Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-n2cccn2)cc1
Yield: 80 %

Procedure:
Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 4-methoxybromobenzene (1.0 mmol). The crude product is purified by flash chromatography on silica gel to provide the desired product (80% GC yield).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([NH2:38])[C:32]=2[CH:31]=[N:30]1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]1[C:37]2[C:32](=[C:33]([NH:38][CH2:6][C:4]([OH:5])([CH2:3][C:2]([C:12]3[C:20]4[O:19][CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)([CH3:11])[CH3:1])[C:7]([F:8])([F:9])[F:10])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[N:30]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: Nc1cccc2c1cnn2-c1ccc(F)cc1F
Product: CC(C)(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1F)C(F)(F)F)c1cccc2c1OCC2

Procedure:
Prepared similarly to Example 1 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and 1-(2,4-difluorophenyl)-1H-indazol-4-amine (Intermediate 4).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27](O)[CH3:28])[CH2:22][CH2:21]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]([O:15][CH:27]([CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1)[CH3:28])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)CN1CCOCC1
Reactant: CSCCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CSCCC(NC(=O)OCc1ccccc1)C(=O)OC(C)CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-4-methylsulfanylbutyric acid (1.13 g; 2.76 mmol), 1-(morpholino)propan-2-ol (0.57 ml; 4 mmol), EDC (0.768 g; 4 mmol), DMAP (0.488 g; 4 mmol) in dichloromethane (5 ml) was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give 1-(morpholinoprop-2-yl 2-(benzyloxycarbonylamino)-4-methylsulfanylbutyrate as a foam. Yield=55%.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([C:16]([F:19])([F:18])[F:17])=[C:10]([CH2:12][CH2:13][CH2:14][OH:15])[N:11]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([O:15][CH2:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=3)[O:8][C:9]=2[C:16]([F:18])([F:19])[F:17])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-c2nc(CCCO)c(C(F)(F)F)o2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc(CCCOS(=O)(=O)c3ccc(C)cc3)c(C(F)(F)F)o2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
3-[2-(p-Tolyl)-5-trifluoromethyloxazol-4-yl]-1-propanol (6.40 g) synthesized according to the method of Kawase et. al. (Chem. Pharm. Bull., 46, 749–756 (1998)) was dissolved in 35 ml of dichloromethane. To the solution were added sequentially 293 mg of 4-(dimethylamino)pyridine, 4.7 ml of triethylamine and 5.13 g of p-toluenesulfonyl chloride, and stirred for 3 hours at room temperature. To the reaction solution was added ethyl acetate, and washed with water, 10% hydrochloric acid and an aqueous solution of saturated aqueous sodium hydrogen carbonate solution sequentially, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 10.08 g of the objective compound as pale brown crystals. M.p. 57–58° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=O.[Sn]>C(O)(=O)C.Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: Cc1ccc2c(c1)C(=O)NC2=O
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CNC2=O
Yield: 50.4 %

Procedure:
Step 1 A mixture of 5-methylisoindoline-1,3-dione (5.00 g, 31.0 mmol) and tin shavings (8.84 g, 74.5 mmol) in acetic acid (30 mL) and concentrated hydrochloric acid (15 mL) was heated at reflux for 3 h. The hot solution was filtered and the residual tin shavings were washed with acetic acid. The filtrate was concentrated and the residue was diluted with DCM (200 mL), and washed with water (20 mL) and brine (20 mL), dried and concentrated. The precipitate which formed during the concentration was collected by filtration and washed with DCM (5 mL) and dried under vacuum to give 5-methylisoindolin-1-one (2.3 g, 50%). 1H NMR (400 MHz, chloroform-d) δ 7.70 (1 H, d, J=7.77 Hz), 7.43 (1 H, s), 7.35 (1 H, d, J=7.77 Hz), 4.46 (2 H, s), 2.48 (3 H, s). Mass spectrum m/z 148.0 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=3[CH:17]=[C:9]12>C(Cl)Cl>[OH:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=3[CH:17]=[C:9]12
Reactant: COc1ccnc2c1cc1n2C(=O)NCC1OC1CCCCO1
Solvent: ClCCl
Product: COc1ccnc2c1cc1n2C(=O)NCC1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 107.2 %

