Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[OH:38])/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:39]1[O:50][C:49]2[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][C:41]=2[O:40]1>ClCCl>[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[O:38][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][C:49]4[O:50][CH2:39][O:40][C:41]=4[CH:42]=3)/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)/C(=N\OC(=O)c1ccc2c(c1)OCO2)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
Triethylamine (6.7 ml) was added with stirring to an ice-cooled suspension of 10 g of 2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetic acid in 140 ml of anhydrous dichloromethane. The suspension turned to a clear, faint yellow solution after ten minutes. A solution of 3,4-methylenedioxybenzoyl chloride (3.4 g) in 25 ml of dichloromethane was dropwise added and the mixture was stirred at room temperature for one hour. The insoluble crystals were removed by filtration and the filtrate was washed twice with 20 ml of 1N hydrochloric acid and 30 ml of saturated sodium chloride solution each, and dried over anhydrous sodium sulfate. The dried filtrate was concentrated under reduced pressure, and the viscous brown residue (14.2 g) was purified by silica gel column chromatography using chloroform/methanol (20-10:1) as eluent, affording 2.3 g of the objective compound as light brown crystals.
Reaction SMILES: [OH:1][CH:2]([C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23](Br)([CH3:26])([CH3:25])[CH3:24]>C1CCCCC1.ClCCl.[Ag-]=O>[C:23]([O:1][CH:2]([C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)Br
Reactant: CCOC(=O)C(O)c1cc2ccccc2n1-c1ccccc1
Agent: O=[Ag-]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1cc2ccccc2n1-c1ccccc1
Reaction time: 24 h
Yield: 33.5 %

Procedure:
A mixture of ethyl 2-hydroxy-2-(1-phenyl-1H-indol-2-yl)acetate (5b) (50 mg, 0.17 mmol), silver (I) oxide (130 mg, 0.56 mmol) and tertbutylbromide (114 μL, 1.02 mmol) in cyclohexane (4 mL) and dichloromethane (2 mL) was vigorously stirred for 24 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired ether oxide (5c) as a white solid (20 mg, 0.057 mmol, 33%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Li]CCCC.[F:10][CH:11]([F:31])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=[O:26])=[O:21])=[CH:15][CH:14]=1>C1COCC1.COCCOC>[F:10][CH:11]([F:31])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[C:20]([C:22]2[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]([OH:26])[C:3]#[C:2][CH2:1][OH:4])[CH:23]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: C#CCO
Reactant: O=Cc1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C(C(=O)c1cccc(C(O)C#CCO)c1)c1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A stirred solution of propargyl alcohol (0.1 g, 1.78 mmol) in dry THF at −78° C. under nitrogen was treated dropwise with 1.9 M n-BuLi (1.88 mL, 3.57 mmol) over 10 min, stirred for 0.5 h and warmed to 0° C. A 3 mL portion of this solution was added to a stirred solution of 3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]benzaldehyde (0.15 g, 0.49 mmol) in dry DME at 0° C. under nitrogen. After 10 min, the reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (30% to 70% ethyl acetate/petroleum ether) gave 1-[4-(difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1,2-dione as a clear oil, 52 mg (29% yield). Using essentially the same procedure described in Example 1, step c, and employing 1-[4-(difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1,2-dione (0.052 g, 0.14 mmol), the title compound was obtained as a slight brown foam, 0.031 g (52% yield), identified by NMR and mass spectral analyses. MS (ES+): 416 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:11][C:12]1[C:17]([O:18][CH2:4][C:3]2[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=2[F:10])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Nc1ncccc1O
Reactant: Fc1cccc(F)c1CBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
A mixture of 2,6-difluorobenzyl bromide (25 g, 0.121 mol) and 2-amino-3hydroxypyridine (12.1 g, 0.11 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to yield a solid (18.5 g, 65%), m.p. 124°-128° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[S:9][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1ccccc1Br
Reactant: OB(O)c1cccs1
Product: Fc1ccccc1-c1cccs1

