Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.ClCCl.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1
Temperature: 100 °C
Yield: 77.1 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (85 mg, 0.23 mmol) and 4-fluoro-benzyl bromide (164 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) and a mixture of water (10 mL) and brine (10 mL) were added. The organic layer was washed with 10% aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-60% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-(4-fluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (105 mg, 78%) as an off-white solid. ES(+)-MS (M+H) 413.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[C:5]([CH3:17])[CH:6]=[C:7]([C:13](OC)=[O:14])[CH:8]=2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[C:5]([CH3:17])[CH:6]=[C:7]([CH2:13][OH:14])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1cc(C)c2nc(C)c(C)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2cc(CO)cc(C)c2nc1C

Procedure:
Prepared by reducing 691 mg of methyl 2,3,8-trimethyl-quinoxaline-6-carboxylate with 300 mg of lithium aluminium hydride (95%) in 15 ml tetrahydrofuran at ambient temperature.
Reaction SMILES: N1C=CC(N)=NC1=O.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:37][CH2:38][C:39]1[N:40]=[C:41]2[CH:46]=[CH:45][N:44](C3C=CC(F)=CC=3)[C:43](=[O:54])[N:42]2[CH:55]=1>>[Cl:37][CH2:38][C:39]1[N:40]=[C:41]2[CH:46]=[CH:45][N:44]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:12]=3)[C:43](=[O:54])[N:42]2[CH:55]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: Nc1cc[nH]c(=O)n1
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Product: O=c1n(-c2cccc(C(F)(F)F)c2)ccc2nc(CCl)cn12

Procedure:
2-chloromethyl-6-(3-trifluoromethyl-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from cytosine and 3-(trifluoromethyl)phenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: O.C([O-])(=O)C.[Na+].[CH3:7][N:8]([CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[CH3:9].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>C(OCC)(=O)C.C(O)(=O)C>[CH3:9][N:8]([CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:13][CH:12]=1)[CH3:7]
Reactant: C=C(C)C(=O)Cl
Reactant: CN(C)Cc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=C(C)C(=O)Nc1ccc(CN(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 5 l three-necked flask were placed 1 l of water and 225.5 g. of sodium acetate. After dissolution of the sodium acetate with stirring, the resulting solution was cooled on an ice bath and 375 g. of p-dimethylaminomethylaniline and 400 ml of acetic acid were added thereto. The resulting mixture was cooled until the temperature became below 10° C. To the cooled mixture was added dropwise 287.4 g. of methacrylic acid chloride gradually to the extent that the temperature in the flask might not exceed 10° C. After completion of the dropwise addition, the stirring was continued for 30 minutes at the same temperature, followed by further stirring for 2 hours without the ice bath. To the reaction mixture thus obtained were added 500 ml of ethyl acetate and a solution of 400 g. of sodium hydroxide in 600 ml of water and the resulting mixture was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the ethyl acetate was removed by distillation. The residue was dissolved in 300 ml of benzene and poured into 3.2 l of cooled n-hexane to precipitate the desired product. White crystal mp.(melting point): 65.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].CC(N1CCCC(C(C)=O)=C1)C>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: COc1cccc(C(=O)N2CCCC3=C2CC(C)(C)CC3=O)c1

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin5(6H)-one was reacted with 3-methoxybenzoyl chloride according to the procedure of Part (b) of Example 1 to give 7,7-dimethyl-1,2,3,4, 7,8-hexahydro-1-(3-methoxybenzoyl)-quinolin-5(6H)-one (20) as a pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CN2CCCC2=O)cc1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and pyrrolidin-2-one. m/e+ 374 for C19H18Cl2N3O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.49 (d, J=1.5 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.33 (m, 3H), 4.93 (s, 2H), 3.11 (t, J=6.9 Hz, 2H), 2.43 (m, 5H), 1.92 (m, 2H) ppm.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1NN)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=[N:34][CH:35]([P:44]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:45])[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C>[NH2:34][CH:35]([P:44]([O:46][CH2:47][CH3:48])([O:49][CH2:50][CH3:51])=[O:45])[C:36]([O:38][CH2:39][C:40]([Cl:42])([Cl:43])[Cl:41])=[O:37]
