Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([C:41]4[CH:45]=[CH:44][O:43][N:42]=4)[CH2:25][C:26](N4[C@@H](CC5C=CC=CC=5)COC4=O)=[O:27])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH:46]O.[Li+].[OH-].Cl>C1COCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([C:41]4[CH:45]=[CH:44][O:43][N:42]=4)[CH2:25][C:26]([OH:27])=[O:46])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCc1ccc(-c2ccc(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)s2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc(COc3ccc([C@H](CC(=O)O)c4ccon4)cc3)s2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
To a solution of 60.6 (26 mg, 0.042 mmol) in THF (0.4 mL) were added 30% H2O2 (47 μL, 0.42 mmol) and 1N LiOH (0.21 mL, 0.21 mmol) at 0° C. The mixture was stirred for 1 h at 0° C., adjusted to pH 3 with aqueous HCl, and extracted with EtOAc. The combined organics were washed with 1N Na2SO3 (pH 3) and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (10-45% EtOAc/hexane) and further purified by preparative thin layer chromatography (50% EtOAc/hexane) to afford 60 (1.6 mg, 8%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, 1H), 7.48 (d, 2H), 7.18 (m, 4H), 7.14 (d, 1H), 7.04 (d, 1H), 6.94 (d, 2H), 6.07 (d, 1H), 5.17 (s, 2H), 4.55 (t, 1H), 3.35 (dd, 1H), 2.98 (dd, 1H), 2.61 (t, 2H), 1.60 (m, 2H), 1.37 (m, 2H), 0.93 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH:22]C=O)[CH:6]=[C:7]([CH2:11][P:12]([O:18]C(C)C)([O:14]C(C)C)=[O:13])[CH2:8][CH2:9][F:10])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH2:22])[CH:6]=[C:7]([CH2:11][P:12]([OH:14])([OH:18])=[O:13])[CH2:8][CH2:9][F:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCF)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(CCF)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.52 g (1.36 mmol) of 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is dissolved in 3.5 ml of dichloromethane, and 0.7 ml (5.45 mmol) of trimethylbromosilane is added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 3.5 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 2.4 ml of ethanol, and a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222° (decomp.) is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Cl:23]CCCl>C(O)(=O)C.O.C(=O)(O)[O-].[Na+].S(=O)(O)[O-].[Na+]>[CH2:15]([O:14][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[C:4]([C:1](=[O:3])[CH2:2][Cl:23])[CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCCCl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Temperature: 65 °C
Reaction time: 4.5 h

Procedure:
5-acetyl-7-benzyloxy-1H-quinolin-2-one (7.0 g, 23.86 mmol) is dissolved in a mixture of 1,2-dichloroethane (147 mL), glacial acetic acid (43 mL), and water (7 mL) and combined with N-benzyltrimethylammonium-dichloriodate (19.0 g, 54.58 mmol). The mixture is stirred for 4.5 hours at 65° C., then diluted with sodium bicarbonate solution and 5% sodium bisulfite solution and stirred for 5 minutes. The precipitate formed is filtered off, washed with water (2×20 mL) and dried in the oven. Yield: 6.0 g (77%); mass spectroscopy:
Reaction SMILES: CO.[NH2:3][C:4]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=1)=[O:7].[BH4-].[Na+]>C(OC(=O)C)C>[NH2:3][C:4]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:5]=1[CH:6]([OH:7])[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)c2cc(Cl)ccc2N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(C(O)c2cc(Cl)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.4 %

Procedure:
To a methanol (40 ml) solution of 2-amino-4′-(2-tert-butoxycarbonylaminoethyl)-5-chlorobenzophenone (2.0 g) was added sodium borohydride (0.5 g). The mixture was stirred for 30 minutes at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and, then, dried over anhydrous MgSO4, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography to give the object 2-amino-5-chloro-α-[4-(2-tert-butoxycarbonylaminoethyl)phenyl]benzyl alcohol (2.2 g) as a colorless oily product.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:23]1([CH3:26])[CH:24]=[CH:25][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(N)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 64 %

