Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.O1CCCC1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To an ice-cooled mixture of 4-methoxythiophenol (15 g, 0.11 mol), triethylamine (28 mL, 0.20 mol) and tetrahydrofuran (150 mL) was added ethyl bromoacetate (21 g, 0.13 mol), and the mixture was stirred overnight at room temperature. Ethanol (10 mL) was added, the solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10:1) to give title compound (22 g, yield 92%). oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][C:23]1([CH2:28][NH2:29])[CH2:27][CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>C(#N)C>[NH2:29][CH2:28][C:23]1([CH3:22])[CH2:27][CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:17])[C:10]=2[F:16])[CH2:24]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1(CN)CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(C)(CN)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 0.60 g (2.02 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.28 g (2.45 mmol) of 3-methyl-3-pyrrolidinemethanamine, 0.61 g (6.06 mmol) of triethylamine, and 20 mL of acetonitrile was refluxed for 4 hours, then stirred at room temperature overnight. The precipitate was removed by filtration, washed with ether, and dried in vacuo to give 0.61 g of the title compound, mp 182°-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13](=[O:23])[CH2:14][NH:15]C(=O)OC(C)(C)C)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl>O1CCOCC1.C([O-])(O)=O.[Na+]>[NH2:15][CH2:14][C:13]([C:12]1[C:3]([O:2][CH3:1])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:23]
Reactant: COc1nc2ccccc2cc1C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nc2ccccc2cc1C(=O)CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
F1 was solubilized in dioxane (30 mL) and treated with 16 mL of 4N HCl in dioxane at 0° C. Mixture was stirred for 1 h at room temperature, poured in sat. aq. NaHCO3 and extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound which was used as such in the next step. MS (ES+) C12H12N2O2: 217 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].N1C=CC=CC=1>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:10])[O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminopyridine (1.97 g, 20.9 mmol) in DCM (75 mL) at 0° C. was added 4-nitrophenyl chloroformate (4.21 g, 20.9 mmol) and pyridine (1.7 mL, 20.9 mmol). Then, the mixture was stirred at RT overnight. The white precipitated was filtered off and washed with DCM (2×50 mL), and then dried in vacuo to give the title compound as a white solid, which was used in the next step without further purification. MS (ESI, positive ion) m/z: 260 (M+H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:9][C:10]3[O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)(C)C>[CH:1]1([O:6][C:7]2[C:8]([O:18][CH2:19][CH2:20][CH2:21][N:36]3[CH2:35][CH2:34][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:38][CH2:37]3)=[CH:9][C:10]3[O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]=3[CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCOc1cc2oc(=O)ccc2cc1OC1CCCC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=c1ccc2cc(OC3CCCC3)c(OCCCN3CCC(c4ccccc4)CC3)cc2o1
Yield: 48 %

Procedure:
Method B (30 h at 45° C.); starting materials: 6-(cyclo-pentyloxy)-7-[3-(methanesulfonyloxy)propoxy]-2H-1-benzopyran-2-one (example 72) and 4-phenylpiperidine; yield 48%; fusion point 96°-97° C. (from TBME and isopropanol). Fumarate: method E; yield 83%; fusion point 171°-173° C. (from acetone).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:85]O[C@@:5]2(O[C@H:8]3[C@@H:10](O)[C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@H:19]6[CH2:24][C@@H:23]([O:25][C@@H]7O[C@H](CO)[C@H](O[C@@H]8O[C@H](CO)C(O)[C@H](O[C@@H]9OC[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O[C@@H]8O[C@H](CO)[C@H](O)[C@H](O[C@@H]9O[C@H](CO)[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O)[C@H](O)[C@H]7O)[C@H:22](O)[CH2:21][C@:20]6([CH3:80])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:81])[C@H:7]3[C@@H:6]2[CH3:83])[CH2:4][CH2:3]1.C1(=O)OC(=O)C=C1.C(N1CCCC1=O)=C>>[CH3:85][CH:2]([CH2:3][CH2:4][CH2:5][C@H:6]([C@@H:7]1[C@:12]2([CH3:81])[C@H:11]([C@H:16]3[C@H:15]([CH2:14][CH2:13]2)[C@:20]2([CH3:80])[C:19]([CH2:24][C@H:23]([CH2:22][CH2:21]2)[OH:25])=[CH:18][CH2:17]3)[CH2:10][CH2:8]1)[CH3:83])[CH3:1]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1[C@@H](O)[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[C@@H]6O[C@H](CO)[C@H](O[C@@H]7O[C@H](CO)C(O)[C@H](O[C@@H]8OC[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O[C@@H]7O[C@H](CO)[C@H](O)[C@H](O[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: C=CN1CCCC1=O