Reactant: CCOP(=O)(OCC)C(N=Cc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOP(=O)(OCC)C(N)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,4-dinitrophenyl hydrazine (1.875 g., 9.47 mMol) and p-toluenesulfonic acid monohydrate (1.800 g., 9.47 mMol) in ethanol (200 ml.) is stirred at room temperature for 45 minutes. To the resulting orange suspension is added trichloroethyl N-benzylidene-α-amino-diethylphosphonoacetate (3.881 g., 9.02 mMol) in a small volume of chloroform. The mixture is stirred for 30 minutes at room temperature, then filtered to remove benzaldehyde 2,4-dinitrophenyl hydrazone. The filtrate is evaporated in vacuo to an orange oil which is taken up in water (50 ml.) and washed with chloroform (4 × 25 ml.) to remove the remainder of the hydrazone. The aqueous phase (pH 2) is cooled in ice, adjusted to pH 10 with 2 N NaOH, saturated with NaCl, and extracted with methylene chloride (2 × 25 ml). The combined extracts are dried over MgSO4 and evaporated in vacuo to give trichloroethyl α-amino-diethylphosphonoacetate as a pale yellow liquid.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:21])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:30]>C(Cl)Cl>[Cl:30][C:2]1[N:7]2[N:8]=[C:9]([CH3:21])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2c(C)nn3c(O)cc(C)nc23)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2c(C)nn3c(Cl)cc(C)nc23)c(OC)c1
Reaction time: 2 h

Procedure:
Slurry 7-hydroxy-2,5-dimethyl-3-(2,4-dimethoxyphenyl)-pyrazolo[1,5-a] pyrimidine in 10 mL POCl3 and reflux at 130° C. under N2. After 2 h, monitoring by TLC (alcohol Rf=0.5, chloride Rf=1.0; EtOAc as eluent), quench the reaction carefully at ambient temperature by diluting with 50 mL CH2Cl2 and pouring slowly into non-stirring saturated NaHCO3. Adjust stirring speed to control rate of quenching of residual POCl3 and stir until gas evolution ceases. Separate the layers and extract the aqueous layer with CH2Cl2 (2×50 mL). Pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil, which is used directly without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([N+:14]([O-])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N1CCCC1>>[N:1]1([C:7]2[N:8]=[CH:9][C:10]([NH2:14])=[C:11]([NH2:13])[CH:12]=2)[CH2:6][CH2:5][CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Solvent: C1CCNC1
Product: Nc1cnc(N2CCCC2)cc1N

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 151.1 and 151.2, except pyrrolidine was used in place of morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[C:9]#[C:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:21])[C:9]#[C:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:6][CH:7]=1
Reactant: OC(C#CCCCOC1CCCCO1)c1ccc(Cl)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(C#CCCCOC1CCCCO1)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
A solution of 16.60 g (53.7 mmol) of 1-(4-chlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hex-2-yn-1-ol, prepared in stage 5.1., is added dropwise to a suspension, cooled with an ice bath, of 93 g (1.07 mol) of manganese dioxide in 500 ml of dichloromethane. Stirring is continued for 1.5 hours, then the mixture is filtered through celite and the filter cake is rinsed with dichloromethane. The filtrates are evaporated to produce 16.3 g (53.1 mmol) of product in the form of a yellowish oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[N+]=[N-])[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11].[CH2:29]([OH:31])[CH3:30]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh].C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([O:31][CH2:29][CH3:30])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:20]=1)[CH3:11]
Reactant: CCO
