Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:6])[CH:3]=[N:4][OH:5].S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>>[NH2:21][C:20]1[CH:19]=[N:18][C:2]([CH3:6])=[CH:3][N:4]=1.[NH2:23][C:22]1[C:19]([C:20]#[N:21])=[N:18][C:2]([CH3:6])=[CH:3][N+:4]=1[O-:5]
Reactant: N#CC(N)C#N
Reactant: CC(=O)C=NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1c[n+]([O-])c(N)c(C#N)n1
Product: Cc1cnc(N)cn1

Procedure:
The intermediate 2-amino-5-methylpyrazine is prepared stepwise, starting with 2-oxopropanal 1-oxime. This oxime is allowed to react with aminomalononitrile tosylate [prepared by the method of Ferris et al., J. Am. Chem. Soc. 88, 3829 (1966)], to yield 2-amino-3-cyano-5-methylpyrazine 1-oxide. The pyrazine 1-oxide prepared in this manner is allowed to react with phosphorous trichloride to yield 2-amino-3-cyano-5-methylpyrazine. This 2-amino-3-cyano-5-methylpyrazine is hydrolyzed with aqueous sodium hydroxide to yield 2-amino-3-carboxy-5-methylpyrazine, which, when heated in tetrahydronaphthalene, is decarboxylated to yield the desired 2-amino-5-methylpyrazine.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].Cl[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1.O>O1CCCC1>[CH3:17][C:16]1[C:11]([O:5][CH2:4][C:3]([O:7][CH2:8][CH3:9])=[O:6])=[N:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=1
Reactant: CCOC(=O)CO
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ncc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (116 mg: 60%) was suspended in tetrahydrofuran (4 mL). While the suspension was cooled on ice, ethyl glycolate (273 μL) was added. The mixture was stirred at room temperature (20 to 30° C.) for 30 min. Subsequently, 2-chloro-3-methyl-5-nitropyridine (200 mg) was added to the mixture portionwise at room temperature (20 to 30° C.) and the mixture was stirred at room temperature (20 to 30° C.) for 3 hours. Water was then added to the reaction mixture and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure to afford 310 mg of the crude desired product of Compound 19 as a brown amorphous.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H]4CCCNC4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H:43]4[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]4)C(F)=CN=3)=CNC2=NC=1.[CH:50]([N:53]([CH:56](C)C)CC)([CH3:52])[CH3:51].N(CCC)=C=[O:61]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][CH:44]4[CH2:43][CH2:48][CH2:47][CH2:46][N:45]4[C:56]([NH:53][CH:50]([CH3:52])[CH3:51])=[O:61])[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CCCN=C=O
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCCCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2Cl2 (1.4 mL) and DMF (0.3 mL) was added N,N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol) followed by isocyanatopropane (0.120 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 439.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[C:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])#[CH:33]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][C:5]1[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[N:7][C:2]([C:33]#[C:32][Si:34]([CH3:37])([CH3:36])[CH3:35])=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:4]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C#C[Si](C)(C)C)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 125 °C
Reaction time: 96 h
Yield: 67.8 %

Procedure:
0.90 g (1.99 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3), 0.042 g (0.06 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.021 g (0.11 mmol) of copper(I) iodide were suspended in 2.0 ml of triethylamine. After addition of 2.14 ml=1.50 g (15.0 mmol) of ethinyltrimethylsilane, the reaction vessel was sealed, heated up to 125° C. and stirring continued for four days. The reaction mixture was then poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.693 g (68%) of the title compound as dark brown oil. MS: 514.4 (MH+).
Reaction SMILES: CC(N(C(C)C)CCOC1C=C(NC(=O)C2C=CC(C3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=CC=2)C=CC=1OC)C.CC(N(C(C)C)CCOC1C=C(NC(=O)C2C=CC(C3SC=CN=3)=CC=2)C=CC=1OC)C.[CH3:66][CH:67]([N:69]([CH:96]([CH3:98])[CH3:97])[CH2:70][CH2:71][O:72][C:73]1[CH:74]=[C:75]([NH:81][C:82]([C:84]2[CH:85]=[N:86][C:87](C3C=CC=CC=3)=[CH:88][CH:89]=2)=[O:83])[CH:76]=[CH:77][C:78]=1[O:79][CH3:80])[CH3:68].CC(N(C(C)C)CCOC1C=C(NC(=O)C2C=CC(C3C=CN=CC=3)=CC=2)C=CC=1OC)C>>[CH3:98][CH:96]([N:69]([CH:67]([CH3:68])[CH3:66])[CH2:70][CH2:71][O:72][C:73]1[CH:74]=[C:75]([NH:81][C:82]([C:84]2[CH:85]=[N:86][CH:87]=[C:88]([N:25]3[CH:26]=[CH:27][CH:28]=[CH:29]3)[CH:89]=2)=[O:83])[CH:76]=[CH:77][C:78]=1[O:79][CH3:80])[CH3:97]
Reactant: COc1ccc(NC(=O)c2ccc(-c3ccccn3)cc2)cc1OCCN(C(C)C)C(C)C
Reactant: COc1ccc(NC(=O)c2ccc(-c3ccccc3)nc2)cc1OCCN(C(C)C)C(C)C
Agent: COc1ccc(NC(=O)c2ccc(-c3ccncc3)cc2)cc1OCCN(C(C)C)C(C)C
Agent: COc1ccc(NC(=O)c2ccc(-c3nccs3)cc2)cc1OCCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2cncc(-n3cccc3)c2)cc1OCCN(C(C)C)C(C)C

