Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:26])[C:8]([C:12]3[CH:16]=[C:15]([NH:17][C:18](=[O:25])[CH2:19][C:20](OCC)=[O:21])[NH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1>CO.O1CCCC1.O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:26])[C:8]([C:12]3[CH:16]=[C:15]4[N:17]=[C:18]([OH:25])[CH:19]=[C:20]([OH:21])[N:14]4[N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2nc3cc(F)ccc3nc2C)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(F)cc2nc1-c1cc2nc(O)cc(O)n2n1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
To a suspension of ethyl 3-{[3-(7-fluoro-3-methylquinoxalin-2-yl)-1H-pyrazol-5-yl]amino}-3-oxopropanoate (30.0 g, 84.0 mmol) in methanol (210 mL), tetrahydrofuran (210 mL) and water (210 mL) was added 4-dimethylaminopyridine (51.3 g, 420 mmol) at ambient temperature. After being stirred at 85° C. for 5 h, the reaction mixture was diluted with ethyl acetate (750 mL) and water (750 mL) at ambient temperature. And the insoluble material was filtered off. The filtrate was washed with water (450 mL). The combined aqueous layer was washed with ethyl acetate (500 mL×2), and acidified to pH 2 with conc. Hydrochloric acid (17.0 mL) at ambient temperature, and then stirred for overnight. The resulting precipitate was collected and washed with water to give 2-(7-fluoro-3-methylquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol. MS (APCI): m/z 312 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:3]([CH3:12])[C:2]=1[F:1]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc(F)c1C
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(F)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of N-(3-fluoro-2-methylphenyl)acetamide (72A) (1.71 g, 10.2 mmol) in acetic acid (15 mL) at 0° C. was added bromine (1.68 mL, 32.8 mmol) over 15 min. The mixture was stirred at rt for 2 h, and was then poured into ice (50 g). The mixture was filtered and concentrated under reduced pressure to give the title compound (2.26 g). LCMS: m/z 246[M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[S:19][C:20](S(C)(=O)=O)=[N:21][N:22]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.[OH-:37].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[S:19][C:20]([OH:37])=[N:21][N:22]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3F)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1nnc(-c2ccc3[nH]cc(-c4ccc(F)cc4F)c3c2)s1
Reaction time: 0.17 h
Yield: 11.28 %

Procedure:
A solution of 2-(3-(2,4-difluorophenyl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (0.010 g, 0.018 mmol), dioxane (0.5 mL), and NaOH (1 M, 0.1 mL) was heated in a Biotage microwave for 10 min at 100° C., then at 120° C. for an additional 10 min. The mixture was purified by preparative HPLC (20-90% AcCN/H2O/0.1% TFA) to give 5-(3-(2,4-difluorophenyl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-ol (1 mg, 2.068 μmol, 11.28%). MS (ESI, pos. ion) m/z: 330 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (1H, s), 7.67-7.75 (1H, m), 7.53-7.64 (3H, m), 7.07-7.15 (2H, m).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH2:12][CH3:13])(=[O:10])[C:5]([O:7]CC)=O.C(O)C.[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH3:26]>CO>[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH2:26][C:5](=[O:7])[C:4]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1ncc([N+](=O)[O-])n1C
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ncc([N+](=O)[O-])n1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 180 parts of a 30 percent strength by weight sodium methylate solution in methanol, 146 parts of diethyl oxalate and 150 parts by volume of ethanol is added in the course of 30 minutes, at 60° C., to a suspension of 141 parts of 1,2-dimethyl-5-nitroimidazole in 250 parts by volume of ethanol. After stirring for one hour at 60° C., the mixture is cooled and the sodium enolate of ethyl 1-methyl-5-nitroimidazol-2-yl-pyruvate is filtered off. The salt is then introduced into 1,300 parts by volume of 3 percent strength by weight hydrochloric acid, whilst stirring. The mixture is stirred for a further half-hour and the product is then filtered off. 190 parts (79% of theory) of ethyl 1-methyl-5-nitroimidazol-2-yl-pyruvate of melting point 141° C. (after recrystallization from ethanol) are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
4-Nitrobenzenethiol (23.99 mmol, 4.653 g) and sodium hydride (32.9 mmol, 1.314 g) were combined in tetrahydrofuran and stirred at 0° C. for 30 minutes. tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (36.0 mmol, 10.05 g) was added and the reaction mixture stirred and heated overnight at 60° C. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and water, the organic layer was separated, dried, and concentrated under vacuum. The residue was purified by silica column chromatography (eluting with a 0-10% methanol/dichloromethane gradient) to afford the title compound (2.90 g).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([NH:11][C@H:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[O:10])[CH:3]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:30]([C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([NH:11][C@H:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[O:10])[CH:3]=1)#[N:31]
Reactant: CN(C)C=O
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1c[nH]c(=O)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)c[nH]c1=O

