Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:5][CH2:6][OH:7].N1C=CN=C1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].CN(C)C=O>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[CH2:5][CH2:6][O:7][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: COC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
In a flask under argon was placed (S)-2-benzyloxycarbonylamino-4-hydroxy-butyric acid methyl ester (535 mg, 2.0 mmol) in tetrahydrofuran (5 mL). To this mixture was then added imidazole (330 mg, 4.8 mmol) and t-butyl dimethyl silyl chloride (360 mg, 2.4 mmol) and within a minute solids started to appear and N,N-dimethylformamide (1 mL) was added to solubilize the material. The mixture was stirred for 16 h at 25° C. and then diluted with water (50 mL) and the aqueous layer extracted with diethyl ether (2×50 mL) dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes) afforded (S)-2-benzyloxycarbonylamino-4-(t-butyl-dimethyl-silanyloxy)-butyric acid methyl ester (478 mg, 63%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH3:11][C:12](=O)[C:13](=O)[CH3:14].C([OH:21])CCC>CCOCC>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([C:2](=[O:21])[N:7]=1)=[N:10][C:13]([CH3:14])=[C:12]([CH3:11])[N:9]=2
Reactant: Cc1nc(N)c(N)c(Cl)n1
Reactant: CC(=O)C(C)=O
Reactant: CCCCO
Solvent: CCOCC
Product: Cc1nc(=O)c2nc(C)c(C)nc2[nH]1
Temperature: 77.5 °C
Reaction time: 1 h

Procedure:
A mixture of 6-chloro-2-methylpyrimidine-4,5-diamine (3.2 g, 20 mmol) and 2,3-butanedione (3.6 g, 42 mmol) in n-butanol (40 mL) was stirred at 75-80° C. for 1 h. After cooling, the reaction was diluted with Et2O (50 mL) and the solid collected by suction filtration. This was dried in vacuo affording, 2,6,7-trimethylpteridin-4(1H)-one (3.9 g), as a gold powder which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:11]([C:9]1[N:10]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[C:6]2[N:7]([C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(NCCN)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cn2c(=O)[nH]nc2c(NCCNS(=O)(=O)c2ccccc2)n1

Procedure:
A solution of 50 mg of 8-(2-amino-ethylamino)-6-tert-butyl-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one, 97 mg of phenylsulfonyl chloride and 61 mg of diisopropylethylamine in DMF (1.0 mL) was stirred at ambient temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with water and then sat. sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to provide the title compound as a white solid. MS (M+H+)=391.4.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:12]>>[NH2:12][C@H:2]([C:1]([OH:11])=[O:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 40 h

Procedure:
A microorganism was grown in the same manner as described in Section 11 above. From 30 g of the collected and washed cells, L-phenylalanine ammonia-lyase was extracted and purified according to the same procedure as described in Section 11 above. The purified L-phenylalanine ammonia-lyase was dissolved in 20 ml of a NH4OH—(NH4)2SO4 buffer solution (pH 10.0) containing 8M NH The resulting solution was placed in a dialysis tube (a product of Union Carbide Corp.), which was sealed at both ends. This tube was immersed in a reaction mixture prepared by adding 4 g of cinnamic acid to 200 ml of a NH4OH—(NH4)2SO4 buffer solution (pH 10.0) containing 8M NH3. The reaction was carried out at 30° C. for 40 hours with gentle stirring of the outer liquid. After that time, the procedure of Section 13 was repeated to obtain 2.0 g of L-phenylalanine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:15][N:16]1[CH2:20][CH:19]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:18][C:17]1=[O:28].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH:13]=[N:15][N:16]3[CH2:20][CH:19]([CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[O:18][C:17]3=[O:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: NN1CC(CN2CCCCC2)OC1=O
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Agent: Cl
Product: O=C1OC(CN2CCCCC2)CN1N=Cc1ccc(-c2ccc(Cl)cc2)o1

Procedure:
5-(4-Chlorophenyl)-2-furancarboxaldehyde [prepared as described in U.S. Pat. No. 4,882,354, to Huang et al. (assigned to Norwich Eaton Pharmaceuticals, Inc.,) issued Nov. 21, 1984; see cols. 7 & 8, hereby incorporated by reference] (3.92 g, 19.0 mmole) and 3-amino-5-(1-piperidinyl)methyl-2-oxazolidinone (3.78 g, 19.0 mole)[(prepared as described in U.S. Pat. No. 2,802,002 to Gever, (assigned to Norwich Eaton Pharmaceuticals, Inc. issued Aug. 6, 1957, see Example I, Part A, hereby incorporated by reference herein) in 150 ml of alcohol is treated with 3 ml of concentrated hydrochloric acid (pH ca. 3). The reaction mixture is stirred and heated at reflux for 2.5 hours. The mixture is chilled and filtered to give crude 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-5-(1-piperidinylmethyl)-2-oxazolidinone hydrochloride, which is purified by one recrystallization from nitromethane (activated charcoal) yielding 3.2 g.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=2[CH:5]=[C:4]([NH2:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:10]2[O:9][C:8]([Si:11]([CH3:12])([CH3:14])[CH3:13])=[CH:7][C:6]=2[CH:5]=[C:4]([NH:15][S:25]([C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[O:17][CH3:16])(=[O:27])=[O:26])[CH:3]=1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: C[Si](C)(C)c1cc2cc(N)cc(Br)c2o1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(Br)c2oc([Si](C)(C)C)cc2c1
Yield: 99.4 %

