Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](F)=[O:20])=[N:17][CH:18]=1>O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:4][CH:2]([CH3:3])[CH3:1])=[O:20])=[N:17][CH:18]=1
Reactant: CC(C)O
Reactant: O=C(F)c1ccc(F)cn1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added drop-wise at room temperature to the 5-fluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight, poured into a reparatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.17 g (23% yield, 96% LC purity) of desired product as an off-white solid. GC/MS results were consistent with the chemical formula of isopropyl 5-fluoropicolinate: 70 eV EIMS (GC) m/z=142 (43%), 124 (100%), 97 (97%), 96 (93%), 43 (59%). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.8 Hz, 1H), 8.18 (dd, J=8.8, 4.4 Hz, 1H), 7.52 (ddd, J=8.7, 7.9, 2.9 Hz, 1H), 5.34 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 163.63 (s), 162.32 (s), 159.71 (s), 144.84 (d, J=3.8 Hz), 138.46 (d, J=24.8 Hz), 126.78 (d, J=5.4 Hz), 123.31 (d, J=18.5 Hz), 69.71 (s), 21.81 (s). 19F NMR (376 MHz, CDCl3) δ −120.51.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1ccc(C(=C(c2ccccc2)c2ccc(C)cc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A suspension of 4-methylbenzophenone (1, 3.6 g, 10.0 mmol), TiCl4 (1.9 g, 10.0 mmol), and Zn dust (1.3 g, 20.0 mmol) in dry THF (100 mL) was refluxed for 20 g. Afterward, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the crude product was purified on a silica-gel column using DCM as eluent. 1,2-Bis(4-methylphenyl)-1,2-diphenylethene was isolated as white solid in 94% yield. 1H NMR (300 MHz, CDCl3), δ (TMS, ppm): 7.11-7.00 (m, 10H), 6.91 (d, 8H), 2.26 (d, 6H). δ (75 MHz, CDCl3) 144.8, 141.6, 141.1, 136.6, 132.0, 131.9, 129.0, 128.2, 126.9, 21.9. m/z (FAB) 360.2 [M+ ]; calc. 360.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Br)=[O:10])=[CH:4][CH:3]=1.[C:12]([S-:14])#[N:13].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([S:14][C:12]#[N:13])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Br)Cc1ccc(Cl)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSC(=O)Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
4-Chlorophenylacetyl bromide (12.2 g, 52.3 mmol) was suspended in ethanol (50 ml) and heated to 60° C.–70° C. An aqueous solution (10 ml) of KSCN (5.59 g, 57.5 mmol) was added by small portions, and after addition, the mixture was stirred at 80° C. for 10 min. The reaction mixture was left standing at room temperature for 4 hrs. Water (150 ml) was added and the precipitated solid was collected by filtration. The residue was washed twice with water (150 ml) and dried under reduced pressure to give the title compound (10.1 g, 91%).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]([NH:9]C(=O)OCC1C=CC=CC=1)[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]>C1COCC1.[Pd]>[NH2:9][C@H:4]([C:2]([NH2:1])=[O:3])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of benzyl [(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate (Step 1, 3.7 g, 14 mmol) in THF (40 mL) was added 10% Pd/C (710 mg). The flask was evacuated and flushed with H2 gas and this process was repeated three times. The flask was filled with H2 gas (4 atm) and stirred for 3 h at rt. Then the reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give the title compound as white solid (crude; 1.8 g)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:32]([CH:33]=1)[C:15]1[N:16]([C:25]3[CH:26]=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:17](=[O:24])[C:18]3[C:23]([C:14]=1[N:13]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3.C(N(CC)CC)C>ClCCl>[Cl:31][C:28]1[N:27]=[CH:26][C:25]([N:16]2[C:15]3[N:32]4[CH:33]=[C:9]([NH:8][C:5](=[O:7])[CH3:6])[CH:10]=[CH:11][C:12]4=[N:13][C:14]=3[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
Acetic anhydride (1.5 equiv., 0.829 mmol, 0.084 g) was added to a cooled (0° C.) solution of compound 53 (1.0 equiv., 0.553 mmol, 0.200 g) and triethylamine (1.5 equiv., 0.829 mmol, 0.085 g) in dichloromethane (6 ml). The reaction mixture was stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure, and the resulting residue purified by column chromatography (dichloromethane/methanol 9:1; Rf=0.3) affording N-[6-(6-chloro-pyridin-3-yl)-5,6-dihydro-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]-acetamide (56) (0.105 g, yield=47%, purity (LC)=90%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1ccc(C2=NCCc3c(Br)cccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: FC(F)(F)c1ccc(C2NCCc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added 5-bromo-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline (1.18 g, 3332 μmol, from step 2), MeOH (5 mL), sodium borohydride (117 μL, 3332 μmol, Aldrich). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with water (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 40% EtOAc/hexanes to give 5-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline. MS (ESI pos. ion) m/z: 356 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][C:7]1[CH:8]=[C:9]([CH:10]([CH3:12])[CH3:11])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cccc(C=O)c1O
