Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[O:21]1[CH2:26][CH2:25][CH:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:27]([CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[O:28])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCOCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A solution of 1-(4-chlorophenyl)ethanone (2.0 g, 12.9 mmol) in anhydrous THF was cooled in a dry ice acetone bath and treated with sodium hexamethyldisilazid (14.2 mL, 1M in THF, 14.2 mmol). The resulting solution was stirred for 1 h at −78° C. and a solution of tetrahydro-pyran-4-carbonyl chloride (1.92 g, 12.9 mmol) in THF was slowly added. The resulting solution was stirred for 30 min at −78° C., allowed to warm up to room temperature and stirred for 5 h. The reaction was quenched by adding 6N HCl and extracted with EtOAc (×3). The organic fractions were combined and washed with sat. NaCl, dried over Na2SO4 and evaporated under vacuum. The resulting residue was purified by silica-gel column chromatography to give 2 g (58%) of 1-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione. 1-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione 100 mg (0.375 mmol) and the free base of the corresponding hydrazine (1.1 equivalent) were dissolved in acetic acid and heated at 100° C. for 18 h. Acetic acid was removed under vacuum and the residue was purified by reverse phase HPLC.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1.CC(=O)OCC>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: COc1ccc2c(c1)CNCC2
Agent: c1ccc2ncncc2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CN(c1ncnc3ccc(I)cc13)CC2
Yield: 55.7 %

Procedure:
0.75 g of 4-chloro-6-iodoquinazoline, 0.58 g of 7-methoxy-1,2,3,4-tetrahydroisoquinoline and 0.64 ml of triethylamine in 5 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 2 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 22 min.), giving 0.60 g of 6-iodo-4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)quinazoline as yellowish solid (yield 57%, content 93%); MS-FAB (M+H+)=418.0; Rf (polar method): 1.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:10]\[NH:11][CH3:12])/[CH3:9].[Cl-].Cl[CH:15]=[N+](C)C.CN(C)[CH:21]=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:21]=[O:22])=[CH:12][N:11]([CH3:15])[N:10]=1
Reactant: C[N+](C)=CCl
Reactant: CN/N=C(/C)c1ccccc1Cl
Reactant: CN(C)C=O
Agent: [Cl-]
Product: Cn1cc(C=O)c(-c2ccccc2Cl)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A 100 mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen and charged with (Z)-1-[1-(2-chlorophenyl)ethylidene]-2-methylhydrazine (2.00 g, 10.9 mmol, 1.00 equiv), (chloromethylidene)dimethylazanium chloride (12.7 g, 99.2 mmol, 9.06 equiv) and N,N-dimethylformamide (40 mL). The resulting solution was stirred overnight at 50° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of saturated sodium carbonate solution (100 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, washed with brine (2×100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to yield 1.00 g (41% yield) of 3-(2-chlorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde as a yellow solid. LCMS (ESI, m/z): 221 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[Li+].[OH-].Cl>C1COCC1.CO>[Cl:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:15])=[O:2])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 77.6 %

