Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O.[Cu]=O>[N:12]1[N:13]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[N:14]=[CH:15][CH:16]=1
Reactant: c1c[nH]nn1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCc2cc(-n3nccn3)ccc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 54.4 %

Procedure:
To a solution of 5-bromo-1-indanone (5.0 g, 24 mmol) and 1H-triazole (4.90 g, 71.1 mmol) in 20 mL of DMF was added Fe(acac)3 (838 mg, 2.37 mmol), copper (II) oxide (188 mg, 2.36 mmol) and potassium carbonate (3.27 g, 23.7 mmol). The reaction mixture was degassed with nitrogen for 10 minutes. The mixture was stirred at 90° C. for 6.5 hours and at 80° C. for 15 hours. The cooled reaction mixture was diluted with ethyl acetate and water. The biphasic mixture was passed through a thin Celite® pad, which was washed thoroughly with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. Filtration and solvent removal afforded the crude product which was purified by silica chromatography using an ISCO (Teledyne Isco Inc., Lincoln Nebr.) column eluting with a 0-40% ethyl acetate/heptanes gradient to give the desired product as a pale yellow solid (2.60 g, 55%). MS (ES+) 200.1 (M+H)+. 1H NMR (CDCl3) δ 2.85 (t, 2H), 3.24 (t, 2H), 7.83-7.90 (m, 3H), 8.15 (d, 1H), 8.21 (s, 1H).
Reaction SMILES: CN([CH:4]=[O:5])C.CC(C)([O-])C.[K+].[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>O.C1COCC1>[CH3:19][Si:20]([CH3:22])([CH3:21])[CH2:23][CH2:24][O:25][CH2:26][O:5][CH2:4][O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cccnc1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOCOc1cccnc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of DMF (100 mL) and THF (100 mL), was added solid potassium tert-butoxide (17.96 g, 0.16 mol). After all of the solid had dissolved, the solution was cooled to ≦5° C. and 3-hydroxypyridine (14.25 g, 0.15 mol) was added all at once. After stirring for 10 minutes, the mixture was cooled to −10° C. and SEM-Cl, 25 g, 0.15 mol) was added dropwise at such a rate that the internal temperature remained at ≦−5° C. After the addition was complete, the mixture was stirred at 0° C. for 1 hour, then at room temperature for 2 hours. The mixture was poured into water (600 mL), then extracted with ether (3×150 mL). The ether extracts were combined, washed sequentially with 2N NaOH (100 mL), water (50 mL), and saturated NaCl solution (100 mL), dried (MgSO4) and concentrated to give a brown liquid. Distillation gave the desired ether 9 as a colorless liquid (20.8 g), b.p. 95-99° C. @ 0.03 mm Hg.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]>>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21
Reactant: Fc1ccc(N2CCNCC2)cc1Cl
Product: CCC1(CCCCN2CCN(c3ccc(F)c(Cl)c3)CC2)C(=O)Nc2cc(F)ccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 from 3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-4-fluorophenyl)-piperazine.
Reaction SMILES: [S:1](=[O:4])(=O)=[O:2].[O:5]1[CH2:10][CH2:9]OCC1.[C:11]1([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[N:17]1([C:11]2[CH:16]=[CH:15][C:14]([S:1]([N:17]3[CH2:11][CH2:12][CH2:13][CH2:9][C:10]3=[O:5])(=[O:4])=[O:2])=[CH:13][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: c1ccc(N2CCCCC2)cc1
Reactant: O=S(=O)=O
Reactant: C1COCCO1
Solvent: ClCCl
Product: O=C1CCCCN1S(=O)(=O)c1ccc(N2CCCCC2)cc1
Yield: 111.1 %

Procedure:
To a solution, cooled to between 0° C. and -5° C., comprising 8.46 g of sulphur trioxide in 45 cm3 of methylene chloride, there are added dropwise 9.3 g of dioxane followed by 17.1 g of N-phenylpiperidine dissolved in 45 cm3 of methylene chloride. The mixture is allowed to return to room temperature, then heated to reflux for 1 hour and evaporated to dryness, the residue is neutralized with 10% strength sodium carbonate solution, the aqueous phase is concentrated and the residue is dried and treated with 200 cm3 of phosphoryl chloride and 21.8 g of phosphorus pentachloride for 12 hours at room temperature. The mixture is evaporated to dryness, the residue is taken up in chloroform with a little water, the organic phase is separated, dried over sodium sulphate and filtered and the solvent is evaporated off. 19 g of expected product are obtained, which product is used as it is in the next stage.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([O:16]CC)(=[O:15])C>C(OCC)C.CCCCCC>[Cl:2][CH2:3][CH2:4][CH2:5][NH:6][C:13](=[O:15])[O:16][C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Reactant: NCCCCl
Agent: Cl
Solvent: CCOCC
Product: O=C(NCCCCl)Oc1ccccc1
Yield: 40.4 %

