Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([O:32][CH2:33][C:34]#[N:35])[CH:26]=[CH:25]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]3[NH:38][N:37]=[N:36][N:35]=3)[CH:28]=2)[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(Cc2ccccc2)c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 97.5 °C
Yield: 102.5 %

Procedure:
To a stirred solution of the {[6-(1-benzyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (87.0 g, 189.71 mmol) in DMF (900 mL) under N2 was added NaN3 (61.665 g, 948.54 mmol) and NH4Cl (50.737 g, 948.54 mmol). The reaction was heated between 95-100° C. for 1.33 h then cooled. The reaction mixture was rotovap'd to a residue and the residue partitioned between EtOAc (2000 mL) and 1 N HCl (600 mL). The layers were shaken, separated, and the organic layer washed with 1 N HCl (2×300 mL), H2O (3×300 mL), and brine (2×300 mL), dried over Na2SO4, filtered, rotovap'd and triturated with hexane to give an off-white solid (97.5 g). The product was purified by refluxing the solid in diethyl ether (2000 mL), concentrating to about a liter and cooling. The solids were collected and dried in vacuo to give the product as a white solid (77.4 g, 154.3 mmol, 81%) with dec. 111-114° C.; 1H NMR (DMSO-d6) δ 0.72 (t, J=6.9 Hz, 3H) 1.10-1.20 (m, 4H), 1.50-1.60 (m, 2H), 2.67 (t, J=7.8 Hz, 2H), 5.30 (s, 2H), 5.62 (s, 2H), 6.81 (d, J=7.3 Hz, 2H), 7.02-7.20 (m, 5H), 7.30 (dd, J=2.4, 9.0 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.44 (dd, J=1.5, 8.2 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.84-7.90 (m, 3H) 16.9 (s, 1H); IR (solid) 2920, 2850, 1610, 1390, 1200, 860, and 750, cm1; mass spectrum [ESI], m/z 502 (M+H)+;
Reaction SMILES: O[C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][F:26])[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:14]([CH:11]1[CH2:10][CH2:9][CH:8]([CH:5]2[CH2:6][CH2:7][C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH2:24][CH2:25][F:26])=[CH:3][CH2:4]2)[CH2:13][CH2:12]1)[CH2:15][CH3:16]
Reactant: CCCC1CCC(C2CCC(O)(c3ccccc3OCCF)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(C2CC=C(c3ccccc3OCCF)CC2)CC1

Procedure:
The crude 1-hydroxy-4-(4-propylcyclohexyl)cyclohexyl-2-fluoroethoxybenzene obtained in the first step was dissolved in toluene. p-Toluene sulfonic acid monohydrate was added and refluxed while heating for two hours under dewatering by using a Dean-Stark apparatus. The reaction mixture was poured into an aqueous saturated sodium hydrogen carbonate solution and extracted with toluene. The organic layer was washed with water and then with an aqueous saturated sodium chloride solution successively and, after dying over anhydrous magnesium sulfate, concentrated under a reduced pressure. The residue was purified by silica gel column chromatography to obtain 4-(4-propylcyclohexyl)cyclohexenyl-2-fluoroethoxybenzene.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CN1C=CN=C1.CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCc1ccc(C)cc1)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CON=C(C(=O)O)c2csc(N)n2)cc1
Yield: 93.7 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)acetate (syn isomer, 4.00 g.), 1 N sodium hydroxide solution (19.5 ml.), 1-methylimidazole (214 mg.), methanol (40 ml.) and tetrahydrofuran (25 ml.) were treated in a similar manner that of Example P-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)acetic acid (syn isomer, 3.42 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3ccc(Cl)cc3nc2OC)CC1
Yield: 92 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 92%). 1H NMR (300 MHz, CDCl3): δ 3.17 (s, 4H), 3.82 (s, 4H), 3.89 (s, 3H), 4.15 (s, 3H), 6.89-6.97 (m, 3H), 7.06 (m, 1H), 7.45 (m, 1H), 7.75 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:42]1([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:54][C:51]1[CH:50]=[CH:49][C:48]([N:42]2[CH2:47][CH2:46][N:45]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:13]([F:14])([F:15])[F:16])=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:44][CH2:43]2)=[CH:53][CH:52]=1
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 58.7 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (467 mg, 1.08 mmol, 59%) was obtained.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]3[N:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:27][N:26]=3)=S)[CH2:19][CH2:18]1)(=[O:16])=[O:15])=[CH:8]2.O.[NH2:38][NH2:39]>[Hg](Cl)Cl.C(Cl)Cl>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[N:38][NH2:39])[C:25]3[N:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:27][N:26]=3)[CH2:19][CH2:18]1)(=[O:16])=[O:15])=[CH:8]2
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCN(C(=S)c2ncc(-c3ccncc3)cn2)CC1
Reactant: NN
Agent: Cl[Hg]Cl
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: NN=C(c1ncc(-c2ccncc2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6899.4 %

