Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:25])[C@@H:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:29]>C(#N)C>[Br-:26].[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:28](=[O:29])[CH2:27][N+:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:25])[CH:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccc(F)cc1F
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1ccccc1)C2)c1ccc(F)cc1F
Product: [Br-]
Yield: 43.5 %

Procedure:
To a solution of (R)-phenyl-phenylamino-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Diastereoisomer 1 of C2) (50 mg, 0.15 mmol) in acetonitrile (1 mL), is added 2-bromo-1-(2,4-difluoro-phenyl)-ethanone (35 mg, 0.15 mmol) and the mixture reacted in a closed vessel under MW irradiation for 1 hour at 100° C. (UPLC-MS monitoring: complete conversion). The solvent is evaporated and the resulting crude is purified by flash chromatography (DCM/MeOH=95/5) to obtain the title compound as a white solid (37.3 mg, 44% yield, bromide salt, single diastereoisomer).
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:26])[NH:17][C:18]3[C:23]/2=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)/[CH:9]=1.[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>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.O>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:25])[NH:17][C:16](=[O:26])/[C:15]/2=[C:10]1\[CH:9]=[C:8]([C:34]2[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][CH:33]=2)[C:12]([CH3:14])([CH3:13])[O:11]\1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)c(F)cc43)OC2(C)C)cc1
Temperature: 86 °C

Procedure:
To 10 ml, of 1,4-dioxane, was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (250 mg, 0.73 mmol), 4-methoxycarbonylphenylboronic acid (158 mg, 0.88 mmol), PdCl2(PPh3)2 (25 mg, 0.036 mmol), 2M Na2CO3 aqueous solution (1.5 mL, 3.0 mmol). The mixture was heated at 86° C. under N2 for 2 hours, cooled to room temperature and poured into 100 mL of water. The brown precipitates were filtered, washed with water and dried to give the crude product. Purification through silica gel column with 1-2% MeOH/CHCl3 led to methyl 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate as orange/red solid. Yield: 112 mg, 39%.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]3[CH2:14][CH2:13][CH2:12][CH:7]3[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]3[CH2:14][CH2:13][CH2:12][CH:7]3[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:27])=[O:26]
Reactant: Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A stirred solution of 7-amino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide (150 mg; 0.5 mmol) and triethylamine (70 μl; 0.5 mmol) in THF (1 ml) was added a solution of CH3SO2Cl (40 μl; 0.5 mmol) in THF (1 ml) and stirred at rt. over night. The reaction mixture was evaporated to dryness, suspended in H2O and extracted by EtOAc. The combined organic fractions were evaporated to dryness. Column chromatography gave 40 mg product. M.p. 177-180° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH:24]([O-:26])=[O:25].[NH4+]>[Pd].CO>[NH:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1.[CH:24]([OH:26])=[O:25]
Reactant: O=C[O-]
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: O=CO
Product: c1ccc2[nH]c(CC3CCNCC3)nc2c1
Yield: 65.5 %

Procedure:
A mixture of 66 mg of 1-benzyl-4-((1H-benzimidazol-2-yl)methyl)piperidine (from EXAMPLE 164, Step A), 66 mg of 10% palladium on carbon and 68 mg of ammonium formate in 10 mL of MeOH was heated at reflux for 3 h. The mixture was cooled and filtered through celite. Concentration afforded 37 mg of the title compound as a foamy solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:21](=[O:22])[N:7]2[C@H:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][C@H:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:23].[OH-].[K+].[C:26]([O-:29])(=[S:28])[CH3:27].[K+].Cl.[N+](=[CH2:34])=[N-]>CO.O>[C:26]([S:28][CH2:2][CH2:3][N:4]1[C:21](=[O:22])[N:7]2[C@@H:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][C@H:11]([C:12]([O:14][CH3:34])=[O:13])[N:6]2[C:5]1=[O:23])(=[O:29])[CH3:27].[C:26]([S:28][CH2:2][CH2:3][N:4]1[C:21](=[O:22])[N:7]2[C@H:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][C@H:11]([C:12]([O:14][CH3:34])=[O:13])[N:6]2[C:5]1=[O:23])(=[O:29])[CH3:27]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)[C@H]1C=C[C@@H](c2ccccc2)n2c(=O)n(CCCl)c(=O)n21
Reactant: CC([O-])=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1C=C[C@@H](c2ccccc2)n2c(=O)n(CCSC(C)=O)c(=O)n21
Product: COC(=O)[C@H]1C=C[C@H](c2ccccc2)n2c(=O)n(CCSC(C)=O)c(=O)n21
Temperature: 80 °C
Reaction time: 20 h
Yield: 27 %
Yield: 1 %

