Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]([NH:11][C@H:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:4](=[O:22])[N:3]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1.[H][H]>[Pd].CO>[CH3:38][C:2]1([CH3:1])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]([NH:11][C@H:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:4](=[O:22])[N:3]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@H](C)CC(=O)O)N1C(=O)N(Cc2ccc(C=Cc3ccccc3)cc2)C(C)(C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)N[C@H](C)CC(=O)O)N1C(=O)N(Cc2ccc(CCc3ccccc3)cc2)C(C)(C)C1=O

Procedure:
The compound was prepared by catalytic hydrogenation of the styryl compound obtained in Example 1 (Pd/C, 1 bar hydrogen overpressure, methanol, room temperature).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[NH:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.IC.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:18][C:17]1[CH:16]=[CH:15][N:14]([CH3:21])[C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(-c2noc(-c3[nH]ccc3Cl)n2)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc(Cl)c1-c1nc(-c2ccc(Cl)cc2)no1
Temperature: 85 °C
Yield: 37.1 %

Procedure:
A mixture of 3-(4-chloro-phenyl)-5-(3-chloro-1H-pyrrol-2-yl)-[1,2,4]-oxadiazole (30.0 mg, 0.11 mmol), iodomethane (0.08 ml, 0.17 mmol) and potassium carbonate (23 mg, 0.17 mmol) in dimethylformamide (2 ml) was heated at 85° C. for 4 h. It was diluted by water (20 ml) and the mixture was extracted by EtOAc. The extracts were evaporated, and the residue was purified by column chromatography (EtOAc: Hexane=1:1) to give 12.0 mg (37%) of the title compound. 1H NMR (CDCl3): 8.11–8.07 (m, 2H), 7.50–7.45 (m, 2H), 6.84 (d, J=3.0 Hz, 1H), 6.28 (d, J=3.3 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH2:26][C:27](O)=[O:28])[CH2:22][C:23](O)=[O:24]>C1(C)C=CC=CC=1.CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([B:15]3[O:17][C:27](=[O:28])[CH2:26][N:21]([CH3:20])[CH2:22][C:23](=[O:24])[O:16]3)=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Yield: 75.5 %

Procedure:
A slurry of (4-(4-fluorophenethoxy)phenyl)boronic acid (122 g, 469 mmol) and 2,2′-(methylazanediyl)diacetic acid (76 g, 516 mmol) in anhydrous toluene (500 mL) and DMSO (200 mL) was refluxed for 4 h. Then, cooled, diluted with EtOAc (500 mL), washed with water (5×200 mL), brine (2×100 mL), dried (MgSO4), filtered and concentrated to give light orange foam which was purified by flash chromatography using 5-40% acetone/CH2Cl2 (5% increment per 2-lit) to afford 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (131.38 g, 354 mmol, 75% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J=8.4 Hz, 2H), 7.28-7.24 (m, 2H), 7.04-6.99 (m, 2H), 6.92 (d, J=8.5 Hz, 2H), 4.17 (t, J=6.9 Hz, 2H), 4.00 (d, J=16.6 Hz, 2H), 3.76 (d, J=16.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H), 2.54 (s, 3H). LCMS (M+H)=372.3.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[NH2:11][OH:12].C(Cl)Cl>O.C(Cl)(Cl)Cl>[CH2:7]([O:6][C:4](=[O:5])[C:3](=[N:11][OH:12])[CH2:2][Br:1])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NO
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CBr)=NO

Procedure:
Ethyl bromopyruvate (5.0 mL, 39.8 mmol) was added to hydroxylamine hydrochloride (2.52 g, 36.2 mmol) in H2O (10 mL) and CHCl3 (10 mL). The reaction mixture was capped and stirred overnight at 23° C. at which time CH2Cl2 and H2O were added, the layers separated, the organics dried over Na2SO4, and the volatiles removed on a rotary evaporator to yield 7.58 g (100%) of as a white solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.26 (t, J=7.12 Hz, 3 H) 4.20 (s, 2 H) 4.24 (m, 2 H) 13.19 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].F[C:25]1[CH:30]=[C:29](F)[C:28]([F:32])=[CH:27][C:26]=1[S:33]([CH:36]1[CH2:40][CH2:39][O:38]C1=O)(=[O:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:32][C:28]1[C:29]([O:1][C:2]2[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=2)[C:5]([NH:7][C:8]2[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[O:6])=[CH:30][C:25]2[O:38][CH2:39][CH2:40][CH2:36][S:33](=[O:35])(=[O:34])[C:26]=2[CH:27]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Reactant: O=C1OCCC1S(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cc3c(cc2F)S(=O)(=O)CCCO3)cc(C(=O)Nc2cnc(C)cn2)c1
Yield: 14.3 %

