Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH2:3]([NH:10][CH2:11][CH2:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][C:18]2[CH:25]=[CH:24][C:21](C#N)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[C:33](=[O:36])(O)[O-].[Na+]>C(OCC)C.O1CCCC1>[CH2:3]([NH:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:25]=[CH:24][C:21]([C:33](=[O:36])[CH3:1])=[CH:20][CH:19]=2)=[CH:26][CH:27]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Reactant: [Li]C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.4M Methyl Lithium in diethyl ether was added to a dry flask then cooled to 0° C. A solution of 4-[4-(2-Benzylamino-ethyl)-phenoxy]-benzonitrile (2.5 g, 7.6 mmol) (see example 4) in dry tetrahydrofuran (25 mL) was added dropwise to the reaction then stirred at 0° C. for 60 minutes. 3M Sulfuric Acid (12.7 mL, 38 mmol) was added dropwise then the reaction was heated at 50° C. for 3 hours. The reaction was cooled to room temperature then poured into saturated aqueous sodium bicarbonate solution then extracted with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield 3.1 g of crude product, which was purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield 1-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-ethanone (0.6 g) which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][C:15]=1[CH3:16].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][C:15]=1[CH3:16])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)sc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a mixture of {3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (0.95 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.58 g), tributylphosphine (0.85 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.06 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.83 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([CH3:34])([O:9][C:10]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33])[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=[O:11])[CH3:8].C(N(CC)CC)C>O1CCCC1>[CH3:8][C:7]([CH3:34])([O:9][C:10]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)=[O:11])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1N)C1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1NS(C)(=O)=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 12 h

Procedure:
1.64 ml. (21 mmol) of methanesulphonyl chloride was added dropwise to a solution of 7.91 g (20 mmol) of N-(1,1-dimethylethoxycarbonyl)-N-[(2-aminophenyl)methyl]-1-(phenylmethyl)-4-piperidineamine and 3.0 ml (21 mmol) of triethylamine in 100 ml of tetrahydrofuran and the mixture was then kept for 12 hours at ambient temperature. It was then diluted with 100 ml of EE and extracted twice with 70 ml of saturated sodium hydrogen carbonate solution. The ethyl acetate phase was dried over sodium sulphate and concentrated by evaporation in vacuo. 8.7 g (92% of theoretical) of a colourless substance were obtained, Rf 0.85 (El D), which were used in the next step without any further purification.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[C:28]1([S:34]([CH2:37][C:38]2[C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42](OS(C(F)(F)F)(=O)=O)[C:41]([CH2:56][CH3:57])=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O:58]1[CH2:63][CH2:62][CH2:61][CH2:60][CH:59]1[N:64]1[C:68](B2OC(C)(C)C(C)(C)O2)=[CH:67][CH:66]=[N:65]1>>[C:28]1([S:34]([CH2:37][C:38]2[C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42]([C:68]3[N:64]([CH:59]4[CH2:60][CH2:61][CH2:62][CH2:63][O:58]4)[N:65]=[CH:66][CH:67]=3)[C:41]([CH2:56][CH3:57])=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OS(=O)(=O)C(F)(F)F
Agent: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1-c1ccnn1C1CCCCO1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-(trifluoromethanesulphonyloxy)benzoate (Intermediate 127) and 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester as an opaque foam which was used without further characterization.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)[CH:19]=2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:37]([O:39][NH2:40])C.N1C=CC=CC=1>C(O)C.CCOC(C)=O>[CH3:37][O:39][N:40]=[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:35])[CH:26]=2)[CH:19]=1)[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: Cc1cc(Nc2cccc(C(=O)CCN3CCC(Cc4ccccc4)CC3)c2)c2ccccc2n1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CON=C(CCN1CCC(Cc2ccccc2)CC1)c1cccc(Nc2cc(C)nc3ccccc23)c1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
