Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:14]=2)[C:4]2([CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH2:3]1.C[Si]([N:28]=[C:29]=[N:30][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:19]([C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:4]2([CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:3][C:2]3=[N:30][C:29]#[N:28])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC32CCOCC2)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC2(CCOCC2)c2ccc(-c3cccc(C#N)c3)cc21
Reaction time: 1 h

Procedure:
To a solution of 3-(3-oxo-2,2′,3,3′,5′,6′-hexahydrospiro[indene-1,4′-pyran]-5-yl)benzonitrile (42 mg, 0.139 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.28 mL, 0.28 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.1 mL, 0.427 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (15 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give the desired product as white solid, which was used for next step without further purification. MS ESI+ve m/z 328 (M+H)30.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH3:1][C:2]1([CH3:22])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:31])[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: Cc1cccnc1C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
248 mg of 3.4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-6-nitro-2H-1-benzopyran were dissolved in 20 ml of dichloromethane at room temperature and 222 mg of m-chloroperbenzoic acid were added. After stirring at room temperature overnight the solution was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and evaporated. The resulting solid was triturated with diethyl ether, filtered off and recrystallized from acetonitrile to give 133 mg of 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-yl)-3-methylpyridine N-oxide of melting point 218°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]#[N:16])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.Cl.C(N(CC)CC)C.[N-:29]=[N+:30]=[N-:31].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]3[NH:31][N:30]=[N:29][N:16]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: N#CCN1C2CCC1CC(Oc1ccc(Cl)c(Cl)c1)C2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1ccc(OC2CC3CCC(C2)N3Cc2nnn[nH]2)cc1Cl
Temperature: 61 °C
Reaction time: 120 h

Procedure:
To 1 g of [3-(3,4-dichloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-acetonitrile in 25 ml anhydrous toluene was added 0.7 g of triethylamin hydrochloride and 0.3 g sodium azide. The reaction mixture was stirred at 60-62° C. for 5 days, the product precipitated from the mixture and was isolated by filtration. Yield 0.27 g (24%) Mp. 233-235° C. (sublimation).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21](C=O)=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:20][CH:19]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(C(F)(F)F)cc2)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.7 g of NaH 60% dispersion in oil, 58 mL of 1.6M n-butyl lithium in hexane, 11.5 g of 4-trifluoromethylbenzaldehyde and 250 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then 30 minutes at room temperature. The crude product was triturated from diethyl ether to afford a solid (m.p. 155°-156° C.). 1H NMR (CDCl3) δ2.83 (dd, 1H), 2.99 (dd, 1H), 3.58 (dd, 2H), 5.76 (dd, 1H), 7.50-7.76 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:16]1[C:15]([C:14]([F:13])([F:25])[F:24])=[CH:19][C:18]([C:20]([F:21])([F:22])[F:23])=[N:17]1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 95.8 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (1.81 g), 3,5-bis(trifluoromethyl)-1H-pyrazole (2.0 g) and potassium carbonate (1.63 g) were stirred in DMF (20 ml) at 60° C. for 1 hour. After finishing the reaction, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride (100 ml) and dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-3,5-bis-(trifluoromethyl)-1H-pyrazole (3.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12](F)[CH:11]=2)=[CH:6][CH:5]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:22][CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(-c2cc(F)ncc2Cl)cc1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(NC(C)C)ncc2Cl)cc1
Temperature: 90 °C
Yield: 67 %

Procedure:
4-(5-Chloro-2-fluoropyridin-4-yl)-benzoic acid methyl ester (90 mg, 0.34 mmol) was dissolved in DMSO in a screw cap tube and 0.5 mL isopropylamine was added. The tube was sealed and heated to 90° C. for 2 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to an oil, which was purified by chromatography on silica (EtOAc 0 to 20%/hexanes) to give 70 mg of 4-(5-chloro-2-isopropylamino-pyridin-4-yl)-benzoic acid methyl ester, 0.23 mmol, 67% yield. 1H NMR 500 MHz (CDCl3): 8.08 (m, 3H), 7.45 (d, 2H), 6.22 (s, 1H), 4.37 (d, 1H), 3.88 (s, 3H), 3.80 (m, 1H), 1.17 (d, 6H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]([C:16](=[O:24])[NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11](B(O)O)[CH:12]=2)[N:7]=1.Br[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[CH:32]2>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]([C:16]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:24])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][CH:33]=[CH:32]4)[CH:12]=2)[N:7]=1
Reactant: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(B(O)O)cc12
Reactant: Brc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(-c3ccc4[nH]ccc4c3)cc12
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 6.4 %

