Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]([N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=1I)=[CH:7][CH:8]=[N:9]2)([O-])=O.C(Cl)(=O)C(Cl)=O.COC1C=C(C(I)=CC=1OC)C(O)=O.CN(C)CCNC1C2C(=CC=CC=2[N+]([O-])=O)N=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[CH:13][CH:12]=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN(C)C)c2ccnc3cccc([N+](=O)[O-])c23)cc1OC
Agent: CN(C)CCNc1ccnc2cccc([N+](=O)[O-])c12
Agent: COc1cc(I)c(C(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(=O)n(CCN(C)C)c3c4ccccc4ncc3c2cc1OC
Yield: 73 %

Procedure:
Synthesis of N-(quinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-5,6-dimethoxybenzamide (8d). Oxalyl chloride (2.1 g, 16.2 mmol) was added to a solution of 3,4-dimethoxy-6-iodobenzoic acid (1.5 g, 4.87 mmol) in anhydrous methylene chloride (40 mL), and the stirred mixture was refluxed for 4 hours. The mixture was then concentrated to dryness under reduced pressure. The acid chloride was redissolved in 40 mL of anhydrous methylene chloride, and this solution was added to a solution of 7d (870 mg, 4.05 mmol) and triethylamine (4.0 g, 40.0 mmol) in methylene chloride (30 mL), and the resulting mixture was stirred at reflux for 2 hours. The reaction mix was cooled and washed with saturated sodium bicarbonate (3×75 mL), and extracted with 5% aqueous HCl (4×100 mL). The combined aqueous extracts were basified with 30% NaOH and then extracted with chloroform (3×75 mL). Combined organic extracts were then dried (MgSO4) and evaporated to give 1.45 g of the amide, in 73% yield; 1H NMR (CDCl3) δ 2.23 (s, 6H), 2.63 (m, 2H), 3.07 (s, 3H), 3.68 (s, 3H), 3.93 (m, 1H), 4.62 (m, 1H), 6.26 (s, 1H), 7.00 (s, 1H), 7.44 (d, 1H, J=4.4), 7.69 (m, 2H), 8.11 (m, 2H), 8.75 (d, 1H, J=4.4); 13C NMR (CDCl3) δ 45.6, 47.0, 55.3, 56.0, 56.7, 82.5, 110.2, 121.6, 122.8, 125.8, 127.6, 130.0, 130.5, 130.6, 133.8, 146.9, 148.1, 149.6, 149.8, 150.8, 169.8; IR (CHCl3) 1650;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:46][N:47]([CH3:54])[C:48]1[CH2:49][NH:50][CH2:51][CH2:52][N:53]=1.C(N(C(C)C)CC)(C)C>>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:50]3[CH2:51][CH2:52][N:53]=[C:48]([N:47]([CH3:54])[CH3:46])[CH2:49]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CN(C)C1=NCCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN=C(N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 101.8 %

Procedure:
Following a procedure similar to that described in Preparation 1(i), but using 446 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 178 mg of N,N'-carbonyldiimidazole, 289 mg of 3-dimethylamino-1,2,5,6-tetrahydropyrazine bis(trifluoroacetate) and 289 μl of diisopropylethylamine, 460 mg of the title compound were obtained, as a powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][NH:19][C:20]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:15]>C1C=CC=CC=1.O1CCCC1>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][NH:19][C:20]1[C:25]([NH:26][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:15]
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccccn1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccccn1

Procedure:
Under a nitrogen atmosphere, triethylamine (0.30 mole) and a solution of freshly prepared acid chloride of 2-pyridine carboxylic acid (0.150 mole), obtained by heating at reflux 2-pyridine carboxic acid and excess thionyl chloride in benzene and then azeotropic distillation with benzene, in dry tetrahydrofuran (50 ml) were added simultaneously (dropwise) to a stirred and chilled (10°-20° C.) solution of freshly prepared N-(3-amino-2-pyridinyl)glycine ethyl ester prepared by reducing N-(3-nitro-2-pyridinyl)glycine ethyl ester (0.106 mole) in 200 ml of dry tetrahydrofuran. The reaction mixture was stirred overnight at room temperature and was filtered. The filtrate was concentrated in vacuo and dissolved in ethyl acetate (250 ml). The solution was washed with saturated sodium bicarbonate solution (3×75 ml), water (2×75 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was crystallized from isopropyl ether-tetrahydrofuran giving 26.5 g (83%). A 3.0-g sample was twice recrystallized from isopropyl ether-tetrahydrofuran to give 2.4 g of a white needles, mp 98°-100° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C3C=CC=CN=3)[CH2:13][CH2:12]2)[N:3]=1.[Br:23][C:24]1[CH:25]=[N:26][C:27](I)=[N:28][CH:29]=1>CN(C)C(=O)C>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:14]2[CH2:15][CH2:16][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:12][CH2:13]2)=[N:28][CH:29]=1
Reactant: Brc1cnc(I)nc1
Reactant: Cc1cccc(C#CC=C2CCN(c3ccccn3)CC2)n1
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C#CC=C2CCN(c3ncc(Br)cn3)CC2)n1
Yield: 64.1 %

