Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:23][C:24]1([CH3:37])[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[C:30]2[CH:29]=[C:28](O)[CH:27]=[CH:26][C:25]1=2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:28]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:37])([CH3:23])[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[C:30]=3[CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)o1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (318 mg), 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenol (409 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (500 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyloxy)propyl]oxazole was obtained as a yellow oil (400 mg, 79%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[C@H:27]2[C@@H:17]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:28]=3[C:25]([CH2:26]2)=[CH:24][NH:23]4)[CH2:16][C@@H:15]([CH2:29][OH:30])[CH2:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:30][CH2:29][C@@H:15]1[CH2:16][C@H:17]2[C@@H:27]([CH2:26][C:25]3[C:28]4[C:22](=[CH:21][CH:20]=[CH:19][C:18]2=4)[NH:23][CH:24]=3)[N:13]([CH3:12])[CH2:14]1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C[C@H](CO)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
5.0 g of p-toluenesulfonyl chloride was added in small portions to a mixture of 5.0 g of 6-methylergolin-8β-ylmethanol and 50 ml of pyridine while stirring, and the resulting mixture was stirred for 3 hours. After completion of the reaction, 4 ml of water was added to the mixture which was then stirred for 30 minutes. The mixture was diluted with ice-water, rendered alkaline with potassium carbonate and allowed to stand. The precipitated crystals were separated by filtration, washed with water and dried to obtain 6.9 g of the titled compound as colorless crystals. The crystals thus obtained were recrystallized from dichloromethane-isopropyl acetate to obtain colorless leaflets having a melting point of 195°-199° C. (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1.[CH2:15]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:38][CH:37]=1
Reactant: NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a 0° C. solution of 0.674 g 2-(aminomethyl)-pyridine, 20 ml methylene chloride and 1.83 ml pyridine is added, dropwise over 20 minutes, 2.0 g of product from Example 3 dissolved in 25 ml of methylene chloride. The reaction is stirred at 0° C. for 2 hours followed by stirring at room temperature for 17 hours. The reaction mixture is partitioned between chloroform and saturated sodium bicarbonate, washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica g81:75% ethyl acetate/hexane) to give 1.51 g of the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([S:21][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: SCc1ccccc1
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCCSCc1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Potassium carbonate (5 g) and 1-bromo-5-chloropentane (4.9 g) were added to a solution of benzylmercaptan (3 g) in dimethylformamide (40 ml), and the mixture was stirred at 70-80° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3 g of 5-benzylthiopentyl chloride.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[NH:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([N:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A solution of 10.00 g of BOC-Tyr(Bzl)-OH dissolved in 50 ml of dichloromethane was mixed with 6.53 g of H-Pro-OBzl.HCl. To this mixture, under cooling at -5° C., 4.93 ml of WSC was added, followed by stirring at -5° C. for one hour and at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was mixed by shaking with ethyl acetate and 1N hydrochloric acid and separated into liquid layers. The ethyl acetate layer was washed successively twice with 1N hydrochloric acid, twice with saturated aqueous sodium chloride, three times with 5% aqueous sodium hydrogen carbonate and twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 14.46 g (yield: 96.1%) of BOC-Tyr(Bzl)-Pro-OBzl as oily product. Rf1 =0.71.
Reaction SMILES: Cl.NCCC(NN[C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=O.S1C=CC=C1S(Cl)(=O)=[O:33]>>[Cl:26][C:24]1[CH:23]=[CH:22][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH2:17][N:11]([C:9]([OH:10])=[O:33])[C:12]=2[CH:25]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Product: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-[(2-thienylsulfonyl)amino]propyl hydrazide (30) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and 2-thiophenesulfonyl chloride in the same manner as described in Example 10 on a 1.9 mmol scale to yield 0.48 g (50%) of product. Analysis calculated for C21H19N4O5ClS2 (M.W. 506.99): C, 49.26; H, 4.36; N, 12.77; Cl, 6.99; S, 12.65. Found: C, 49.05; H, 4.40: N, 12.66; Cl, 7.13; S, 12.88.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:22])=[N:11][C:12]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[NH2:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([O:16][CH:17]([CH3:21])[C:18]([N:33]([CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[CH2:32][CH2:31]2)[CH3:34])=[O:20])=[N:11][C:10]=1[CH3:22]
Reactant: CNC1CCN(CC2CC2)CC1
Reactant: Cc1nc(OC(C)C(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OC(C)C(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1N

Procedure:
The title compound was synthesized from Compound 12 and 1-(cyclopropylmethyl)-N-methyl-piperidine-4-amine in the same manner as in Example 64.
