Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[C:9]([C:12]1[CH:30]=[C:15]2[C:16]([C:22]3[CH:23]([CH3:29])[CH2:24][C:25](=[O:28])[NH:26][N:27]=3)=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[N:14]2[N:13]=1)(=[O:11])[CH3:10]>C1COCC1>[OH:11][C:9]([C:12]1[CH:30]=[C:15]2[C:16]([C:22]3[CH:23]([CH3:29])[CH2:24][C:25](=[O:28])[NH:26][N:27]=3)=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[N:14]2[N:13]=1)([CH3:5])[CH3:10]
Reactant: C1CCOC1
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)=O)nn12
Agent: C[Mg]Br
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)(C)O)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 0.90 mol/L methyl magnesium bromide-tetrahydrofuran solution (0.614 mL) was added dropwise to a solution of the compound of Example 241 (55.4 mg) in THF (5 mL) at −78° C. in an argon atmosphere. The mixture was allowed to gradually warm to room temperature and was stirred for 3 hours. Subsequently, a second portion of 0.90 mol/L methyl magnesium bromide-tetrahydrofuran solution (0.614 mL) was added dropwise at −78° C. and the mixture was stirred at room temperature for another 3 hours. The reaction was then quenched by adding a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a pale yellow powder (14.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CO[C:21]([C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)=N>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH2:9][NH:10][C:21]([C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)=[N:11]2)=[CH:6][CH:7]=1
Reactant: COC(=N)c1cnccn1
Reactant: NCC(N)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CO
Product: Fc1ccc(C2(c3ccc(F)cc3)CNC(c3cnccn3)=N2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine (500 mg) in methanol (10 mL) was added pyrazineimidic acid methyl ester (385 mg), and the mixture was stirred at room temperature for 18 hrs. After concentrating the reaction mixture, the residue was dissolved in ethyl acetate (50 ml), washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1) to give the objective compound (446 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].C(N(CC)CC)C.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:26][CH:25]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:33])=[CH:26][CH:25]=1
Reactant: O=C(O)C=Cc1ccc(Cl)nc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(Cl)nc2)cc1F
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (51 mg, 0.201 mmol) was suspended in THF and treated with triethylamine (23 mg, 0.22 mmol) and then the resulting mixture was stirred for 10 mins. 3-(6-chloro-pyridin-3-yl)-acrylic acid (37 mg, 0.201 mmol) was added to the reaction mixture followed by DMTMM (61 mg, 0.22 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×2), brine, and then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (74 mg, 96%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].Br[CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[C:1]([NH:4][C:5]1[C:6]([CH:7]=[O:8])=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1C=O
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(COc2cccc(NC(C)=O)c2C=O)cc1