Solvent: CC#N
Product: CC(C)c1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.4 %

Procedure:
2-hydroxy-3-isopropylbenzaldehyde (20.19 g) was dissolved in acetonitrile (160 mL), and N-bromosuccinimide (17.80 g) was added to the solution at 0° C., and then the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (25.88 g) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=S)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1.[NH3:19]>>[NH2:19][C:8]1[CH:7]2[CH2:14][CH2:15][CH2:16][CH:6]2[C:5]2[CH:4]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: N
Reactant: FC(F)(F)c1ccc2c(c1)C1CCCC1C(=S)N2
Product: NC1=Nc2ccc(C(F)(F)F)cc2C2CCCC12
Yield: 76 %

Procedure:
Analogously to Example 4, 8-(trifluoromethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (93 mg, 0.34 mmol) in 7N methanolic ammonia solution (20 ml) is reacted to form 66 mg (76%) of product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[C:14]1([CH2:13][NH:20][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A sample of m-nitrobenzoyl chloride, 7.4 g in 300 ml of ethyl acetate was treated with 11 ml of benzyl amine. After 30 minutes, the mix was washed with 100 ml of water. The ethyl acetate layer was concentrated hot to 100 ml and diluted with heptane until solids formed, and then the mix was stirred overnight and allowed to cool to 20° C. The solids were then collected to give N-phenylmethyl-3-nitrobenzamide. m.s. (M+H)+ =257
Reaction SMILES: [Na].Cl.CO[C:5]([C:7]1[C:8]2[C:9](CN)=[CH:10][NH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=O.C[OH:19]>>[CH2:5]1[C:7]2[C:8]([C:12](=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:9][CH:10]=[N:11]1
Reactant: COC(=O)c1cccc2[nH]cc(CN)c12
Reactant: CO
Agent: Cl
Agent: [Na]
Product: O=C1C=CC=C2CN=CC=C12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium metal (19.2 g) is dissolved in absolute methanol (1 l.) with ice-water cooling. To the clear solution is added a solution of 3-(aminomethyl)indole-4-carboxylic acid methyl ester hydrochloride (102.7 g), described in Example 3, in absolute methanol (1 l.). The addition is done in portions within a few minutes. After stiring for 1.5 hr at room temperature the solution is concentrated to near dryness and ice cold water (250 ml) is added to the crystalline residue. The precipitate is collected, washed with cold water and dried to give the title compound, mp. 232°-234°C, identical to the product of Preparation A of this example.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:9]([C:8]2[C:4]([CH2:3][O:2][CH3:1])=[N:5][N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH:7]=2)[OH:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COCc1nn(-c2cccc(OC)c2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COCc1nn(-c2cccc(OC)c2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (5 mL) of 3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (0.30 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (2.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.40 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44]I>>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH3:44])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CI
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a −78° C. solution of 98.2 g (156 mmol) of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 185, Step C) and 10.0 mL (160 mmol) of methyl iodide in dry, degassed THF (400 mL) was added 200 mL (200 mmol) of a degassed 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly over 20 min. The orange solution was stirred at −78° C. for 1.5 h and then warmed to 0° C. and stirred for an additional 1.5 h. The reaction was quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 5-55% EtOAc/hexanes, gradient elution) provided the title compound as a light yellow foam.
