Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[N:6][C:7]=1F.[C:32]([NH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CN1CCOCC1.CN1CCCC1=O>CCOC(C)=O>[Cl:1][C:2]1[C:7]([N:43]2[CH2:42][CH2:41][CH:40]([NH:39][C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:45][CH2:44]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Cl)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3nn(COCC[Si](C)(C)C)c4cnc(-c5cccnc5)cc34)ccc2Cl)CC1
Temperature: 120 °C

Procedure:
In a pressure tube was charged with 3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (103.4 mg, 0.2268 mmol), 4-(N-Boc-amino)-piperidine (136.24 mg, 0.6803 mmol), 4-Methylmorpholine (249.30 uL, 10 mmol), and N-Methylpyrrolidinone (3 mL). The mixture was heated at 120° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed 3 times with water. The organic layer was dried with MgSO4, and then concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford tert-butyl 1-(3-chloro-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate. It was dissolved in 1,4-Dioxane (5 mL) and treated with 4.0 M of Hydrogen chloride in 1,4-Dioxane (5 mL) overnight. The mixture was concentrated, and the residue was purified by reverse phase HPLC to afford 241 as an off-white solid (8.7 mg, 19%). 1H NMR (400 MHz, DMSO) δ 9.24 (d, J=10.3 Hz, 2H), 8.99 (s, 1H), 8.61 (s, 1H), 8.42 (d, J=7.5 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.56 (d, J=4.4 Hz, 1H), 3.99 (d, J=12.0 Hz, 2H), 3.09 (d, J=12.4 Hz, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.56 (d, J=11.1 Hz, 2H). ESI MS m/z=406.1 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.CC([O-])(C)C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=2)=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of 4-amino-2-chlorophenol (Aldrich, 430 mg, 3.0 mmol) in DMF (2.0 mL) at room temperature was added KOt-Bu (352 mg, 3.2 mmol). The mixture was allowed to stir at room temperature for 1 h. To the solution were then added 4-chloropicolinamide (468 mg, 3.0 mmol) and K2CO3 (221 mg, 1.6 mmol). The resulting suspension was heated at 90° C. overnight. After cooling down, the suspension was diluted with 100 mL of EtOAc and 50 mL of H2O. The organic layer was separated and washed with brine (2×25 mL) and dried over MgSO4. After filtration and concentration, the solid was triturated with 50 mL of DCM. The solid was then collected and washed with DCM (2×20 mL), EtOAc (5.0 mL) and dried to give 4-(4-amino-2-chlorophenoxy)picolinamide (320 mg, 40% yield). MS(ESI+): m/z 264.12/266.07 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[F:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cccc(F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(F)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (46.0 μL, 0.26 mmol) was added to 8-fluoro-3-carboxy-coumarin (50.3 mg, 0.24 mmol) and HATU (100.5 mg, 0.26 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (50.0 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo for final product: LCMS (ESI) m/z 400 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)[C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:43][C:42]2[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:46][CH:45]=2)[CH:36]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3ccc(C(F)(F)F)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-[(pyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.936 g) and 4-(trifluoromethyl)benzyl chloride (0.592 mL) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-{[1-(4-trifluoromethylbenzyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.25 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 133, 5-hydroxy-N-(6-methoxypyridin-3-yl)-N-{[1-(4-trifluoromethylbenzyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained. melting point: 199-200° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:33]2[CH2:35][CH2:34]2)[C:15]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:33]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]([C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:19][CH:18]=2)=[O:16])[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(-c3ccc(S(C)(=O)=O)cc3)nc2)C2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1

Procedure:
The title compound is prepared from 4-{cyclopropyl-[2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester by treatment with trifluoroacetic acid in dichloromethane. LC (method 10): tR=1.20 min; Mass spectrum (ESI+): m/z=401 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[H][H]>[Pd].O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1cc(N)ccc1F

Procedure:
A suspension of 10 grams of 2-fluoro-5-nitroanisole and 100 ml. of dioxane is reduced catalytically under 40 p.s.i. of hydrogen and 1.0 gram of 5% Pd/C. After the uptake of hydrogen ceases, the catalyst is filtered, and the filtrate is concentrated in vacuo to yield 4-fluoro-3-methoxyaniline.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][OH:9])[CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:20])=[O:19]
Reactant: OCCC1CCCOC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1CCCOC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-(tetrahydro-2H-pyran-3-yl)ethanol (1.54 gm) and triethylamine (3.3 ml) in dichloromethane (25 ml) was cooled (ice bath) and methanesulphonyl chloride (1.19 ml) added dropwise with stirring over 5 min. The reaction slowly warmed to ambient temperature as the ice bath melted. After 16 h the mixture was washed with saturated aq. sodium hydrogen carbonate, the aqueous layer extracted twice with dichloromethane and the combined extracts washed with dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as a brown oil, yield 2.38 g.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([C@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=O)=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[H][H].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Pd]>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C1CC[C@@H](C(=O)c2ccc(-c3ccccc3)cc2)N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1

