Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](I)(C)(C)C.C[C@:7]([NH:35]C(OC(C)(C)C)=O)([CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:8]([O-:10])=[O:9].[C:43](=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:43][O:10][C:8](=[O:9])[C@@H:7]([NH2:35])[CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)[O-]
Reactant: O=C([O-])O
Agent: C[Si](C)(C)I
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
TMSI (1.56 mL, 10.63 mmol) was added dropwise to a stirred solution of (2R)-methyl-tert-butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionate (4.47 g, 8.66 mmol) in anhydrous methylene chloride (50 mL). The reaction was stirred for 10 mins. and then poured into 1N sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3×50 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a yellow oil (3.43 g, 95%): Rf=0.65 (10% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 7.86 (2H, d, J=8 Hz, Ar—H), 7.64-7.72 (6H, m, Ar—H), 7.61 (1H, d, J=8 Hz, Ar—H), 7.42 (1H, d, J=8 Hz, Ar—H), 7.21 (1H, td, J=7, 2 Hz, Ar—H), 7.14 (1H, td, J=7, 2 Hz, Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 3.80 (2H, s, PhCH2), 3.62 (3H, s, OMe), 3.56 (1H, t, J=6.5 Hz, CHN), 2.68 (1H, dd, J=6.5, 3 Hz, CHHCHN), 2.63 (1H, dd, J=6.5, 3 Hz, CHHCHN), 2.04 (2H, br s, NH2).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4](=[O:6])[CH3:5].[Br:9]Br.C(=O)(O)[O-].[Na+]>CO.C(#N)C.C(#N)C>[Br:9][CH2:5][C:4](=[O:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1]
Reactant: BrBr
Reactant: COC(OC)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COC(OC)C(=O)CBr
Yield: 70.4 %

Procedure:
A solution of 1,1-bis(methyloxy)-2-propanone (40.1 mL, 339 mmol) in 5% (v/v) methanol/acetonitrile (200 mL) was cooled to <5° C. while stirring. A 1 mL portion of a solution of bromine (17.44 mL, 339 mmol) in acetonitrile (30 mL) was added and the mixture was stirred until the solution was decolorized. The remainder of the bromine solution was added to the reaction mixture over 6-8 hrs while maintaining an internal temperature of <10° C. The mixture was stirred at RT overnight. Sodium bicarbonate (30.2 g, 360 mmol) was added and the mixture was stirred for 1 hr, then filtered. The filtrate was concentrated and t-butyl methyl ether (30 mL) and heptane (15 mL) were added. The mixture was washed with aqueous sodium bicarbonate (6.0 g in 60 mL water) and the organic layer was dried over sodium sulfate. The solvent was evaporated to give the title compound (47.03 g, 70%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 4.64 (s, 1H), 4.13 (s, 2H), 3.35 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21](=S)[NH2:22])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.IC.CO[CH:28](OC)[CH2:29][NH2:30].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.CCOC(C)=O>[NH:30]1[CH:29]=[CH:28][N:22]=[C:21]1[C:12]1[S:11][C:10]([C:9]2[C:2]([CH3:1])=[N:3][N:4]3[CH:8]=[CH:7][S:6][C:5]=23)=[N:14][C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(CN)OC
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=S)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(-c2ncc[nH]2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carbothioamide (223 mg, 0.6 mmol) obtained in the similar manner described in Example 111-B(ii) in acetone (12 mL), was added iodomethane (75 μL, 1.2 mmol), and the mixture was stirred at rt for 2 h. The solvent was evaporated, and the residue was suspended in AcOH (12 mL). To the residue was added aminoacetaldehyde dimethylacetal (100 μL, 0.9 mmol), and the mixture was stirred at 90° C. for 16 h. The reaction mixture was allowed to cool to rt, then concentrated, and the residue was dissolved in THF (12 mL). To the solution was added 6N hydrochloric acid (400 μL, 2.4 mmol), and the mixture was stirred at 70° C. for 2 h. The reaction mixture was allowed to cool to rt, and then were added saturated aqueous solution of sodium bicarbonate (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL), and the organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=20/80→100/0) to give the title compound (133 mg, 61%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1)=O>CS(C)=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][N:8]=[CH:13][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1)=[O:6]
Reactant: O=Cc1ccc(C(=O)O)c2ccccc12
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NN=Cc1ccc(C(=O)O)c2ccccc12)c1ccc(O)c(Cl)c1
Reaction time: 16 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (1.53 g, 8.23 mmol) in DMSO (20 mL) was added a solution of 4-formylnaphthoic acid (1.65 g, 8.23 mmol) in DMSO (2 mL). After stirring the solution for 16 hr, the reaction was diluted with ethyl acetate (30 mL) and water (30 mL). A precipitate formed. The precipitate was collected, washed with hexane and dried to give the product as a white solid in quantitative yield.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mo:6]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mo+4:6].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: [Mo]
Agent: O=S(=O)([O-])[O-]
Product: [Mo+4]

