Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:8]([CH3:23])([CH3:22])[CH2:9][C:10]([C:18]([F:21])([F:20])[F:19])([O:13][Si](C)(C)C)[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.O.O.O>C1COCC1>[F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:8]([CH3:23])([CH3:22])[CH2:9][C:10]([OH:13])([C:18]([F:21])([F:20])[F:19])[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1C(C)(C)CC(CO)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(F)cccc1C(C)(C)CC(O)(CO)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
4.11 g (10.75 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentan-1-ol is dissolved in 61 ml of THF, mixed with 3.39 g (10.746 mmol) of Bu4NF trihydrate, and stirred for one hour at room temperature. The reaction mixture is poured into water and extracted twice with diethyl ether. The organic phases are washed as usual with water and brine. After the desiccant is dried and filtered off, and after the solvent is spun in, the remaining residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 2.71 g (81.4%) of the desired compound is isolated.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:47])[S:27]([C:30]2[CH:39]=[CH:38][C:37]3[NH:36][C:35](=[O:40])[C:34]4[NH:41][CH:42]=[C:43]([C:44]([OH:46])=[O:45])[C:33]=4[C:32]=3[CH:31]=2)(=[O:29])=[O:28])=[CH:22][CH:21]=1>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:47])[S:27]([C:30]2[CH:39]=[CH:38][C:37]3[NH:36][C:35](=[O:40])[C:34]4[NH:41][CH:42]=[C:43]([C:44]([O:46][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:45])[C:33]=4[C:32]=3[CH:31]=2)(=[O:29])=[O:28])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)OCCCNC(=O)OC(C)(C)C)c3c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
9 mg (0.04 mmol) of 3-bromo-N-tert-butoxycarbonyl-propylamine and 8 mg (0.06 mmol) of potassium carbonate are added to a solution of 21 mg (0.05 mmol) of 8-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid dissolved in 0.5 mL of dimethylformamide. The reaction mixture is stirred for 18 hours at room temperature then the solvents are evaporated. The residue is purified by chromatography on silica (eluent cyclohexane/ethyl acetate 2/8) then triturated in diethyl ether to give 6 mg (21%) of 3-tert-butoxycarbonylamino-propyl 8-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylate in the form of a white solid.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Li+].[CH3:17][CH:18]([N-]C(C)C)C.C1COCC1.ICC>C1COCC1>[CH2:3]([CH:2]([CH2:17][CH3:18])[C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5])[CH3:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CCCC(=O)c1ccc(NC(C)=O)cc1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(CC)C(=O)c1ccc(NC(C)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-butyrylphenyl)acetamide (3 g, 14.6 mmol) in THF (300 mL) was added 2.0 M LDA THF (18.3 mL) at −78° C. and then the reaction mixture was stirred for 1 h at −78° C. Iodoethane was added and stirred overnight at RT. The reaction mixture was quenched with sat. aq. NH4Cl and then extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and then concentrated. The crude product was purified by preparative TLC using 50% ethyl acetate in hexane as eluent to afford N-(4-(2-ethylbutanoyl)phenyl)acetamide as white solid. MS (ES+): m/z 234.28 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([C:25]3[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:32][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]([CH3:15])=[C:13]2[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(F)cc23)cc1
Reaction time: 15 h
Yield: 55.7 %

Procedure:
To a solution of {6-fluoro-3-methyl-4-[4-(toluene-2-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (20 mg, 0.04 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (19.3 mg, 0.46 mmol) in water (1 mL) at room temperature. The resulting clear solution was stirred for 15 hours and then THF was removed under vacuum. Water (30 mL) was added and the mixture was acidified with 1.0N hydrochloric acid. The resulting solids were collected by filtration and washed with water and hexanes. After drying in air, {6-fluoro-3-methyl-4-[4-(toluene-2-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (10 mg, 52%) was isolated as off-white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.27 (d, J=7.9 Hz, 1 H), 8.04 (d, J=8.2 Hz, 2 H), 7.88 (dd, J=8.8, 6.0 Hz, 1 H), 7.81 (s, 1 H), 7.61 (t, J=7.5 Hz, 1 H), 7.48-7.55 (m, 1 H), 7.48 (d, J=8.2 Hz, 2 H), 7.40 (d, J=7.5 Hz, 1 H), 7.22 (td, J=8.8, 2.1 Hz, 1H), 6.65 (dd, J=11.2, 2.1 Hz, 1 H), 3.86 (s, 2 H), 2.52 (s, 3 H), 2.11 (s, 3 H). HRMS (ES−) calcd. for C26H20FO4S [(M−H)−] 447.1072, obsd. 447.1070.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7]1[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) [prepared according to the procedure described in J. Org. Chem., 40, 2743 (1975)] in 200 ml of methanol at ambient temperature was added a solution of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 2.73 g; 11.2 mmoles) [prepared according to Belgian Pat. No. 779,775] in 25 ml of methanol. After stirring for 30 minutes, a methanolic solution of the title compound was produced. The TLC (Silica/CH2Cl2 :CH3OH (90:10)] gave Rf=0.44.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[N:14]=[C:15]([S:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[S:16][C:17]=1[N+:18]([O-:20])=[O:19]>C(Cl)Cl>[Cl:12][C:13]1[N:14]=[C:15]([S:21]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:6])[S:16][C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1ccc(Sc2nc(Cl)c([N+](=O)[O-])s2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)c2nc(Cl)c([N+](=O)[O-])s2)cc1