Procedure:
To a sealed tube under argon atmosphere was added (2-(furan-2-yl)-4-(pyridin-3-ylcarbamoyl)quinolin-6-yl)boronic acid (0.120 g) in DMF (4 ml) and the vessel was purged with argon under stirring for 5 minutes. After 5 minutes, a 2N aqueous solution of potassium carbonate was added (1.8 ml, 11 eq) and the tube was purged with argon under stirring for 5 minutes. 5-bromoindole (0.057 g, 0.9 eq) was then added and the vessel was purged with argon under stirring for 15 minutes. Finally tetrakistriphenylphosphine palladium(0) (0.011 g, 0.03 eq.) was added under argon and the tube was sealed. The reaction mixture was heated to 90° C. for 5 hours. The completion of the reaction was monitored by TLC using ethyl acetate:hexanes (5:5) as a mobile phase. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 ml) and then washed with water (5*10 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation and the crude product was subjected to purification by high performance liquid chromatography to provide 2-(furan-2-yl)-6-(1H-indol-5-yl)-N-(pyridin-3-yl)quinoline-4-carboxamide (0.008 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.34 (s, 1H), 11.19 (s, 1H), 9.00 (m, 1H), 8.41 (m, 1H), 8.35 (m, 1H), 8.30 (m, 1H), 8.20 (m, 1H), 8.12 (m, 2H), 7.85 (m, 1H), 7.70 (m, 1H), 7.4 (m, 1H), 7.58 (m, 1H), 7.50 (m, 2H), 7.43 (m, 1H), 7.12 (m, 1H), 6.54 (m, 1H); m/z 431.2 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])#[N:8].[Cl-].[OH:19][NH3+:20]>CO>[OH:19][NH:20][C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])=[NH:8]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: N=C(NO)c1cccc(C(=O)O)c1

Procedure:
1382 g (10.0 mop of potassium carbonate are added in portions with stirring to a suspension, held at 30° C., of 500 g (3.40 mol) of 3-cyanobenzoic acid in 8 l of methanol. 695 g (10.0 mol) of hydroxylammonium chloride are subsequently added in small portions at an internal temperature of 40-45° C. The reaction mixture is then heated at the boil for 15 hours. The reaction mixture is evaporated in vacuo, and the residue is dissolved in water and acidified using 37% aqueous hydrochloric acid. The resultant precipitate is filtered off with suction, washed with water and dried in vacuo: 3-(N-hydroxycarbamimidoyl)benzoic acid as colourless crystals; m.p. 208° C.; ESI 181 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH:7]=1
Reactant: OB(O)c1cc(F)ccc1O
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(F)ccc2O)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a degassed mixture of 1,4-dioxane:water (4:1, 15 mls) was added (5-fluoro-2-hydroxyphenyl)boronic acid (0.781 g, 5.0 mmol), methyl 6-chloronicotinate (0.86 g, 5.0 mmol), potassium carbonate (2.08 g, 15.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) and the resulting mixture stirred at 80° C. for 2 h. After this time additional tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) was added and then heating continued at 80° C. for 3 h. The mixture was then stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue suspended in ethyl acetate (50 ml). The suspension was filtered through a plug of arbocel and the filtrate concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium carbonate (3×100 ml). The aqueous washings were combined and extracted with ethyl acetate (3×50 ml). The ethyl acetate layers were combined, dried with anhydrous MgSO4 and concentrated in vacuo to afford a solid which was recrystallised from dichloromethane/heptane to afford the title compound as a yellow solid (0.71 g) (57%). 1H NMR (400 MHz, CDCl3) □ ppm 9.14 (1H, s), 8.46-8.40 (1H, m), 7.91-7.86 (1H, m) 7.53-7.46 (1H, m), 7.11-7.03 (1H, m), 7.02-6.96 (1H, m), 3.99 (3H, s). LRMS: AP m/z 248 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:18]([F:21])=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2ccc(F)cc2)c1
Yield: 117.1 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (125 mg, 0.324 mmol), 4-fluoroboronic acid (64 mg, 0.46 mmol) and palladium (II) acetate gave the title compound as a white solid (76 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.48 (t, 2H), 7.44-7.29 (m, 2H), 7.21-7.00 (m, 3H), 5.27 (s, 1H), 4.68-4.55 (m, 1H), 3.29-2.10 (m, 6H), 1.67 (d, J=9.4 Hz, 6H), 2.01-0.69 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 163.9, 161.4, 159.8, 157.3, 154.8, 143.5, 132.2, 130.9, 127.9, 127.8, 127.4, 125.9, 125.8, 116.2, 116.0, 115.7, 115.5, 71.4, 66.1, 55.9, 47.6, 46.7, 30.0, 39.7, 25.6, 24.8, 19.8 ppm. Purity: 98% UPLCMS (210 nm); retention time 0.96 min; (M+1) 400.9.
Reaction SMILES: [Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5].CCN(C(C)C)C(C)C.C([O:42][CH2:43][C:44](Cl)=[O:45])(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:43](=[O:42])[CH2:44][OH:45])[CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)C(=O)CO)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
To a solution of 2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (177 mg, 0.39 mmol) in 1,2-dichloroethane (5 ml) was added DIPEA (0.35 ml, 2.01 mmol) followed by acetoxyacetyl chloride (0.1 ml, 0.93 mmol) and the reaction stirred at 65° C. for 3 h. The solution was cooled, treated with saturated aqueous NaHCO3 (25 ml) and extracted with CH2Cl2 (3×15 ml). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 96:4:0 then 88:10:2) provided the desired amide (88 mg, 41%) as a brown oil. To a solution of the acetate from above (80 mg, 0.14 mmol) in MeOH (5 ml) was added K2CO3 (67 mg, 0.49 mmol) and the reaction stirred overnight. The mixture was concentrated then diluted with CH2Cl2 (25 ml) and saturated aqueous NaHCO3 (20 ml). The aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 96:4 then 9:1) afforded COMPOUND 65 (48 mg, 59%) as a pale yellow foam and a mixture of two rotational isomers. 1H NMR (CDCl3) δ 0.94-0.99 (m, 3H), 1.19-1.43 (m, 2H), 1.50-1.73 (m, 5H), 2.09-2.14 (m, 1H), 2.35 and 2.38 (s, total 3H), 2.51-2.57 (m, 1H), 2.70-2.85 (m, 3H), 3.19-3.40 (m, 1H), 3.75-3.82 (m, 1H), 3.98-4.28 (m, 5H), 6.93-6.95 (m, 1H), 7.02-7.05 (m, 1H), 7.12-7.15 (m, 1H), 7.23-7.35 (m, 1H), 7.86-7.88 and 8.57-8.60 (m, total 1H); ES-MS m/z 513 (M+H). Anal. Calcd. for C23H30N4O3SCl2.0.3H2O: C, 53.24; H, 5.94; N, 10.80. Found: C, 53.27; H, 5.88; N, 10.54.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:9][C:10]([F:14])([F:13])[CH2:11][NH:12][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NCC(F)(F)F)c1cccs1