Procedure:
To a solution of 10b (25 mg, 0.08 mmol) in CH2Cl2 (5 ml) 4N aq. HCl (5 ml) was added and the mixture was stirred at room temperature for 45 min. The organic solution was separated and extracted with 4N aq. HCl. The aqueous solution was filtered and evaporated to obtain 6,7,8,9-Tetrahydro-6-hydroxy-4-methoxypyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidin-9-one (20 mg, 95%) as hydrochloride salt as a light orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH2:40][CH2:41][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:3][CH:4]=2)[CH:17]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCCCC3)cc2)c1
Yield: 78 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-piperidin-1-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:17][C:16]1[CH:18]=[CH:19][C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccc(N)c([N+](=O)[O-])c2)c1
Temperature: 85 °C

Procedure:
A stirred solution of 3-cyanophenyl boronic acid (812 mg) and tetrakis(triphenylphosphine) palladium (150 mg) in tetrahydrofuran (4 mL) under at atmosphere of nitrogen was treated with 4-bromo-2-nitroaniline in tetrahydrofuran (10 mL). The reaction mixture was heated at 85° C. for 48 hours, then cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) to give 4′-amino-3′-nitro-biphenyl-3-carbonitrile (224 mg) as a yellow solid. LC-MS (METHOD B): RT=3.21 minutes, 240.3 (M+H)+. (b) 2-nitro-4-pyridine-3-yl-phenylamine
Reaction SMILES: C(C1[CH:9]([C:10]2C=CC(Cl)=CC=2)[NH:8][C:7]([C:17]2[CH:22]=[CH:21]C(OC)=CC=2OCC)=N1)CCC.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47]CN(C)[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]2[CH2:65][CH2:64]CC2)=[CH:31][CH:30]=1>>[CH2:60]([CH:36]1[CH:35]([C:32]2[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=2)[N:39]([C:40]([N:42]2[CH2:47][CH2:10][CH:9]([N:8]3[CH2:7][CH2:17][CH2:22][CH2:21]3)[CH2:44][CH2:43]2)=[O:41])[C:38]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[O:57][CH2:58][CH3:59])=[N:37]1)[CH2:61][CH2:65][CH3:64]
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCCCC1N=C(c2ccc(OC)cc2OCC)NC1c1ccc(Cl)cc1
Product: CCCCC1N=C(c2ccc(OC)cc2OCC)N(C(=O)N2CCC(N3CCCC3)CC2)C1c1ccc(Cl)cc1

Procedure:
[4-Butyl-5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 4-butyl-5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 13) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 567.3106, calculated for C32H44N4O3Cl [(M+H)+]567.3097.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:16][CH2:15]2.[ClH:26].[CH3:27]COCC>CO>[ClH:26].[ClH:26].[CH3:27][O:24][C:23](=[O:25])[CH2:22][CH:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]3[NH:3][CH2:4][CH2:5][CH2:6][N:1]=3)[CH:13]=2)[CH2:18]1
Reactant: CCOCC
Reactant: O=C(O)CC1CCc2cc(OCCCNC3=NCCCN3)ccc2C1
Agent: Cl
Solvent: CO
Product: COC(=O)CC1CCc2cc(OCCCNC3=NCCCN3)ccc2C1
Temperature: 25 °C