Procedure:
2-Fluorobromobenzene and thiophene-2-boronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(2-fluorophenyl)thiophene as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][CH3:26].Cl>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][O:25][CH3:26])[CH2:11][CH2:10]1
Reactant: OC1(c2cccc(Cl)c2Cl)CCNCC1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(O)(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-dichlorophenyl)piperidin-4-ol (0.44 g, 1.81 mmol), acetonitrile (20 ml), potassium carbonate (0.5 g, 3.6 mmol), 1-bromo-2-methoxyethane (0.17 ml, 2.0 mmol). Yield: 0.3 g, 54%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether. M.p. 135-137° C. MS m/z (relative intensity, 70 eV) 305 (M+, 1), 303 (M+, 1), 260 (63), 258 (bp) 240 (31).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][F:78])([CH2:75][F:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[F:78][CH2:77][C:74]1([CH2:75][F:76])[O:73][B:72]([OH:79])[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH:68]=[CH:69][C:70]1=2
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2c(c1)B(O)OC2(CF)CF)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (116 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by prep-TLC to provide the title product.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([CH2:8][N:9]2[CH2:30][C@H:29]([OH:31])[CH2:28][C@H:10]2[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([N:9]2[CH2:30][C@H:29]([OH:31])[CH2:28][C@H:10]2[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]2)=[O:12])=[O:37])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H]2C[C@@H](O)CN2Cc2ccc(C(=N)N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)c1ccc(C(=O)N2C[C@H](O)C[C@H]2C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
A solution of 1.60 g of t-butyl [[1-[(4R)-1-(p-amidino-benzyl)-4-hydroxy-L-prolyl]-4-piperidinyl]oxy]acetate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at room temperature for 2 hours and evaporated. The residue is dissolved in ethanol and treated with ether. Suction filtration and drying of the precipitate gives 1.25 g of [[1-[(4R)-1-(p-amidino-benzoyl)-4-hydroxy-L-prolyl]-4-piperidinyl]oxy]acetic acid trifluoroacetate. M.p. 220° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>>[C:20]([C:23]1[NH:24][N:25]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([F:18])[C:12]([C:13]#[N:14])=[C:15]([F:17])[CH:16]=3)=[N:5]2)=[O:29])[CH:27]=1)(=[O:22])[CH3:21]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)n[nH]1
Yield: 27.3 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.7 g, 2.67 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.494 g, 3.20 mmol), HOBt (0.433 g, 3.20 mmol), DIPEA (0.558 ml, 3.20 mmol) and EDCI (0.614 g, 3.20 mmol) using the method of Example 34(d) producing 0.29 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (m, 3H), 4.32 (m, 2H), 4.44 (m, 1H), 6.97 (m, 1H), 7.31 (m, 1H), 7.71 (m, 2H), 7.83 (m, 1H), 8.44 (m, 1H), 14.15 (m, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[N:13]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[CH:11][CH:10]=1>C(O)(=O)C>[C:5]([NH:8][C:9]1[N:13]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]([F:22])([F:24])[F:23])=[CH:16][C:15]=2[Cl:25])[N:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: Nc1ccnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 9 h
Yield: 76.9 %

Procedure:
3.7 ml (0.038 mol) of acetic anhydride are added to 100 g (0.036 mol) of 5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole in 60 ml of glacial acetic acid, and the mixture is stirred at room temperature for 9 hours. For working-up, the reaction mixture is added dropwise to 300 ml of ice-water, and the precipitate formed is filtered off, washed with water and dried in vacuo at 50° C. 8.9 g (77% of theory) of 5-acetamido-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole of melting point 144°-146° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3]([O:5][CH2:6]C)=[O:4].[BH4-].[Na+]>CO>[F:14][C:2]([F:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH:3]([O:5][CH3:6])[OH:4]
Reactant: CCOC(=O)C(F)(F)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(O)C(F)(F)c1ccccn1
Reaction time: 0.92 h
Yield: 108.5 %

