Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)=[C:16]([F:27])[C:15]=1[F:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OCC)(=O)C.N>C1COCC1>[CH2:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]2)=[C:16]([F:27])[C:15]=1[F:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc([C@H]2CC[C@H](O)CC2)c(F)c1F
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (1.47 g) was suspended in THF (200 ml). 4-(4′-Hexyloxy-2,3,-difluorophenyl)-cyclohexanone (s-14) (20.0 g) dissolved in THF (50 ml) was added dropwise to the suspension in the temperature range of −20° C. to −10° C., and the stirring was continued in this temperature range for another 2 hours. After the completion of the reaction had been confirmed by means of GC analysis, ethyl acetate and then a saturated aqueous solution of ammonia were added to the reaction mixture under ice-cooling and deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic phase was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by recrystallization from heptane to give trans-4-(4′-hexyloxy-2,3,-difluorophenyl)-cyclohexanol (s-29) (16.3 g). The yield based on the compound (s-27) was 81.0%.
Reaction SMILES: NC([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19]([C:21]3([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:23][CH2:22]3)=[O:20])=[C:13]([F:34])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)=O.O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C[N:52](C)C=O>>[NH2:52][C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19]([C:21]3([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:22][CH2:23]3)=[O:20])=[C:13]([F:34])[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1
Solvent: O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
Benzyl 1-{[(4-{[2-(aminocarbonyl)pyridin-4-yl]oxy}-2,5-difluorophenyl)amino]carbonyl}cyclopropanecarboxylate (1.55 g) was dissolved in N,N-dimethylformamide (33 ml). Water (0.299 ml) and iodobenzene diacetate (1.18 g) were added at room temperature, and the mixture was stirred for 15 hours and 20 minutes. Iodobenzene diacetate (215 mg) was added again and the mixture was stirred for 2 hours and 20 minutes. Water (150 ml) was added to the mixture, and the mixture was stirred for 1 hour, and partitioned after the addition of a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and ethyl acetate (300 ml). The organic layer was washed with water (200 ml, twice) and brine (150 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (1.217 g, 83%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cn4)cc3)(CC1)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)OC5)cc3)nc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a reaction vial containing methyl 2-(4-(4-(5-(5-tert-butyl-1,3,4-oxadiazol-2-ylamino)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (55 mg, 0.12 mmol) was added THF (1.5 ml) and a solution of 1N NaOH (0.35 ml, 0.35 mmol). The mixture was stirred vigorously at room temperature for overnight. The resulting mixture was concentrated to dryness and the residue was taken up in water. The mixture was acidified with 1N HCl to a pH of between 3 and 4 affording a thick residue. The residue was concentrated to dryness and taken up in MeOH to form fine slurry. The slurry was filtered and washed with small amount of MeOH and water to afford the title compound as white solid after drying (36 mg, 67% yield). HR/MS (M+H)+ found 463.2354. calc. 463.2345. RT: 5.76 (Condition Z). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (br. s, 1H) 10.78 (br. s, 1H) 8.76 (d, J=2.78 Hz, 1H) 8.04-8.13 (m, 1H) 7.90-8.01 (m, 3H) 7.41 (d, J=8.59 Hz, 2H) 3.90 (s, 2H) 2.29 (s, 2H) 1.82-2.08 (m, 8H) 1.36 (s, 9H)
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C@@H:6]([CH2:11][N+:12]([O-])=O)[CH2:7][CH:8]([CH3:10])[CH3:9])C.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:10][CH:8]([CH2:7][C@H:6]([CH2:11][NH2:12])[CH2:5][C:4]([OH:15])=[O:3])[CH3:9]
Reactant: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
