Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of (2S,3R)-allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (1.36 g, 6.43 mmol), 2-chloro-5-(trifluoromethyl)pyridine (1.75 g, 9.645 mmol), and Cs2CO3 (4.2 g, 12.86 mmol) in DMF (20 mL) was stirred at 80° C. for 2 days. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound. ESI-MS (m/z): 358 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.C1COCC1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:38](=[O:39])[O:40][CH2:41][CH3:42])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25 mg, 59 μmol) was dissolved in a mixture of abs. THF (2.5 ml) and abs. pyridine (48 ml). At room temperature, ethyl chloroformate (32 mg, 297 μmol, 5 eq.) was added and the mixture was heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 86% of theory).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]=1[CH2:25][S:26][C:27]1[CH2:31][C:30]([CH3:33])([CH3:32])[O:29][N:28]=1.O>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]=1[CH2:25][S:26]([C:27]1[CH2:31][C:30]([CH3:33])([CH3:32])[O:29][N:28]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nc(-c2ccccc2)c(CSC2=NOC(C)(C)C2)c1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccccc2)c(CS(=O)C2=NOC(C)(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
0.87 g of m-chloroperbenzoic acid (purity: 70%, 3.54 mmoles) was added, with ice-cooling, to a solution of 0.85 g (2.53 mmoles) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 30 ml of chloroform. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.48 g (yield: 53.9%) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfinyl)-5,5-dimethyl-2-isoxazoline as a transparent viscous substance.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]3[CH:28]=[C:29]([Cl:33])[C:30](I)=[CH:31][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:34])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:35]1([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]3[CH:28]=[C:29]([Cl:33])[C:30]([C:38]4[CH:37]=[CH:36][C:35]([CH:41]5[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]5)=[CH:40][CH:39]=4)=[CH:31][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:34])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: CCOP(=O)(OCC)c1cc(Oc2nc3cc(I)c(Cl)cc3n2Cc2ccccc2)ccc1C
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1cc(Oc2nc3cc(-c4ccc(C5CCCCC5)cc4)c(Cl)cc3n2Cc2ccccc2)ccc1C
Temperature: 130 °C

Procedure:
To a solution of [5-(1-Benzyl-6-chloro-5-iodo-1H-benzoimidazol-2-yloxy)-2-methyl-phenyl]-phosphonic acid diethyl ester (5.2 g, 8.5 mmol) in toluene (30 ml) was added 4-cyclohexylbenzeneboronic acid (3.5 g, 17 mmol), tetrakis(triphenylphosphine)palladium(0) (983 mg, 0.9 mmol), and then potassium carbonate (4.7 g, 34 mmol) in a solution of H2O (15 ml). The resulting mixture was heated in a microwave reactor at 130° C. for 15 minutes, and then quenched with saturated ammonium chloride solution. The mixture was then partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, and then dried with MgSO4. The crude mixture was then purified by flash chromatography (SiO2, 80 g). The title compound was eluted with 60% EtOAc in Hexane.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][C@H:28]([OH:32])[C:29]([OH:31])=[O:30].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][C@H:28]([OH:32])[C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: NCC[C@H](O)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1nc(C(=O)NCC[C@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 93.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 4-amino-2-(S)-hydroxy-butyric acid (112 mg, 0.94 mmol) (Aldrich) in 0.5 M NaOMe/MeOH (1.25 mL, 0.63 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (60 mL), acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound 119 mg (0.29 mmol) in 93% yield. LC-MS ESI−: 406.00 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)[O-])c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: COc1cccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Yield: 63 %

Procedure:
Intermediate 7 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give tert-butyl 2-(3-methoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (194 mg, 63%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.19 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.47-7.52 (m, 2H), 7.26-7.37 (m, 2H), 6.98-7.08 (m, 1H), 5.25-5.29 (m, 1H), 4.70 (br s, 1H), 3.82 (s, 3H), 3.60 (s, 3H), 3.36-3.49 (m, 1H), 2.49 (d, J=16.0 Hz, 1H), 2.25-2.33 (m, 1H), 2.16-2.23 (m, 1H), 1.90-1.97 (m, 1H), 1.50-1.70 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:17][C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc2cc(F)c(=O)[nH]c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2cc(F)c(Cl)nc2c1
Yield: 97 %

