Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:13]3([CH2:15][CH2:14]3)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[O:10][CH:9]([C:20]([O:22]C)=[O:21])[O:8][C:7]=2[C:24]=1[O:25][CH3:26].[OH-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:13]3([CH2:15][CH2:14]3)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[O:10][CH:9]([C:20]([OH:22])=[O:21])[O:8][C:7]=2[C:24]=1[O:25][CH3:26]
Reactant: COC(=O)C1Oc2ccccc2C2(CC2)c2ccc(OC)c(OC)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1OC)OC(C(=O)O)Oc1ccccc1C21CC1
Reaction time: 1.3 h

Procedure:
A solution of 76 mg (0.23 mmol) of methyl 3',4'-dimethoxyspiro(cyclopropane-1,12'(12'H)-dibenzo[d,g][1,3]dioxocin)-6'-carboxylate in 0.46 ml of tetrahydrofuran was combined with 0.172 ml (0.35 mmol) of 2N aqueous sodium hydroxide and the mixture stirred for 1.3 hour. The resulting mixture was diluted with 0.5 ml of water, extracted with ether, and then acidified with 1N aqueous hydrochloric acid. The resulting mixture was extracted 3 times with 1 ml portions of ether and the combined ethereal extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain the title compound in quantitative yield as a white solid. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:4]2[O:3][C:2]([NH:17][C:18]3[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.599 g, 2.42 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.451 g, 2.42 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)phenyl) methane sulfonamide 33 (0.393 g, 41% yield) as a solid. MS (ES) m/z 398 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2C=C[CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1.[Li].C(C1N=C(C([O-])=O)[S:34]C=1)(C)C.NC1C(Cl)=C(OC)C=CC=1C(=O)C>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[S:34][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1
Reactant: CC(C)c1csc(C(=O)[O-])n1
Reactant: COCCOc1ccc2c(Cl)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Agent: COc1ccc(C(C)=O)c(N)c1Cl
Agent: [Li]
Product: COCCOc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
4,8-Dichloro-2-(4-isopropyl-thiazol-2-yl)-7-(2-methoxy-ethoxy)-quinoline was prepared in a similar fashion as 4,8-Dichloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinoline except that the lithium salt of 4-isopropyl-thiazole-2-carboxylate was used instead of 6-isopropyl-pyridine-2-carboxylic acid and 1-(2-Amino-3-chloro-4-methoxy-phenyl)-ethanone was used instead of 1-[2-amino-3-chloro-4-(2-methoxy-ethoxy)-phenyl]-ethanone
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([N:16]1[CH2:22][CH2:21][CH:20]([C@H:23]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])[CH:19]([OH:34])[CH:18]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:17]1=[O:42])[CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([N:16]1[CH2:22][CH2:21][CH:20]([C@H:23]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:24])[CH:19]([O:34][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:18]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:17]1=[O:42])[CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)N1CCC([C@@H](C)COCc2ccccc2)C(O)C(Cc2ccccc2)C1=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)N1CCC([C@@H](C)COCc2ccccc2)C(O[Si](C)(C)C(C)(C)C)C(Cc2ccccc2)C1=O

Procedure:
A single isomer of the alcohol (62) is dissolved in DMF and treated with imidazole (2 equivalents) and t-butyldimethylsilyl chloride (1.05 equivalents) at room temperature overnight. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic extracts are dried over MgSO4 and evaporated at reduced pressure. The residue is purified by flash chromatography to give (63).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[N+:18]([O-])([OH:20])=[O:19]>OS(O)(=O)=O>[CH3:17][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:12]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-p-tolyl-3-trifluoromethyl-pyridine (8.4 mmol) in H2SO4 (6 mL) cautiously add fuming HNO3 (2 ml). Stir the mixture for 60 minutes at room temperature. Pour the mixture onto ice-water (30 mL), extract with EtOAc, neutralize with 1 N NaOH, dry over Na2SO4, and concentrate under vacuum to obtain 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](Br)[N:7]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:20]=2)[N:7]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cn1cc(Br)nc(N)c1=O
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)nc(N)c1=O
Yield: 17.9 %