Agent: O=C1C=CC(=O)O1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h

Procedure:
The sticks were each placed into 100 uL solution of an A-C-B reagent in wells of a 96 well microwell plate. The reagent was a conjugate of digitonin (A) linked to horseradish peroxidase (B) through a maleic anhydride-N-vinylpyrrolidone copolymer (C) and was used at a concentration of approximately 1 μg/mL. The sticks were left in the solution for 15 minutes at room temperature, after which they were removed and placed into new wells of a microwell plate containing 200 μL of wash solution. The microwell plate was agitated to effect washing and after 1 min the sticks were removed to new wells containing 200 μL of fresh wash solution and again agitated for 1 min. Washing with agitation was done a third time, after which the sticks were removed and placed in 100 uL of a substrate solution (Enhanced K-Blue reagent). The sticks were incubated with the substrate solution, in the dark, for 15 minutes at room temperature, and then removed. One hundred (100) μL of 1 N sulfuric acid were added to the wells with the substrate solution to stop further reaction and the optical density of the resulting solution was read at 450 nm on a plate reading spectrophotometer, to provide a measure of the amount of cholesterol in the skin sample.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5]>CCO.CCOC(C)=O.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH:3]([O:2][CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[CH:13][CH:12]=1
Reactant: COC(=O)C(OC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C(OC)c1ccc(N)cc1
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution of methyl 2-methoxy-2-(4-nitrophenyl)acetate (0.42 g, 1.87 mmol) in absolute EtOH (15 mL) was degassed by alternately putting under house vacuum and argon three times for several minutes each then 10% Pd/C (0.19 g) was added. The mixture was stirred under H2 (1 atm.) for 3 hrs then diluted with EtOAc and filtered through a pad of Celite and silica gel. The filtrate was concentrated in vacuo. Purification by chromatography (25-40% EtOAc-hexanes) provided methyl 2-(4-aminophenyl)-2-methoxyacetate as a yellow oil containing impurities (0.6 g from two batches, 77% yield). The compound was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[OH:9].[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:20][O:21][C:22]=2[N:23]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[O:9][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:20][O:21][C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC1CCCC(C)C1O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCCC(C)C1Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a solution of 2,6-dimethylcyclohexanol (0.23 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-[(2,6-dimethylcyclohexyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.51 g, 77%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][CH:5]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)OS(C)(=O)=O.[NH2:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][CH:5]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[NH:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)OS(C)(=O)=O)cc1
Reactant: Nc1cnc2ccccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Temperature: 60 °C

Procedure:
To a solution of ethyl(+/−)-4-(4,4,4-trifluoro-1-((methylsulfonyl)oxy)butyl)benzoate (123 mg, 0.347 mmol) in acetonitrile (1.74 mL) was added 3-amino quinoline (60.6 mg, 0.416 mmol), followed by potassium phosphate (155 mg, 0.694 mmol). The resulting mixture was heated to 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave ethyl(+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.92 (d, J=7.8 Hz, 1H), 7.50-7.44 (m, 3H), 7.44-7.35 (m, 2H), 6.81 (d, J=2.5 Hz, 1H), 4.62-4.54 (m, 1H), 4.44-4.33 (m, 3H), 2.36-2.10 (m, 4H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:26]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][CH2:2][OH:26])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: O=[O+][O-]