Procedure:
A total of 4.35 g (0.025 mol) of 3-chloroperoxybenzoic acid are added in portions (about 8 portions) to a solution of 5.2 g (0.018 mol) of 4-chloro-2-(4-methylphenylmercapto)-5-nitrothiazole (compound No. 57 according to the invention) in 200 ml of methylene chloride at room temperature in the course of about 50 hours. The mixture is then concentrated to dryness in vacuo at room temperature and the residue which remains is stirred intensively with excess aqueous sodium bicarbonate solution, filtered off, washed with water and dried. 4-Chloro-2-(4-methylphenylsulphinyl)-5-nitrothiazole of melting point 112° C. (from cyclohexane) is obtained.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][CH:18]([CH2:20][NH:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH2:4]1.C(N(CC)CC)C.CC1(C)[O:39][C@H:38]([C:40](Cl)=[O:41])[CH2:37][O:36]1>C(#N)C>[OH:39][C@@H:38]([CH2:40][OH:41])[C:37]([N:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][CH:18]([CH2:20][NH:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH2:4]1)=[O:36]
Reactant: C1=C(c2ccc(C3=NOC(CNc4ccon4)C3)cc2)CCNC1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C([C@@H](O)CO)N1CC=C(c2ccc(C3=NOC(CNc4ccon4)C3)cc2)CC1
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
(5RS)-3-(4-(1,2,5,6-Tetrahydropyrid-4-yl)phenyl)-5-(3-isoxazolylaminomethyl)-4,5-dihydro-isoxazole dihydrochloride (397 mg, 1 mM) was suspended by stirring in acetonitrile (15 ml) under nitrogen, triethylamine (404 mg, 4 mM) added, and the mixture cooled to 0° C. (4S)-2,2-Dimethyl-1,3-dioxolan-4-ylcarbonyl chloride (328 mg, 2 mM) was added dropwise, stirring continued for 30 minutes at 0° C., then for 18 hours allowing the temperature to rise to ambient. Solvent was evaporated, the residue treated with water (25 ml) and extracted into dichloromethane (4×20 ml). The extracts were washed with brine (25 ml), dried (magnesium sulfate), and evaporated. The residue was dissolved in tetrahydrofuran (40 ml), treated with hydrochloric acid (2N, 2 ml), and stirred 48 hours at ambient temperature. Potassium carbonate (2 g) was added, the mixture stirred 30 minutes and filtered. After removal of solvent, the residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 5 to 10% methanol in dichloromethane. Relevant fractions were combined to give the desired product (125 mg). MS (ESP): 413 (MH+) for C21H24N4O5 NMR (CDCl3) δ: 2.54 (br, 2H); 3.18 (dd, 1H); 3.26 (m overlapped by H2O, 2H); 3.47 (dd, 2H); 3.55 (m, 1H); 3.74 (m, 2H); 4.13 (br, 1H); 4.26 (m, 1H); 4.38 (m, 1H); 4.67 (d, 1H); 4.89 (overlapping m, 2H); 5.96 (d, 1H); 6.26 (br, 1H); 6.37 (t, 1H); 7.50 (d, 2H); 7.62 (d, 2H); 8.34 (d, 1H).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH:14]=O)=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH:14]2[NH:6][C:1](=[O:5])[CH:2]([CH3:4])[O:3]2)=[CH:10][CH:9]=1
Reactant: CC(O)C(N)=O
Reactant: O=CCOc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1OC(COc2ccc(Cl)cc2)NC1=O
Yield: 2.4 %

