Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[C:22](Cl)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:19]=1.CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:21]=[C:22]([NH:12][S:11](=[O:13])(=[O:14])[NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:23]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]
Reactant: CC(C)c1ccc(NS(N)(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Temperature: 45 °C
Reaction time: 60 h
Yield: 26.7 %

Procedure:
To a solution of 4-i-propyl-phenyl sulfamic acid amide (642 mg; Referential Example 17) in DMF (9 ml) was added sodium hydride (250 mg). The mixture was warmed to 45° C. for 30 min. Then, 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (1.044 g) was added and the reaction mixture was stirred for 60 h at r.t. After acidic work up and chromatography over silicagel with Hex/EtOAc=2/5, 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (0.42 g) can be isolated.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH:8]=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
A 4.87 g portion of magnesium was placed in a two-necked round bottom flask. The flask was flamed several times and 37.4 g of m-bromoanisole and 200 ml of tetrahydrofuran were added. As soon as the reaction stopped it was refluxed for 1 hour and then added to a boiling solution of 52.68 g of tetradecyl bromide in tetrahydrofuran. Then 10 ml of lithium cupric chloride was added and the mixture was refluxed for 1.25 hours, stirred at room temperature for 16 hours, quenched with water, washed with ammonium chloride solution, brine, dried and the solvent removed. The resulting oily residue was distilled in a Kugelrohr apparatus giving 52.4 g of the desired compound as a clear oil, B.P. (120°/0.5 mm).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.C(OO)(=[O:17])C>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[N+:5]([O-:17])=[CH:6][CH:7]=1
Reactant: CC(=O)OO
Reactant: Cc1ccnc(-c2cc(C)ccn2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccnc(-c2cc(C)cc[n+]2[O-])c1
Temperature: 23 °C
Reaction time: 50 h

Procedure:
27.6 g (0.15 mol) of 4,4'-dimethyl-2,2'-bipyridine are dissolved in 300 ml of dichloromethane. 86 ml of a 1.837-molar solution of peracetic acid in ethyl acetate are added dropwise at 23°-28° C. After stirring for 50 hours at 23° C., the mixture is concentrated in vacuo. 27.2 g (90% of theory) of 4.4'-dimethyl-2,2'-bipyridine 1-oxide crystallise from ethylbenzene/petroleum ether; melting point 80°-130° C. (over a range).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([N:23]3[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]3[CH3:29])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([N:23]3[C:24]([CH3:29])=[CH:25][CH:26]=[C:27]3[CH3:28])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Yield: 101.2 %

Procedure:
Using a procedure similar to Example 23, step (a), 4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (35 mg, 0.08 mmol) was stirred in MeOH in the presence of 5% Pd—C (20 mg) to afford 30 mg (100%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C21H30N4O2, 371.2 (M+H), found 371.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]1[C:29]([OH:36])=[N:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34]>ClCCl>[OH:36][C:29]1[C:28]([CH2:27][NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:2]=2[CH3:1])=[C:33]([CH3:34])[CH:32]=[C:31]([CH3:35])[N:30]=1
Reactant: Cc1cc(COc2ccccc2)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3ccccc3)cc2C)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
2-Methyl-4-(phenoxymethyl)benzoic acid (42 mg, 0.17 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyfluoroniumhexafluorophosphate (99 mg, 0.26 mmol), triethylamine (0.1 mL) and dichloromethane (15 mL) were stirred at 25° C. for half hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.17 mmol) was added to the mixture. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (20 mL), dried over sodium, filtered, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(phenoxymethyl)benzamide as a white solid (50 mg, 78%). LRMS (M+H+) m/z: calcd 376.18. found 376. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.11 (t, J=4.8 Hz, 1H), 7.28-7.20 (m, 5H), 7.00-6.84 (m, 3H), 5.86 (s, 1H), 5.07 (s, 2H), 4.27 (d, J=4.8 Hz, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
6.648 g of methylsulphonyl-acetic acid ethyl ester in 20 ml of DMF are added dropwise at -25°, within 25 minutes, to 1.745 g of sodium hydride dispersion (55% in oil) in 40 ml of DMF. The solution is subsequently stirred for 30 minutes at -25°, then 6.84 g of benzyl bromide in 40 ml of DMF are added dropwise. The reaction mixture is then stirred for 1 hour at room temperature, left to stand overnight and concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water, dried, concentrated by evaporation and purified by flash chromatography on 700 g of silica gel 60 (eluant E). 1H-NMR (DMSO-d6): 1.1 ppm (t, 3H); 3.05 (s, 3H), 3.1-3.6 (m, 2H); 3.9-4.3 (m, 3H); 7.25 (m, 5H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:6][CH:5]=1.[CH3:31]I>CN(C)C=O.[Cl-].[NH4+]>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH2:28][CH3:29])([O:30][CH3:31])[CH2:26][CH3:27])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCC(O)(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC(CC)(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
Sodium hydride (60% in oil, 21.8 mg, 0.546 mmol) was added to a stirred solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentan-3-ol (200 mg, 0.456 mmol) in N,N-dimethylformamide (2.0 mL) at room temperature. After stirring 5 min, methyl iodide (97.0 mg, 0.684 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (174 mg, 0.384 mmol, 84%).