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)=[N+]=[N-]
Agent: [Rh]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Rhodium (II) acetate dimer (33 mg) was added to a mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-diazopropanoate (2.80 g), ethanol (2.16 mL) and benzene (50 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes, heated at reflux for a further 15 minutes, then cooled and evaporated in vacuo. The residue was chromatographed on silica gel using 1.5% methanol in dichloromethane as eluent to afford the title compound as a gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].[H-].[Na+].C1[CH2:20][O:19][CH2:18]C1>O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:18][O:19][CH3:20])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1cccc(OCOC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (3-Hydroxy-phenyl)-acetic acid ethyl ester (27.6 g) in THF was added NaH (7.35 g), MOM-CI (14.8 g) slowly at 0°. After stirred for 14 h at the same temperature, the reaction mixture was warmed to room temperature. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=15:1 to 10:1) to afford the product as colorless oil. (31.2 g, 90.9%)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[C:7](OCC)(=[O:14])[CH2:8][C:9](OCC)=[O:10].CC[O-].[Na+]>CCO>[N:1]1[N:2]2[C:7]([OH:14])=[CH:8][C:9]([OH:10])=[N:6][C:3]2=[CH:4][CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)n2nccc2n1
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To 1H-pyrazol-3-amine (12.3 g, 148.0 mmol) in EtOH (50 mL) was added diethyl malonate (25.0 mL, 164.7 mmol), 21 wt % NaOEt in EtOH (110 mL, 294.6 mmol) and additional EtOH (50 mL). The resulting mixture was then heated at 80° C. under an atmosphere of argon for 16 hours, at which time the reaction was allowed to cool to room temperature. The reaction mixture was then concentrated in vacuo until almost dry, before H2O (500 mL) was added. Vigorous stirring aided the dissolving of solids, at which time conc. HCl was added until pH˜2 was attained (solid precipitate formed). The precipitate was collected and dried by vacuum filtration giving pyrazolo[1,5-a]pyrimidine-5,7-diol as a tan solid (17.13 g, 113.4 mmol, 77%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][CH2:7][O:8]/[N:9]=[CH:10]/[C:11]1[C:12]([F:34])=[C:13]([F:33])[C:14]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:15]([CH:23]=1)[C:16]([NH:18][O:19][CH2:20][CH2:21][OH:22])=[O:17])=[O:5])[CH3:2].ClC(Cl)C(O)=O>ClCCl>[CH2:1]([NH:3][C:4]([CH2:6][CH2:7][O:8][NH:9][CH2:10][C:11]1[C:12]([F:34])=[C:13]([F:33])[C:14]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:15]([CH:23]=1)[C:16]([NH:18][O:19][CH2:20][CH2:21][OH:22])=[O:17])=[O:5])[CH3:2]
Reactant: CCNC(=O)CCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Product: CCNC(=O)CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To (E)-5-[(2-ethylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (40 mg, 0.067 mmol) obtained in Step B was added dichloromethane (2 ml). The mixture was stirred at room temperature, and borane-pyridine complex (400 and dichloroacetic acid (40 μl) were added thereto. After stirring for 1 hour, the reaction mixture was poured into purified water, and the resultant mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-[(2-ethylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (C-18, 29 mg, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1([CH2:28][NH:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=3)[CH2:34][CH2:33]2)[CH2:27][CH2:26]1>C1COCC1>[CH:25]1([CH2:28][N:29]([CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=3)[CH2:36][CH2:37]2)[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([O:11][CH3:12])[CH:4]=2)[CH2:27][CH2:26]1
Reactant: Fc1ccc(OC2CCN(CCNCC3CC3)CC2)cc1F
Reactant: COc1cc(C(=O)O)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(CCN2CCC(Oc3ccc(F)c(F)c3)CC2)CC2CC2)ccc1F
Reaction time: 2 h