Procedure:
16.9 g (0.19 mole) of lactamide was added to a solution containing 32.3 g (0.19 mole) of (4-chlorophenoxy)acetaldehyde and 0.2 g of p-toluenesulfonic acid in 500 ml of toluene. The mixture was refluxed with stirring for 5 hours while water was removed azeotropically Toluene was removed under reduced pressure and the residue, which contained at least two major compounds, was purified by silica chromatography to give 1.1 g of 2-(4-chlorophenoxymethyl)-5-methyl-4-oxazolidinone, cis isomer, as a white crystalline solid melting at 84°-86°.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.I[C:28]1[C:29](=[O:43])[NH:30][C:31](=[O:42])[N:32]([CH:41]=1)[C@@H:33]1[O:40][C@H:37]([CH2:38][OH:39])[C@@H:35]([OH:36])[CH2:34]1.[CH3:44][O:45][C:46](=[O:49])[CH:47]=[CH2:48]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:46](/[CH:47]=[CH:48]/[C:28]1[C:29](=[O:43])[NH:30][C:31](=[O:42])[N:32]([CH:41]=1)[C@@H:33]1[O:40][C@H:37]([CH2:38][OH:39])[C@@H:35]([OH:36])[CH2:34]1)([O:45][CH3:44])=[O:49]
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 70 °C
Yield: 70.3 %

Procedure:
A mixture of Pd(OAc)2 (0.316 g, 1.41 mmol), PPh3 (0.741 g, 2.82 mmol), and triethylamine (4.9 mL) in 1,4-dioxane (50 mL) was stirred at 70° C. until an intense red colour had developed. To this 5-iodo-2′-deoxyuridine (10 g, 28.24 mmol) and methylacrilate (4.862 g, 56.48 mmol, 5.1 mL) in 1,4-dioxane (20 mL) were added and the mixture stiffed at refluxed for 30 mins. The reaction was filtered while still hot and the 20 filtrate cooled over night at 4° C. The resulting pale yellow precipitate was filtered, washed with DCM and dried in vacuo to give the product as white solid (6.2 g, yield 70.7%).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[N:31]=[C:32]=[S:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[NH:31][C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:33]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: S=C=Nc1cc(Cl)ccc1Cl
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cc(Cl)ccc4Cl)CC3)nc21

Procedure:
Pipemidic acid (51 mg, 0.168 mmol) and 2,5-dichlorophenyl isothiocyanate (20 μL, 0.140 mmol) were used. Purification on silica yielded compound 20 in Table 1, below (42.7 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 9.39 (s, 1H), 9.06 (s, 1H), 7.57 (d, J=2.39 Hz, 1H), 7.42-7.36 (m, 1H), 7.20 (d, J=7.35 Hz, 1H), 4.55-4.39 (m, 2H), 4.31-4.02 (m, 8H), 1.52 (t, J=6.88 Hz, 3H) ppm.
Reaction SMILES: [NH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1.[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[C:15]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=[CH:17][C:18]([C:21]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]3[NH:1][N:2]=[CH:3][C:4]=3[CH2:5][CH2:6]2)=[O:22])=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)NCCc1cn[nH]c1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2cn[nH]c2-c2ccccc21

Procedure:
As described for Example 26, 2 mmol of 1,4,5,6-tetrahydropyrazolo[4,3-d][1]benzazepine is reacted with 5 mmol of [1,1'-biphenyl]-4-carbonyl chloride. The product is stirred in methanol with 2N NaOH for 16 hours and the mixture concentrated and extracted with ethyl acetate. The extract is washed with 1M citric acid, NaHCO3, H2O, dried (Na2SO4) and the solvent removed to give the product of the example as a solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[C:26]([O:31]C)=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[C:26](=[O:31])[NH:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cccnc4OC)c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3ccnc(-c4ccc[nH]c4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 170 °C
Reaction time: 336 h