Reaction SMILES: [Na].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([OH:11])=[CH:5][C:4]=2[O:3]1.[Br:12][CH2:13][CH:14]=[CH:15][CH2:16]Br>COCCOC>[Br:12][CH2:13][CH:14]=[CH:15][CH2:16][O:11][C:6]1[CH:7]=[CH:8][C:9]2[O:10][CH2:2][O:3][C:4]=2[CH:5]=1
Reactant: BrCC=CCBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: [Na]
Solvent: COCCOC
Product: BrCC=CCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.4 g (0.04 mol) of sodium salt of 3,4-methylendioxyphenol are added at -20° to a solution of 8.6 g (0.04 mol) of 1,4-dibromo-2-butene in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 0° for 3 hours and subsequently at room temperature for 1 hour. The solvent is distilled off at reduced pressure and the residue is taken up in ether. The ether solution is extracted with saturated salt solution, is dried with sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane/ethyl acetate 9:1. The 5-(4-bromo-2-butenyloxy)-1,3-benzodioxol is obtained as colourless oil.
Reaction SMILES: C(O)C.[CH3:4][C:5]1[N:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][CH:6]=1.Cl.[OH:14][NH2:15].C([O-])([O-])=O.[K+].[K+]>>[CH3:4][C:5]1[N:10]=[C:9](/[CH:11]=[N:15]/[OH:14])[CH:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: Cc1cccc(C=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc(/C=N/O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To 6-methylpicolinaldehyde ethanol solution (642 mg, 5.3 mmol/2.1 mL) was added hydroxyamine hydrochloride (368 mg, 5.3 mmol) and K2CO3 aqueous solution (0.88 g/4.2 mL). The resulting solution was then heated to reflux via external oil bath for 30 min. The reaction mixture was cooled down to 0° C., and stirred for 30 min. The white solid suspension was collected via filtration, and the filter cake was washed with some ice-cold water. The filter cake was air dried, and further dried under high vacuum as the first crop product (0.565 g). The filtrates were combined, and concentrated to dryness. The residue was redissolved in water (2 mL), cooled to 0° C. and stirred for 20 min. The solid product was collected via filtration as the second crop of product (70 mg) as light yellow solid. The two crops of product were combined to provide (E)-6-methylpicolinaldehyde oxime (88%). LCMS (m/z) 136.9 (MH+) 0.21 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[OH:18].Br[C:20]1[CH:21]=[C:22]([C:27]2[O:28][C:29]3[C:30]([N:35]=2)=[N:31][CH:32]=[CH:33][CH:34]=3)[C:23]([NH2:26])=[N:24][CH:25]=1.[F-].[Cs+]>CO.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:7]2[CH:6]=[CH:5][C:4]([OH:18])=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:21][C:22]=1[C:27]1[O:28][C:29]2[C:30]([N:35]=1)=[N:31][CH:32]=[CH:33][CH:34]=2
Reactant: Nc1ncc(Br)cc1-c1nc2ncccc2o1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COc1cc(-c2cnc(N)c(-c3nc4ncccc4o3)c2)ccc1O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A mixture of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90 mg), 5-bromo-3-oxazolo[4,5-b]pyridin-2-yl-pyridin-2-amine (100 mg), caesium fluoride (0.038 g) and bis(triphenylphosphine) palladium chloride (12.06 mg) were suspended in methanol (2 ml) and sealed into a microwave tube. The reaction was degassed, purged with nitrogen and heated to 120° C. over a period of 20 minutes in the microwave reactor. The solvent was removed; the residue was diluted with water (20 ml) and stirred for 30 min. The mixture was filtered, washed with water (3×10 ml), dried; and washed with diethyl ether (4×15 ml) and dichloromethane/diethyl ether (10 ml) and dried overnight to give 4-(6-amino-5-(oxazolo[4,5-b]pyridin-2-yl)pyridin-3-yl)-2-methoxyphenol (100 mg); NMR Spectrum: (DMSOd6) 3.88 (s, 3H), 6.87 (d, 1H), 7.09 (dd, 1H), 7.24 (d, 1H), 7.48 (dd, 1H), 7.73 (bs, 2H), 8.25 (dd, 1H), 8.46 (d, 1H), 8.55 (dd, 1H), 8.60 (d, 1H), 9.09 (s, 1H); Mass spectrum: M+H+ 335.