Procedure:
A solution of 3-amino-5-bromo-1-methylpyrazin-2-one (81.0 mg, 0.4 mmol), (3-methylsulfonylphenyl)boronic acid (120.0 mg, 0.6 mmol), Cs2CO3 (391.0 mg, 1.2 mmol), Pd(PPh3)4 (20.0 mg, 0.017 mmol) in dioxane (20.0 mL) and water (2.0 mL) was stirred at 95° C. for 12 h under N2. The mixture was concentrated and purified by silica gel chromatography (PE: EA=3:2) to give the title compound (20.0 mg, 18%). 1H NMR (DMSO-d6 400 MHz): δ 8.35 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J=8.0 Hz, 1H), 6.93 (brs, 2H), 3.50 (s, 3H), 3.24 (s, 3H). LCMS (M+H)+ 280.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10]N=[N:8][C:7]=2[O:6][CH2:5]1.[Cl:13][C:14]1N=C2OCC(=O)C2=CC=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[N:8][C:14]([Cl:13])=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: CON=C1COc2nnccc21
Reactant: O=C1COc2nc(Cl)ccc21
Product: CON=C1COc2nc(Cl)ccc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 6-chlorofuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one;
Reaction SMILES: [CH3:1][C:2]([OH:12])([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])[C:3]#[CH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:12][C:2]([CH3:1])([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])[C:3]#[CH:4])(=[O:26])[CH3:25]
Reactant: C#CC(C)(O)CCC(C)=C(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C#CC(C)(CCC(C)=C(C)C)OC(C)=O
Temperature: 40 °C

Procedure:
650.0 g of 3,6,7-trimethyl-6-octen-1-in-3-ol and 0.63 g of p-toluene sulfonic acid in water are mixed and heated up to a temperature of 40° C. 479.3 g of acetic acid anhydride are added within 2 hours. After ca. 20 hours the reaction mixture is cooled down and distilled to obtain 3,6,7-trimethyl-6-octen-1-in-3-yl acetate.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[F:24])[N:20]=[C:19]([NH2:25])[C:18]([CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:17]3)[CH:10]=[CH:11][CH:12]=1.Cl.O>C(OCC)C>[NH2:25][C:19]1[C:18]([CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:17][C:16]2[C:21](=[CH:22][C:23]([F:24])=[C:14]([S:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[CH:2]=[O:1])[CH:15]=2)[N:20]=1
Reactant: Nc1nc2cc(F)c(Sc3cccc(C4OCCCO4)c3)cc2cc1CC1CCOCC1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: Nc1nc2cc(F)c(Sc3cccc(C=O)c3)cc2cc1CC1CCOCC1