Procedure:
Technical grade MoO3 was slurried in the leach solution so as to obtain a 2:1 weight ratio of leach to solids. Slurries were heated to 75°-85° C. and maintained at that temperature for two hours. The slurries were stirred vigorously during the digestion. The molybdenum oxide was separated from the leach solution by filtration. Percent of the molybdenum lost to the leach was determined. The molybdic oxide was then washed twice. Washing involved slurrying the oxide in 70°-80° C. water for 10 minutes and filtering to separate it from the wash. Percent of molybdenum lost to washes was determined. Efficiencies are tabulated in Table I. The better efficiency was obtained by the leach containing NH4NO3. The substitution of nitrate ion for sulfate ion is apparently responsible for the better efficiency. Presence of sulfate ion increases molybdenum solubility in acid solution by forming molybdenum sulfate complexes. When some of the sulfate ion is replaced with nitrate ion, molybdenum solubility decreases. Presence of additional nitrate ion increased oxidation of molybdenum IV to molybdenum VI, resulting in less molybdenum in the sludge after NH4OH digestion.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][O:14]C2C=C(C)C=CC=2N[C:10]1=[O:21].CCN=C=NCCCN(C)C.C(OC(N[C@@H](CO)C(O)=O)=O)(C)(C)C.F[C:48]1[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[CH:50][C:49]=1[N+:58]([O-])=O>CCOCC.CCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:10][O:21][C:48]2[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[CH:50][C:49]=2[NH:58][C:15]1=[O:14]
Reactant: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1F
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCC
Solvent: CCOCC
Product: N[C@H]1COc2cc(C(F)(F)F)ccc2NC1=O
Reaction time: 2 h

Procedure:
In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate except in Step 3 1.2 eq. EDCI was used and the reaction mixture was stirred for 2 h and in Step 4 the mixture was stirred for 1 h and the material obtained was tritrurated with Et2O/pentane, (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (4.96 g, 24.2 mmol) and 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (5.05 g, 24.2 mmol) were converted to the title compound (1.6 g) as a pale yellow solid.
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:8])[CH3:7].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:16]([N:14]1[CH:10]([O:9][CH:6]([CH3:8])[CH3:7])[CH2:11][CH2:12][C:13]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)OC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)OC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
11.7 cm3 of a 1.6M solution of n-butyllithium in hexane is added at -70° C. to a solution of 2.5 g of 5-isopropyloxy pyrrolidin-2-one in 60 cm3 of tetrahydrofuran, while maintaining the temperature between -70° C. and -65° C. Agitation is carried out for 30 minutes under these conditions then a solution of 2.46 g of benzoyl chloride in 8 cm3 of tetrahydrofuran is added, maintaining the temperature between -65° C. and -70° C. The temperature is allowed to return to the ambient over 2 hours. After evaporation to dryness and then chromatography on silica (eluent: ethyl acetate-n-hexane 1-3), 2.78 g of the product sought is obtained.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[OH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[ClH:11].[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:41]2[CH2:42][CH2:43][CH:38]([OH:37])[CH2:39][CH2:40]2)=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: OC1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(O)CC2)cc(OC)c1
Product: Cl

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with 4-hydroxypiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)-phenyl]-5-(4-hydroxypiperidin-1-yl)pentan-1-one hydrochloride, m.p. 220-222° C.
Reaction SMILES: Cl[C:2]1[C:11]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.[K]>CN(C)C=O>[CH3:18][N:17]([CH:16]=[N:15][S:12]([C:11]1[C:2]([O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:3]([N+:20]([O-:22])=[O:21])[CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:14])=[O:13])[CH3:19]
Reactant: Oc1cccnc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)N=CN(C)C)c1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2cccnc2)c(S(=O)(=O)N=CN(C)C)c1
Temperature: 0 °C