Procedure:
The title compound was prepared following the procedure described for the compound of Example 59, but substituting NMP with N,N-dimethylacetamide and substituting 2-fluoropyridine with 5-bromo-2-iodopyrimidine and reacting the mixture at r.t. Purification was carried out by automated flash liquid chromatography (Horizon™-Biotage) eluting with CHCl3-1.4 N MeOH NH3 100:0.5. White solid. Yield: 64.1%.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].[CH3:11][O:12][CH2:13]Cl.[CH2:15]([O:17][CH2:18]C)C>CN(C=O)C>[CH3:11][O:12][CH2:13][O:4][C:3]1[CH:10]=[CH:9][C:7]([O:8][CH2:15][O:17][CH3:18])=[CH:6][CH:5]=1
Reactant: Oc1ccc(O)cc1
Reactant: COCCl
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(OCOC)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
Stir a suspension of sodium hydride (60% in mineral oil, 3.81 g, 95.45 mmol) in anhydrous DMF (50 mL) under nitrogen atmosphere at 0° C. and add a solution of hydroquinone (5.00 g, 45.45 mmol) in anhydrous DMF (50 mL) dropwise. Add to this suspension methoxymethyl chloride (7.2 mL, 95.45 mmol) dropwise with additional gas evolution noted. Allow the reaction to warm to ambient temperature and stir for one hour. Quench the reaction with water and add diethyl ether. Wash the organic layer with 1N sodium hydroxide and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate/hexane to yield 1,4-bis-methoxymethoxy-benzene 6 (5.64 g, 63%) as a clear oil. 1H NMR (CDCl3): 6.97 (s, 4H), 5.11 (s, 4H), 3.47 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>ClCCl>[C:14]([NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC1=NN(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CC(=O)NC1=NN(c2ccc(Cl)cc2)CC1

Procedure:
3-Amino-1-(p-chlorophenyl)-2-pyrazoline (5 g) was added to acetic anhydride (4.0 ml) at room temperature. On stirring with a glass rod the mixture became warm and afforded a dark red liquid. The mixture was taken up in dichloromethane (100 ml) washed (water, 100 ml; saturated sodium bicarbonate, 100 ml; water, 100 ml), dried over sodium sulphate and the solvent removed in vacuo to afford the title compound (m.p. 171°-173°).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][CH:16]3[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21]3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCC1CCC(N)CC1
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Product: CC(C)(C)OC(=O)CCC1CCC(NC(=O)c2cc3cc(C#N)ccc3o2)CC1
Yield: 38.5 %

Procedure:
In the same manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (203 mg, 1.08 mmol) and t-butyl 3-(4-aminocyclohexyl)propionate (295 mg, 1.30 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to give 165 mg of t-butyl 3-[4-[(5-cyano-2-benzofuranyl)carbonylamino]cyclohexyl]propionate as a colorless solid (38%).
Reaction SMILES: [CH3:1]O.S(Cl)([Cl:5])=O.[NH2:7][C@@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[ClH:5].[CH3:1][O:17][C:16](=[O:18])[C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CO
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](N)Cc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled solution of methanol (1000 ml), was charged thionyl chloride (100 ml, 1.361 moles) at 5° C.±3° C. under nitrogen atmosphere. D-Phenyl alanine (100 grams, 0.602 moles) was added at 5° C.±3° C. and further stirred for 30 minutes. The temperature was raised to 25° C. The reaction mass was further stirred for 12 hours and concentrated at 50° C. under reduced pressure to form a residue. The residue was stirred in toluene (500 ml). The solid was isolated by filtration, washed with toluene (2×500 ml) and dried at 50-55° C. under vacuum to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C@H:6]1[C@@H:12]([CH2:13][CH3:14])[O:11][CH:8](OC)[C@@H:7]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.[Sn](Cl)(Cl)(Cl)Cl.ClCCl.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:13]([C@H:12]1[O:11][C@H:8]2[C@H:7]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][C:22]=32)[C@H:6]1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=1[F:1])[CH3:14]
Reactant: CC[C@H]1OC(OC)[C@H](OCc2cccc(C)c2)[C@H]1OCc1ccccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC[C@H]1O[C@@H]2c3ccc(C)cc3CO[C@@H]2[C@H]1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
0.62 g of methyl 5-deoxy-3-O-(2-fluorobenzyl)-5-C- methyl-2-O-(3-methylbenzyl)-D-xylofuranoside (a mixture of alpha and beta forms) obtained in 1) was dissolved in 10 ml of acetonitrile and 4.97 ml of tin tetrachloride (a 1.0 M dichloromethane solution) were added under cooling with ice. The resulting mixture was stirred at room temperature for 3 hours and then poured into a saturated aqueous sodium hydrogen carbonate solution with ice. The organic phase was thoroughly washed with water and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain an oily product. The crude product was purified by silica gel chromatography (developing solvent: n-hexane:ethyl acetate=5:1) and 0.39 g of the target compound was obtained. (Yield: 68.4%)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[N+:24]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O)C.C(=O)([O-])O.[Na+]>[Fe].C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[NH2:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NCc1ccccc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NCc1ccccc1
Reaction time: 4 h
Yield: 28 %