Procedure:
Prepared from VII and 4-toluidine. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 64%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3016, 2853, 2228, 1731, 1641, 1605, 1581, 1554, 1505, 1458, 1376, 1353, 1304, 1268, 1215, 1165, 1130, 976, 831, 811; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=9.0 Hz), 8.07 (s, 1H), 7.76 (d, 1H, J=9.0 Hz), 7.20-7.17 (m, 2H), 7.12-7.05 (m, 2H), 2.32 (s, 3H); HRMS calcd for C17H12N5S (M+H+): 318.0813, found 318.0811.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13](=O)[NH:12][CH:11]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O.Cl>C(#N)C.O1CCOCC1>[Cl:23][C:13]1[N:12]=[CH:11][C:10]([CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cc2c[nH]c(=O)c3cccnc23)cn1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccc(Cc2cnc(Cl)c3cccnc23)cn1
Temperature: 25 °C

Procedure:
396 mg (1.48 mmol) of 8-[(6-methoxy-pyridin-3-yl)-methyl]-6H-[1,6]naphthyridin-5-one in 24 ml of acetonitrile are mixed, whilst excluding air, with 1.4 ml (15 mmol) of phosphorus oxychloride and 0.78 ml of 4 N HCl in dioxan and stirred for 96 h at 65° C. After cooling to RT, partial concentration by evaporation takes place on a RE, then 40 ml of ice water and 10 ml of NH3 solution are added and extraction carried out 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 5-chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine (contaminated with a little 5-chloro-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine); FAB-MS: (M+H)+=286; HPLC(gradients20-100) tRef=10.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1/[CH:10]=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(NN)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])=O.[Na+].COCCOC>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C\c1ccc(O)c(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)CCc1ccc(O)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl (2Z)-3-(2,3-dichloro-4-hydroxyphenyl)prop-2-enoate (270 mg, 1.03 mmol, 1.00 equiv), TsNHNH2 (193 mg, 1.04 mmol, 1.00 equiv), NaOAc (424 mg, 5.17 mmol, 5.00 equiv), ethylene glycol dimethyl ether (10 mL), water (1 mL). The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 150 mg (52%) of ethyl 3-(2,3-dichloro-4-hydroxyphenyl)propanoate as a red solid.
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH3:12][C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:14]=[CH:15][C:16](=[O:18])[CH3:17].[N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=1>CO>[CH3:12][C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:14]=[CH:15][C:16](=[O:18])[CH2:17][CH:31]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1
Reactant: C1=NCCCC1
Reactant: CC(=O)C=CC(C)=Cc1ccccc1
Agent: COC(=O)[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C=CC(=O)CC1CCCCN1)=Cc1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
Magnesium methyl carbonate (1.2 moles, 2 N in dimethylformamide) is heated to 120°C. under an atmosphere of carbon dioxide. The compound 5-methyl-6-phenyl-3,5-hexadien-2-one, 53.0 g (0.285 mole) is added and the mixture is stirred at 120°C. for a period of 4 hours under a stream of nitrogen while permitting the methanol that forms to escape. The mixture is allowed to cool under an atmosphere of carbon dioxide and 57.0 g (0.68 mole) of 2,3,4,5-tetrahydropyridine (as α-tripiperidein) is added and stirred at room temperature under an atmosphere of carbon dioxide for a period of 70 hours. The reaction mixture is poured into a concentrated HCl-ice mixture and extracted with methylene dichloride. The extracts are combined, washed with water, dried over anhydrous sodium sulfate, and the solvent removed. The crude 5-methyl-6-phenyl-1-(2-piperidyl)-3,5-hexadein-2-one which remains is recrystallized twice from isopropyl alcohol as the hydrochloride salt and is obtained in 48% yield (41.6 g) and has a M.P. of 179-80°C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH:18]([C:20](=O)[CH3:21])[CH3:19]>CO>[CH3:16][C:5]1[CH:6]=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:2]2[N:3]([C:18]([CH3:19])=[C:20]([CH3:21])[N:1]=2)[N:4]=1
Reactant: Cc1cc(OCc2ccccc2)c(N)nn1
Reactant: CC(=O)C(C)Br
Solvent: CO
Product: Cc1cc(OCc2ccccc2)c2nc(C)c(C)n2n1
Temperature: 25 °C