Procedure:
4,5-Dichloro-2-nitrobenzoic acid piperidine amide. A solution of 4,5-dichloro-2-nitrobenzoic acid methyl ester (0.29 g, 1.16 mmol) in 1:1 THF/methanol (4 mL) was stirred as 1 N aqueous LiOH (2 mL) was added. After 1 h, the mixture was acidified with 1 N HCl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to provide crude 4,5-dichloro-2-nitrobenzoic acid as a light yellow solid (0.26 g, 0.90 mmol, 77%). The acid was refluxed in 4 mL thionyl chloride for 2 h, and the crude reaction mixture was concentrated in vacuo. Residual thionyl chloride was removed by the repeated addition and in vacuo stripping of DCM. The acid chloride was placed under high vacuum for 10 min, and then taken up in dry DCM (5 mL). The mixture was cooled in an ice bath. Piperidine (0.46 g, 5.4 mmol, 0.53 mL) was added, and the reaction mixture was allowed to stand at 0° C. overnight. The mixture was diluted with DCM, washed with 1 N HCl (2×), 5% aqueous NaHCO3 and brine, and dried (MgSO4). Filtration and concentration provided 0.32 g of the desired amide, which could not be separated from an impurity (10%) that corresponded to the product of displacement of a chlorine by an additional equivalent of piperidine. HPLC (reversed-phase): RT=9.35 min (90%), 10.58 (10%). MS (ESI): major m/z 303 [M+H]+, minor m/z 352 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Product: CS(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Yield: 48 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and methanesulfonyl chloride gives the title compound in 48% yield as a tan solid, mp 210.7° C. 1H NMR (CDCl3) δ 2.72-3.58 (br m, 7H), 6.49 (s, 1H), 6.74 (s, 1H), 6.96-7.49 (m, 12H); MS (ES) 398 (M+Na), 374 (M−H). HPLC shows 98% purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:16](=[C:17]([CH:22]=[O:23])[CH:18]=[CH:19][C:20]=4[Cl:21])[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:24])[CH:3]=1.[CH2:25]([Mg]Br)[CH3:26]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([OH:23])[CH2:25][CH3:26])[C:16]=4[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:24])[CH:3]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
To a solution of 1-(4-bromo-2-chlorophenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.00 g, 2.352 mmol) in tetrahydrofuran (12.0 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 1.18 mL, 3.528 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether/ethyl acetate to give the title compound as a colorless solid (925.8 mg, 2.034 mmol, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:30])=[N:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Br)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-hydroxymethylpyridine (1 g, 5.32 mmol) was dissolved in dichloromethane (26.6 ml) and cooled to 0° C. Triphenylphosphine (1.604 g, 6.12 mmol) was added followed by carbon tetrabromide (2.028 g, 6.12 mmol) which caused the reaction to become yellow and heterogeneous. After 48 h, the mixture was concentrated by half and directly purified by silica gel column chromatography (0-37%, EtOAc-hexanes) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 8.64 (t, J 2.7 Hz, 1H), 7.82 (m, 1H), 7.35 (dd, J 7.8 & 3.1 Hz, 1H), 4.51 (s, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:11][C:12]2[N:16]3[N:17]=[C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[CH2:27]([NH2:29])[CH3:28].[CH2:30]1COCC1>[Fe]>[CH2:27]([N:29]1[C:2]2[CH:3]=[C:4]([S:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)[CH:5]=[CH:6][C:7]=2[N:8]=[CH:30]1)[CH3:28]
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc([N+](=O)[O-])c(F)c4)n3n2)cn1
Reactant: CCN
Reactant: C1CCOC1
Agent: [Fe]
Product: CCn1cnc2ccc(Sc3nnc4ccc(-c5cnn(C)c5)nn34)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To 3-(3-fluoro-4-nitro-phenylsulfanyl)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine (50 mg, 0.135 mmol) was added a 2 M solution of ethylamine in THF (1 mL). The reaction mixture was stirred at 70° C. for 1 h, then it was concentrated in vacuo. The residue was suspended in formic acid (1 mL) and iron powder (75 mg, 1.35 mmol) was added. The reaction mixture was stirred at 100° C. for 16 h, then it was cooled to room temperature and the stir bar was removed with most of the iron. The mixture was concentrated in vacuo and the resulting residue was treated with 2 M aqueous sodium hydroxide. The precipitate was filtered, washed with water then diethyl ether. It was then diluted in 2 mL of DMSO, filtered through a 0.45 um filter, and the crude mixture was purified directly by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) to provide 25 mg of 3-(3-ethyl-3H-benzoimidazol-5-ylsulfanyl)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine as a white solid (49% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:3][O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10].[H][H]>CO.[Pd]>[OH:1][CH:2]([CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:3][O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CCCC(=O)NCCNCC(O)COc1ccccc1C=CC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)NCCNCC(O)COc1ccccc1CCC(=O)OC
Yield: 85.3 %