Reaction SMILES: C([CH:8]([CH2:24][CH2:25][NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH2:35])[N:9](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(OC(C)(C)C)=O.N(CCCI)=[N+]=[N-]>[Pd]>[NH2:35][CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][CH2:8][NH2:9]
Reactant: CC(C)(C)OC(=O)C(CCNCCCCNCCCN)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: [N-]=[N+]=NCCCI
Product: NCCCNCCCCNCCCN

Procedure:
Monoquaternary spermine containing hydrophilic head-group was prepared in a similar way to compound 3. Briefly, TriBoc-Spermine was reacted with excess of 1-azido-3-iodo-propane in the presence of excess TBA. The resulting quaternarized derivative was hydrogenised under (Pd—C) and Boc protecting group were removed using gaseous HCl in dry methanol.
Reaction SMILES: C1([C@@H](C(C2C=CC=CC=2)O)[OH:8])C=CC=CC=1.C1(C)C=CC=CC=1.[Cl:24][C:25]1[C:26]2[S:46][CH2:45][CH2:44][C:27]=2[N:28]=[C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[N:30]=1.CC(OO)(C)C>O>[Cl:24][C:25]1[C:26]2[S@:46](=[O:8])[CH2:45][CH2:44][C:27]=2[N:28]=[C:29]([N:31]2[CH2:32][CH2:33][N:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[CH2:35][CH2:36]2)[N:30]=1
Reactant: OC(c1ccccc1)[C@@H](O)c1ccccc1
Reactant: Clc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Agent: CC(C)(C)OO
Solvent: O
Solvent: Cc1ccccc1
Product: O=[S@@]1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Temperature: 0 °C
Yield: 88 %

Procedure:
Using a jacketed reactor with mechanical stirring at 400 rpm, charge (S)-Hydrobenzoin (292 mg) and toluene (50 mL), followed by Ti(i-PrO)4 (0.20 mL) and water (0.25 mL). Stir the mixture at 20° C. for 30 min. then charge 4-Chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine (3a, 5.00 g) and stir the mixture for 15 min at 20° C. before being cooling to 0° C. (it took 20 min). Charge TBHP (70% aqueous) (0.75 mL) to the reaction mixture and stir for 23 h at 0° C. Reaction reached 96% conversion and 89% ee. Quench with 5% Na2SO3 (20 mL). Separate the layers and extract the aqueous layer with dichloromethane (50 mL). Combine organic layers and wash with water (20 mL), dry (MgSO4), filter, and concentrate affording the desired sulfoxide in (4.6 g, 88% yield, 89% ee). The product may be recrystallized from THF/water (5:1) with good recovery to yield material >96% ee. NMR (400 MHz, CDCl3) δ 7.16-7.26 (m, 2H), 6.80-6.90 (m, 2H), 3.90-4.20 (m, 4H), 3.75-3.90 (m, 1H), 3.00-3.30 (m, 7H); 13C NMR (400 MHz, CDCl3) δ 177.5, 162.5, 160.7, 149.8, 129.4, 125.7, 123.9, 118.2, 49.6, 46.5, 44.7, 44.4, 33.7 (3 signals missing due to overlap); LCMS (ESI) for C16H17Cl2N4OS (M+H)+: calcd. 383.1, obsvd. 383.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=3)[N:24]=2)[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)(Cl)Cl.CN(C)C=O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:1][CH2:2][CH2:3][O:4][S:5]([C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)(=[O:7])=[O:6])=[CH:27][CH:26]=3)[N:24]=2)[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCCO)cc1
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(-c3cn4cc(Br)ccc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 12.2 %

Procedure:
To 10 mL of a solution of 639 mg (corresponding to 2.95 mmol) of 2-hydroxyethyl-p-toluenesulfonate in tetrahydrofran, 388 mg (corresponding to 1.34 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine and 780 mg (corresponding to 2.97 mmol) of triphenylphosphine were added. Further, 6 mL of N,N-dimethylformamide was added thereto to completely dissolve the contents. To the reaction mixture, 0.58 mL (corresponding to 2.95 mmol) of diisopropylazodicarboxylate was added. After the reaction mixture was stirred at room temperature for 17 hours, the reaction solution was concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=65/35). Insoluble matter in chloroform was filtered out of fractions containing a target compound. Further, the resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 79.7 mg (corresponding to 164 μmol) of 6-bromo-2-[4′-(2″-p-toluenesulfonyloxyethoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1-3, Step 4).
