Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=1[O:25][CH3:26])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46]([NH2:49])(=[O:48])=[O:47]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:49][S:46]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH3:39])(=[O:47])=[O:48])=[O:22])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (125.9 g) in tetrahydrofuran (3.0 L, distilled from sodium benzophenone ketyl) (prepared by heating at 50° C. until dissolution was complete, followed by cooling to room temperature with an ice-water bath) was added 4-dimethylaminopyridine (56.6 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (102.4 g), and the mixture was stirred one hour. To the mixture was added 2-methylbenzenesulfonamide (67.1 g), and the reaction mixture was stirred about 3 days (for convenience). The reaction mixture was diluted with ethyl acetate (2.0 L) and washed with 1N hydrochloric acid (twice) and brine (3 times, until neutral), and the aqueous extracts were back washed with ethyl acetate. The combined ethyl acetate solution was dried (MgSO4), and partially evaporated to give a slurry of solid in ethyl acetate (about 0.5 L) which was refrigerated overnight. Collection of the solid afforded the crude product (158.5 g, 88%, essentially pure by TLC) as a light pink solid. Recrystallization by dissolution in hot tetrahydrofuran (1.5 L), filtration while hot, dilution with ethyl acetate (2.0 L), and boiling down to a final volume of about 2.5 L afforded a first crop of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (105.5 g, 59%) as a white solid; mp 211°-213° C.; NMR (250 MHz, DMSO-d6): 2.60 (s, 3H, ArCH3), 3.76 (s, 3H, NCH3), 3.82 (s, 3H, CO2CH3), 3.92 (s, 3H, ArOCH3), 4.04 (s, 2H, ArCH2Ar'), 7.15 (d, 1H), 7.22 (s, 1H), 7.38-7.58 (m, 6H), 7.75 (dd, 1H), 8.03 (dd, 1H), 8.17 (d, 1H). (Two additional crops (35.5 g, 20%) and crude product (39.5 g) from concentration of the mother liquors were also obtained.)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:36][N:37]=[CH:38]S(O)(=O)=O>CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([O:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH:38]=[N:37][NH2:36])[CH2:2][CH2:3]2)[CH:10]=1)(=[O:18])=[O:19]
Reactant: Cc1cc(OCC2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: NN=CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCC2CCN(C=NN)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Yield: 36.3 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-4-yl)methoxy]-5-methylphenyl ester (396 mg, 1.0 mmol), as prepared in the preceding step, in DMF (10 mL), N,N-diisopropylethylamine (0.5 mL) and aminoiminomethanesulfonic acid (248 mg, 2.0 mmol) was stirred at room temperature overnight. The DMF was removed in vacuo and the residue was purified by flash column chromatography (90:10 methylene chloride:methanol saturated with NH3) to give the title compound as a white foam (159 mg, 36%). 1H-NMR (300 MHz, CDCl3) δ 1.45 (m, 2H), 1.92 (m, 3H), 2.21 (s, 3H), 3.07 (t, 2H), 3.69 (d, 2H), 4.09 (d, 2H), 6.46 (d, 1H), 6.49 (s, 1H), 6.56 (s, 1H), 7.28 (s, 3H), 7.39 (t, 1H), 7.62 (m, 2H), 7.95 (dd, IH). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H24N3O4SCl: 438.1 (M+H), 460.1 (M+Na), Found: 438.3, 460.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37]2)(=[O:33])=[O:32].N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:17]\[C:14]1[NH:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=2[C:15]=1[CH3:16])(=[O:32])=[O:33]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 79.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (60 mg, 0.21 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (67 mg, 0.19 mmol) were dissolved in 3 ml of ethanol, and added with 52 μl of piperidine the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-ylidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydro pyrrolo[3,2-c]azepin-4(1H)-one 70 (95 mg, yield 79%) as an orange solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:25])[C:9]1=[O:26])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][CH:35]=1>CN(C=O)C.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:25])[C:9]1=[O:26])(=[O:3])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(Cl)c3)cc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1c(=O)c2c(cc(-c3cccc(Cl)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 85 °C
Yield: 50 %

Procedure:
To a mixture of 3-(6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (60 mg, 0.16 mmol), K2CO3 (110 mg, 0.80 mmol) in DMF (2 ml) was added 1-chloro-4-(chloromethyl)benzene (51 mg, 0.32 mmol). The reaction was heated at 85° C. for 2 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (40 mg, 50% yield) as an oil. LCMS: MH+ 500 and TR=1.847 min. Used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:26])=[CH:23][C:22]=1[O:36][CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:26])=[CH:23][C:22]=3[O:36][CH3:37])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NCCCN(C)C)ccc1N
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Yield: 53.6 %