Procedure:
3-Hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (634 mg, 2 mmol), 3-[(2,4,5-trifluorophenyl)sulfonyl]dihydrofuran-2(3H)-one (560 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol) in acetonitrile (10 mL) were heated at 160° C. for 2 h and 170° C. for 30 minutes in a microwave reactor. Water was added to the reaction mixture and the phases separated. The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organics washed with 1M hydrochloric acid, a saturated sodium bicarbonate solution, brine and dried (MgSO4) and evaporated. The residue was dissolved in methanol and heated to reflux on a steam bath. The residual solid was removed by hot filtration and the filtrate evaporated to a residue which was chromatographed on alumina, eluting with 10% methanol in DCM, to give the desired compound as a clear foam (152 mg). 1H NMR δ (CDCl3): 1.27 (d, 3H), 2.32-2.38 (m, 2H), 2.49 (s, 3H), 3.31 (t, 2H), 3.34 (s, 3H), 3.43-3.47 (m, 1H), 3.49-3.54 (m, 1H), 4.15 (t, 2H), 4.53-4.57 (m, 1H), 6.72 (d, 1H), 6.77 (t, 1H), 7.08 (t, 1H), 7.25 (t, 1H), 7.71-7.74 (m, 1H), 8.07 (d, 1H), 8.25 (s, 1H), 9.45 (d, 1H); m/z 532 (M+H)+, 530 (M−H)−
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[C:9]([C:11](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:12](OCC)=[O:13])#[N:10].Cl>O.O1CCCC1>[NH:5]1[C:9]([C:11]2[C:12](=[O:13])[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:17]=2)=[N:10][N:7]=[N:6]1
Reactant: CCOC(=O)C(C#N)=CNc1ccccn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Yield: 38.6 %

Procedure:
Aluminum chloride (0.74 g., 5.56 mmoles) was carefully added to tetrahydrofuran (33 ml.) at -20°. Sodium azide (1.08 g., 16.6 mmoles) was then added and the mixture heated under reflux for 30 minutes. After the addition of ethyl 2-cyano-3-(2-pyridylamino)acrylate (1.0 g., 4.6 mmoles) the mixture was again heated under reflux for 18 hours. The mixture was cooled in an ice bath, treated with water (170 ml.) and acidified to pH 2 with 6N hydrochloric acid. The resulting suspension was stirred with cooling for 2 hours and then filtered. The collected solid was recrystallized from N,N-dimethylformamide to give the title compound (0.38 g., 38.5%), m.p. 308°-309° (decomp).
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].O1CCCC1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](=[O:30])[C:27](Cl)=[O:28])=[CH:18]1>O>[CH3:1][N:2]([C:27](=[O:28])[C:26]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([CH3:16])[CH:18]=1)=[O:30])[N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CNN=C(C)CS(C)(=O)=O
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(CS(C)(=O)=O)=NN(C)C(=O)C(=O)c1cn(C)c2ccccc12
Reaction time: 2 h
Yield: 72 %

Procedure:
To a 50 ml volume three-necked flask, 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1) (2.22 g) and tetrahydrofuran (anhydrous) (10 ml) were added under a nitrogen atmosphere. To the mixture, 2-(1-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (26-a) (3.0 g) was added dropwise under ice-cooling, and stirred for 2 hours. The reaction mixture was added to iced water, and the precipitated solids were collected by filtration, washed with water and hexane, and dried under reduced pressure to give 3.4 g of 1-methyl-1-[2(1-methyl-1H-indol-3-yl)-2-oxoacetyl]-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-203-(13)28).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][CH:8]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[O:21]1[CH2:25]CC[CH2:22]1>CCCCCC>[CH3:22][O:21][CH:25]=[CH:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH:8]([CH3:7])[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: CCCC(C)Oc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCC(C)Oc1ccc(C=COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing butyllithium dissolved in hexane was added to a solution containing 120 g of methoxymethyltriphenylphosphoni bromide dissolved in tetrahydrofuran (THF), in an atmosphere of argon, and the mixture was stirred for one hour at room temperature. A solution of the compound (30) dissolved in THF was added thereto and stirring was continued for two hours. The reaction solution was washed with water, was dried over magnesium sulfate, and was then concentrated. The residue was purified by column chromatography to obtain 1-(2-methoxyethenyl)-4-(1-methylbutyloxy)benzene (31).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:8][CH2:7]2.[OH:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.O.[Pd].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.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>[F:23][C:5]1[CH:4]=[CH:3][C:2]([C:29]2[CH:30]=[C:25]([OH:24])[CH:26]=[CH:27][C:28]=2[O:34][CH3:35])=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:10]2
Reactant: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCc2c(F)ccc(Br)c2C1
Reactant: COc1ccc(O)cc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(O)cc1-c1ccc(F)c2c1CN(C(=O)[C@@H]1C[C@H]1c1ccccc1)CC2
Temperature: 100 °C
Reaction time: 62 h

