Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([N:17]1[CH2:21][CH2:20][C:19](=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:10]([N:17]1[CH2:21][CH2:20][CH:19]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(C)nc(NC2CCN(Cc3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
A mixture of 2-amino-4,6-dimethylpyridine (2.0 g), 1-benzylpyrrolidin-3-one (2.9 g), acetic acid (2.9 mL), and chloroform (34 mL) was ice-cooled, followed by addition of sodium triacetoxyborohydride (4.9 g), and the mixture was stirred for 18 h while heating slowly to room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide to make it basic, and then the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=65:35) to obtain 1-benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g). (2) 1-Benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g) was dissolved in methanol (13 mL), followed by addition of 20% Pd(OH)2/C (0.26 g), and the mixture was stirred at room temperature for 20 h under hydrogen atmosphere. The catalyst was removed by Celite filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol=19:1) to obtain 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.10 g). (3) A mixture solution of 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.73 g), 4-trifluoromethoxyphenylacetic acid (0.12 g), EDC.HCl (0.12 g), HOBt.H2O (0.12 g), and chloroform (1.0 mL) was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with chloroform and washed with 1 M aqueous sodium hydroxide and brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19:1) and then crystallized with hexane and diethyl ether to obtain the title compound (0.14 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](Cl)[CH3:9].[C:24]([O-:27])(=[O:26])[CH3:25].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:24]([O:27][CH:8]([C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)[CH3:13])[C:2]=1[Cl:1])[CH3:9])(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: CC(Cl)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC(C)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl

Procedure:
In 50 ml of acetic acid was dissolved 3.1 g of 5-chloro-6-(1-chloroethyl)-4-[1-(4-difluoromethoxyphenyl)ethylamino]-pyrimidine, and to the mixture were added 3.0 g of potassium acetate and 3.0 g of potassium carbonate. The mixture was refluxed under heating for 30 hours.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Product: O=C(Cl)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]benzoic acid (15 g, 0.035 mol) in thionyl chloride (75 mL) is heated at 60° C. for 2 hours and concentrated in vacuo to give the title product.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]3[N:19]=[CH:20][C:21]4[CH:26]=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:24]([CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[C:22]=4[N:23]=3)=[N:15][CH:16]=1)=[O:10])[CH2:2]2.[CH3:37][C:38]([CH3:40])=O>C(Cl)Cl>[CH:32]1([N:24]2[C:22]3[N:23]=[C:18]([NH:17][C:14]4[CH:13]=[CH:12][C:11]([C:9]([N:3]5[CH2:4][CH:5]6[N:8]([CH:38]([CH3:40])[CH3:37])[CH:1]([CH2:7][CH2:6]6)[CH2:2]5)=[O:10])=[CH:16][N:15]=4)[N:19]=[CH:20][C:21]=3[CH:26]=[C:25]2[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Solvent: ClCCl
Product: CC(C)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (42 mg, 0.086 mmol) in 6 ml of DCM, acetone (0.6 ml) was added and the resulting reaction mixture was stirred for 1H at room temperature. Na(AcO)3BH (55 mg, 0.26 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. When LCMS showed the reaction was complete the reaction mixture was diluted with DCM, washed with sat NaHCO3 (2×), brine. The combined aqueous layers were backextracted with DCM and the combined organic layers were dried over Na2SO4, filtered and purified by column chromatography (0-20% MeOH/CHCl2) which gave 7-cyclopentyl-2-(5-(8-isopropyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (64 mg, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[C:6]=1[Cl:7].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:27])([F:28])[F:29])=[N:4][N:5]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:41])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[C:6]=1[Cl:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)c(Cl)c2Cl)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)c(Cl)c2Cl)cc1S(=O)CC(F)(F)F
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
