Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-ethoxycarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]1([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[C@@H:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][C:23]4([CH2:25][CH2:24]4)[CH2:22][NH:21]3)=[O:19])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)C>[C:6]1([N:12]2[CH2:13][CH2:14][N:15]([C:18]([C@@H:20]3[C@@H:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][C:23]4([CH2:24][CH2:25]4)[CH2:22][N:21]3[C:2]([O:4][CH3:5])=[O:3])=[O:19])[CH2:16][CH2:17]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)N1CC2(CC2)C[C@H](C(=O)OC(C)(C)C)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl chloroformate (55 μL, 700 μL) was added to a solution of tert-butyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (248.4 mg, 0.62 mmol) and di-isopropylethylamine (0.70 mmol, 0.125 mL) in 5 mL acetonitrile. The mixture was stirred at RT for 3 h. Solvent was removed to afford a residue which was dissolved in ethyl ether (15 mL), washed with water (3×2 mL) and dried over Na2SO4. The solution was filtered and concentrated to afford 281 mg of the 7-tert-butyl 5-methyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5,7-dicarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([SH:17])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([S:17][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: Fc1ccccc1-c1nnc2ccc(S)nn12
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Sc1ccc2nnc(-c3ccccc3F)n2n1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-thiol (1 mmol) and cesium carbonate (1.5 equiv.) in DMF (5 mL) was added ethyl 2-bromobutyrate (1.5 equiv.) and the mixture was stirred at 70° C. for 3 hours. The reaction was monitored by thin-layer chromatography and was shown to be complete at this time. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column, to furnish ethyl 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)butanoate.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=O.N1CCCCC1>N1C=CC=CC=1.O>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[NH:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([O:22][C:23]([F:24])([F:25])[F:26])=[C:14]([Cl:13])[CH:15]=1
Reactant: CC(=O)c1c(O)cc(C)[nH]c1=O
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(O)c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 0.50 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, 0.74 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 6 mg of pyridine and 0.1 ml of piperidine was heated under refluxing for 4 hours. After cooled to room temperature, 40 ml of water was added to the reaction mixture, precipitated crystals were filtered, and this was washed with tetrahydrofuran, then with ethyl acetate to obtain 0.41 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-32)] as a yellow crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CC(C)([O-])C.[K+].C([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])#N.[OH-].[K+]>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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)CO.COCCOC>[S:9]1[C:5]2[CH:4]=[CH:3][C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:10][C:6]=2[CH:7]=[CH:8]1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: Brc1ccc2sccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: OCCO
Solvent: O
Product: O=C(O)Cc1ccc2sccc2c1
Yield: 78 %

Procedure:
To 1,2-dimethoxyethane (1.00 L) solution of 250 g of 5-bromobenzothiophene were added 276 g of potassium tert-butoxide and 174 g of tert-butyl cyanoacetate. Thereto were added 8.23 g of dichlorobis(triphenylphosphine)palladium(II) and 6.15 g of triphenylphosphine at 80 to 85° C., which was then refluxed for 2 hours. Next, to the reaction mixture were added 500 mL of ethylene glycol, 250 mL of water and 263 g of potassium hydroxide, which was then refluxed for 4 hours. To the reaction mixture were added 1.50 L of water and 12.5 g of kieselguhr (celipure, product of Advanced Minerals Company). After insoluble matter was filtered off, to the filtrate was added 250 mL of toluene, and the aqueous layer was separated. To the aqueous layer were added 375 mL of toluene and 375 mL of ethyl acetate, the pH was adjusted to 1 with 505 mL of hydrochloric acid, and the organic layer was separated. The organic layer was treated with 12.5 g of activated carbon. The solvent was distilled off under reduced pressure, to which was added toluene. The precipitate was collected by filtration to provide 176 g of 2-(1-benzothiophen-5-yl)acetic acid as white solid form.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][O-:24].[Na+]>C(O)CCCC>[NH2:1][C:2]1[N:10]=[C:9]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCC[O-]
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Solvent: CCCCCO
Product: CCCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 130 °C
Yield: 57 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (150 mg, 0.58 mmol) and sodium pentylate (318 mg, 2.89 mmol) were dissolved in 1-pentanol (50 ml) and then the solution was stirred under heating at 130° C. for 5 hours. The reaction mixture was evaporated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (103 mg, yield 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>ClCCl>[Cl:19][CH2:20][C:21]([N:9]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1NCCCc1cccnc1
Solvent: ClCCl
Product: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)CCl
Temperature: 25 °C

