Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:22][NH:23][CH3:24]>C(O)C>[CH3:22][N:23]([CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:24]
Reactant: CNC
Reactant: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Solvent: CCO
Product: COC(=O)c1cccc2nc(-c3cccc(CN(C)C)c3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.2 %

Procedure:
Methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (70 mg, 0.2 mmol) and dimethylamine (72 mg, 1.6 mmol) were added to ethanol (30 mL) and the mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated under reduced pressure to obtain methyl 2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (74 mg, yield 86%). LC-MS (ESI) m/z 310 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:17])[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:4]=1[N+:18]([O-])=O>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:17])[CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[CH:5][C:4]=1[NH2:18]
Reactant: COc1ccc(N(C)CC2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N(C)CC2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a stirred solution of 3.5 g (12.5 mmol) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-ylmethyl)-amine in 230 ml methanol was added 70 mg 10% palladium on charcoal and the mixture was then stirred for 18 hours at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate concentrated in vacuo to afford 2.20 g (70%) 4-methoxy-N1-methyl-N1-(tetrahydropyran-4-ylmethyl)-benzene-1,3-diamine as a dark brown oil. ES-MS m/e (%): 251 (M+H+, 100).
Reaction SMILES: C[Al](C)C.CCCCCC.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[NH:27][C:28]1[N:42]([CH3:43])[C:31]2=[N:32][C:33]([O:40][CH3:41])=[C:34]([C:36](OC)=[O:37])[CH:35]=[C:30]2[N:29]=1>C1COCC1.O.C(O)(=O)C.CO>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:36]([C:34]2[CH:35]=[C:30]3[N:29]=[C:28]([NH:27][C:21]4[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=4[Cl:19])[N:42]([CH3:43])[C:31]3=[N:32][C:33]=2[O:40][CH3:41])=[O:37])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)n(C)c2nc1OC
Agent: C[Al](C)C
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1nc2c(cc1C(=O)Nc1ccc(Br)cc1)nc(Nc1c(Cl)cccc1Cl)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 M trimethyl aluminium solution in hexane (0.35 mL, 0.35 mmol) was added to 4-bromo-aniline (50 mg, 0.31 mmol) in 3.0 mL THF and the mixture stirred at ambient temperature for 1 h. Then methyl 2-(2,6-dichlorophenylamino)-5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate (0.10 g, 0.26 mmol) was added and the mixture stirred at 60° C. for 16 h. Then methanol and acetic acid were added, the mixture poured into water. The precipitate was filtered off, washed with water and dried. Then the product was purified by preparative HPLC (RP Symmetry C18, 8 μm; eluent gradient: (water+0.15% formic acid)/acetonitrile=85:15→0:100).
Reaction SMILES: [F:1][C:2]([F:26])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[F:26][C:2]([F:1])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N+:23]([O-:35])=[CH:22][CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccncc3)n2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg (1.37 mmol)of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4(4-pyridyl)-2-pyrimidineamine are suspended in 10 ml of methylene chloride; 430 mg (1.37 mmol) of m-chloroperbenzoic acid are added and the reaction mixture is stirred for 4 h at RT. After extraction with water and 2N aqueous sodium hydroxide solution, the organic phase is dried and concentrated using a rotovapor. Chromatography (methylene chloride/methanol=19:1 to 9:1) and subsequent crystallisation (methylene chloride/diethyl ether) give N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(N-oxido-4-pyridyl)-2-pyrimidineamine in the form of lemon-yellow crystals; FAB-MS: 381 (M+ +H), m.p. 191°-192°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[C:10](=O)[O:9][C:8]([CH3:12])=[N:7]1.[CH3:17][NH2:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:12][C:8]1[N:18]([CH3:17])[C:10](=[O:9])[C:6](=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[O:2][CH3:1])[N:7]=1
Reactant: CN
Reactant: COc1ccccc1C=C1N=C(C)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccccc1C=C1N=C(C)N(C)C1=O
Temperature: 80 °C

