Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([CH2:6][CH:7]([CH3:21])[CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2)=[O:5])C.CC[O-].[Na+].[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH3:34]>C(O)C>[CH3:26][N:27]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH3:34])[C:4]([CH2:6][CH:7]([CH3:21])[CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2)=[O:5]
Reactant: CCOC(=O)CC(C)COc1ccc2[nH]c(=O)ccc2c1
Reactant: CNC1CCCCC1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)N(C)C1CCCCC1C

Procedure:
2.7 Grams of 6-(3-ethoxycarbonyl-2-methylpropoxy)carbostyril, 0.5 g of sodium ethylate and 5 ml of N-methyl-2-methylcyclohexylamine are added to 100 ml of ethanol, and the mixture is reacted in an autoclave under 110 atm. and at 140° to 150° C. for 6 hours. After cooling, the reaction solution is concentrated under reduced pressure and the residue is dissolved in 200 ml of chloroform, washed with a 1% aqueous K2CO3 solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na2SO4. The solvent is distilled off and the residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 20/1 (V/V) chloroform-methanol) and the obtained crude crystals are recrystallized from benzene-ligroin, resultantly obtaining 1.0 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needle-like crystals with melting point of 146°-149° C.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH2:9][C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:8].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].I[CH2:22][N:23]([CH3:25])[CH3:24]>C(OCC)C>[CH3:6][N:7]([CH2:9][C-:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:22][N:23]([CH3:25])[CH3:24])[CH3:8].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: CN(C)CI
Reactant: CN(C)C[c-]1cccc1
Agent: [Fe+2]
Agent: [Li]CCCC
Agent: c1cc[cH-]c1
Solvent: CCOCC
Product: CN(C)Cc1ccc[c-]1CN(C)C
Temperature: -70 °C
Reaction time: 4 h

Procedure:
n-Butyllithium (Aldrich, 2.5 molar in hexane, 24 ml, 54 mmol) is added to a solution of (dimethylaminomethyl)ferrocene (Aldrich, 13.13 g, 10.69 ml, 48.97 mmol) in diethyl ether (80 ml) under nitrogen at a temperature of 25° C. and the reaction mixture stirred for 4 hours. The resulting red solution is then cooled to approximately −70° C. in a dry ice/acetone bath and Eschenmosers salt (ICH2NMe2)(Aldrich, 10 g, 54 mmol) is added. The reaction is allowed to warm to room temperature and stirred overnight.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCCOC3CCCCO3)c2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCO)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of methyl 6-(3-(6-(tetrahydro-2H-pyran-2-yloxy)hexyloxy)phenyl) picolinate (12), (260 mg, 0.63 mmol) in methanol (1 mL) was added catalytic p-toluenesulfonic acid monohydrate (26 mg) and the mixture was stirred at RT for 2-4 h. The reaction was monitored by TLC (ethyl acetate:hexane 1:1). After completion the volatiles were removed in vacuo and the oily residue dissolved in ethyl acetate. The solution was washed with bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by gradient flash chromatography (ethyl acetate:hexane) to provide 135 mg (65%) of 13. TLC Rf=0.34 (ethyl acetate:hexanes 1:1), MS m/z 330 (M+H)+
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH3:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][CH:29]([CH3:35])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC(C)CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 84%), MS (ISP) m/z=429.5 [(M+H)+], mp 182.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 4-methyl-pentanoic acid.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O>[O:14]=[C:10]1[CH2:11][CH2:12][CH2:13][C:8]([CH2:7][CH2:6][CH:2]=[O:1])=[CH:9]1
Reactant: O=C1C=C(CCC2OCCO2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)=O
Product: O=CCCC1=CC(=O)CCC1

Procedure:
A solution of 3-(2-(1,3-dioxolan-2-yl)ethyl)cyclohex-2-en-1-one (3.00 g), acetone (60.0 ml) and perchloric acid (3N, 10.0 ml) is stirred for 4 hr at 20°-25°. Aqueous saturated sodium bicarbonate (150 ml) is added and the mixture concentrated. Aqueous workup provides the title compound, IR (neat) 2950, 1720, 1666, 1257, 1194, 969, 732 cm-1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.O>C(Cl)Cl>[CH3:21][O:22][CH2:23][O:11][C:5]1[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: COCCl
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(Br)cc1C(C)=O