Procedure:
Coupling of the amine (4.5 g, 15.9 mmol) from Step 1 with 2-methoxy-5-methylphenylsulfonyl chloride (3.5 g, 15.9 mmol) in dichloromethane (200 mL) using pyridine as a base (3.2 mL, 40 mmol) required 2.5 hours at ambient temperature. Washing the resulting mixture with water, drying and concentration yielded 7.4 g (100%) of N-(7-bromo-2-trimethylsilanyl-benzofuran-5-yl)-2-methoxy-5-methyl-benzenesulfonamide as a dark orange solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:30]=[C:31]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C@@H:47]([C:61]([OH:63])=O)[CH2:48][C:49]3[CH:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[C:52]([NH2:59])=[C:51]([Cl:60])[CH:50]=3)=[O:45])[CH2:40][CH2:39]2)[CH2:36][CH2:35][C:34]2[CH:64]=[CH:65][CH:66]=[CH:67][C:33]=2[NH:32]1.[NH:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:78][CH2:77][CH2:76][C@@H:75]2[C:79]([O:81][CH2:82][CH3:83])=[O:80])[CH2:70][CH2:69]1>CN(C=O)C>[O:30]=[C:31]1[N:37]([CH:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C@H:47]([CH2:48][C:49]3[CH:54]=[C:53]([C:55]([F:57])([F:58])[F:56])[C:52]([NH2:59])=[C:51]([Cl:60])[CH:50]=3)[C:61]([N:68]3[CH2:69][CH2:70][CH:71]([N:74]4[CH2:78][CH2:77][CH2:76][C@@H:75]4[C:79]([O:81][CH2:82][CH3:83])=[O:80])[CH2:72][CH2:73]3)=[O:63])=[O:45])[CH2:42][CH2:43]2)[CH2:36][CH2:35][C:34]2[CH:64]=[CH:65][CH:66]=[CH:67][C:33]=2[NH:32]1
Reactant: CCOC(=O)[C@H]1CCCN1C1CCNCC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
64 mg (0.20 mmol) TBTU and 28 μL (0.20 mmol) triethylamine were added to a solution of 100 mg (0.18 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF and stirred for 10 min at RT. 45 mg (0.20 mmol) ethyl (R)-1-piperidin-4-yl-pyrrolidine-2-carboxylate were added to the reaction mixture and this was shaken overnight at RT. After filtration through a syringe filter the reaction solution was purified by HPLC without further working up. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][O:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)[CH3:14]
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ccc(Cl)c2cccnc12)OCC

Procedure:
180 g of 5-chloro-8-hydroxyquinoline, 237 g of 2-bromoacetaldehyde diethyl acetal and 200 g of potassium carbonate are stirred for 4 h at 120° C. in 800 ml of dimethylformamide. After cooling, the mixture is poured into 2.5 liters of water, and the product is filtered off under suction and dried in vacuo, melting point 51°-53° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O[NH:53][C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)=[NH:55]>CN(C=O)C.O1CCOCC1>[N:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[C:54]1[N:55]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:9][N:53]=1
Reactant: O=C(O)c1ccccn1
Reactant: N=C(NO)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: c1ccc(-c2noc(-c3ccccn3)n2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
To a solution of the appropriate pyridine carboxylic acid (1 eq.) and DIPEA (3 eq.) in DMF is added PyBOP (1.05 eq.) at 0° C. The mixture is stirred for 15 min at 0° C. The appropriate N-hydroxy pyridine-carboxamidine (1.05 eq.) is added and stirring is continued for 1 to 8 h at 0° C. to rt. The reaction is monitored by LC-MS. Upon complete conversion, the reaction is quenched with water and sat. aq. NaHCO3-solution. The mixture is extracted with diethyl ether, EA or DCM. The org. extracts are dried over MgSO4, filtered and evaporated to give the crude hydroxyamidine ester. This material is dissolved in dioxane and the resulting solution is stirred at 70-90° C. for 4 to 24 h. The solvent is removed in vacuo and the crude product is purified by either CC on silica gel, chromatography on prep. TLC plates or by HPLC to give the desired 3,5-dipyridyl-[1,2,4]oxadiazol in 30-80% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[C:13](Cl)(=[O:17])C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:13]([C:7]1[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9][C:8]=1[CH3:10])=[O:17])([CH3:25])[CH3:24]
Reactant: COc1ccc2cc(C)oc2c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)N
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(C(=O)NC(C)C)c(C)oc2c1
Yield: 71 %

