Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:23])=[C:12]([CH2:19]C(O)=O)[CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:23])=[C:12]([CH3:19])[CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 25 °C
Yield: 88 %

Procedure:
The crude {3-[(3-bromo-5-chlorophenyl)oxy]-2-fluoro-4-nitrophenyl}acetic acid was dissolved in CH3CN (150 mL) and Cu2O (1.18 g, 8.22 mmol) was added. A condenser was attached and the heterogeneous mixture was heated to reflux for 3 h. The reaction mixture was cooled to RT, filtered through Celite and the solvent evaporated. The crude brown oil was purified by column chromatography (5% to 70% EtOAc/hexanes gradient) to afford the title compound (13.0 g, 88% over three steps) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.94-7.91 (m, 1H), 7.49-7.45 (m, 2H), 7.22 (s, 1H), 7.14 (s, 1H), 2.34 (s, 3H).
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH:22]([CH3:24])[CH3:23])[C:20](=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:26][CH3:27])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29]>>[OH:1][CH:3]([CH2:4][NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]([CH:22]([CH3:23])[CH3:24])[C:20](=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:26][CH3:27])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)N
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C(C)C)c(=O)c2c1
Product: COc1ccc2nc(-c3ccc(OCC(O)CNC(C)(C)C)cc3)n(C(C)C)c(=O)c2c1

Procedure:
This compound was prepared analogous to Example 1 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-isopropyl-6-methoxy-3,4-dihydro-quinazolin-4-one and tert. butylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9]C)=[O:7])=[CH:4][CH:3]=1.[C:13]1([CH:19]2[CH2:24][C:23](=[O:25])[O:22][C:20]2=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC#N>CC(O)C>[CH3:9][O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([NH:1][C:20](=[O:21])[CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][C:23]([OH:25])=[O:22])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC(C)O
Solvent: CC#N
Product: COC(=O)c1ccc(NC(=O)C(CC(=O)O)c2ccccc2)cc1

Procedure:
Ethyl 4-aminobenzoate (910 mg, 5.50 mmol) and phenyl succinic anhydride (1070 mg, 6.00 mmol) were dissolved in 40 mL abs. CH3CN and stirred overnight at r.t. The solid precipitate was isolated and digirated with 2-propanol, dried in vacuum, dissolved in DCM and washed with citric acid. 4-{[4-(methoxycarbonyl)-phenyl]amino}-4-oxo-3-phenylbutanoic acid was isolated as a crystalline solid (980 mg, 2.88 mmol). M.p. 212° C.; TLC (cyclohexane/EtOAc 7/3) Rf 0.17; 1H NMR (400 MHz, D6-DMSO) δ 1.39 (t, J=7.2 Hz, 3H); 2.75 (dd, J=3.7 Hz, J=17.2 Hz, 1H); 3.42 (dd, J=3.7 Hz, J=17.2 Hz, 1H); 4.09 (dd, J=3.7 Hz, J=17.2 Hz, 1H); 4.35 (q, J=7.2 Hz, 2H); 7.33–7.41 (m, 5H), 7.75 (mc, 2H), 7.94 (mc, 2H). The regiochemistry was determined using NOESY NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([CH3:11])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O>[NH2:9][CH2:8][C:7]1[C:2]([OH:1])=[N:3][C:4]([CH3:11])=[N:5][C:6]=1[CH3:10]
Reactant: Cc1nc(C)c(C#N)c(O)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C)c(CN)c(O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
A mixture of 4-hydroxy-2,6-dimethylpyrimidine-5-carbonitrile (2.7 g, 18.1 mmol), lithium aluminium hydride (2.1 g, 54.3 mmol), and tetrahydrofuran (80 mL) was stirred at 25° C. for 4 hours. Water (5 mL) was added to the mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 5-(aminomethyl)-2,6-dimethylpyrimidin-4-ol as a white solid (525 mg, 19%). LRMS (M+H+) m/z: calcd 153.09. found 153.
Reaction SMILES: [C:1]([CH:9]1[C:14](=O)[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:23][NH2:24]>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[C:9]3[CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13][C:14]=3[NH:24][N:23]=2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)c2ccncc2)C1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccncc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a mixture of tert-butyl 3-isonicotinoyl-4-oxopiperidine-1-carboxylate (7.4 g, 24.3 mmol) and TEA (10.15 ml) in ethanol was added hydrazine (3.65 ml, 73 mmol). The reaction mixture was stirred at room temperature for overnight. The solvent was removed under vacuum and DCM (50 ml) was added, followed by water (50 ml). The organic layer was collected, washed with brine and dried over sodium sulfate. Removal of solvent gave the desired product (7 g). LC-MS found 301.2 (M+H)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]1(O)[CH2:16][CH2:15][CH2:14][CH:13]=1.C1(O)CCCC1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:12]2[CH2:16][CH2:15][CH2:14][CH:13]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: OC1=CCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: OC1CCCC1
Product: Clc1nc(Cl)c2ncn(C3=CCCC3)c2n1

