Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2]([CH3:1])=[N:14][NH:15]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 150 °C
Yield: 60 %

Procedure:
To a solution of 2-fluoro-4-methoxyacetophenone (1.90 g, 11.3 mmol) in ethanol (20 ml) was added hydrazine hydrate (1.4 ml, 45.0 mmol) and heated at reflux temperature for 6 h. This mixture was evaporated to a residue and ethylene glycol (10 ml) was added. The mixture was heated at 150° C. for 18 h, cooled to room temperature, diluted with water (50 ml), and extracted with dichloromethane (3×60 ml). The combined extracts were washed with brine (10 ml), dried (MgSO4) and evaporated to a residue, which was crystallized from ethyl acetate to give a solid (1.1 g, 59%): MS(ES) m/z 163 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1>FC(F)(F)C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
In trifluoroacetic acid (2.0 mL) and water (0.2 mL) was dissolved 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (202 mg), and the solution was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the pH of the residue was made 4 with a saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated brine, the organic layer was separated and concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (137 mg).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[C:15]([CH:25]([CH3:27])[CH3:26])[C:14]=2[CH:28]=O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:28][C:14]1[C:15]([CH:25]([CH3:27])[CH3:26])=[N:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:18][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
A solution of carbon tetrabromide (2.204 gm, 6.65 mmol) in CH2 Cl2 (8 ml) was added over a 12 minute period to a cold (-12° C.) solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.415 gm, 4.43 mmol) (the preparation of which is described in Example 1) and triphenylphosphine (3.488 gm, 13.3 mmol) in CH2Cl2 (25 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and stripped to give a yellow oil. The oil was chromatographed (flash, Merck SiO2, 40% CH2Cl2 in hexane) to give 3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine as a colorless foam (2.152 gm, 100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21]>CN(C=O)C.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:21][C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[Cl:11]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
36.6 mL (416 mmol) of 1,2-dibromoethane is dissolved in 200 mL of DMF and 11.5 g (83.3 mmol) of potassium carbonate is added. 7.20 g (41.6 mmol) of 2-chloro-4-nitrophenol in 40 mL of DMF is slowly added dropwise to this mixture. The mixture is stirred for 3 hours at ambient temperature. The solvent is eliminated, the residue is taken up in ethyl acetate and washed with saturated saline solution. The organic phase is dried over sodium sulfate. The solvent is eliminated and the residue is purified through a silica gel column with a gradient of petroleum ether/ethyl acetate (4:1 to 9:1). Yield: 7.9 g (68% of theory); Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate=3:1); C8H7BrClNO3.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1.N#N.[Br-].[CH2:16]([Zn+])[CH2:17][CH3:18]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: CCC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1cccc(C(=O)OCC)n1
Temperature: 25 °C

Procedure:
A solution of ethyl 6-bromopicolinate (8 g, 34.8 mmol, purchased from AK Scientific, Inc., Union City, Calif.) in THF (200 mL) was sparged with N2 at 0° C. for 20 min. To the mixture under N2 atmosphere was added Pd(PPh3)4 (3.21 g, 2.78 mmol) and a solution of propylzinc bromide (100 mL, 0.5 M in THF, 50.0 mmol) dropwise over 30 min. The mixture was removed from the ice bath and heated to reflux for 18 h. After that time the solution was cooled to rt, poured into saturated aqueous NH4Cl solution (18 mL), diluted with water (30 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water and sat. aq. NaCl solution and were dried over Na2SO4. After removal of the organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0 to 50% EtOAc/hexanes provided the title compound. Mass Spectrum (ESI) m/z=194.0 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[O:20]=[C:21]1[NH:26][C:25](=[O:27])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][NH:22]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:22]2[CH:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25](=[O:27])[NH:26][C:21]2=[O:20])=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CCOC(=O)c1c[nH]c(=O)[nH]c1=O