Procedure:
This material was prepared from 6-methoxy-2-methylbenzofuran 12a (500 mg, 3.1 mmole) by acylation with oxalyl chloride in the presence of AlCl3, followed by treatment with isopropylamine in a manner as previously described for example 1c to give 540 mg (71%) of an off-white solid. 1H NMR (DMSO-d6) δ 7.80 (1H, d, J=7.8 Hz), 7.50 (1H, d, J=8.6 Hz), 7.14 (1H, d, J=2.2 Hz), 6.89 (1H, dd, J=8.6, 2.2 Hz), 4.09 (1H, m), 3.76 (3H, s), 2.56 (3H, s), 1.16 (6H, d, J=6.6 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@@H:7]([OH:24])[C:6]1=[O:25].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C1C=CC=CC=1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C@@H:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@@H:7]([O:24][C:35](=[O:36])[NH:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[C:6]1=[O:25]
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)Nc2ccc(F)cc2)cc1
Reaction time: 7 h

Procedure:
10 Grams (0.268 mole) of the compound prepared under (A) were dissolved in 100 ml of anhydrous benzene and subsequently added with 3.02 ml (0.0269 mole) of 4-fluoro-phenylisocyanate, then the resulting solution was stirred on an oil bath at 30°-35° C. for 7 hours. After evaporating the solvent, the residue was taken up with anhydrous diethyl ether and the obtained white precipitate was recovered by filtration.
Reaction SMILES: [CH2:1]([Br:4])[C:2]#[CH:3].[Na].[CH:6](=[N:13][OH:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[Br:4][CH2:1][C:2]1[O:14][N:13]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: C#CCBr
Agent: [Na]
Solvent: ClCCl
Product: BrCc1cc(-c2ccccc2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of propargyl bromide (1.51 ml, 20 mmol) in dichloromethane (15 ml) and aqueous sodium hyopchlorite (22.4 ml, 10%, 30 mmol) at 0° C. was added dropwise with stirring benzaldoxime (2.42 g, 20 mmol) in dichloromethane (15 ml). When addition was complete the ice bath was removed and the reaction stirred for a further 2 h. The organic layer was separated and the aqueous layer washed with dichloromethane (2×20 ml) then the combined organic layers dried (MgSO4). Solvent removal under reduced pressure gave a solid which was recrystallised from 40°-60° C. petroleum ether fraction to give the desired isoxazole (2.64 g, 11.1 mmol, 55%); mp 82°-3° C., δH (CDCl3) 4.40 (2H, s, CH2 --Br), 6.50 (1H, s, CH-4), 7.3-7.9 (5H, m, C6H5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12](OCC)=[O:13].C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[CH2:11][S:9][C:3]=2[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Br)cc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSc2cc(Br)ccc2N1
Yield: 81.9 %

Procedure:
A mixture of 2-amino-5-bromo-benzenethiol (20 g, 0.1 mol), ethyl bromoacetate (19 g, 0.1 mol), and sodium bicarbonate (8.8 g, 0.1 mol) in DMF (200 ml) was heated to reflux for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated to obtain the crude 7-bromo-4H-benzo[1,4]thiazin-3-one (20 g, 82%). A small portion of sample was recrystallized from ethanol to afford pure 7-bromo-4H-benzo[1,4]thiazin-3-one: mp 212-213° C.; MS (EI) m/z 243/245 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:24])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>O1CCOCC1.O>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:24])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]([CH3:12])[CH3:11])[CH2:5][CH2:6]2)=[CH:35][CH:34]=1
Reactant: CCCCOC(C(=O)NC1CCNCC1)(c1ccccc1)C(C)C
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCOC(C(=O)NC1CCN(Cc2ccc(OC)cc2)CC1)(c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(4-Piperidinyl)-2-butoxy-3-methyl-2-phenylbutanamide (invention compound, Compound No. 27) (4.5 g) was dissolved in dioxane (25 ml) and water (25 ml). To the resulting solution, potassium carbonate (0.7 g) and 4-methoxybenzyl chloride (0.8 g) were added, followed by stirring at room temperature for 2 days. To the reaction mixture, was added water (40 ml). The resulting mixture was extracted with an ethyl acetate. The extract was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by a silica gel column to obtain the invention compound (Compound No. 29, 0.60 g, 26.4%) as a colorless oil.
Reaction SMILES: [CH3:1][Li].[CH:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1.BrC[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCCC1>[C:15]([CH:14]([CH2:13][CH2:12][CH2:11][CH3:10])[CH2:1][C:4]1[CH:3]=[CH:7][CH:6]=[C:5]=1)([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCCCCBr
Reactant: [Li]C
Reactant: C1=CCC=C1
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC1=C=CC=C1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of CH3Li(1.95 M, 0.65 mole, 333 ml.) was added under nitrogen to a magnetically stirred solution of freshly distilled cyclopentadiene (60 ml., 0.68 mole) in dry tetrahydrofuran (THF) (550 ml.) with ice bath cooling. To this resulting white suspension ethyl 7-bromoheptanoate (120 g., 0.54 mole) was added dropwise over a period of one-half hour. The mixture was allowed to warm to room temperature and stirred for 3 hours. The resulting clear solution was poured into water and extracted with ether (3 1). The extract was washed twice with water, one with saturated brine, dried (MgSO4) and evaporated at room temperature. This process gave almost pure 2-carboethoxyhexyl-2-cyclopentene-1,4-diene (I).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]1.[CH2:11](O)[CH2:12][OH:13].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]1[CH2:12][O:13][C:2]2([CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]2)[O:1]1
Reactant: N#CCN1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCN1CCC2(CC1)OCCO2
Yield: 97.1 %

