Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[C:24]([C:30](OCC)=[O:31])=[CH:23]2>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[C:24]([C:30](=[O:31])[CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:23]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1C
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C(=O)CC(=O)OC(C)(C)C)cc2cc(Cl)ccc21
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of LHMDS (20.1 mL, 1.0 M in THF, 20.1 mmol) in THF (10 mL), was added tert-butyl acetate (2.71 mL, 20.1 mmol). After 30 min, a solution of the title compound of Example 11 Step A (1.59 g, 6.7 mmol) in THF (10 mL) was added. After 30 min, the reaction mixture was placed in a 0° C. bath, and was stirred at this temperature for 3 h, whereupon it was quenched by addition of sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30%, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS C, tr=2.38 min, m/z 252.2 [M−tBu+H]+; 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J=2.0 Hz, 1H), 7.34 (dd, J=9.0, 2.0 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 7.21 (s, 1H), 4.06 (s, 3H), 3.87 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH:14]=[N:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: Nc1cccc(Cl)c1
Product: CN(C)C=Nc1cccc(Cl)c1
Yield: 100.5 %

Procedure:
A mixture of 3-chloroaniline (63.8 g, 0.50 mol) and dimethylformamide dimethyl acetal (106 ml, 0.75 mol) was heated at 100° for 2 h and evaporated at 60° at 0.5 mm Hg to give 91.8 g amber oil; ms 183.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:7].[CH:8]1[N:13]=[C:12](Cl)[C:11]2[N:15]=[CH:16][N:17]([C@@H:18]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@H:19]3[OH:26])[C:10]=2[N:9]=1.C(N(CC)CC)C>O1CCOCC1>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:12]1[C:11]2[N:15]=[CH:16][N:17]([C:10]=2[N:9]=[CH:8][N:13]=1)[C@@H:18]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@H:19]1[OH:26]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@H](O)[C@@H]1O
Temperature: 100 °C
Yield: 18.4 %

Procedure:
Trans-2-hydroxycyclopentylamine (0.35 g, 3.46 mmol)(prepared by reaction of cyclopentene oxide with ammonia in a sealed vessel: see example 11) was reacted with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-9H-purine) (0.5 g, 1.7 mmol) in dioxan (30 ml) in the presence of triethylamine (0.93 g, 9 mmol). The reaction mixture was heated at 100° C. for 70 h, cooled and evaporated. The resultant residue was purified by flash chromatography eluting with a mixture of ethyl acetate and methanol (19:1). The fractions found to contain the highest amounts of N-[(1R, trans)-2-hydroxycyclopentyl]adenosine following HPLC examination, were combined and evaporated to a solid (0.17 g). Recrystallisation from methanol provided the pure N-[(1R, trans)-2-hydroxycyclopentyl]adenosine (0.11 g, 18%) mp 233°-235° C. 1H NMR (DMSO-d6)δ 1.43-2.12 (6H, 4m, --CH2CH2CH2 --), 3.52-3.59 (1H, m, H-5'a), 3.54-3.71 (1H, m, H-5'b), 3.97 (1H, q, H-4'), 4.07 (1H, br, --C HOH) 4.15 (1H, q, H-3'), 4.61 (1H, q, H-2'), 4.87, 5.21, 5.41-5.47 (4H, d & 3m, OH groups), 5.89 (1H, d, H-1'), 7.75 (1H, br d, --NH), 8.21 and 8.37 (H-2 and H-8).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C.C(OCC)(=O)C>[C:12]([Si:16]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13]
Reactant: OC1CC=CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CC=CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.9 %

Procedure:
Cyclopent-3-en-1-ol (10 g, 118.9 mmol) was dissolved in DMF (100 mL) at 0° C., then 1H-imidazole (17.29 mL, 261.5 mmol) was added, followed by tert-butyl(chloro)-dimethylsilane (21.5 g, 142.7 mmol). The mixture was warmed to room temperature and stirred for 14 h. The mixture was diluted with ethyl acetate (300 mL), washed with 5% aqueous LiCl solution (2×100 mL) and brine (50 mL), then dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by chromatography, eluting with 0-10% EtOAc in hexane, to afford the title compound (17.2 g, 73%) as a colourless clear liquid. δH (250 MHz, CDCl3) 5.66 (s, 2H), 4.53 (tt, J 7.0, 3.6 Hz, 1H), 2.57 (dd, J 15.2, 6.8 Hz, 2H), 2.27 (dd, J 15.3, 3.6 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C(C)=CC=CC=1C.BrC1C=C(NC(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(F)c1F
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Solvent: Cc1cccc(C)n1
Product: O=C(/C=C/c1ccccc1)Nc1cccc(F)c1F

