Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[C:6]([O:19][CH2:20][CH3:21])[CH:5]=1.Cl>CO.C1COCC1.[OH-].[Na+]>[CH2:20]([O:19][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]=1[C:13]1[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=1)[C:3]([OH:22])=[O:2])[CH3:21]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnn(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3,5-Diethoxy-4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid methyl ester (895 mg) was dissolved in a mixed methanol/THF solution (16 mL, 5/3), aqueous 1 M NaOH solution (6 mL) was added to it, and stirred at 50° C. for 5 hours. The reaction liquid was cooled to room temperature, and aqueous 1 M HCl solution (6 mL) was added to it, and the solvent was evaporated away under reduced pressure. The resulting solid was taken out through filtration, washed with water and ether, and dried under reduced pressure to obtain the title compound as a pale yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Si:1]([O:8][CH2:9]/[CH:10]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (Aldrich, 15 g, 86.05 mmol) in DCM (200 mL) at room temperature was added copper(II) sulfate (41.2 g, 258.16 mmol) and (S)-2-methylpropane-2-sulfinamide (Aldrich, 15.64 g, 129.08 mmol). The reaction mixture was stirred overnight at room temperature, then filtered through celite, washed with DCM and concentrated to afford an oil. Silica gel chromatography (0%-25% ethyl acetate/hexanes) afforded the title compound (14.73 g, 61.7%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][C:19]([CH2:22][CH2:23]I)([F:21])[F:20])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CNC=[O:28].O>CCOCC>[C:1]([CH2:14][C:15]([CH2:18][C:19]([CH2:22][CH2:23][OH:28])([F:21])[F:20])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(CCI)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CNC=O
Solvent: CCOCC
Solvent: O
Product: OCCC(F)(F)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Then C4F9(CH2CF2)2CH2CH2I (10 g) and N-methylformamide (8.9 mL) were heated to 150° C. for 26 h. The reaction was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (3 mL) and p-toluene sulfonic acid (0.09 g) were added to the crude ester, and the reaction was stirred at 70° C. for 15 min. Then ethyl formate and ethyl alcohol were distilled out to give a crude product. The crude alcohol was dissolved in ether, washed with aqueous sodium sulfite, water, and brine in series, and dried over magnesium sulfate. The product was distilled to give C4F9(CH2CF2)2CH2CH2OH: bp 90˜94° C. at 2 mmHg Pascals).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+](=[CH2:26])=[N-]>ClCCl.C(O)C.CCOCC>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH3:26])=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=[N+]=[N-]
Reactant: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2ccccc21

Procedure:
A solution of 1.6 g of 1-hexyl-3-ethoxycarbonyl-4-hydroxy-2(1H)-quinolinone in dichloromethane (20 ml) and ethanol (2 ml) was treated with excess diazomethane in ether for 10 mins and is then evaporated. The crude methylation product upon chromatography on silica gel yielded 1-hexyl-3-ethoxycarbonyl-4-methoxy-2(1H)-quinolinone (1.0 g). This product (1 .0 g) in dry toluene (10 ml) was cooled to -78° C. and a 1M solution of diisobutyl aluminum hydride (4.3 ml) was added dropwise in 10min. After 2.5 hours stirring at-78° C. the reaction mixture was worked up by stirring with aqueous ammonium chloride/1N hydrochloric acid followed by extraction with methylene chloride. The crude reduction product was chromatographed on silica gel and crystallized from ethyl acetate/hexane to give 1-hexyl-3-formyl-4-methoxy-2(1H)-quinolinone as a crystalline solid. That the expected product was obtained was confirmed by the spectral data: MS (FAB): m/e 288 (M.+ +1); NMR (CDCl3): δ4.12 (s, 3H, OCH3), 10.5 (s, 1H, CHO).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
