Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:9]([CH2:29][CH3:30])[CH2:10][CH2:11][N:12]([CH2:26][CH2:27]O)[C:13](=[O:25])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:8].Cl.[NH2:32][CH2:33][CH2:34][C:35]1[C:43]2[S:42][C:41](=[O:44])[NH:40][C:39]=2[C:38]([OH:45])=[CH:37][CH:36]=1.C([BH3-])#N.[Na+].N>ClCCl.CO.O.C(O)(=O)C.C(N(CC)CC)C.CS(C)=O>[CH2:7]([N:9]([CH2:29][CH3:30])[CH2:10][CH2:11][N:12]([CH2:26][CH2:27][NH:32][CH2:33][CH2:34][C:35]1[C:43]2[S:42][C:41](=[O:44])[NH:40][C:39]=2[C:38]([OH:45])=[CH:37][CH:36]=1)[C:13](=[O:25])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:8]
Reactant: CCN(CC)CCN(CCO)C(=O)CCOCCc1ccccc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: Cl
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCN(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C(=O)CCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of dimethyl sulfoxide (0.10 g) in dichloromethane (1 mL) was added to oxalyl chloride (0.083 g) in dichloromethane (10 mL) at −78° C. The reaction was stirred for 15 minutes and then a solution of N-(2-diethylaminoethyl)-N-(2-hydroxyethyl)-3-phenethyloxy-propanamide (Example 12a), 0.20 g) in dichloromethane (1 mL+1 mL wash) was added and the reaction mixture was stirred for a further 15 minutes. Triethylamine (0.30 g) was added and the reaction mixture was allowed to warm to room temperature over 1 hour. The mixture was subsequently diluted (dichloromethane, 30 mL), the organics washed with saturated sodium hydrogencarbonate solution (20 mL) and then brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a crude aldehyde product which was used immediately. The crude product was dissolved in methanol (10 mL) and 7-(2-aminoethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (0.15 g) added along with acetic acid (0.1 mL) and water (0.1 mL). After stirring at room temperature for 30 minutes, sodium cyanoborohydride (0.022 g) was added and the reaction mixture was stirred overnight. Ammonia (7N in methanol, 1 mL) was added and the mixture was concentrated. The crude residue was purified by flash silica column chromatography eluting with 1% ammonia; 5%-7% methanol in dichloromethane. The isolated product was dissolved in dichloromethane and treated with 4 N hydrogen chloride in 1,4-dioxane (0.5 mL) and concentrated. The oily residue was triturated with ether, decanting the ether and concentrating to afford the titled compound as a white solid (0.032 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]([NH:10][NH2:11])=[O:9])=[CH:5][S:6][CH:7]=1.[N:12]([O-])=O.[Na+]>Cl.C(O)(=O)C.C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4]([C:8]([N:10]=[N+:11]=[N-:12])=[O:9])=[CH:5][S:6][CH:7]=1
Reactant: COc1cscc1C(=O)NN
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cscc1C(=O)N=[N+]=[N-]
Temperature: 25 °C

Procedure:
4-Methoxy-3-thiophenecarboxylic acid hydrazide (20 g, 0.116 mol) in 3N hydrochloric acid (200 ml), acetic acid (200 ml) and chloroform (300 ml) was cooled to 0°. Sodium nitrite (8 g, 0.116 mol) in water (25 ml) was added dropwise whilst maintaining the temperature at 0°. On completion of the addition the reaction mixture was allowed to warm up to room temperature. The organic layer was separated, washed with sodium bicarbonate solution (3 times), dried over sodium sulphate and the solvent evaporated without heat to give the title compound as a buff-coloured solid, 21.2 g.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:6](COCC[Si](C)(C)C)[C:5]=1[CH3:24])(=[O:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>CCO>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(-c2ccncc2)n(COCC[Si](C)(C)C)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1c(C)[nH]c(-c2ccncc2)c1C
Temperature: 85 °C
Yield: 28.2 %