Procedure:
A mixture of (0.01 mole) 3-amino-6-methyl-4-phenylmethoxypyridazine, [prepared following the methodology of Becket, et al. J. Pract. Chem., 311, 285(1969) and references cited therein], and (0.012 mole) 2-bromo-3-butanone in methanol is heated for 24 hours in a bath maintained at 100°. The mixture is cooled to room temperature and partitioned between aqueous sodium bicarbonate and methylene chloride. The layers are separated and the aqueous phase extracted with methylene chloride. The organic extracts are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to give 6-methyl-8-phenylmethoxy-2,3-dimethylimidazo[1,2-b]pyridazine.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37]([NH:39][C@@H:40]([CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[C:41]([OH:43])=O)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C@:51]12([CH3:61])[C:57]([CH3:59])([CH3:58])[CH:54]([CH2:55][CH2:56]1)[CH2:53][CH:52]2[NH2:60]>CN(C=O)C>[C:32]([O:36][C:37](=[O:38])[NH:39][C@H:40]([C:41](=[O:43])[NH:60][C@H:52]1[CH2:53][C@@H:54]2[C:57]([CH3:59])([CH3:58])[C@@:51]1([CH3:61])[CH2:56][CH2:55]2)[CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)([CH3:33])([CH3:34])[CH3:35]
Reactant: CC1(C)C2CC[C@@]1(C)C(N)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@H]1C[C@H]2CC[C@]1(C)C2(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
3.53 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.4 mmol, 1.0 equiv.), 1.25 g of 1-hydroxybenzotriazole (9.2 mmol, 0.5 equiv.) and 7.3 ml of Hünig's base were added to a solution of 5.0 g of (S)-2-tert-butoxycarbonylamino-3-cyclohexylpropionic acid (Boc-Cha-OH, 18.4 mmol, 1.0 equiv.) in DMF (60 ml) at 0° C. under argon, and the mixture was stirred for 30 min. Then 2.83 g of (R)-(+)-bornylamine (18.4 mmol, 1.0 equiv.) and 3.7 ml of Hünig's base were added, and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with NaHCO3 (saturated, aq.) and extracted three times with ethyl acetate. The combined organic phases were washed twice with water and dried over Na2SO4 and concentrated. Purification by flash chromatography on silica gel with heptane/ethyl acetate mixtures as eluent afforded 6.58 g (88% yield) of the title compound as a colorless oil.
Reaction SMILES: BrC1C=[C:4]2[C:8](=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6](C(OCC)=O)=[C:5]2[S:25](Cl)(=O)=O.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:33]2[S:53](Cl)(=[O:55])=[O:54].N1CCOCC1.N1CCSCC1>>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:33]2[S:53]([N:7]1[CH2:6][CH2:5][S:25][CH2:4][CH2:8]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: C1CSCCN1
Solvent: C1COCCN1
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)N1CCSCC1

Procedure:
The titled compound was prepared using the procedures described in Steps B and C of Example 2, replacing in Step B ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with thiomorpholine. Proton NMR for the product was consistent with the titled compound. ESI+MS: 389.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]=[O:16])[CH:11]=[CH:10][C:9]=2[OH:17])=[O:5])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]=[O:16])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C=O)ccc(O)c2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(C=O)ccc(OCc3ccccc3)c2[nH]1