Procedure:
3-Fluoro-7-methoxyquinol-2(1H)-one (300 mg, 1.55 mmol), (prepared as in Tetrahedron, Vol. 52, No. 9, pp. 3223–3228, 1996), was dissolved in thionyl chloride (3 ml), treated with DMF (1 drop) and heated at reflux for 1 hour. The excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene (3×). The residue was basified to pH8 with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (3×20 ml). The organic solution was washed with water and brine then dried (MgSO4) and evaporated to dryness to give 2-chloro-3-fluoro-7-methoxyquinoline (320 mg, 97%).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])[O:3][CH2:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:8]=[C:7]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[N:6]=1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>O1CCOCC1>[CH3:29][Si:2]([CH3:1])([C:25]([CH3:28])([CH3:27])[CH3:26])[O:3][CH2:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:21]([NH:22][C:33]([NH:32][CH2:30][CH3:31])=[O:34])=[CH:23][CH:24]=2)[N:6]=1
Reactant: C[C@H]1COCCN1c1cc(CO[Si](C)(C)C(C)(C)C)nc(-c2ccc(N)cc2)n1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2nc(CO[Si](C)(C)C(C)(C)C)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 120 °C

Procedure:
4-[4-[(Dimethyl-tert-butyl-silyl)oxymethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (250 mg) was dissolved in 1,4-dioxane (4 mL) and ethyl isocyanate (0.144 mL) added. The reaction was heated to 120° C. for 1 hour in a microwave reactor. The reaction was concentrated in vacuo then the residue chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (106 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]2[C:7](=[O:30])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]2[C:7](=[O:30])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:22])=[O:21])[CH:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:33][N:34]1[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 35.8 %

Procedure:
A solution of tert-butyl (Z)-4-({6-methoxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0400 g, 0.0621 mmol) in methylene chloride (2 mL) was added with a 4 N solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 11 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated to obtain (Z)-6-methoxy-7-(piperazin-1-ylmethyl)-2-[(1-tosyl-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.0121 g, 35%).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:33](=O)[CH3:34]>>[CH2:33]([N:4]1[CH2:5][CH2:6][C@@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[C@H:2]([F:1])[CH2:3]1)[CH3:34]
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1
Reactant: CC=O
Product: CCN1CC[C@@H](Oc2cccc3ccc(-c4cnc5cc(OCCOC)ccn45)nc23)[C@H](F)C1

Procedure:
Prepared from 8-((trans)-3-fluoropiperidin-4-yloxy)-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinoline according to the procedure for Example 29, using acetaldehyde in place of formaldehyde. MS APCI (+) m/z 465.1 (M+1) detected.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:10])[C:7]=1[O:8]C.B(Br)(Br)[Br:12].CO>C(Cl)Cl>[NH2:10][C:6]1[C:5]([Br:12])=[CH:4][CH:3]=[CH:2][C:7]=1[OH:8]
Reactant: BrB(Br)Br
Reactant: COc1c(N)cccc1Br
Solvent: ClCCl
Solvent: CO
Product: Nc1c(O)cccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To an ice cooled solution of 6-bromo-2-anisidine (1.01 g, 5 mmol) in methylene chloride (30 mL) was slowly added a 1.0 M solution of boron tribromide in methylene chloride (10 mL, 10 mmol) via syringe. The reaction was slowly warmed to room temperature and stirred overnight. Methanol (10 mL) was added and the solvents removed by rotoevaporation to give the title compound (0.87 g, 92% yield).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Dy+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:26]1([O:32][CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:34]([CH:36]([CH2:40][CH3:41])[C:37](O)=[O:38])[CH3:35].O>C1(C)C=CC=CC=1>[CH3:33][O:32][C:26]1[CH:31]=[CH:30][C:29]([C:37](=[O:38])[CH:36]([CH2:40][CH3:41])[CH2:34][CH3:35])=[CH:28][CH:27]=1
Reactant: COc1ccccc1
Reactant: CCC(CC)C(=O)O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Dy+3]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)C(=O)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 43.7 %