Procedure:
A solution of 3.0 g (0.008 mole) of methyl 2-[2-hydroxy-3-[N-[2-(methylpropionamido)ethyl]amino]propoxy]cinnamate in 100 ml of methanol was treated with 0.3 g of 10% Pd-C catalyst and hydrogenated at 40 psi until no further uptake of hydrogen was observed (about 48 hr.). The catalyst was removed by filtration and the filtrate concentrated under reduced pressure to a solid, which was recrystallized from methanol:ether to provide 2.5 g (83%) of product, having a melting point of 119°-120° C. The IR and NMR spectra and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[F:26][C:27]1[CH:28]=[C:29]([CH:37]=[C:38]([F:46])[C:39]=1[CH2:40]OS(C)(=O)=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:40][C:39]3[C:38]([F:46])=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[CH:28][C:27]=3[F:26])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 2 h
Yield: 98450.5 %

Procedure:
A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (60 g, 0.16 mmol), tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (51 g, 0.16 mol, 1.0 eq.) and Cs2CO3 (62 g, 0.19 mol, 1.2 eq.) in MeCN (680 mL) was stirred for 2 h and evaporated to give a residue. The residue was diluted with water (1.5 L) and extracted with CH2Cl2 (1 L). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (95 g, quant). 1H NMR (400 MHz, CDCl3) δ 7.40-7.42 (d, 2H), 7.19 (s, 1H), 7.14-7.16 (d, 1H), 6.76-6.80 (t, 2H), 6.51 (s, 1H), 6.41-6.49 (m, 3H), 4.07 (s, 2H), 3.75 (s, 3H), 1.58 (s, 9H), 1.47 (s, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:10][CH2:9][CH2:8][C:7]2([CH3:11])[CH:3]1[CH2:4][CH2:5][CH:6]2[CH:12]([CH3:22])[CH2:13][CH:14]1[O:18][C:17](=[O:19])[C:16]([OH:21])([CH3:20])[CH2:15]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1C1C=CC=C[NH+]=1.[Cr](Cl)([O-])(=O)=O>C(O)(C)C.C(Cl)Cl>[CH3:11][C:7]12[CH:6]([CH:12]([CH3:22])[CH2:13][CH:14]3[O:18][C:17](=[O:19])[C:16]([OH:21])([CH3:20])[CH2:15]3)[CH2:5][CH2:4][CH:3]1[C:2](=[O:1])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(CC1CC(C)(O)C(=O)O1)C1CCC2C(O)CCCC12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1ccc(-c2cccc[nH+]2)[nH+]c1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(CC1CC(C)(O)C(=O)O1)C1CCC2C(=O)CCCC21C

Procedure:
A solution of 90.0 mg (0.290 mmol) of [3R-[3 beta,5S,(5beta,(R*)-1R*-(1 beta,3a alpha,4alpha,7a beta)]]-dihydro-5-[2-(octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl)-2-methylethyl]-3-hydroxy-3-methyl-2(3H)-furanone in 4 ml. of dry methylene chloride was treated at room temperature with 340.0 mg (1.162 mmol) of 2,2'-bipyridinium chlorochromate for 5.5 hours. A few drops of isopropyl alcohol were then added and the resulting mixture diluted with 50 ml of methylene chloride, filtered through Celite® filter aid. After evaporation of the solvent, the residue was dissolved in 100 ml. of ethyl acetate, extracted with 3×20 ml. of 1N hydrochloric acid and then with 3×30 ml of brine. The organic phases were combined, dried and evaporated to give 89.0 mg (quantitative yield) of [3R-[3 beta,5S,(5 beta,(R*)-1R*-(1 beta,3a alpha,7a beta)]]-dihydro-5-[2-(octahydro-7a-methyl-1H-inden-4-one-1-yl)-2-methylethyl]-3-hydroxy-3-methyl-2(3H)-furanone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:21].C(N(CC)CC)C>C(#N)C>[CH2:20]([O:22][C:23](=[O:33])[CH2:24][N:25]([CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:21]
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: CCOC(=O)CNCc1ccccn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccn1)Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12

Procedure:
150 ml (0.46 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 98 mg (1.1 equiv.) of N-(2-pyridylmethyl)-glycine ethyl ester and 0.076 ml (1.2 equiv.) of triethylamine are stirred at reflux in 5 ml of acetonitrile for 20 hours. The mixture is concentrated by evaporation and the residue is suspended in diethyl ether and filtered. After drying, the title compound is obtained in the form of a white powder.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Reactant: C1COCCN1
Product: O=C1Nc2ncnc(N3CCOCC3)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Yield: 35 %