Procedure:
Thiophene-2-carboxylic acid was coupled to trifluoroethyl amine using HBTU utilizing a procedure described in Example 1, Step 2 below except substituting HOBt with HBTU to give thiophene-2-carboxylic acid (2,2,2-trifluoroethyl)amide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([CH3:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.[OH-].[Na+].O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N+:12]([O-:30])=[C:11]([CH3:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2nc(C)c(C)c(OCc3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)c(OCc1ccccc1)c(C)c(C)[n+]2[O-]
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 83.4 %

Procedure:
To an ice-cold solution of 4-(benzyloxy)-2,3,6-trimethylquinoline (1.36 g) in chloroform (25 mL) was added m-chloroperbenzoic acid (75%, 1.35 g), and the mixture was stirred for 4.5 hours. A 1M aqueous sodium hydroxide solution (10 mL) and water (10 mL) were added to the reaction mixture, followed by extraction with chloroform (20 mL). The organic layer was washed sequentially with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to obtain 4-(benzyloxy)-2,3,6-trimethylquinoline-1-oxide (1.20 g).
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)C.[C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH3:15].[Li]>>[C:18]([O:17][C:14](=[O:16])[CH2:15][C:4]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)=[O:13])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccnc(C#N)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from 2-cyano-isonicotinic acid ethyl ester [CAS-No. 58481-14-4] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light brown solid (7.70 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[O:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[O:20]1[CH2:21][CH:22]=[C:23]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(C3=CCOCC3)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.4 g, 4.76 mmol) in dioxane (6 mL) was added 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.0 g, 4.76 mmol), Pd(dppf)Cl2DCM (408 mg, 0.5 mmol) and sat. NaHCO3 solution (2 mL). The mixture was stirred at 100° C. for 2 h under nitrogen. The mixture was cooled to rt and diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 930 mg (86%) of the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.13-2.16 (2H, m), 2.53 (2H, s), 2.65 (2H, t, J=6.4 Hz), 2.96 (2H, t, J=6.0 Hz), 3.94 (2H, t, J=5.6 Hz), 4.34 (2H, s), 6.26 (1H, s), 7.25 (1H, d, J=5.6 Hz), 7.33 (1H, d, J=8.4 Hz), 7.99 (1H, d, J=8.0 Hz). [M+H] Calc'd for C15H16O2, 229. Found, 229.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:17][O:18][C:19](=[O:45])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:41](=[CH:42][CH:43]=1)[O:40][C:27]1([CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[CH2:26][C:25]2=[O:44]>CC(C)=O>[CH3:17][O:18][C:19](=[O:45])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:41](=[CH:42][CH:43]=1)[O:40][C:27]1([CH2:28][CH2:29][N:30]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:31][CH2:32]1)[CH2:26][C:25]2=[O:44]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(F)cc3)CC1)O2
Temperature: 50 °C
Reaction time: 54 h
Yield: 94.2 %

Procedure:
K2CO3 (414 mg, 3 mmol) and 1-(2-bromo-ethyl)-4-fluoro-benzene (0.21 ml, 1.5 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (254 mg, 0.752 mmol, Intermediate 1, hydrochloride salt) in acetone (10 ml). The mixture was stirred at 50° C. for 54 h, then the solvent was evaporated and the residue was partitioned between water and DCM. The organic phase was dried, then evaporated and the crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1 to 98:2) to give (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (300 mg) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(O)=S
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 16 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-methylthiobutanoic acid (7.86 g) and ethyl 4-aminophenylacetate (3.64 g) were condensed in dichloromethane (80 ml) in the presence of N,N'-dicyclohexylcarbodiimide (5.28 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (1.67 g).