Procedure:
To a solution of (S)-5-bromo-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (0.080 g, 0.170 mmol) in DMF (0.5 mL) was added zinc(II) cyanide (0.043 mL, 0.681 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol). The resulting mixture was then subjected to a microwave irradiation at 130° C. for 30 min. Then, the mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.63 (d, J=2.5 Hz, 1H), 8.51 (d, J=4.7 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 7.55-7.73 (m, 6H), 7.47 (dt, J=8.5, 4.4 Hz, 1H), 6.75 (s, 1H). MS (ESI pos. ion) m/z: 417.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10]CCOCCOCCO)=[O:9])(=[O:3])[CH3:2].[Cl-].C(OC1C(=CC=CC=1)C(O)=O)(=O)C.[CH2:40]([OH:44])[CH:41]([OH:43])[CH3:42]>>[CH2:40]([OH:44])[CH:41]([OH:43])[CH3:42].[C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O-:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OCCOCCOCCO)c(O)c1C(C)=O
Agent: CC(=O)Oc1ccccc1C(=O)O
Agent: [Cl-]
Solvent: CC(O)CO
Product: CC(=O)c1ccc(C(=O)[O-])c(O)c1C(C)=O

Procedure:
The compound (V) was prepared according to the procedure described in Example 1 for the synthesis of (XIX), starting from 5,6 g of the chloride of acetylsalicylic acid, 3.8 ml of TEA and 1.06 g of 1.2-propanediol. The product was purified by flash chromatography utilizing an eluent mix constituted by ethylether/hexane 6:4 (v/v). The intermediate fractions were collected, the solvent was evaporated under reduced pressure and 0.55 g of 1.2-propanediol-bis-acetylsalicylate (V) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[CH3:14][NH:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH2:12])[N:15]([CH3:14])[N:16]=2)=[CH:4][CH:3]=1
Reactant: N#CCC(=O)Cc1ccc(Cl)cc1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(Cc2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.8 %

Procedure:
A solution of 4-(4-chloro-phenyl)-3-oxo-butyronitrile (200 mg, 1 mmol, 1.0 equiv) and N-methylhydrazine (153 mg, 3.32 mmol, 3.2 equiv) in 4 mL of ethanol was heated at 100° C. in a sealed tube. After 4 d, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a yellow solid (188 mg, 80%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1)#[N:2].[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH2:13]([O:12][C:1]1[CH:3]=[C:4]2[C:5](=[C:10]([NH2:11])[N:2]=1)[N:6]=[CH:7][CH:8]=[CH:9]2)[CH3:14]
Reactant: N#CCc1cccnc1C#N
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2cccnc2c(N)n1
Yield: 14 %