Procedure:
To a mixture under N2 of (8-bromo-5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-((1R,2R)-2-phenyl-cyclopropyl)-methanone (289 mg, 0.76 mmol, 1.00 eq.), 5-hydroxy-2-methoxyphenylboronic acid (131 mg, 0.76 mmol, 1.00 eq.) and sodium carbonate (324 mg, 3.05 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (15 mL), tetrakis(triphenylphosphine) palladium (0) (44 mg, 0.04 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 62 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (30 mL) and water (30 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×15 mL), dried over MgSO4 and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 28 fractions of 40 mL, Heptane+10% AcOEt to Heptane+50% AcOEt) to yield the title product as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:16][C:15]=3[CH:25]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(Cl)Cl.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:16][C:15]=3[CH:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
To a solution of N-(1-{5-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (922 mg, 2.73 mmol) obtained in Example 156 in methylene chloride (50 mL) was added 1M boron tribromide-methylene chloride solution (5.46 mL, 5.46 mmol) at −78° C., and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was warmed to 0° C., and methanol was added thereto. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate to give the title compound (774 mg, yield 88%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][C:4]=1/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.FC(F)(F)C1C=CC(CP(=O)(OCC)OCC)=CC=1.C(C1C=C(C=CC=1OC)C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(OC)c(/C=C/c2ccc(C(F)(F)F)cc2)c1
Agent: CCOC(=O)c1ccc(OC)c(C=O)c1
Agent: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Product: COc1ccc(C(=O)O)cc1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from ethyl 4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]-benzoate, which had been synthesized from diethyl (4-trifluoromethylbenzyl)phosphonate and ethyl 3-formyl-4-methoxybenzoate obtained in step C of Example 1-2-1, in accordance with the same procedure as in the methods described in step B of Example 2-2-1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[F:24])[N:20]=[N:19][C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:17]2[OH:30]>CN(C=O)C>[CH:8]1([N:20]2[C:21]3[C:16](=[CH:15][C:14]([F:13])=[C:23]([F:24])[CH:22]=3)[C:17](=[O:30])[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:19]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1nnc2cc(F)c(F)cc2c1O
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C2CCCC2)c2cc(F)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
Potassium carbonate and iodocyclopentane were added to a DMF solution of ethyl 6,7-difluoro-4-hydroxycinnoline-3-carboxylate, for stirring at 80° C. for 40 minutes, to obtain ethyl 1-cyclopentyl-6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylate.
Reaction SMILES: [CH2:1]([N:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10](O)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:30])CC>ClCCl>[CH2:1]([N:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:30])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To ethyl 3-(benzyl(cyclohexyl)amino)-2-hydroxy-2-methylpropanoate (7 g, 21.9 mmol) in 50 ml of dichlormethane at −78° C., was added DAST (4.3 ml, 32.8 mmol) dropwise. The reaction mixture was gradually warmed up to room temperature and stirred for 2 h. It was then diluted to dichloromethane, washed by NaHCO3, brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=40:1 to 20:1) to give 6.8 g product (97%) as light yellow liquid. [M+H] calc'd for C19H28FNO2, 322; found 322.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=[O:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH3:24][Mg]Br.O>C(OCC)C>[OH:18][CH:17]([C:15]1[C:14]([C:19]([F:21])([F:22])[F:20])=[N:13][N:12]([CH2:11][C:7]2[NH:8][C:9](=[O:10])[C:4]3[CH:3]=[C:2]([CH3:1])[S:23][C:5]=3[N:6]=2)[CH:16]=1)[CH3:24]
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: Cc1cc2c(=O)[nH]c(Cn3cc(C(C)O)c(C(F)(F)F)n3)nc2s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 7.9 %

Procedure:
1-((6-Methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (100 mg, 0.292 mmol) was dissolved in diethyl ether (10 mL) and cooled to −78° C. with a dry ice/acetone bath. The reaction was performed under a nitrogen atmosphere. Methylmagnesium bromide (35 mg, 0.292 mmol) was added dropwise and the reaction mixture allowed to warm to RT and stirred for 2 h. Water was added and the reaction mixture extracted into EtOAc (×3). The combined EtOAc layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by preparative reverse phase HPLC gave the title product (8 mg, 0.023 mmol, 8%).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[C:6]([OH:12])=[CH:7][CH:8]=[CH:9][C:10]=1[OH:11])=[O:4].[C:13](OCC)(=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[OH:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:3](=[O:4])[CH:2]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(O)cccc1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2c(O)cccc2o1
Temperature: 25 °C