A mixture of Example 209 (0.40 g, 0.86 mmol), ethoxyamine hydrochloric acid (0.22 g, 2.63 mmol,) and pyridine (0.19 g, 2.47 mmol) in anhydrous ethanol (3.0 mL) was heated under reflux overnight. The reaction was allowed to cool to room temperature and diluted with EtOAc (100 mL). Upon sequential washings with 1 N NaOH (2×100 mL) and brine (100 mL), the organic solution was dried over Na2SO4 and evaporated to dryness. The resulting residue was purified via flash silica gel chromatography to give the desired product (100 mg, 24%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH:14]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][NH:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]3[CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ccccc2C1C1CCCCC1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Cyclohexyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17](Cl)[N:16]=1>C1COCC1.O>[Cl:21][C:19]1[CH:20]=[C:15]([Cl:14])[N:16]=[C:17]([NH:9][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=[CH:7][N:6]=2)[CH:18]=1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccnc(Nc2cc(Cl)cc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(trifluoromethyl)pyridin-2-amine (3.24 g, 20.0 mmol) and sodium hydride (1.2 g, 30 mmol) in THF (60 mL) was stirred at 0° C. under nitrogen for 1 hour, and then 2,4,6-trichloropyridine (3.62 g, 20.0 mmol) was added. The reaction was stirred at 25° C. for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give 4,6-dichloro-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine. MS ESI calc'd. for C11H7Cl2F3N3 [M+H]+ 308. found 308. 1H NMR (400 MHz, CD3OD): δ 8.49 (d, J=5.6 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.19 (d, J=1.2 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13]([C:14]#[N:15])=[C:12]([C:16]#[N:17])[N:11]([CH3:18])[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(O[C:25](=O)[CH3:26])(=O)C.N1C=C[CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[C:7]([O:8][CH2:31][C:30]#[CH:29])=[CH:6][C:5]([N:9]2[C:13]([C:14]#[N:15])=[C:12]([C:16]#[N:17])[N:11]([CH2:18][CH2:25][CH3:26])[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: Cn1c(C#N)c(C#N)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Product: C#CCOc1cc(-n2c(C#N)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Reaction time: 0.17 h

Procedure:
The product of Example 32, 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5-dicyano-3-methyl-1,3-dihydro-2H-imidazol-2-one, (VIII) (200 mg, 0.68 mmol) was stirred in 10 mL pyridine at room temperature. To this mixture was added acetic anhydride (100 mg, 0.98 mmol). After stirring for 10 minutes the mixture was poured over a mixture of ice/HCl and filtered. Recrystallization from ethyl acetate/heptane gave 60 mg of 1-(4-chloro-2-fluoro-5-acetoxyphenyl)-4,5-dicyano-3-methyl-1,3-dihydro-2H-imidazol-2-one (VI) (m.p. 164°-6° C.).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[C:18]=[O:19].[CH2:20]([CH:22]([NH:25][OH:26])[CH2:23][CH3:24])[CH3:21]>>[OH:26][N:25]([CH:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[C:18]([NH:17][C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:19]
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: [N-]=C=O
Reactant: CCC(CC)NO
Product: CCC(CC)N(O)C(=O)Nc1cccc(Oc2ccccc2)c1

Procedure:
Using the method of Compound 76, 3-phenoxybenzoic acid (3.47 g, 16 mmole) was converted to the corresponding isocyanate then reacted with N-(1-ethylpropyl)hydroxylamine (2.5 g, 24 mmole) to provide 3.2 g of the desired product as white plates, m.p. 110.6°-111.4° C. Analysis: Calculated for C18H22N2O3 : %C, 68.77; %H, 7.05; %N, 8.91; Found: %C, 68.4; %H, 6.67; %N, 8.89.
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:22]=[C:21]([NH:23][C:24]3[C:29]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:28][C:27]([S:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[CH:26][N:25]=3)[S:20][N:19]=2)[CH2:14][CH2:13]1)[CH2:3][NH:4]C(=O)OC(C)(C)C.[ClH:44]>C(Cl)Cl.CO.O1CCOCC1>[ClH:44].[ClH:44].[NH2:4][CH2:3][C:2]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[N:22]=[C:21]([NH:23][C:24]3[C:29]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:28][C:27]([S:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[CH:26][N:25]=3)[S:20][N:19]=2)[CH2:16][CH2:17]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
tert-Butyl 2-oxo-2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethylcarbamate (0.098 g, 0.16 mmol) was dissolved in CH2Cl2:MeOH (1:1, 20 mL) and added 5 mL of 4M HCl in dioxane and stirred for 2 hours. The reaction was concentrated and dried in high vacuum oven to provide 2-amino-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone dihydrochloride (0.081 g, 78% yield). 1H NMR (d6-DMSO) δ 12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 8.13 (m, 3H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.43 (t, 2H), 7.21-7.11 (m, 5H), 4.32 (d, 1H), 3.90 (m, 2H), 3.70 (m, 2H), 3.48 (m, 1H), 3.26-3.02 (m, 2H), 2.94 (t, 1H), 2.06 (d, 2H), 1.76-1.53 (m, 2H).