Procedure:
2,6-Dichloro-9-cyclopentenylpurine is prepared from 2,6-dichloropurine and cyclopentenol essentially as described in Example 1, Scheme A, step a, but substituting cyclopentenol for cyclopentanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[S:31]
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=S
Temperature: 100 °C
Reaction time: 8 h
Yield: 127.6 %

Procedure:
To a mixture of ethyl 3-(3,4-difluorobenzyl)-2-oxopiperidine-3-carboxylate (2.8 g) in toluene (50 ml) was added Lawesson's reagent (2.67 g) at room temperature, and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.64 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-(2-fluoro-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=429.0 [M+H]+.
Reaction SMILES: ClC1C(Cl)=C(C2C=CC=CC=2)N=C(C(Cl)=O)C=1.[F-].[K+].[F:20][C:21]1[C:26]([F:27])=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=[C:23]([C:34](F)=[O:35])[CH:22]=1.C(N(CC)CC)C.[CH:44]([OH:47])([CH3:46])[CH3:45]>S1(CCCC1)(=O)=O.O>[F:20][C:21]1[C:26]([F:27])=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=[C:23]([C:34]([O:47][CH:44]([CH3:46])[CH3:45])=[O:35])[CH:22]=1
Reactant: O=C(F)c1cc(F)c(F)c(-c2ccccc2)n1
Reactant: CC(C)O
Agent: O=C(Cl)c1cc(Cl)c(Cl)c(-c2ccccc2)n1
Agent: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1cc(F)c(F)c(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a solution of 4,5-dichloro-6-phenylpicolinoyl chloride (1.76 g, 6.14 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, ˜100 ppm H2O) was added potassium fluoride (2.14 g, 36.9 mmol). The reaction mixture was heated at 130° C. for 24 h. Reaction mixture was analyzed by GC-MS and 19F NMR. (Data for 4,5-difluoro-6-phenylpicolinoyl fluoride, GC-MS: m/z=237, 189; 19F NMR (376 MHz, Toluene-d8) δ 17.03 (s), −124.14 (d, J=19.1 Hz), −140.76 (d, J=19.1 Hz). Reaction was allowed to cool to room temperature and triethylamine (1.1 mL, 7.7 mmol) and isopropanol (0.7 mL, 9.2 mmol) were added. After stirring for 1.5 h, the reaction mixture was diluted with water (100 mL) and transferred to a separatory funnel. The reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×50 mL). The combined organic extracts were washed with water (3×50 mL) and saturated NaCl (50 mL) and concentrated under reduced pressure to provide a brown oil. The crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate) to provide 1.2 g (70% yield) of isopropyl 4,5-difluoro-6-phenyl-picolinate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.07-7.99 (m, 2H), 7.89 (dd, J=9.4, 5.3 Hz, 1H), 7.56-7.42 (m, 3H), 5.31 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.89 (d, J=3.4 Hz), 156.74 (dd, J=264.2, 12.5 Hz), 148.07 (dd, J=268.9, 10.8 Hz), 146.99 (dd, J=309.2, 10.8 Hz), 145.45 (s), 134.12-133.60 (m), 130.20 (s), 129.05 (d, J=5.9 Hz), 128.64 (s), 113.56 (d, J=16.0 Hz), 70.14 (s), 21.86 (s). 19F NMR (376 MHz, CDCl3) δ−125.22 (dd, J=17.7, 9.5 Hz), −144.74 (dd, J=17.7, 5.4 Hz). LRMS. Calcd. C15H13F2—NO2: 277.09. Found: m/z=277 (M+), 218, 191.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)O)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])=[O:41])=[CH:36][CH:35]=1>>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:41])=[CH:38][CH:39]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccc(OC(F)(F)F)cc2)nc1OCc1ccccc1)C1CCCCC1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccc(OC(F)(F)F)cc3)nc2OCc2ccccc2)C2CCCCC2)cc1
Yield: 55.7 %