Procedure:
In a μwave tube, 6-(3-[1,3]dioxan-2-yl-phenylsulfanyl)-7-fluoro-3-(tetrahydro-pyran-4-ylmethyl)-quinolin-2-ylamine (45 mg, 0.1 mmol) was placed with HCl (conc.) (0.5 mL), H2O (0.5 mL) and diethyl ether (0.2 mL) were reacted via μwave @ 300W, 130° C. for 12 min. The resulting mixture was worked up by removal of solvent to yield a residue, which was purified by silica column chromatography (50% EtOAc/heptanes) to yield a solid.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.O>[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:3][CH2:4][C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1
Reactant: C1=COCCC1
Reactant: O=Cc1ccc(CO)o1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N#N
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(COC2CCCCO2)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask under inert atmosphere (N2), to a mixture of 5-hydroxymethyl-2-furaldehyde (100 g, 0.79 mol) and pyridinium toluene-4-sulfonate (10 g, 0.04 mol) in CH2Cl2 (1 L) was added 3,4-dihydro-2H-pyran (150 mL, 1.62 mol) while keeping the internal temperature below 28° C. (water bath). The reaction mixture was stirred at rt for 5 h. Water (1 L) was added, the layers separated and the org. layer washed with water (500 mL) and evaporated to dryness to give crude 5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-carbaldehyde as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[Cl:17][C:18]([Cl:23])([Cl:22])[C:19]([N:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:20]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(N1Cc2ccccc2C1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Triethylamine (3.48 mL, 25.0 mmol) was added to a solution of isoindoline (4.98 g, 25.0 mmol) in chloroform (100 mL) at room temperature and the mixture was cooled in ice. Trichloroacetic acid chloride (2.79 mL, 25.0 mmol) was added dropwise thereto and the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to afford 2,2,2-trichloro-1-(1,3-dihydro-2 H-isoindol-2-yl)ethanone as a purple powder (6.59 g).
Reaction SMILES: [CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:29])[N:12]2[C:15](=[C:26]([OH:28])[CH3:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:29])[N:12]2[C:15](=[C:26]([O:28][S:31]([CH3:30])(=[O:33])=[O:32])[CH3:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 0.92 h

Procedure:
One adds to a solution of benzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (1.424 g) in tetrahydrofuran (15 ml), triethylamine (0.96 ml), and methanesulfonyl chloride (0.28 ml) at -30° to -20° C., stirs for 55 minutes to give benzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, adds morpholine (0.40 ml) and stirs for 5 hours at -10° C. to +3° C. to give benzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)-acetate, cools to -35° C. to -30° C., adds pyridine (0.27 ml) and bromine in carbon tetrachloride (1 mmole/ml: 3.2 ml), and stirs for 20 minutes to give benzyl α-[3-benzyl- 7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]hept-2-en-6-yl]-α-(1-morpholino-2-bromoethylidene)acetate, adds 5% hydrochloric acid (13 ml) and methanol (50 ml), and kept at 0° C. overnight to hydrolyze and cyclize giving the cephem product. The solvent is removed under reduced pressure, and the residual solution is extracted with ethyl acetate. The extract solution is washed with saturated saline and water, dried over sodium sulfate, and purified by chromatography over silica gel containing 10% water. The fractions containing the product are combined and evaporated. Recrystallization of the residue from a mixture of methanol, ether, and hexane gives benzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate. m.p. 149°-162° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH:35](O)=[O:36].C(N)=O>C(O)C>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]1[CH:33]=[CH:34][C:16]([CH2:15][N:7]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[CH:17][CH:18]=1)[CH:35]=[O:36])[CH2:31][CH3:32]
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: O=CO
Solvent: CCO
Solvent: NC=O
Product: CCCN(CCC)CCCCN(C=O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
The compound (82.9 mg) obtained in Example 52-3 was dissolved in ethanol (1.0 ml) and added with formic acid (50 μl) and formamide (50 μl). The whole was stirred at an outside temperature of 10° C. for 3 hours. The solution was added with additional formic acid (60 μl) and the whole was stirred for 15 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution to adjust the pH to 11. The aqueous layer was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (27.0 mg) of the subject compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>CC(O)=O.CC(O[Na])=O>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:12]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)CCl
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: O=C(CCl)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a solution of 4-aminophenol (1.0 g, 9.1 mmol) in CH3COOH (3.5 mL) and saturated CH3COONa (3.5 mL), chloroacetylchloride (0.72 mL, 9.1 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, washed with water (3×25 mL) and dried over vacuum to isolate the intermediate 17a as white solid (0.690 g, 3.71 mmol, 40% yield). 1H NMR (DMSO, 400 MHz) δ 10.03 (s, 1H), 9.27 (s, 1H), 7.36 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H) 4.182 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:35][CH2:34][CH2:33][NH:32][C:31](=[O:36])[O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)NCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 75 %