Procedure:
3-Acetyl-2,4-dimethyl-5-(4-pyridyl)-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole (1.12 g, 3.39 mmol) was dissolved with EtOH (10 mL) and 10% aqueous HCl solution (30 mL) and the mixture was heated at 85° C. for 4 hours. After cooling, the mixture was neutralized with saturated aqueous NaHCO3 solution. The whole was extracted with ethyl acetate (150 mL×2), and the combined organic layers were washed with brine (50 mL), dried over MgSO4, and concentrated in vactio. The resulting solid was a mixture of 3-acetyl-1-hyroxymethyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole and 3-acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole. This mixture was suspended with saturated aqueous sodium acetate solution and then heated at reflux temperature for 15 minutes. After cooling, this mixture was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was recrystallized from ethyl acetate-hexane to give the title product (205 mg, 28% yield) as a pale yellow solid.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].[CH2:24](B(CC)CC)[CH3:25]>O>[CH2:24]([C:7]1[CH:8]=[C:9]([CH2:10][C:11]#[N:12])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH3:25]
Reactant: COc1ccc(CC#N)cc1Br
Reactant: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(CC#N)ccc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
N,N-Dimethylformamide (75 ml) was added to 3-bromo-4-methoxybenzyl cyanide (9.0 g, 40 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane adduct (400 mg, 0.49 mmol) and potassium carbonate (24.0 g, 174 mmol) at room temperature. Further, triethylborane (1M n-hexane solution, 50 ml, 50 mmol) was added dropwise thereto and the reaction mixture was stirred at 70° C. for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=8/1-5/1) to give (3-ethyl-4-methoxyphenyl)acetonitrile (2.6 g, yield: 38%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:11]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(S(F)(F)(F)(F)F)cc1Cl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(F)(F)(F)(F)F)cc1Oc1ccc(F)cc1
Temperature: 120 °C
Yield: 32 %

Procedure:
300 mg of methyl 2-chloro-4-pentafluorosulfanylbenzoate, 113 mg of 4-fluorophenol and 659 mg of Cs2CO3 were dissolved in 1.5 ml of DMF (anhydrous) and stirred at 120° C. The mixture was then allowed to cool and was diluted with 10 ml of EA and washed 3 times with 5 ml of water each time. Drying over MgSO4 was followed by removal of the solvent in vacuo. 120 mg of an amorphous solid were obtained and were chromatographed on reversed phase silica gel:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][OH:15]>>[CH3:14][O:15][C:3]([C:2]1[N:11]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:12][CH3:13])[CH:4]=2)[S:10][C:7]=1[CH3:6])=[O:12]
Reactant: CO
Reactant: COc1cc(NC(N)=S)ccc1Cl
Product: COC(=O)c1nc(Nc2ccc(Cl)c(OC)c2)sc1C
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 8.7 g (40.1 mmol) 1-(4-chloro-3-methoxyphenyl)-thiourea and 7.5 g (0.44 mmol) α-methylchloropyruvate (J. Chem Soc. Perkin 1, 1982, 2, 159) in 140 ml methanol was heated under reflux for 5 h, cooled to room temperature and volatiles were removed. The residue was dissolved in dichloromethane and washed successively with 25% aq. ammonia and water. Water phases were extracted thrice with dichloromethane, the organic phases were pooled, dried with MgSO4 and the solvent removed in vacuo. The residue was purified by chromatography on silica gel with heptane/ethyl acetate (1:2) to give 6.2 g (50%) of the title compound as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=3[CH:22]=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=4[CH:22]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccc3ccc(Cl)cc3n2)c(C=O)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=Cc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Yield: 86.7 %

Procedure:
A mixture of 7-chloro-2-(2,4-diformylphenoxymethyl)-quinoline (5.7 g) and pyridine hydrochloride (11.4 g) in toluene (140 ml) was stirred under reflux for 2 hours. After being cooled, the appeared crystals were collected, washed with toluene and water. The resulting crystals were washed with ethanol (100 ml) and dried to give 7-chloro-2-(5-formylbenzofuran-2-yl)quinoline (4.67 g).
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[O:1]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)COc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 30 g. of phenoxyacetic acid, 100 ml. of ethanol and 10 ml. of sulfuric acid is refluxed for 22 hours, cooled, poured into ice water and extracted with methylene chloride. The organic extract is washed with water to neutrality, dried over sodium sulfate and evaporated to dryness under vacuum, to yield ethyl phenoxyacetate, b.p. 123°/17 mm.Hg.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.Cl.[O:13]([NH2:15])[CH3:14]>N1C=CC=CC=1.C(OC(=O)C)C>[CH3:14][O:13][N:15]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CON
Reactant: O=C1CCc2ccc(F)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CON=C1CCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of 6-fluoro-indan-1-one (0.5 g, 3.33 mmol) in pyridine (10 ml) was added the HCl salt of methoxylamine (0.31 g, 3.66 mmol) and stirred at room temperature for overnight. The reaction mixture was diluted with ethylacetate (50 ml), acidified with 3N HCl, and washed with 1N HCl, water and brine sequentially. The solution was dried (Na2SO4) and concentrated to yield 0.48 g (81%) of product. MS (ESI+) m/z 180 (M+H)+;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.C([Sn](CCCC)(CCCC)[C:34]1[O:35][CH:36]=[CH:37][N:38]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:19])([F:18])[F:20])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:34]1[O:35][CH:36]=[CH:37][N:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: O=S(=O)(Oc1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-c1ncco1
Yield: 35.8 %