Procedure:
Dysprosium (III) trifluoromethanesulfonate (3.66 g as a wet solid), anisole (1.08 g) and 2-ethylbutanoic acid (1.16 g) were refluxed together in 125 mL toluene with azeotropic removal of the lower water layer (Dean-Stark apparatus). After 48 hours, the mixture was cooled and extracted with 3×25 mL water, then by 2×25 mL saturated sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate, filtered, then concentrated down in vacuo to give para-methoxy-2-ethylbutyrophenone (0.90 g, 44% yield) as an amber-colored oil, which was practically pure by 1H NMR analysis. Removal of water from the three water extracts recovered 3.54 g as a damp, off-white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([O:21]CC4C=CC=CC=4)[CH:18]=[CH:17][C:15]=3[CH:16]=2)[O:8][C:7](=[O:29])[C:6]=1[CH3:30])(=[O:3])[CH3:2]>CCO.O1CCOCC1.[Pd]>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=3[CH:16]=2)[O:8][C:7](=[O:29])[C:6]=1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(-c2cc3ccc(OCc4ccccc4)cc3o2)oc(=O)c1C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(=O)Oc1c(C)c(-c2cc3ccc(O)cc3o2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-acetyloxy-6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one (500 mg) in EtOH (50 ml) and 1,4-dioxane (50 ml) there was added 10% Pd/C (100 mg), and the mixture was vigorously stirred at room temperature for 3 hours under a hydrogen gas atmosphere. The reaction solution was celite filtered, and then the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to obtain 4-acetyloxy-3,5-dimethyl-6-(6-hydroxybenzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]1([O:13][CH3:14])[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].P(=O)(O)(O)O.O>C1(C)C(C)=CC=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:4][C:3]1([CH3:5])[C:10]2[C:11](=[CH:12][C:6]([O:13][CH3:14])=[C:7]([OH:8])[CH:9]=2)[CH2:1][CH2:2]1
Reactant: C=CC(=C)C
Reactant: COc1ccccc1O
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1cc2c(cc1O)C(C)(C)CC2
Reaction time: 8 h
Yield: 38.4 %

Procedure:
449 g of isoprene, stabilized with 1.4 g of phenothiazine, were added dropwise over the course of 6 hours to a solution of 744 g of guaiacol, 76 g of 85% strength phosphoric acid and 6 ml of water in 1.4 liters of xylene at 110° C. To complete the reaction, stirring of the mixture was continued overnight at 110° C. The acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gave 443 g of 3,3-dimethyl-5-hydroxy-6-methoxy-indane, boiling point: 145- 46° C/12 mm Hg, melting point 43.5° - 44.5° C. ##STR35##
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C1COCC1.[NH4+].[Cl-]>[Zn].CO>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=2[C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:2]([F:1])[CH:23]=1
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1C#Cc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(N)c2C#Cc2ccccn2)c(F)c1
Temperature: 60 °C
Yield: 78 %

Procedure:
A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine (35 mg, 0.1 mmol), THF (1.5 mL) and MeOH (1.5 ml) was treated with zinc dust (65 mg, 1.0 mmol) and NH4Cl (53 mg, 1.0 mmol) and heated at 60° C. for 45 min. The reaction mixture was cooled, filtered and concentrated under vacuum. The residue was partitioned between EtOAc and saturated aq. NaHCO3 solution. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give the title compound (25 mg, 78%) as a brown solid. MS (ESI+): m/z 321.2 (M+H)+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>N1C=CC=CC=1>[CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[CH3:13][C:12]1[CH:14]=[CH:15][C:9]([S:6]([O-:5])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C=CCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 141.3 %