Procedure:
The compound was prepared from 2,3-difluoroaniline (5 g, 38.7 mmol) and cinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine (6.8 mL, 58 mmol) as described for Intermediate 18 to give a colorless solid, 7.4 g (74%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11]([N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:19])[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CNc1ccccc1
Reactant: Cc1ccccc1Nc1nc(Cl)c2sccc2n1
Solvent: ClCCl
Product: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2sccc2n1
Yield: 40.1 %

Procedure:
2-(2-Methylphenylamino)-4-chlorothieno[3,2-d]-pyrimidine (1.5 g, 0.0054 mol) and N-methylaniline (1.16 g, 0.0054 mol) were heated in an oil bath at 140° for 2 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 2N hydrochloric acid (3×100 ml), then sodium carbonate solution. The dichloromethane extracts were dried over magnesium sulphate, filtered and evaporated to give a solid. Recrystallization from methanol gave the title compound, (0.75 g) m.p. 198°-200°.
Reaction SMILES: [C:1]([CH:7]([OH:13])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.O>[Si:19]([CH:10]([OH:11])[CH:9]([OH:12])[CH2:8][CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[OH:13])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)C(=O)C(O)CC(O)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)C(O)CC(O)C(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 1 (70 g, 0.368 mol) in CH2Cl2 (2.0 L) is added imidazole (31.3 g, 0.46 mol) and tert-butyldimethylsilyl chloride (58.2 g, 0.386 mol) and stirred at room temperature for 3 h. The reaction mixture is diluted with water, the organic layer separated and washed with water and brine and then dried over MgSO4. After filtration, the filtrate is concentrated and the residue is purified on a silica gel column using ethyl acetate:hexanes as eluent to give 91.2 g (81%) of product as an oil: 1H NMR (DMSO-d6): δ 4.66 (d, J=5.2 Hz, 1H), 4.14-3.90 (m, 2H), 3.54-3.25 (m, 3H), 1.84-1.72 (m, 1H), 1.51-1.39 (m, 1H), 1.10 (s, 9H), 0.83 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:28][CH2:27][C@H:26](O)[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.C(N(S(F)(F)F)CC)C>ClCCl>[CH:23]1([C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH2:28][CH2:27][CH:26]=[CH:25][CH2:24]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Oc1ccc(C2CC=CCC2)c(O)c1
Temperature: -78 °C
Reaction time: 15 h
Yield: 37.5 %

Procedure:
To a round bottomed flask was added cis/trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (208 mg) and dichloromethane (3 ml). The resulting solution was cooled to −78° C., and diethylaminosulfur trifluoride (69 μl) added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 15 hr. The reaction mixture was partitioned between water (10 ml) and dichloromethane (20 ml), the layers were separated and the aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic phases were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was dissolved in tetrahydrofuran (3 ml) and tetrabutylammonium fluoride (0.81 ml, 1.0M in tetrahydrofuran) and stirred at room temperature for 15 hr. The reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml) and the layers were separated. The aqueous phase was extracted with ethyl acetate (3×20 ml) and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, 3:7 v/v) furnished the title compound (34 mg, 38%) as an off-white solid. δH (CD3OD): 1.69-1.86 (2H, m), 2.00-2.19 (4H, m), 3.09 (1H, tt), 5.67-5.80 (2H, m), 6.16 (1H, d), 6.20 (1H, dd), 6.91 (1H, d); m/z (ES−) 198 (M−H−).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]([S:49](Cl)(=[O:51])=[O:50])=[N:47][CH:48]=1>O1CCCC1>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:49]([C:46]2[CH:45]=[CH:44][C:43]([O:42][CH3:41])=[CH:48][N:47]=2)(=[O:50])=[O:51])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(S(=O)(=O)Cl)nc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)nc1
Yield: 93 %