Procedure:
2.33 g of 4-formyl-7-hydroxyindole-2-carboxylic acid ethyl ester is combined with 1.8 ml of benzyl bromide, 1 g of potassium carbonate, and 100 ml of acetone and heated under reflux for 4 hours. The reaction mixture is then evaporated to dryness, combined with water, and extracted with ethyl acetate. The organic phase is washed twice with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated, and recrystallized from ethyl acetate/hexane, thus obtaining 1.8 g of 7-benzyloxy-4-formylindole-2-carboxylic acid ethyl ester, mp 131°-132° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:22].C(Cl)Cl.C([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=O)C>C(N(CC)CC)C>[C:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:11]=3)[C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cn(-c2ccccc2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(-c2ccccc2)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
Alternately, the title compound is prepared as follows: To a solution of 1.6 g. of compound (III) (R1 =C2H5, R=phenyl, X=Cl) (product of 1(c) in 50 ml. of methylene chloride is added 1 ml. of triethylamine and 710 mg. of N-acetylpiperazine. After heating for 2 hours, the solvent is washed with 50 ml. of 1N HCl solution and then with water. The methylene chloride solution is dried and evaporated to dryness, yielding 2.1 g. of compound (I) ##STR14##
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].P([O-])([O-])(O)=O.[Na+].[Na+].[Cl:18]CCl.ClCl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:18])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(=O)Nc1ccccn1
Agent: ClCl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(Cl)cn1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In 300 ml of water, 13.6 g (0. lmol) of 2-acetamidopyridine (Id) was dissolved. To this solution, 35.5 g (0.25 mol) of disodium hydrogenphosphate and 100 ml of dichloromethane were added in this order. While this mixture was stirred, 8.0 g (0.11 mol) of chlorine was introduced thereto at 0° C. for 30 minutes. Then the mixture was further stirred at the same temperature for 2 hours. After the mixture was brought back to room temperature, it was separated into a water layer and an extract layer. Thereafter, the water layer was further extracted with 100 ml of dichloromethane and then washed with saturated brine. The resulting extract layer was dehydrated by sodium sulfate anhydride. When dichloromethane was evaporated off, 16.0 g (yield: 94.0%) of 2-acetamido-5-chloropyridine (IIj) was obtained as a pale brown crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:22]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:28])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C1CCC(=O)O1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A solution of 5-chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) in dry pyridine (2.5 ml) and dry tetrahydrofuran (50 ml) was cooled. To the solution was dropwise added a solution of succinic anhydride (1.1 g) in dry tetrahydrofuran (5 ml) under stirring. The mixture was refluxed for 2 hours and then left overnight. The reaction mixture was treated in the same manner as that in Example 6 to yield the title compound as colorless crystals (2.5 g).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CO.[CH3:22][C:23]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:36][O:37][CH3:38])[CH:34]=[O:35]>CCOCC>[CH3:38][O:37][N:36]=[C:33]([C:34]1[O:35][CH:12]=[N:11][CH:10]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:24]1[CH:39]=[C:40]([CH3:43])[CH:41]=[CH:42][C:23]=1[CH3:22]
Reactant: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: CON=C(c1cnco1)c1ccccc1COc1cc(C)ccc1C
Yield: 44.6 %

Procedure:
p-Toluenesulfonylmethylisocyanide (0.23 g, 1.2 mmol), potassium carbonate (0.18 g, 1.3 mmol) and methanol (2 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.30 g, 1 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl oxazol-5-yl ketone O-methyloxime (0.15 g, 44.6%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:30][CH:31]=3)=[CH:19][CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)SCCc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(OCCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
Methyl 2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoate (77 mg, 0.14 mmol) was dissolved in 2.5 ml of a 4:1 mixture of THF and water and cooled on an ice-bath. Lithium hydroxide (6.9 mg, 0.29 mmol) was added. Water was added after 2 days of stirring at room temperature. The THF was evaporated under reduced pressure. The aqueous phase was acidified with 1M HCl and extracted with EtOAc three times. The organic phases were pooled, washed (water, brine), dried (MgSO4) and evaporated. The crude product was purified using preparative HPLC (eluent: CH3CN/5% CH3CN-waterphase containing 0.1M NH4Oac). 24 mg of the desired product (yield 30%) was obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O1C2C=CC=CC=2CC(=O)N1.[CH3:38][Si:39]([CH2:42][S:43][CH2:44][CH:45]([NH2:47])[CH3:46])([CH3:41])[CH3:40]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:47][CH:45]([CH3:46])[CH2:44][S:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[O:13])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CC(N)CSC[Si](C)(C)C
Agent: O=C1Cc2ccccc2ON1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC(C)CSC[Si](C)(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 80 °C

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (0.23 g, 0.51 mmol) in tetrahydrofuran was added 1-trimethylsilylmethylthio-2-propylamine (0.103 g, 0.58 mmol), and the reaction mixture was heated to 80° C. for 3 hours and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was chromatographed on silica gel with hexanes/ethyl acetate as eluent (5:1) to afford the title compound, a compound of the present invention, as a white solid (73 mg), m.p. 151–153° C.