Procedure:
A mixture of 0.07 g (0.24 mmole) of 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292), 0.067 g (0.26 mmole) of 4-amino-N-(3-dimethylamino-propyl)-3-methoxy-benzamide, 0.069 g (0.36 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-0:100) gave 0.065 g of give 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-296) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][C:4](=C)[CH2:3]1.O.CC1C=CC=C(C)N=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:29])C>C1COCC1.O=[Os](=O)(=O)=O>[CH3:1][C:2]1([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][C:4](=[O:29])[CH2:3]1
Reactant: C=C1CC(C)(NC(=O)OCc2ccccc2)C1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CC1(NC(=O)OCc2ccccc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Crude benzyl (1-methyl-3-methylidenecyclobutyl)carbamate (20.6 mmol) was dissolved in THF (10 mL), then water (0.100 mL), 2,6-dimethylpyridine (0.400 mL, 3.4 mmol), OsO4 (2.5% wt in 2-methyl-2-propanol, 0.340 mL, 0.027 mmol), and PhI(OAc)2 (1.0 g, 3.07 mmol) were added and the reaction mixture was stirred at rt for 3 hrs. The reaction was quenched with sat. sodium thiosulfate (20 mL) and extracted with EtOAc (two×30 mL). The combined organics were washed with sat. aqueous copper sulfate (three×50 mL), dried over MgSO4 and concentrated. The residue was purified via flash chromatography (eluting with 10%-20% EtOAc/heptanes) to give the title compound (558 mg, 12% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.31-7.47 (m, 5H) 5.12 (s, 3H) 3.36-3.64 (m, 2H) 2.96-3.12 (m, 2H) 1.63 (s, 3H)); m/z (APCI+) for C13H15NO3 234.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[C:11]([CH2:18]N(CC)CC)[C:10]=3[OH:24])[N:8]=[C:4]2[CH:3]=1.[Cl:27][C:28]1[CH:46]=[CH:45][C:31]2=[N:32][N:33]([C:35]3[CH:40]=[C:39]([CH2:41][CH2:42][OH:43])[CH:38]=[CH:37][C:36]=3[OH:44])[N:34]=[C:30]2[CH:29]=1.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:18]([C:37]1[CH:38]=[C:39]([CH2:41][CH2:42][OH:43])[CH:40]=[C:35]([N:33]2[N:32]=[C:31]3[CH:45]=[CH:46][C:28]([Cl:27])=[CH:29][C:30]3=[N:34]2)[C:36]=1[OH:44])[C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][OH:17])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:24]
Reactant: OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reactant: CCN(CC)Cc1cc(CCO)cc(-n2nc3ccc(Cl)cc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: OCCc1cc(Cc2cc(CCO)cc(-n3nc4ccc(Cl)cc4n3)c2O)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Yield: 55 %

Procedure:
In 100 ml of xylene were dissolved 37.0 g (93.9 mmols) of crude 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 10 and 27.2 g (93.9 mmols) of the purified product of 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol synthesized in Example 7. 5 ml of methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. The subsequent treatment was carried out in the same manner as in Example 12, giving 30.8 g of 2,2'-methylenebis[6-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol] as pale yellow crystals (yield 55.0%, purity 99.0%).
Reaction SMILES: [CH3:1][CH:2]([C:4]([C:6]1[C:11]([OH:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[OH:14])=[O:5])[CH3:3].O.[B].[CH3:17][C:18]([CH3:22])=[CH:19][CH2:20]O>O1CCOCC1.CCOCC>[CH3:3][CH:2]([C:4]([C:6]1[C:7]([OH:14])=[CH:8][C:9]([OH:13])=[C:10]([CH2:20][CH:19]=[C:18]([CH3:22])[CH3:17])[C:11]=1[OH:12])=[O:5])[CH3:1].[CH3:17][C:18]([CH3:22])=[CH:19][CH2:20][C:10]1([CH2:6][CH:4]=[C:2]([CH3:3])[CH3:1])[C:9]([OH:13])=[CH:8][C:7]([OH:14])=[C:6]([C:4](=[O:5])[CH:2]([CH3:1])[CH3:3])[C:11]1=[O:12]
Reactant: CC(C)=CCO
Reactant: CC(C)C(=O)c1c(O)cc(O)cc1O
Agent: [B]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)=CCC1(CC=C(C)C)C(=O)C(C(=O)C(C)C)=C(O)C=C1O
Product: CC(C)=CCc1c(O)cc(O)c(C(=O)C(C)C)c1O
Reaction time: 4 h

