Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([C:30]4[CH:31]=[CH:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=4)[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: O=C(c1cccc(I)c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2cccc(C(=O)c3cn(C4CCCC4)c4ncnc(Cl)c34)c2)cc1
Yield: 47 %

Procedure:
A solution of (4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-iodo-phenyl)-methanone (100 mg, 0.22 mmol), 4-(dimethylamino)Phenyl boronic acid (42.9 mg, 0.26 mmol), PdCl2(PPh3)2 (7.7 mg, 0.011 mmol), and K2CO3 (45.6 mg, 0.33 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was heated to 90° C. After 24 h the reaction was diluted with EtOAc and filtered through celite. The filtrate was washed with water, dried over Na2SO4, and concentrated. Purification by flash column chromatography (hexanes/ethyl acetate 8:2) afforded the title compound as a white solid (46 mg, 47%). MS: 445.1/447.1 (MH+); HPLC Rf: 8.05 min. (HPLC method 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33](O)=[O:34])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl.C(N(C(C)C)C(C)C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[NH:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccccc1Nc1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccccc4Nc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C

Procedure:
4-(6,7-Dimethoxyquinolin-4-yloxy)benzenamine (60 mg, 202 μmol), 2-(4-fluorophenylamino)benzoic acid (56 mg, 243 μmol), and HATU (108 mg, 283 μmol) were combined in a resealable tube. DCM (1012 μl, 202 μmol) and N-ethyl-N-isopropylpropan-2-amine (71 μl, 405 μmol) were added, and the reaction mixture in the tube was allowed to stir at RT. Upon completion (as judged by LCMS), the reaction mixture was concentrated in vacuo, dissolved in minimal DMSO and purified by preparative HPLC {15-85% (0.1% TFA in CH3CN) in H2O over 20 min}. Fractions containing pure product were combined and neutralized with saturated aqueous NaHCO3 then extracted with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo to afford pure N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-2-(4-fluorophenylamino)benzamide as a off-white solid. MS Calcd for C30H24FN3O4: [M]+=509. Found: [M+H]+=510.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([OH:20])=O)[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].Cl.Cl.[CH3:33][C:34]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:38])[C:35]([NH2:37])=[O:36]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([N:42]4[CH2:41][CH2:40][N:39]([C:34]([CH3:38])([CH3:33])[C:35]([NH2:37])=[O:36])[CH2:44][CH2:43]4)=[O:20])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)(C(N)=O)N1CCNCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Agent: Cl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCN(C(C)(C)C(N)=O)CC3)n(C)c2n1

Procedure:
2-(2-Ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid was coupled with 2-methyl-2-(piperazin-1-yl)propanamide dihydrochloride according to General Procedure K to give 566. LCMS m/z: 281.3 (2M+H+)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:13]([CH:16]=[C:17](SC)[S:18][CH3:19])([O-:15])=[O:14]>C(#N)C>[N+:13]([CH:16]=[C:17]([S:18][CH3:19])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:15])=[O:14]
Reactant: NCCSCc1ncccc1Br
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1ncccc1Br

Procedure:
A solution of 2-[(2-aminoethyl)thiomethyl]-3-bromopyridine (from the dihydrobromide, 3.0 g) and 1-nitro-2,2-bis-methylthioethylene (1.21 g) in acetonitrile (30 ml) was set aside at room temperature for 3 days. The product was chromatographed on a column of silica gel with elution by ethyl acetate, to give 1-nitro-2-methylthio-2-[2-((3-bromo-2-pyridyl)methylthio)ethylamino]ethylene (1.2 g), m.p. 79°-80° (from ethanol-ether).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][N:22]=[C:16]2[CH2:15]1)=[O:13].C1C(=O)N([Br:30])C(=O)C1>CN(C)C=O>[Br:30][C:20]1[N:17]2[CH2:18][CH2:19][N:14]([C:12]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=3[Cl:1])=[O:13])[CH2:15][C:16]2=[N:22][CH:21]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2ccnc2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)cnc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (E1) (5.68 g, 17.23 mmol) was dissolved in N,N-dimethylformamide (DMF) (100 mL) and treated with NBS (3.22 g, 18.09 mmol). The solution was stirred at 25° C. for 16 h and the bulk of the DMF was removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and saturated sodium bicarbonate solution (100 ml). The aqueous phase was extracted with dichloromethane (5×100 ml) during which filtration through celite was required to remove emulsions and precipitated succinimide. The combined organic extracts were washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated to a crude oil. The crude product was purified by flash chromatography (Isolera, 340 g, 0-100% methanol:dichloromethane (1:9)/dichloromethane) to afford an oil that was triturated with hexane to afford a solid of desired product in 5.90 g.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][C@H:10]1[O:11][C:40](=[O:41])[C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Yield: 80 %