15.6 Grams (0.1 mol) of 4-hydroxy-2-fluorobenzoic acid was dissolved in 140 ml of dichloromethane. To the mixture were consecutively added 16 ml of triethylamine, 0.1 g (0.11 mol) of n-decanoic acid chloride and 0.97 (0.0079 mol) of dimethylaminopyridine, and the mixture was stirred at room temperature for a whole day. 10% Hydrochloric acid in an amount of 50 ml was added, and the mixture was subjected to extraction with 100 ml of ether three times. The organic layer was washed with a sodium chloride aqueous solution three times and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was washed with 400 ml of hexane to give 25.5 g of the intended product.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][N:26]=2)[C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:7]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([N:32]([CH2:33][CH3:34])[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][N:26]=2)[C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:7]=1)[CH3:31]
Reactant: CCNCC
Reactant: O=C(N[C@H]1CCCc2ccccc21)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-(5-fluoro-2-nitrophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide (12.77 mmol, 5 g), diethylamine (25.55 mmol, 1.87 g), and K2CO3 (31.93 mmol, 4.41 g) in DMF (30 mL) was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate, and the resulting solution was washed with water (2×), and then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel to give a yellow solid. (4.73 g, 83%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:11]([CH3:12])=[C:10]([CH3:13])[CH:9]=[C:7]([CH3:8])[C:6]=1[CH3:14])=[O:4].CN(C)C=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O>[N:20]1([CH2:2][C:3]([C:5]2[C:11]([CH3:12])=[C:10]([CH3:13])[CH:9]=[C:7]([CH3:8])[C:6]=2[CH3:14])=[O:4])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: Cc1cc(C)c(C)c(C(=O)CBr)c1C
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(C)c(C(=O)Cn2ccnc2)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture containing 2.55 g of 3-bromoacetyl-durene, prepared as described in Example 4, 3 ml of dimethylformamide and 3.40 g of imidazole, was stirred for 8 hours at 80° C. At the end of the reaction, the mixture was cooled to room temperature and 25 ml of water were added. The precipitate thus obtained was filtered off, dried and crystallized from benzene to give 1.5 g of the title compound. M.P. 176°-8° C., yield 62%.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1.N1C=C(B(O)O)C=N[CH:37]=1>>[N:13]1([C@H:11]2[CH2:12][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:10]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:18][CH2:37]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: OB(O)c1cncnc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2ccc3nc([C@H]4C[C@H](N5CCCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 71A for the product of Example 1E, and substituting 1-methyl-4-1H-pyrazoleboronic acid pinacol ester for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 7.89-7.97 (m, 2H) 7.80 (s, 1H) 7.65 (s, 1H) 7.55 (dd, J=8.39, 1.68 Hz, 1H) 3.97 (s, 3H) 3.74-3.83 (m, 1H) 3.30-3.41 (m, 1H) 2.46-2.61 (m, 8H) 1.56-1.71 (m, 8H). MS: (M+H)+=367.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[O:20]1CCC[CH2:21]1>>[C:13]1([NH:12][C:21]([N:7]2[CH2:8][CH:4]([OH:3])[CH2:5][C:6]2=[O:9])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: C[Si](C)(C)OC1CNC(=O)C1
Reactant: C1CCOC1
Agent: Cl
Product: O=C1CC(O)CN1C(=O)Nc1ccccc1
Yield: 72 %

Procedure:
A 8.14 g quantity of 4-trimethylsilyloxy-2-pyrrolidone [Farmaco Edizione Scientifica, 36, 845-855 (1981)] was dissolved in 100 ml of tetrahydrofuran, 7.62 g of N,N'-carbonyldiimidazole was added to the solution, and the mixture was refluxed for 20 hours. With addition of 4.38 g of aniline, the mixture was further refluxed for 7 hours, then cooled and stirred at room temperature for 0.5 hour with addition of 150 ml of 1N hydrochloric acid. The solvent was distilled off in a vacuum, the residue was subjected to silica gel column chromatography to obtain crystals from an eluate of chloroform/methanol=30/1. The crystals were recrystallized from acetone-hexane, giving 7.44 g of 1-phenylcarbamoyl-4-hydroxy-2-pyrrolidinone (yield 72%) having a melting point of 104° to 104.5° C.