Procedure:
In a mixed solvent of ethanol (100 ml) and methylene chloride (100 ml) was suspended 1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]thiocarbonyl]piperazine (499 mg) at room temperature, followed by the successive addition of hydrazine monohydrate (146 μg) and mercury (II) chloride (272 mg). The resulting mixture was stirred at room temperature for 4 hours. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column (8% methanol—methylene chloride). Methylene chloride was added and the resulting mixture was concentrated. Yellow crystals thus precipitated were collected by filtration and dried, whereby the title compound (100 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=[C:3]1[C:12]([OH:14])=O.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:12]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][N:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1n[nH]c2ccccc2c1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: O=C(NCc1ccc(Cl)cc1)c1n[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.2 %

Procedure:
4-Oxo-1,4-dihydro-3-cinnolinecarboxylic acid (0.10 g, 0.53 mmol) is dissolved in 5 mL DMF. To this is added 4-chlorobenzylamine (0.07 ML, 0.58 mmol) and the reaction mixture is stirred at room temperature for 5 min. EDC (0.11 g, 0.57 mmol) and HOBt (0.08 g, 0.56 mmol) are added and the reaction is stirred at room temperature over 2 days. The mixture is poured into 30 mL H2O. A brown precipitate formed which is filtered. The crude product is triturated with hot EtOAc, filtered and dried to yield 0.012 g (7%) of the desired product. Physical characteristics are as follows: m.p. 269-271° C.; 1H NMR (300 MHz, DMSO) δ 14.2, 10.0, 8.17, 7.87, 7.74, 7.56, 7.38, 4.53; MS (fab) m/z 314 (M+H)+, 316, 315, 299, 298, 297, 127, 125, 123, 58.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[N:6][CH:7]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[N:4]=[CH:3][C:2]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=3)=[CH:7][N:6]=2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1ccc(Nc2ncc(Br)cn2)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27 (9.7 mmol) in 1,4-dioxane (29 mL) is added 4-(trifluoromethoxy)phenylboronic acid (10.7 mmol), Na2CO3 (29.2 mmol of 1.8 M aq. solution) and Pd(PPh3)4 (1.46 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 100° C. for 12 h. The reaction mixture is diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The organic layer is separated, dried over Na2SO4 and concentrated. Purification by preparative HPLC (ACN gradient 10-70%) affords N-(4-methyl-3-nitrophenyl)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine 28b. MS (m/z) (M+1)+: 390.1.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCCCCOc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCCCCCCCCOc1ccccc1
Reaction time: 8 h

Procedure:
250 mg of 11-phenoxy undecanoic acid (commercial) is mixed with 2 ml of pure thionyl chloride and the whole is left overnight at ambient temperature. In this way 265 mg of expected product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[OH-].[Na+].[CH2:12](Cl)Cl>C(OCC)(=O)C>[CH2:12]1[O:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[CH:3][C:4]=2[O:9]1
Reactant: Cc1ccc(O)c(O)c1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)OCO2
Temperature: 100 °C
Yield: 71.9 %