Procedure:
Under an atmosphere of nitrogen, 981 mg (5.00 mmol) of (2,4,6-trihydroxyphenyl) (2-propyl) ketone (4) was dissolved in 10.0 ml of dioxane, cooled with cold water at about 10° C., and stirred. Into the stirred solution, 554 ml (639 mg, 4.50 mmol, 0.900 equivalent) of boron trifluorideether complex was added by the use of a microsyringe. The resultant mixture was further stirred for 15 minutes and then a dioxane (9 ml) solution of 861 mg of 3-methyl-2-butenol was slowly added dropwise. After four hours, the reaction solution was poured into 100 ml of ether. The ether layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over sodium sulfate. The produced solution was distilled under a reduced pressure to remove the solvent and obtain 1.76 g of a crude product in the form of a red viscous oily substance. The crude product was treated by silica gel column chromatography (50 g of Wako Gel C-300, and eluted sequentially with 200 ml each of petroleum ether:ether at varying ratios=9:1, 7:3, and 5:5) to isolate 417 mg of {3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-propyl) ketone (23) and 338 mg of 2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(2-methyl-1-oxopropyl) cyclohexa-3,5-dienone (13).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].N1CCCCC1>C(O)C>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:26]2/[C:25](=[O:27])[NH:24][C:23](=[O:28])[S:22]/2)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cn(-c3ccccc3)nc2OCc2ccccc2)S1
Yield: 87.8 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (2.50 g), 1,3-thiazolidine-2,4-dione (1.05 g), piperidine (0.15 g) and ethanol (80 mL) was heated under reflux for 1 hr. The reaction mixture was concentrated, and the obtained crystals were washed with ethanol to give (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-1,3-thiazolidine-2,4-dione as yellow crystals (2.97 g, yield 87%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: >300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([OH:16])=O)[CH3:2].CCN(C(C)C)C(C)C.Cl.[CH2:27]1[C:39]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:32]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:31]=2[CH2:30][CH2:29][NH:28]1>C1COCC1.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([N:28]1[CH2:29][CH2:30][C:31]2[N:32]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39]=2[CH2:27]1)=[O:16])[CH3:2]
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)c1c(OCC)ccc3ccccc13)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
Step a): To a solution of 2-ethoxynaphthoic acid (22 mg, 0.1 mmol), N′,N′,N′,N′tetramethyl-O-(7-azabenzotriazole-1-yl)-uronium-hexafluorophosphate (38 mg, 0.1 mmol) and DIEA (51 μl, 0.3 mmol) in THF/DMF (4:1, 1 ml) is added Intermediate 1 (29 mg, 0.1 mmol) in one portion and the reaction mixture is stirred at rt overnight. Then, the solvent is evaporated and the residue purified by silica gel column chromatography (6% MeOH in CH2Cl2/aqueous NH4OH 9:1) affording ethyl [2-(2-ethoxy-naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl]-acetate (43 mg) as a glassy brown solid in 93% yield.
Reaction SMILES: [Na+].[CH:2]1([N:5]2[C:9]([C:10]([O-:12])=O)=[C:8]([C:13]3[CH:14]=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=3)[N:7]=[C:6]2[C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)[CH2:4][CH2:3]1.C(OC(=O)CN(C1CC1)C(=O)C1C=CC=C([O:45][C:46]([F:49])([F:48])[F:47])C=1)C.[N:55]1([CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH2:59][CH2:58][CH2:57][CH2:56]1>>[CH:2]1([N:5]2[C:9]([C:10]([N:63]3[CH2:64][CH2:65][CH:60]([N:55]4[CH2:59][CH2:58][CH2:57][CH2:56]4)[CH2:61][CH2:62]3)=[O:12])=[C:8]([C:13]3[CH:14]=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=3)[N:7]=[C:6]2[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([O:45][C:46]([F:49])([F:48])[F:47])[CH:26]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CN(C(=O)c1cccc(OC(F)(F)F)c1)C1CC1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CSc1ncc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)[O-])cn1
Agent: [Na+]
Product: CSc1ncc(-c2nc(-c3cccc(OC(F)(F)F)c3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1

Procedure:
In analogy to the procedure described for example 2, the title compound has been obtained by coupling of 3-cyclopropyl-5-(2-methylsulfanyl-pyrimidin-5-yl)-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid sodium salt (prepared in analogy to the sequence described for the preparation of intermediate 10, but using [cyclopropyl-(3-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester instead of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester in step 10A) with 4-pyrrolidin-1-yl-piperidine to give the title compound as yellow amorphous solid. MS: 573.2 (MH+).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[NH2:24][C:25]([CH3:37])([CH3:36])[CH2:26][NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(#N)C>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][CH2:26][C:25]([NH:24][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:3]=2[CH3:23])([CH3:36])[CH3:37])=[CH:35][CH:34]=1)#[N:33]
Reactant: COC(=O)c1nc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CC(C)(N)CNc1ccc(C#N)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(NC(C)(C)CNc2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 50 °C
Reaction time: 9 h
Yield: 23.1 %