Reaction SMILES: [F:1][C:2]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4].[BH4-].[Na+]>C1C=CC=CC=1.C(O)C>[F:1][C:2]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4]
Reactant: O=Cc1ccc(OC(F)=C(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: OCc1ccc(OC(F)=C(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 4-(trifluorovinyloxy)benzaldehyde (about 35 mmol) in benzene/ethanol (75/75 mL) at room temperature was added sodium borohydride (1.8 g, 1.3 eq). The resulting mixture was stirred at room temperature for 3 h. Under reduced pressure, all the solvent was evaporated. The residue was extracted by CH2Cl2 for 1 h and dried over sodium sulfate. The product was purified by chromatography using CH2Cl2 as the eluent to afford 4-(trifluorovinyloxy)benzyl alcohol as colorless oil (5.0 g, yield 68%). 1H NMR (CDCl3): δ 7.36 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 4.67 (s, 2H), 2.03 (s, 1H).
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1>>[CH2:17]([O:4][C:3](=[O:5])[CH:2]([SH:1])[CH3:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(S)C(=O)O
Product: CC(S)C(=O)OCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser, hot plate (equipped with magnetic stirring apparatus) and spin bar are placed 21.6 grams benzyl alchol; 29.6 grams of 2-mercaptopropionic acid; and 0.5 grams of para-toluene sulphonic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].O1[C:15]2([CH2:20][CH2:19][CH:18]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)=O)[CH2:17][CH2:16]2)[O:14]CC1>O1CCCC1.C(OCC)C.CC(C)=O.Cl>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([CH2:22][CH2:21][CH:18]2[CH2:19][CH2:20][C:15](=[O:14])[CH2:16][CH2:17]2)[CH2:25][CH2:26]1
Reactant: O=C(CC1CCC2(CC1)OCCO2)N1CCN(c2ccccn2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C1CCC(CCN2CCN(c3ccccn3)CC2)CC1
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A slurry of lithium aluminum hydride (LiAlH4) (7.48 g, 197 mmol) in 180 mL of tetrahydrofuran (THF) is cooled to 0° C. and treated with aluminum chloride (AlCl3) (8.76 g, 65.7 mmol) in 180 mL of diethyl ether. The reaction was stirred for 30 minutes and the 2-(1,4dioxaspiro[4.5]dec-8-yl)-1-[4-(2-pyridinyl)-1-piperazinyl]-ethanone (22.7 g, 65.7 mmol) was added in portions over 1 hour. The reaction is allowed to stir for 18 hours and is quenched with 8 mL of water and 18 mL of a 50% sodium hydroxide (NaOH) solution. The reaction is stirred for 1 hour and filtered through a pad of Celite. The filter cake is washed with 300 mL of diethyl ether. The combined organic extracts are concentrated to give a white solid which is dissolved in a 230 mL of a 1:1 mixture of acetone and 10% aqueous hydrochloric acid (HCl) solution. After stirring at room temperature for 60 hours, the acetone is removed under reduced pressure, and the pH of the reaction mixture is adjusted to pH 9 with concentrated ammonium hydroxide solution. The aqueous mixture is extracted with two 250 mL portions of chloroform, and the combined organic fractions are dried with sodium sulfate. The solvents are removed under reduced pressure, and the residue is triturated with diethyl ether to give 14.3 g 4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-cyclohexanone as a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:15][CH2:14][CH:13]([F:16])[F:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCC(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
To a solution of p-toluensulfonyl chloride (7.0 g, 36.7 mmol) and 2,2-difluoroethanol 25a (2.00 g, 24.3 mmol, purchased from Linkchemical Co., Ltd) in dichloromethane (20 mL) was added triethylamine (10.2 mL, 73.1 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was adjusted with saturated aqueous ammonium chloride to pH 7 and washed with water (10 mL×2). The organic layer was washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 25b as light yellow oil (3.4 g, 59.0%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.82 (d, 2H), 7.40 (d, 2H), 5.93 (m 1H), 4.18 (m, 2H), 2.47 (s, 3H).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH2:11][CH2:10]1.[Na].C1(=O)NC(=O)CC1.[H-].[Na+]>O.CN(C=O)C>[CH:2]1([N:13]2[C:9](=[O:15])[CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: O=C1CCC(=O)N1
Reactant: BrC1C=CCCCC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1C1C=CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromocycloheptene (1.75 g) was added dropwise at room temperature to a DMF suspension (10 ml) of sodium succinimide prepared from succinimide (0.99 g) and 60% sodium hydride (0.40 g). This mixture was stirred at room temperature for 24 hours, poured into water (10 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.09 g of N-(2-cycloheptenyl)succinimide [Compound (214)].