Procedure:
A solution of trifluoromethanesulfonic acid 2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl ester (45 mg, 0.104 mmol), 2-(tributylstannyl)oxazole (70 mg, 0.196 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) and copper(I) iodide (15 mg, 0.079 mmol) in 1,4-dioxane (4 ml) was heated at 170° C. for 30 min using a Smith Synthesizer microwave apparatus. The mixture was evaporated in vacuo and the residue was purified by chromatography (silica gel, 8% Et2O/CH2Cl2), followed by trituration with diethyl ether, to give 13 mg (35%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 7.37 (1H, s), 7.42 (1H, dd, J 8.7, 10.2 Hz), 7.85 (1H, s), 8.19 (1H, ddd, J 8.8, 4.6, 2.4 Hz), 8.66 (1H, s), 8.82 (1H, dd, J 9.1, 2.4 Hz), 8.86 (1H, s); MS (ES+) m/z 350.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].Br[C:34]#[N:35]>C1COCC1.O.C(Cl)Cl>[NH2:35][C:34]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]2[N:1]=1
Reactant: N#CBr
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(N)nc4c(C)cc(C)nc43)cc2)cc1
Yield: 70.9 %

Procedure:
To a stirred solution of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (300 mg, 0.66 mmol) in THF (6 ml) was added a solution of BrCN (175 mg, 1.65 mmol) in water (2 ml). The resultant mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 and washed with brine. The organic layer was dried over MgSO4 and filtered. After concentration in vacuo, the residue was purified by preparative TLC (CH2Cl2/MeOH=10/1) to afford 224 mg (71%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([OH:26])[CH:20]=3)=[N:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.Cl[CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:20]=3)=[N:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)CCCCl
Reactant: COC(=O)c1ccc(-c2ncc(Cl)cc2Cl)c(-c2ccc(Cl)c(O)c2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ncc(Cl)cc2Cl)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of 2 g (4.88 mmol) of methyl 3,5-dichloro-2′-(4-chloro-3-hydroxyphenyl)-2,3′-bipyridine-6′-carboxylate in 20 mL of anhydrous DMF placed under argon are added 1.15 g (7.32 mmol) of 3-chloro-N,N-dimethylpropane-1-amine hydrochloride and 4.77 g (14.64 mmol) of cesium carbonate. The reaction medium is stirred for 18 hours at 90° C., cooled to room temperature and then concentrated under reduced pressure. The residue is taken up in 250 mL of EtOAc and washed with 250 mL of aqueous 5% Na2CO3 solution and then with 100 mL of water. After drying over Na2SO4 and concentrating under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a DCM/methanol gradient of from 0 to 15% methanol. After concentrating under reduced pressure, 1.82 g of methyl 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate is obtained in the form of a gum.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH2:29]Br.C(Br)C1C=CC=CC=1>O.C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([O:16][CH2:29][C:28]1[CH:31]=[C:32]([C:35]([F:37])([F:38])[F:36])[CH:33]=[CH:34][C:27]=1[C:26]([F:25])([F:39])[F:40])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(CBr)c1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
(1R*,2R*,5R*)-8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 151 mg, 0.52 mmol) was treated with sodium hydride (41 mg, 60% in oil, 1.03 mmol) at 0° C. in a solution of THF (2 ml) and allowed to warm to room temperature. The mixture was recooled to 0° C. and 2,5-bis(trifluoromethyl)benzyl bromide (0.24 ml, 1.30 mmol) added and the mixture heated to 50° C. for 2 days. A further 1.30 mmol of the benzyl bromide was added and the mixture further heated for 50° C. for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow solid. This was purified by flash column chromatography [25% ethyl acetate in iso-hexane] to give the title compound.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH2:11]([Si:15](OC)([O:18][CH3:19])[O:16][CH3:17])[CH:12]([CH3:14])[CH3:13]>O1CCCC1>[CH2:11]([Si:15]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])([O:18][CH3:19])[O:16][CH3:17])[CH:12]([CH3:14])[CH3:13]
Reactant: CO[Si](CC(C)C)(OC)OC
Reactant: CCNCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCN(CC)[Si](CC(C)C)(OC)OC
Temperature: 42.5 °C
Yield: 79 %