Procedure:
A solution of 3 g (42 mmol) 3-buten-1-ol in 10 mL dry pyridine was cooled in an ice bath. Tosyl chloride (7.9 g, 42 mmol), was added. After stirring for 3 h the mixture was poured into 30 mL of an ice/concentrated HCl 4/1 v/v solution, extracted with 60 mL diethyl ether and dried overnight in the freezer over MgSO4. The mixture was filtered and the ether evaporated to yield 7.22 g (76%) of 3-buten-1-ol 4-methylbenzene sulfonate as a yellow oil. 1H NMR (CDCl3): δ 2.39-2.53 (m, 2H, J=6.5 and 6.9 Hz, CH2—CH═CH2; and s, 3H, CH3—Ar), 4.08 (t, J=6.5 Hz, 2H, CH2OSO2), 5.09-5.15 (m, 2H, JZ═10.4, JE=16.6, Jgem=3.1 Hz, CH2—CH═CH2), 5.57-5.82 (m, 1H, JZ=10.4, JE=16.6, J =6.9 Hz, CH2—CH═CH2), 7.38 and 7.72 (d, 4H, J=8.6 Hz, Ar).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:3](=[O:21])[NH:4][N:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=c1c(Cl)c(OCC2CCCC2)cnn1C1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]ncc(OCC2CCCC2)c1Cl
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
A solution of 4-chloro-5-cyclopentylmethoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (1.63 g, 5.21 mmol) in methanol (10 mL, 0.52M) was treated with a 6N aqueous hydrochloric acid solution (4.4 mL). The reaction solution was heated to 110° C., where it stirred for 2.5 h and was then allowed to cool to 25° C. The reaction was then diluted with water (100 mL) and brought to basic pH with a 4N aqueous sodium hydroxide solution. This solution was extracted with methylene chloride (1×100 mL). The aqueous layer was then acidified with a 3N aqueous hydrochloric acid solution. The resulting white precipitate was collected by filtration, washed with water, and dried in vacuo to afford 4-chloro-5-cyclopentylmethoxy-2H-pyridazin-3-one (1.06 mg, 89%) as a white solid; ES+-HRMS m/e calcd for C10H13N2O2Cl [M+H+] 229.0739, found 229.0738. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.40 (m, 2H), 1.47-1.68 (m, 4H), 1.70-1.82 (m, 2H), 2.22-2.38 (m, 1H), 4.22 (d, J=6.8 Hz, 2H), 8.19 (s, 1H), 13.28 (brs, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[C:23]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[C:29]3[S:30][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=3)[CH:8]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Product: COc1cc(-c2cc3nccc(-c4ccc(C(C)=O)s4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 5-acetyl-2-thiopheneboronic acid (26.32 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a yellow solid (15 mg, 26%). (HPLC (method F): 88%, RT: 3.84 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.56 (d, J=5.1, 1H), 8.22 (d, J=4.0, 1H), 8.12 (d, J=3.8, 1H), 7.79 (d, J=1.0, 1H), 7.78 (d, J=5.1, 1H), 7.40 (s, 2H), 3.94 (s, 6H), 3.76 (d, J=0.9, 3H), 2.63 (s, 3H); MS (m/z) 410 [M+H]+, RT: 2.5 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[O:13]=O.[Bi]>[Pd]>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([C:2]([OH:13])=[O:1])=[O:4]
Reactant: O=O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [Pd]
Agent: [Bi]
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Yield: 85 %

Procedure:
A palladium-bismuth catalyst is disclosed in the specification of Japanese Patent Laid-Open No. 163340/1982 which relates to a process for producing 2-keto-L-gulonic acid. In this process, a hydroxyl group of L-sorbose (ketose) is oxidized with oxygen in the presence of a catalyst containing palladium and bismuth to obtain 2-keto-L-gulonic acid in a yield of 85%. The process of the present invention is characterized in that not the hydroxyl group but an aldehydo group of glucose (aldose) is oxidized to obtain gluconic acid. The process of the present invention is different from the above-mentioned process in the functional group to be oxidized and the intended product. It has been unknown in the prior art that the palladium-bismuth catalyst selectively oxidizes only the aldehydo group of glucose as an aldose, leaving the hydroxyl group non-oxidized.