Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH2:13][OH:14])C(O)=O)=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:15])[CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: O=C(O)[C@@H](CCO)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H](CCO)c1ccc(F)cc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (S)-2-(4-fluorophenyl)-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (S)-1-(4fluorophenyl)-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH3:30])[NH:25][C:24]1=[O:31]>>[ClH:19].[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:20][CH2:21][CH2:22][N:23]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:30])[NH:25][C:24]2=[O:31])[CH2:13][CH2:12]1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: Cc1cc(=O)n(CCCCl)c(=O)[nH]1
Product: Cc1cc(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c(=O)[nH]1
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)pheny]piperazine and 3-(3-chloropropyl)-6-methyl-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-6-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 218°-220° C.; Anal.: Calcd. for C20H25F3N4O3.(HCl)2 : C, 48.10; H, 5.44; N, 11.22%; Found: C, 47.85; H, 5.48; N, 11.08%;
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([O:20]C)=O)[CH:12]=[CH:11][C:10]=2[CH2:9]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[K].[NH2:23][OH:24].C(O)(=O)C>CO>[CH2:1]([S:5]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([NH:23][OH:24])=[O:20])[CH:12]=[CH:11][C:10]=2[CH2:9]1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)N1CCc2nc(C(=O)OC)ccc2C1
Reactant: NO
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCS(=O)(=O)N1CCc2nc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a microwave vial containing methyl 6-(butylsulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76 mmol, 1.76 M in MeOH). The solution was shaken at rt for 1 h, then acetic acid (0.102 mL, 1.8 mmol) was added to quench excess base. The solvent was then concentrated. To the resulting residue was added DMSO (1.2 mL) and after filtration, the solution underwent purification via prep-HPLC to give 6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide (13.3 mg, 28.3%). LC-MS: (FA) ES+ 314; 1H NMR (Methanol-d4, 300 MHz) δ 7.97 (d, J=8.1 Hz, 1 H), 7.76 (d, J=7.9 Hz, 1H), 4.59 (s, 2 H), 3.70 (t, J=6.0 Hz, 2 H), 3.13 (m, 4 H), 1.77 (m, 2 H), 1.47 (m, 2 H), 0.95 (t, J=7.3 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH2:20].ON1C2C=CC=C[C:25]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.CN1CCOCC1>ClCCl>[CH3:18][O:19][N:20]([CH3:25])[C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: On1nnc2ccccc21
Reactant: CON
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.4 %

Procedure:
A mixture of 8.30 g (34.6 mmol) of N-(t-butyloxycarbonyl)-L-leucine, 4.03 g (41.5 mmol) of methoxyamine hydrochloride, 5.60 g (41.5 mmol) of 1-hydroxybenzotriazole, 8.55 g (41.5 mmol) of dicyclohexylcarbodiimide, and 4.56 ml (41.5 mmol) of 4-methylmorpholine in 200 ml of dichloromethane was stirred at ambient temperature for 24 h. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N HCl, and the organic phase was washed sequentially with aqueous NaHCO3 and saturated brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexane provided 7.16 g (76%) of the desired compound (Rf 0.21, 3:1 hexane:ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:19][CH2:20][OH:21].[C:22](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3([C:10]([F:13])([F:11])[F:12])[O:21][CH2:20][CH2:19][CH2:22][O:14]3)=[N:6][C:5]=2[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: OCCCl
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)OCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (2.13 g; 7.51 mmol), 2-chloroethanol (1.90 mL; 22.7 mmol) and potassium carbonate (3.13 g; 22.6 mmol) were dissolved in DMF (14 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then diluted with ethyl acetate (100 mL), washed with water (80 mL) and brine (2×80 mL). The extracts were dried over Na2SO4, filtered, concentrated to a light brown solid and the light brown solid purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=O)[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26].C(O)(=O)C.O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:10])=[N:25][NH:26][C:14]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(C(=O)c1ccc(SC)cc1)c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Yield: 95.7 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-(4-(methylthio)phenyl)-3-oxopropanoate(1.33 g, 4 mmol), prepared according to the method of Example 1A(ii), hydrazine hydrate (0.25 mL, 4.2 mmol), and acetic acid (0.25 mL, 4.2 mmol) in dioxane (50 mL), and water (5 mL) was refluxed for 24 hours and then concentrated in vacuo. Water was added to the residue, and the solid was filtered and dried in vacuo to provide the desired product (yield: 1.15 g; 95%). MS (DCI-NH3) m/z 301 (M+H)+, 318 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ2.47 (s, 3H), 7.12 (t, J=9 Hz, 2H), 7.26 (m, 6H).
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.C[NH2+]C.[CH3:31][CH2:32][O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([C:32]2[CH:31]=[CH:3][CH:2]=[CH:1][CH:6]=2)=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC[O-]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Agent: C[NH2+]C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(-c2ccccc2)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino)-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (6 g), a 2M ethanolic solution of sodium ethylate (10.5 cc) and α-methylthio-4-phenylacetophenone (5.1 g) in ethanol (150 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-biphenylyl)-5-methylthio-6-oxo-2,4-hexadienoate (2.8 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Li+].[OH-]>CO.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Temperature: 100 °C