Procedure:
Following the same general procedure described in Example 1, a flask was charged with one mol of isopropylmagnesium chloride in 500 ml of tetrahydrofuran under a dry nitrogen atmosphere and stirred. To this was added 1.05 mol (76.8 g) of diethylamine over a period of one hour. During the addition of the diethylamine to the reaction mixture, the pot temperature was maintained at 40-45° C. After the addition was complete, the reaction mixture was refluxed for 30 minutes to complete the evolution of the gas. The reaction mixture was cooled to a pot temperature of 50° C. and one mol (178 g) of isobutyltrimethoxysilane was added over a period of one hour. The reaction mixture was refluxed at a pot temperature of 75° C. for four hours to complete the reaction. The isobutyl(diethylamino)dimethoxysilane was filtered under a nitrogen atmosphere from the magnesium methoxychloride salt. The salt cake was washed with ether (2×200 ml) to obtain the residual isobutyl(diethylamino)dimethoxysilane. The combined filtrate was distilled to a pot temperature of 100° C. to remove the lighter fraction and the residue distilled under reduced pressure to yield 153 g of isobutyl(diethylamino)dimethoxysilaie as a colorless oil (purity>98%); bp 104° C./30 mm. The total yield was 79% of theoretical.
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[N:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][N:13]=1.O.C(OCC)C>N1C=CC=CC=1>[C:18]1([C:15]2[N:16]=[CH:17][C:12]([NH:11][C:1](=[O:9])[O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cnc(-c2ccccc2)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenyl chlorocarbonate (15.05 mL) was added at 0° C. to a solution of 2-amino-5-phenylpyrazine (17.12 g) in pyridine (200 mL). The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water (200 mL) and ethyl ether (200 mL). The whole was stirred to provide a suspension containing the subject compound as a crystal. The crystal was collected by filtration and further washed with ethyl ether (50 mL) and then dried under reduced pressure to provide the subject compound (24.57 g) as colorless crystals (melting point 192-198° C., decomposed).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5](N)=[C:4]([CH3:12])[CH:3]=1.N([O-])=O.[Na+].C(Cl)Cl.[BrH:20]>O>[Br:20][C:5]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[CH3:12]
Reactant: Br
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)cc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A suspension of 4-fluoro-2-methyl-6-nitroaniline (5.1 g, 30 mmol) in water (38 mL) and aqueous HBr (15 mL, 40%) was refluxed for 10 minutes and then cooled to 0° C. A solution of NaNO2 (2.07 g, 30 mmol) in H2O (12 mL) was added dropwise at a temperature <10° C. The diazonium solution was stirred for 30 minutes at a temperature of 0° C. to 5° C. and was then added slowly to a stirred mixture of CuBr (4.33 g, 30 mmol) in aqueous HBr (12 mL, 40%) and water (23 mL) at RT. The mixture was stirred at RT for 30 minutes and then on a steam bath for 1 hour. The reaction mixture was cooled to RT, DCM (50 mL) was added, and the mixture was washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography, eluting with petroleum ether to give the title compound as an oil (2.0 g, 28%). 1H NMR (400 MHz, CDCl3) δ ppm 7.23 (1H, dd, J1=2.4 Hz, J2=7.2 Hz), 7.14 (1H, dd, J1=2.8 Hz, J2=8.8 Hz), 2.44 (3H, s).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:6]1)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[NH:5]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:6]1
Reactant: CCCCOC(=O)/C=C/c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)/C=C/c1cc[nH]c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of (E)-butyl 3-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]acrylate (10.0 g, 28.7 mmol) in 200 mL of THF was added tetra-n-butylammonium fluoride trihydrate (7.5 g, 23.8 mmol, 0.83 equiv.) at room temperature under N2. The solution was stirred for 30 min at room temperature, diluted with EtOAc (500 mL), and washed with water (2×100 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:5 to afford (E)-butyl 3-(1H-pyrrol-3-yl)acrylate (4.0 g, 72%) as a light yellow solid. LC-MS (ESI) m/z 194 (M+H+).
Reaction SMILES: B(F)(F)F.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(Cl)Cl.[CH2:32](O)[CH2:33][OH:34]>>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][C:25]4([O:34][CH2:33][CH2:32][O:28]4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C3CCC(=O)CC3)cc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 0.67 h
Yield: 96 %

Procedure:
Boron trifluoride diethyletherate (3.3 mL, 26.0 mmol) was added dropwise via a syringe to a stirred solution of 4-(4-oxocyclohexyl)phenyl 4-methylbenzenesulphonate (2.49 g, 7.23 mmol) in dry DCM/ethylene glycol (15 mL/14.11 mL) cooled with an isopropanol/ice bath and stirred for 40 minutes. The mixture was poured onto water (50 mL) and extracted with DCM (2×100 mL). The organic phase was washed with 10% sodium hydrogen carbonate solution (100 mL) then dried and concentrated by evaporation to give the title compound (2.685 g, 96%) as a solid; 1H NMR δ 1.54-1.66 (4H, m), 1.68-1.75 (4H, m), 2.43 (3H, s), 2.54-2.60 (1H, m), 3.86-3.89 (4H, s), 6.91-6.95 (2H, m), 7.21-7.25 (2H, m), 7.46-7.48 (2H, m), 7.73-7.75 (2H, m); MS m/e M+Na+ 411.