Agent: Cl
Product: CCOC(=O)c1cn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)[nH]c1=O

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate. M/e+ 425 for C21H18ClN4O4 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 8.32 (d, J=6.9 Hz, 1H), 7.67 (m, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.31 (t, J=7.3 Hz, 1H), 6.93 (t, J=6.96 Hz, 1H), 5.49 (s, 2H), 4.10 (q, J=6.9 Hz, 2H), 1.16 (t, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:20])[C:13]3[C:14](=[CH:16][N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([N+:21]([O-:23])=[O:22])=[CH:6][N:5]=1)[CH3:2].[Br:24]Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:24][C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:20])[NH:11][C:10]([C:9]3[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[C:7]([N+:21]([O-:23])=[O:22])[CH:8]=3)=[N:15][C:14]=12
Reactant: CCOc1ncc([N+](=O)[O-])cc1-c1nc2cn(C)nc2c(=O)[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ncc([N+](=O)[O-])cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the title compound of Example 52 (6.9 g, 21.8 mmol), bromine (1.35 mL, 26.2 mmol), and sodium acetate (2.7 g, 32.7 mmol) in acetic acid (100 mL) was heated under reflux for 7 h, then allowed to cool. Additional bromine (0.35 mL, 6.8 mmol) was added and the reaction stirred at room temperature for a further 18 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was partitioned between dichloromethane and water and the resulting precipitate filtered off, washed with dichloromethane, water, then diethyl ether and dried.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:24][CH3:25])([O:22][CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5]>C(O)C.[Ni]>[CH3:23][O:22][C:15]([C:11]1[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH:13][CH:12]=1)([O:24][CH3:25])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C(C)(SC)c1cccc(C(OC)(OC)c2ccccc2)c1
Agent: [Ni]
Solvent: CCO
Product: COC(=O)C(C)c1cccc(C(OC)(OC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Methyl α-methylthio-α-[m-(α,α-dimethoxybenzyl)phenyl]-propionate (211 mg) was dissolved in 1 ml of ethanol, and 5 ml of an ethanol suspension of 2 cc of Raney nickel (W-II) was added. The mixture was stirred at room temperature for 1 hour. The insoluble matter was separated by filtration, and washed with 40 ml of ethanol. The filtrate and the washing are combined and concentrated under reduced pressure, and 30 ml of methylene chloride was added to the residue. The insoluble matter was separated by filtration, and the solvent was evaporated off under reduced pressure to afford 159 mg of methyl α-[m-(α,α-dimethoxybenzyl)phenyl]propionate as an oil in a yield of 86%.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[Br:15])[CH:2]=[CH2:3].C[Sn](C)(C)[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=2)=[N:11][C:10]=1[Br:15])[CH:2]=[CH2:3]
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: C=CCn1ccnc1-c1sc(Br)nc1Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Temperature: 115 °C
Yield: 54.1 %

Procedure:
To a solution of 5-(1-allyl-1H-imidazol-2-yl)-2,4-dibromo-1,3-thiazole (5.00 g, 14.3 mmol) in 1,4-dioxane (133 mL) was added N-[4-(trimethylstannyl)pyridine-2-yl]acetamide (5.14 g, 17.2 mmol), lithium chloride (1.82 g, 43.0 mmol), copper (I) iodide (0.818 g, 4.30 mmol) and tetrakis (triphenylphosphine)palladium(0) (1.24 g, 1.07 mmol). The flask was purged with argon and then the mixture was heated at 115° C. for 4 hours. The reaction was allowed to cool to room temperature, and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (3.13 g, 54%). LCMS: (FA) ES+ , 406. 1H NMR (400 MHz, d6-DMSO) δ: 10.77 (s, 1H), 8.66-8.61 (m, 1H), 8.49-8.44 (m, 1H), 7.61-7.56 (m, 1H), 7.49-7.45 (m, 1H), 5.98-5.87 (m, 1H), 5.19-5.12 (m, 1H), 4.95-4.88 (m, 1H), 4.70-4.64 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][OH:37]>CN(C=O)C.O>[OH:37][CH2:36][CH2:35][N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: OCCBr