Procedure:
4-(2′-Methoxybenzylidene)-2-methyl-4H-oxazol-5-one (5 g) was dissolved in ethanol (100 ml) and aqueous methylamine solution (20 ml) and potassium carbonate (7 g) were added. The mixture was heated at 80° C. for 7 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give the title compound (2 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([NH:13][CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:29][CH:26]3[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:22])[CH2:24][CH2:25]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCN[C@@H](C)Cc1ccc2c(c1)CCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
To a solution of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamine (2.38 grams, 11.6 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxaldehyde (2.47 grams, 11.6 mmol) in dichloroethane (20 ml) was added sodium triacetoxyborohydride (3.67 grams,17.4 mmole). The reaction mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with water, dried over potassium carbonate and concentrated under reduced pressure to leave a residue, which was purified by flash chromatography on silica gel using 30% ethyl acetate in hexane. Appropriate fractions were combined and concentrated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine as a oil (3.78 g, 82%), M+H 403.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[O:26])=[CH:20][CH:19]=1>C1COCC1>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:26])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[CH:22][CH:23]=1
Reactant: COC(C)=O
Reactant: O=CCc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CC(O)Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A solution of diisopropylamine (0.241 mL, 1.72 mmol) in anhydrous THF (1.5 mL) was treated with n-BuLi (1.6 M in hexane, 0.7 mL, 1.72 mmol) at −78° C. The mixture was kept at this temperature for 1 h, and then a solution of methyl acetate (0.137 mL, 1.72 mmol) in anhydrous THF (1 mL) was added at −78° C. The reaction mixture was stirred for 1 h at −78° C., and a solution of 2-(biphenyl-4-yl)acetaldehyde (S90, 282 mg, 1.43 mmol) in anhydrous THF (2 mL) was added. The reaction mixture was stirred for another hour, then quenched by the addition of saturated aqueous NH4Cl, which was extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 50% Et2O-hexanes) yielded the title compound (226 mg, 58%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.64 (dd, 2H, J=7.2 Hz), 7.58 (dd, 2H, J=8.0 Hz), 7.49 (t, 2H, J=7.6 Hz), 7.38 (t, 1H, J=7.0 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.38-4.34 (m, 1H), 3.71 (s, 3H), 3.35 (s, 1H(—OH)), 2.97-2.82 (m, 2H), 2.61-2.43 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 172.7, 140.5, 139.1, 136.6, 129.6, 128.5, 126.9, 126.7, 68.7, 51.4, 42.3, 40.3.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[O:21][CH2:22][CH2:23][O:24]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[O:21][CH2:22][CH2:23][OH:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCOC3CCCCO3)c(C3CCCCC3)c2s1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCO)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of methyl 6-cyclohexyl-5-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-thieno[3,2-b]pyrrole-2-carboxylate (863 mg, 1.63 mmol) in tetrahydrofuran (4.0 ml) and methanol (4.0 ml) was added 6N hydrochloric acid (4.0 ml) and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give methyl 6-cyclohexyl-5-[2-(2-hydroxyethyloxy)-3-nitrophenyl]-4H-thieno[3,2-b]pyrrole-2-carboxylate (628 mg, yield 86%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:37]=[CH:36][C:8]2[N:9]([CH2:24][C:25]3[CH:29]=[C:28]([C:30]4[S:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[O:27][N:26]=3)[C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>>[Cl:35][C:32]1[S:31][C:30]([C:28]2[O:27][N:26]=[C:25]([CH2:24][N:9]3[C:8]4[CH:36]=[CH:37][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=[C:10]3[C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:21][CH2:22]4)[CH2:16][CH2:15]3)[CH:29]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc2c(c1)nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc2c(c1)nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
7.84 g (14.52 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester were dissolved in 400 mL MEOH. 72.59 mL (72.59 mmol) of a 1 M aqueous LiOH-solution were added and the resulting mixture was stirred for 7 h at 60° C. The solution was concentrated to a volume of approx. 200 mL and acidified by the addition of a 4 M aqueous HCl-solution until pH≈1 was reached. After 30 minutes the resulting precipitate was filtered off and washed several times with cold MeOH. Recrystallization from MEOH gave pure 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid in form of a colorless, crystalline solid. The title compound was obtained as its monohydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:3]=1[CH:4]=[N:5]O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[C:20]([O:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:3]=1[C:4]#[N:5])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCc1ccc(O)c(C=NO)c1
Solvent: O
Product: CCCCCCCCCc1ccc(OC(C)=O)c(C#N)c1
Reaction time: 1 h