Reaction SMILES: [CH:1]1([CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>>[C:12]([O:10][CH2:9][CH2:8][CH2:7][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:11])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Cl
Reactant: CC(CCCO)C1CCCC1
Product: CCC(=O)OCCCC(C)C1CCCC1
Yield: 90.1 %

Procedure:
4-Cyclopentylpentan-1-ol (4.0 g; 23 mmol) was esterified with propionyl chloride (3.1 g; 34 mmol) according to example 3 to give 4.4 g (84.5% yield) of 4-cyclopentylpent-1-yl propanoate.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]([C:14](=[O:23])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:13])C1C=CC=CC=1>[Pd].CO>[NH2:10][CH2:11][CH:12]([OH:13])[C:14]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: O=C(NCC(O)C(=O)NCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC(O)C(=O)NCc1ccccc1
Yield: 76.7 %

Procedure:
(2-Benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid benzyl ester (372.4 mg, 1.134 mmol) was dissolved into 3 mL of MeOH and added 10% Pd/C (100 mg) and placed under balloon pressure H2 overnight. Filtered the reaction mixture through diatomaceous earth and concentrated on a rotary evaporator to give 169 mg, 76.7% of 3-amino-N-benzyl-2-hydroxy-propionamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:15][CH:16]([OH:18])[CH3:17]>>[Cl:1][C:2]1[N:7]=[C:6]([O:18][CH:16]([CH3:17])[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)O
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of 2,4-dichloropyrimidine (5.0 g, 34 mmol) in 2-propanol (84 mL) was added Cs2CO3 (12 g, 37 mmol) and the mixture was stirred at rt for 16 h. The reaction was then heated to 65° C. for 3 h, after which time the reaction was filtered and concentrated. Purification on silica using a gradient solvent system of 0-10% EtOAc/Hexanes furnished 2-chloro-4-(propan-2-yloxy)pyrimidine (2.4 g, 41%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J=5.7, 1H), 6.56 (d, J=5.7, 1H), 5.38 (hept, J=6.2, 1H), 1.34 (d, J=6.2, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25](I)[CH:26]([CH3:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[N:14][N:13]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Reactant: CC(C)CI
Product: COc1ccc(-c2nn(CC(C)C)c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Yield: 75.1 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and isobutyl iodide as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 75.1%.
Reaction SMILES: [I:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][S:5]([NH:8][C:9]1[N:10]=[CH:11][S:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:7])=[O:6].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[CH2:37][CH:38]([F:40])[F:39])(=O)=O>C(#N)C>[F:39][CH:38]([F:40])[CH2:37][N:8]([S:5]([CH2:4][C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[I:1])(=[O:7])=[O:6])[C:9]1[N:10]=[CH:11][S:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1scnc1NS(=O)(=O)Cc1ccccc1I
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1scnc1N(CC(F)F)S(=O)(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2.1 g (4.8 mmol) of methyl 4-{[(2-iodobenzyl)sulfonyl]amino}-1,3-thiazole-5-carboxylate were dissolved in 20 ml of acetonitrile, and 0.9 ml (5.3 mmol) of N,N-diisopropylethylamine was added at RT. The reaction mixture was stirred at RT for 5 min and then a solution of 1.54 g (7.2 mmol) of difluoroethyl trifluoromethane-sulfonate in 5 ml of acetonitrile was added dropwise within 10 min. The reaction mixture was stirred at RT for 12 h and then concentrated to dryness. The residue was purified by means of preparative HPLC(C18—SiO2, gradient acetonitrile/water 20:80 to 100:0). This gave 2.09 g of methyl 4-{(2,2-difluoroethyl)[(2-iodobenzyl)-sulfonyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[C:15]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.[N:35]1([CH2:40][CH:41](O)[CH2:42][CH3:43])[CH:39]=[CH:38][N:37]=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:35]1([CH2:40][CH:41]([O:13][C:14]2[C:15]([CH2:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]3)[CH2:42][CH3:43])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccc1
