene (40 ml) was degassed with nitrogen and heated in a sealed vessel for 16 h at 120° C. The next day, the reaction mixture was cooled to RT, filtered, and concentrated in vacuo. The crude was eluted on a silica gel column with 15% to 22% EtOAc/hexanes gradient system to yield a yellow-brown oil.
Reaction SMILES: B.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:8][CH:7]=[CH:6]2.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C1COCC1.O>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][CH2:7][CH2:6]2
Reactant: Fc1cc2cc[nH]c2cc1-c1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2c(cc1-c1ccccc1)NCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A mixture of 6-bromo-5-fluoro-1H-indole (0.214 g, 1 mmol), phenylboronic acid (0.171 g, 1.4 mmol), sodium carbonate (1.06 g, 10 mmol), Pd(PPh3)4 (0.116 g, 0.1 mmol), 1,2-dimethoxyethane (5 mL) and water (5 mL) was stirred under nitrogen at 85° C. for 18 h. The mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-50% Et2O in petrol) gave 5-fluoro-6-phenyl-1H-indole (0.202 g, 95%) as a pale green solid. MS: [M+H]+=212. A solution of borane in THF (1 M, 1.42 mL) was added to 5-fluoro-6-phenyl-1H-indole (0.20 g, 0.95 mmol) under nitrogen with external cooling using an ice-MeOH bath. The resulting mixture was stirred at 0° C. for 0.5 h, then TFA was added dropwise over 0.1 h. The mixture was stirred at 0° C. for 1 h then a solution of sodium hydroxide (0.8 g, 20 mmol) and water (5 mL) was added dropwise over 0.1 h. The resulting mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% Et2O in petrol) gave the title compound (0.17 g, 85%) as an oil. MS: [M+H]+=214.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(CCBr)cc1
Reaction time: 0.67 h
Yield: 84.4 %

Procedure:
To a stirred solution of ethyl 2-[4-(2-hydroxyethyl)-phenoxy]-2-methylpropionate (474 mg) and triphenylphosphine (591 mg) in dichloromethane (10 ml) was added carbon tetrabromide (748 mg) under ice-cooling, and the mixture was stirred for 40 minutes. Rough purification of the reaction mixture by flash column chromatography on silica gel (eluent: diethylether) and further purification of the fraction by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=10/1) gave ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropionate (500 mg). 1H-NMR (CDCl3) δ ppm: 1.25 (3H, t, J=7.1 Hz), 1.59 (6H, s), 3.09 (2H, t, J=7.8 Hz), 3.52 (2H, t, J=7.8 Hz), 4.23 (2H, q, J=7.1 Hz) 6.79 (2H, d, J=8.7 Hz), 7.07 (2H, d, J=8.7 Hz)