Procedure:
A mixture of 4-methylcatechol (26.0 g, 209.4 mmol) and NaOH (18.4 g, 461.0 mmol) in CH2Cl2 (40.0 mL) was heated to 100° C. under nitrogen for 2 hours. The solution was allowed to cool to ambient temperature and diluted with ethyl acetate (500 mL). The mixture was washed with NaHCO3 (200 mL) and H2O (2×200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude oil. Flash chromatography eluting with hexane (100%) gradient to ether/hexane (1:1) afforded the title intermediate as a colorless oil 20.5 g (71.9%).
Reaction SMILES: CN(C)C(=O)C.[CH2:7]([N:9]([CH2:33][CH3:34])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([S:29](O)(=[O:31])=[O:30])[CH:19]=2)=[CH:12][CH:11]=1)[CH3:8].P(Cl)(Cl)([Cl:37])=O>C(#N)C>[CH2:7]([N:9]([CH2:33][CH3:34])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([S:29]([Cl:37])(=[O:31])=[O:30])[CH:19]=2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCN(CC)c1ccc(N=Nc2ccc(OCCOC)c(S(=O)(=O)O)c2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CCN(CC)c1ccc(N=Nc2ccc(OCCOC)c(S(=O)(=O)Cl)c2)cc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
10 ml of N,N-dimethylacetoamide was added dropwise to a mixture of 13 g of N,N-diethyl-4-[4-(2-methoxyethoxy)-3-sulfophenylazo]-aniline prepared in Step (1) described above, 100 ml of acetonitrile and 13 ml of phosphorus oxychloride while the reaction mixture was maintained at a temperature of 30° C. or lower. After completion of the addition, the mixture was allowed to stand with stirring over a period of 3 hours and then, it was poured little by little into 500 ml of ice water. The crystals thus precipitated were recovered by filtration, washed with 200 ml of water and air-dried. Yield 11.0 g, Melting Point 103°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([CH2:19][OH:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:21]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>N1C=CC=CC=1>[CH3:22][S:23]([O:20][CH2:19][CH:17]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:21]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:18]1)(=[O:25])=[O:24]
Reactant: OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methanol (1.00 g, 3.29 mmol) in dry pyridine (10 mL) at room temperature was added dropwise MsCl (1.23 g, 10.74 mmol) at 0° C. Then the reaction mixture was stirred at room temperature for 2 hours under N2 protection. The reaction was poured into water and filtered. The filter cake was washed with water and dried to provide (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl methanesulfonate (1.20 g, yield: 90.1%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.37˜7.51 (m, 2H), 7.28˜7.33 (m, 2H), 7.18˜7.24 (d, J=8.4 Hz, 1H), 6.9-6.98 (m, 1H), 6.65˜6.72 (m, 1H), 4.46˜4.53 (m, 1H), 4.31˜4.38 (m, 1H), 2.90 (s, 3H). MS (M+H)+: 383.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].S(OCCC)(O[CH2:32][CH2:33][CH3:34])(=O)=O.CO>C1COCC1>[C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:26][CH2:32][CH2:33][CH3:34])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCCOS(=O)(=O)OCCC
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2
Reaction time: 0.17 h

Procedure:
130 mg (0.35 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in THF (8 ml), and 0.39 ml (0.39 mmol) of N′″-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane) is added. Then 68 μl (0.41 mmol) of di-n-propyl sulfate are added to the dark red solution. The decolorized solution is stirred for 10 min, then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 63 mg (43% of theory) of the title compound as a white solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:29]2[CH:34]=[CH:33][C:32]([O:35]CC3C=CC=CC=3)=[CH:31][CH:30]=2)=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21][Cl:22])=[CH:14][CH:13]=1)C1C=CC=CC=1.C(OCCOC1C=CC(/C(/C2C=CC=CC=2)=C(\C2C=CC=CC=2)/CCCl)=CC=1)C1C=CC=CC=1>>[Cl:22][CH2:21][CH2:20]/[C:19](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:18](\[C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)/[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=1
Reactant: ClCCC(=C(c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: ClCC/C(=C(\c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1
Product: OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccc(O)cc2)cc1