Procedure:
A solution of 10.0 g of N-(2,6-dimethylphenyl)-3-pyridinepropanamine in 75 ml of dichloromethane was added dropwise to a cold (20° C.) solution of 3.5 ml of chloroacetylchloride in 35 ml of dichloromethane. The cooling bath was removed and the reaction was allowed to warm to room temperature over 30 minutes followed by the addition of excess aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and evaporated to give 13.4 g of product as a dark oil which was used directly in the next steps, that is, in Examples 20 and 21.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14](Br)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1>>[C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(N)c(Br)c1
Reactant: OB(O)C1=CCCCC1
Product: CC(=O)OCC(COC(C)=O)c1ccc(N)c(C2=CCCCC2)c1

Procedure:
The title compound was prepared according to the Suzuki coupling procedure of Example 9, step (a) using acetic acid 3-acetoxy-2-(4-amino-3-bromo-phenyl)-propyl ester (as prepared above) and cyclohex-1-enyl boronic acid: Mass spectrum, (ESI, m/z): Calcd. for C19H25NO4, 332.1 (M+H). found 332.1.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CCO>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][C:12]2[CH:20]=[CH:21][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:15]=1
Reactant: c1ccc(COc2ccc(Oc3cccnc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(Oc2cccnc2)cc1
Reaction time: 8 h
Yield: 110.5 %

Procedure:
The product from step 1 (130 mg, 0.469 mmol) was added to a vial containing THF (1 ml), EtOH (2.5 ml), 10% Pd/C (110 mg, 0.0469 mmol), charged with H2 and left to stir under H2 atmosphere overnight. The Pd/C was removed by filtering the reaction mixture through celite. The resulting solution was concentrated to give the title compound (97 mg, 100%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:5]=1[CH2:6][NH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10](Cl)[N:9]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([CH:30]=1)[NH2:29]>C1COCC1>[F:3][C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:5]=1[CH2:6][NH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]([NH:29][C:28]2[CH:30]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=2[N+:31]([O-:33])=[O:32])[N:9]=1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NCc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(NCc2c(F)cccc2F)n1
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of N-(2,6-difluorobenzyl)-2-chloro-5-nitropyrimidin-4-amine (150 mg) and 5-fluoro-2-nitroaniline (78 mg) in THF (10 mL) at RT. The mixture was stirred for 30 min, quenched via the addition of sat. aq. NH4Cl, extracted with DCM and purified by preparative HPLC to give a low yield of N4-(2,6-difluorobenzyl)-N2-(5-fluoro-2-nitrophenyl)-5-nitropyrimidine-2,4-diamine (75) (24 mg), MH+=421.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:24][CH2:25][CH2:26][CH3:27])C1C=CC=CC=1>CO.[Pd]>[CH2:24]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[N:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1cc2c(N3CCCC3)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1cc2c(N3CCCC3)ccnc2cc1O
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 1.02 g (2.83 mmol) of the 7-benzyloxy-6-butyl-4-pyrrolidin-1-yl-quinoline, product of example 33, dissolved in 50 ml of MeOH was treated with 0.33 g of palladium on charcoal (10%) and then hydrogenated at RT for 2 h until TLC analysis indicated the completion of the reaction. The catalyst was filtered off, the solution was concentrated in vacuo and the residue was dried in a high vacuum to give 0.65 g (82%) of the 6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol as a light yellow solid. ISP mass spectrum, m/e: 271.3 (M+1 calculated for C17H22N2O: 271).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:16]/[C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Br:12])[CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(/N=C/c2cccc(Br)c2)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
The mixture solution of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 3-bromo-benzaldehyde (13.3 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-phenyl)-meth-(E)-ylidene]amino}-benzoic acid methyl ester (22.6 g, quant.) as a light yellow solid: MS (ESI) M+1=318.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:18])[CH3:2].Cl[CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[N:9]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:18])[CH3:2]
Reactant: CCOC(=O)CCn1c(=O)[nH]c2ccc(C#N)cc21
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccc(C#N)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of 3-(6-Cyano-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid ethyl ester (0.1 g, 0.39 mmol) in DMA (3 mL) were added 1-(chloromethyl)naphthalene (0.1 g, 0.58 mmol) and K2CO3 (0.11 g, 0.81 mmol). The reaction mixture was stirred at 65° C. for 16 h. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 20 mg (13%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:21](F)=[CH:20][C:5]([C:6]([C:8](=[CH:14][NH:15][C@H:16](C)[CH2:17][OH:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](F)[C:3]=1[F:24].[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[C:3]([F:24])=[CH:4][C:5]2[C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]3[CH2:16][C@@H:17]([CH3:25])[O:18][C:21]=1[C:20]=23
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=CN[C@H](C)CO)C(=O)c1cc(F)c(Br)c(F)c1F
Agent: [K+]
Product: CCOC(=O)c1cn2c3c(c(Br)c(F)cc3c1=O)O[C@H](C)C2