Procedure:
Using {3-(benzyloxy)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}(cyclohexyl)methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.26 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.39 g, 56%) was obtained as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][N:5]([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[CH2:4]1
Reactant: CC1(O)CCNC1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(c1ccccc1)N1CCC(C)(O)C1
Reaction time: 12 h
Yield: 75.2 %

Procedure:
According to Example 15, 3-methylpyrrolidin-3-ol hydrochloride was synthesized. To a 100 mL reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (1 g, 7.2 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol) and acetonitrile (15 mL). To the resulting mixture was slowly added a solution of 2-bromoethylbenzene (1.2 g, 6.48 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. To the residue was added a mixed solution of dichloromethane and water for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product. The crude product was purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=30:1 (volumetric ratio)) to produce 3-methyl-1-phenylethylpyrrolidin-3-ol (1 g) in a yield of 75.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18](I)[CH:19]=[CH:20][C:13]=3[O:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18]([C:33]#[C:32][CH2:31][OH:34])[CH:19]=[CH:20][C:13]=3[O:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(I)cc2c1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(C#CCO)cc2c1=O
Temperature: 25 °C

Procedure:
Under an argon atmosphere, a mixture of N-(4-chlorobenzyl)-6-iodo-4-oxo-4H-1,2-benzoxazine-3-carboxamide (Preparation 18, 0.117 g), dichlorobis (triphenyl-phosphine)palladium (12.8 mg), copper(I) iodide (3.7 mg), and triethylamine (1 mL) in THF (6 mL) is cooled in an ice-brine bath. A solution of propargyl alcohol (32 mg) in THF (3 mL) is added slowly via a syringe to the reaction mixture. The reaction mixture is stirred at ice-brine temperature for 2 h and then allowed to warm to room temperature overnight. The mixture is concentrated in vacuo and the residue is flash chromatographed on silica gel (230-400 mesh, 8 g), eluting with 1% methanol in dichloromethane, pooling desirable fractions and concentrating in vacuo provides the title compound as a pale yellow solid. Physical characteristics: m.p. 117-120° C.: 1H NMR (400 MHz, DMSO-d6) δ 4.35, 4.50, 5.55, 7.42, 7.77, 7.97, 9.4; 13C NMR (DMSO-d6) δ 49.2, 49.3, 67.8, 79.4, 81.8, 91.8, 117.5, 119.8, 120.2, 126.6, 128.3, 129.0, 131.6, 137.2, 138.8, 155.2, 159.2, 160.3, 165.2; MS (FAB) m/z 369 (MH+, 99); HRMS (FAB) m/z 369.0645 (C19H13ClN2O4+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1O)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].O[C:22]1C=CC(O)=CC=1C(O)=O.C([O-])([O-])=O.[K+].[K+].S([O:43][CH3:44])(OC)(=O)=O>CC(C)=O>[CH3:22][O:3][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:43][CH3:44])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1OC

Procedure:
To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from 2,5-dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1, 12 mmol) in acetone (50 mL) was added K2CO3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed onto SiO2, and purified by column chromatography (50% EtOAc/50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g): mp 115-118° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([CH2:16][N:17]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([CH2:16][NH2:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1CCN(C(=O)OC(C)(C)C)CC1CN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1CN

Procedure:
To a stirred solution of 3-azidomethyl-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.74 mmol, 0.2 g) in ethyl acetate (5 mL) was added 10% palladium on carbon (0.1 g, wet), and the resultant reaction mixture was subjected to hydrogenation using a balloon full of hydrogen for 1 h. The catalyst was filtered through a pad of celite, washed the celite pad with methanol, and the combined filtrate was concentrated under reduced pressure to provide 3-aminomethyl-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](/[CH:14]=[N:15]/[NH:16][C:17]3[N:22]=[CH:21][C:20]([C@H:23]([N:28]4[CH2:32][CH2:31][C@@:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:33])[CH2:29]4)[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][C:5]=1[F:42])[CH3:2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:22]4[CH:21]=[C:20]([C@H:23]([N:28]5[CH2:32][CH2:31][C@@:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:33])[CH2:29]5)[C:24]([F:27])([F:25])[F:26])[CH:19]=[CH:18][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:42])[CH3:2]
Reactant: CCOc1cc2nc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1cc2nc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Yield: 85.8 %