Yield: 4.9 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzoic acid (0.082 g) in THF (1 ml) was added carbonyldiimidazole (0.078 g) and the resulting solution stirred at room temperature for 10 minutes before addition of the product of Step e (0.15 g) in THF (1.5 ml). The mixture was stirred for 2 hours and the solvent removed by evaporation to yield a colourless gum. Purification by reverse phase HPLC (with a gradient eluent system 25% MeCN/NH4OAc(aq) (0.1%) to 95% MeCN//NH4OAc(aq) (0.1%)) gave the title compound (0.011 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](OC)(OC)(OC)[CH3:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]4[O:24][C:29]([CH3:30])=[N:26][N:25]=4)=[CH:27][CH:28]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC(C)(OC)OC
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Product: Cc1nnc(-c2ccc(O[C@H]3CC[C@H](C(=O)N4CCN(C(C)C)CC4)CC3)cc2)o1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 100 mg (0.26 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid hydrazide and 4 ml of trimethyl orthoacetate was stirred for 10 min at 120° C. using microwave reactor. After evaporation, the mixture was diluted with AcOEt, washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 15 mg (14%) of the title compound. MS (m/e): 413.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[C:19]([CH3:27])=[N:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1.[NH4+].[Cl-]>CO.[Zn]>[NH2:24][C:21]1[N:20]=[C:19]([CH3:27])[C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCN(C)CC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 4-methyl-N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (0.400 g, 1.074 mmol) in MeOH (20 mL) was treated with NH4Cl (2.00 g, 37.4 mmol) followed by zinc powder (1.00 g, 15.29 mmol) and the mixture stirred at RT overnight. The solids were removed via filtration, washed with DCM and the filtrate concentrated to dryness. The residue was treated with DCM and a few drops of MeOH, the solids again removed via filtration and the filtrate concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)-4-methylpiperazine-1-carboxamide (290 mg, 79%). MS (ESI) m/z: 343.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(O)C>[CH2:13]([O:20]/[N:21]=[C:7]1\[CH2:6][CH2:5][C:4]2[C:8]\1=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Brc1ccc2c(c1)CC/C2=N\OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To 5-bromoindanone (5.66 g) in 60 mL ethanol was added 5.57 g O-benzylhydroxylamine hydrochloride and 3.2 mL pyridine. The mixture was stirred at ambient temperature for 5 hours. The volatiles were removed under vacuum and the solid residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to afford crude product as an amber oil. The crude material was crystallized from hexane to afford 5.43 g (84% yield) light tan solid. 1H NMR (CDCl3) was consistent with the desired product. LC/MS indicated a single peak with a M+1 molecular ion of m/z 318.1 by positive ESI.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11]=2[N:12]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:11]=3[N:12]=2)[CH2:24][CH2:23]1
Reactant: Sc1nc2c(ccc3ccccc32)o1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3c(ccc4ccccc43)o2)CC1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (498 mg) was dissolved in anhydrous toluene (8 ml), the resulting solution was mixed with 2-mercaptonaphtho[1,2-d]oxazole (400 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (2.2 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)naphtho[1,2-d]oxazole (94.9 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.Cl.CN>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:31][CH3:29])=[O:25])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Agent: CN
Agent: Cl
Solvent: CN1CCCC1=O
Product: CNC(=O)c1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzoic acid (Example 69,40 mg, 0.1 mmol) in 1-methyl-2-pyrrolidinone (0.3 mL) was added 1,1′-carbonyldiimidazole (19.5 mg, 0.12 mmol). After stirring for 30 minutes, methylamine hydrochloride (8.1 mg, 0.12 mmol) was added and the reaction stirred for 4 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10% ethanol/ethyl acetate, to give the title compound. δH (500 MHz, d6 DMSO): 8.63 (1H, d, J=4.5 Hz), 8.04-7.94 (6H, m), 7.88-7.82 (3H, m), 7.42-7.34 (2H, m), 7.32-7.26 (1H, m), 7.14 (1H, td, J=1.9, 8.4 Hz), 2.76 (3H, d, J=4.5 Hz); m/z (ES+) 414 [MH+].