Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[N:9]1[CH2:15][C:16]1[CH:21]=[C:20]([C:22](OC)=[O:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]>C1COCC1.[Cl-].[Na+].O>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[N:9]1[CH2:15][C:16]1[CH:21]=[C:20]([CH2:22][OH:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2C(C)CCCC2C)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2CN2C(C)CCCC2C)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 69.9 %

Procedure:
LAH (1.0 M solution in THF) (0.088 mL, 0.088 mmol) was added slowly to a solution of 66.69B (0.034 g, 0.088 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 25 minutes and then was poured into brine (2 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:1 EtOAc/hexane) and gave 66.69C (22 mg) as a colorless oil.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[C:3](=O)[CH2:4][CH2:5]2.[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][SH:11]>C(OCC)C.C(N(CC)CC)C>[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][S:11][C:2]1[C:6](=[O:1])[CH2:5][CH2:4][CH:3]=1
Reactant: O=C1CCC2OC12
Reactant: CCCCCC(C)(O)CS
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCC(C)(O)CSC1=CCCC1=O
Yield: 69.3 %

Procedure:
2,3-Epoxycyclopentanone (1.47 g) and 2.0 g of 2-hydroxy-2-methylheptyl mercaptan were dissolved in 30 ml of diethyl ether, and 30 drops of triethylamine were added. They were reacted at room temperature for 2 hours. The solvent was distilled off from the reaction mixture to afford 4.01 g of a crude product. The crude product was chromatographed on a dry column with cyclohexane/ethyl acetate (=8/2) to afford 2.07 g of 2-(2-hydroxy-2-methylheptylthio)cyclopent-2-en-1-one in a yield of 69%. The product had the following characteristics.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CN(C=[O:27])C>FC(F)(F)C([O-])=O.[Ag+]>[OH:27][CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
To a stirred solution of ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (50 g, 0.127 moles, 1 eq) in dry DMF (300 ml) under a positive N2 flow was added silver trifluoroacetate (42.02 g, 0.191 moles, 1.5 eq) all at once as a solid. This was stirred at room temperature for 3.5 hrs. The reaction was partitioned between ethyl ether (1.5 L) and water (500 ml). The phases were separated and the organic phase was washed twice with water (500 ml). After separation of the phases, the organic fraction was dried with Na2SO4, filtered and concentrated in vacuo. The crude trifluoroacetate product was used without characterization. Ethanol (300 ml) was added and the reaction was refluxed for 10 hrs. After cooling to room temperature the ethanol was removed in vacuo to yield 42 g (100%) of the title compound. The product was used without purification.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:16])[CH2:6][C:7]#[C:8][CH2:9][O:10][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])(=[O:3])[CH3:2].[H][H]>[Ni].C(O)C>[C:1]([O:4][C@H:5]([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])(=[O:3])[CH3:2]
Reactant: CCOC(C)OCC#CC[C@@H](C)OC(C)=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(C)OCCCC[C@@H](C)OC(C)=O
Yield: 101.3 %

Procedure:
Alternatively, hydrogenation was run using a mixture of Raney nickel (10 g of slurry) and 5-(R)-acetoxy-1-ethoxyethoxy-2-hexyne (40 g, 0.17 mole) in ethanol (100 ml). The mixture was shaken with hydrogen gas (60 psi) on a Parr shaker for 5 hours. After filtration of the catalyst, the filtrate was evaporated under vacuum. Residual oil was dissolved in hexanes (100 ml) and the mixture was filtered to remove suspended particles. Evaporation of the solvent under reduced pressure provided 5-(R)-acetoxy-1-ethoxyethoxyhexane (40 g).
Reaction SMILES: N[C@H](C(O)=O)CCCNC(=N)N.[CH2:13]([N:15]([C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])[CH3:14].C(O)[C@@H]1O[C@H](O[C@]2(CCl)O[C@H](C[Cl:54])[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H](O)[C@H]1Cl>O>[ClH:54].[CH2:13]([N:15]([C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:22])[NH2:23])[CH3:14]
Reactant: OC[C@@H]1O[C@H](O[C@]2(CCl)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H](O)[C@H]1Cl
Agent: CCCCCCCCCCCC(=O)N(CC)[C@@H](CCCNC(=N)N)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Product: Cl
Reaction time: 0.33 h