Procedure:
a Fluorescent Indo-Coumarinyl Analog: Compound 27cc, N-{2-(Coumarin-3-carboxylamido)ethyl}-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide, was synthesized by the method depicted in FIG. 6. Briefly, indomethacin was complexed with tert-Butyl-2-aminoethylcarbamate for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF). A yellow solid of tert-Butyl 2-[2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamido]ethylcarbamate was produced as a yellow solid at 75% yield. This product was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(2-Aminoethyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide hydrochloride as a brown solid with a yield of 98%, which was reacted with N,N-diisopropylethylamine (DIPEA) in dichloromethane for 5 minutes at room temperature prior to the addition of Coumarin-3-carboxylic acid, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), and N,N-diisopropylethylamine (DIPEA) in dichloromethane. The reaction proceeded for 16 hours at room temperature and produced Compound 27cc as a yellow solid (35% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C@H:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:7]21[CH3:18])[CH3:2].F[B-](F)(F)F.[O:24]=[N+:25]=[O:26]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([N+:25]([O-:26])=[O:24])[CH:12]=1)[N:9]([CH3:13])[C@H:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:7]21[CH3:18])[CH3:2]
Reactant: CCOc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOc1cc([N+](=O)[O-])c2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C

Procedure:
A degassed solution, under nitrogen, of 3.70 g of (3aS-cis)-5-ethoxy-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole in 50 ml of dry chloroform was treated with 2.00 g of nitronium tetrafluoroborate at a reaction temperature of +10°. After twenty minutes, the reaction was quenched by the addition of ice and saturated sodium bicarbonate solution with vigorous stirring. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to an oil. This was purified by chromatography over silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to an oil which crystallized from hexane to afford crystals of pure (3aS-cis)-5-ethoxy-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-7-nitropyrrol[2,3-b]indole, mp 106°-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=O>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:3]3[N:4]=[CH:5][C:6]([C:7]([C:9]4[S:10][CH:11]=[CH:12][N:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[CH:21]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Nc1n[nH]cc1C(=O)c1nccs1
Product: O=C(c1nccs1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
As described for Example 1, (3-amino-1H-pyrazol-4-yl)-2-thiazolyl-methanone was reacted with 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one to give the product as colorless crystals, mp 262°-264° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:17][CH:18]([CH3:20])[CH3:19])[C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][NH:8][CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH:18]([CH3:20])[CH3:19])[C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][N:8]([CH2:9][CH:10]([O:11][CH3:12])[O:13][CH3:14])[S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: COC(CNCc1cc(Br)cc(OC(C)C)c1C)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CN(Cc1cc(Br)cc(OC(C)C)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.9 %

Procedure:
To a mixture of N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-2,2-dimethoxyethanamine (108c, 3.5 g, 10 mmol) and Na2CO3 (1.6 g, 15 mmol) in THF (40 mL) and H2O (20 mL) was added TsCl (2.0 g, 11 mmol). The reaction mixture was stirred at room temperature for 5 hours, then extracted with EtOAc (4×40 mL). The combined organic layers were washed with H2O (2×30 mL) and brine (2×100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=5:1) to give N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (108d, 4.7 g, 93%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl.[C:50](SC)(=[NH:52])[CH3:51]>O>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][C:50](=[NH:52])[CH3:51])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Reactant: CSC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=N)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of DMF were added 58 mg of sodium carbonate and 119 mg of methyl ethanimidothioate hydrochloride, followed by stirring at 60° C. for 1 hour. Thereafter, while stirring at 60° C., 233 mg of sodium carbonate and 478 mg of methyl ethanimidothioate hydrochloride were further added in four divided portions every 1 hour. After cooling the reaction solution, water was added thereto, followed by extraction with chloroform-isopropyl alcohol (5:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-aqueous ammonia) and then crystallized with ethyl acetate to obtain 113 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(ethanimidoylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.