Procedure:
A solution of 200 g (0.57 mole) of methyl 4-chloro-5-dimethylaminomethyleneaminosulfonyl-3-nitro-benzoate and 93 g (0.7 mole) of potassium 3-hydroxypyridine in 1 l of dimethylformamide is stirred for 1.5 hours at 80° C. and, after cooling, is introduced into 4-5 l of ice-water, while stirring vigorously. The product which has precipitated is filtered off, washed with H2O and recrystallized from dimethylformamide/CH3OH.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:15](=[O:18])([O-])[O-:16].[Na+].[Na+].[C:21](#[N:23])[CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:8]2[CH2:22][CH2:21][N:23]([C:15]([O:16][C:6]([CH3:11])([CH3:7])[CH3:4])=[O:18])[CH2:10][CH:9]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC#N
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: [Na+]
Product: CCOC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a flask containing a portion of the enol triflate prepared above (8.00 g, 24.2 mmol) were added 4-ethoxycarbonylphenylboronic acid (6.09 g, 31.4 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (1.693 g, 2.42 mmol). Acetonitrile (100 mL) and sodium carbonate (60 mL, 1.0 M aqueous, 60.0 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 18 h, then was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 231.9 [M-Boc]+; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 6.20-6.10 (m, 1H), 4.37 (q, J=7.0 Hz, 2H), 4.10 (br m, 2H), 3.66-3.64 (m, 2H), 2.54 (br m, 2H), 1.50 (s, 9H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([OH:11])=O)=[C:7](C3C=NC(O)=CC=3)[N:6]=[C:5]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.C([O:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][N:46]=1)C(O)=O)C1C=CC=CC=1.[N:47]1([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:51][CH2:50][CH2:49][CH2:48]1>>[CH:1]1([N:4]2[C:8]([C:9]([N:55]3[CH2:56][CH2:57][CH:52]([N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)[CH2:53][CH2:54]3)=[O:11])=[C:7]([C:40]3[CH:44]=[CH:45][N:46]=[C:38]([OH:37])[CH:39]=3)[N:6]=[C:5]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1c(-c2ccc(O)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Reactant: O=C(O)c1ccnc(OCc2ccccc2)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C(c1c(-c2ccnc(O)c2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 2, the title compound has been obtained by coupling of 3-cyclopropyl-5-(2-hydroxy-pyridin-4-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (prepared in analogy to the sequence described for the preparation of intermediate 9, but using 2-benzyloxy-isonicotinic acid instead of 6-benzyloxy-nicotinic acid in step 9A) with 4-pyrrolidin-1-yl-piperidine to give the title compound as yellow amorphous solid. MS: 542.2 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8]C)=O)[CH2:2]1.O.[NH2:11][NH2:12]>>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([NH:11][NH2:12])=[O:8])[CH2:2]1
Reactant: NN
Reactant: COC(=O)C1CCOC1
Solvent: O
Product: NNC(=O)C1CCOC1
Reaction time: 3 h
Yield: 74 %

Procedure:
Into around-bottom flask, was placed hydrazine hydrate (20 mL). To this was added methyl tetrahydrofuran-3-carboxylate (compound 38.1, 390 mg, 3.00 mmol, 1.00 equiv) dropwise with stirring. The resulting mixture was stirred at 50° C. in an oil bath. After 3 h, the reaction mixture was concentrated and dried under reduced pressure to yield 0.29 g (74%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[NH:24][CH2:25][CH3:26]>CC(C)=O.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([N:24]([C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)[CH2:25][CH3:26])[CH:27]=[CH:28][CH:29]=1
Reactant: CCNc1cccc(OC)c1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(c1cccc(OC)c1)c1nc(=O)c2cccnc2s1
Yield: 82.6 %