Procedure:
A series of films containing varying amounts of the arginine derivative compound they hydrochloride salt of ethyl lauroyl arginine designated Compositions A, B and C were prepared by using the ingredients listed in Table VI below. In preparing the film, the hydroxyl propylmethylcellulose polymer ingredient (Methocel E5LV) and carrageenan as added at a temperature of 70° C. to 90° C., to half the amount of total deionized water used, and the solution stirred for 20 minutes at a slow speed using IKA Labortechnik Model RW20DZMixer. The remaining amount of water maintained at room temperature (21° C.) was then added and the mixing continued for 40 minutes. To this solution was added the corn starch ingredient (Cerestar Polar Tex Instant 12640) and the mixture stirred for an additional 20 minutes until the starch was completely dispersed and a homogenous mixture was formed. To this mixture was added sucralose and mixed for 10 minutes after which the emulsifier Tween 80 was added and mixed for an additional 5 minutes. Thereafter, flavor was thoroughly mixed for an additional 30 minutes to form a flurry emulsion to which as a final step the hydrochloride salt of ethyl lauroyl arginine HCL (ELAH) dispersed in canola oil was slowly added until evenly dispersed in the film ingredient slurry. The emulsion was then cast on a polyethylene coated paper substrate and dried in a convection oven at 110° C. to form a solid thin (30 to 60 μm thick) film.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:33]=[CH:32][C:10]([CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)=[CH:9][CH:8]=1)=[O:5])C.S(=O)(=O)(O)O.O>CS(C)=O>[C:4]([CH2:6][C:7]1[CH:33]=[CH:32][C:10]([CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 93.6 %

Procedure:
3-(4-Ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (110 mg, 0.25 mmol, prepared in Example 32) was dissolved in DMSO (3 ml) at 50° C., admixed with 50% sulfuric acid (2 ml) at 100° C., and then heated under reflux for 1 hour. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (96 mg, 93%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:15]([O:17]C)=O)=[CH:3][CH:2]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23].N#N>C(O)CC>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:15]([C:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=[CH:2][CH:3]=1)=[O:17]
Reactant: COC(=O)c1cccc2cc3ccccc3nc12
Reactant: CN(C)CCN
Agent: N#N
Solvent: CCCO
Product: CN(C)CCNC(=O)c1cccc2cc3ccccc3nc12
Yield: 64.9 %

Procedure:
A solution of methyl acridine 4-carboxylate (1.83 g, 7.72 mmol) and N,N-dimethylethylenediamine (3.40 g, 38.6 mmol) in n-propanol (80 ml) was flushed with N2, and the mixture was heated at reflux for three days under N2. Solvent was then removed under reduced pressure, and the residue was partitioned between CH2Cl2 (100 ml) and 1M Na2CO3 (100 ml). The organic layer was evaporated and the residue chromatographed on alumina, eluting with CH2Cl2 /MeOH (199:1) to give N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) (1.47 g, 61%), mp (dihydrochloride salt from MeOH/EtOAc) 162-165° C.
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3](B(O)O)[CH:2]=1.Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24]2.C(=O)([O-])[O-].[Na+].[Na+].Cl>ClCCl.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.COCCOC>[CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24]3)[CH:2]=1
Reactant: OB(O)c1ccc2c3c(cccc13)-c1ccccc1-2
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Oc1ccc2cc(-c3ccc4c5c(cccc35)-c3ccccc3-4)ccc2c1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
Under the atmosphere of argon, 2.7 g of fluoranthene-3-boronic acid, 2.0 g of 6-bromo-2-naphthol, 0.31 g of tetrakis(triphenylphosphine)palladium (0), 27 mL of 1,2-dimethoxyethane and 13.5 mL of an aqueous 2M sodium carbonate solution were placed in a flask, and the resulting mixture was stirred under reflux while heating for 4 hours. After cooling to room temperature, 2M hydrochloric acid was added to the reaction solution to allow it to be acidic, and the reaction solution was extracted with dichloromethane. An aqueous phase was removed and an organic phase was washed with saturated saline, and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, residues were dispersed and washed with dichloromethane, whereby 2.75 g (yield 89%) of 6-(fluoranthen-3-yl)-2-naphthol as an intended product was obtained.
Reaction SMILES: CO[CH:3]=[N:4][C:5]1[C:10]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:16].[OH-].[Na+].C(OCC)(=O)C.CCCCCC>CS(C)=O.[Cl-].[NH4+]>[Cl:16][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[NH:4][CH:3]=[C:11]2[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COC=Nc1c(Cl)cccc1CS(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CS(=O)(=O)c1c[nH]c2c(Cl)cccc12