(S)-5-Methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl) (10.4 g) were dissolved in 160 mL of MeOH. 4 g of 10% Pd/C and 20 g of ammonium formate were added. After a few minutes an exothermic reaction was observed. After 30 minutes HPLC analysis indicated complete conversion. The catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to a volume of about 20 mL. Water (20 mL) was added, then the solution was again concentrated unter reduced pressure to about 20 mL. Then 50 mL of 6N aqueous HCl were added and the mixture was refluxed for 6 hours. After complete conversion, the reaction mixture was concentrated under reduced pressure to about 20 mL. Water (20 mL) and 2-propanol (40 mL) were added and the reaction mixture was heated to 45° C. KOH was added until a pH of 7 was reached. The product started to crystallize. Within about 60 minutes the reaction mixture was cooled down to 10° C. Stirring was continued for 1 hour, then the product was isolated by filtration. The filter cake was washed with 90 mL of a 1:1 mixture of cold H2O/2-propanol. After drying, 5.9 g of substantially pure pregabalin (purity 98.0%) were obtained (yield: 81%).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([CH3:27])=[CH:15][C:14]=1Br)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>O1CCOCC1.CCOC(C)=O.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:20]([O:19][C:17]1[C:16]([CH3:27])=[CH:15][C:14]2[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:12][C:13]=2[CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(Br)c(NC(=S)NC(=O)c2ccccc2)cc1OCc1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2sc(NC(=O)c3ccccc3)nc2cc1OCc1ccccc1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
To a solution of 1-benzoyl-3-(5-benzyloxy-2-bromo-4-methyl-phenyl)-thiourea II (1.0 g, 2.20 mmol) in 1,4-dioxane (30 mL) was added sequentially Pd2(dba)3 (0.12 g, 0.12 mmol), dppf (0.07 g, 0.12 mmol) and KOtBu (0.75 g, 3.30 mmol) at room temperature under N2 atmosphere. The resulting reaction mixture was heated at 80° C. for 6 h. After completion of reaction (TLC monitoring), the reaction mixture was diluted with EtOAc and filtered through celite bed-bed. The filtrate was concentrated and purified over silica gel (100-200 M, 20% EtOAc-Hexane) to obtain the desired product (0.50 g, 61%). 1H NMR (400 MHz, DMSO-d6): δ 2.31 (s, 3H), 5.23 (s, 2H), 7.33 (m, 1H), 7.39 (m, 3H), 7.52 (m, 2H), 7.54 (m, 2H), 7.64 (m, 1H), 7.76 (s, 1H), 8.13 (d, J=7.60 Hz, 2H) and 12.77 (br s, 1H). MS: 375.19 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:26])[CH3:25])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CC(=O)Cl
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.65 g, 1.9 mmol) in acetonitrile (10 mL), was added acetyl chloride (0.13 mL, 1.8 mmol) and N,N-diisopropyl ethylamine (0.70 mL, 4.3 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as a light yellow solid (104 mg, 16% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 3.93 min (99.0%); mp, 293-291° C.; 1HNMR (DMSO-d6)1.92 (s, 3H, CH3), 2.14-2.20 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.73-4.77 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.31-7.76 (m, 3H, Ar), 8.22 (t, J=6 Hz, 1H, CH2NH); 13C NMR (DMSO-d6) δ 20.78, 22.60, 23.26, 30.58, 41.49, 56.48, 117.65, 124.48, 125.42, 133.83, 141.06, 148.44, 154.75, 160.95, 169.32, 169.51, 172.58. LCMS MH=343; Anal Calcd For C17H18N4O4: C, 59.64; H, 5.30; N, 16.37. Found: C, 59.46; H, 5.05; N, 16.24.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].II.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>[Cu].O.CN1CCCC1=O>[NH:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: c1c[nH]cn1
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: [Cu]
Agent: II
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCOc1ccc(-c2ncc[nH]2)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Temperature: 180 °C

Procedure:
A stirred mixture of 2-(5-bromo-2-n-propoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 11; 0.6 g, 0.0016 mol), anhydrous potassium carbonate (0.22 g, 0.0016 tool), copper bronze (0.1 g, 0.0016 mol), iodine (0.051 g, 0.004 mol), imidazole (0.55 g, 0.008 mol) and 1-methyl-2-pyrrolidinone (20 ml) was heated at 180° C. under a nitrogen atmosphere for 6 hours. The mixture was cooled and poured into water (150 ml), then the resulting mixture extracted with a dichloromethane-methanol mixture (9:1, 4×40 ml ). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum. The semi-solid residue was chromatographed on silica gel (10 g) using a methanol in dichloromethane elution gradient (0-4% ). Evaporation of the appropriate fractions gave the title compound which crystallized from ethyl acetate as colorless needles (0.016 g, 3%); Rf 0.5 (silica; dichloromethane-methanol 95:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([O:10][C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc(F)c1O
Product: COc1cccc(F)c1Oc1nc(Cl)ncc1Cl

Procedure:
2,5-Dichloro-4-(2-fluoro-6-methoxy-phenoxy)-pyrimidine was prepared from 2-Fluoro-6-methoxy-phenol and 2,4,5-Trichloropyrimidine in an analogous manner to Example 1230a. (1.95 g, 96%) LCMS 290 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1H), 7.38-7.34 (m, 1H), 7.10-7.03 (m, 2H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][CH:23]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[CH2:24]2)=[C:13](/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([CH:23]1[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[CH2:24]1)[C:17](=[O:18])[CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1NC1CCC(c2cccc(F)c2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1ccc2cc(SCc3ccccc3)ccc2n1C1CCC(c2cccc(F)c2)C1
Temperature: 100 °C
Reaction time: 36 h
Yield: 23.5 %

Procedure:
A 25-mL pressure vessel was charged with (E)-ethyl 3-(5-(benzylthio)-2-((3-(3-fluorophenyl)cyclopentyl)amino)phenyl)acrylate (800 mg, 1.682 mmol), methanol (8.4 ml), and a solution of sodium methoxide in methanol (0.5 M, 3.4 mL, 1.682 mmol). The reaction. vessel was sealed with a Teflon cap and the yellow reaction mixture was warmed to 100° C. After 36 h, additional solution of sodium methoxide in methanol (0.5 M, 3.4 mL, 1.682 mmol) was added and the reaction vessel was sealed and warmed to 100° C. After 12 h, the reaction mixture was allowed to cool to ambient temperature and concentrated under reduced pressure to furnish a yellow residue, which was purified by flash column chromatography (50-g Biotage column, eluent: gradient, 20 to 30% EtOAc in heptane) to afford 6-(benzylthio)-1-(3-(3-fluorophenyl)cyclopentyl)quinolin-2(1H)-one (170 mg, 0.396 mmol, 23.53% yield). m/z (ESI) 430.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:16]=[C:17]([C:24]2[S:28][C:27]([CH2:29][CH2:30][C@@H:31]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:32][C:33]3[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=3)=[N:26][N:25]=2)[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>C1COCC1>[C:46]([O:45][C:44]([NH:43][C@@H:31]([CH2:32][C:33]1[CH:34]=[N:35][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:37][CH:38]=1)[CH2:30][CH2:29][C:27]1[S:28][C:24]([C:17]2[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:16]=2)=[N:25][N:26]=1)=[O:50])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)Cc1ccc(C(F)(F)F)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(CC[C@H](Cc3ccc(C(F)(F)F)nc3)NC(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (48 mg, 1263 μmol) was added to a solution of diethyl malonate (191 μL, 1263 μmol) in THF (2 mL) and the mixture was stirred at room temperature for 15 minutes. This mixture was added to a solution of tert-butyl (R)-4-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (171 mg, 316 μmol) in THF (3 mL) and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the residue was partitioned between saturated aqueous NH4Cl (15 mL) and DCM (15 mL). The layers were separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 40% to 70% EtOAc/hexanes) to provide diethyl 2-(5-(5-((R)-3-(tert-butoxycarbonylamino)-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)malonate (204 mg, 95% yield) as a yellow solid. LCMS (API-ES) m/z: 703.6 (M+Na+).
