Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH2:9].[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]=1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=1.O>O1CCOCC1>[CH3:5][O:6][CH2:7][CH2:8][NH:9][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH2:22][C:12]2[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:14][O:15][C:11]=2[CH3:10])=[N:25][CH:26]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: COCCN
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: COCCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 2.0 mL, 4.0 mmol) was added dropwise (exothermic) to a solution of 2-methoxyethylamine (300 mg, 4.0 mmol) in dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0 mmol) in dioxane (3 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 days and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (280 mg, 76%) which was obtained as a colourless oil. MS: m/e=368.1 [M+H]′.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]4[N:20]=[CH:21][N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:23]=4)[CH:16]=[C:15]([F:43])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]4[N:20]=[CH:21][NH:22][CH:23]=4)[CH:16]=[C:15]([F:43])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)c3)n2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4c[nH]cn4)c3)n2)nc1
Temperature: 25 °C
Yield: 13.1 %

Procedure:
To a solution of 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(1-trityl-1H-imidazol-4-yl)phenyl)-1,2,4-oxadiazole (20.0 mg, 0.04 mmol) in tetrahydrofuran (0.5 ml) added hydrochloric acid (0.14 ml, 2N aqueous). The resulting reaction mixture was heated at reflux for 45 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), washed successively with sodium hydroxide (30 ml, 1 N aqueous), water (30 ml) and brine (30 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The isolated residue was purified on silica gel using 5% methanol in dichloromethane to yield the title compound (1.7 mg) as a beige solid. 1H-NMR (CDCl3), δ (ppm): 9.64 (bs, 1H), 8.69 (d, 1H), 8.44 (s, 1H), 8.29 (dd, 1H), 7.81 (m, 3H), 7.61 (dt, 1H), 7.54 (s, 1H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11]>>[CH:1]([CH2:12][C:10](=[CH2:11])[C:9]([OH:14])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=C(C)C(=O)O
Reactant: C=Cc1ccccc1
Product: C=C(CC=Cc1ccccc1)C(=O)O

Procedure:
Styrene methacrylic acid copolymer was prepared by using the same procedures as in Example 1 except 67 parts of styrene and 3 parts of methacrylic acid was used in place of 70 parts of styrene. The resulting copolymer had a number average molecular weight of 3,800, a glass transition temperature of 70° C., and a non-volatile content of 99.8%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13]C(OC(C)(C)C)=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.OS(O)(=O)=O>CO.O1CCOCC1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccnc2)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccc(Cn2ccnc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
The title compound from Step B above (7.64 g, 27.95 mmoles) was dissolved in methanol (148 mL) and 10% conc. H2SO4 in dioxane (v/v) (380.8 mL) was added. The solution was stirred at 25° C. for 4 h. The solution was diluted with methanol and BioRad AG® 1-X8 (OH−) resin was added until the pH was basic. The resin was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on silica gel using 2.5% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (4.36 g, 90%): CIMS: m/z 174.25 (MH+); δH (CDCl3), 3.44 (2H, bs, NH2), 5.02 (2H, s, CH2-Im), 6.39 (1H, s, Im-H5), 6.55 (1H, d, Ar—H4), 6.62 (1H, dd, Ar—H5), 6.91 (1H, s, Im-H4), 7.07 (1H, s, Ar—H2), 7.13 (1H, m, Ar—H6) and 7.54 ppm (1H, s, Im-H2); δC (CDCl3) CH2: 50.8; CH: 113.4, 114.8, 117.2, 119.5, 129.8, 130.0, 137.7; C, 137.6, 147.1.