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2′-methoxy-2,3′-bipyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (24.2 mg, 0.040 mmol) and lithium iodide (150 mg) in pyridine (2.0 mL) was heated in microwave at 170° C. for 3.5 hours. Reaction mixture was cooled to room temperature and allowed to stand for 14 days, diluted with ethyl acetate. Organic layer was washed with 5% AcOH solution (3×), brine, dried (MgSO4), filtered, concentrated, and purified using Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give desired product. LCMS-ESI+: calc'd for C30H27ClN3O4S: 560.1 (M+H+); Found: 560.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.78 (dd, J=11.1, 6.9 Hz, 2H), 8.28 (d, J=6.0 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J=6.1 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.64-7.53 (m, 3H), 6.73 (dd, J=6.8 Hz, 1H), 5.28 (s, 1H), 2.62 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N+:17]([O-:9])=[CH:18]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Aqueous meta-chloroperbenzoic acid (65%, 29 g) was added to a solution of 5-bromoisoquinoline (20.7 g) in chloroform (250 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and small amounts of chloroform and diethyl ether were added to the residue. The deposit was filtrated to obtain compound (1a) (11.8 g, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.[BrH:11].BrBr.O>C(O)(=O)C>[Br:11][CH2:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Br
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)CBr)cc1
Temperature: 30 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a stirring solution of 20 g (150 mmol) of 4-methylacetophenone in 100 mL of glacial acetic acid was added catalytic amount of HBr (0.5 mL) followed by 21.40 g (134 mmol) of bromine dissolved in acetic acid (30 mL) dropwise at 10-15° C. The reaction mixture was stirred at 25-35° C. for 5 hrs, then poured into water (100 mL). The solid that separated was filtered to give the required product (20 g, 65%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8](=[N:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:16][N:15]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)(=[O:27])[CH3:26]
Reactant: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)ON=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
0.93 g of 3,5-di-t-butyl-4-hydroxybenzophenone oxime was dissolved in pyridine, and 0.28 g of acetyl chloride was added dropwise at room temperature. Thereafter, the mixture was stirred for 20 minutes. The reaction mixture was poured into ice water, extracted with benzene, washed with 4% HCl, water and a saturated aqueous solution of sodium bicarbonate, and dried. The solvent was distilled off, and the resulting crystals were recrystallized from ether/n-hexane to give 3,5-di-t-butyl-4-hydroxybenzophenone O-acetyloxime.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH:11]1[C:12]2[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28][CH3:29])=[O:27])[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(CCl)c1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2c3ccccc3Oc3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a solution of phenoxazine (2.20 g) in tetrahydrofuran (30 ml) was added potassium tert-butoxide (2.69 g) at 0° C. The mixture was stirred at 0° C. for 10 minutes, and then a solution of methyl 3-(chloromethyl)benzoate (2.44 g) in tetrahydrofuran (20 ml) was added. The mixture was stirred at 25° C. for 30 minutes, and then evaporated. The residue was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (40:1-20:1) and recrystallization from a mixture of hexane and ethyl acetate to give e methyl 3-(phenoxazin-10-ylmethyl)benzoate (1.12 g) as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22].[Se](=O)=[O:24]>O1CCOCC1.O>[CH3:1][N:2]1[C:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([C:18]([OH:24])=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22]
Reactant: CN1C(=O)NC(=O)C12Cc1cc3ccc(C=O)nc3cc1C2
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)NC(=O)C12Cc1cc3ccc(C(=O)O)nc3cc1C2

Procedure:
A mixture of (±)-2,3′-dimethyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione (500 mg, 1.78 mmol, described in Intermediate 19) and selenium dioxide (592 mg, 5.33 mmol) in dioxane (30 mL) and H2O (3 mL) are heated at reflux for 18 h. The reaction mixture is allowed to cool, filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give the title compound. MS: m/z=312 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]([N:22]1[C:18](=[O:28])[C:19]2[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21]1=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)NCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
To a solution of (2-hydroxy-2-phenyl-ethyl)-carbamic acid tert-butyl ester (34.4 g, 145.0 mmol), phthalimide (21.3 g, 145 mmol), and PPh3 (49.4 g, 188.5 mmol) was added drop-wise DEAD (32.8 g, 188.5 mmol) under stirring at 0° C. After addition, the mixture was stirred at room temperature for an additional 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate, 20:1 to 5:1) to give [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as a white solid. (Yield 39 g, 74%).
Reaction SMILES: [CH3:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]1=[O:10].[CH3:17]O>S(=O)(=O)(O)O>[CH3:17][O:8][C:7]([C:5]1[O:6][C:2]([CH3:1])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3](=[O:10])[CH:4]=1)=[O:9]
Reactant: CC1(c2ccccc2)OC(C(=O)O)=CC1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1=CC(=O)C(C)(c2ccccc2)O1

Procedure:
A mixture of 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (0.4 g, described in Example 4), absolute methanol (50 ml), and sulfuric acid (3 drops) is refluxed overnight and evaporated. The residue is diluted with 50 ml of diethyl ether, and the solution is washed quickly with saturated sodium bicarbonate and water, dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from diethyl ether to obtain the title compound (0.32 g) mp 60°-62° C. and nmr (CDCl3) δ1.81(s), 3.99(s), 6.25(s) and 7.42(m).