Procedure:
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2-pyridinyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2-thiazolyl)benzamide; N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-6-phenyl-3-pyridinecarboxamide; and N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4-pyridinyl)benzamide
Reaction SMILES: C[O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Se](=O)=O.[O:15]1CCOC[CH2:16]1>O.C(OCC)(=O)C>[OH2:2].[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([CH:3]=[O:2])=[O:5]
Reactant: COCC(=O)c1ccccc1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)C=O

Procedure:
5 g of 2-methoxyacetophenone are dissolved in 30 ml of dioxane, and a solution of 4.8 g of selenium dioxide in 3 ml of water is added thereto. The mixture is refluxed for 6 hours. After the reaction is completed, insoluble materials are removed by filtration and the filtrate is condensed. The residue thus obtained is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, an aqueous sodium bicarbonate solution and water, successively. Then, said solution is dried and evaporated to remove solvent. 4.9 g of 2-methoxyphenylglyoxal hydrate are thereby obtained as a crude oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23]Cl.[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26]([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:10]=2[CH:11]=1
Reactant: CNC
Reactant: ClCCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Product: CN(C)CCCCOc1ccc2c(=O)cc(-c3ccccc3)oc2c1

Procedure:
The compound was prepared by a method similar to Example 1 from 7-hydroxyflavone, 1-bromo-4-chlorobutane and dimethylamine: mp 95°-96° C.
Reaction SMILES: [Cl:1][O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:32]=[N:33]/[OH:34])[CH:17]=3)[C:12]2=[O:35])=[CH:7][CH:6]=1.[F:36][C:37]1[CH:48]=[CH:47][C:40]2[N:41]=[C:42]([C:44]([CH3:46])=[CH2:45])[O:43][C:39]=2[CH:38]=1>ClCCl>[Cl:1][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:32]3[CH2:45][C:44]([C:42]4[O:43][C:39]5[CH:38]=[C:37]([F:36])[CH:48]=[CH:47][C:40]=5[N:41]=4)([CH3:46])[O:34][N:33]=3)[CH:17]=2)[C:12](=[O:35])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26]
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(/C=N/O)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: C=C(C)c1nc2ccc(F)cc2o1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCc1c(Cl)c2cc(C3=NOC(C)(c4nc5ccc(F)cc5o4)C3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
Sodium hypochlorite (1.408 mL, 0.912 mmol) was added to a stirred, room temperature mixture of (E)-tert-butyl 5-(2-(4-fluorophenyl)-6-((hydroxyimino)methyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (100 mg, 0.228 mmol) and 6-fluoro-2-(prop-1-en-2-yl)benzo[d]oxazole (40.4 mg, 0.228 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for overnight. The reaction was checked with LCMS and starting material was all consumed. The mixture was diluted with dichloromethane (10 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1×6 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane=50% to give tert-butyl 5-(4-chloro-6-(5-(6-fluorobenzo[d]oxazol-2-yl)-5-methyl-4,5-dihydroisoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (48 mg, 0.074 mmol) as a yellow solid, 648.0 (M+H+); and tert-butyl 5-(6-(5-(6-fluorobenzo[d]oxazol-2-yl)-5-methyl-4,5-dihydroisoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (26 mg, 0.042 mmol) as a yellow solid which were deprotected with TFA as in Example 5.1 to give Examples 6.1 and 6.2 respectively.
Reaction SMILES: [CH2:1]([CH:8]1[C:12]([OH:13])=[CH:11][C:10](=[O:14])[N:9]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+].O>C(#N)C>[CH2:1]([C@H:8]1[C@@H:12]([OH:13])[CH2:11][C:10](=[O:14])[N:9]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N2C(=O)C=C(O)C2Cc2ccccc2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(N2C(=O)C[C@H](O)[C@@H]2Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a mixture of 4-(2-benzyl-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-chlorobenzonitrile (400 mg) and acetic acid (0.60 mL) in acetonitrile (20 mL) was added sodium borohydride (86 mg) at 0° C. in small portions. The mixture was warmed to room temperature, and stirred for 3 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 310 mg, 77%).
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[C:21]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].[H-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[C:15]([O:14][C:12]([N:11]1[CH:10]([CH3:19])[C:9](=[O:8])[CH:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:22]1[C:21]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=C(/C=C/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1C(=O)C(C(=O)OCc2ccccc2)C(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5.59 g (20.0 mmol) of (R)—N-tert-butoxycarbonylalanine benzyl ester and 5.92 g (20.0 mmol) of dibenzyl fumarate in 60 mL of toluene was added 1.60 g (40 mmol) of 60% NaH in mineral oil. The reaction was stirred at ambient temperature under N2 for 24 h, then diluted with 300 mL of diethyl ether. The solution was extracted with 1M HCl(aq.) (1×50 mL), saturated NaHCO3(aq.) (3×50 mL), and brine (1×50 mL), dried over MgSO4, filtered, and concentrated to provide the titled compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([C:27]([F:30])([F:29])[F:28])([C:23]([F:26])([F:25])[F:24])[OH:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][S:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([S:32][CH3:31])[CH:38]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:21]([C:27]([F:29])([F:30])[F:28])([C:23]([F:25])([F:26])[F:24])[OH:22])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CSc1cccc(B(O)O)c1
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: COCCOC
Solvent: CCO
Product: CSc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 11.2 %