Procedure:
To a solution of {6-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-propoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic acid (25 mg) in MeOH (2 mL) was added HCl in MeOH and the solution was heated to reflux for 3 h. The reaction was cooled to room temperature and concentrated under reduced pressure to afford a tan oil. Ether was added, the contents were swirled and the solvent decanted. Lyophilization of the oily residue gave the title compound as a hygroscopic, ivory solid (29 mg). NMR (300 MHz, MeOH-d4) δ6.84 (d, J 8.20 Hz, 1H), 6.61-6.56 (m, 2H), 3.92 (t, J=5.75 Hz, 2H), 3.59 (s, 3H), 3.28-3.21 (m, 5H), 2.72-2.68 (m, 3H), 2.33-2.24 (m, 3H), 2.09-2.06 (m, 1H), 1.92 (t, J=7.09 Hz, 2H), 1.87-1.77 (m, 3H), 1.37-1.19 (m, 2H); MS (+ESI) m/z 360 (M+H)+; Calculated for C20H29N3O3.2 HCl: C, 55.56; H, 7.23; N, 9.72. Found: C, 55.15; H. 7.10; N, 9.88.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][O:19][C:20]=3[N:21]=2)[CH2:7][CH2:6]1)=[O:4]>Cl.C(OCC)(=O)C.C(OCC)(=O)C>[O:19]1[C:20]2[N:21]=[C:11]([N:8]3[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]3)[CH:12]=[CH:13][C:14]=2[CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: COC(=O)N1CCN(c2ccc3c(n2)OCCN(C(=O)OC(C)(C)C)C3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)N1CCN(c2ccc3c(n2)OCCNC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A solution of the compound (0.21 g) obtained in step 2 in a mixture of 4N hydrogen chloride/ethyl acetate (5 mL) and ethyl acetate (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was made basic with aqueous sodium hydroxide solution. The organic layer was washed with brine, and concentrated to give the title compound (0.13 g, 83%) as a white powder.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].CO[C:24]([C@@H:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:25].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl.C(N(CC)CC)C.Cl>CN(C)C=O>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:33]2[C:17](=[O:18])[C:16]([C:11]3[NH:10][C:9]4[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=4[S:13](=[O:15])(=[O:14])[N:12]=3)=[C:24]([OH:25])[CH:26]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]23)=[CH:40][CH:39]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)C3CCCCCC3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.1 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.299 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.5 mL). cis-2-(4-Fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (0.084 g, 0.299 mmol) was added followed by a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.314 mL, 0.314 mmol). The mixture stirred at 25° C. for 1.5 h. Triethylamine (0.122 mL, 0.897 mmol) was added and the mixture stirred at 50° C. for 16 h. Upon cooling, the mixture was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The product was extracted into ethyl acetate (100 mL). The organic layer was filtered to remove the N,N′-dicyclohexylurea precipitate and then further washed with 1.0 M aqueous hydrochloric acid solution (50 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; column 1: 50-70% ethyl acetate in hexanes; column 2: 1-5% methanol in dichloromethane) afforded the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.049 g, 0.087 mmol, 29%), as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.23-1.38 (3H, m), 1.46-1.73 (6H, m), 1.93-2.02 (1H, m), 2.72-2.80 (1H, m), 2.98 (3H, s), 3.03 (1H, s), 4.07 (1H, d, J=14.9 Hz), 5.01 (1H, d, J=15.5 Hz), 7.12 (2H, t, J=9.1 Hz), 7.18-7.25 (1H, m), 7.33-7.37 (3H, m), 7.43 (1H, s), 7.51-7.56 (1H, m), 9.81 (1H, s). LC-MS (ESI) calcd for C25H27FN4O6S2 562.14, found 563.2 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].I[CH:42]1[CH2:46][CH2:45][O:44][CH2:43]1>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:42]3[CH2:46][CH2:45][O:44][CH2:43]3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: IC1CCOC1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCOC3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.7 %

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 8 mg, 0.039 mmol) in DMF (1.0 ml) was added K2CO3 (13 mg, 0.092 mmol) and catalytic amount of NaOH, 3-iodotetrahydrofuran (Compound 29, 120 mg, crude). The reaction was stirred at room temperature for 2 days, and purified by a short silica gel column to yield the title compound (8 mg, 86%).
Reaction SMILES: [CH3:1][C:2](=[CH2:21])[C:3](=[O:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[OH:22]O.C(#N)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CO.O>[CH3:21][C@:2]1([C:3](=[O:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:5][CH:6]2[CH2:10][CH2:9][NH:8][C:7]2=[O:11])[CH2:1][O:22]1
Reactant: C=C(C)C(=O)[C@H](CC1CCNC1=O)NC(=O)OC(C)(C)C
Reactant: OO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: N#Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCNC1=O)C(=O)[C@@]1(C)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of tert-butyl ((2S)-4-methyl-3-oxo-1-(2-oxopyrrolidin-3-yl)pent-4-en-2-yl)carbamate (200 mg, 0.67 mmol) in methanol (10 mL) at 0° C. was added 30% H2O2 (1.5 g, 1.4 mmol) followed by addition of benzonitrile (520 mg, 5.00 mmol) and DIPEA (0.87 mL, 5.0 mmol). The reaction mixture was stirred for 8 h at ambient temperature and then diluted with water (25 mL). The resulting mixture was extracted with EtOAc (50 mL×2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=2:1) to afford tert-butyl ((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-(-2-oxopyrrolidin-3-yl) propan-2-yl)carbamate (95 mg, 45% yield) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH2:15]([NH2:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:15]([NH:25][C:12]([CH:10]1[CH2:9][S:8][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:11]1)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNC(=O)C1CSC(c2cccnc2)N1