Procedure:
[II; R=C2H5, R'=H, R"=CH3 ] was prepared by cyclization of the compound of part (c) above with potassium carbonate according to the procedure of Example 1(c). The crude product was used directly in the next reaction.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 73 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using 2,2,2-trifluoroethylamine instead of aminomethylcyclopropane, to the title compound (119 mg, 73%) which was obtained as a white solid. MS: m/e=411.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[CH:9][S:8][C:7]=3[C:6]=2[N:15]=1.C(O)(=O)C.[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[Br:20][C:9]1[S:8][C:7]2[C:6]3[N:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: Clc1ccc2c(n1)-c1sccc1CCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc2c(n1)-c1sc(Br)cc1CCO2
Temperature: 2.5 °C
Reaction time: 18 h

Procedure:
9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.33 g, 18.2 mmol) was dissolved in methylene chloride (40 mL, 600 mmol)/acetic acid (40 mL, 700 mmol). The solution was cooled down to 0-5° C. and added a solution of N-Bromosuccinimide (3.57 g, 20.0 mmol) in 10 mL of DCM slowly. The reaction mixture was stirred for 18 hours. After removal of the solvents, the residue was partitioned between ethyl acetate and saturated sodium carbonate aqueous solution. The organic layer was washed with water, brine and dried over sodium sulfate. After filtration, the filtrate was concentrated to give 2-Bromo-9-chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene. 1HNMR (DMSO, 400 MHz): δ 7.48 (d, J=8.4 Hz, 1H, ArH), 7.28 (d, J=8.4 Hz, 1H, ArH), 7.18 (s, 1H, ═CH), 4.32 (t, J=4.4 Hz, 2H, CH2), 3.17 (t, J=4.4 Hz, 2H, CH2).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[NH2:12][C:13]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:14]=1[C:15]([NH:17][O:18][CH2:19][CH:20]=[CH2:21])=[O:16].O>O1CCOCC1>[CH2:19]([O:18][N:17]1[C:15](=[O:16])[C:14]2[C:13](=[CH:25][C:24]([F:26])=[C:23]([F:27])[CH:22]=2)[NH:12][C:1]1=[O:2])[CH:20]=[CH2:21]
Reactant: C=CCONC(=O)c1cc(F)c(F)cc1N
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOn1c(=O)[nH]c2cc(F)c(F)cc2c1=O