Reaction SMILES: [N:1]1([CH2:6][C:7]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:18])[F:17])[O:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].O>CO>[N:1]1([CH:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:18])([F:19])[F:17])[OH:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1ccccc1C1OC1(Cn1cncn1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(C(=Cn1cncn1)c1ccc(Cl)cc1)c1ccccc1C(F)(F)F

Procedure:
4 g of 2-(1,2,4-triazol-1-ylmethyl)-2-(4-chlorophenyl)-3-(2-trifluoromethylphenyl)oxirane are dissolved in 80 ml of methanol and, after addition of 1.2 g of sodium methylate, refluxed for one hour. The solution is then cooled to room temperature (20° C.), 50 ml of water are added and the mixture is extracted by shaking several times with methyl tert-butyl ether. The isolated organic phase is washed twice with water, dried over sodium sulfate and concentrated, resulting in 3.8 g (95 %) of 1-(1,2,4-triazol-1-yl)-2-(4-chlorophenyl)-3-(2-trifluoromethylphenyl)-1-propen-3-ol, melting point 161° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH3:16][N:8]1[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c[nH]c(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
The compound prepared in Example 130 (0.204 g) was suspended in N,N-dimethyl formamide (4 mL) and cooled to 0° C. Potassium carbonate (0.279 g) was added and then iodomethane (0.069 mL). The reaction mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature and stirred at room temperature for further 1 hour. The reaction mixture was diluted with ethyl acetate and washed sequentially with sodium bicarbonate aqueous solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography to furnish the title compound (0.130 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:25])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:18]2[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:25])=[CH:22][CH:23]=2)([OH:34])[CH3:35])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(C)(O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
112 mg of the compound [22-1] was dissolved in 5 mL of tetrahydrofuran, and cooled to 0° C. Thereafter, 320 μL of methylmagnesium chloride (3.0M tetrahydrofuran solution) was added thereto, and the mixture was stirred for 1.5 hours while heating back to room temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the solution was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-30/70), to obtain 53 mg of benzyl-4-[1-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-1-hydroxyethyl]piperidine-1-carboxylate [22-2] (hereinafter, referred to as the compound [22-2]).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=O)[C:2]1=2.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl[Sn]Cl>C1COCC1>[CH2:15]([C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([CH2:5][CH2:4][CH2:3][CH2:2][CH2:12][CH2:11][CH2:7][CH3:6])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Reactant: CCCCCCCC[Mg]Br
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: CCCCCCCCc1c2ccsc2c(CCCCCCCC)c2ccsc12
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a 100 mL flask under nitrogen was added 4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (1.1 g, 5.0 mmol) and anhydrous THF (10 mL). The mixture was heated to reflux and octylmagnesium bromide (20 mmol, 10 mL, 2.0 M in Et2O) was added dropwise. After refluxing for 2 hours more, SnCl2 solution (7.3 g in 19 mL 10% HCl) was slowly added dropwise. The mixture was kept at 60° C. for 1 hour. After cooling down, the organic phase was separated. The water phase was extracted with ether once and the organic phases were combined and dried over Na2SO4. Purification by column chromatography with hexane as eluent gave a yellow oil (780 mg, yield 37.6%). 1H NMR (CDCl3, 500 MHz) δ=7.48 (d, J=5.5 Hz, 2H), 7.47 (d, J=5.5 Hz, 2H), 3.20 (t, J=7.5 Hz, 4H), 1.75-1.88 (m, 4H), 1.43-1.54 (m, 4H), 1.21-1.42 (bs, 16H), 0.90 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2I)[CH2:3][CH2:2]1.[CH3:17][N:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]1=[O:33].C([O-])([O-])=O.[Na+].[Na+].CC(=O)OCC>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:22]2[CH:21]=[CH:20][C:19](=[O:33])[N:18]([CH3:17])[CH:23]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CS(=O)(=O)c1ccc(CCC2CC2)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2CCC2CC2)ccc1=O
Yield: 55 %

Procedure:
The title compound of step 3 (120 mg, 0.34 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (89 mg, 0.37 mmol), Na2CO3 (72 mg, 0.68 mmol) and Pd(dppf)Cl2 (15 mg) in DMF/H2O (6 ml/1.5 ml) under N2 were heated at 100° C. for 1 h. EA extractive work up and preparative TLC (PE: EtOAc=0:1) gave the title compound (62 mg, 55%). 1H NMR (CD3OD, 400 MHz): δ 7.92 (dd, J1=2.4 Hz, J2=5.6 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.65-7.61 (m, 2H), 6.69 (m, J=9.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.89-2.86 (m, 2H), 1.51-1.45 (m, 2H), 0.68-0.65 (m, 1H), 0.45-0.40 (m, 2H), 0.04-0.00 (m, 2H). LCMS: 332 (M+1)+
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]#[C:22][CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:21]#[C:22][CH3:23]
Reactant: CC#CCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylxanthine (1.1 g) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (1.0 g) and 1-bromo-2-butyne (0.64 ml) were added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.3 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (1.3 g) was dissolved in N,N-dimethylformamide (15 ml), and N-chlorosuccinimide (0.89 g) was added while cooling on ice. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.1 g of 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione. The resulting 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (1.4 g) and 1-piperazine carboxylic acid tert-butyl ester (2.8 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, then the organic layer was washed with water and saturate brine, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=1)[C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57]>ClCCl>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=1)[C:5]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:6]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1F
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
3-chloro-4-(4-chloro-3-(trifluoromethyl)phenoxy)-2-fluorobenzoic acid (Preparation 153, 0.133 g, 0.360 mmol) was slurried in dichloromethane (0.6 mL). N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (100 mg, 0.54 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol) and N,N-diisopropylethylamine (75 μL, 0.43 mmol) were added to the slurry. The reaction mixture was stirred 20 minutes then methanesulfonamide (100 mg, 1.1 mmol) was added and the stirring continued for 18 hours at ambient temperature. The solvent was removed in vacuo to leave a residue. The residue was purified by semi-preparative reverse phase HPLC (Phenomenex 100×21.2 mm 10 micron C18 column. 20 mL/minutes. Gradient 85% A to 100% B over 25 minutes. Solvent A: 7800 water/200 acetonitrile/8 trifluoroacetic acid. Solvent B: 7200 acetonitrile/800 water/8 trifluoroacetic acid, 254 nM UV detection) to afford the title compound as a white solid (132 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[C:12]2[N:13]=[C:14]([NH2:30])[N:15]=[C:16]([C:17]3[N:21](COCC[Si](C)(C)C)[N:20]=[CH:19][CH:18]=3)[C:11]=2[N:10]=[N:9]1)([O-:3])=[O:2].[ClH:34]>CO.O1CCOCC1>[ClH:34].[N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[C:12]2[N:13]=[C:14]([NH2:30])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][NH:20][N:21]=3)[C:11]=2[N:10]=[N:9]1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2c1nnn2Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(-c2cc[nH]n2)c2nnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 3-(3-nitrobenzyl)-7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (156 mg, 0.34 mmol) in MeOH (2 mL) was treated with 4-M HCl in dioxane (4 mL) stirred at room temperature for 2 h, concentrated in vacuo, triturated with Et2O and filtered to give the title compound (110 mg, 97%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:10][C:11]1[O:12][C:13]2[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[C:16]([O:25][C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[C:14]=2[CH:15]=1.O>CN(C=O)C>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:16]2[C:14]3[CH:15]=[C:11]([CH2:10][N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])[O:12][C:13]=3[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: O=C1CCCN1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CN3CCCC3=O)oc2c1
Yield: 24.8 %

Procedure:
To a solution of 2-ketopyrrolidine (75.1 mg, 0.882 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 44 mg, 1.1 mmol) at room temperature. After stirring the reaction for 30 min, ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285a) (200 mg, 0.441 mmol) was added. The mixture was stirred at room temperature for another 2 h. Water was added to the reaction, and the product was extracted with CHCl3. The combined organic layer was dried and concentrated. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 95/5) to give the title compound (50 mg, 25%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 1.98-2.14 (m, 2 H) 2.42 (t, J=8.10 Hz, 2 H) 3.06 (s, 3 H) 3.44 (t, J=7.06 Hz, 2 H) 4.38 (q, J=7.16 Hz, 2 H) 4.58 (s, 2 H) 6.49 (d, J=0.75 Hz, 1 H) 7.04-7.12 (m, 2 H) 7.61 (d, J=1.13 Hz, 1 H) 7.83-7.94 (m, 2 H) 8.05 (t, J=1.13 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:10]2[NH:14][CH2:13][CH:12]([CH2:15][CH3:16])[O:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20]>CC(C)=O>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]([CH:10]2[N:14]([C:23](=[O:24])[NH:22][CH:19]([CH3:21])[CH3:20])[CH2:13][CH:12]([CH2:15][CH3:16])[O:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCC1CNC(c2ccc(Cl)c(C(F)(F)F)c2)O1
Reactant: CC(C)N=C=O
Solvent: CC(C)=O
Product: CCC1CN(C(=O)NC(C)C)C(c2ccc(Cl)c(C(F)(F)F)c2)O1
Reaction time: 8 h

Procedure:
Four and six-tenths grams of 2-(3-trifluoromethyl-4-chlorophenyl)-5-ethyl-1,3-oxazolidine was combined with 1.5 g of isopropyl isocyanate in 25 ml of anhydrous acetone and allowed to stand overnight protected form moisture. The mixture was stripped on the rotary evaporator giving a gum. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:44])([F:43])[C:17]1[CH:18]=[C:19]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH:23]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:21].[CH3:45][N:46]1[C:55]2[CH2:54][CH2:53][N:52]3[CH:56]=[CH:57][N:58]=[C:51]3[C:50](=[C:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[C:49]=2[CH:48]=[CH:47]1.C([O-])([O-])=O.[K+].[K+]>ClCCCl.O.C(O)(=O)C>[F:15][C:16]([F:44])([F:43])[C:17]1[CH:18]=[C:19]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:20]([N:22]1[CH2:27][CH2:26][C@@H:25]([N:62]2[CH2:63][CH2:64][C:59](=[C:50]3[C:49]4[CH:48]=[CH:47][N:46]([CH3:45])[C:55]=4[CH2:54][CH2:53][N:52]4[CH:56]=[CH:57][N:58]=[C:51]34)[CH2:60][CH2:61]2)[CH2:24][C@@H:23]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:21]
Reactant: O=C1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2ccccc2)C1
Reactant: Cn1ccc2c1CCn1ccnc1C2=C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1ccc2c1CCn1ccnc1C2=C1CCN([C@@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
Sodium triacetoxyborohydride (8.5 g) and acetic acid (2.4 g) were added dropwise to a mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone (4.3 g) and 5,6,7,10-tetrahydro-7-methyl-10-(4-piperidinylidene)imidazo[1,2-a]pyrrolo[3,2-d]azepine (2.7 g) in 1,2-dichloroethane (100 ml) and the mixture was stirred at RT overnight. Water and K2CO3 (5 g) were added and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried, filtered and the solvent evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 96/4 to 85/15). The pure fractions were collected and evaporated, yielding 1.04 g (15%) of fraction 1 and 0.26 g (4%) of (±)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(5,6,7,10-tetrahydro-7-methylimidazo[1,2-a]pyrrolo[3,2-d]azepin-10-ylidene)-1-piperidinyl]-2-(phenylmethyl)piperidine (comp. 2; mp. 141.5° C.). Fraction 1 was repurified by HPLC over NH2-Kromasil (eluent: 100% CH2Cl2). The pure fractions were collected and the solvent was evaporated, yielding 0.75 g (11%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(5,6,7,10-tetrahydro-7-methylimidazo[1,2-a]-pyrrolo[3,2-d]azepin-10-ylidene)-1-piperidinyl]-2-(phenylmethyl)piperidine (comp. 3; mp. 133.0° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH:33]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:34]1=[O:49]>C1COCC1>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH:33]([C:11]3[S:12][C:8]([C:6]4[CH:5]=[C:4]([NH:13][C:14]5[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=5)[CH:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][N:10]=3)[C:34]2=[O:49])=[CH:46][CH:45]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: COc1ccc(CN2CCCCC(Br)C2=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCCC(c3ncc(-c4cc(C)cc(Nc5nccc(C(F)(F)F)n5)c4)s3)C2=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 4, 150 mg, 0.446 mmol) in THF (5 ml) at −78° C., was added lithium diisopropylamide (1.8M in tetrahydrofuran, 0.75 ml, 1.350 mmol). The mixture was stirred at −78° C. for 1 h, and 3-bromo-1-(4-methoxybenzyl)azepan-2-one (146 mg, 0.468 mmol) was added. The mixture was stirred at −78° C. for 2 hr, and the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to afford a residue, which was purified by chromatography on silica gel (ethyl acetate/hexanes=3/7) to afford 1-(4-methoxybenzyl)-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one (134.5 mg, 0.237 mmol, 53.1% yield). ESI: [M+H]+ m/z 568.2.