Reaction SMILES: [N:1]([C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]([CH3:15])[CH3:14])=[C:2]=[O:3].[C:16]1([S:22]([C:25]2([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[C:16]1([S:22]([C:25]2([CH2:30][NH:31][C:2]([NH:1][C:4]3[C:5]([CH:13]([CH3:15])[CH3:14])=[CH:6][CH:7]=[CH:8][C:9]=3[CH:10]([CH3:11])[CH3:12])=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCC1(S(=O)(=O)c2ccccc2)CCCC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(S(=O)(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
In a tube, under nitrogen, 157 mg (0.77 mmol) of 2-isocyanato-1,3-diisopropylbenzene is added to a solution of 168 mg (0.7 mmol) of C-(1-benzenesulfonyl-cyclopentyl)-methylamine in 3.5 ml of dichloromethane. The reaction mixture is stirred at RT for 3 h. The solvent is evaporated with a nitrogen stream. The paste obtained is taken up in heptane (5 mL) for crystallization. The white powder obtained is chromatographed on silica gel (dichloromethane then dichloromethane/methanol, 98/2, v/v). The oil obtained is crystallized from heptane. After filtration and drying, 135 mg of 1-(1-benzenesulfonylcyclopentylmethyl)-3-(2,6-diisopropyl-phenyl)-urea is obtained in the form of a white powder (m.p.=124° C., Yield=44%).
Reaction SMILES: Br[C:2]1(Br)[C:4]2([CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]2)[CH2:3]1.[PH2](O)=O>O.C(#N)C>[CH2:3]1[C:4]2([CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]2)[CH2:2]1
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OC(C)(C)C)CC2(Br)Br
Agent: O=[PH2]O
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@H]1CC2(CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To the solution of (6S)-5-tert-butyl 6-methyl 1,1-dibromo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (69 mg, 0.167 mmol) in water (1 mL) and ACN (0.5 mL) were added the hypophosphorous acid (0.078 mL, 0.96 mmol), TEA (0.27 mL, 1.92 mmol) and V-50 (4.5 mg, 0.0167 mmol). The solution was degassed and was heated at 90° C. for 15 hours. After being cooled, the solution was diluted with H2O, extracted with EtOAc (×3) and was dried (Na2SO4), concentrated. The crude product was treated under the conditions above for another 15 hours. After cooled, the solution was diluted with H2O (10 mL) and tuned to pH 4 by adding aq HCl (4 N). The aqueous phase was extracted with EtOAc (×3), dried (Na2SO4). After concentrated under vacuum, the title compound was obtained as colorless oil (20 mg, 42%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1)=[O:21]
Reactant: O=C(Cl)c1ccco1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Product: O=C(c1ccco1)N1CCC2(CC1)Cc1ccccc1O2

Procedure:
A sample of 5.8 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7, is treated with 4.8 g of 2-furoyl chloride according to the procedure of Example 18 to provide an off-white solid. This solid is purified by three recrystallizations from hexane to provide the product, 2,3-dihydro-1'-(2-furoyl)spiro[benzofuran-2,4'-piperidine], mo 102°-103° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
A mixture of 32.4 g of α,α,α-trifluoro-m-cresol, 27.62 g of p-fluoroacetophenone, 55.2 g of potassium carbonate and 250 ml of N,N-dimethylacetamide is heated under Argon overnight with vigorous stirring at 150°-155° C. After cooling the mixture is added to 500 ml of water and extracted with benzene. The combined extracts are washed with two 100 ml portions of 5% NaOH, 100 ml of H2O, 100 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a brown liquid which is distilled to give the product as a pale yellow oil (bp 122°-142° C. @ 0.2 mm).
