Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[C:31](B(O)O)[CH:30]=[N:29]2)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O.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>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH:32]=[C:31]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]4)=[CH:4][CH:3]=3)[CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cnn(-c4ccc(F)cc4)c3)cc2)C1
Temperature: 150 °C
Yield: 36.6 %

Procedure:
A mixture of (S)-tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (100 mg, 0.29 mmol), 1-(4-fluorophenyl)-1H-pyrazole-4-ylboronic acid (60 mg, 0.29 mmol), tribasic potassium phosphate (124 mg, 0.585 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.5 mg, 0.0117 mmol) in dimethylacetamide (2 ml) was placed in a microwave tube, closed and heated at 150° C. for 10 min using a microwave synthesizer (Personal Chemistry Emrys Optimizer). After cooling water (10 ml) was added, and the reaction mixture was extracted with ethyl acetate. The aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (12 g silica gel, 10 to 50% ethyl acetate in heptane) to yield a light brown solid (45 mg, 36%). MS (ISP): 424.1 ([M+H]+).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:21][C@H:22]([CH2:27][OH:28])[C@H:23]([CH2:25][CH3:26])[CH3:24])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:21][C@H:22]([CH:27]=[O:28])[C@@H:23]([CH3:24])[CH2:25][CH3:26])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Molecular sieves (15 g, 4 Å) were stirred in dry CH2Cl2 (175 mL) for 10 min. Then a mixture of pyridinium chlorochromate (8.6 g, 39.9 mmol) and silica gel (9 g) was added and the mixture was stirred an additional 10 min. To the suspension was added 5-chlorothiophene-2-sulfonyl isoleucinol (4 g, 13.4 mmol) dissolved in CH2Cl2 (15 mL) and the resulting slurry was stirred for 2 h. The reaction mixture was filtered and the solvent was removed. The residue was subjected to a Biotage™ eluting with 20% EtOAc/hexane to give 3.22 g (81%) of the aldehyde (LCMS=294.21 (M−H), rt=1.10 min).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:13][OH:14])[N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=12>CN(C=O)C.C1(C)C=CC=CC=1.O=[Mn]=O>[N:1]1[CH:2]=[C:3]([CH:13]=[O:14])[N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=12
Reactant: OCc1cnc2sc3ccccc3n12
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1cnc2sc3ccccc3n12
Yield: 101 %

Procedure:
A solution of imidazo[2,1-b]benzothiazole-3-methanol (Formula J-2) (2.0 g) in DMF (30 mL) and toluene (200 mL) was treated with MnO2 (4.5 g) and the mixture was azeotropically distilled for 4.5 hours. A second change of MnO2 (2.0 g) and distillation for 1 hour completed the conversion. The suspension was filtered, the combined filtrate and ethyl acetate washes of the cake were concentrated, the residue was diluted with water, and filtered to yield imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) (2.0 g). Crude imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) was used without further purification.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:14]=[C:13](F)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].O>C1COCC1>[F:3][C:4]1[CH:14]=[C:13]([NH:2][CH3:1])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CN
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Reaction time: 3 h

Procedure:
A 2M solution of MeNH2 in THF (21.6 mL; 43.3 mmol) is added dropwise to a solution of ethyl 2,4-difluoro-5-nitrobenzoate (5.0 g; 21.6 mmol) in THF (70 mL) at −5° C. The mixture is left overnight at rt whereafter an additional portion of 2M MeNH2 in THF (10.0 mL; 2 M; 21.6 mmol) is added at 0° C. After 3 h at rt, water is added and the mixture is concentrated. The resulting precipitate is filtered off and dried to give the sub-title compound. Yield: 5.0 g (96%).
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1C=[CH:17][NH:18]2>ClC(Cl)C>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:7]([CH:6]=[O:10])=[CH:17][NH:18]2
Reactant: COc1cccc2[nH]ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COc1cccc2[nH]cc(C=O)c12
Yield: 96.3 %