Procedure:
A solution of tert-butyl (S)-1-((S)-1-(6-((E)-2-((7-ethoxy-6-fluoroquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ylcarbamate (6.320 g, 10.70 mmol) and iodobenzene diacetate (3.447 g, 10.70 mmol) in DCM (50 mL) was stirred overnight at ambient temperature. The reaction was concentrated under reduced pressure and the residue subjected to chromatography (10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes over 4 column volumes) to give tert-butyl (S)-1-((S)-1-(3-(7-ethoxy-6-fluoro quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ylcarbamate (5.406 g, 9.18 mmol, 85.83% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:26]C)=[C:19]([O:24][CH3:25])[CH:20]=3)[C:15]=2[CH:28]=O)[C:6]([N+:11]([O-])=O)=[CH:7][C:8]=1[O:9][CH3:10]>C(Cl)(Cl)Cl>[CH2:25]1[O:26][C:18]2[C:19](=[CH:20][C:21]3[CH:22]=[CH:23][C:14]4[C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=5[N:11]=[CH:28][C:15]=4[C:16]=3[CH:17]=2)[O:24]1
Reactant: COc1cc(-c2ccc3cc(OC)c(OC)cc3c2C=O)c([N+](=O)[O-])cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncc3c4cc5c(cc4ccc3c2cc1OC)OCO5
Yield: 60 %

Procedure:
Using a procedure similar to that described in Example 1, except replacing the compound 17 used therein with compound 18, the title compound was prepared in 60% yield; mp>250° C.; IR (Nujol) 1680; UV (CHCl3) 285, 360, 380 nm (log ε=3.01, 2.21, 2.47); 1H NMR δ4.10 (3H, s), 4.14 (3H, s), 6.15 (2H, s), 7.28 (1H, s), 7.68 (1H, s), 7.83 (1H, s), 7.97 (1H, d, J=9.2), 8.16 (1H, s), 8.28 (1H, d, J=9.2), 9.85 (1H, s); 13C NMR δ56.7, 100.3, 102.1, 102.2, 106.1, 109.2, 118.4, 127.5, 128.9, 131.2, 131.7, 140.8, 145.6, 145.7, 148.4, 149.9, 150.4, 151.7, 176.1; HRMS calcd for C20H15NO4: 333.1001; found: 333.0999.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.[OH-].[K+].CS(O[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(=O)=O>CO>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:2]1
Reactant: Sc1nc[nH]n1
Reactant: CS(=O)(=O)OCC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1nc(SCC2CCCC2)n[nH]1
Yield: 95.8 %

Procedure:
1,2,4-Triazole-3-thiol (49.0 g; 0.484 mol) and 86% potassium hydroxide (32.0 g; 0.484 mol) were dissolved in methanol (500 ml) and refluxed for 1 h. The solution was then evaporated to dryness, and the residue redissolved in methanol (500 ml). Cyclopentylmethyl methanesulfonate (86.0 g; 0.484 mol) was added, the solution stirred under reflux for 8 h, and at room temperature overnight. The solution was evaporated and the residue dissolved in ether (500 ml) and water (1 1). The aqueous layer was separated and extracted with another portion of ether (500 ml). The ether solutions were combined, washed with saturated brine (500 ml), dried (MgSO4), filtered and evaporated, to afford cyclopentylmethyl 1,2,4-triazol-3-yl sulfide (85.0 g; 96%) as a waxy, white solid. NMR - d(CDCl3 ; 60 MHz) 1.0-2.4 (10H, m), 3.2 (2H, d, J=7 Hz), 8.1 (1H, s) and 13.4 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9]2)=[N:5][N:6]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]([C:38](=O)[CH2:39][CH2:40][CH3:41])[C:33](OCC)=[O:34])=[C:27]([F:43])[CH:26]=1)#[N:18].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:34])[N:7]([C@H:8]3[CH2:9][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11]3)[C:4]3[N:5]([N:6]=[C:2]([CH3:1])[N:3]=3)[C:38]=2[CH2:39][CH2:40][CH3:41])=[C:27]([F:43])[CH:26]=1)#[N:18]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: CCOC(=O)C1CC(Nc2nnc(C)[nH]2)C1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(=O)OCC)C2)c2nc(C)nn12

Procedure:
A solution of ethyl 3-[(5-methyl-4H-1,2,4-triazol-3-yl)amino]cyclobutanecarboxylate (7.85 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (23.15 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.62 mL) in N,N-diethylaniline (70 mL) was stirred at 180° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=85/15→65/35 (volume ratio)] to give the title compound as a pale-yellow amorphous compound (1.89 g, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (800 mg, mmol) and lithium hydroxide monohydrate (27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml5/ml) was stirred for 3 h at room temperature. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid in 88% yield (670 mg).