Procedure:
3-Chloropropylaminehydrochloride (6.5 g, 50 mmol) was used for reaction in the same manner as Production Example 310-1, purification was performed by silica gel column chromatography (hexane/ethyl acetate system), the obtained crystals were suspended in diethyl ether and diluted with hexane, and the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (4.316 g, 20.20 mmol, 40.40%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C@@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[N:16]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:15]=3)[N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:10]1)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:59]([N:61]=[C:62]=[O:63])[CH3:60]>ClCCl.[Cu]Cl>[CH3:39][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([C:62]([NH:61][CH2:59][CH3:60])=[O:63])[C:7]([C@@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[N:16]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:15]=3)[N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:10]1)=[O:8]
Reactant: CN(C)CCCNC(=O)[C@@H]1C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]2N(C(=O)OC(C)(C)C)C1
Reactant: CCN=C=O
Agent: Cl[Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)N(CCCN(C)C)C(=O)[C@@H]1C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]2N(C(=O)OC(C)(C)C)C1
Temperature: 35 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a solution of 15.5 g (28.67 mmol) of N-[3-(dimethylamino)propyl]-1,6-di(tert-butoxycarbonyl)-ergoline-8β-carboxamide (XVII, R2=tert-butyl) in 350 ml of dichloro-methane 0.8 g of triphenylphosphine, 0.3 g of copper(I) chloride and 6.8 ml (86 mmol) of ethyl isocyanate was sequentially added, and the reaction mixture was stirred at 35° C. for 4 hours. The reaction mixture was concentrated in vacuum and the product was purified on a silica plug to give 16.9 g (96.4%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Br:12])=[CH:9][C:8](OC)=[CH:7][CH:6]=2.[F:15][B-:16]([F:19])([F:18])[F:17].[N:20]#[O+].C1[CH2:26][O:25]CC1>>[F:15][B-:16]([F:19])([F:18])[F:17].[Br:12][C:11]1[C:2]([N+:1]#[N:20])([O:25][CH3:26])[CH2:3][N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2ncc(N)c(Br)c2c1
Reactant: N#[O+]
Reactant: C1CCOC1
Agent: F[B-](F)(F)F
Product: COC1([N+]#N)CN=c2ccccc2=C1Br
Temperature: -2.5 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
3-Amino-4-bromo-6-methoxyquinoline (18.4 g, 0.0727 mole) was dissolved in dry THF (250 mL) and the solution was cooled to −8° C. (EtOH-ice bath). Nitrosonium tetrafluoroborate (9.34 g, 0.08 mole) was added in portions over 10 min, keeping the temperature less than −2° C. The mixture was stirred at −5 to 0° C. for 30 min, then the yellow precipitate was filtered off and washed sequentially with cold THF and hexane. Drying in vacuo gave the title compound (19.4 g, 76%) an insoluble orange-yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][Zn+])=[O:32].Cl.ClCCl>C1COCC1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:40]=[CH:39][CH:38]=[C:35]([CH2:36][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:9]=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[C:11]4[C:24]([F:26])([F:27])[F:25])=[CH:18][CH:19]=2)[CH:34]=1
Reactant: FC(F)(F)c1cccc2c(-c3ccc(Br)cc3)n(Cc3ccccc3)nc12
Reactant: COC(=O)c1cccc(C[Zn+])c1
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Cc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Benzyl-3-(4-bromo-phenyl)-7-trifluoromethyl-2H-indazole (43 mg, 0.1 mmol) and 4 mg of bis[triphenylphosphine]palladium(II) chloride were dissolved in THF. After 5 minutes, 0.4 ml of a 0.5M solution of 3-(methoxycarbonyl)-benzylzinc bromide in THF (0.2 mmol) were added and the reaction mixture was stirred at room temperature overnight. 1M HCl-solution and dichloromethane were added, and the phases were separated. The resulting product was obtained after flash chromatographic purification using n-heptane/ethyl acetate, 90:10, as eluent. Yield: 47 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH:18]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=1[C:32]([F:35])([F:34])[F:33].[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH:18]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=1[C:32]([F:35])([F:34])[F:33])[C:39]([CH:36]1[CH2:38][CH2:37]1)=[O:40]
Reactant: FC(F)(F)c1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1CNCc1ccccn1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: O=C(C1CC1)N(Cc1ccccn1)Cc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 482.4 %