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][N:14]=C(O)[N:12]=1.[CH3:20][NH:21][C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][N:14]=[C:4]([O:3][C:2](=[O:1])[N:21]([CH3:20])[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[N:12]=1
Reactant: CNc1cccc(C)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Oc1nccc(C(F)(F)F)n1
Solvent: C1CCOC1
Product: Cc1cccc(N(C)C(=O)Oc2nccc(C(F)(F)F)n2)c1
Reaction time: 1 h
Yield: 6.6 %

Procedure:
At 0° C. diphosgene (0.99 g, 5.00 mmol) was added to a stirred solution of 4-trifluoromethyl-2-hydroxypyrimidine (1.64 g, 10.0 mmol) in tetrahydrofuran (25 ml). The cooling bath was removed and stirring was continued at room temperature for 1 hour. Methyl-m-tolyl-amine (0.30 g, 2.50 mmol) was added to one-fourth of the solution. After stirring overnight at room temperature the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (20:80)) followed by preparative HPLC, yielding the title compound (51 mg, 7%) as a colourless oil.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]([O-:27])=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:28]1([CH:34]=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH:24]([CH:34]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:35])[C:25]([O:27][CH3:1])=[O:26])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C([O-])CCc1ccccc1OCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Reactant: O=CC1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of lithium diisopropylamide (1.55M in n-hexane) in tetrahydrofuran (2 ml) was added a solution of 3-(2-benzyloxyphenyl)propionate (140 mg) in tetrahydrofuran (1.4 ml) and the mixture was stirred for 30 minutes. Cyclohexanecarbaldehyde (80 mg) was added. After being stirred for 30 minutes at the same temperature, the mixture was quenched by 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with aqueous sodium bicarbonate solution and brine successively, dried and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 60% diethyl ether - hexane) to afford less polar isomer of methyl (2RS,3SR)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (isomer A) (56.2 mg) and more polar isomer of methyl (2RS,3RS)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (isomer B) (74.4 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3][C:4]1[CH:23]=[CH:22][C:7]2[O:8][C:9]([CH3:21])([CH3:20])[C@@H:10]([OH:19])[C@H:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3=[O:18])[C:6]=2[CH:5]=1.[OH:26]OS([O-])=O.[K+].[OH2:32]>CO>[F:25][C:2]([F:1])([F:24])[S:3]([C:4]1[CH:23]=[CH:22][C:7]2[O:8][C:9]([CH3:20])([CH3:21])[C@@H:10]([OH:19])[C@H:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3=[O:18])[C:6]=2[CH:5]=1)(=[O:26])=[O:32].[F:25][C:2]([F:1])([F:24])[S:3]([C:4]1[CH:23]=[CH:22][C:7]2[O:8][C:9]([CH3:20])([CH3:21])[C@@H:10]([OH:19])[C@H:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3=[O:18])[C:6]=2[CH:5]=1)=[O:26]
Reactant: CC1(C)Oc2ccc(SC(F)(F)F)cc2[C@@H](N2CCCCC2=O)[C@@H]1O
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2CCCCC2=O)[C@@H]1O
Product: CC1(C)Oc2ccc(S(=O)C(F)(F)F)cc2[C@@H](N2CCCCC2=O)[C@@H]1O
Yield: 7 %
Yield: 64 %

Procedure:
0.2 g (5.3 mmol) of 6-trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-piperidinyl)-2H-benzo(b)pyran-3-ol are dissolved in 7 ml of methanol and a suspension of 1 g of Oxone® in 5 ml of water is added at 0° C. with stirring. After stirring for 5 days at room temperature, the mixture is diluted using 20 ml of water and extracted using chloroform (50 ml). After drying and evaporating, 220 mg of white crystals remain. By means of HPLC (eluent 98:2 chloroform:methanol), 140 mg (64% of theory) of 6-trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-piperidinyl)-2H-benzo(b)pyran-3-ol and 15 mg (7% of theory) of 6-trifluoromethylsulphinyl-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-piperidinyl)-2H-benzo(b)pyran-3-ol are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH3:22][C:23]1([CH3:43])[C:27](=[O:28])[C:26]2[CH:29]=[C:30]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]([CH3:34])=[C:32]([CH3:33])[C:25]=2[O:24]1>C1COCC1.O>[OH:28][C:27]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[C:26]2[CH:29]=[C:30]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]([CH3:34])=[C:32]([CH3:33])[C:25]=2[O:24][C:23]1([CH3:43])[CH3:22]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: Cc1c(NC(=O)OC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(NC(=O)OC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1ccc(C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromocumene (6.25 g, 31.4 mmol) in THF (50 mL) was added dropwise a solution of n-butyllithium in hexane (1.60 M, 19.6 mL, 31.4 mmol) under arogon atmosphere at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction solution was added dropwise a solution of tert-butyl (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Reference Example 59 (500 mg, 2.02 mmol) in THF (5 mL) at the same temperature, and the reaction solution was stirred at room temperature for 1 hour, followed by addition of water, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain oily tert-butyl (3-hydroxy-3-(4-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate. A mixture of said compound with trifluoroacetic acid (10 mL) was added triethylsilane (1.0 mL, 6.4 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue was added a saturated sodium hydrogen carbonate solution to alkalify the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain the free salt of the title compound. Then, it was made hydrochloride in a 4 N hydrochloric acid/methanol solution to obtain 2.03 g (yield 37%) of the title compound. Melting point: 166-168° C. (decomp.) (methanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[F:15])[CH:2]=1.C(=O)(O)[O-].