Procedure:
A solution of 52.6 parts of 2-hydroxy-5-nonyl-benzaldoxime (in which the nonyl group is a mixture of branched chain isomers; prepared as described in Example 1 of Belgian Pat. No. 796835) in 60 parts of acetic anhydride was stirred and boiled for 1 hour. The cooled solution was poured into water, stirred for 30 minutes and extracted into 2 × 150 parts of chloroform. The extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated at 50° C under vacuum to yield 61.6 parts of 2-acetoxy-5-nonylbenzonitrile as a brown oil. The 61.6 parts of the acetoxy compound were mixed with 200 parts of ethanol and 300 parts of a 2N solution of sodium hydroxide and the mixture stirred and boiled under reflux for 11/2 hours. The cooled solution was acidified with hydrochloric acid, diluted with water and extracted into chloroform. The extracts were water washed, dried over anhydrous magnesium sulphate and evaporated to give 53.1 parts of 2-hydroxy-5-nonylbenzonitrile as a brown oil.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][CH3:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[C:7]2=[O:15].[C:25]([Cu])#[N:26].[C-]#N.[K+]>CN1C(=O)CCC1>[F:14][C:10]1[C:11]([NH:12][CH3:13])=[C:2]([C:25]#[N:26])[C:3]2[CH:4]=[CH:5][N:6]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[C:7](=[O:15])[C:8]=2[CH:9]=1
Reactant: N#C[Cu]
Reactant: CNc1c(F)cc2c(=O)n(-c3ccc([N+](=O)[O-])cc3)ccc2c1Br
Agent: [C-]#N
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1c(F)cc2c(=O)n(-c3ccc([N+](=O)[O-])cc3)ccc2c1C#N
Temperature: 50 °C
Yield: 130 %

Procedure:
A 110 mg (0.28 mmol) portion of 5-Bromo-7-fluoro-6-methylamino-2-(4-nitro-phenyl)-2H-isoquinolin-1-one (Example 107) and 55 mg (2.2 equiv) of CuCN in 1.4 mL of NMP was heated to 200° C. for 2 h. After cooling to 50° C., 10 mL of 10% aq KCN was added, and mixture was stirred, filtered, washed with water and dried to give 123 mg (130%) of 7-Fluoro-6-methylamino-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinoline-5-carbonitrile. A 50 mg (0.15 mmol) portion of this 5-cyano material was reduced with 36 mg of Raney Nickel (Aldrich) in 1:1:2 water/AcOH/pyridine containing 58 mg of sodium hypophosphite. The reaction was then extracted 3 times with ethyl acetate, drying over Na2SO4 (anh.), and concentration in vacuo afforded 10 mg (20%) of the resulting aniline. This material was then coupled using the method described in Example 13 to give 7.8 mg (46%) of 5-chloro-N-[({4-[5-cyano-7-fluoro-6-(methylamino)-1-oxoisoquinolin-2(1H)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+=532.1 (Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.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.O>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1cc(Br)cc(C(=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: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of 3-bromo-5-methylbenzoic acid (3.0 g, 13.95 mmol, 1.0 eq), 3-fluorophenylboronic acid (2.34 g, 16.74 mmol, 1.2 eq) and Na2CO3 (5.91 g, 55.8 mmol, 4.0 eq) in a mixture of EtOH (10 mL), DMF (40 mL) and H2O (10 mL) was added Pd(PPh3)4 (806 mg, 0.7 mmol, 0.05 eq). The mixture was stirred at 100° C. overnight. Water was added and the aqueous layer extracted with EtOAc. The organic extract was discarded and the aqueous layer was acidified to pH 4-5 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were filtered through silica gel and concentrated to give the title compound as a white solid (2.0 g, 62%)
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([NH:31]N)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:21]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1cccc2ccccc12
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=365.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]([OH:10])[CH2:8][CH3:9])=[CH:5][N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1
Reactant: CCC(O)c1cnc(Br)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(=O)c1cnc(Br)s1
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a solution of 1-(2-Bromo-thiazol-5-yl)-propan-1-ol (175 mg, 0.79 mmol) in dichloromethane (10 mL) was added Dess-Martin periodinane (334 mg, 0.79 mmol). The reaction was stirred for 2 h, then diluted with dichloromethane (50 mL), washed with sat. sodium bicarbonate solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes gave 1-(2-bromo-thiazol-5-yl)-propan-1-one (75 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@H:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[NH3:31]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@H:7]([CH2:10][C:11]([NH2:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: N
Reactant: CCOC(=O)C[C@@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Product: NC(=O)C[C@@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 45 h
Yield: 27.4 %