Reaction SMILES: [OH2:1].O.P([O-])(O)(O)=O.[Na+].CC(=CC)C.[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH3:32])[CH:28]=[C:27]2[CH:33]=[O:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Na+]>C(O)(C)(C)C.O>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH3:32])[CH:28]=[C:27]2[C:33]([OH:1])=[O:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C=O)c2cccc(OCc3ccccc3)c2n1
Reactant: O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: CC(C)(C)O
Product: Cc1cc(C(=O)O)c2cccc(OCc3ccccc3)c2n1
Yield: 98.5 %

Procedure:
To a stirred solution of sodium dihydrogenphosphate dihydrate (788 mg) and 2-methyl-2-butene (885 mg) in tert-butanol (12 ml) and water (3 ml) was added 8-benzyloxy-4-formyl-2-methylquinoline (700 mg) and sodium chloride (79% purity, 457 mg) successively at ambient temperature. After being stirred for one and half an hour, the reaction was quenched with water (12 ml), then the pH of the mixture was adjusted to about 3-4 by addition of 1N hydrochloric acid. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The organic phase was concentrated in vacuo and the residual solid was triturated with diethyl ether to give 8-benzyloxy-4-carboxy-2-methylquinoline (729 mg, 98.5%) as a pale yellow powder.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1.[FH:40].[K].CCCC[N+](CCCC)(CCCC)CCCC.F.F.[F-].ClC1C=CC=CC=1>C1(C)C=CC=CC=1>[F:40][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CO3)CC2)c2ncnn12
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K]
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CF)CC2)c2ncnn12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 4′-({4-[trans-4-(oxiran-2-ylmethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.25 g), potassium hydrogen fluoride (0.075 g), tetra-n-butylammonium dihydrogentrifluoride (0.015 g) and chlorobenzene (1 mL) was stirred at 120° C. for 5 hr. Potassium hydrogen fluoride (0.075 g) and tetra-n-butylammonium dihydrogentrifluoride (0.014 g) were added, and the mixture was stirred at 120° C. for 16 hr. Toluene was added, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:8][CH:9]=1
Reactant: C=C(C)C(=O)NCCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C=C(C)C(=O)NCCc1ccc(N)cc1
Reaction time: 4 h

Procedure:
Subsequently, N-[2-(4-nitrophenyl)ethyl]methacrylamide (1.20 g) was dissolved in ethanol (15 mL) and water (5 mL). Ammonium chloride (364 mg) and iron powder (933 mg) were added, and the reflux was performed at 80° C. for 4 hours. Iron powder was collected by the filtration, and the filtrate was evaporated under the reduced pressure. Water and ethyl acetate were added to the residual oil and the organic layer was separated. The organic layer was washed with water and brine, dried over anhydrous sodium filfate, and evaporated to give the desired compound as a pale red oily substance. The yield was 1.01 g (97%). Spectrum data of 1H-NMR (400 MHz, CDCl3) is shown for the obtained compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][N:13]1C(=O)CCC1.C1COCC1>[C-]#N.[Zn+2].[C-]#N.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd]>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CN1CCCC1=O
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CCC2=O
Temperature: 120 °C

Procedure:
To a mixture 5-bromo-indan-1-one (1 g, 4.7 mmol), zinc cyanide (1.11 g, 9.4 mmol) in NMP/THF (2 mL/4 mL) in a sealed tube, is added palladium bis(tri-t-butyl-phosphine) (120 mg, 5% mmol). The mixture is purged with N2 and heated at 120° C. for 3 h. Then the reaction mixture is cooled to rt, diluted with H2O, and extracted with EtOAc (3×20 mL). The combined organic phases are washed with saturated ammonium chloride aqueous solution and brine and dried over Na2SO4. The crude product obtained after concentration is purified by silica gel column chromatography with mixed solvent hexanes/EtOAc (5/1-3/1) to afford 1-oxo-indan-5-carbonitrile as a light yellow solid: ESMS m/z 158.0 (M+H+).