Reaction SMILES: Br[CH2:2][CH3:3].[O:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[C:11]([C:14](=[O:24])[CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:13][C:5]1=2.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.CCOCC>[O:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[C:11]([C:14](=[O:24])[CH:15]([CH2:2][CH3:3])[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH:12]=[CH:13][C:5]1=2
Reactant: O=C(CC(=O)c1ccc2c(c1)OCCO2)c1ccccc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCC(C(=O)c1ccccc1)C(=O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Bromoethane (0.87 mmol) was added slowly to a solution 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione (XX) (0.39 mmol) and K2CO3 (1.58 mmol) in DMSO (4 mL) stirred at room temperature under nitrogen. The solution was further stirred overnight at room temperature under nitrogen. The solution was poured into a mixture of water and ether. The etheric layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to get 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-ethyl-3-phenylpropane-1,3-dione 17 as colorless viscous oil (35% yield). 1H NMR (DMSO-d6, 400 MHz): δ ppm 0.93 (t, J=7.4 Hz, 3H), 1.93 (m, 2H), 4.28 (m, 2H), 4.33 (m, 2H), 5.60 (t, J=6.5 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 7.51-7.55 (m, 4H), 7.66 (m, 1H), 7.98 (d, J=7.3 Hz, 2H); ESIMS found C19H18O4 m/z 311 (M+H) and 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,2-diethyl-3-phenylpropane-1,3-dione 18 as a white solids. ESIMS found C21H22O4 m/z 339 (M+H).
Reaction SMILES: O[C:2]1[C:7]2[C:8](=[O:12])O[IH](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH2:8]([O:12][C:14]1[CH:4]=[CH:3][CH:2]=[CH:7][C:15]=1[CH2:16][CH:17]=[O:13])[C:7]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: O=C1O[IH](=O)c2cccc(O)c21
Product: O=CCc1ccccc1OCc1ccccc1

Procedure:
0.104 mol of hydroxy-1-oxo-benzo[d][1,2]iodoxol-3-one is added to 0.08 mol of [2-(2-benzyloxy)phenyl]ethanol in 500 ml of tetrahydrofuran. The reaction mixture is heated at reflux for 2 hours and then cooled. The precipitate is filtered off and the filtrate is evaporated.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[NH:34])=[CH:31][CH:30]=1)[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:17]=1.CO.C(N(CC)CC)C.[CH3:47][O:48][C@H:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:50]([OH:52])=[O:51]>C(O)(=O)C>[CH3:47][O:48][C@H:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:50]([OH:52])=[O:51].[F:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C@@H:15]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH2:35])=[NH:34])=[CH:36][CH:37]=1)[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[N:17]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: CO[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 60 °C
Yield: 38.8 %

Procedure:
A suspension of 4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}benzamidine hydrochloride (4.73 g, purity 92%, 8.2 mmol) and methanol (131 mL) was heated to 60° C. to bring into solution. Triethylamine (1.71 mL, 12.3 mmol) was added thereto at 60° C., and the resulting mixture was stirred for minutes or more. To the suspension obtained, (R)-(−)-α-methoxyphenylacetic acid (2.73 g, 16.4 mmol) and acetic acid (4.35 mL) were added to bring the same into solution. The solution obtained was allowed to cool to 35° C., and a seed crystal of the captioned compound was added thereto, and the resulting mixture was stirred at room temperature for 20 hours and at 0° C. for 3 hours. The resulting solid was filtered, sequentially washed with ethanol (13 mL) and tert-butyl methyl ether (13 mL), and then dried at room temperature under reduced pressure to obtain the captioned compound (2.1 g) as a white solid.