Reactant: CCC(O)Cn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(Cn1ccnc1)Oc1ccc2c(c1CS(=O)(=O)c1ccccc1)CCCC2=O
Reaction time: 144 h
Yield: 29 %

Procedure:
Diethyl azodicarboxylate (0.16 mL, 0.99 mmol) was added over 10 min to a mixture of 6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone (300 mg, 0.99 mmol), 1-(1H-imidazol-1-yl)-2-butanol (165 mg, 1.08 mmol), triphenylphosphine (260 mg, 0.99 mmol) and tetrahydrofuran (2 mL) under nitrogen. The resulting mixture was stirred for 6 d, whereupon it was concentrated. The residue was purified by dry-flash column chromatography (SiO2, 1-9% 2-propanol-dichloromethane) to give 6-[1-(1H-imidazol-1-ylmethyl)propoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a foam, 125 mg, 29% yield. NMR spectrum was consistent with structure. MS EI: M+• 438.1608 (M+• 438.1613).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([C:3]1[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:1]=1[OH:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(O)cc1
Solvent: CC(=O)O
Product: CC(=O)c1cc(O)ccc1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of hydroquinone in 500 ml of acetic acid, 102 g(1 mol) of acetic anhydride was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and acetic acid was distilled under vacuum. 1 liter of toluene was added to the reaction mixture and the unreacted excess hydroquinone was filtered and collected (recovered amount: 110 g, recycled without any purification process). A desired monoacetyl hydroquinone was obtained by evaporating the residue under vacuum. (Yield: 149.1 g(98%). mp: 60-62° C., 1H-NMR(200 MHz, CDCl3, ppm) 2.25(s, 3H), 5.78 (br, 1H), 6.70 (d,2H), 6.88 (d, 2H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C:17]1[CH:18]=[C:19]([C:23]#[N:24])[O:20][C:21]=1[CH3:22].[C:25]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:25]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][C:28]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]#[N:24])[O:20][C:21]=2[CH3:22])=[CH:27][CH:26]=1
Reactant: Cc1oc(C#N)cc1CO
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(C#N)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79.2 %

Procedure:
Diisopropylazodicarboxylate (1.84 g, 10.6 mmoles) was added to a solution of 4-hydroxymethyl-5-methyl-furan-2-carbonitrile (147) (1.32 g, 9.6 mmoles), biphenyl-4-ol (1.63 g, 9.6 mmoles) and triphenylphosphine (4.3 g, 16.35 mmoles) in tetrahydrofuran (50 mL) with stirring and cooling to 0° C. under an argon atmosphere. After 5 minutes, the cooling was removed and the mixture stirred at room temperature for 16 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate phase was washed with brine and dried. After the solvent was evaporated, the residue was purified by flash chromatography (silica, gradient elution with 5% to 10% ethyl acetate in cyclohexane) to afford compound 148 as a white solid (2.2 g). IR (powder) CN st. 2225 cm−1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH2:21][O:22][CH3:23])=[CH:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:15]([CH2:21][O:22][CH3:23])[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: COCC(=CC(=O)OC)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCC(CC(=O)OC)c1cccc(O)c1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 102.B (mixture of geometric isomers) (0.11 g, 0.35 mmol) in EtOAc (2 mL) was added Pd/C (10 wt. %) (0.019 g, 0.018 mmol) under N2. The mixture was purged with H2, stirred overnight under a H2 balloon, filtered through silica gel (EtOAc), and concentrated. The crude product was purified by silica gel flash chromatography (10-40% EtOAc/hexane) to afford 102.C (0.060 g, 76%) as a pale yellow oil.