0.35 g of 4,5-dichloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 0.15 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.35 g of 4,5-dichloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S(O[CH2:27][C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:27][C:28]1([CH2:32][O:1][C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:31][O:30][CH2:29]1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC2(C)COC2)cc(C(=O)OC)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 5-hydroxyisophthalate (500 mg), (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (915 mg), and potassium carbonate (850 mg) in N,N-dimethylformamide (3 mL) is stirred at 50° C. for 5 h. The reaction mixture is diluted with water and the precipitate is filtered off, washed with water, and dried to give the title compound. LC (method 7): tR=0.97 min; Mass spectrum (ESI+): m/z=295 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][C:10]([O:12]CC)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH-].[Na+:16]>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:9][C:10]([O-:12])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[Na+:16]
Reactant: CCOC(=O)Cc1ncccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccnc1CC(=O)[O-]
Reaction time: 7 h

Procedure:
A stirred solution of ethyl 2-(3-methoxypyridin-2-yl)acetate (0.17 g, 0.871 mmol) in THF (2.5 mL) at room temperature was treated with 3 M aqueous NaOH (0.581 mL, 1.74 mmol). After 7 h, the mixture was concentrated to remove the THF and the aqueous residue was frozen on dry ice and lyophilized to provide sodium 2-(3-methoxypyridin-2-yl)acetate as a white solid. A quantitative yield was assumed and the material used without further purification. Mass spectrum m/z 168 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1[CH:17]=[C:16](Cl)[C:15]([N+:19]([O-])=O)=[CH:14][C:13]=1[N+:22]([O-])=O)[CH3:8].C(O)(=O)C>ClCCl.[Zn]>[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1[CH:17]=[C:16]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:15]([NH2:19])=[CH:14][C:13]=1[NH2:22])[CH3:8]
Reactant: C1CCNCC1
Reactant: CCOC(=O)Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(N2CCCCC2)c(N)cc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Piperidine (120 mg) was added to a solution of (5-chloro-2,4-dinitro-phenyl)-acetic acid ethyl ester (150 mg) in dichloromethane (5 mL) and the resulting mixture was stirred at room temperature for 10 minutes. Glacial acetic acid (0.3 mL) and zinc dust (1 scoop) were added and the reaction mixture was stirred at room temperature for 20 minutes. The resulting mixture was filtered through a CELITE™ pad, the filter cake was washed with dichloromethane and the filtrate was evaporated under reduced pressure. The residue was then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give (2,4-diamino-5-piperidin-1-yl-phenyl)-acetic acid ethyl ester. This material was dissolved in toluene (2.5 mL) and heated at 150° C. in a microwave reactor for 10 minutes. The reaction mixture was then cooled, evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH, 95/5) to give 30 mg of 6-amino-5-piperidin-1-yl-1,3-dihydro-indol-2-one. MS=232 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([I:15])=[N:6][CH:7]=1
Reactant: II
Reactant: Oc1cncc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1cc(Cl)cnc1I
Reaction time: 5 h
Yield: 95.8 %

Procedure:
To a solution of 5-chloropyridin-3-ol [CAS no 74115-12-1] (15 g, 116 mmol) in sodium carbonate (1 M in water, 232 ml, 232 mmol) at 23° C. was portionwise added iodine (29.4 g, 116 mmol) and the mixture was stirred for 5 h. Poured onto 1 M hydrochloric acid (300 ml), adjusted pH by additional hydrochloric acid to pH 1, the precipitate was filtered off, washed with water, dissolved in ethyl acetate, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left the 5-chloro-2-iodopyridin-3-ol (28.33 g, 111 mmol, 95.8% yield) as a light brown solid. MS (ISP): m/z=256.1 [(M+H)+] and 258.2 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:32])[C:6]=2[CH:33]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:32])[C:6]=2[CH:33]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2oc3ccc(Cl)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)NCCC(=O)O)cc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl]amino}propanoate (196 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.50 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.50 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (170 mg, 92%) as a white solid.