Reaction SMILES: [CH3:1]P(=O)(OCC)OCC.O1CCCC1.C([Li])CCC.[CH:20](=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])O1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O>[CH2:20]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])[CH:1]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1OC(=Cc2ccccc2)c2ccccc21
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Diethyl methylphosphonate (1.94 g.) suspended in 50 ml. of dry tetrahydrofuran is treated with 1.1 equivalents of butyl lithium in hexane under nitrogen at about -78°. After 10 minutes, one equivalent of benzalphthalide in 10 ml. of tetrahydrofuran is added while maintaining the temperature at about -78°. The reaction mixture is allowed to warm to room temperature and then left to stand at room temperature for 3 hours. The reaction mixture is diluted with water and then extracted with ether. The ether extracts are combined, washed with water, dried and the solvent removed under vacuum. The residue is chromatographed on silica eluting with methylene chloride:hexane (4:1) to afford 3-benzylind-2-en-1-one and a small amount of starting material.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH:10]1([NH2:13])[CH2:12][CH2:11]1.O1CCCC1.C([BH3-])#N>C(O)(=O)C>[CH:10]1([NH:13][CH:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:2])[CH2:12][CH2:11]1
Reactant: CC(=O)c1ccccn1
Reactant: NC1CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(NC1CC1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
A mixture of 2-acetylpyridine (250 mg, 2.06 mmol), cyclopropylamine (111 mg, 1.94 mmol), anhyd tetrahydrofuran (15 mL) and acetic acid (1.5 mL) is stirred at room temperature for 10 min. MP-cyanoborohydride (1.2 g, 2.82 mmol) is added and the mixture is stirred overnight. The reaction is filtered through a Varian mega bond elut SCX and the resin washed with methanol (20 mL). The resin is then washed with 7 N methanolic ammonia (60 mL) and the eluent is evaporated. The residue is purified by chromatography on an ISCO Redisep 10 g cartridge eluting with ethyl acetate to afford cyclopropyl(1-pyridin-2-yl)ethylamine (245 mg, 73% yield) as oil. A hydrochloride salt is prepared by dissolving the amine (50 mg, 0.308 mmol) in methanol (2 mL), adding 1 M ethereal hydrochloric acid (0.8 mL), some methanol is removed, more ether added and the hydrochloride salt is collected by filtration (50 mg, 69% yield as gray solid). RT=1.69 min; MS 163 (M+1); 1H NMR (δ, ppm): 9.5 (2H, br s), 8.69 (1H, d), 7.94 (1H, dd), 7.69 (1H, d), 7.47 (1H, m), 4.59 (1H, q), 1.58 (3H, d), 0.6-0.96 (4H, m).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH2:24]O)[S:22][CH:23]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH2:24][N:51]4[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]4)[S:22][CH:23]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CNC1
Reactant: OCc1cc(-c2noc(-c3ccc(Cc4ccccc4)cc3)n2)cs1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2cc(-c3noc(-c4ccc(Cc5ccccc5)cc4)n3)cs2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {4-[5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (95 mg, 0.27 mmol) that was obtained in Example 6 (6a), carbon tetrabromide (0.18 g, 0.54 mmol), triphenylphosphine (0.14 g, 0.54 mmol), ethyl 3-azetidinecarboxylate hydrochloride (67 mg, 0.41 mmol), and N,N-diisopropylethylamine (0.12 ml, 0.68 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (6:4) as the developing solvent to afford the title compound (84 mg) in a yield of 68% as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1c(O)cc(O)cc1O
Reactant: CC(C)=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1c(O)cc(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
In 250 ml of anhydrous tetrahydrofuran was dissolved 50.0 g of 2',4',6'-trihydroxyacetophenone, and 123.15 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 37.23 g of 1-chloro-3-methyl-2-butene was dropped into the solution over a period of 20 minutes and a reaction was carried out at room temperature for 24 hours. After the reaction, the reaction mixture was extracted with 2 l of ethyl acetate, and the ethyl acetate layer was washed with water (500 ml×4 times), shaken with a saturated aqueous solution of sodium chloride (300 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from a mixed solvent of benzene and petroleum ether to obtain 38.6 g (yield=55.0%) of 2',4',6'-trihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a yellow prism.