Procedure:
2-Acetylamino-6-hydroxybenzaldehyde (0.45 g, 0.0025 M), ethyl 4-bromomethylbenzoate (0.51 g, 0.0025 M), anhydrous potassium carbonate (0.38 g), sodium iodide (50 mg) and 95% ethanol (20 ml) were reacted together (41/2 hr) to give ethyl 4-(3-acetylamino-2-formylphenoxymethyl)benzoate, m.p. 116°-119° C. (ethanol). (Found: C, 66.76; H, 5.61; N, 3.87%. C19H19NO5 requires C, 66,85; H, 5.61; N, 4.10%).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35].N1C2C(=NC=CC=2)N(O)N=1.C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.CCCCCC.CN(C=O)C>[CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=1)[C:10]([N:33]([O:34][CH3:35])[CH3:32])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a 250 mL round bottom flask was added crude (S)-2-(dibenzylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid, DMF (700 mL), N,O-dimethylhydroxylamine hydrochloride (25.3 g, 259 mmol), TEA (36.0 mL, 259 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (17.6 g, 130 mmol), and 1,3-dicyclohexylcarbodiimide (26.7 g, 130 mmol) at 0° C. The mixture was allowed to warm to room temperature. After 18 hours, the mixture was diluted with 1 L ether, and the precipitate was filtered through a coarse scintered glass funnel washing with ether. The filtrate was washed with brine (4×200 mL) and the organic layer was again passed through a coarse scintered glass funnel. The aqueous layer was extracted with ether (200 mL), and the combined ether layers were washed with brine (100 mL) and passed through a coarse scintered glass funnel. The organic layers were dried over sodium sulfate and evaporated providing a cloudy yellow oil. The oil was passed through a medium scintered glass funnel washing with ether, and the filtrate was evaporated to provide a clear yellow oil. The crude product was loaded onto a 1.5 kg silica gel column in hexane and eluted at 400 mL/minute 0% to 70% EtOAc in hexane to provide (S)-2-(dibenzylamino)-N-methoxy-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (26.52 g, 67.3% yield) as a light yellow oil. LCMS (ES+) m/z=457.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.50 (dt, J=3.67, 1.79 Hz, 3H) 3.09-3.19 (m, 3H) 3.31 (s, 3H) 3.68-3.76 (m, 2H) 3.77-3.85 (m, 2H) 7.16-7.34 (m, 12H) 7.63 (d, J=8.22 Hz, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:8]=[CH:7][N:6]=1)=[O:4].O.O.[OH-].[Li+]>C1COCC1.CO>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COCCCCc1ccnc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCCCc1ccnc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a mixture of 4-(4-Methoxy-butyl)-pyridine-2-carboxylic acid methyl ester ((107 mg, 0.48 mmol, 1 equiv) in THF (1.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (30.2 mg, 0.72 mmol, 1.5 equiv). The mixture was stirred at rt for 4 h and diluted with methanol (20 mL). Then H+ resin (0.4 g) was added and the mixture was shaken for 10 minutes. The resin was washed with methanol (1×), 1:1 acetonitrile/water (1×), and acetonitrile (1×). The product was eluted with 5% TEA in methanol (4×) and acetonitrile (1×). The combined organic solvents were evaporated and co-evaporated with toluene to give 4-(4-Methoxy-butyl)-pyridine-2-carboxylic acid (63.4 mg, 63%): 1H NMR (300 MHz, CD3OD) δ 8.47–8.43 (m, 1), 7.98–7.94 (m, 1), 7.43–7.37 (m, 1), 3.41 (t, J=6.3, 2), 3.30 (s, 3), 2.75 (t, J=7.5, 2), 1.80–1.55 (m, 4).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([N:10]1[C:15](=O)[CH2:14][O:13][C@@H:12]2[C:17]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C@@H:11]12)([CH3:9])[CH3:8].[OH-].[Na+].[CH3:29][S:30]([OH:33])(=[O:32])=[O:31]>O1CCCC1.CCOCC>[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].[F:26][C:24]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][CH2:21][C@@H:11]3[C@H:12]([O:13][CH2:14][CH2:15][N:10]3[CH:7]([CH3:9])[CH3:8])[C:17]=2[CH:25]=1
Reactant: CC(C)N1C(=O)CO[C@@H]2c3cc(F)ccc3OCC[C@H]21
Agent: CS(=O)(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)N1CCO[C@@H]2c3cc(F)ccc3OCC[C@H]21
Reaction time: 16 h

Procedure:
To a suspension of 2.1 g of lithium aluminum hydride in 200 ml of tetrahydrofuran was added 6.06 g of trans-4a,5,6,11b-tetrahydro-4-isopropyl-10-fluoro-2H-[1]benzoxepino[5,4-b]-1,4-oxazin-3(4H)-one in portions and the mixture was then refluxed for about one hour. The mixture was then cooled in ice, decomposed by the addition of 6 ml of 10% aqueous sodium hydroxide solution, and stirred for 16 hours. The solids present in the reaction mixture were separated by filtration and washed with water and the solvent was evaporated from the filtrate to leave a residual oil. The oil was dissolved in ether and a solution of methanesulfonic acid in ether was added until no more cloudiness occurred on addition. The solid was then separated by filtration and triturated in ether to give a tacky solid. This solid was recrystallized from a mixture of methanol and ethyl acetate to give trans-10-fluoro-4-isopropyl-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine methanesulfonate melting at about 163°-165° C.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.S(C)C.ClCCl.[Cl:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[C:31]([Cl:36])[C:30]=1[C:37](=[O:39])[CH3:38]>Cl.CO>[Cl:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[C:31]([Cl:36])[C:30]=1[C@@H:37]([OH:39])[CH3:38]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C

Procedure:
To (R)-2-methyl-CBS-oxazaborolidine (Aldrich or Callery Chemical Co, 1M in toluene, 1 eq.) at −45° C. is added BH3. Me2S (1.06 eq.). To the previous solution is added at −30° C. a 1M dichloromethane solution of 1-(2,6-dichloro-3-fluorophenyl)ethanone. After completion of the reaction, excess MeOH is added followed by IN HCl. After warming up to room temperature, the resulting mixture is filtered through a pad of celite and silica gel and washed with 30% EtOAc in hexane. The solvent is removed under reduced pressure and the resulting oil is purified by flash chromatography (20% EtOAc in hexane) to afford (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (optically enriched).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:23])([F:25])[F:24])[N:9]=3)[CH:3]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(3,4-Dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.37) (0.40 g, 0.89 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.275 g, 1.07 mmol) according to the general procedure VI. Obtained as white foam (0.45 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.C(O)(C)C.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Yield: 95 %