Procedure:
To a solution of 2-acetyl-4-bromophenol (3.63 g, 16.9 mmol) in methylene chloride (20 ml) on ice bath were added diisopropylethylamine (5.88 ml, 33.8 mmol) and chloromethyl methyl ether (1.92 ml, 25.3 mmol) with stirring. The mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give 4-(methoxymethyl) oxy-3-acetylbromobenzene (4.35 g, quantitatively).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]1[S:11][C:12]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][C:14]=1[C:15](=[O:16])[NH2:17])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1sccc1C(N)=O
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Nc1sc(S(=O)(=O)Cl)cc1C(N)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Neat ClSO3H (29 mL, 440 mmol) is cooled to 0° C., and 2-acetylamino-thiophene-3-carboxylic acid amide (8.1 g, 44 mmol) is added in portions over a period of 15 min. The mixture is then stirred at 50° C. for 3 h, cooled to room temperature, and then poured slowly to ice cold water. The resulting suspension is washed twice with EtOAc, the combined organic fractions are dried over MgSO4, filtered and evaporated to give the desired product, which is used as such.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12].[CH:13](OCC)=[O:14]>>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][CH:13]=[O:14]
Reactant: COc1cccc(CCN)c1C
Reactant: CCOC=O
Product: COc1cccc(CCNC=O)c1C

Procedure:
{2-[2-Methyl-3-(methyloxy)phenyl]ethyl}amine (Preparation 10; 1.75 g; 10.6 mmol) was heated under reflux with ethyl formate (97%; 15 ml) for 15 h. Removal of the solvent gave the crude product (ca. 2 g), which was purified by chromatography on silica gel, eluting with a gradient of 13-63% ethyl acetate in cyclohexane, to give the title compound (1.57 g).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH3:27])[C:7](=[C:9]3[S:13][C:12](=[N:14][C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[NH:23][CH2:24][CH3:25])[C:18]#[N:19])[NH:11][C:10]3=[O:26])[S:8][C:4]=2[CH:3]=1.[C:30]([O:34][C:35]([NH:37][C:38]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=S)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.C(Cl)(Cl)Cl.Cl[Hg]Cl>[CH2:18]([N:11]1[C:10](=[O:26])[C:9](=[C:7]2[N:6]([CH3:27])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:38]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:37][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[CH:3][C:4]=3[S:8]2)[S:13][C:12]1=[N:14][C:15]1[CH:16]=[C:17]([C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH3:25])[C:17]1[CH:20]=[CH:21][CH:22]=[CH:15][CH:16]=1
Reactant: CCNc1ccc(C#N)cc1N=C1NC(=O)C(=C2Sc3cc(N)ccc3N2C)S1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 173.1 %

Procedure:
To a stirred mixture of the product of Example 272 (77 mg, 0.15 mmol), N,N′-di-(tert-butoxycarbonyl)thiourea (50 mg, 0.18 mmol) and TEA (70 μL, 0.5 mmol) in anhydrous DMF (1.5 mL) at 0° C. was added HgCl2 (49 mg, 0.18 mmol). The resulting mixture was stirred at 0° C. for 30 min, then at ambient temperature overnight. The mixture was diluted with CHCl3, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with MeOH-DCM (0:100 to 20:80) to afford the title compound (98 mg, 87%). 1H-NMR (CDCl3): δ 11.62 (1H, br s), 10.43 (1H, br s), 8.02 (2H, m), 7.45-7.20 (7H, m), 7.02 (1H, d), 6.49 (1H, t), 5.16 (2H, s), 3.82 (3H, s), 3.04-2.96 (2H, m), 1.43 (9H, s), 1.35 (9H, s), 1.02 (3H, t); MS(ESI): 756 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]#N)[C:11]=3[CH:17]=2)=[N:4][N:3]=1.C(O)=[O:19]>[Ni].O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([CH:15]=[O:19])[C:11]=3[CH:17]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2ccc3occ(C#N)c3c2)o1
Reactant: O=CO
Agent: [Ni]
Solvent: O
Product: Cc1nnc(-c2ccc3occ(C=O)c3c2)o1
Yield: 55 %