Procedure:
(E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2Cl2 (3 mL). To this was added TEA (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min After 10 min, the reaction mixture was cooled to 0° C., and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then was washed with water and satd aq NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J=10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M−H]−); IR (thin film) 1645, 1115, 808 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:29])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[H-].[Na+].I[CH2:38][CH3:39].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:29])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=3)[C:14]([F:16])([F:15])[F:17])[N:8]2[CH2:38][CH3:39])=[CH:4][C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3ccc(F)c(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3ccc(F)c(C(F)(F)F)c3)C(F)(F)F)n(CC)c2cc1Cl
Yield: 65.7 %

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (0.42 g, 0.82 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (6 ml). Sodium hydride (60%; 0.028 g, 0.72 mmol) was added and the mixture was stirred while cooling with ice for 2 h. Iodoethane (0.10 g, 0.65 mmol) was added. The reaction mixture was thawed while stirring within 36 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (4/1) and gave 0.23 g (53% of theory) of ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:9])=[N:7][CH:8]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)#[N:22]>>[CH3:20][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[CH:13]=2)=[C:6]([CH3:9])[N:7]=[CH:8][C:3]=1[CH2:2][O:1][C:26]1[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: Cc1ncc(CO)c(C)c1OCc1cccc(C#N)c1
Product: Cc1ncc(COc2ccc(C#N)cc2)c(C)c1OCc1cccc(C#N)c1
Yield: 47.3 %

Procedure:
The coupling of 3-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (26) (1.0 mg, 3.70 mmol) and 4-cyanophenol (885 mg, 7.40 mmol), as described in Example 9, gave 4-[4,6-dimethyl-5-(3-cyano-benzyloxy)-pyridin-3-ylmethoxy]-benzonitrile (69) (646 mg, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25]CC)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[CH:6][C:5]([C:18]2([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: CCOC(=O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.8 %

Procedure:
Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (80 mg) dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.68 (d, 2H), 7.55 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 3.97 (d, 2H), 2.64 (m, 2H), 1.95 (m, 2H), 1.77 (m, 4H), 1.21 (m, 1H), 0.45 (m, 2H), 0.18 (m, 2H);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[CH2:41]([C@H:48]1[CH2:52][O:51][C:50](=[O:53])[NH:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O1CCNC1=O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([N:49]3[C@@H:48]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:52][O:51][C:50]3=[O:53])=[O:19])=[CH:20][CH:21]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2ccc(OCCCC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To a -70° C. solution in THF (100 mL) of 4-[4-(4-cyanophenyl)phenoxy]butanoic acid (1.00 g, 3.66 mmol), prepared as in Example 3, was added triethylamine (0.64 mL, 4.62 mmol) and pivaloyl chloride (0.49 mL, 3.91 mmol). The reaction mixture was stirred for 15 minutes at -70° C., 45 minutes at 0° C., and then was cooled back to -70° C. In a separate flask, n-butyllithium (2.5M in hexanes, 2.56 mL, 6.40 mmol) was added via syringe to a -78° C. a solution in THF (50 mL) of (S)-(-)-4-benzyl-2-oxazolidinone. The oxazolidinone anion solution was then added to the mixed anhydride solution via cannula. The reaction mixture was then warmed slowly to ambient temperature and stirred overnight. The reaction mixture was quenched with aqueous 1M HCl and extracted with ethyl ether. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting white solid was azeotroped with ethyl ether and purified by chromatography on silica gel (2% methanol-dichloromethane) to give N-[4-(4-(4-cyanophenyl)phenoxy)butanoyl]-(S)-(-)-4-benzyl-2-oxazolidinone (1.30 g, 82%).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([NH:22][C:23]5[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.[C:31](Cl)(=[O:33])[CH3:32].N1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1([CH3:30])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([N:22]([C:23]5[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[C:31](=[O:33])[CH3:32])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: Cc1ccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(C)nc1)c1ccc2c(c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Yield: 47.5 %