Procedure:
206 parts of 3,5-dichloroanthranilic acid are introduced into 200 parts of isopropanol and 800 parts of 18 percent strength by weight hydrochloric acid. A solution of 100 parts of NaNO2 in 140 parts of water are run in at 80° C., resulting in the uniform evolution of nitrogen. The mixture is cooled, 500 parts of water are added and the product is filtered off. 182 parts (95% of theory) of 3,5-dichlorobenzoic acid of melting point 178°-180° C. are obtained.
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([C:13](N(OC)C)=[O:14])[N:10]([CH3:19])[C:9]=2[CH:20]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([C:13](=[O:14])[CH3:1])[N:10]([CH3:19])[C:9]=2[CH:20]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1nc2ccc(Br)cc2n1C
Solvent: C1CCOC1
Product: CC(=O)c1nc2ccc(Br)cc2n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium chloride (1.0 M in THF, 4.70 ml) was added dropwise to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzimidazole-2-carboxamide (700 mg) in THF (10 ml) at 0° C. The mixture was stirred at 0° C. under Ar atmosphere for 30 min. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated ao in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc), and the resulting solid was washed with IPE to give the title compound (360 mg) as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].[CH3:6][C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([Li])CCC.[Cl-].[Li+]>CCCCCC.C(OCC)C.C1COCC1>[CH3:1][Si:2]([Cl:3])([CH3:5])[CH:15]1[C:14]2[C:9](=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:6]
Reactant: CC1=Cc2cccc(-c3ccccc3)c2C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Reaction time: 3 h

Procedure:
23 g (180 mmol) of dimethyldichlorosilane was dissolved in 200 ml of dry n-hexane (dried over Na-K alloy), to which was added a solution of 2-methyl-7-phenylindenyllithium (i.e., a solution of 7.4 g (36 mmol) of 2-methyl-7-phenylindene in 70 ml of dry diethyl ether to which was dripped down 22.5 ml of a 1.6 M hexane solution of n-butyllithium at -78° C., followed by stirring at room temperature for 3 hours and by addition of 50 ml of THF) under ice cooling. The mixture was stirred as was at room temperature for 3 hours to deposit white salt of lithium chloride. After standing the mixture so that the white salt precipitated, the supernatant was extracted with a syringe and transferred into another flask and low boiling components (solvent and unreacted dimethyidichlorosilane) were distilled off under reduced pressure at 8 mmHg to obtain dimethyl(2-methyl-4-phenylindenyl)silyl chloride.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([NH2:17])=[CH:12][C:13]=32)[CH2:6]1)(=[O:4])=[O:3].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1.C(O)(C)C.C(=O)(O)[O-].[Na+]>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N1CC2CC(C1)c1cc(N)ccc12
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(S(C)(=O)=O)C2)ncc1Cl
Temperature: 130 °C
Yield: 31.1 %

Procedure:
Into a microwave tube was dissolved 10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (58.0 mg, 0.194 mmol) in isopropyl alcohol (1 mL, 10 mmol). The tube was heated in the microwave at 130° C. for 20 minutes. The reaction solution was poured into saturated sodium bicarbonate solution and was extracted with methylene chloride (6×20 ml). The reaction was dried over magnesium sulfate filtered and was rotovaped to a clear oil. The crude product was chromatographed on silica gel (12 g Isco column) and eluted with a gradient of 0-15% methanol in methylene chloride to yield -[5-Chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (31.0 mg, 31%) as a white powder. MP: 163.5-165.0° C.; 1H-NMR (CDCl3) δ 10.97 (s, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.55-7.42 (m, 2H), 7.21-7.09 (m, 3H), 6.40 (br s, 1H), 3.40-3.28 (m, 3H), 3.18 (br s, 1H) 3.10 (br s, 1H), 3.02 (dd, J=5.05, 3H), 2.42-2.30 (m, 1H), 2.08-2.00 (m, 1H), 1.90 (s, 3H), 1.81 (d, J=10.9 Hz, 1H), 1.32-1.21 (m, 2H), 0.90-0.81 (m, 2H).
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:43])[N:20]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[CH:21]3OC)=[O:15])=[CH:11][CH:10]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:43])[N:20]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:21]3)=[O:15])=[CH:11][CH:10]=1
Reactant: COC1c2cccc(NC(=O)c3ccc(Cl)s3)c2C(=O)N1CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2)c1ccc(Cl)s1
Reaction time: 8 h