Procedure:
Ethyl {(3R)-7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21b, 2.00 g, 4.64 mmol) dissolved in ammonia (7 M in MeOH) (49.7 mL, 348.2 mmol) sealed and stirred at rt for 45 h. The solvent was evaporated and the residue (616 mg crude brown oil) was dissolved in DMSO and MeOH. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-50% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min. The compounds were detected by UV at 253/280 nm. Pure fractions were pooled and the most of the ACN was evaporated. The residue was partitioned between EtOAc and water. The combined organic phases were concentrated in vacuo. Addition of DMSO/ACN and water a precipitate was observed. The solvents were removed in vacuo and water was added to the residue and stirred at rt over night and filtered off to give pure title compound according to LCMS. 511 mg of off white solids were isolated, yield 27.4%.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[C:7]([N+:14]([O-])=O)[CH:6]=1.C>CO.[Fe](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[C:7]([CH:6]=1)[NH2:14]
Reactant: CC(C)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(Cl)cc1N
Yield: 93.8 %

Procedure:
A solution of hydrazine hydrate (1.7 mL, 35.1 mmol) in methanol (12 mL) was added drop wise to a solution of 4-chloro-2-nitro-1-(propan-2-yl)benzene (1.75 g, 8.8 mmol) in methanol (40 mL), in the presence of iron (III) chloride (146 mg, 0.9 mmol) and activated charcoal (146 mg) and the reaction mixture was stirred under reflux for 7 h. The solid was filtered over celite, the filtrate concentrated and purified by flash chromatography (hexane/EtOAc 9/1) to obtain the title compound as a light-pink oil (1.4 g, 94%).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>C(Cl)(Cl)Cl.CS(C)=O>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([O:35][C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn2c3c(c(OC4CCN(C(=O)OC(C)(C)C)C4)c(F)cc3c1=O)OCC2C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.3 %

Procedure:
To a mixture of 263 mg of ethyl 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine6-carboxylate, 318 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 194 mg of DBU and 3 ml of DMSO was added 74 mg of 55% sodium hydride while the former was stirred at room temperature for 2.5 hours. After the resultant mixture was stirred at room temperature, the reaction mixture was diluted with chloroform and then successively washed with 10% citric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness. The residue was purified by chromatography on silica gel (chloroform/methanol: 100/1), whereby 220 mg of ethyl 10-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-9-fluoro2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylate was obtained.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH:4]=[O:5])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OCC)(=O)C>C1C=CC=CC=1>[Br:16][CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([N:3]([CH2:1][CH3:2])[CH:4]=[O:5])[O:7][C:8]=2[CH:14]=1
Reactant: CCN(C=O)c1nc2ccc(C)cc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCN(C=O)c1nc2ccc(CBr)cc2o1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
The mixture of 2-(N-ethylformamido)-6-methylbenzoxazole (7.6 g), N-bromosuccinimide (6.6 g) and benzoyl perioxide (0.2 g) in benzene (150 ml) was refluxed for 70 minutes and the mixture was cooled to ambient temperature. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated in a mixture of diisopropyl ether and n-hexane to give 6-bromomethyl-2-(N-ethylformamido)benzoxazole (6.18 g).