Procedure:
A mixture of Example 60 (17 mg, 0.04 mmol), acetyl chloride (3.2 mg, 0.4 mmol) and pyridine (0.5 mL, 0.8 mmol) in THF (10 mL) was stirred at r.t. for 2 days. It was concentrated in vacuo and purified by preparative HPLC (Method 7) to give the title compound (8.8 mg, 47%) as an off-white solid. δH (CDCl3) 8.53-8.34 (1H, m), 8.31-8.18 (1H, m), 7.60-7.51 (1H, m), 7.24-7.11 (1H, m), 7.03-6.88 (2H, m), 5.23 (1H, br s), 4.47-4.28 (2H, m), 4.14-3.98 (2H, m), 2.94-2.80 (2H, m), 2.63-2.48 (3H, m), 2.27-2.07 (3H, m), 1.40 (6H, s). LCMS (ES+) 464 (M+H)+, RT 2.70 minutes (Method 2).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[N:19]=[C:18]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccsc3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1nc(-c2ccsc2)nc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4-(4-thiophen-3-yl-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.17 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL) dropwise. The resulting solution was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated, then re-dissolved in CH2Cl2 and concentrated. The residue was dissolved in a mixture of CH2Cl2/MeOH (4:1, 5 mL), neutralized with Na2CO3, and stirred at room temperature for 30 min. The resulting solid was filtered, washed with CH2Cl2, and the filtrate was concentrated to yield a yellow gummy solid, which was used without purification.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].FC(F)(F)C(O)=O.[CH3:12][C:13]([C:15]1([CH2:22][OH:23])[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)=[O:14]>C(Cl)Cl.O>[CH3:12][C:13]([C:15]1([CH2:22][O:23][C:2](=[O:1])[NH2:3])[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)=[O:14]
Reactant: CC(=O)C1(CO)CC2C=CC1C2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1(COC(N)=O)CC2C=CC1C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.7 %

Procedure:
52 g (0.8 mole) of sodium cyanate, followed dropwise by 95.8 g (0.84 mole) of trifluoroacetic acid, are added to a solution of 66.4 g (0.4 mole) of 2-hydroxymethylnorborn-5-en-2-yl methyl ketone in 120 ml of methylene chloride at 20° C., with slow stirring. The mixture is then stirred for 5 hours at room temperature, after which it is diluted with water. It is then repeatedly extracted with methylene chloride and the organic phases are combined and dried over sodium sulfate. After distilling off the solvent, a crystalline residue (83.1 g=99%) is obtained, and this is recrystallized from ethyl acetate. 45.8 g of 2-carbamyloxymethylnorborn-5-en-2-yl methyl ketone, of melting point 118°-119° C., are obtained.
Reaction SMILES: [CH:1]([N:3]([CH3:6])[CH2:4][OH:5])=O.[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([C:14]([NH2:16])=[O:15])[S:10][N:9]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:4]([N:3]([CH2:1][NH:16][C:14]([C:11]1[S:10][N:9]=[C:8]([Cl:7])[C:12]=1[Cl:13])=[O:15])[CH3:6])=[O:5]
Reactant: CN(C=O)CO
Reactant: NC(=O)c1snc(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CN(C=O)CNC(=O)c1snc(Cl)c1Cl
Yield: 47.1 %

Procedure:
At room temperature, 15 g (0.164 mol) of N-formyl-N-hydroxymethyl-methylamine are added with stirring to a mixture of 32.3 g (0.164 mol) of 3,4-dichloro-isothiazole-5-carboxamide and 245 ml of glacial acetic acid. At room temperature, 37 g (0.362 mol) of concentrated sulphuric acid are then added dropwise with stirring, the reaction mixture being cooled with ice. The reaction mixture is subsequently stirred at room temperature for 29 hours and then, with ice-cooling, admixed with 400 ml of water. The resulting mixture is extracted four times with 200 ml of methylene chloride and the combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The oily residue that remains is chromatographed over silica gel using ethyl acetate. Concentration of the eluate gives 20.7 g (42.6% of theory) of N-(N-formyl-N-methyl-aminomethyl)-3,4-dichloro-isothiazole-5-carboxamide in the form of a crystalline solid of melting point 87 to 88° C.