Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([Cl:41])[CH:40]=1)[C:35](Cl)=[O:36]>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([Cl:41])[CH:40]=1)[C:35]([N:9]([CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:8])=[O:36]
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1cc(Cl)cc(Cl)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 350 μl (2.5 mmol) of 3,5-dichlorobenzoyl chloride, and after purification, 400 mg (50%) of 3,5-dichloro-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methylbenzamide are obtained in the form of a white solid with a melting point of 106° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][CH3:7]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([NH2:13])=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][CH3:7]
Reactant: CCOCc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOCc1cc(N)c(F)cc1Br
Temperature: 80 °C
Yield: 86.9 %

Procedure:
To a flask containing 50 ml of glacial acetic acid heated to 80° C. was added 4 g (0.07 mole) of iron powder. This was followed by the dropwise addition of a solution of 2 g (0.007 mole) of ethyl 2-bromo-4-fluoro-5-nitrobenzyl ether in 60 ml of acetic acid while maintaining the temperature between 80° C. and 85° C. After 30 minutes the reaction mixture was cooled to room temperature and was filtered. The solvent was evaporated under reduced pressure, and the residue was dissolved in 250 ml of diethyl ether. This solution was washed successively twice with 50 ml of water, once with 50 ml of a saturated, aqueous solution of sodium bicarbonate, and twice with 50 ml of water. The solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, yielding 1.51 g of ethyl 2-bromo-4-fluoro-5-aminobenzyl ether. An additional 0.1 g of product was obtained by extracting the water washes with diethyl ether.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[CH3:8][O:9][C:10](=[O:29])[CH:11]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20](N)[CH:19]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.ClC1C=CC=CC=1Cl>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:29])[CH:11]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:1])[CH:19]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(N)c1
Agent: N#[O+]
Solvent: ClCCl
Solvent: Clc1ccccc1Cl
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of nitrosonium tetrafluoroborate (215 mg, 1.84 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated dropwise with a solution of 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (500 mg, 1.54 mmol) in a small amount of methylene chloride. The resulting reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then allowed to warm to 25° C. and was treated with 1,2-dichlorobenzene (6 mL). The resulting reaction mixture was heated at 100° C. for 1 h, during which time, the methylene chloride was distilled off. After 1 h at 100° C., the reaction mixture was allowed to cool to 25° C. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate to elute 1,2-dichlorobenzene then 2/1 hexanes/ethyl acetate) to afford impure 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester as a yellow oil. Repurification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded pure 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester (214 mg, 42%) as a pale yellow oil which solidified upon sitting at 25° C. to a pale yellow solid: mp 66-68° C.; EI-HRMS m/e calcd for C16H21FO4S (M+) 328.1144, found 328.1148.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][OH:18])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[C:21]1([CH2:27]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][O:18][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: OCc1ccccc1C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2C2CCC3(CC2)OCCO3)cc1

Procedure:
When the bridging group is carbonyl, the Grignard reagent of 8-bromo-1,4-dioxaspiro[4.5]decane is first prepared. The precursor 8-bromo-1,4-dioxaspiro[4.5]decane is prepared by the method of E. I. Snyder (JOC, 36, 403 (1971)). The Grignard reagent is in turn reacted with an appropriately substituted or unsubstituted benzaldehyde, for example, 3-trifluoromethylbenzaldehyde and then treated with aqueous ammonium chloride, yielding [(1,4-dioxaspiro[4.5]decan-8-yl)(phenyl)]methanol. The so-prepared alcohol is treated with sodium hydride in toluene, and then is reacted with phenylmethyl bromide, yielding phenylmethyl [(1,4-dioxaspiro[4.5]decan-8-yl)(phenyl)]methyl ether. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, as previously described, affording the corresponding phenylmethyl [(cyclohexanon-4-yl)(phenyl)]methyl ether. The ether is then reacted with cyanoguanidine, as previously described, yielding the appropriate 2,4-diamino-6-[(phenylmethoxy)(phenyl)methyl]-5,6,7,8-tetrahydroquinazoline. The tetrahydroquinazoline is then cleaved with hydrogen gas in the presence of 5% palladium on charcoal, yielding the corresponding [(2,4-diamino-5,6,7,8-tetrahydroquinazolin- 6-yl)(phenyl)]methanol. Using the method of D. Swern (Tetrahedron, 34, 1651-1660 (1978)), the methanol is oxidized with oxalyl chloride and dimethyl sulfoxide in methylene chloride, yielding the targeted 2,4-diamino-6-phenylcarbonyl-5,6,7,8-tetrahydroquinazoline. Example 9 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[O:14]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.ClCCl>[CH:8]([C:6]1[N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=[C:2]([CH3:1])[CH:7]=1)=[O:14]
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(C)cc(NC(C)=O)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cc(C)cc(C=O)n1
Temperature: -80 °C
Reaction time: 0.08 h