Procedure:
In a bomb tube of stainless steel (Parr) fitted with an internal cylindrical glass vessel and magnetic stirrer, methyl 6-iodo-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (SM1, 1447 mg, 3.3 mmol), 4-(2-amino-2-methylpropylamino)benzonitrile (750 mg, 4.0 mmol), triethylamine (3.2 mL, 23 mmol) and acetonitrile (35 mL) were mixed. The mixture was purged with argon for 10 minutes. After adding bis(tributylphosphine)palladium (120 mg, 0.23 mmol), the bomb tube was sealed, evacuated and back-filled with carbon monoxide five consecutive times. The contents of the bomb tube were stirred under carbon monoxide (6.5 bar) at 50° C. for 9 h. LC-MS indicated about 50% conversion to desired product and unreacted SM. The dark red-brown solution was concentrated to dryness, dissolved in ethyl acetate (200 mL), washed with water (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated with silica to dryness. Flash chromatography on silica with ethyl acetate/n-heptane (1:3 and 1:1) as eluents gave methyl 6-(1-(4-cyanophenylamino)-2-methylpropan-2-ylamino)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (0.38 g, 22%) as a yellow solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O.[NH3:16].O.Cl>O1CCCC1>[F:14][C:8]1[CH:7]=[CH:6][C:5]([S:2](=[O:4])(=[O:3])[NH2:16])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: N
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1

Procedure:
A solution of 5-chlorosulfonyl-2-fluorobenzoic acid (7.0 g) and 28% ammonia water (20 ml) in tetrahydrofuran (70 ml) is stirred at 0° C. for 1.5 hours. The reaction mixture is poured into water (200 ml), acidified with concentrated hydrochloric acid, and extracted with chloroform. The extracts are washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is washed with diethyl ether to give the title compound (5.0 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:21]=1)[CH2:16][C:17]([OH:19])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:47]([NH:49][NH2:50])=[O:48]>C(OCC)(=O)C>[CH:29]1([O:28][C:22]2[CH:21]=[C:20]([CH:15]([N:8]3[C:7](=[O:34])[C:6]4[C:10](=[CH:11][CH:12]=[CH:13][C:5]=4[NH:4][C:1](=[O:3])[CH3:2])[C:9]3=[O:14])[CH2:16][C:17]3[O:18][CH:47]=[N:49][N:50]=3)[CH:25]=[CH:24][C:23]=2[O:26][CH3:27])[CH2:30][CH2:31][CH2:32][CH2:33]1.[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([NH:50][N:49]=[C:47]=[O:48])=[O:19])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(CC(=O)NN=C=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Product: COc1ccc(C(Cc2nnco2)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1

Procedure:
N-[2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]-1,3-dioxoisoindolin-4-yl]acetamide was prepared by the procedure of Example 1. Reaction of 3-[4-(acetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.3 mmol), carbonyidiimidazole (0.77 g, 4.8 mmol) and formic hydrazide (314 mg, 4.7 mmol) in ethyl acetate (20 mL) gave crude 3-[4-(acetylamino)-1,3-dioxoisoindolin-2-yl]-N-carbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)propanamide, which was then reacted with phosphorus oxychloride (1.0 mL, 10.7 mmol) in acetonitrile (15 mL). The product was isolated as a yellow solid (555 mg, 28% overall yield): mp, 115.0-117.0° C.; 1H NMR (CDCl3) δ 1.62-1.97 (m, 8H, C5H8), 2.27 (s, 3H, CH3), 3.76 (dd, J=5.6, 15.9 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.40 (dd, J=10.7, 15.8 Hz, 1H, CHH), 4.76-4.82 (m, 1H, OCH), 5.78 (dd, J=5.5, 10.7 Hz, 1H, NCH), 6.84 (d, J=8.1 Hz, 1H, Ar), 7.09-7.15 (m, 2H, Ar), 7.47 (d, J=7.2 Hz, 1H, Ar), 7.65 (t, J=7.5 Hz, 1H, Ar), 8.32 (s, 1H, CH), 8.76 (d, J=8.4 Hz, 1H, Ar), 9.48 (s, 1H, NH); 13C NMR (CDCl3) δ 23.99, 24.85, 27.58, 32.68, 51.71, 55.95, 80.53, 111.75, 114.46, 115.10, 118.03, 119.88, 124.82, 129.77, 130.95, 135.94, 137.48, 147.77, 150.21, 152.99, 163.85, 167.36, 169.07, 167.71; Anal Calcd for C26H26N4O6+0.1 hexane: C, 64.01; H, 5.53; N, 11.22. Found: C, 64.01; H, 5.58; N, 10.97. (HNMR showed the product contained 10% of hexane).