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (3 g, 7.5 mmol) in CH2Cl2 (50 mL) was treated with O3 at −78° C. till the mixture turned blue. Then NaBH4 (285 mg, 75 mmol) was added to the solution at 0° C., and the reaction solution was stirred at room temperature for 3 hours. The reaction was quenched by H2O, and the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (2.5 g, 84%). 1H NMR (CDCl3): 1.48 (t, 3H), 2.05-2.41 (m, 4H), 2.71-2.92 (m, 2H), 3.51 (m, 1H), 3.71 (m, 1H), 5.58 (m, 1H), 6.73 (d, 2H), 7.12 (m, 2H), 7.23-7.45 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH3:17])=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:28].[Na+]>CO.O1CCCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH3:17])=[CH:12][CH:11]=1)=[O:28]
Reactant: COC(=O)CCCCCSc1ccc(N(C)Cc2ccc(Cl)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCCS(=O)c1ccc(N(C)Cc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 6-(4-((4-chlorobenzyl)-methylamino)-phenylsulfanyl)-hexanoic acid methyl ester (840 mg, 2.1 mmol) in methanol (60 mL) and tetrahydrofuran (30 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (504 mg, 2.3 mmol) in distilled water (20 mL). The mixture was heated at reflux for 1 hour. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL), and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (50:50:1 ethyl acetate:40-60° C. ether:triethylamine). The title compound was obtained as a colourless oil (759 mg, 87%).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[N:15]O)([O-:4])=[O:3]>C(O)(=O)C>[ClH:1].[N+:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[NH2:15])([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1cccc2c1CCCC2=NO
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cccc2c([N+](=O)[O-])cccc12
Temperature: 100 °C

Procedure:
In a 100 mL flask equipped with a reflux condenser, an inlet tube for hydrogen chloride gas and a thermometer were placed 2.1 g of 5-nitro-1-tetralone oxime and 40 mL of acetic acid. While bubbling hydrogen chloride gas, the mixture was heated at 100° C. for 4 hours with stirring by a stirring bar. After allowing the mixture to be cooled to room temperature, a precipitated 5-nitro-1-aminonaphthalene hydrochloride was collected by filtration and rinsed with a small amount of acetic acid. After drying in vacuo, 5-nitro-1-aminonaphthalene hydrochloride (1.0 g) was obtained. No naphthalene derivatives isomerized in the amino or nitro group were detected.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[B:34]1(B2OC(C)(C)C(C)(C)O2)[O:38]C(C)(C)C(C)(C)[O:35]1.C([O-])(=O)C.[K+]>CS(C)=O>[O:16]=[C:5]1[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=[C:2]([B:34]([OH:38])[OH:35])[CH:3]=[C:4]1[C:17]1[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=2[N:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 95 °C

Procedure:
4 g of 6-chloro-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanylethoxy-methyl) -1H-benzimidazol-2-yl]-2H-pyridazin-3-one (example 46), 4.1 g of bis(pinacolato)diboron, 0.19 g of (1,1 ′-bis(diphenylphosphine)-ferrocene)palladium(II) chloride-dichloromethane complex and 2.3 g of potassium acetate are dissolved in 60 ml of DMSO. The solution is degassed with argon and heated at 95° C. for 2.5 hours. For workup, 600 ml of water are added, the mixture is extracted several times with dichloromethane and the organic phase is washed with saturated sodium chloride solution and dried using a phase separator cartridge. After the solvent has been distilled off, the crude product is purified by preparative RP-HPLC (0-100% acetonitrile in water (+0.01% trifluoroacetic acid)).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:3]=1[C:18]#[N:19].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:52]([NH2:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl>[CH2:52]([NH:59][C:7]([C:5]1[S:6][C:2]([Br:1])=[C:3]([C:18]#[N:19])[C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=[O:9])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1c(Br)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Br)sc(C(=O)NCc2ccccc2)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.6 %

Procedure:
5-bromo-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboxylic acid (0.623 g, 1.65 mmol), 1-Hydroxybenzotriazole hydrate (0.253 g, 1.65 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.570 g, 2.97 mmol) were taken up in DCM (30 mL) and the mixture was stirred for 5 minutes at room temperature. N,N-Diisopropylethylamine (0.460 mL, 2.64 mmol) was added followed by benzylamine (0.216 mL, 1.98 mmol) and the solution was stirred at room temperature overnight. The mixture was quenched with water, extracted with DCM (3×50 mL), washed with water, brine, dried over Na2SO4, filtered and evaporated. The residue was purified using ISCO chromatography on silica gel, elution with 10-25% EA in hexanes to give the product (0.574 g, 74%). LCMS: (FA) ES+, 465, 467, 469. 1H NMR (400 MHz, d1-chloroform) δ: 7.46 (d, J=2.00 Hz, 1H), 7.32-7.27 (m, 4H), 7.26-7.23 (d, J=7.78 Hz, 1H), 6.99-6.96 (m, 2H), 5.38 (bs, 1H), 4.36 (d, J=5.52 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[N:12]1.Cl[Sn]Cl>>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[N:12]1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)nn1
Agent: Cl[Sn]Cl
Product: Cc1cn(-c2ccc(N)cc2F)nn1
Yield: 95.9 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-4-methyl-[1,2,3]-triazole (Intermediate 22) (38.3 g, 0.173 mol) and SnCl2 2H2O (200 g, 0.886 mol) were reacted as described for Intermediate 27 to give the crude title compound as a off-white solid (31.9 g), which was used directly for the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH:11]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1CC=C(c2ccncc2[N+](=O)[O-])CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cnccc1C1=CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-(3-nitropyridin-4-yl)cyclohex-3-enone (1.0 eq) in methanol (0.2 M) was added sodium borohydride (1.8 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 2 hr. Methanol was removed under reduced pressure. The residue was dissolved with ethyl acetate (200 mL), and washed with sat NaCl (30 mL). The organic was dried with MgSO4, filtered and concentrated to give 4-(3-nitropyridin-4-yl)cyclohex-3-enol (85%). The crude product was used in the next step without further purification. LC/MS (m/z): MH+=221.0, Rt=0.55
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH2:17]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)CCNCc1ccccc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: CN(C)CCN(Cc1ccccc1)c1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 3.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 448 using 6 (200 mg, 0.87 mmol) and N′-benzyl-N,N-dimethylethane-1,2-diamine (0.67 ml, 3.47 mmol) to provide 450 (11 mg, 3% yield) as a white powder. LC-MS (M+H=373, obsd.=373). 1H NMR (400 MHz, DMSO-D6) δ 11.61 (s, 1H), 9.88 (m, 1H), 8.76 (d, J=7.5, 1H), 8.45 (d, J=3.4, 1H), 8.08 (d, J=9.0, 1H), 7.57 (s, 1H), 7.20 (m, 6H), 7.10 (d, J=7.0, 1H), 4.86 (s, 2H), 4.02 (m, 4H), 2.89 (d, J=4.7, 6H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([C:22](F)=[O:23])=[CH:12][N:11]=1.Cl>CN(C=O)C.O>[NH2:2][C:1]1[N:16]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[C:14]2[N:15]=[C:10]([Cl:9])[N:11]=[CH:12][C:13]=2[C:22](=[O:23])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: CC(C)(O)CNc1nc(Cl)ncc1C(=O)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)Cn1c(N)c(C(N)=O)c(=O)c2cnc(Cl)nc21
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution, cooled to 2-5°C. on an ice bath, of 4.4 g (52.36 mmol) of cyanoacetamide in 70 mL of anhydrous DMF are added portionwise 4.19 g (104.72 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C., and this suspension is then added rapidly to a solution of 12.35 g (49.87 mmol) of the acid fluoride prepared in step 17.2 in 70 mL of anhydrous DMF, precooled to 2-5°C. The mixture is stirred overnight at room temperature and is then cooled to 2-5°C. on an ice bath, and 2.09 g (52.36 mmol) of 60% sodium hydride are added portionwise. The reaction mixture is stirred for 3 hours at room temperature and then poured into a mixture of ice, 100 mL of water and 150 mL of aqueous 1N HCl. The yellow precipitate formed is isolated by filtration, rinsed with water and then dried in an oven. After triturating in methanol and drying in an oven, 8.84 g of the expected product are finally obtained in the form of a yellow solid. Yield=57%.