[Na+].C1COCC1.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:34]([NH:11][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:13]([F:14])[CH:12]=1)([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(F)c(-c2cccnc2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)c(-c2cccnc2)c(F)c1)OCc1ccccc1

Procedure:
4-(3-Pyridyl)-3,5-difluoroaniline (PREPARATION 2, 625 mg, 3.03 mmol), sodium bicarbonate (382 mg, 4.55 mmol, 1.5 eq) and dry THF (60 ml) are combined. The resulting mixture is placed under an atmosphere of nitrogen and benzylchloroformate (394 μl, 4.55 mmol, 1.5 eq) is added. The reaction is allowed to stir at 20°-25°. After this time, the reaction is added to methylene chloride (150 ml) and washed with saturated sodium bicarbonate then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to a solid which is puffed by silica gel chromatography (200 g of silica gel, eluted with acetonitrile/chloroform (3/97-1 l, 5/95-2 l), the title compound is recovered as a solid, mp 188°-190°; FTIR (neat) cm-1 3030, 1737, 1642, 1478, 1408, 1231, 1029, 723; MS (EI, m/z) 340, 296, 232, 205, 91, 79; NMR (CD3CL3) δ 8.59, 8.53-8.51, 7.95-7.92, 7.56-7.51, 7.44-7.31, 7.28 and 5.21.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1
Reactant: Clc1ncc2cn[nH]c2n1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Clc1ncc2cnn(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 92 %

Procedure:
A suspension of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.65 mmol), benzene boronic acid (1.5 eq), copper acetate (2 eq) and pyridine (2 eq) in dichloromethane (2 mL) was heated in the microwave at 80° C. for 15 min. After cooling to rt, the mixture was filtered and the resulting filtrate concentrated to give 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine as a green oil (138 mg, 92%) which was used without further purification in the next step.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=O.N1CCCCC1>C(Cl)(Cl)Cl>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][C:26]([F:27])([F:28])[F:29])=[C:17]([Cl:16])[CH:18]=1
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: O=C(C=Cc1ccc(OC(F)(F)F)c(Cl)c1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A mixture of 2.25 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 2.25 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 20 ml of chloroform and 0.7 ml of piperidine was heated under refluxing for 2 hours and 30 minutes. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography. Resulting crystals were washed with 40 ml of t-butyl methyl ether to obtain 1.49 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (1c-6)] was obtained as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[S:18]([CH2:22][CH2:23]O)[CH2:19][CH2:20][OH:21].Cl.CN(C)CCCN=C=NCC.CCOCC.CCCCCC>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:23][CH2:22][S:18][CH2:19][CH2:20][OH:21])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: OCCSCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCSCCO)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 15.0 g, 65 mmol), 2,2′-thiodiethanol (40 g, 325 mmol) and N,N-dimethylaminopyridine (DMAP, 1.59 g, 13 mmol) in dichloromethane (400 mL) at room temperature was added 1-(3-(dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 14.98 g, 78 mmol) as a solid, in portions. After stirring for 3 hours at room temperature, TLC analysis indicated the reaction was complete. The reaction mixture was partitioned between CH2Cl2 and water, and the water layer was washed with more CH2Cl2. The combined organic layer was washed with water, 0.1 N HCl, water, brine, and dried over magnesium sulfate. The solution was concentrated under vacuum, and the residue was purified via column chromatography, 5% ethyl acetate/dichloromethane. The appropriate fractions were combined, and the solvent evaporated. Trituration of the residue with ether/hexane gave the title compound as a white solid (17.72 g, 81% yield). Mp 58–61° C. 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=8.6 Hz, 2H), 7.67 (d, J=0.9 Hz, 1H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.14(dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 3.86 (q, J=7.2 Hz, 1H), 3.60 (app q, J=6.0 Hz, 2H), 2.69 (t, J=6.6 Hz, 2H), 2.61 (t, J=5.9 Hz, 2H), 2.00 (t, J=6.2 Hz 1H), 1.59 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 352 (MNH4+); Anal. calcd. for C18H22O4S: C, 64.65; H, 6.63, S, 9.59. Found: C, 64.62; H 6.59; S, 9.47.