Reaction SMILES: Br[CH:2]([CH3:37])[C:3]([C:5]1[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:8](=[O:22])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=O.[C:38]([NH2:41])(=[O:40])[CH3:39].C1(C)C(C)=CC=CC=1.OS(O)(=O)=O>O.CC#N>[CH3:39][C:38]1[O:40][C:2]([CH3:37])=[C:3]([C:5]2[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)=[O:24])[C:8](=[O:22])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[C:10]=2[CH3:11])[N:41]=1
Reactant: Cc1c(C(=O)C(C)Br)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(N)=O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)c(C)o1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A mixture of 5-(2-bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (130 mg, 0.22 mmol), acetamide (262 mg, 4.4 mmol), xylene (300 μl) and conc. H2SO4 (10 μl) was heated with stirring for 2 h. The reaction was diluted with water and CH3CN and purified on preparative HPLC, affording the title compound (45 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]O)=[N:19][N:18]=[C:17]1[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:33]2[C:29](=[O:39])[C:30]3=[CH:38][CH:37]=[CH:36][CH:35]=[C:31]3[C:32]2=[O:34])=[N:19][N:18]=[C:17]1[CH2:23][CH2:24][N:25]([CH3:26])[CH3:27]
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 2',5-dichloro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in 1,2-dimethoxyethane is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 2',5-dichloro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4,-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(OC)N(C)C.[CH2:26]1COC[CH2:27]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:26]([CH3:27])=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: C1CCOC1
Agent: COC(OC)N(C)C
Product: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 9.0 g of 4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 9703986 A1 19970206) (37 mmoles, 1 eq.) in 40 ml of THF, were added 8.1 ml of dimethylformamide dimethyl acetal (55.4 mmoles, 1.5 eq.). The reaction mixture was then stirred at 50° C. for 4 hours under nitrogen. The solvent was removed under reduced pressure, the residue dissolved in 40 ml of toluene, and 400 mg of para toluene sulfonic acid were added. The mixture was then heated at 100° C. under nitrogen for 18 hours, the volatiles were removed under reduced pressure and the residue was partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride/methanol as eluant (98:2 v/v to 95:5 v/v) to afford 8.07 g of the title compound as a white solid (81%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].[C:29](ON1C(=O)CCC1=O)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O1CCCC1>[CH2:32]([O:31][C:29]([N:3]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:1][CH3:2])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCNCCCOc1cc(CNC(=O)OC(C)(C)C)ccc1-c1ccccc1
Solvent: C1CCOC1
Product: CCN(CCCOc1cc(CNC(=O)OC(C)(C)C)ccc1-c1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
To a solution of tert-butyl N-[2-(3-ethylaminopropoxy)-biphenyl-4-ylmethyl]carbamate (0.41 g) in tetrahydrofuran (4.0 mL) was added N-carbobenzoxyoxysuccinimide (0.260 g), and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.46 g).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:5]=1[NH:6][C:7]([CH3:20])([CH3:19])[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1>C1COCC1.[Fe]>[Cl:3][C:4]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]([CH3:20])([CH3:19])[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: CC(C)(Cc1ccc2ccccc2c1)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Cc1ccc2ccccc2c1)Nc1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a mixture of water (50 mL) and iron powder (3.78 g, 67.7 mmol) at 65° C. was added concentrated hydrochloric acid (1.0 mL) dropwise and the mixture was stirred for 15 min. The aqueous layer of the mixture was poured out and a solution of 2-chloro-N-(2-methyl-1-(naphthalen-2-yl)propan-2-yl)-4-nitroaniline (2.4 g, 6.76 mmol) in THF (50 mL) was added to the above processed iron powder. The mixture was stirred further at 65° C. for 30 min. The mixture was then cooled to rt and filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a white solid (1.86 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][OH:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:12][CH3:11])=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CO
Product: COC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 1-liter flask fitted with a stirrer, addition funnel, condenser, and drying tube containing diethyl ether (200 ml) and methanol (anhd.; 64 g,; 2.0 moles] is added dropwise m-fluorobenzoyl chloride (317 g,; 2.0 moles) at room temperature over a 3 hour period. Additional methanol (10 ml) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is then filtered through a bed of silicic acid and the solvent removed under vacuum to afford 285 grams of methyl 3-fluorobenzoate (92.5% yield). This was identical to the product prepared in Example 2A.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.P(Br)(Br)([Br:14])=O>>[Br:14][C:5]1[C:4]2[CH:9]=[CH:10][O:11][C:3]=2[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=c1[nH]cc(Br)c2occc12
Reactant: O=P(Br)(Br)Br
Product: Brc1ncc(Br)c2occc12
Temperature: 70 °C
Yield: 75.7 %

Procedure:
A mixture of 7-bromo-5H-furo[3,2-c]pyridin-4-one (21.2 g, 99 mmol) and POBr3 (31.2 g, 109 mmol) was heated at 70° C. for 5 min, then heated to 120° C. for 2 h. After cooled to rt, the solid was crashed and quenched with aqueous Na2CO3 (200 mL), then diluted with EtOAc (300 mL). The insoluble material was filtered off through a pad of Celite. The organic phase was collected and dried over Na2SO4. The crude material was purified by silica gel chromatography eluting with Hexanes-EtOAc (90:10→85:15) to give the title compound as a white solid (20.75 g, 68%). 1H NMR (CDCl3, 400 MHz): δ=6.91 (d, J=2.3 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 8.37 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20].O=[C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19]/[N:20]=[C:25](/[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)\[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CON)c1
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CC/C(=N\OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1)c1ccccc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
After a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (600 mg), methyl 4-oxo-4-phenylbutyrate (371 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heated to reflux for 40 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (570 mg, yield 61%) as a colorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.