Procedure:
The title compound (35% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and morpholine according to the procedure described for Example 14. MS-EI 453 [M+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:30][N:31]([CH3:41])[C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:30][N:31]([CH3:41])[C:32]1[N:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]3[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:34][CH:33]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N(C)C)nc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.079 g, 0.172 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (0.034 g, 0.206 mmol). The product was triturated from EtOAc spiked with DCM, and dried in a hi-vacuum oven for 4 h. The title compound was collected as a white solid (49 mg, 56%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3H), 1.45 (d, J=6.57 Hz, 6H), 1.51-1.64 (m, 2H), 2.12 (s, 3H), 2.42 (s, 3H), 2.52-2.59 (m, 2H), 3.08 (s, 6H), 4.38 (d, J=5.05 Hz, 2H), 4.96-5.09 (m, 1H), 5.90 (s, 1H), 6.75 (d, J=9.09 Hz, 1H), 7.31 (d, J=1.26 Hz, 1H) 7.86 (d, J=1.26 Hz, 1H), 7.96 (dd, J=8.97, 2.65 Hz, 1H), 8.40 (t, J=4.93 Hz, 1H), 8.55 (d, J=2.27 Hz, 1H) 11.50 (s, 1H); LCMS (ES+) m/z: 501.1.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])[CH3:4]>C(O)(=O)C>[Br:1][C:9]1[S:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:6]([O:5][CH2:3][CH3:4])[CH:10]=1.[Br:1][C:10]1[C:6]([O:5][CH2:3][CH3:4])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[S:8][CH:9]=1
Reactant: CCOc1ccsc1C(=O)OC
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOc1c(Br)csc1C(=O)OC
Product: CCOc1cc(Br)sc1C(=O)OC
Temperature: 25 °C

Procedure:
Bromine was added to an acetic acid solution of methyl 3-ethoxythiophene-2-carboxylate, followed by stirring at room temperature. The product was separated by silica gel column chromatography to obtain methyl 5-bromo-3-ethoxythiophene-2-carboxylate (F: 265, 267) and methyl 4-bromo-3-ethoxythiophene-2-carboxylate (F: 265, 267).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[N:15]1([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[CH:25][CH:26]=3)[N:14]([CH3:13])[C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][N:9]=1
Reactant: COc1nccc(C(=O)O)c1N
Reactant: CN
Reactant: O=Cc1ccc(OCCCN2CCCC2)cc1
Product: COc1nccc2c(=O)n(C)c(-c3ccc(OCCCN4CCCC4)cc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 3-amino-2-methoxyisonicotinic acid, methylamine and 4-(3-pyrrolidin-1-ylpropoxy)benzaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH2:14][OH:15])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH2:14][O:15][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
Subsequently, to a solution of [(1S)-1-(hydroxymethyl)propyl]carbamic acid benzyl ester (4.27 g, 19.1 mmol) in dimethylformamide (128 ml) were added t-butyldiphenylsilyl chloride (5.97 ml, 22.9 mmol) and imidazole (1.56 g, 22.9 mmol) in an ice bath. The mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→4:1) as the eluant to afford [(1S)-1-(t-butyldiphenylsilyloxymethyl)propyl]carbamic acid benzyl ester (9.48 g, yield 100%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@@H:26]([C@H:28]2[CH2:32][O:31]C(C)(C)[O:29]2)[CH3:27])[N:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@H:26]([CH3:27])[C@H:28]([OH:29])[CH2:32][OH:31])[N:12]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step vi) (0.13 g) in DCM (5 mL) was added iron (III) chloride hexahydrate (0.26 g). The reaction mixture was stirred at ambient temperature for 1.5 h, then saturated aqueous sodium bicarbonate (1 mL) was added. The layers were separated and the aqueous material extracted with DCM (×3) and ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residual pale yellow solid was slowly precipitated from DCM, filtered and the resulting material washed with minimal cold DCM (2×1 mL) to afford the title compound as a white powder. Yield: 64 mg.