Procedure:
0.23 ml (1.4 mmol) of triethylsilane is added to a solution of 378 mg (0.704 mmol) of tert-butyl 4-[2-(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1-methoxy-3-oxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-piperidinecarboxylate in 12 ml of dichloromethane and 0.65 ml of trifluoroacetic acid. The mixture is stirred overnight, concentrated and taken up in dichloromethane. The solution is washed with 1N sodium hydroxide solution, dried and concentrated. The residue is crystallized using diethyl ether. The resulting solid is purified further by chromatography on silica gel (gradient from dichloromethane/methanol 95:5 to dichloromethane/methanol/triethylamine 9:1:0.1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:11]=1[NH2:12]>C(#N)C.C(O)(=O)C>[Br:1][C:15]1[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[C:11]([NH2:12])=[C:10]([Cl:9])[CH:16]=1
Reactant: Nc1c(Cl)cccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(Br)cc1C(F)(F)F

Procedure:
N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of 2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) in acetonitrile (10 mL) and acetic acid (3 mL) at room temperature. The mixture was stirred at reflux to 18 h. The reaction mixture was then filtered through Celite and concentrated to give the title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[N:28]=[CH:27][C:26]([N+:34]([O-:36])=[O:35])=[C:25]2Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1.CN(C)C=O.O>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[N:28]=[CH:27][C:26]([N+:34]([O-:36])=[O:35])=[C:25]2[CH:9]([C:10]#[N:11])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccc(C#N)cc1
Reactant: COc1cc2ncc([N+](=O)[O-])c(Cl)c2cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncc([N+](=O)[O-])c(C(C#N)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Under a nitrogen atmosphere, 4-cyanophenylacetonitrile (3.86 g, 27.12 mmol) is dissolved in dry tetrahydrofuran (185 ml). Sodium hydride (60% dispersion in paraffin oil, 2.17 g, 54.25 mmol) is subsequently added in portions with ice-bath cooling, and the mixture is stirred for a further 30 min. A suspension of 6-benzyloxy-4-chloro-7-methoxy-3-nitro-quinoline (9.35 g, 27.12 mmol) in N,N-dimethylformamide (50 ml) is then added at room temperature, and the mixture is subsequently stirred for a further 2 h. When the reaction is complete, the mixture is added to 2.5 l of water and neutralised using 1.0 M hydrochloric acid with vigorous stirring. After stirring for 30 min, the suspension is acidified to about pH 2, and, after a further 30 min, the precipitate obtained is filtered off with suction, rinsed with water and dried overnight in a high vacuum. The crude product is subsequently purified over flash silica gel (solvent gradient cyclohexane/0-50% by vol. of ethyl acetate), giving 4-[(6-benzyloxy-7-methoxy-3-nitroquinolin-4-yl)cyanomethyl]benzonitrile (11.31 g, 25.11 mmol) as a solid having a melting point of 147.9° C. MS: 451.1 (M+H+), TLC (HPTLC) (HPTLC): Rf=0.68 (cyclohexane/ethyl acetate 1:1 parts by volume).
Reaction SMILES: [I-].CO[N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N+:6]([CH3:13])=[CH:5]1.[CH3:14][NH2:15]>>[CH3:13][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]=[C:5]1[NH:15][CH3:14]
Reactant: CN
Reactant: COn1c[n+](C)c2ccccc21
Agent: [I-]
Product: CNc1nc2ccccc2n1C
Yield: 20 %

Procedure:
3-N-Alkoxyimidazolium salts are also known. For example, 3-N-methoxy-1-N-methylbenzimidazolium iodide has been shown to react with methylamine to afford 1-methyl-2-methylaminobezimidazole in approximately 20% yield (S. Takahashi et al., Chem. Pharm. Bull. 14(4):375-385 (1966)). While this reaction was reported to proceed under relatively mild conditions (i.e., 20°-25° C. for 1 hour), the difficulty in obtaining large quantities of 3-N-oxide starting material renders this approach to 2-substituted imidazoles particularly undesirable.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].[CH3:12]O>>[CH3:12][O:10][C:9]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)=[O:11]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Product: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 25 °C

Procedure:
A solution of 5-nitro-1H-pyrazole-3-carboxylic acid (17, Aldrich, cat. no. 41,483-2) in MeOH was prepared. While stirring, HCl was bubbled through the solution for 2 min. The reaction mixture was refluxed for a time sufficient for complete esterification and allowed to cool to rt. The solvent was removed by rotary evaporation. The crude material was basified by addition of saturated aqueous NaHCO3 and extracting with EtOAc. The combined organic extracts were dried over MgSO4 and filtered. The filtrate was rotary evaporated and dried under vacuum to yield 18.