Procedure:
Ethyl difluoro(2-pyridyl)acetate (1.00 g, 4.97 mmol, from Procedure 35, Step B) was dissolved in CH3OH (15 mL) in a 3-neck round bottom flask fitted with a mechanical stirrer, and the resulting solution was cooled in a dry ice/isopropanol bath. Sodium borohydride (114 mg, 3.0 mmol) was added in 2 portions 15 min. apart. After an additional 55 min., the cold reaction was quenched by the addition of saturated aq. ammonium chloride (6.5 mL) over 12 min. After 10 min., the cooling bath was removed and the mixture was stirred for 35 min. before being diluted with saturated aq. brine (100 mL) and extracted with ethyl acetate (4×75 mL). The combined organic layers were dried (sodium sulfate), decanted, and evaporated to give 1.02 g of crude 2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol as an amber oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH2:9]1[O:11][CH:10]1[CH2:12]O.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>C1COCC1.C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:12][CH:10]2[CH2:9][O:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OCC1CO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnn(CC2CO2)c1
Yield: 47.7 %

Procedure:
To a stirred, cooled (0° C.) solution of 4-nitro-1H-pyrazole (1.0 g, 8.8 mmol), glycidol (0.58 mL, 8.8 mmol) and triphenylphosphine (2.14 g, 10.6 mmol) in THF (40 mL) was added DIAD (2.25 mL, 11.4 mmol). After 24 h the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed (brine), dried (anhydrous MgSO4) and concentrated. Flash chromatography (Isolera, silica, 50 g, 0-90% ethyl acetate in petroleum ether) afforded 4-nitro-1-(oxiran-2-ylmethyl)-1H-pyrazole as an off-white solid (0.71 g, 48% yield). LCMS (UPLC, low pH), RT=0.74 min.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(O)C1
Temperature: 2.5 °C
Reaction time: 0.42 h
Yield: 66.6 %

Procedure:
To a cold (ice bath) solution of Rac-3-Oxo-cyclopentanecarboxylic acid tert-butyl ester (1.43 g) in methanol (9 mL) was added sodium borohydride (0.293 g). The mixture was stirred 25 min at 0-5° C. then concentrated in vacuo. Ethyl acetate was added to the residue and the mixture was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with dichloromethane/methanol (19:1 v/v) as eluant to afford the title compound (0.963 g, 67%) as colorless oil. MS (EI): 187.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([I:10])=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:18])=[O:19])=[CH:4][C:5]2[O:9][C:8]([I:10])=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CNC(=O)c1c(I)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a suspension of 5-bromo-2-iodo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (177 mg, 90% purity, 0.34 mmol) and K2CO3 (140 mg, 1.01 mmol) in DMF (3 mL) was added dropwise CH3I (79 mg, 0.68 mol) at 0° C. under N2, and then the mixture was stirred at 80° C. for 1 hour. After concentrated in vacuum, the residue was suspended in H2O and extracted with DCM. The residue was purified by column chromatography (eluted with DCM: EtOAc from 10:1 to 2:1) to give 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.66 (s, 1H), 6.27 (s, 1H), 3.32 (s, 3H), 3.08 (d, J=4.8 Hz, 3H), 2.89 (s, 3H). MS (M+H)+: 487/489.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15]Cl.[C:22]([O:31][CH3:32])(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25]>C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[C:22]([O:31][CH3:32])=[O:30]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylformamide (DMF)(100 ml), potassium carbonate (17.97 g) and 2,4-dichlorobenzyl chloride (21.50 g) were added to methyl salicylate (15.22 g), and the mixture was stirred at room temperature overnight. Ethyl acetate (1000 ml) was added to the reaction mixture, and the resulting mixture was washed with brine (700 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude methyl 2-(2,4-dichlorobenzyloxy)benzoate. Methanol (100 ml), THF (100 ml), water (20 ml) and 85% potassium hydroxide (7.92 g) were added to the crude product thus obtained, and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. Water (300 ml) was added to the residue, and the pH of the mixture was adjusted to not more than 2, and the resulting crystals were separated by filtration, dried to give 2-(2,4-dichlorobenzyloxy)benzoic acid (29.30 g) as colorless crystals.
Reaction SMILES: [N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:26]2=[N:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[C:25]2[N:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:29]4[CH:30]=[C:25]5[N:24]=[C:23]([CH3:22])[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:48])[CH3:47])[C:26]5=[N:27][CH:28]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1COCC[Si](C)(C)C
Reactant: Ic1ccc2ncnc(N3CCCc4ccccc43)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc2n1COCC[Si](C)(C)C
Yield: 56.3 %