Procedure:
The crude N-(2-chloro-6-methanesulfonylmethyl-phenyl)-formimidic acid methyl ester of Step 5 was dissolved in dry DMSO (20 ml) and treated with 2 g powdered sodium hydroxide. The reaction mixture was vigorously stirred at room temperature for 1 h after which tlc (1:1 ethyl acetate:hexane, followed by 3:7) showed a single principal product, somewhat less polar than starting material. The reaction mixture was diluted with 100 ml of a 10% ammonium chloride solution and extracted with ethyl acetate, washed twice with water, and the crude solution was passed through a short silica gel column and eluted with ethyl acetate to remove colored impurities. The resulting crystalline 7-chloro-3-methanesulfonyl-1H-indole weighed 2.21 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Solvent: CCO
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
200 parts of ethanol is slowly added to a solution, heated to 70°C, of the diazonium salt prepared as described in Example 1 from 412 parts of 3,5-dichloroanthranilic acid; elimination of nitrogen immediately takes place with evolution of heat. The mixture is stirred for another 15 minutes and 350 parts (92% of theory) of 3,5-dichlorobenzoic acid having a melting point of 176° to 178°C is isolated as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([F:15])[CH:3]=1.[Cl-].[C:17]([O:21][C:22](=[O:25])[CH2:23][Zn+])([CH3:20])([CH3:19])[CH3:18].CCOCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[F:15][C:4]1[CH:3]=[C:2]([CH2:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:25])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1
Reactant: Fc1cc(-c2ccc(Br)cc2F)ccn1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a sealed tube were added 4-(4-bromo-2-fluorophenyl)-2-fluoropyridine 207-3 (210 mg, 0.76 mmol), 0.5 M (2-tert-butoxy-2-oxoethyl) zinc(II) chloride 86-5 in ether (2.3 mL, 1.14 mmol), Pd(dba)2 (22 mg, 0.04 mmol), Q-phos (54 mg, 0.07 mmol) and THF (5 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 100° C. for 1 hour. After cooling to room temperature, all the solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give tert-butyl 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetate 207-5. MS m/z 306.2 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=[CH:15][C:16]2N(O)N=[N:19][C:17]=2C=1.C(N)CC.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:19][CH2:17][CH2:16][CH3:15])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: On1nnc2ccccc21
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCCN
Product: CCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.3 %

Procedure:
4-Azidobenzoic acid (866 mg, 5.20 mmol), HOBt (710 mg, 5.20 mmol, 1.0 eq.) and n-propylamine (0.568 ml, 7.60 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.22 g, 6.24 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid (2.0 g, including residual solvent).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[NH:17]1[CH:21]=[CH:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:2][C:11]2[CH:6]=[CH:7][C:8]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)=[CH:9][CH:10]=2)[N:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1n[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4-oxo-1,4-dihydrocinnoline-3-carboxylate (427 mg, 1.96 mmol) was dissolved in degassed N,N-dimethylformamide (5 mL) and treated with 1-[4-bromomethyl)phenyl]-1H-pyrazole (510 mg, 2.15 mmol, 1.1 equiv) and potassium carbonate (325 mg, 2.35 mmol, 1.2 equiv). The mixture was stirred under nitrogen at ambient temperature for 18 hours and then partitioned between water and ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gradient gel chromatography (100:0 to 90:10; chloroform:methanol), providing the titled compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:30]#[N:31])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:30]#[N:31])[CH2:20][CH2:21]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3C#N)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(F)ccc1OC1CCN(CC[C@H]2CC[C@H](N)CC2)CC1