Procedure:
A cooled solution of 12.08 g (0.036 mol) of cis-2-(2-chloroethyl)-2,3,5,8-tetrahydro-1,3-dioxo-8-phenyl-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid in 180 ml of methanol was treated with a solution of 2.37 g (0.036 ml) of potassium hydroxide in 15 ml of methanol. The methanol was removed by evaporation and the residue was dissolved in 150 ml of dimethyl sulphoxide. The solution was treated with 4.90 g (0.043 mol) of potassium thioacetate and the mixture was stirred at 80° C. for 20 hours. The cooled mixture was diluted with 150 ml of water, acidified with 2-M hydrochloric acid and extracted with ether. The combined extracts were dried over magnesium sulphate and evaporated to give a yellow oil which was treated with diazomethane in the usual manner. The resulting yellow oil was chromatographed on silica gel using chloroform/ethyl acetate (4:1) for the elution to give 3.8 g (27%) of methyl trans-2-(2-acetylthioethyl)-2,3,5,8-tetrahydro-1,3-dioxo-8-phenyl-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 101°-102° C. (from ethyl acetate) and 0.1 g (1%) of methyl cis-2-(2-acetylthioethyl)-2,3,5,8-tetrahydro-1,3-dioxo-8-phenyl-1H-1,2,4-triazolo[1,2-a]pridazine-5-carboxylate in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1>CCO.C(O)(=O)C.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][O:12][C:11]2=[O:14])=[CH:17][CH:18]=1
Reactant: O=C1OCC(c2ccc(Cl)cc2)=NN1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(CN2N=C(c3ccc(Cl)cc3)COC2=O)cc1

Procedure:
A suspension of the compound obtained in Step D (42.02 mmoles) in a mixture of EtOH (350 ml) and acetic acid (26 ml) is heated at reflux for 5 minutes. Powdered iron (309 mmoles) and FeCl3.6H2O (2.1 mmoles) are added to the resulting solution. The reaction mixture is stirred at reflux overnight. After evaporation, water (250 ml) is added to the residue and then sonicated for 2 minutes. The mixture is made alkaline (pH 12) using aqueous 2M sodium hydroxide solution, then diluted with AcOEt (500 ml) and then filtered over Celite. The phases are separated and the aqueous phase is extracted with AcOEt. The organic phases are combined. The organic phase obtained is washed with water and then with saturated NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue is triturated in ethyl ether, filtered and dried in vacuo to yield the title product in the form of a white powder, which is used directly in the next Step.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 96.3 %