Procedure:
Methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate (˜1 g, ˜4.41 mmol) was dissolved in MeOH/H2O (4:1, 50 mL) and then LiOH (0.36 g, 15 mmol) was added. The mixture was heated at reflux for 2 h at 100° C. The analytical HPLC indicated the starting material was consumed, the mixture was cooled to 0° C. and 2 M HCl solution was added bring the pH ˜4. MeOH was removed in vacuo and the acid was precipitated. The acid was collected by filtration and dried in vacuo and used without further purification. ESI-MS (m/z): 217 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 12.87 (br s, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.39-7.27 (m, 3H), 3.85 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=[O:11]>C1COCC1>[CH2:1]([CH:10]([C:6]1[S:5][CH:9]=[CH:8][CH:7]=1)[OH:11])[CH3:2]
Reactant: O=Cc1cccs1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cccs1
Temperature: 23 °C

Procedure:
A 1.0M solution of ethylmagnesium bromide in THF (100 mL) is cooled to -78° C. and 2-thiophene carboxaldehyde (9.35 mL) is added. The reaction is allowed to warm to 23° C. for 1 h, then recooled to -78° C. and quenched with saturated ammonium chloride. After allowing to warm to 23° C., the reaction is extracted with ether (800 mL) and the ethereal layer is washed with water (2×150 mL) and brine. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The product is purified by chromatography over silica gel(2 kg), eluting with 30% ether in pentane to give 13.4 g of the title product as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:12][C:13]2[CH:18]=[N:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
A mixture of 2,5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen atmosphere. To this slurry were added copper (I) trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The resulting suspension was heated to 105° C. and stirred for 2 h before being cooled to RT. The toluene was decanted, and water (8 L) and EtOAc (8 L) were added. The resulting mixture was stirred until the solid was completely dissolved. The EtOAc layer was separated and the pH of the aqueous layer was adjusted to pH 2˜3 with 6N HCl. The aqueous layer was extracted with EtOAc (3×5 L). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 1.28 Kg of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid. This material was used in next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:10](C(OC(C)(C)C)=O)[CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN([CH:50]=[O:51])C.[CH3:52][OH:53]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[NH:10]1[C:3]2[C:2]([C:52]([O:51][CH3:50])=[O:53])=[CH:7][N:6]=[CH:5][C:4]=2[CH:8]=[CH:9]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)n1ccc2cncc(Br)c21
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc2cc[nH]c12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 7-bromo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.20 g), 1,3-bis(diphenylphosphino)propane (0.028 g), palladium acetate (0.015 g), DMF (4.0 mL), methanol (6.0 mL), and triethylamine (0.28 mL) was stirred at 80° C. for 2 days under carbon monoxide atmosphere. The reaction mixture was left to be cooled and replaced with argon. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30 to 60%) to obtain methyl 1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.081 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]([OH:17])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H-].[Na+].[O:20]1[CH:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=2[CH3:32])[CH2:21]1>CN(C=O)C>[CH3:32][C:26]1[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH2:23][CH:22]([OH:20])[CH2:21][N:1]1[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]1=[O:17]
Reactant: Cc1cccc(OCC2CO2)c1C
Reactant: O=C(O)C1CCCN1c1ncccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(O)CN2C(=O)C3CCCN3c3ncccc32)c1C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a stirred solution of the product of Example 1 (2.7 g., 0.015 mole) in 40 ml. of dry DMF was added 0.6 g. of sodium hydride (0.025 mole of 50% dispersion in mineral oil). After the evolution of gases subsided, 2.6 g. (0.015 mole) of 1,2-epoxy-3-[2,3-dimethylphenoxy]propane was added. The reaction mixture was stirred overnight and DMF was evaporated in vacuo and the residue was extracted with 200 ml. of diethyl ether. The ether layer was dried and concentrated in vacuo to 30 ml. TLC indicated the presence of two products, one of which is a major component (about 80%). The ether layer was cooled overnight and the separated solid was filtered and recrystallized from diethyl ether to afford 1.8 g. (51% yield) of the title compound m.p. 123°-125° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].CC(C)=O.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:20]=1[NH2:21]>O>[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:20]=1[NH:21][C:2]([NH:3][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:1]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(C)c1N
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(C)c1NC(=S)NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To 51.0 g. (0.68 mole) of ammonium thiocyanate in 300 ml. acetone is added 86.8 g. (0.62 mole) of benzoyl chloride. The reaction mixture is refluxed for about 5 min. and then 81 g. (0.62 mole) of 2,6-dimethylaniline in 200 ml. acetone is added at a rate to maintain reflux. The mixture is refluxed for 11/2 hours, cooled, poured into 11/2 liters of ice and water, filtered to obtain 1-(2,6-dimethylphenyl)-3-benzoylthiourea.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[F:20].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Cc1cc(Br)cc(C(=O)O)c1C
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(F)c(F)c2)cc(C(=O)O)c1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of 5-bromo-2,3-dimethyl-benzoic acid (500 mg, 2.18 mmol, 1.0 eq), (3,4-difluorophenyl)boronic acid (378.6 mg, 2.40 mmol, 1.1 eq) and Na2CO3 (693 mg, 6.54 mmol, 3.0 eq) in a mixture of EtOH (2.5 mL), DMF (10 mL) and H2O (2.5 mL) was added Pd(PPh3)4 (126 mg, 0.11 mmol, 0.05 eq) under nitrogen. The mixture was stirred at 100° C. overnight. After cooling to room temperature, water was added and the diluted reaction mixture filtered through celite. The aqueous layer was extracted with EtOAc and the organic extract was discarded. The remaining aqueous layer was acidified to pH 2 by addition of 3M HCl. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (400 mg, 70%).
Reaction SMILES: C(O[CH:5]1[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[ClH:40]>CCOCC>[C:26]([O:25][C@H:24]1[C@@H:29]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:30][C@H:5]([Cl:40])[C@H:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:15]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:28])[CH3:27]
Reactant: Cl
Reactant: CC(=O)OC1O[C@H](COCc2ccccc2)[C@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CCOCC
Product: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H](Cl)O[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1,4-di-O-acetyl-2,3,6-tri-O-benzyl-D-galactopyranose (4.64 g, 8.67 mmol) in ether (10 mL) is treated with ethereal hydrogen chloride (0.2 g/mL, 25 mL). The mixture is stirred at room temperature during 48 h. The solvents are evaporated under reduced pressure so as to afford an oil. Flash chromatography on silica gel and elution with a graded mixture of carbon tetrachloride and ethyl acetate will afford 4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl chloride as an oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O.[Cu]I>[CH3:4][O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=1)=[O:7]
Reactant: C[O-]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Temperature: 120 °C
Yield: 168.5 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and CuI (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: [Br:1]CC[CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br-:1].[C:22]1([P+:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]2[O:5][CH2:6][CH2:7][O:8]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCC1OCCO1
Product: [Br-]
Product: c1ccc([P+](c2ccccc2)(c2ccccc2)C2OCCO2)cc1
Temperature: 80 °C
Yield: 87.2 %