Procedure:
2-(3-Pyridyl)thiazolidine-4-carboxylic acid and decylamine were used as the starting materials and treated the same manner as in Example 39 to give N-decyl-2-(3-pyridyl)thiazolidine-4-carboxamide. Yield, 80%. Melting point 88° C.
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[C:1]3[OH:12])=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Oc1ccc2cccc(O)c2c1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc2ccc(N3CCN(Cc4ccccc4)CC3)cc12

Procedure:
A suspension of 25 g (0.156 mol) of naphthalene-1,7-diol, 35 ml (0.202 mol) of 1-benzyl-piperazine and 60 g (0.316 mol) of sodium disulphite in 250 ml of water is refluxed for four days under nitrogen. After cooling, the precipitate is filtered off, washed with water and dried in a drying cupboard.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15]Cl>>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: O=C1Nc2ccccc2C1=O
Product: O=C1C(=O)N(Cc2c(Cl)cccc2Cl)c2ccccc21

Procedure:
N-(2,6-dichlorobenzyl)-isatin was prepared by the method of Example 1, Step A from isatin and 2,6-dichlorobenzyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][C:3]1=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20]>C(=S)=S>[C:19]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][C:5]2([CH3:12])[CH3:13])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CN1C(=O)CC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Temperature: 0 °C
Yield: 74.2 %

Procedure:
21.5 g of 3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 43 g of carbon disulphide and the solution was treated with 85 g of aluminium chloride. 17.8 g of acetyl chloride were slowly added dropwise thereto while cooling with ice and stirring vigorously. The mixture was subsequently heated at reflux for 1.5 hours, cooled and treated cautiously with ice-water. The resulting mixture was extracted three times with ethyl acetate and the ethyl acetate extracts were washed with water, dried and evaporated. The thus-obtained brownish oil was filtered over silica gel [eluting agent: hexane/ethyl acetate (2:1)] and then recrystallized from hexane/ethyl acetate. There were obtained 19.5 g of 6-acetyl-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone in the form of colourless crystals of melting point 75°-77° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](I)[C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:11](=[O:18])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH2:12].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([NH:12][C:11](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: O=Cc1cnc(Br)cc1I
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(Br)ncc1C=O
Temperature: 90 °C
Yield: 29.9 %

Procedure:
A mixture of 6-bromo-4-iodonicotinaldehyde (50 mg, 0.2 mmol), tert-butyl carbamate (28 mg, 0.24 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg, 0.03 mmol), palladium acetate (5 mg, 0.02 mmol), and cesium carbonate (100 mg, 0.32 mmol) in 1,4-dioxane (1 mL) was heated at 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a white solid (18 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 9.93 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 1.55 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>O1CCOCC1>[CH2:9]([O:11][C:12]([NH:14][C:15]([NH:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=1)=[S:16])=[O:13])[CH3:10]
Reactant: Nc1cc(Br)ccn1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 4-bromopyridin-2-amine (10.4 g, 60.1 mmol) in dioxane (242 ml) is added ethoxycarbonyl isothiocyanate (7.88 g, 6.8 ml, 60.1 mmol) at 25° C. The resulting mixture is stirred for 4 hours at 25° C. The solvent is evaporated, the solid yellow residue diluted with ethyl acetate and washed with water and brine. The organic layer is separated, dried over magnesium sulfate and the solvent is removed in vacuo affording 1-ethoxycarbonyl-3-(4-bromo-pyridin-2-yl)-thiourea (17.37 g, 95%) as a yellow solid. mp.: 107-110° C. MS: m/z=304.0, 305.9 (M+H+).