Procedure:
1-[4-(2-Benzyloxyethoxy)-phenyl]-1-(4-benzyloxyphenyl)-4-chloro-2-phenylbut-1-ene (1.0 g, 1.74 mmol) was debenzylated by the same method as Z-1-[4-(2-benzyloxyethoxy)-phenyl]-4-chloro-1,2-diphenyl-but-1-ene described in example 3. The residue was crystallised from the mixture of ethanol and water (1:1). Yield 0.3 g.
Reaction SMILES: B(Br)(Br)Br.CSC.[C:8]([CH2:11][NH:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3([C:30]4[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=4)[CH2:29][CH2:28]3)=[O:26])=[CH:20][CH:19]=2)[CH2:14]1)(=[O:10])[CH3:9].O>ClCCl>[C:8]([CH2:11][NH:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)=[O:26])=[CH:22][CH:23]=2)[CH2:14]1)(=[O:10])[CH3:9]
Reactant: COc1ccc(C2(C(=O)Nc3ccc(N4CCC(NCC(C)=O)C4)cc3)CC2)cc1
Agent: BrB(Br)Br
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CC(=O)CNC1CCN(c2ccc(NC(=O)C3(c4ccc(O)cc4)CC3)cc2)C1

Procedure:
Boron tribromide-dimethyl sulfide (460 mg) was added to a solution of 1-(4-methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (540 mg) in dichloromethane (5.5 ml) at 0° C. After a reaction time of 12 hours at room temperature, water was added to the mixture, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, concentrated and purified by chromatography (silica gel, toluene/ethanol/ethyl acetate 8:1:1 with addition of 0.1% triethylamine). This resulted in the product with the molecular weight of 393.49 (C23H27N3O3); MS(ESI): 394 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][CH:22]([CH3:26])[C:23](Cl)=[O:24].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:23](=[O:24])[CH:22]([CH3:26])[CH3:21])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)C(C)C)sc2-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 82.2 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.53 mmol) in N,N-dimethylacetamide (20 mL) was added 2-methylpropionyl chloride (0.20 g, 1.91 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.52 g, yield 83%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:9][C:7]=1[NH2:8].O.O.[Sn](Cl)Cl>O.Cl>[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:9][C:7]=1[NH:8][NH2:1]
Reactant: CC(C)Oc1cc(N)c(Cl)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(NN)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution of 15.8 g (0.23 mole) of sodium nitrite in 100 mL of water was added to a stirred solution of 50.0 g (0.23 mole) of 2,4-dichloro-5-(1-methylethoxy)aniline in 250 mL of concentrted hydrochloric acid at 0° C. over 30 minutes. After complete addition, the mixture was stirred at 0° C. for 30 minutes. A solution of 114.0 g (0.506 mole) of tin (II) chloride dihydrate in 125 mL of concentrated hydrochloric acid was added dropwise to the reaction mixture. After complete addition, the mixture was stirred for one hour. The resultant white slurry was filtered. The filter cake was added to a 20% aqueous sodium hydroxide solution and stirred for 30 minutes. The basic mixture was filtered, and the filter cake recrystallized from methanol and water to yield 37.0 g of 2,4-dichloro-5-(1-methylethoxy)phenylhydrazine.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:50][CH2:49][CH2:48][N:47]([C:51](=[N:53][C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[CH:60][CH:59]=4)=[O:55])[CH3:52])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:50][CH2:49][CH2:48][N:47]([C:51](=[N:53][C:54]([O:56][CH2:57][C:58]3[CH:59]=[CH:60][C:61]([N+:64]([O-:66])=[O:65])=[CH:62][CH:63]=3)=[O:55])[CH3:52])[CH2:46][CH2:45]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
2.1 ml of trifluoroacetic acid and 67 μl of trifluoromethanesulfonic acid were added to a solution of 285 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)homopiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (ii) above] in 414 μl of anisole, and the resulting mixture was stirred for 1 hour, whilst ice-cooling. At the end of this time, the reaction mixture was worked up by the same procedure as described in Preparation 1(iv), to give 296 mg of the title compound, as a powder.