Reaction SMILES: [F:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].Cl>C1COCC1.CCOC(C)=O>[Cl:10][C:9]1[C:2]([F:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH2:4][NH:5][C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: NCc1cccc(Cl)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(=O)NCc1cccc(Cl)c1F
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-3-chlorobenzylamine (1 g, 6.27 mmol) and TEA (1.05 mL, 7.52 mmol) in THF (20.9 mL) was added acryloyl chloride (0.61 mL, 7.52 mmol) dropwise and the reaction mixture was stirred at 23° C. for 2 h. The reaction mixture was diluted in EtOAc, HCl 1N was added and the layers separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were dried, filtered and concentrated to dryness. The crude residue was purified by flash column chromatography on silica gel (xyclohexane/EtOAc gradient 100:0 to 1:1) to give the desired material. TLC, Rf (c-hexane/EtOAc 5:5)=0.41; MS (LC/MS): 214.0 [M+H]+; tR (HPLC conditions b): 3.35 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3](CC(OCC)=O)[CH2:2]1.[CH2:13]([O:15][C:16](=[O:24])[CH2:17]C1C=CC=CN=1)[CH3:14]>>[N:1]1([CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC1CCCNC1
Reactant: CCOC(=O)Cc1ccccn1
Product: CCOC(=O)CN1CCCCC1

Procedure:
The reaction was run in the same manner as ethyl 3-piperidinylacetate, starting with commercially available ethyl-2-pyridylacetate (4.00 g; 24.5 mmol). This gave ethyl 2-piperidinylacetate (2.41 g) as a light yellow oil without further purification. MS m/z (positive ion) 172 (MH+; 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)CBr
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC(C)C

Procedure:
The title compound, MS: m/e=274.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 1-bromo-2-methylpropane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:11].[CH2:14]([N:16]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:15]
Reactant: CCNCCCN1CCc2cccc3c2C1CC3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCN1CCc2cccc3c2C1CC3)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
4-Methylbenzenesulfonyl chloride (20.9 mg, 0.11 mmol) was added to a solution of Ethyl-[3-(2,2a,4,5-tetrahydro-1H-3-aza-acenaphthyl en-3-yl)-propyl]-amine dihydrochloride (31.7 mg, 0.1 mmol) and N,N′-diisopropylethylamine (64.6 mg, 0.5 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (18.0 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C([O-])(=O)C.[Na+]>CN(C=O)C.[Pd]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:12]=[CH:11][C:10]#[N:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC#N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC=Cc1ccc(C=O)cc1
Temperature: 130 °C
Reaction time: 10 h
Yield: 72.8 %

Procedure:
A stock solution consisting of 0.0260 g (3.125×10-5 mol) of diacetato-bis-(tris-o-tolylphosphine)-palladium(II) in 50 ml of DMF is prepared under argon. 1 ml of stock solution, 4.63 g (25 mmols) of 4-bromobenzaldehyde, 1.83 ml (27.5 mmols) of acrylonitrile and 2.26 g (27.5 mmols) of anhydrous sodium acetate are added to 9 ml of DMF under argon, and the reaction mixture is stirred at 130° C. for 10 hours. 2.86 g (18.2 mmols) of 4-formylcinnamonitrile are obtained, corresponding to a yield of 73% of theory (conversion figure 29200; Pd content 0.0025 mol %).