Procedure:
The title compound was prepared analogously to example 1 (1.4) starting from Trans(4-{2-[4-(2-Cyano-4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester and trifluoroacetic acid MS (m/e): 346.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:15][C:16]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:17])([CH2:11][C:12]([CH3:14])=[CH2:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[I:27]I>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:10])[CH2:11][C:12]([CH2:14][I:27])([CH3:13])[S:17][C:16]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:15]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: II
Reactant: C=C(C)C[C@](C)(NC(=S)NC(=O)c1ccccc1)c1ccc(F)c(Br)c1
Solvent: ClCCl
Product: CC1(CI)C[C@@](C)(c2ccc(F)c(Br)c2)N=C(NC(=O)c2ccccc2)S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a 0° C. solution of (S)-N-(2-(3-bromo-4-fluorophenyl)-4-methylpent-4-en-2-ylcarbamothioyl)benzamide (1.3 g, 3.0 mmoles, 1.0 equiv) in dichloromethane (40 mL) is added iodine (1.5 g, 5.9 mmoles, 2.0 equiv). The reaction is stirred at 0° C. for 1 h and gradually warmed to room temperature. The reaction mixture is quenched with saturated aqueous sodium thiosulfate. The aqueous layer is extracted with dichloromethane. The combined organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (82% yield): MS (m/z): 561, 563 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:3][CH:4]1[CH2:8][CH2:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CCC(OCc2ccccc2)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Sodium hydride (60% oil dispersion, 2.1 g, 53 mmol) was added in portions to a solution of diethyl 3-hydroxycyclopentane-1,1-dicarboxylate 27 (11 g, 48 mmol), benzyl bromide (9.7 g, 53 mol), and n-tetrabutylammonium iodide (100 mg) in dry DMF (50 mL) at 25° C. (Step 25). The mixture was stirred for 1 hr at 65° C., poured onto ice and then extracted with ether (2×50 mL). The ##STR8## combined either extract was washed with water (3×50 mL) and driedover MgSO4. Chromatography on silica gel (10:90 ethyl acetate/hexane, Rf=0.38) afforded 11.6 g (75%) of the benzyl ether 28; 1H NMR (CDCl3) δ 1.3 (t, J=7.2 Hz, 6H, CH3), 1.7-2.7 (m, 6H, CH2), 4.2 (q, J=7.2 Hz, 4H, O=COCH2), 4.1 (m, 1H, O--CH), 4.6 (s, 2H, O--CH2), 7.3 (s, 5H, phenyl).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH2:10])[CH3:9])=[CH:3][CH:2]=1.[C:26](OCC)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O-:33])=[O:32]>>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH:10][C:26]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[CH3:9])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCC(=O)[O-]
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Product: C[C@H](NC(=O)CCCCC(=O)O)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1

Procedure:
Compounds of Examples 67 to 71 were prepared in the same manner as in Example 66 except that (1S, 2S)-2-(4-biphenylyl)-3-(3,4-dichlorophenyl)-1-methylpropylamine and monoethyl adipate used as the starting materials in the above reaction were changed to the respective corresponding amine compounds and/or monoester derivatives.
Reaction SMILES: O/[CH:2]=[C:3](/[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)\[C:4]([O:6]C)=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)(C)C>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][C:3]2[C:4](=[O:6])[NH:17][C:18](=[S:19])[NH:20][CH:2]=2)=[CH:14][N:13]=1
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Reactant: NC(N)=S
Solvent: CC(C)O
Product: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Temperature: 83 °C
Yield: 39.8 %

Procedure:
A mixture of (Z)-methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (10 g, 42.0 mmol) and thiourea (6.39 g, 84 mmol) in isopropanol (200 mL) was heated at 83° C. overnight. After removing the solvent, the residue was dissolved in water, washed with diethyl ether twice and acidified with AcOH to pH=4.5. The resulting solid was filtered and concentrated in vacuo to afford the title compound (4.4 g, 16.70 mmol, 39.8% yield) as yellow solid. LCMS: rt=1.31 min, [M+H+]=251
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]([CH3:12])=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:13])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18](S(C)(=O)=O)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([O:13][C:4]2[CH:5]=[CH:6][C:7]3[S:11][CH:10]=[C:9]([CH3:12])[C:8]=3[C:3]=2[CH:1]=[O:2])[N:17]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1csc2ccc(O)c(C=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C=O)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture comprising 2.1 g of 4-formyl-5-hydroxy-3-methylbenzothiophene, 2.4 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.8 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 70° C. for 3 hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 3.1 g (yield: 86%) of the desired compound.