Procedure:
5.0 g N-(4-methyl-6-vinyl-pyridin-2-yl)-acetamide (compound F5) are dissolved in a mixture of each 200 ml methanol and dichloromethane and cooled to −80° C. Subsequently, ozone is passed into the solution (flow 20-25 l/h ozone). After 5 min ozone treatment is stopped. Thereafter, nitrogen is applied for 5 min and 7.44 g of triphenylphosphane are added while stirring is continued. The solution is allowed to warm up to r.t. Subsequently, the volatile components are removed in vacuo and the residue is purified by chromatography on silica gel (eluent cyclohexane/ethyl acetate 3:1) to afford 2.72 g of the title compound as colourless solid. M.p. 202° C. GC-MS: 178.2 (M+). TLC: Rf=0.50 (cyclohexane/ethyl acetate 1:1). [Remark: Occasionally remaining traces of triphenylphosphine oxide can be removed by dissolving crude product in ethyl acetate followed by cooling to precipitate triphenylphosphine oxide.]
Reaction SMILES: C(O)C.[F:4][CH:5]([F:17])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N+:14]([O-])=O.[Cl-].[Ca+2].[Cl-]>O.[Zn]>[F:4][CH:5]([F:17])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[NH2:14]
Reactant: Cc1cccc(OC(F)F)c1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1cccc(OC(F)F)c1N
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of 400 ml of absolute ethanol, 50 ml of water, 72.6 g of zinc dust, 53.3 g of the 2-(difluoromethoxy)-6-methylnitrobenzene, (Example 3A), and a solution of 20.0 g of calcium chloride dissolved in 60 ml of water was refluxed for three hours, allowed to stand overnight, refluxed for an additional hour, and then an additional 43 g of zinc dust and a solution of 18 g of calcium chloride dissolved in 50 ml of water was added. Refluxing for an additional three hours was required to drive the reaction to completion. The reaction was vacuum filtered through Celite®, the filter cake rinsed with 300 ml of ethanol and the filtrate concentrated to a volume of 100 ml. The liquid was diluted with 300 ml of ethyl acetate, 80 ml of 10% sodium hydroxide solution and 100 ml of water. A precipitate formed which was removed by vacuum filtration through Celite. The filter cake was rinsed with 200 ml of ethyl acetate. The phases were separated and the organic phase was dried with sodium sulfate, filtered and concentrated to yield 25.8 g of the desired intermediate as a black oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[C:9]2=[O:19])=[CH:4][CH:3]=1.[OH-].[Li+]>C(O)C.O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9]2=[O:19])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O
Reaction time: 3 h