Procedure:
To a suspension of 2-(4-benzylamino-3-nitrophenyl)benzoxazole (see Working Example 17-1) (340 mg, 0.985 mmol) was added 10% aqueous acetic acid solution (5 mL), ethanol (8 mL), and iron powder (165 mg, 2.95 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, this was filtered through Celite and then extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give an oil that was purified by silica gel column chromatography to yield the title compound (87 mg, 28% yield) as brown crystals.
Reaction SMILES: C(Cl)Cl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:14]([O:17][C:18]1[C:19]([CH3:32])=[C:20]([CH3:31])[C:21]2[O:25][C:24]([CH2:27][OH:28])([CH3:26])[CH2:23][C:22]=2[C:29]=1[CH3:30])(=[O:16])[CH3:15]>C(N(CC)CC)C>[C:14]([O:17][C:18]1[C:19]([CH3:32])=[C:20]([CH3:31])[C:21]2[O:25][C:24]([CH:27]=[O:28])([CH3:26])[CH2:23][C:22]=2[C:29]=1[CH3:30])(=[O:16])[CH3:15]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(CO)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(C=O)O2
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
To a methylene chloride solution (50 ml) of oxalyl chloride (2 ml) was added dropwise at -60° C. dimethylsulfoxide (4 ml). The mixture was stirred for 10 minutes, and there was then added dropwise a methylene chloride solution (10 ml) of 5-acetoxy-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran [5.0 g (19 mmol)]. The reaction mixture was stirred for 15 minutes, and there was added triethylamine (15 ml), and the mixture was stirred for further 10 minutes. The reaction mixture was washed with water and dried, followed by distilling off the solvent. The residue was crystallized from isopropylether-hexane to obtain 5-acetoxy-2-formyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (yield 96.7%), m.p. 78°-79° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Yield: 40 %

Procedure:
A solution of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (237.5 mg, 0.68 mM) in 10 mL THF and 40 mL concentrated aqueous ammonium hydroxide was sonicated for 20 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 89.7 mg (40%) of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5-6.9 (m, 7H), 6.65 (m, 2H), and 5.75 (s, 2H). IR (KBr, cm−1) 3395, 3192 (br), 1621, 1599, 1580, 1564, 1491, 1455, 1334, 1261, and 774. MS (ES) m/e 333, 335.
Reaction SMILES: [ClH:1].[S:2]1[CH2:6][CH:5]([CH:7]([CH3:24])CN2CCN(C3C(OC)=CC=CN=3)CC2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S([C:33]1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:40][O:41][C:42]1[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH:50]([CH3:54])[CH2:49]2)=[N:44][CH:45]=[CH:46][CH:47]=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:24][CH2:33][N:51]2[CH2:52][CH2:53][N:48]([C:43]3[C:42]([O:41][CH3:40])=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:49][CH:50]2[CH3:54])[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COc1cccnc1N1CCNC(C)C1
Reactant: COc1cccnc1N1CCN(CC(C)C2CSc3ccccc32)C(C)C1
Agent: Cl
Product: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1

Procedure:
The title compound was prepared (1.04 g, 70%, mp 189°-193° C.) in a manner analogous to the preparation of 1-[2-(2,3-dihydro-benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 7) by the reaction of 3-benzo[b]thienpropanol tosylate with 1-(3-methoxy-2-pyridinyl)-3-methylpiperazine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.O1CCCC1.C([Li])CCC.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O.C(O)C>[CH2:22]([C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: c1csc(-c2cccs2)c1
Reactant: CCCCCCCCBr
Agent: [Li]CCCC
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccsc1-c1cccs1
Reaction time: 10 h
Yield: 65.1 %