Procedure:
1.1 3.25 g of sodium are dissolved in portions in 300 ml of ethanol with stirring. A solution of 4.3 g of 2,6-dihydroxyacetophenone and 15.5 ml of diethyl oxalate in 25 ml of ethanol is subsequently added dropwise. The reaction mixture is subsequently heated at 80° for 3 hours. The mixture is cooled to room temperature, and 10 ml of 32% HCl are added dropwise. The mixture is heated at 90° for 30 minutes and cooled, and the solvent is removed. Conventional work-up gives 5.9 g of 5-hydroxy-2-ethoxycarbonyl-chromone (“AA”).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)=[CH:8][C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, aluminum chloride (1.95 g, 14.6 mmol) is slurried in dichloromethane (50 mL) then 4-chloro-3-sulfamoyl benzoyl chloride is added and allowed to stir at ambient temperature for 30 minutes. Anisole (683 mg, 6.3 mmol) is added in 2 mL methylene chloride. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-cold 6 N HCl and extracted with dichloromethane to give a colorless oil. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded a white foam which is crystallized three times from ether to afford the title compound. 1H NMR (MeOD) δ 3.9 (s, 3H), 7.1 (d, 2H, J=8.84 Hz), 7.7-8.0 (m, 4H), 8.4 (d, 1H, J=1.96 Hz). MS (m/z): 326 (M+1). CHN Calc C, 51.62; H, 3.71; N, 4.3. Found C, 51.70; H, 3.76; N, 4.22. M.P. 156-158° C.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.N.[F:23][C:24](I)([F:26])[F:25]>O1CCCC1>[F:23][C:24]([F:26])([F:25])[S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: Fc1ccc(-c2cnc(S)nc2-c2ccc(F)cc2)cc1
Reactant: FC(F)(F)I
Agent: N
Solvent: C1CCOC1
Product: Fc1ccc(-c2cnc(SC(F)(F)F)nc2-c2ccc(F)cc2)cc1

Procedure:
2-Mercapto-4,5-bis(4-fluorophenyl)pyrimidine (5.04 g) was placed in a flask into which was condensed ~125 ml liquid ammonia. The resultant slurry was diluted with 30 ml tetrahydrofuran and cooled to -78°. Trifluoromethyl iodide (1.9 ml) was introduced as a gas and the cold bath was then removed. The reaction mixture was irradiated with a General Electric 275 W sun lamp for 2 hours. The ammonia was allowed to evaporate and the tetrahydrofuran removed in vacuo. The residue was dissolved in methylene chloride, washed with water and brine, dried and concentrated on the rotary evaporator. Crystallization from ethanol gave the title compound (2.1 g), m.p. 80°-83°. Infrared and H-NMR were consistent with the assigned structure. MS 368 (M+).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH:3]=[CH2:4].B1C2CCCC1CCC2.C([O-])([O-])=O.[K+].[K+].[CH2:31]([O:33][C:34](=[O:46])[CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42](Br)=[CH:41][N:40]=1)[CH3:32]>C1COCC1.CN(C=O)C.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:31]([O:33][C:34](=[O:46])[CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:4][CH2:3][CH2:2][CH2:1][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])=[CH:41][N:40]=1)[CH3:32]
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CCCCc1ccc(Br)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-5 (4.23 g, 21 mmol) in degassed THF (20 mL) at 0° C. was added dropwise a solution of 9-BBN (50.4 mL of 0.5 M in THF, 25.2 mmol) and the mixture stirred for 18 hours at ambient temperature. K2CO3 (5.0 g, 35.8 mmol) and 5-2 (5.0 g, 17.4 mmol) were added, followed by a premixed and aged (70° C. for 30 min) suspension of Pd(OAc)2 (0.54 g, 2.4 mmol) and DPPF (1.45 g, 2.6 mmol) in degassed DMF (20 mL). The resulting mixture was stirred for 18 hours at 70° C., cooled, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated. To the stirring residue dissolved in THF (200 mL) was added water (75 mL) and NaHCO3 (16.5 g) and after 10 minutes, NaBO3.H2O (24 g). After vigorous stirring for 30 minutes, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to an oil. The residue was chromatographed on silica gel (20–40% EtOAc/hexane) to give 5-6 as a yellow solid.