Procedure:
A solution of dry DMF (0.75 g) in 50 ml dichloroethane was cooled to 0° C. and placed under nitrogen. Oxalyl chloride (1.03 g) dissolved in dichloroethane (5 ml) was added dropwise with stirring. The solution was stirred until no more bubbling was observed (about 15-20 m). 4-Methoxyindole (1.0 g, 6.7 mmole) was added to the solution as a solid and the reaction mixture was stirred at room temperature for four hours. The reaction was quenched by careful addition of 10% sodium carbonate solution. The two phase mixture was stirred at room temperature for 2 hours. The layers were separated and the aqueous layer was extracted with methylene chloride, and the combined organic extracts were dried and evaporated to dryness. The crude residue was passed through a short silica gel column, eluting with 3:7 ethyl acetate:hexane to 1:1 ethyl acetate:hexane to yield 1.13 g (95%) of 4-methoxy-1H-indole-3-carbaldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:13][CH3:14])([O:11][CH3:12])[CH3:10].C([Li])(C)(C)C.[F:20][C:21]([F:37])([F:36])[C:22]1[CH:35]=[CH:34][C:25]([CH:26]=[N:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:12][O:11][C:9]([O:13][CH3:14])([CH3:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:36])([F:37])[F:20])=[CH:35][CH:34]=1)[NH:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29]
Reactant: COC(C)(Cc1ccccc1Br)OC
Reactant: CC(C)(C)[S@@](=O)N=Cc1ccc(C(F)(F)F)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(Cc1ccccc1C(N[S@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Bromo-2-(2,2-dimethoxypropyl)benzene (4.00 g, 15.43 mmol) was dissolved in 150 mL THF and tert-butyllithium (18.160 mL, 30.871 mmol) was added dropwise at −78° C. After addition a solution of (R)—N-(4-(trifluoromethyl)-benzylidene)-2-methylpropane-2-sulfinamide (8.5608 g, 30.871 mmol) in THF (10 mL) was added and stirring was continued for 10 min in the cold. The reaction was hydrolyzed with 50 mL water and the mixture was warmed to RT. TLC showed a 1:1 mixture of the 2 diastereomers. No attempt was undertaken to separate the isomers. Glass column chromatography provided the title compound as a mixture of diastereomers. MS (ESI, positive ion) m/z: 412.0 (M+1; hydrolysis of the dimethyl acetal to the corresponding ketone).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[CH:35]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH:35]1([C:40]([C:2]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=2[O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Reactant: O=C(Cl)C1CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)C3CCCC3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. Cyclopentanecarbonyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 7 hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (14 mg, yield 13%).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>C1COCC1.C(Cl)Cl>[Cl:26][C:5]1[CH:6]=[C:7]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])[C:2]([C:32]([C:33]2[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])=[O:42])=[N:3][CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.6 ml (1.2 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of a solution of phthalic anhydride (148mg, 1.0 mmol) in 1 ml of DCM. The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration the residue was purified by flash chromatograph (70% ethyl acetate in hexane) to afford 80 mg of title compound as an off white solid. MS: (M+H)/z =564.0, (M-32)/z =532.0.
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](O)=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>CN(C=O)C.CCOC(C)=O>[CH3:29][C:28]1[CH:27]=[CH:26][O:25][C:24]=1[C:22]([NH:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[CH:10]=[N:9][CH:8]=[C:7]([CH:12]=2)[C:5]([N:4]=[S:2]([CH3:1])([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][C:38]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[O:39])=[CH:34][CH:35]=2)=[O:3])=[O:6])[CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: C1COCCN1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)N4CCOCC4)cc3)c2)c1
Reaction time: 0.33 h
Yield: 40.9 %

Procedure:
3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid (0.050 g, 0.090 mmol) was dissolved in DMF (1 mL) then treated with BOP (0.051 g, 0.117 mmol) and TEA (0.050 mL, 0.360 mmol) and allowed to stir for 20 min. Morpholine (0.015 mL, 0.180 mmol) was then added and the reaction was allowed to stir for an additional 4 h. The resulting reaction mixture was dissolved in EtOAc (5 mL) and then extracted with brine (2×5 mL). The organic layer was then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was then purified via column chromatography (silica gel, gradient eluant mixture of MeOH in EtOAc: 0% to 0% MeOH) give the title compound (0.023 g, 41%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[C:8]([C:12]([O:14][CH2:15][C:16]([NH2:18])=[S:17])=[O:13])([CH3:11])([CH3:10])[CH3:9].ClCCl>C(O)C>[CH3:10][C:8]([CH3:11])([CH3:9])[C:12]([O:14][CH2:15][C:16]1[S:17][CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:18]=1)=[O:13]
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: O=C(O)C(=O)CBr
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCc1nc(C(=O)O)cs1
Reaction time: 15 h