Procedure:
Since both the α and β isomers yielded the same β-bromide (compound 9), it was decided to skip the column purification and instead use the mixture as such. In this case, 2,3,4-tri-O-benzyl-L-fucopyranose (compound 6) (25 g, 55 mmol) was treated with p-nitrobenzoyl chloride (compound 7) as described above and the crude material (33.0 g) was dissolved in CH2Cl2 (100 mL) and simply filtered through a short column of silica gel. This removed the color and other polar material. This procedure furnished the anomeric mixture of esters (compound 8) as a gummy material (25.7 g, yield 80%).
Reaction SMILES: [C:1]([CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6])(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C.O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:4]([C:5]#[N:6])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1](=[O:3])[CH3:2])=[CH:16][CH:15]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(=O)C(C#N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)C(C#N)(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of α-acetylphenylacetonitrile (1.0 g, 6.3 mmol) in acetonitrile (25 mL) was added 4-chlorobenzyl bromide (1.3 g, 6.3 mmol) and cesium carbonate (8.2 g, 25 mmol). After stirring at room temperature for 2 h, the reaction mixture was poured into ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness, and the residue was purified on a silica gel column eluting with 1 to 5% ethyl acetate in hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.5-6.9 (m, 9H), 3.56 (d, 1H), 3.37 (d, 1H), 2.22 (s, 3H). LC-MS: m/e 306 (M+Na)+ (3.0 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[Br:14]C(Br)(Br)C=O.C(OCC)(=O)C>N1C=CC=CC=1.CN(C)C=O>[Br:14][CH2:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=CC(Br)(Br)Br
Reactant: COc1ccc2nc(C)ccc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2nc(CBr)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
A solution of 10 g (57.7 mmol) of 6-methoxy-2-methylquinoline and 30 drops of pyridine in 40 mL of N,N-dimethylformamide was stirred at 60° C. while a solution of 16.21 g (57.7 mmol) of tribromoacetaldehyde in 20 mL of N,N-dimethylformamide was added over 15 min. The reaction mixture was stirred for another 2 hr and then cooled and poured onto 600 mL of ice-water. Work-up with ethyl acetate was carried out in the usual manner. The crude product was purified by flash chromatography on 800 g of silica gel, eluting with hexane-ethyl acetate (4:1) afforded 4.45 g (30.6%) of the title compound as a violet solid. An analytical sample was obtained by recrystallization from ethanol to give colorless crystals, mp 103° C.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>C(O)C.O.O1CCOCC1.O>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)C)nc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(C(=O)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of ethyl 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (266 mg, 1.06 mmol) and lithium hydroxide (102 mg, 4.25 mmol) in ethanol:water:dioxane (1:1:1, 6 mL) was warmed to 40° C. and stirred overnight. The mix cooled to RT, diluted with water (25 mL) and washed with ether (20 mL). The aqueous phase made acidic with 3N HCl (pH˜2) and extracted with ethyl acetate (2×15 mL). The combined ethyl acetate layers were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (199 mg, 84% yield) as a white solid. MS (ESI) m/z: 223.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:10]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([OH:18])[C:8](=[O:19])[O:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:10]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([O:18][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])[C:8](=[O:19])[O:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)C1(CSCc2ccco2)OC(=O)C(O)=C1SCc1ccco1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CSCc2ccco2)OC(=O)C(OC(=O)C(C)(C)C)=C1SCc1ccco1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of 4-hydroxy-5-oxo-3-(2-furanylmethylsulfanyl)-2-[(2-furanylmethylsulfanyl)-methyl]-2,5-dihydrofuran-2-carboxylic acid ethyl ester (0.3 g, 0.73 mmol) in methylene chloride (25 mL) were added pyridine (0.19 mL, 2.36 mmol) and trimethylacetyl chloride (0.22 mL, 1.77 mmol, 2.4 eq) under argon atmosphere. The mixture was gently refluxed overnight under argon and then evaporated. The residue was purified by column chromatography eluted with a mixed solvent of hexane and ethyl acetate (4:1, v/v) affording 0.3181 g of 4-(2,2-dimethyl-propionyloxy)-3-(furan-2-ylmethylsulfanyl)-2-(furan-2-ylmethylsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester as light yellow oil. 1H NMR (CDCl3, 300.16 MHz) δ (ppm): 7.40-7.37 (m, 2H), 6.35-6.25 (m, 4H), 4.35 (s, 2H), 4.33-4.22 (m, 2H), 3.90 (d, J=14.7 Hz, 1H), 3.80 (d, J=14.7 Hz, 1H), 3.29 (d, J=15.1 Hz, 1H), 2.97 (d, J=15.1 Hz, 1H), 1.37 (s, 9H) and 1.29 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3, 75.48 MHz) δ (ppm): 174.35, 166.32, 163.84, 150.29, 148.27, 144.72, 143.10, 142.64, 136.15, 111.00, 110.47, 109.44, 108.98, 87.64, 63.40, 39.30, 36.15, 29.62, 28.02, 26.99 and 14.04. MS (ESI, rel. int.) m/z: 495 (M+H+, 25), 517 (M+Na+, 100).