Procedure:
To a 1 L round bottom flask was added 3-(cyanomethyl)picolinonitrile (3.56 g, 24.9 mmol), absolute ethanol (400 mL), followed by sodium ethoxide (11.1 mL, 21% solution w/v, 29.9 mmol). The mixture was stirred at reflux for 3 h. The solvent was then concentrated and the resultant residue was dissolved in ethyl acetate (200 mL), washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel to yield 6-ethoxy-1,7-naphthyridin-8-amine as a pale yellow solid (0.66 g, 3.49 mmol, 14%). 1H NMR (400 MHz, CDCl3): δ ppm 8.53 (dd, J=3.95, 1.76 Hz, 1H), 7.83 (dd, J=8.35, 1.76 Hz, 1H), 7.39 (dd, J=8.35, 4.39 Hz, 1H), 6.15 (s, 1H), 5.87 (br. s., 2H), 4.22 (q, J=7.03 Hz, 2H), 1.45 (t, J=7.03 Hz, 3H). LC/MS m/z 190 [M+H].
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:25]=1.N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[CH3:31][O:30][C:28]1[CH:29]=[C:24]([O:23][CH3:22])[N:25]=[C:26]([NH:32][C:33]([NH:1][S:2]([C:5]2[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:3])=[O:4])=[O:34])[N:27]=1
Reactant: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 166 mg (0.5 mmol) of methyl 2-(aminosulfonyl)-4-[(2,2,2-trifluoroethlidene)hydrazino]-benzoate and 137.5 mg (0.5 mmol) of phenyl (4,6-dimethoxy-pyrimidin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 86.1 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 15 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 20 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using dichloromethane as an eluent, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). The title compound was obtained as a white solid. Yield: 162 mg (64%). Melting point: 201°-202° C. Its physicochemical properties are shown in Table 4.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:35][CH3:36])=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])(=[O:14])=[O:13])[CH:11]=1)(=[O:5])=[O:4])=[CH2:2].[NH:37]([CH3:39])[CH3:38].C1COCC1>C1COCC1>[CH3:38][N:37]([CH3:39])[CH2:2][CH2:1][S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:35][CH3:36])=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])(=[O:13])=[O:14])[CH:11]=1)(=[O:4])=[O:5]
Reactant: CNC
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)CCN(C)C)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxy-benzenesulfonylamino) -phenyl]-amide (0.5 mmol), as prepared above, in dry THF (10 mL), Me2NH-THF solution (2.5 mL; 2 M Me2NH in THF solution) was added. The resulting reaction mixture was stirred at room temperature for 30 min. After removal of the solvent under vacuum, the residue obtained was purified by flash column chromatography eluting with EtOAc then DCM/methanol (100:2 to 100:10) to give 290 mg of benzo[b]thiophene-2-sulfonic acid {2-[5-(2-dimethylaminoethanesulfonyl)-2-methoxybenzenesulfonylamino]phenyl}-amide. LC: Tr 0.99 min; MS: 610.7 (M+1)+.
Reaction SMILES: [CH2:1]([OH:7])[C@H:2]([OH:6])[CH2:3][CH2:4][OH:5].C(=O)(O)[O-].[Na+].[CH3:13][C:14]([CH3:16])=O>Cl(O)(=O)(=O)=O.O>[C:14](=[C:1]([OH:7])[C@H:2]([OH:6])[CH2:3][CH2:4][OH:5])([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: OCC[C@@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CC(C)=C(O)[C@H](O)CCO
Reaction time: 0.17 h
Yield: 31 %

Procedure:
(R)-(+)-1,2,4-Butanetriol (0.7 g, 6.6 mmol), prepared as described in step a) above, was stirred for 1.5 h in acetone (50 ml) containing 3 drops of conc. perchloric acid, a satured solution of sodium bicarbonate in water (5 ml) was added and the stirring was continued for additional 10 min. The precipitate was filtered off and the filtrate evaporated under reduced pressure (2.7 kPa, 30° C.). The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate (5 ml) and brine (5 ml), and dried over magnesium sulphate. Evaporation of the solvent and distillation gave the title compound as a colourless oil (0.3 g, 2.05 mmol, 31%): b.p. 104°-106° C. at~2.7 kPa. nD20 =1.4390.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[C:7](=[N:9][OH:10])[NH2:8].[C:15](OC(=O)C)(=O)[CH3:16]>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[C:7]1[N:8]=[C:15]([CH3:16])[O:10][N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(/C=C/c1cccc(Cl)c1F)=NO
Product: Cc1nc(/C=C/c2cccc(Cl)c2F)no1
Reaction time: 2 h
Yield: 75.6 %

Procedure:
6.4 g (0.03 mol) of (E)-3-chloro-2-fluoro-cinnamamide oxime are introduced into 50 ml of acetic anhydride and the mixture is stirred for 2 hours at reflux temperature. The entire batch is subsequently concentrated in vacuo, the residue is stirred with sodiumcarbonate solution and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and the solvent is distilled off. 5.1 g (75.6 % of theory) of (E)-3-(3-chloro-2-fluoro-styryl)-5-methyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[NH2:39][CH2:40][CH2:41][N:42](C)[C:43](=O)OC(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:39][CH2:40][CH2:41][NH:42][CH3:43])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(CCN)C(=O)OC(C)(C)C
Product: CNCCNc1nc(-c2cc(NC(=O)c3cccs3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and 1,1-dimethylethyl (2-aminoethyl)methylcarbamate: LC-MS m/z 547 (M+H)+, 1.80 min (ret time).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)(C)(C)C>>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:16]2[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[CH:14][N:15]=2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cn2)CC1