Procedure:
To a suspension of sodium hydride (60% in oil, 168 mg) in tetrahydrofuran (10 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (970 mg), 15-crown-5 (925 mg) and a solution of 5-methoxypyridine-2-sulfonyl chloride (984 mg) in tetrahydrofuran (15 mL) at room temperature, and the mixture was stirred for 30 min. The reaction mixture concentrated under reduced pressure to a half volume, diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=17:3→1:1) to give the title compound as a yellow oil (yield 1.38 g, 93%).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[N:15][CH:16]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[N:15][C:14]([NH:17][C:18]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH2:45][CH2:44][CH3:43]
Reactant: O=C(Nc1ccc(C2=CCNCC2)cn1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: CCCC(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccccc4C3)nc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting butyryl chloride for acetyl chloride and N-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.92-8.95 (bs, 1H), 8.32-8.35 (m, 1H), 7.64-7.97 (m, 2H), 6.94-7.38 (m, 4H), 6.16-6.22 (bs, 1H), 4.45-5.02 (m, 4H), 4.08-4.15 (m, 2H), 3.62-3.68 (m, 2H), 2.23-2.65 (m, 4H), 1.46-1.64 (m, 2H), 0.87-0.93 (m, 3H); MS (ESI(+)) m/e 391 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
To a mixture of 4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70°-75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture is chromatographed (silica gel, toluene/ethyl acetate, 7/3) to give 2-(4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:15]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C@@H:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:15]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C@@H:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 78 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed oxalyl chloride (0.080 mL, 0.92 mmol) and methylene chloride (0.7 mL). The solution was cooled to 78° C. prior to the dropwise addition of dimethyl sulfoxide (0.080 mL, 1.13 mmol) in methylene chloride (0.3 mL). After stirring the solution for 45 min, a solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-hydroxypiperidine-1,2,3-tricarboxylate (266 mg, 0.567 mmol) in methylene chloride (1 mL) was added dropwise and the solution was allowed to gradually warm to ca. 0° C. over 1.5 h. The reaction mixture was cooled to 78° C. prior to the dropwise addition of triethylamine (0.240 mL, 1.72 mmol) and stirring was continued for 3 h with gradual warming to ca. 0° C. The reaction was quenched by the dropwise addition of 5% citric acid (2 mL) and diluted with methylene chloride (15 mL). The organic layer was washed with brine (2×5 mL), dried (NaSO4), and concentrated in-vacuo to afford 264 mg (100%) of the desired ketone as a sticky yellow oil. LCMS (ESI): 490 (M+Na+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:17])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Into a solution of 3-fluoro-4-nitro-benzoic acid (4.0 g, 21.6 mmol) in anhydrous CH2Cl2 (200 mL) at 0° C. was slowly added oxalyl chloride (2.45 mL, 28.0 mmol) and a drop of DMF. The solution was stirred and allowed to warm to RT overnight before concentrating under reduced pressure to give 3 (4.39 g, 100%).
Reaction SMILES: [F:1][C:2]1([C:15](OCC)=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1([CH2:15][OH:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (2 g) was taken up in tetrahydrofuran (20 ml) and cooled in an ice bath. Lithium aluminum hydride (1.0M in dioxane, 5.09 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with water and with 1M aqueous NaOH solution and then stirred another 1 hour at room temperature. The mixture was extracted with ethyl acetate, and the extracts were combined and washed with water and with brine, dried over MgSO4, filtered and concentrated under vacuum. The crude product was used without further purification.
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.[CH3:19]O>[Pd]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH3:19])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1
Reactant: CO
Reactant: CN(C)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Agent: [Pd]
Product: CNc1ccc(NC)c(N2CCCCC2)c1
Yield: 100 %