Procedure:
A mixture of 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-carbonitrile (1.00 g, 4.44 mmol), Raney-nickel (2.0 g), formic acid (16 mL) and water (4 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/tetrahydrofuran=1/1) and recrystallized from hexane/tetrahydrofuran to give the title compound (558 mg, yield 55%) as colorless crystals.
Reaction SMILES: Cl.C([N:4]([CH2:7][CH3:8])CC)C.[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(Cl)(=O)=O>C(Cl)Cl>[C:9]([N:4]1[CH2:7][CH2:8]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
Amine 182 (2.59 g, 10.2 mmol) was dissolved in 5% HCl/MeOH (30 mL) and the solution was stirred for 3 h at room temperature. Additional 5% HCl/MeOH (10 mL) was added stirring 1 h and the solvent was evaporated to afford 2.52 g of the HCl salt as a tan solid after high vacuum. To a suspension of the HCl salt in CH2Cl2 (50 mL) at 0° C. was added triethylamine (3.55 mL, 25.5 mmol) followed by the addition of solid trityl chloride (5.55 g, 12.8 mmol) in one portion. The mixture was stirred at 0° C. for 1 h and then was warmed to room temperature stirring for 2 h. The reaction was cooled to 0° C., triethylamine (3.6 mL, 25.5 mmol) was added and methane sulfonyl chloride (0.97 mL, 12.5 mmol) was added, stirring the resulting mixture for 1 h at 0° C. and for 22 h at room temperature. The reaction was evaporated and the residue was partitioned between diethyl ether (200 mL) and water (200 mL). The organic phase was washed with water (200 mL) and the combined aqueous phases were extracted with diethyl ether (200 mL). The combined organic extracts were washed with water (100 mL), saturated NaCl (200 mL) and were dried (Na2SO4), filtered, and evaporated. The crude product was purified on silica gel (1/1-hexane/CH2Cl2) to afford N-trityl aziridine 183 (3.84 g, 86%) as a white foam: 1H NMR (CDCl3) δ7.4-7.23 (m, 16H), 4.32 (m, 1H), 3.81 (s, 3H), 3.06 (dt, 1H, J=1.8, 17.1), 2.94-2.86 (m, 1H), 2.12 (m, 1H), 1.85 (t, 1H, J=5.0).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[C:16](O)([CH3:18])[CH3:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>S(=O)(=O)(O)O>[NH:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:18])=[CH2:17])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(=O)Nc1ccc(Nc2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(Nc2ccccc2)cc1
Reaction time: 0.3 h
Yield: 80.6 %

Procedure:
4.85 Grams (0.018 moles) N-(4-anilinophenyl)-2-hydroxyisobutyramide from Example 3 was dissolved in 43.6 grams concentrated sulfuric acid at room temperature in a large test tube. The test tube was then placed in a boiling water bath for 18 minutes before being rapidly cooled in a stream of cold water. This reaction solution was then added dropwise to 800 milliliters of stirred cold water over a 45 minute period. The light green product was filtered off, washed with water and dried in the air to give 3.66 grams N-(4-anilinophenyl)methacrylamide (81% yield). Analysis showed a purity of 92.1%.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:25][Mg+].[Br-].Cl>C1COCC1.O>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([OH:24])[CH3:25])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[Mg+]
Reactant: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Yield: 886.4 %

Procedure:
A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.15 g, 0.44 mmoles) and MeMgBr (0.36 ml of 3M solution in ether, 1.1 mmoles) was stirred in THF at −20° C. to 0° C. for 30 minutes. Reaction mixture was diluted with water, acidified to pH=3 with 2N HCl, then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.13 g, 3.9 mmoles).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=4)=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cncn1C1CCCc2cc(-c3ccc(F)cc3)ccc21
Temperature: 150 °C

Procedure:
A flask is charged with 3-(6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester (0.225 g, 0.520 mmol), 4-fluorophenylboronic acid (0.145 g, 1.041 mmol), aqueous sodium carbonate (2M, 1.30 mL, 2.60 mmol) and DMF (35 mL). Tetrakis(triphenylphosphine) palladium (0.060 g, 0.052 mmol) is added and the mixture is heated to 150° C. in a sealed tube under microwave irradiation conditions for 12 minutes. The reaction is cooled to room temperature, diluted with water and extracted with dichloromethane. The organic phase is dried with Na2SO4, filtered, and concentrated to give a residue, which is purified by silica gel chromatography (hexanes-ethyl acetate mixtures) to give 3-[6-(4-fluoro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3H-imidazole-4-carboxylic acid isopropyl ester. MS: (ESI) m/z 379.2 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-[6-(4-fluoro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.45 (d, J=6.3 Hz, 3 H), 1.47 (d, J=6.3 Hz, 3 H), 1.75-1.86 (m, 1 H), 1.93-2.02 (m, 1 H), 2.31-2.47 (m, 2 H), 2.99 (ddd, J=17.0, 9.3, 5.6 Hz, 1 H), 3.13 (dt, J=17.0, 5.3 Hz, 1 H), 5.36 (sept, J=6.3 Hz, 1 H), 6.61 (t, J=5.1 Hz, 1 H), 7.19-7.25 (m, 3 H), 7.51 (dd, J=8.1, 2.0 Hz, 1 H), 7.57 (s, 1 H), 7.66-7.72 (m, 2 H), 8.34 (d, J=1.5 Hz, 1 H), 8.65 (d, J=1.3 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:57]1([CH2:62][C@@H:63]2[CH2:67][CH2:66][CH2:65][NH:64]2)[CH2:61][CH2:60][CH2:59][CH2:58]1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:64]1[CH2:65][CH2:66][CH2:67][C@H:63]1[CH2:62][N:57]1[CH2:61][CH2:60][CH2:59][CH2:58]1)=[O:6])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 74 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and (2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidine in tetrahydrofuran. Yield: 74%; Rf value: 0.10 (silica gel: dichloromethane/ethanol=4:1); C26H29Cl2N5O2 (514.454); mass spectrum: (M+H)+=514/516/518 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[C:24]([C:31]3[CH:39]=[CH:38][C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2].[Cl-].[NH4+]>[Zn]>[CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:39]=[CH:38][C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[CH:25]=[C:26]([NH2:28])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc([N+](=O)[O-])c2)c1CCC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(N)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Yield: 87.2 %