Procedure:
4-[5-(4-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from N-(4-tert-butyl-phenyl)-6-chloro-nicotinamide and 1-Boc-piperazine following a procedure similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was obtained after silica gel column purification with 10-30% EtOAc in hexanes gradient. HRMS m/z calcd for C25H34N4O3 [M+H]+: 439.2704. Found; 4392700.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CC1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.068 mMol) cyclopropanecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 311(M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:18][C:19](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:20]>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1)(=[O:20])[CH3:18]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Nc1ccc(/C=C/C(=O)c2cccnc2)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(/C=C/C(=O)c2cccnc2)cc1

Procedure:
Ketone 30t was prepared from aniline 30r (0.045 mmoL), treated with 500 μL of a solution 40% anhydrous acetic in pyridine at room temperature for 2 hours. The solvent was removed and the product was precipitated with 1N NaOH. The solid was washed with water and obtained as a yellow solid (77% yield). mp 191-193° C. 1H NMR (CDCl3) δ 9.21 (s, 1H), 8.79 (s, 1H), 8.27 (dt, 1H, J=7.9 Hz, 1.8 Hz), 7.78 (d, 1H, J=15.7 Hz), 7.59 (s, 4H), 7.39 (m, 3H), 2.19 (s, 3H). 13C NMR (CDCl3) δ 189.42, 169.02, 153.39, 149.99, 145.83, 140.87, 136.29, 133.97, 130.08, 124.07, 120.50, 120.03, 25.11. HRMS (FAB) calcd for C16H15N2O2 ([M+H]+): 267.1128. found 267.1141.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]4[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1>>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]5[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:27]=[CH:26][N:25]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(-c4ccnc(F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 65 mg, 0.181 mmol) and 2-fluoropyridine-4-boronic acid (Frontier Scientific, Logan, USA, 33 mg, 0.236 mmol) to give the title compound as a pink solid. (HPLC: tR 2.55 min (Method A); M+H=375 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.08 (s, 1H), 8.35-8.26 (m, 1H), 8.22-8.13 (m, 1H), 8.10-8.01 (m, 1H), 7.84-7.76 (m, 1H), 7.43-7.35 (m, 1H), 7.29-7.23 (m, 1H), 7.23-7.16 (m, 1H), 6.73 (s, 1H), 3.68 (s, 3H), 3.60 (s, 3H))
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-])=O.[Cl:16][CH2:17][C:18](Cl)=O.P(Cl)(Cl)(Cl)=O>[Ni].C(O)C>[Cl:16][CH2:17][C:18]1[O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N:13]=1
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)CCl
Agent: [Ni]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccc2oc(CCl)nc2c1

Procedure:
Ethyl 4-hydroxy-3-nitrobenzoate (32 g) prepared according to the method described in J. Org. Chem., vol. 26, p. 2223 (1961) was subjected to reduction under increased pressure at 70 atm in the presence of a Raney Nickel catalyst in absolute ethanol (200 ml). The product was then caused to react with chloroacetyl chloride, and was subsequently subjected to ring closure with phosphorous oxychloride to yield 2-chloromethyl-5-ethoxycarbonylbenzoxazole (27.3 g). The chloromethyl compound (10 g) was caused to react with dimethylamine to yield 2-dimethylaminomethyl-5-ethoxycarbonylbenzoxazole (6 g), which was subsequently subjected to reduction with lithium aluminium hydride in anhydrous tetrahydrofuran (60 ml) thereby to obtain 2-dimethylaminomethyl-5-hydroxymethylbenzoxazole (2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1.[CH3:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[C:14]([CH3:27])[C:12]=1[NH2:13]>>[CH3:9][O:8][C:4]1[N:3]=[C:2]([C:16]2[CH:15]=[C:14]([CH3:27])[C:12]([NH2:13])=[C:11]([CH3:10])[CH:17]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Reactant: COc1nccc(Cl)n1
Product: COc1nccc(-c2cc(C)c(N)c(C)c2)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 4-chloro-2-methoxypyrimidine and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 60° C. LC (method 14): tR=0.89 min; Mass spectrum (ESI+): m/z=230 [M+H]+.