Procedure:
The process is commenced by placing about 3 g of bithiophene in a round bottom flask with a side arm (for introducing an inert gas), followed by adding an anhydrous tetrahydrofuran to dissolve the bithiophene. The temperature of the solution is then lowered to −78° C. (using liquid nitrogen plus ethanol as coolant). Thereafter, about 5.8 ml of n-butyl lithium (n-BuLi) (2.5 M, dissolved in hexane) is gradually drop-added to the solution. After the temperature of the solution has returned to room temperature, the solution is continuously mixed for about 15 minutes. After this, 2.5 ml of 1-bromooctane (Br—C8H17) is added, and the solution is continuously stirred for about 10 hours. The reaction was carried out under the inert gas all the time. After a predetermined reaction time is reached, deionized water is added to terminate the reaction. An extraction is performed by adding ether to the solution. An organic layer is then collected. Another extraction of the organic layer is performed using a saturated sodium hydrogen carbonate aqueous solution, deionized water and a saturated sodium chloride solution, respectively. The resulting crude product is then purified using column chromatography (eluent is hexane) to obtain an intermediate product octylbithiophene (the yield is about 65.1%).
Reaction SMILES: CN1CCN(C)[C:4](=[O:9])[C:3]1=[O:10].[CH3:11][CH:12]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:14][Li].[CH3:22][CH:23]([CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH2:25]Br.[Li].Cl>CCOCC>[CH3:31][CH:30]([CH2:29][CH2:28][CH2:27][CH:23]([CH3:22])[CH2:24][CH2:25][C:4](=[O:9])[C:3](=[O:10])[CH2:14][CH2:13][CH:12]([CH3:11])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH3:32]
Reactant: CN1CCN(C)C(=O)C1=O
Reactant: CC(C)CCCC(C)CCBr
Reactant: [Li]CCC(C)CCCC(C)C
Agent: Cl
Agent: [Li]
Solvent: CCOCC
Product: CC(C)CCCC(C)CCC(=O)C(=O)CCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 1,4-dimethylpiperazine-2,3-dione (2.08 g, 1.46×10−2 mol) in 50 ml of dry Et2O was added 3,7-dimethyloctyl lithium (0.45M solution in Et2O, 65 ml, 2.9×10−2 mol, freshly prepared from 3,7-dimethyloctyl bromide and lithium) by a syringe. After 40 min of stirring at room temperature under N2, the solution was hydrolyzed with 100 ml of 10% HCl and extracted with CHCl3. The combined organic layers were washed with saturated aqueous NaHCO3 and dried over Na2SO4. The product was chromatographed on silica gel with 3:1 hexane:CHCl3 as the eluent. Yield=4.446 g (91% based on 65 ml of 0.45M 3,7-dimethyloctyl lithium in Et2O). 1H NMR (250 MHz, CDCl3): δ 2.69-2.78 (m, 4H, —CH2CO), 1.06-1.65 (m, 20H, (CH3)2CHCH2CH2CH2CH(CH3)CH2CH2CO), 0.87 (d, 6H, J=9.0 Hz, —CH3), 0.86 (d, 12H, J=9.5 Hz, —CH3). CI MS m/z: 338.3175 (M+) (calcd 338.318).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[CH3:13][C:14]([C:17]([NH2:19])=[NH:18])([CH3:16])[CH3:15].Cl.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:14]([C:17]1[NH:18][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])[N:19]=1)([CH3:16])([CH3:15])[CH3:13]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1nc(-c2cccc(C#N)c2)c[nH]1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 3-(2-bromoacetyl)benzonitrile (500 mg, 2.23 mmol), tert-butylcarbamidine hydrochloride (610 mg, 4.46 mmol), potassium carbonate (770 mg, 5.58 mmol), and acetonitrile (10 mL) was refluxed for 1 hour. After the reaction was completed, the mixture was left to cool to room temperature. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to give 3-(2-tert-butyl-1H-imidazol-4-yl)benzonitrile (500 mg, 2.22 mmol, yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]CS(C)(=O)=O)[CH2:25][CH2:24]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.N1(CC[NH:65][S:66]([CH3:69])(=[O:68])=[O:67])CCNCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[CH2:27][CH2:28]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:47])([CH3:48])[CH3:49])(=[O:43])=[O:44])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)NCCN1CCNCC1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Agent: Cl
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C37H48N6O6S2Cl3 [(M+H)+] 841.2137, observed 841.2129.