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:27])([F:26])[S:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:30]1([CH2:29][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([S:15][C:14]([F:26])([F:13])[F:27])=[CH:21][CH:20]=2)[C:23]([OH:25])=[O:24])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)Cc1ccc(SC(F)(F)F)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5 M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at −78° C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71° C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]=C)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:8]1[CH2:31][CH:30]([CH2:32][OH:34])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(CO)O3)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (135 mg, 0.30 mmol) in DCM (4 mL) and methanol (1 mL) at −78° C. was bubbled ozone until the solution turned faint blue. NaBH4 (91 mg, 2.41 mmol) and methanol (˜2 mL) was added under an atmosphere of nitrogen and the reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo, quenched with 4N HCl/dioxane, concentrated in vacuo, then diluted with methanol-water (1:1), microfiltered and purified by prep LCMS (1-99% ACN/Water, 5 mM HCl modifier) to give [8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (50 mg, 34%). ESI-MS m/z calc. 452.6. found 453.5 (M+1)+; Retention time: 1.18 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(Cl)c2n1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 15, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (50 mg, 20%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=475. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.40-5.56 (m, 2H), 7.65 (m, 1H), 7.79-7.95 (m, 4H), 8.10 (m, 1H) and 8.95 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.05 (s, 3F).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[CH3:35]N(C=O)C.[H-].[Na+]>C(Cl)(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH:33]=[CH:32][CH:35]=[C:31]([O:34][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=2[F:16])[CH2:30]1)=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C=CC=C(Oc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
To a mixture of 1.20 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.50 g of 1-t-butoxycarbonyl-3-hydroxypyrrolidine and 1,5 ml of DMF was added 483 mg of 55% sodium hydride while the former was stirred under ice cooling. The resultant mixture was stirred for further 20 hours at room temperature. The reaction mixture was diluted with chloroform and then successively washed with 10% aq. citric acid solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue thus obtained was recrystallized from ethanol, whereby 1.48 g of the title compound was obtained as pale green powder.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:5]1[C:9]([CH:29]=[O:30])=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCn1cc(C(OC)OC)nc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCn1c(-c2ccccc2)nc(C(OC)OC)c1C=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-butyl-4-dimethoxymethyl-2-phenyl-1H-imidazole 209 (2.74 g, 10 mmol) in anhydrous THF under nitrogen at −78° C., n-BuLi (1.6 M in hexane, 7.5 ml, 12 mmol) is added dropwise and the mixture is continued stirring at this temperature for 30 min. After anhydrous DMF (4 mL) is added, the mixture is stirred at room temperature for 16 h. Saturated ammonium chloride and ethyl acetate were added at 0° C. and the the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography to yield the desired product as a white solid. Yield: 1.94 g; LC-MS (MH+): 303. 1H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 7.60–7.56 (m, 2H), 7.51–7.46 (m, 3H), 5.63 (s, 1H), 4.32 (t, J=6.3 Hz, 2H), 3.47 (s, 6H), 1.73–1.63 (m, 2H), 1.28–1.16 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1ccc(OC)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(OC)cc1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
2-Methyl-1,4-bis(methyloxy)benzene (6.12 g, 40 mmol) was dissolved in acetic acid (20 mL) and heated at 40° C. A solution of nitric acid (4.32 g) in acetic acid (10 mL) was added to above solution drop wise over 5 minutes. The reaction mixture was stirred at 40° C. for 30 min (yellow precipitates formed), then room temperature for 30 min and then diluted with water (300 mL). The precipitate was collected by filtration, washed with water, and dried in the air for 16 h to afford the title compound (7.56 g, 96%) as a yellow solid. MS (ES) m/e 198 [M+H]+.