Procedure:
A solution of 10.0 g of 4-oxo-1-piperidineacetonitrile, 22.6 g of ethylene glycol and 0.62 g of anhydrous p-toluenesulfonic acid in 100 ml of toluene was refluxed for 6 hours with Dean-stark dehydrating apparatus. After cooling, the reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was dried, and the solvent was evaporated to give a pale brown liquid. The resulting liquid was purified by alumina column chromatography using ethyl acetate—n-heptane (1:3) as an eluting solvent to give 12.8 g of a colorless liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O:21][CH2:22][CH3:23])(=[O:20])/[CH:13]=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)CC(NCCC[Si](OC)(OC)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl N-(3-trimethoxysilylpropyl)aminosuccinate was prepared as follows: 51.0 g of 3-aminopropyltrimethoxysilane (Silquest® A-1110, GE Advanced Materials) were introduced as an initial charge, with thorough stirring, 49.0 g of diethyl maleate were added slowly at room temperature and the mixture was stirred at room temperature for 8 hours.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15](I)=[CH:14][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:23][N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:25]3[N:24]([CH3:23])[CH:28]=[CH:27][CH:26]=3)=[CH:14][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccn3C)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-ethyl-3-(7-iodo-5-pyridin-3-yl-benzothiazol-2-yl)-urea (0.10 g, 0.24 mmol) in DMF (2.0 mL) was added N-methyl-2-tributylstannyl-1H-pyrrole (0.18 g, 0.47 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.027 g, 0.024 mmol). The reaction mixture was again degassed for half an hour and then heated at 120° C. for 20 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off, added water and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified by prep-HPLC to provide the title compound as off white solid (0.005 g, 6.0%).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]#[N:18])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[CH:20]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH2:16][C:17]#[N:18])=[CH:14][C:9]=2[CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:20][C:21]=1[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1Cc1cccc2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(O)c(Cc2cccc3ccccc23)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
2.55 ml (2.55 mmol, 3.00 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 367.3 mg (0.85 mmol) 3-(2-Isobutyl-4′-methoxy-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)propionitrile (65) in 40 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 2 h at 0° C. and then for 14 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 334.9 mg (0.80 mmol, 93.91%) 3-(4′-Hydroxy-2-isobutyl-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)-propionitrile (66) as an oily white solid. Rf (hexanes/EtOAc (2+1))=0.36. 1H-NMR (500 MHz, CDCl3): δ=0.56 (d, 6H, J=6.62 Hz, 2*CH3), 1.48 (m, 1H, CH), 2.26 (d, 2H, J=7.41 Hz, CH2), 2.58 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.89 (t, 2H, J=7.41 Hz, CH2CH2CN), 4.44 (s, 2H, CH2Naphthyl), 4.80 (s, br., 1H, OH), 6.83 (d, 1H, J=8.20 Hz), 6.85 (d, 1H, J=2.05 Hz), 6.96-7.00 (m, 3H), 7.04 (d, 1H, J=7.41 Hz), 7.25 (m, 1H), 7.36 (m, 1H), 7.44 (m, 2H), 7.73 (d, 1H, J=8.20 Hz), 7.83 (m, 1H), 8.03 (m, 1H). MS (EI): m/z=419 (2), 335 (14), 293 (22), 253 (8), 161 (18), 160 (100), 91 (18). HR-MS (EI): Calcd. for C30H29NO: 419.224914. Found: 419.225626.