Procedure:
To a solution of bromopyruvic acid (0.37 g, 2.22 mmol) and 2-(tert-butylcarbonyloxy)thioacetamide (0.41 g, 2.22 mmol) in ethanol (20 ml) was added 4 A molecular sieves (2 g). After stirring for 15 h, 20 mL of dichloromethane was added. The mixture was stirred 5 min and filtered to give the product as a yellow solid.
Reaction SMILES: [C:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC[O:26][CH2:27][CH3:28].Cl>[OH-].[Na+]>[C:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH:20][C:27](=[O:26])[CH2:28][CH2:17][CH2:18][CH2:19][C:21]([OH:23])=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)CCCCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
Nε-Lauroyl-L-lysine (30 g) was dissolved in 0.2M aqueous NaOH solution (1 L), and ether was added. Adipic acid monoethyl ester acid chloride (26.4 g) was added to the ether layer, and the mixture was stirred at room temperature for 24 hr. To the aqueous solution was added hydrochloric acid with stirring, and the mixture was adjusted to about pH 1. The precipitated crystals were filtered and recrystallized to give Nε-lauroyl-Nα-(5-carboxypentanoyl)-L-lysine (27.42 g, yield 66%). 4.566 g thereof was dissolved in methanol (50 ml), 1M aqueous NaOH solution (10 ml) was added, and the mixture was stirred at room temperature for 3 hr. The solution was filtered, the solvent was removed, and the obtained solid was recrystallized. yield 4.7 g, 99%.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[O:7][C:8]([O:10][CH2:11][CH3:12])=[N:9][C:4]=2[CH:3]=1.[N:16]1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[C:23]([NH:16][C:15]1[CH:2]=[CH:3][C:4]2[N:9]=[C:8]([O:10][CH2:11][CH3:12])[O:7][C:6](=[O:13])[C:5]=2[CH:14]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cl
Reactant: c1ccncc1
Reactant: CCOc1nc2cc(N)ccc2c(=O)o1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc2nc(OCC)oc(=O)c2c1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one (0.2 m mol., 41 mg) and dry pyridine (0.1 ml) in dry dichloromethane (4 ml) at room temperature under anhydrous conditions was added ethyl chloroformate (0.05 ml, 0.52 m mol.) in one portion. After stirring for one hour, the reaction mixture was diluted with dichloromethane (16 ml), washed successively with water (15 ml), 5% CuSO4) and evaporated to dryness. The residue was stirred in anhydrous ether (2 ml) and filtered to afford 53 mg (95%) of the title compound, 7-carboethoxyamino-2-ethoxy-4H-3,1-benzoxazin-4-one as a colorless powder; m.p. 191°-193° C.; IR (KBr): νmax 3310 cm-1 (NH), 1735 cm-1 (ester, carbamyl); 1640 cm-1 (C=N); H'NMR (CDCl3): δ1.34 ppm (t, J=7.1 Hz, 3H, CH3CH2OCON), 1.44 ppm (t, J=7.1 Hz, 3H, CH).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH:19]=[CH:18]1>>[CH2:10]([N:8]([O:9][CH:19]1[CH2:18][C:17](=[O:23])[NH:21][C:20]1=[O:22])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=O)N1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Product: O=C1CC(ON(Cc2ccccc2)Cc2ccccc2)C(=O)N1
Yield: 69.6 %