Procedure:
Phosgene, as a 12.5% solution in toluene (9.4 mL, 12 mmol), was added to a solution of 2-amino-N-allyloxy-4,5-difluorobenzamide (Example Y-3, 2.08 g, 9.1 mmol) in 75 mL of dioxane. The solution was heated at reflux for 20 hours and then poured into 200 mL of water. The aqueous solution was extracted with ethyl acetate, and the combined organic fractions were washed with water and brine and dried over magnesium sulfate. The solution was concentrated to give 2.18 g of the title compound as a solid, mp 220-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]#[N:11])=[C:4]([CH3:12])[CH:3]=1.[Na].Cl.[CH3:15][CH2:16][O:17]C(C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH:9]([C:16](=[O:17])[CH3:15])[C:10]#[N:11])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(C)c1CC#N
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na]
Product: CC(=O)C(C#N)c1c(C)cc(Cl)cc1C
Temperature: 90 °C

Procedure:
Dissolve 4-chloro-2,6-dimethyl phenyl acetonitrile (2.3 g, 179.2 g/mol) in 15 mL EtOAc and add sodium metal (0.35 g, pea-sized fragments). Heat to reflux (90° C. bath temperature) under N2 overnight. Evaporate down to solid and slurry up in Et2O (100 mL); stir vigorously to break up fragments. Filter and wash solid with copious amounts of Et2O. Dissolve solid in H2O to form a clear yellow solution, and add 1.0 N HCl (100 mL) to pH 1. Extract the resulting cloudy solution with CH2Cl2 (3×100 mL) until aqueous layer is clear. Pool and dry the organic layers over Na2SO4, filter and evaporate to yellow oil (1.8 g). TLC: Rf=0.2 using 20% EtOAc/80% hexanes as eluent. LCMS=222.3 (MH+); 220.2 (M−).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:44])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]1[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[O:35][CH3:36])[C:24](=[O:37])[C:23]([C:38]([O:40][CH3:41])=[O:39])=[CH:22][C:21]=1[CH2:42][CH3:43])=[CH:15][CH:14]=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:36][O:35][C:28]1[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=1[CH2:26][N:25]1[C:20]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:44])[C:11]([CH2:10][CH2:9][OH:8])=[CH:19]3)=[C:21]([CH2:42][CH3:43])[CH:22]=[C:23]([C:38]([O:40][CH3:41])=[O:39])[C:24]1=[O:37]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCO[Si](C)(C)C(C)(C)C)n2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCO)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To solution of methyl 6-(2-(2-(tert-butyldimethylsilyloxy)ethyl)-1-methyl-1H-indol-5-yl)-1-(2,4-dimethoxybenzyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (6.10 g, 9.84 mmol) in THF (60 mL) was added TBAF solution (1M THF, 15.0 mL, 15.0 mmol). Reaction mixture was stirred at room temperature for 30 min until starting material was completely consumed. THF was then concentrated and residue was purified by column chromatography (EtOAc/DCM, 0-100% gradient). Methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(2-(2-hydroxyethyl)-1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate was obtained as yellow solid (4.56 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1.[OH:26]O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:26])[CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)c[n+]([O-])cc2Cl)cc1OC1CCCC1
Reaction time: 3 h

Procedure:
A stirred suspension of N-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-4-methoxybenzamide (2.0 g; that is prepared as described in Example 6) in glacial acetic acid (8 mL) is treated with an aqueous solution of hydrogen peroxide (6 mL; 27.5%). The mixture is stirred for 3 hours at 70°-80° C. and then it is treated with a further portion of hydrogen peroxide solution (4 mL), and the solution is stirred for a further 12 hours. The solution is then cooled, basified by treatment with concentrated aqueous sodium hydroxide solution, and extracted with dichloromethane (2×30 mL). The organic extract is washed with brine (30 mL), dried over magnesium sulfate and evaporated. The resulting residue is recrystallized from ethyl acetate, to give 3,5-dichloro-4-(3-cyclopentyloxy-4-methoxybenzamido)pyridine-N-oxide (0.73 g), m.p. 118°-120° C. [Elemental analysis: C,53.0; H,4.4; N,6.8%; calculated for C18H18O4N2Cl2 :0.5H2O: C,53.2;H 4.7;N 6.9%].