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(CCO)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (1) (0.68 mmol) in DMF (8 mL) was added potassium carbonate (0.68 mmol) and 2-bromoethanol (0.68 mmol). The resulting solution was stirred at room temperature overnight. Then, the mixture was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. The product was further purified by reverse-phase chromatography, eluting with 10% to 90% CH3CN in H2O, to afford the title compound (0.025 g, 9%). 1H NMR (300 MHz, DMSO-d6): δ 11.45 (s, 1H), 8.08 (d, J=8.9 Hz, 2H), 7.00 (d, J=9.1 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 4.30-4.55 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.43-3.67 (m, 2H), 3.10-3.43 (m, 7H), 2.77-3.04 (m, 1H), 2.31-2.64 (m, 2H). ESI MS m/z 411 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1)[CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:30][CH:31]=1)[CH2:20][CH3:21]
Reactant: CCCOCCOc1ccc(OB(O)O)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Reaction time: 0.08 h
Yield: 34.5 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) dissolved in methylene chloride (15 ml) was added 4-(2-propoxyethoxy)phenylboric acid (0.67 g) and molecular sieves 4A (0.8 g), and the resulting mixture was stirred for 5 minutes. To the reaction mixture were added cupric acetate (0.27 g) and triethylamine (1.04 ml), and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through celite, and the filtrate was washed with ethyl acetate. The resulting solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to obtain methyl 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.23 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:10][C:11]=1[O:12][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (30.9 g, 114 mmol) was dissolved in CH2Cl2 (800 mL). DIPEA (48.7 mL, 285 mmol) was added, and the reaction mixture was cooled to −78° C. A sol. of Tf2O (24.4 mL, 148 mmol) in CH2Cl2 (25 mL) was added slowly, while maintaining the temperature at −78° C. The mixture was stirred for 30 min at −78° C. The mixture was allowed to warm to rt, and aq. 10% Na2CO3 (400 mL) and ice were added. The layers were separated and the aq. layer was extracted with CH2Cl2 (2×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→EtOAc/heptane 25:75) yielded the title compound (44.0 g, 91%). LC-MS: tR=1.05 min; ES+: 404.44.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:19][CH:18]=[CH:17][C@H:16]1[C:20]#[N:21])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:19][CH:18]=[CH:17][C@H:16]1[C:20]#[N:21])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC=C[C@H]1C#N)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)N1CC=C[C@H]1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
(140 mg, 0.46 mmol) of (3) was dissolved in 0.5 ml of dichloromethane and the mixture was cooled to 0° C. 0.5 ml of trifluoroacetic acid was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was evaporated and the crude product was purified by preparative HPLC, using acetonitrile/water as the eluent. Fractions containing the product were collected and the solvent was evaporated, to afford 25 mg of the title compound (1) as the trifluoroacetic acid salt. Oil, 17% yield. 1H-NMR (MeOH, 200 MHz) δ: 1.20 (s, 9H); 4.08 (s, 1H); 4.46-4.70 (m, 2H); 5.56-5.62 (m, 1H); 5.95-6.02 (m, 1H); 6.22-6.29 (m, 1H). LC-MS, m/z: 208.4 (M+1)
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH2:19][CH2:20][CH3:21])[N:10]=1)[CH2:4][CH3:5])[CH3:2].Cl[C:23](OCC)=[O:24].Cl>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:8]1[C:9]2[N:10]=[C:11]([O:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:13][C:14]=2[N:15]=[C:23]1[OH:24])[CH3:2]
Reactant: CCCOc1ccc([N+](=O)[O-])c(NCCN(CC)CC)n1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCCOc1ccc2nc(O)n(CCN(CC)CC)c2n1

Procedure:
The compound was produced in a manner analogous to Example 4 (or Example 5) starting from 36 grams of 2-(diethylaminoethylamino)-3-nitro-6-n-propoxypyridine and 13.5 grams of ethyl chloroformate produced. Yield: 24 grams M.P. of the hydrochloride 210°-212° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl.Cl[CH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1.[Na]>C(O)C>[C:3]1(=[O:12])[N:2]([O:1][CH2:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]12