Procedure:
The procedure of Example 1 is repeated using 5.33 g (25 mmole) of N,N-dibenzylhydroxylamine and 2.42 g (25 mmole) of maleimide. The residue is purified by preparative HPLC (Silica gel: 4:1 heptane:ethyl acetate eluent) to give 5.4 g (74%) of a colorless gum.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>O.CC#N>[NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: OB(O)c1cncnc1
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3cncnc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide, pyrimidin-5-ylboronic acid, and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate in H2O-MeCN. MS APCI (+) m/z 364 (M+1) detected; 1H-NMR (400 MHz, CDCl3) d 9.21 (s, 1H), 9.01 (s, 2H), 7.50 (s, 1H), 7.43 (d, 1H), 7.27-7.29 (m, 1H), 6.84 (s, 1H), 3.47 (br s, 4H), 2.84 (s, 2H), 1.63-1.72 (m, 4H), 0.94 (t, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][N:16]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(O)C.[OH-:27].[Na+].[OH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]([OH:29])=[O:27])=[CH:17][N:16]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C#N)cn1
Agent: [Na+]
Solvent: CCO
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 52.5 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinonitrile (58.8 g, 190 mmol) was suspended in water (440 mL) and ethanol (600 mL) and treated with 32% sodium hydroxide solution (178 mL 1.92 mol). The mixture was heated to 50-55° C. and subsequently stirred at this temperature for 15 hour. The slightly turbid mixture was polish filtered to remove the ether by-product 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxymethyl-3-(4-fluoro-phenyl)-5-methyl-isoxazole. The first vessel and the transfer lines were rinsed with a mixture of water (50 mL) and ethanol (50 mL). The filtrate was treated at 20-25° C. within one hour with 25% hydrochloric acid (approx. 280 mL) until the pH was <2.0. The resulting suspension was stirred for one hour at room temperature. The crystals were filtered off, washed with a mixture of ethanol (200 mL) and water (200 mL) and subsequently dried at 50° C./<25 mbar until constant weight to afford 52.0 g (83%) of the title acid as an off-white solid with a purity of 99.5%.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20](C(Cl)=O)=[CH:21][CH:22]=[CH:23][CH:24]=1.[NH2:34][CH2:35][CH2:36][C:37]([NH2:39])=[O:38]>>[NH2:39][C:37](=[O:38])[CH2:36][CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18]
Reactant: NCCC(N)=O
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCCC(N)=O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]carbonyl chloride, and 3-aminopropanamide, the title compound was obtained in 71% purity by HPLC. MS(ESI+): m/z=409.
Reaction SMILES: [BrH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:14])[C:9]=2[OH:13])[C:4]1=[O:15].[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1>>[C:16]1(=[N:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([OH:14])[C:9]=3[OH:13])[C:4]2=[O:15])[CH2:19][CH2:18][CH2:17]1.[BrH:1].[CH:16]1([NH:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([OH:14])[C:9]=3[OH:13])[CH:4]2[OH:15])[CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Reactant: O=C1CCC1
Agent: Br
Product: O=C1c2ccc(O)c(O)c2CCC1N=C1CCC1
Product: Oc1ccc2c(c1O)CCC(NC1CCC1)C2O

Procedure:
In a manner similar to that of Example 23, 1 part of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide is reacted with 20 volume parts of cyclobutanone. Via 2-cyclobutylideneamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone, 0.5 part of 2-cyclobutylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide is obtained as colorless crystals melting at 190°-200° C (decomposition). This product was identified as the compound according to Example 35 by mixed melting point.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.[CH2:15]([O:17][C:18]([C:20]#[C:21][C:22](OCC)=[O:23])=[O:19])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]([C:20]1[N:6]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=3)=[CH:4][S:3][C:2]2=[N:1][C:22](=[O:23])[CH:21]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CCc1ccc(-c2csc(N)n2)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2scc(-c3ccc(CC)cc3)n12
Reaction time: 8 h

Procedure:
10 g of 2-amino-4-(4'-ethylphenyl)-thiazole are dissolved in 50 ml of ethanol and 8.4 g of acetylene dicarboxylic acid diethyl ester are added to the resulting solution. After standing overnight, the mixture is concentrated by evaporation in vacuo to dryness at a bath temperature of 40° to 50° C. 50 ml of chlorobenzene are added to the residue, followed by heating unter reflux for 1 hour. After concentration by evaporation in vacuo, the residue is dissolved in ether, treated with carbon, filtered and petroleum ether subsequently added. The product precipitating is washed with a little ether and dried. 3-(4'-ethylphenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 142°-144° C. is thus obtained.