Procedure:
The reaction procedure of Example 85 was followed except that 1.891 g (12 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 960 mg of ammonium thiocyanate, 15 ml of acetone, 1.815 g of 3-methoxy-N-ethylaniline and 10 ml of acetone were used. The resulting crude product was then recrystallized from ethanol to obtain 3.107 g of 2-[N-(3-methoxyphenyl)-N-ethylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16])(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16])#[N:2]
Reactant: NC(=O)CN1C(=O)COc2cc(F)ccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#CCN1C(=O)COc2cc(F)ccc21
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of 4-carbamoylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.24 g), toluene (20 ml), thionyl chloride (2.4 g) and N,N-dimethylformamide (3 drops) was stirred at a temperature of 90° C. to 100° C. for 2 hours. The solvent was distilled off from the mixture, and then methylisobutyl ketone (100 ml) was added thereto and the resulting mixed solution was filtered, the filtrate was washed with water, sodiumbicarbonate solution, and water, in that order, and subsequently dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the desired 4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (1.74 g). mp. 111°-113° C.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[C:1](=[O:12])([S:18][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CC(C)CCS
Product: CCCCCCC/C=C/C(=O)SCCC(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and isoamylmercaptan as starting materials to give the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH2:19][CH2:20][CH3:21])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:22]([O:24]C)=[O:23])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][CH2:29]I>O1CCCC1>[CH2:28]([N:18]([CH2:19][CH2:20][CH3:21])[C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:22]([OH:24])=[O:23])=[CH:12][CH:11]=2)[CH3:29]
Reactant: CCI
Reactant: CCCNc1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(CC)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(propylamino)quinoxaline-6-carboxylate (70 mg, 0.21 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (32 mg, 1.32 mmol) and CH3CH2I (1.5 mL), and the reaction was stirred overnight at room temperature. The reaction was then quenched with water (50 mL), adjusted to pH 5 with HCl (3N), and extracted with ethyl acetate (3×40 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the residue, which was purified by Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.03% NH3H2O and CH3CN (10% CH3CN up to 35% in 8 min); Detector, UV 220 nm] to afford 3-(ethyl(propyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (45.0 mg, 62.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[N:13][N:14]([CH3:16])[CH:15]=3)[O:8][C:7](=O)[C:6]=2[CH:25]=1.[OH2:27].[NH2:28][NH2:29].CN1CCCC1=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]([NH:10][C:9]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:13][N:14]([CH3:16])[CH:15]=2)=[O:8])=[C:6]([C:7]([NH:28][NH2:29])=[O:27])[CH:25]=1
Reactant: O
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cn(C)nc3-c3ccccc3Cl)nc12
Solvent: CN1CCCC1=O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cn(C)nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
After 0.19 g of 6-chloro -2-[3 -(2-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.10 g of hydrazine monohydrate and 10 ml of N-methylpyrrolidinone were mixed under ice-cooling, the mixture was stirred at room temperature for 8 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.18 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-3-(2-chlorophenyl)-1-methyl-1H-pyrazole-4-carboxamide of the formula:
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].OO.O.C(OCC)(=[O:25])C>CO>[CH2:1]([S:3]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:25])[CH3:2]
Reactant: CCS[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Reactant: CCOC(C)=O
Agent: OO
Solvent: O
Solvent: CO
Product: CCS(=O)[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.224 g of (3R,4S)-4-ethylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of methanol is added 0.16 ml of 30% aqueous hydrogen peroxide and the mixture is stirred at room temperature for 4 hours. Then, 0.1 ml of 30% aqueous hydrogen peroxide is added, and the mixture is further stirred for 4 hours, followed by addition of 10 ml of water Extraction is carried out with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 0.20 g of (3R,4S)-4-ethylsulfinyl-3-phenoxyacetamido-2-oxoazetidine.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][C@@H:22]([OH:25])[C@@H:21]([OH:26])[CH2:20]1.CNC([C@@H]1CCCNC1)=O>>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:19]3[CH2:24][CH2:23][C@@H:22]([OH:25])[C@@H:21]([OH:26])[CH2:20]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: O[C@@H]1CCNC[C@@H]1O
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: CNC(=O)[C@@H]1CCCNC1
Product: Cc1c(-c2ccc(C(=O)N3CC[C@@H](O)[C@@H](O)C3)s2)noc1C(F)(F)F
Yield: 81 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3S,4R)-3,4-Piperidinediol (CAS [868051-84-7]) in the same manner as the (3R, 4S) isomer (Example 87) to afford product as a colorless solid (303 mg, 81%). LC/MS 5.43 min, [M+1]+ 377.