Procedure:
The product from Example 25C (0.95 g, 2.42 mmol) was dissolved in ethanol/water (4:1, 50 mL) and treated with lithium hydroxide (7.85 g, 328.0 mmol). After stirring for 3 hours at reflux, the reaction was concentrated, diluted with ice/water (50 mL) and neutralized with 1 N HCl. The resulting precipitate was collected by filtration, washed with water (50 mL) and air-dried to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][NH2:13])[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:17]([C:24](O)=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][NH:13][C:24]([C:17]1[C:16]([NH2:15])=[N:21][C:20]([NH2:22])=[C:19]([Cl:23])[N:18]=1)=[O:25])[CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: CCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ((S)-1-aminomethyl-butyl)-carbamic acid tert-butyl ester (1.70 g, 8.40 mmol), 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (1.59 g, 8.43 mmol), N-methylmorpholine (3.8 mL, 34.5 mmol) and HATU (3.2 g, 8.42 mmol) in anhydrous DMF (50 mL) is stirred at RT for 16 h. The reaction mixture is concentrated in vacuo and the resulting residue is purified by column chromatography (basic alumina, MeOH:DCM) to afford the title compound as yellow solid. [M+H]+ 333.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][O:28][NH:29][CH3:30]>C1COCC1>[CH3:27][O:28][N:29]([CH3:30])[C:11](=[O:13])[CH2:10][CH2:9][N:8]([CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (130 g, 0.64 mol) in anhydrous THF was added CDI at 0° C. The resulting mixture was stirred for 1 h at 0° C. To this mixture was added a solution of O,N-dimethylhydroxylamine hydrochloric salt (145.2 g, 0.9 mol) and TEA (90.1 g, 0.9 mol) in THF at rt. The resulting mixture was stirred overnight. Solvent and volatiles were removed under reduced pressure. The residue was purified via column chromatography to give tert-butyl 3-(methoxy(methyl)amino)-3-oxopropyl(methyl)carbamate (120 g, 75.5%) as a colorless oil. 1HNMR (CDCl3, 400 MHz) 1.45 (s, 9H), 2.62-2.71 (m, 2H), 2.87 (s, 3H), 3.17 (s, 3H), 3.48-3.56 (m, 2H), 3.68 (s, 3H)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[S:26]1[CH:27]=[CH:28][C:24]([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])=[CH:25]1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#Cc1ccsc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)Nc1ccccc1C#Cc1ccsc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 3-ethynyl-thiophene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (48 mg, 40%); 1H NMR δ (CDCl3): 8.39 (d, J=8.51 Hz, 1H), 7.9 (br s, 1H), 7.36-7.30 (m, 2H), 7.30-7.21 (m, 3H), 7.02 (t, J=7.24 Hz, 1H), 2.21 (s, 3H); LCMS m/z: 241.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:80]1([CH:86]2[CH2:90][CH2:89][CH2:88][NH:87]2)[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:80]1([CH:86]2[CH2:90][CH2:89][CH2:88][N:87]2[C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)(=[O:13])=[O:14])=[CH:7]3)[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCCC3c3ccccc3)cccc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A vial was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (51.89 mg, 0.100 mmol), Xantphos (11.56 mg, 0.020 mmol), Pd2(dba)3 (9.15 mg, 9.99 μmol), and cesium carbonate (65.1 mg, 0.200 mmol). The vial was flushed with Ar (g), then toluene (999 μl) and 2-phenylpyrrolidine (19.12 μl, 0.130 mmol) were added in sequence. The vial was sealed and heated to 100° C. for 18 h. The mixture was partitioned between EtOAc and water. The layers were separated, and the organic extract was washed with brine. The combined aq. layers were extracted with EtOAc, and the organic layers were combined. The combined solution was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0 to 50% EtOAc/Heptane) to give a clear oil. This oil was taken up in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH, then concentrated. The residue was taken up in diethyl ether, sonicated, then filtered. The collected solid was washed with diethyl ether (twice), dried under a stream of N2 (g) for 10 min, then dried under a high vacuum to give 5-(2-phenylpyrrolidin-1-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (15.25 mg, 0.035 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.76 (br. s., 1H), 8.45 (d, J=9.0 Hz, 1H), 8.31 (d, J=1.7 Hz, 1H), 7.77 (dd, J=2.0, 8.9 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.40 (d, J=7.1 Hz, 2H), 7.33 (t, J=7.9 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 7.18 (t, J=7.5 Hz, 2H), 7.12-7.04 (m, 2H), 6.82 (d, J=4.6 Hz, 1H), 4.86-4.77 (m, 1H), 4.20-4.10 (m, 1H), 3.02 (dt, J=4.7, 8.9 Hz, 1H), 2.47-2.39 (m, 1H), 2.16-2.05 (m, 1H), 2.00-1.78 (m, 2H). m/z (ESI) 436.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Example 28. LC (method 6): tR=1.03 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([CH:20]([F:22])[F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15](OCC)=[O:16])=[CH:7][CH:6]=1.[H-].C([Al+]CC(C)C)C(C)C>>[F:1][C:2]([F:23])([CH:20]([F:21])[F:22])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:9][CH:10]=1
Reactant: CCOC(=O)/C=C/C=C/c1ccc(OCC(F)(F)C(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OC/C=C/C=C/c1ccc(OCC(F)(F)C(F)F)cc1
Yield: 95 %