Procedure:
A similar procedure as described in Example 12, step 4 was used, starting from 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-nitro-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (4.8 g, 7.38 mmol), zinc dust (2.46 g, 36.94 mmol), and ammonium chloride (3.95 g, 73.88 mmol) to obtain 4-{3-[6-(3-amino-5-benzo[1,3]dioxol-5-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (3.99 g, 87%) as a light yellow oil: ES(+)-HRMS m/e calculated for C36H45NO8 (M+H)+ 619.0000, found 619.0000.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-nitro-benzylamine (47.2 mg, 0.25 mmol) in THF (250 μL) is added triethylamine (89 μL) and ethyl sulfonyl chloride (24 μL, 0.25 mmol). The reaction mixture is shaken at ambient temperature for 16 hours. The reaction mixture is then concentrated, methanol is added followed by Novabiochem AM resin to remove unreacted amine. This is then shaken for two hours, filtered, concentrated to yield ethanesulfonic acid 4-nitro-benzylamide, which is used as such for the subsequent reaction.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][NH:16][C:17]([CH2:19][NH:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:15][NH:16][C:17]1[S:2][C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:20][CH:19]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CNC(=O)CNC(=O)c1cccnc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CNc1cnc(-c2cccnc2)s1
Temperature: 25 °C
Yield: 23 %

Procedure:
A suspension of phosphorus pentasulfide (1.73 g, 7.8 mmol) and N-methylcarbamoylmethyl-nicotinamide (1 g, 5 mmol) in dry toluene (10 mL) was stirred at reflux under nitrogen for 16 h. The mixture was cooled to room temperature and then dry pyridine (4 mL) was added. The mixture was stirred at reflux under nitrogen for 8 h, then it was cooled to room temperature and the organic layer was removed. The dark residue was treated with hot saturated aqueous sodium bicarbonate (Na2CO3, 40 mL) and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate (MgSO4), and purified by silica gel chromatography (1% methanol in dichloromethane) to yield a brown amorphous solid (0.22 g, 22%): mp 141-146° C.; 1H NMR (300 MHz, CDCl3) δ 8.97 (d, J=2.4 Hz, 1H), 8.53 (dd, J=5.0, 1.8 Hz, 1H), 8.06 (ddd, J=7.2, 3.3, 0.6 Hz, 1H), 7.31 (ddd, J=5.5, 4.7, 0.5 Hz, 1H), 6.96 (s, 1H), 2.97 (d, J=5.0 Hz, 3H); ESIMS m/z 192 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]2[CH:8]([OH:15])[C:9]([CH3:14])([CH3:13])[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1.I[CH3:19]>CN(C=O)C>[CH3:19][O:15][CH:8]1[C:7]2[CH:16]=[CH:17][C:4]([Br:3])=[CH:5][C:6]=2[S:10](=[O:11])(=[O:12])[C:9]1([CH3:13])[CH3:14]
Reactant: CI
Reactant: CC1(C)C(O)c2ccc(Br)cc2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1c2ccc(Br)cc2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
A cooled (0° C.) suspension of NaH (20.61 mg; 0.52 mmol; 1.00 eq.) in dry DMF was carefully treated with solution of 6-bromo-2,2-dimethyl-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide (Intermediate 244; 150 mg; 0.52 mmol) in anhydrous DMF. The reaction mixture was stirred at RT for 4 min then treated with a 3 M solution of iodomethane (240 μl; 0.72 mmol). The mixture was stirred at RT for 2.5 h, then quenched with water. EtOAc was added, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness to afford a residue, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a white solid.