Procedure:
5-(4-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 2 of Preparation 22, 3-(methylthio)-phenylboronic acid (25.0 mg, 0.15 mmol), Pd(PPh3)4 (11.5 mg, cat.), ethanol 0.5 mL and a 2N sodium carbonate solution (0.5 mL) were added to 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 6.1 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=1>>[Cl:20][C:18]1[CH:19]=[C:14]([NH2:13])[CH:15]=[C:16]([Cl:22])[C:17]=1[O:21][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: COc1cccc2sc(Cl)nc12
Product: COc1cccc2sc(Oc3c(Cl)cc(N)cc3Cl)nc12

Procedure:
3,5-Dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenylamine was synthesized (21%) from 2-chloro-4-methoxybenzothiazole (257) and 4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described in Example 417. 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.0 Hz, 1H), 7.28 (t, J=8.1 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.73 (s, 2H), 5.86 (s, 2H), 3.85 (s, 3H). MS (EI): m/z 341 (M+H).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH3:7])(=[O:5])=[O:4].[H-].[Na+].[CH3:10][C:11]1([CH3:22])[O:20][C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[CH:13]2[O:21][CH:12]12.CCCCCCC>CS(C)=O.C(OCC)(=O)C>[OH:21][CH:12]1[C:11]([CH3:22])([CH3:10])[O:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]1[CH2:1][NH:2][S:3]([CH2:6][CH3:7])(=[O:5])=[O:4]
Reactant: CCS(=O)(=O)NC
Reactant: CC1(C)Oc2ccncc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCCC
Product: CCS(=O)(=O)NCC1c2cnccc2OC(C)(C)C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A solution of 480 mg (3.5 mmol) of N-methylethylsulfonamide in 0.75 ml DMSO (dimethylsulfoxide) is added to a suspension of 27 mg (0.7 mmol) of NaH (60% strength) in 1.5 ml of DMSO. After stirring at room temperature for 2 h, a solution of 0.48 g (2.7 mmol) of 2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclo-propa[a]naphthalene (prepared analogously to G. Burell et al. J. Med. Chem. 33 (1990) 3023-3027) in 6 ml of DMSO is added dropwise. The mixture is heated at 60° C. for 4 h and then stirred overnight at room temperature. The reaction mixture is added to ice water and extracted with ethyl acetate. After removing the solvent in vacuo, the solid obtained is stirred with a mixture of heptane and ethyl acetate and filtered off with suction. 400 mg (67%) of ethanesulfonic acid (3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)methylamide are obtained as a solid (m.p. 163° C.).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[NH:2][N:3]=[C:10]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:9]=1)=[O:22])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)C(C)Oc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C(C)Oc2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 448.5 %

Procedure:
Hydrazine hydrate (41.7 μL, 0.4 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-hexanoic acid ethyl ester (566 mg, 2.14 mmol) in EtOH (4.5 mL). The mixture was stirred at 80° C. for 1 hour. Then, the mixture was stirred at room temperature for 16 hours. Hydrazine hydrate (20 μL, 0.2 mmol) was added and the mixture was stirred at 80° C. for 2 hours. More hydrazine hydrate (41.7 μL, 0.4 mmol) was added and the mixture was stirred at 80° C. for 2 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and solvents evaporated in vacuo to yield (rac)-5-(1-phenoxy-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (467 mg, 78% yield) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[S:8].[CH:13](Br)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([O:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[S:8])([CH3:15])[CH3:14]
Reactant: COC(=S)c1cnc(C)c(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=S)c1cnc(C)c(OC(C)C)c1
Temperature: 60 °C