Procedure:
200 mg of (S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one of example 2 were suspended in 3 ml THF. 20 mg of sulphuric acid and 5 mg of palladium on carbon 10% m/m (W. C. Heraeus GmbH, Type K-0218) were added and the mixture was stirred under 3 bar hydrogen for about 20 hours. The mixture was neutralised with 50 mg sodium carbonate and the precipitate removed by filtration. The filtrate was concentrated to dryness to obtain (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one. 1H-NMR (DMSO): 1.66 (1H, m, 4-CHH); 1.94 (1H, m, 4-CHH); 2.01 (2H, m, 3-CH2); 2.65 (1H, dd, 1-CHH); 2.84 (1H, dd, 1-CHH); 3.78 (1H, m, 5-CH); 7.30 (2H, d, aromatic); 7.33 (1H, m, aromatic); 7.43 (2H, t, aromatic); 7.57 (2H, d, aromatic); 7.63 (2H, m, aromatic); 7.81 (1H, s, NH). m/z: 252 (MH+, 100%).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O.C(N(CC)CC)C>[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To (R)-2-hydroxy-4-methyl-pentanoic acid (1.71 g, 12.9 mmol) in 48 mL of DMF was added sequentially triethylamine (4.9 mL, 35. mmol), HOBt (1.75 g, 12.9 mmol), EDCI•HCl (2.48 g, 12.9 mmol) and piperazine-1-carboxylic acid benzyl ester (2.59 g, 11.8 mmol) at room temperature. The reaction mixture was stirred for 4 h and then diluted with EtOAc (50 mL) and extracted with 50 mL of water. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 40-85% EtOAc-hexanes to give (1.92 g, 49% yield) of 4-(2(R)-hydroxy-4-methyl-pentanoyl)-piperazine-1-carboxylic acid benzyl ester the desired product. LC/MS: m/z 335.4 (M+H)+ at 2.96 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1C(C2C=C[N+:25]([O-:28])=[CH:24][CH:23]=2)C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[N+:25]1([O-:28])[CH:5]=[CH:3][C:2]([CH:1]=[O:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc[n+]([O-])cc1
Reactant: CCOC(=O)CC(C)=O
Agent: N
Solvent: CCO
Product: O=Cc1cc[n+]([O-])cc1

Procedure:
Analogously to the process described in Example 1 there is obtained from 12.3 g of pyridine-4-carboxaldehyde-1-oxide, 25.7 ml of ethyl acetoacetate and 10 ml of 30% aqueous ammonia in 20 ml of absolute ethanol, 2,6-dimethyl-4-(1-oxido-4-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which, after recrystallisation from 100 ml of isopropanol, melts at 229°-231°.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH:25]=[C:26]([CH2:28][O:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>C1COCC1.C(O)C>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:33][CH:32]=3)[CH:25]=[C:26]([CH2:28][O:29][CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(COC)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
To a solution of the 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(4′-methanesulfonyl-5-methoxymethyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (195 mg, 0.29 mmol) in THF (5 mL) and ethanol (5 mL) was added aqueous 1.0 N sodium hydroxide (3 mL) at room temperature. The resulting suspension was stirred for 5 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×30 mL). The combined ethyl acetate extracts were washed with brine solution (50 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent afforded 4-[2-(2-carboxy-ethyl)-3-[6-(-4′-methanesulfonyl-5-methoxymethyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (168 mg, 94%) as a white solid: ES(+)-HRMS m/e calcd for C34H42O9S (M+Na)+ 649.2442. found 649.2440.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=3)[CH:20]=2)[C:11](=[O:26])[CH:10]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:24][C:22]1[N:23]=[C:18]2[CH:17]=[CH:16][C:15]([N:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]3=[O:26])=[CH:20][N:19]2[C:21]=1[CH3:25]
Reactant: Cc1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cn2c1C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1nc2ccc(-n3ccc(O)cc3=O)cn2c1C
Temperature: 130 °C
Yield: 83.9 %

Procedure:
To a stirred solution of 4-(benzyloxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (500 mg) in TFA (21 ml) was added anisole (7 ml), and the reaction mixture was heated at 130° C. for 4 h. The mixture was concentrated in vacuo to afford the title compound (310 mg) as a white solid.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][CH2:10][CH2:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][N:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[CH:34][CH:33]=3)[CH3:31])=[CH:21][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:3]1([CH2:9][CH2:10][CH2:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][N:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[CH:34][CH:33]=3)[CH3:31])=[CH:21][CH:20]=2)[C:13]([OH:15])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NOCCOc1ccc(CC(CCCc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
0.67 g of potassium hydroxide was added to a solution of 1.20 g of ethyl 2-(3-phenylpropyl)-3-[4-[2-[[1-[4(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 19 in 20 ml of ethanol, and the mixture was stirred at 80° C. for 2 hours. After the reaction, the reaction mixture was concentrated. To the residue were added water, ice and ethyl acetate and the pH of the reaction mixture was adjusted to a value of 4 with 3N hydrochloric acid. Then, the ethyl acetate layer was separated. The extract thus obtained was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to obtain 1.10 g of the desired compound as a gum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Cl)[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.ClC1C=C([F:25])C=CC=1CC#N.ClC1C=C(F)C=CC=1C>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:25])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Reactant: N#CCc1ccc(F)cc1Cl
Agent: Cc1ccc(F)cc1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc(F)cc1Cl