Procedure:
Ethyl (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienoate was treated with diisobutyl aluminum hydride in the same manner as in Reference example 21 to obtain the title compound having a melting point of 95 to 97° C. in a yield of 95%.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH2:5][CH2:4]1.[CH:16]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[CH:16]1([CH2:21][CH2:22][C:23]([N:2]([C@H:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[CH2:5][CH2:4]2)[CH3:1])=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CN[C@@H]1CCc2ccc(C(=O)OC)cc21
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)CCC1CCCC1)CC2
Reaction time: 0.25 h
Yield: 58 %

Procedure:
(R)-Methyl 3-(methylamino)-2,3-dihydro-1H-indene-5-carboxylate (A-11) (1.61 g, 7.85 mmol, 1.0 eq.) was dissolved in DCM (50 ml); TEA (2.72 ml, 19.62 mmol, 2.5 eq.) was added at 0° C., and stirring was carried out for 15 minutes. 3-Cyclopentylpropanoic acid chloride (1.38 ml, 8.635 mmol, 1.1 eq.) was then added, and the mixture was stirred for 4 hours at RT. After monitoring by TLC, the reaction mixture was diluted with DCM (100 ml), washed with water (75 ml) and sat. NaCl solution (75 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 20% ethyl acetate in hexane). Yield: 58% (1.5 g, 4.56 mmol)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO.Cl>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (140 mg, 0.41 mmol) and N,N-diisopropylethylamine (320 μl, 2.07 mmol) in N,N-dimethylformamide (5 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (235 mg, 0.61 mmol) and the resulting solution was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Hydroxylamine hydrochloride (113 mg, 0.61 mmol) was then added and the mixture was stirred at room temperature for 20 hours. The mixture was poured into hydrochloric acid (1M, 20 ml) and extracted with ethyl acetate (×3). The combined organic layers were washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99.5:0.5) gradually changing to dichloromethane:methanol (97:3) to afford the title compound as a yellow oil (62 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C([Li])(C)(C)C.[Br:17][C:18]1[CH:19]=[C:20](/[C:26](/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[C:41]#[N:42])=[N:27]\S(C(C)(C)C)=O)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].Cl.CO>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:26]2([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[C:34]3[C:35](=[C:36]([F:40])[CH:37]=[CH:38][CH:39]=3)[C:41]([NH2:42])=[N:27]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(/C(=N\S(=O)C(C)(C)C)c2cccc(F)c2C#N)cc1Br
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1Br
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
A solution of 4-bromo-2-trifluoromethylpyridine (1.76 g, 7.80 mmol) in THF (2 mL) was added dropwise at −100° C. to t-butyllithium (9.17 mL, 15.59 mmol) in THF (15 mL) followed by the addition of (E)-N-((3-bromo-4-methoxyphenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (3.1 g, 7.09 mmol) in THF (10 mL). The reaction mixture was left on a thawing cooling bath for 1 hour and then allowed to reach room temperature and stirred for 2.5 hours. Hydrochloric acid in methanol (1.25 M, 28.4 mL, 35.4 mmol) was added and the reaction was stirred for 1 hour. Silica powder was added and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% 0.1M NH3 in methanol in DCM) to afford the title compound (3.04 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)C1=CCCc2ccc(OC)cc21
Agent: [Pd]
Product: COC(=O)C1CCCc2ccc(OC)cc21

Procedure:
The sub-title compound was prepared according to the method described in Example 1(iv) above from 7-methoxy-3,4-dihydronaphthalen-1-yl-carboxylic acid, methyl ester (3.3 g; 15 mmol; see Example 9(i) above) and Pd/C (10%; 0.5 g). The resultant mixture was filtered through Hyflo and concentrated. The crude product was purified using flash chromatography (Si-gel; heptane:EtOAc; 4:1). Yield 2.4 g (72%).