Procedure:
A mixture of methyl 5-hydroxy-6-methylthionicotinoate (3 g), isopropyl bromide (2.1 mL) and anhydrous potassium carbonate (3 g) in dry dimethylformamide (35 mL) is stirred and heated at 60±5° C. for 18 hours. After cooling the solvent is removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase is washed with brine and dried (MgSO4). Evaporation gives a brown oil which is purified by flash chromatography (pentane/ethyl acetate 4:1 v/v as eluent on silica) to give methyl 5-isopropyloxy-6-methylthionicotinoate (2.36 g) as a pale yellow oil. [Elemental analysis: C, 54.40; H, 6.24; N, 5.88%. calculated: C, 54.75; H, 6.27; N, 5.81%.].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:18])[C:8]=1[O:9][C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23]>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25]([NH:24][C:22](=[O:23])[C:21]2[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:20]=2[F:19])=[O:26])[CH:6]=[C:7]([Cl:18])[C:8]=1[O:9][C:10]([F:17])=[C:11]([F:16])[C:12]([F:14])([F:15])[F:13]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(OC(F)=C(F)C(F)(F)F)c(Cl)c1
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)=C(F)C(F)(F)F)c(Cl)c1
Temperature: 40 °C

Procedure:
Dissolve 0.77 g 3,5-dichloro-4-(1,2,3,3,3-pentafluoropropenoxy) aniline in 8 mL 1,2-dichloroethane under an atmosphere of nitrogen at room temperature. Add 0.50 g 2,6-difluorobenzoyl isocyanate dissolved in 5.8 mL dichloroethane dropwise over a 10 minute period. Stir and warm to 40° C. for a 2 hour period. Chill in ice water bath and filter the white solid 0.93 g, mp 177°-80° C. Proton nmr and mass spectra were consistent with the proposed structure. Anal. calcd C17 H7Cl2F7N2O3 :C, 41.57; H, 1.44; N, 5.70. Found: C, 41.65; H, 1.31; N, 5.59.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].Cl[C:37](OCC)=O>>[CH3:30][N:31]([CH3:35])[C:32]([N:25]1[CH2:24][CH2:23][CH:22]([NH:21][S:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:37])=[CH:11][CH:12]=2)(=[O:29])=[O:28])[CH2:27][CH2:26]1)=[O:33]
Reactant: CCOC(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CN(C)C(=O)Cl
Product: Cc1ccccc1NC(=O)c1ccc(S(=O)(=O)NC2CCN(C(=O)N(C)C)CC2)c2ccccc12

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid o-tolylamide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and dimethylcarbamyl chloride for ethyl chloroformate. Wt.: 35 mg (64%). 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H), 8.45 (d, 1H), 8.33 (d, 1H), 8.05 (d, 1H), 7.80 (d, 1H), 7.71 (m, 2H), 7.54 (s, 1H), 7.30 (m, 2H), 7.20 (m, 2H), 4.68 (d, 1H), 3.43 (m, 2H), 3.30 (m, 1H), 2.71 (s, 6H), 2.68 (m, 2H), 2.34 (s, 3H), 1.62 (m, 1H), 1.31 (m, 2H); LC/MS m/z 493 (M−H)−.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=O.[CH2:25]([NH2:28])[CH2:26][NH2:27]>C(O)C>[N+:22]([C:18]1[CH:17]=[C:16]([C:14]2[C:3]3[CH:4]=[C:5]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)[CH:6]=[CH:7][C:2]=3[NH:28][CH2:25][CH2:26][N:27]=2)[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cc(-c2ccncc2)ccc1F
Reactant: NCCN
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C2=NCCNc3ccc(-c4ccncc4)cc32)c1
Temperature: 180 °C
Yield: 56.2 %

Procedure:
A 5 mL microwave tube was charged with [2-fluoro-5-(4-pyridinyl)phenyl](3-nitrophenyl)methanone (100 mg), ethanol and ethylenediamine (100 mg) then heated to 180° C. for 600 s using microwave irradiation. The reaction was concentrated to dryness and residue was taken up in water then extracted with methylene chloride. The extracts were dried over magnesium sulfate, filtered and concentrated to an oil. Silica gel purification followed by trituration with ether provided 5-(3-nitrophenyl)-7-(4-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepine (60 mg) as a yellow powder. H1 NMR (d6-dmso): 8.42 (d, 2H), 8.28 (s, 1H), 8.27 (d, 1H), 7.84 (d, 1H), 7.66 (m, 2H), 7.38 (d, 2H), 7.26 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 1H), 4.00 (m, 2H), 3.60 (m, 2H). Mass (ES+)=345.3 (100%).