Procedure:
4-(Chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (5.00 g), parahydroxybenzyl alcohol (3.29 g) and potassium carbonate (6.66 g) were suspended in dimethylformamide (25 ml) and the suspension was stirred at 50° C. for 3.5 hr. The reaction mixture was cooled and water (25 ml) was added at not higher than 15° C. The mixture was stirred for about 5 min and at about 5° C. for 1 hr under ice-cooling. The crystals were collected by filtration, washed twice with water (15 ml) and dried under reduced pressure at 50° C. to give the objective product (6.85 g) in a yield of 96%.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[CH:11](Cl)Cl)=[CH:6][CH:5]=1.Cl.C([O:18]CC)C>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:14])[C:11]([OH:18])=[O:1])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(Br)cc1)C(Cl)Cl
Reactant: [OH-]
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
Sodium hydroxide (72 g, 1.8 mol) is dissolved in 650 ml of water. The solution is heated to +60° C. and 1-(4-bromo-phenyl)-2,2-dichloro-ethanone (130 g, 0.48 mol) is added dropwise in order to control the reaction temperature not to exceed +65° C. After the addition is complete, stirring is continued for 1 hour at +60° C. The reaction mixture is then cooled to +15° C. and 95 ml of 10 N hydrochloric acid are added. Subsequently diethyl ether is added and the mixture is stirred vigorously for 30 minutes. The organic phase is separated and the aqueous layer is extracted twice with diethyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to yield (4-bromo-phenyl)-hydroxy-acetic acid. 1H-NMR (300 MHz, CDCl3): 4.95 (s, 1H, CHOH), 7.30 (d, 2H, CH arom.), 7.48 (d, 2H, CH arom.).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=O)=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C)C=O>[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=[N:7][OH:8])=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nn(-c3ccccn3)cc2C=NO)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Add 1.18 g of anhydrous sodium acetate and 1.0 g of hydroxylamine hydrochloride to 3.9 g of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehyde in 12 ml of dimethylformamide, whereupon the temperature of the formed mixture rises slightly. Stir the resulting mixture at room temperature for 4 hours before pouring onto ice and water to obtain a 99% yield of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehydeoxime [m.p. 234.5° to 235° C].
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C[O:37]CC1>CCOC(C)=O>[CH2:23]([O:30][C:31]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:37])[CH2:2][CH2:3]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: C1CCOC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCN(c2ccccc2O)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Piperazinyl phenol (Schweizerhall, 5 g, 30.5 mmol) was dissolved in THF (150 mL), treated with diisopropylethylamine (12.2 mL, 70.0 mmol), and cooled to 0° C. Benzylchloroformate (4.4 mL, 30.5 mmol) was added and the reaction was allowed to warm to room temperature and stir overnight. The solution was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated to give a brown oil. Column chromatography (SiO2, 40% EtOAc/hexanes) gave 28-2 as a white solid. Rf (40% EtoAc/hexanes) 0.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][C:11]2=[N:10]1.P(Br)(Br)([Br:21])=O>ClCCCl.C(Cl)Cl>[Br:21][C:13]1[C:12]2=[CH:18][N:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[CH:16]=[CH:15][N:14]=1
Reactant: [O-][n+]1ccc2nn(-c3c(F)cccc3Cl)cc2c1
Reactant: O=P(Br)(Br)Br
Solvent: ClCCCl
Solvent: ClCCl
Product: Fc1cccc(Cl)c1-n1cc2c(Br)nccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
To a suspension of 2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine 5-oxide (740 mg, 2.8 mmol) in DCE (18 mL) at 0° C. was added phosphorus oxybromide (2.4 g, 8.4 mmol). The reaction mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for an additional 4.5 h. The resultant mixture was diluted with DCM, washed with sodium carbonate (sat. aq.) and then with brine. The organic phase was dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in cyclohexane) to afford the title compound as a white solid (230 mg, 25% yield). LCMS (Method C): RT=3.44 min, m/z: 327 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[C:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:26]>>[Cl:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][C:25]#[N:26])=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:23])[C:9]([OH:14])([C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: COc1ccc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)cn1
Reactant: N#CCc1ccc(B(O)O)cc1
Product: COc1ccc(C(O)(C(C)c2ccc(-c3ccc(CC#N)cc3)cc2Cl)C(F)(F)F)cn1

Procedure:
In analogy to Example 150, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was reacted with 4-cyanomethylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=461.3 [M+H+]
Reaction SMILES: CN1CCCC1=O.F[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:17][CH:18]([CH3:20])[CH3:19])[N:10]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C1C=CC=CC=1>CCCCCC>[F:16][C:12]1[C:11]([NH:17][CH:18]([CH3:20])[CH3:19])=[N:10][C:9]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[C:14]([F:15])[CH:13]=1
Reactant: CC(C)Nc1nc(F)c(F)cc1F
Reactant: COc1ccc(CN)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(NC(C)C)c(F)cc2F)cc1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
To 4.1 g of N-methylpyrrolidone were added all amount of the 2,3,5-trifluoro-6-isopropylaminopyridine as described above together with 3.1 g of p-methoxybenzylamine, and the mixture was stirred at 150° C. for 15 hours and allowed to cool. After adding 50 ml of the mixed solution of benzene and n-hexane (1:1, v/v), the solution was washed twice with 400 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3.9 g of the title compound as a brown crude oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([F:14])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)=[O:4].[Br:15]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([F:14])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[Br:15])=[O:4]
Reactant: COC(=O)c1ccc2[nH]ncc2c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]nc(Br)c2c1F
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 2.2 g of 4-fluoro-1H-5-indazolecarboxylic acid methyl ester obtained in Production Example II-13-c in 20 ml dimethylformamide was added 2.12 g of N-bromosuccinimide at room temperature, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, 120 ml of ethyl acetate was added to the residue. The mixture was sequentially washed with half-saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 3.0 g of the title compound as bright yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)=O.C(Cl)(=O)[C:18](Cl)=[O:19].C(N(CC)CC)C.[OH:30][N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37]>O1CCCC1>[O:37]=[C:32]1[CH2:33][CH2:34][C:35](=[O:36])[N:31]1[O:30][C:18]([C:8]1[O:10][C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])=[N:6][C:7]=1[CH2:11][CH3:12])=[O:19]
Reactant: O=C1CCC(=O)N1O
Reactant: CCC(NC(=O)c1ccccc1Cl)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a stirred slurry of 2-(2-chloro-benzoylamino)-butyric acid (2.84 g, 11.8 mmol) in 60 mL of anhydrous tetrahydro furan, was added oxalyl chloride (10.1 mL, 118 mmol). The mixture was stirred at 50° C. overnight and then the solvent was evaporated in vacuo. The oily residue was treated with toluene and evaporated to remove trace of oxalyl chloride. The residue was then cooled in an ice bath and triethylamine (3.4 mL, 23.6 mmol) was added followed by the addition of 1-hydroxy-pyrrolidine-2,5-dione. The reaction mixture was stirred at 50° C. overnight before the solvent was removed in vacuo. The residue was then purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 5-60% ethyl acetate in hexane for 25 min) to give 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (997 mg, 25% yield) as a light yellow solid. LCMS calcd for C16H13ClN2O5 (m/e) 348, obsd 349 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:5]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=O)[CH2:18][CH2:17]3)[CH:4]=1.[NH2:24][OH:25]>C(O)C>[OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[C:5]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[N:24][OH:25])[CH2:18][CH2:17]3)[CH:4]=1
Reactant: O=C1CCc2cc(-c3cc(CO)oc3-c3ccncc3)ccc21
Reactant: NO
Solvent: CCO
Product: OCc1cc(-c2ccc3c(c2)CCC3=NO)c(-c2ccncc2)o1
Yield: 81 %