Procedure:
A mixture of 180 g of 2-(bromoethyl)-1,3-dioxolane and 260 g of triphenylphosphine was heated at 80° C. for 36 hours and the mixture was cooled and filtered. The product was dissolved in methylene chloride and the solution was poured into 3000 ml of ether. The mixture was stirred and vacuum filtered and the product was empasted with ether to obtain 359 g of triphenyl-(1,3-dioxolan-2-yl)-phosphonium bromide melting at 206° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.Cl[CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[O:25][CH:26]=1>>[CH3:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1/[CH:28]=[CH:27]/[C:24]1[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=2)[N:23]=1
Reactant: Cc1ccccc1/C=C/c1nc(CCl)co1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Product: Cc1ccccc1/C=C/c1nc(COc2ccc(CCCCn3ccnc3CCO)cc2)co1
Yield: 62.1 %

Procedure:
Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (153 mg) and (E)-4-chloromethyl-2-[2-(2-methylphenyl)ethenyl]oxazole (151 mg), the same reaction as Example 1 was carried out to yield the titled compound (167 mg) as colorless crystals.
Reaction SMILES: C(O[C:5]1[O:6][CH2:7][C:8](=[O:16])[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])(C)C.C(OC(C)C)(=O)CC(OC(C)C)=O.ClCC(Cl)=O.[CH3:35][NH:36][CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C.[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][N:57]=2)[C:52]([CH:59]=O)=[CH:51]1>CC(O)C>[NH:50]1[C:58]2=[N:57][CH:56]=[CH:55][CH:54]=[C:53]2[C:52]([CH:59]=[C:7]2[O:6][C:5]([N:36]([CH3:35])[CH2:37][C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)=[C:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[C:8]2=[O:16])=[CH:51]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Reactant: CNCc1cccs1
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Agent: O=C(Cl)CCl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 18.7 %

Procedure:
A solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, N-methyl-N-(2-thienylmethyl)amine (0.061 mg, 0.048 mmol) and triethylamine (0.18 mL, 1.3 mmol) in 2-propanol (2.0 mL) was stirred for 7 days then refluxed for further 24 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) was added then the mixture was refluxed for 24 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0038 g, y. 2%).