Procedure:
0.25 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline, 0.30 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridine, 0.16 g of sodium hydrogencarbonate and 0.09 g of Pd(PPh3)2Cl2 in 5.00 ml of dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 5 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-40% in 20 min), giving 0.19 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline as white powder (yield 50%, content 94%); MS-FAB (M+H+)=523.2; Rf (polar method): 2.54 min.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C[O-].[Na+].CO.C(OC)(=O)CCCCCCCCCCCCCCCCC.C(OC)(=O)CCCCCCCCCCCCCCC.C(OC)(=O)CCCCCCC/C=C\CCCCCCCC.C(OC)(=O)CCCCCCCCCCCCCCC.C(OC)(=O)CCCCCCC/C=C\C/C=C\CCCCC.C(OC)(=O)CCCCCCCCCCCCCCC.CC/C=C\C/C=C\C/C=C\CCCCCCCC(OC)=O.C(OC)(=O)CCCCCCCCCCCCCCC.II>[Ag].CCCCCC>[CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: [Ag]
Agent: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)OC
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC
Solvent: CO
Solvent: CCCCCC
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Reaction time: 8 h

Procedure:
54 mg. of soybean oil (containing by weight fatty acid moieties on a fatty methyl ester basis as follows: palmitic, 9.7%; stearic, 4.6%; oleic, 23.2%; linoleic, 53.9%; linolenic, 7.7%; other, 0.9%) was added to 5 milliliters of hexane (δ=7.3, δD =7.3, δP =0, and δH =0) and 1.0 gram Amberlyst 15 ion exchange resin with 100% of its cationic substituents being silver substituents, in a screw-cap vial. This was placed on a wrist action shaker at 27° C. overnight. A 1.0 milliliter aliquot of the supernatant liquid was removed, freed of hexane with a nitrogen stream, weighed, multiplied by 5 to give 35.5 mg. in the bulk liquid and by difference 18.5 mg. adsorbed. The bulk liquid material was converted to methyl esters with sodium methoxide/methanol, the resulting ester mixture analyzed by gas chromatography and selectivities were calculated according to the aforementioned formula using methyl esters as the components M and N. These selectivities were as follows: methyl stearate/methyl palmitate, 0.4; methyl oleate/methyl palmitate, 1.5; methyl linoleate/methyl palmitate, 5.2; and methyl linolenate/methyl palmitate, 42.4. These selectivities demonstrate that triglycerides of higher Iodine Value were preferably adsorbed and that a soybean oil fraction was produced with dramatically reduced linolenic acid moiety content.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5]2)[CH2:3][N:2]1C(OC(C)(C)C)=O.Cl>C(Cl)Cl.O1CCOCC1>[CH2:3]1[C:4]2([CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:7][CH2:8]2)[CH2:1][NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)OCc3ccccc3)C2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC2(CNC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-benzyl 2-tert-butyl 2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (705 mg, 2.0 mmol) in DCM (1 mL) was treated with hydrogen chloride (5 mL of 4 M, 20 mmol) in dioxane. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to obtain benzyl 2,7-diazaspiro[3.4]octane-7-carboxylate. LC/MS m/z 247.3 [M+H]+.