Procedure:
Using a procedure similar to Example 3, step (c), dimethyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (100 mg, 0.4 mmol, as prepared in the previous step) was stirred with 80 mg 5% Pd—C in 5 mL MeOH under H2 to afford 89 mg (100%) of the title compound as an oil, which was used immediately without further purification. Mass spectrum (ESI, m/z) calcd. for C13H21N3, 220.1 (M+H), found 220.1.
Reaction SMILES: CNN.[C:4]([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=[CH:15]/[C@H:16]2[O:21][CH2:20][C@H:19]([S:22][C@H:23]([CH3:55])[C@@:24]([O:39][C:40](=[O:54])[CH2:41][CH2:42][N:43]3C(=O)C4C(=CC=CC=4)C3=O)([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])[CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[CH2:18][O:17]2)=[C:8]([F:56])[CH:7]=1)#[N:5]>ClCCl>[C:4]([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=[CH:15]/[C@H:16]2[O:21][CH2:20][C@H:19]([S:22][C@H:23]([CH3:55])[C@@:24]([O:39][C:40](=[O:54])[CH2:41][CH2:42][NH2:43])([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])[CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[CH2:18][O:17]2)=[C:8]([F:56])[CH:7]=1)#[N:5]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)CCN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1F
Agent: CNN
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)CCN)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
222.7 mg (4.38 mmol) of methylhydrazine were added to a solution of 100 mg (0.13 mmol) of [(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl]3-(1,3-dioxo-1,3-dihydro-2-isoindolyl)propionate [prepared as described in Step 13(i) above] in 2 ml of dichloromethane in an ice bath. The resulting mixture was stirred at ambient temperature for 20 hours. At the end of this time, the reaction mixture was concentrated and then evaporated to dryness in vacuo. Dichloromethane was added to the resulting residue and the dichloromethane was then evaporated under reduced pressure. The resulting residue was then dissolved in dichloromethane, the solution was allowed to stand at ambient temperature for 12 hours and then concentrated. The residue thus obtained was purified by chromatography on a silica gel (15 g) column using a 9:1 mixture of ethyl acetate and methanol to give 41.5 mg (yield 50%) of the title compound as a pale yellow non-crystalline solid.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.CCCCCC.[CH3:19][C:20]1[CH:21]([C:28](=[O:30])C)[C:22]2([CH2:25][CH2:26][CH:27]=1)[CH2:24][CH2:23]2.C(=O)C.Cl.[Na+].[Cl-].C([O-])(O)=O.[Na+]>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:19][C:20]1[CH:21]([C:28](=[O:30])/[CH:7]=[CH:5]/[CH3:6])[C:22]2([CH2:25][CH2:26][CH:27]=1)[CH2:23][CH2:24]2
Reactant: CC(=O)C1C(C)=CCCC12CC2
Reactant: CC(C)NC(C)C
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C/C=C/C(=O)C1C(C)=CCCC12CC2
Temperature: -10 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
At −78° C. under N2, a solution of diisopropylamine (0.53 ml, 3.72 mmol) in anhydrous THF (2.75 ml) was treated dropwise with a solution of 1.6M n-BuLi in hexane (2.33 ml, 2.75 mmol). The resulting solution was warmed to −10° C., cooled to −78° C., and treated dropwise with a solution of 1-(5-methylspiro[2.5]oct-5-en-4-yl)ethanone (470 mg, 2.87 mmol) in anhydrous THF (2.75 ml). The resulting solution was warmed to −20° C., cooled to −78° C. and treated with a solution of acetaldehyde (0.81 ml, 14.3 mmol) in anhydrous THF (2.75 ml). The resulting solution was warmed to −10° C., cooled to −78° C., and treated slowly with a mixture of 2N HCl (6 ml) and of a saturated aqueous solution of NaCl (3.6 ml). The mixture was then warmed to 0° C., the aqueous phase extracted three times with Et2O and the combined organic phases washed with a saturated aqueous solution of NaHCO3, a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaCl, dried (Na2SO4), and concentrated. The residue (596 mg) was dissolved in toluene (20 ml) and treated with para-toluene sulfonic acid monohydrate (27 mg, 0.143 mmol). The resulting solution was stirred at 80° C. for 3 h, cooled, and poured into a saturated aqueous solution of NaHCO3. The aqueous phase was extracted three times with Et2O and the combined organic phases washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaCl, and concentrated. FC (200 g SiO2, hexane/Et2O 10:0.5) of the crude product (730 mg) gave (E)-1-(5-Methylspiro[2.5]oct-5-en-4-yl)but-2-en-1-one (0.354 g, 64%, 2 steps). Boiling point: 50° C. (0.07 mbar).