Procedure:
The product of Step 3 (150 mg, (0.49 mmol) was heated at reflux in ethanol (10 ml) containing 50% aqueous hydroxylamine (1 ml) for 2 hours. The solution was concentrated in vacuo to an oil and purified by silica gel chromatography eluting with 1:9:90.880 ammonia:ethanol:dichloromethane to afford the title product (128 mg, 81%); MS(ES+) m/e 321 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH:20]=[CH:19][CH:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)=[CH:12][CH:11]=1>CCOC(C)=O.O=[Pt]=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:33])[C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[O:17]2)=[CH:14][CH:15]=1
Reactant: COc1cc(C2C=CC(c3ccc(C(=O)Nc4ccccc4N)cc3)O2)cc(OC)c1OC
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1cc(C2CCC(c3ccc(C(=O)Nc4ccccc4N)cc3)O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 229.2 %

Procedure:
To a degazed solution of 289 (43 mg, 0.096 mmol) in AcOEt (4 mL) was added PtO2 (3 mg, 0.01 mmol) and the reaction mixture was stirred at room temperature under a 1 atm pressure of H2 for 16 h. The reaction flask was purged with N2 then the reaction mixture was filtered through celite, rinsed with MeOH and concentrated. The crude residue was purified three times by flash chromatography on silica gel (MeOH/DCM: 2/98, AcOEt/DCM: 30/70 and AcOEt/CHCl3: 30/70) to afford the title compound 290 (10 mg, 0.22 mmol, 23% yield). 1H NMR (CDCl3) δ (ppm): 8.10 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.96-6.85 (m, 2H), 6.64 (s, 2H), 5.33 (t, J=7.0 Hz, 1H), 5.21 (t, J=7.0 Hz, 1H), 3.89 (s, 6H), 3.85 (s, 3H), 2.59-2.40 (m, 2H), 2.09-1.88 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([CH2:12][NH2:13])[CH2:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]([CH3:23])([CH:19]([N:21]=[O:22])[CH3:20])[CH3:18]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:10][NH:11][C:17]([CH3:23])([CH3:18])[C:19](=[N:21][OH:22])[CH3:20])[CH2:12][NH:13][C:17]([CH3:23])([CH3:18])[C:19](=[N:21][OH:22])[CH3:20])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: NCC(CN)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(N=O)C(C)(C)Cl
Solvent: CO
Product: CC(=NO)C(C)(C)NCC(CNC(C)(C)C(C)=NO)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.9 g of diamine [10] was dissolved in 90 ml methanol and cooled to 0° C., after which 6.5 g of 2-chloro-2-methyl-3-nitrosobutane were added with agitation. After heating to room temperature the mixture was agitated for two hours, boiled with reflux for a further two hours, the solvent was removed and the remaining solid was dissolved in water. The mixture was neutralised with sodium hydrogen carbonate and concentrated and the remaining precipitate was re-crystallised from ethanol.