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CCOCC.O>[CH2:1]([O:3][C:4]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:36])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)OCn1c(SCc2nccc3ccsc23)nc2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)OCn1c(S(=O)Cc2nccc3ccsc23)nc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 279.6 mg (0.700 mmol) of 1-ethoxycarbonyloxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ib-11) in 30 ml of CHCl, was mixed with 226.5 mg (1.05 mmol) of 80% m-CPBA at -10° to -15° C., and stirred for 1 hr. The mixture was treated with 3 ml of saturated aqueous NaHCO3 and 0.6 ml of 10% aqueous sodium sulfite, and after bringing back to room temperature, the solution was mixed with water and extracted with CHCl3. After drying CHCl3 layer over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, whereby brown viscous liquid was obtained. After silica gel column chromatography, the crystals were dispersed with 3 ml of ether, followed by filtration and washed with ether, whereby 158.0 mg (Yield : 54.3%) of the objective compound (Ic-17), 1-ethoxycarbonyloxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl]methylsulfinyl]benzimidazole was obtained as crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:16]P(OCC)(OCC)=O)=[N:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:33]2[N:37]3[N:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:36]3=[N:35][C:34]=2[CH:48]=O)[CH:30]=[CH:31][CH:32]=1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:33]2[N:37]3[N:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:36]3=[N:35][C:34]=2/[CH:48]=[CH:16]/[C:10]2[CH:9]=[CH:8][C:7]3[C:6]([C:4]([OH:3])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cccc2nc(CP(=O)(OCC)OCC)ccc12
Reactant: COc1cccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)c1
Product: COc1cccc(-c2c(/C=C/c3ccc4c(C(=O)O)cccc4n3)nc3c(N4CCOCC4)ccnn23)c1

Procedure:
Compound 73d (53 mg, 0.15 mmol) was reacted under Horner-Emmons coupling conditions with compound 77a (51 mg, 0.15 mmol) using the procedures described in Example 20, Step A to afford compound 77b. Mass spectrum (LCMS, ESI pos.) Calcd. For C29H25N5O4 508.2 (M+H). found 508.2.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:9]=[CH:8]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26]Cl>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][N:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:9]=[CH:8]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1nc[nH]c1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(Cc2ccc(Cl)c(Cl)c2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Potassium t-butoxide (10.9 g) was added with stirring to a solution of diethyl imidazole-4,5-dicarboxylate (20 g, described by Jones, J.A.C.S. 74, 1085 (1952)) in dry dimethylformamide (300 ml) at room temperature and the mixture was stirred for 40 minutes. 3,4-Dichlorobenzyl chloride (20.4 g) was added and the mixture was heated at reflux for 11 hours. The cooled reaction mixture was poured into ice-water (500 ml) and extracted with chloroform (2×200 ml). The combined extracts were washed with water (3×300 ml), dried over magnesium sulphate, filtered and evaporated to dryness. The solid residue was crystallised from methanol (100 ml) to give diethyl 1-(3,4-dichlorobenzyl)imidazole-4,5-dicarboxylate, m.p. 105°-107° C., (13 g) as a colourless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C:7]([CH3:10])([CH3:9])[NH:6][C:5]1=[O:11].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][C:7]([CH3:9])([CH3:10])[NH:6][C:5]1=[O:11])(=[O:21])=[O:20]
Reactant: CC1(C)CN(CCO)C(=O)N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CN(CCOS(C)(=O)=O)C(=O)N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(2-hydroxyethyl)-4,4-dimethylimidazolidin-2-one (5.9 g, 37 mmol) and pyridine (3.6 mL, 44.4 mmol) in 150 mL of anhydrous dichloromethane was added methanesulfonyl chloride (3.3 mL, 43 mmol). The reaction was stirred at room temperature for 20 hours, then diluted with 100 mL of dichlormethane and washed twice with 40 mL of 1 N HCl and once with brine. The organic fraction was dried over sodium sulfate and concentrated in vacuo to 3.54 g of the desired product as white solid. 1H NMR (CDCl3, 400 MHz) δ 1.33 (s, 6H), 3.06 (s, 3H), 3.23 (s, 2H), 3.54-3.57 (t, J=5.2, 2H), 4.36-4.39 (t, J=5.2 Hz, 2H); LRMS (ESI/APCI) m/z 237 [M+H]+.