Reactant: ClCc1cc[nH]n1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1OCc1cc[nH]n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.96 g N-hydroxyphthalimide and 765 mg of 3-chloromethylpyrazole hydrochloride were added to a mixture of 0.28 g of sodium and 20 ml of ethanol under cooling in ice-bath and the resulting mixture was stirred for 2.5 hours at room temperature. The solvent was distilled off and water was added to the residue. The mixture was extracted with chloroform and the extract was washed with SSB and SSC and then dried with sodium sulfate. The solvent was distilled off and the residue was washed with ether to give 3-(phthalimidooxymethyl)pyrazole with mp 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N)C1C=CC=CC=1.[NH2:18][C:19]1[S:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:25]([C:21]2[S:20][C:19]([NH2:18])=[N:23][C:22]=2[CH3:24])=[O:26])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1nc(N)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N)sc1C(=O)NCc1ccc(Cl)cc1
Yield: 15 %

Procedure:
Following the procedure as described in Preparation 1, making variation only as required to use 4-chlorobenzylamine to replace benzylamine to react with 2-amino-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid in 15% yield; 1H NMR (CD3OD, 300 MHz) δ 7.26-7.32 (m, 4H), 4.41 (s, 2H), 2.38 (s, 3H). MS (ES+) m/z 282.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].C[O-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22]Cl>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10]
Reactant: ClCOc1ccccc1Br
Reactant: O=CNc1ccccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=CNc1ccccc1OCOc1ccccc1Br
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
N-(2-hydroxyphenyl)formamide (16.0 g, 130 mmol) was dissolved in 99.9% ethanol (65 ml). Sodium methoxide 7.0 g, 130 mmol) was suspended in 99.9% ethanol (70 ml) and added dropwise over 30 minutes. The resulting mixture was stirred for 30 minutes. 1-Bromo-2-chloromethoxybenzene (26.1 g, 119 mmol, synthesis described in J. Heterocycl. Chem., 11, 1974, 331-337) was added dropwise over 15 minutes. The reaction mixture was stirred for 2.5 h at room temperature, heated at reflux temperature for 2 h, and stirred at room temperature overnight. The mixture was filtered and evaporated. The residue was dissolved in toluene (500 ml) and washed with a saturated sodium carbonate solution (2×200 ml). The organic phase was dried (MgSO4) and evaporated. The residue was suspended in ethanol (40 ml), filtered and washed with ethanol (3×10 ml). After drying, this afforded the product, N-(2-(2-bromophenoxymethoxy)phenyl)formamide (14.1 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.N.C(#[N:13])C>[OH-].[Na+]>[NH2:13][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CC#N
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: NCc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A stainless steel autoclave was charged with 14.99 g of 2-chloro-5-(chloromethyl)pyridine, 63.01 g of 25% aqueous ammonia and 60 ml of acetonitrile and the mixture was stirred on an oil bath at 80° C. for 2 hours. The reaction mixture was diluted with 12.3 g of 30% aqueous sodium hydroxide solution and concentrated. The residue was diluted with 200 ml of ethanol, dried over anhydrous magnesium sulfate and filtered to remove the insolubles. Finally, the filtrate was concentrated and purified by column chromatography (eluent: dichloromethane-methanol (4:1)) to give 7.66 g of 5-(aminomethyl)-2-chloropyridine as a yellow solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([NH:29][CH2:30][C:31]4[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=4)=[N:26][C:27]=3[F:28])=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:28][C:27]1[N:26]=[C:25]([NH:29][CH2:30][C:31]2[CH:32]=[N:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)[CH:24]=[CH:23][C:22]=1[CH2:21][C:12]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=2)[NH:10][CH:11]=1
Reactant: COc1cnc2c(c1)c(Cc1ccc(NCc3ccc(C(F)(F)F)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)nc4)nc3F)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [5-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (577, 0.08 g, 0.13 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.110 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give an off-white solid (P-0187, 8.1 mg, 10%). MS (ESI) [M+H+]+=431.9.