Procedure:
This compound was prepared in an analogous manner to the compound of Example 15 from 2-chloro-4-fluorophenylacetonitrile, which was itself prepared from 2-chloro-4-fluorotoluene (Aldrich, mp. 238° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:14]=2)[CH:10]=[CH:9][N:8]=1>[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN1C(=O)CCC1>[CH:1]1([C:9]2[CH:10]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=4)[N:15]([C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:14]=3)[CH:12]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(Cl)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Br[Mg]C1CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(C3CC3)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 37.9 %

Procedure:
To a tube under nitrogen was added 36.2 ml ZnCl2 (0.5 M in THF, 18.02 mmol) followed by cyclopropylmagnesium bromide (34 ml of 0.5 M in THF soln., 16 mmol). The resultant mixture was stirred for 20 min at r.t. NMP (23 ml) was added, stirred for 5 min followed by 3-(2-Chloro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole (5.5 gm, 10.6 mmol) and Pd[P(tBu)3]2 (0.108 gm, 0.22 mmol). The tube was sealed under nitrogen and stirred at 100 C for 18 hrs. The reaction mixture was then cooled and evaporated to dryness. Silica gel chromatography using 5-20% ethylacetate/hexanes gave 2.1 g of title product.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([N:11]=[N+]=[N-])[CH:10]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2=[N+:14]([O-:16])[O:15][N:11]=[C:9]2[CH:10]=1
Reactant: [N-]=[N+]=Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: [O-][n+]1onc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrophenyl azide (1.2 g) is cautiously heated to reflux temperature in toluene (10 ml) and is heated under reflux for 3 hours. The reaction is cooled, and diluted with benzene, washed with water (3X) and with brine, dried, stripped and purified by prep. TLC (6.5% ethyl acetate/hexane) to give 5-(2-chloro-4-trifluoromethylphenoxy)-benzo-2,1,3-oxadiazole N-oxide, m.p. 60°-61°. (C; X=H, Y=Cl, Y'=H, Z=CF3).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])C([O-])=[O:5].[K+].C(=O)([O-])[O-].[K+].[K+].BrBr>O>[OH2:5].[F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])=[O:7]
Reactant: O=C([O-])C(O)(C(F)(F)F)C(F)(F)F
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C(F)(F)F)C(F)(F)F
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a 50-ml three-necked flask were placed 7.59 g (17.2 mmol) of the aqueous 56.8% potassium 3,3,3-trifluoro-2-trifluoromethyl-2-hydroxypropionate solution prepared in Reference Example 1 and 4.98 g (36 mmol) of potassium carbonate. 25 g of water was added to dissolve the mixture. The pH was 13. 5.75 g (36 mmol) of bromine was added dropwise over 60 minutes while stirring the mixture under heat at 40° C. in a water bath. After the completion of dropwise addition, the reaction was further performed at the same temperature for 3 hours, and the reaction was complete. The pH when the reaction was complete was 7 to 8. Hexafluoroacetone hydrate was obtained at a starting material conversion of 64% with a selectivity of 99% or higher.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.ClCCl.C1(N=C=NC2CCCCC2)CCCCC1.C(OC([N:39]1[C:43]([CH:44]2[CH2:46][CH2:45]2)=[CH:42][C:41]([NH2:47])=[N:40]1)=O)(C)(C)C>C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:47][C:41]3[NH:40][N:39]=[C:43]([CH:44]4[CH2:46][CH2:45]4)[CH:42]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)OCO2)Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.7 %

Procedure:
To a solution of 96.8 mg (0.537 mmol) of 2-(1,3-benzodioxol-5-yl)-acetic acid in 3 ml of dichloromethane 360 mg (0.720 mmol) of polystyrene supported dicyclohexylcarbodiimide (loading=2 mmol/g) and 40 mg (0.179 mmol) of tert-butyl-3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate were added. The mixture was maintained under stirring at room temperature for 96 hours and after that time filtered, washed several times with dichloromethane and evaporated to dryness. The residue was re-dissolved with 3 ml of trifluoroacetic acid 10% V/V in dichloromethane and maintained at room temperature for an hour. The solvent was then evaporated, the residue re-dissolved in dichloromethane and washed with a saturated solution of sodium hydrogenocarbonate. The organic layer was evaporated to dryness to give, after trituration with diethylether, 32 mg (63% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C(O)CCC>[NH2:1][C:2]1[N:7]=[C:6]([NH:24][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1
Reactant: CCCCN
Reactant: Cc1nc(N)nc(Cl)c1Sc1ccc(CC#N)cc1
Solvent: CCCCO
Product: CCCCNc1nc(N)nc(C)c1Sc1ccc(CC#N)cc1

Procedure:
A mixture of the product from step (iv) (525 mg) and butylamine (3 ml) in BuOH (14 ml) was heated under reflux for 5 h. The solvent was evaporated under reduced pressure and the residue partitioned between EtOAc/water. The organics were separated, dried and evaporated under reduced pressure to give the subtitle compound as a gum, 610 mg.