Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=S)[CH:2]=1.[NH:10]([C:12](=[O:33])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:14])[NH2:11].CCN=C=NCCCN(C)C>CC#N>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[O:33][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C@H:22]4[CH2:27][CH2:26][C@H:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[O:14])=[N:10][N:11]=2)[CH:2]=1
Reactant: S=C=Nc1cccnc1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cccnc4)o3)cc2)CC1
Temperature: 80 °C

Procedure:
3-Pyridyl isothiocyanate (41 mg, 0.3 mmol) was added in one portion to a suspension of methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}-phenyl)cyclohexyl]acetate (Intermediate 43, 100 mg, 0.3 mmol) in CH3CN (5 mL) and the reaction mixture was heated at 80° C. for 10 minutes in the microwave and then cooled to room temperature. EDCI (58 mg, 0.3 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 20 minutes. The mixture was cooled to room temperature and filtered to leave a solid. The solid was washed with CH3CN (5 mL) to give the title compound (90 mg, 69%) as a solid; 1H NMR δ 1.12-1.18 (2H, m), 1.45 (2H, q), 1.80 (5H, m), 2.24-2.26 (2H, d), 2.42-2.48 (1H, m), 3.61 (3H, s), 7.23 (2H, d), 7.43-7.46 (1H, m), 7.69-7.71 (2H, m), 8.06-8.09 (1H, m), 8.28-8.29 (1H, m), 8.78 (1H, d), 10.95 (1H, s), 11.22 (1H, s); MS m/e MH+ 436.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>FC(F)(F)C(O)=O.[Pt]=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[N:14]3[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CS(=O)(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCC[C@H]1COCc2nc3c(N)nc4c(c3n21)CCCC4
Reaction time: 24 h
Yield: 33.6 %

Procedure:
N-{3-[(11S)-6-Amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propyl}methanesulfonamide (254 mg, 0.667 mmol) was dissolved in about 3 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (154 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 24 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with a mixture of 2-propanol and CH2Cl2 and the combined filtrates were concentrated under reduced pressure to give a syrup. The syrup was partitioned between H2O and CHCl3. The aqueous layer was made basic by addition of concentrated NH4OH solution until the pH was approximately 12. The layers were separated and the organic portion was washed successively with concentrated NH4OH, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 25-33% CMA/CHCl3) gave a white solid. Crystallization from methanol/ethyl acetate gave N-{3-[(11S)-6-amino-2,3,4,8,10,11-hexahydro-1H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propyl}methanesulfonamide (85 mg) as white crystals, mp 197-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 94.1 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (20 g, 95.1 mmol), 4-methoxybenzyl chloride (11.6 ml, 85.6 mmol), potassium carbonate (26.3 g, 0.19 mol) and acetonitrile (300 ml) was stirred at 60° C. for 6 hrs. The reaction solution was concentrated under reduced pressure, water (300 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-5:1) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-(4-methoxybenzyl)propionate (26.6 g, 85%) as an oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1>ClCCl>[CH:1](=[N:19][C@H:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc([C@H](C)N)cc1
Solvent: ClCCl
Product: COc1ccc([C@H](C)N=Cc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 106.1 %

Procedure:
To a solution of 5.6 g of benzaldehyde in 25 cm3 of dichloromethane are added, with stirring and at a temperature in the region of 20° C., 8.5 g of (S)-1-(4-methoxyphenyl) ethylamine and 5 g of 4 Å molecular sieves. The reaction mixture is stirred for 16 hours at a temperature in the region of 20° C. and then filtered through a sinter funnel containing Celite. The sinter funnel is washed 3 times with 20 cm3 of dichloromethane and the filtrates are combined and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 13.4 g of (S)-N-benzylidene-[1-(4-methoxyphenyl)-ethylamine] are thus obtained, in the form of a light brown oil.
Reaction SMILES: Br[CH:2]([C:5]1[C:6]([Cl:12])=[N:7][C:8]([Cl:11])=[N:9][CH:10]=1)[CH2:3][CH3:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:11][C:8]1[N:7]=[C:6]([Cl:12])[C:5]([CH:2]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH2:3][CH3:4])=[CH:10][N:9]=1
Reactant: COc1ccc(N)cc1
Reactant: CCC(Br)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCC(Nc1ccc(OC)cc1)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(±)-5-(1-Bromopropyl)-2,4-dichloro-pyrimidine (0.26 g; 0.96 mmol) (from Example 7b supra) was dissolved in acetonitrile (2.5 mL). p-Anisidine (0.12 g; 0.96 mmol) (Aldrich), potassium carbonate (0.15 g; 1.05 mmol) and potassium iodide (0.04 g; 0.24 mmol) were added and the mixture was stirred at room temperature. After 16 hours, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40S, 15:85 to 20:80 ethyl acetate-hexanes gradient) gave crude (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-propyl]-(4-methoxy-phenyl)-amine. (Yield 0.19 g; 64.3%). This material again showed 3 peaks for the pyrimidine ring proton in the same ratio as was seen in the starting material. This material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([CH3:10])[CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:11]>C(O)C.[Pd]>[ClH:11].[ClH:11].[NH2:2][CH2:1][C:3]1[C:8]([F:9])=[C:7]([CH3:10])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccnc(C#N)c1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccnc(CN)c1F

Procedure:
A stirred solution of 332 mg (2.44 mmol) of 2-cyano-3-fluoro4-methylpyridine 5-3 in 15 mL of ethanol and 0.61 mL (7.32 mmol) of conc. HCl was hydrogenated over 175 mg of 10% palladium on carbon at 55 psi for 16 h. The catalyst was removed by filtration and the solvents removed at reduced pressure to give 5-4 as a yellow solid: 1H NMR (CD3OD) δ 8.41 (d, 1H, 5.1 Hz), 7.54 (dd, 1H, 5.5, 5.5 Hz), 4.40 (s, 2H), 2.44 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[C:37]([CH3:42])[N:38]=[C:39]([CH3:41])[CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (187 mg, 0.68 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (220 mg, 0.68 mmol) according to the general procedure M. Obtained as an off-white foam (270 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NCC(F)(F)F)nc1
Yield: 73 %

Procedure:
As described for example 23f, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) was converted, using 2,2,2-trifluorethylamine instead of isopropylamine, to the title compound (68 mg, 73%), which was obtained as a white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH:31]=1>C1COCC1.C(OCC)(=O)C>[N:30]1([C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:3]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1c(NC2CCOCC2)nc(Cl)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(NC2CCOCC2)nc(-n2cnc3ccccc32)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 38.4 %

Procedure:
To 100 mg (0.3 mmol) of 2-chloro-5-nitro-6-phenyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine in 5 mL of THF was added potassium carbonate (213 mg, 1.54 mmol, 5.1 equiv.), followed by benzimidazole (106 mg, 0.9 mmol, 3 equiv.) and the reaction mixture was stirred at 70° C. After 2.5 h, heating was discontinued; the reaction mixture was diluted with 70 mL of ethyl acetate, was washed with water and dried (anhydrous MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, elution with 4/1 hexanes/ethyl acetate) to give the desired product (48 mg, 38% yield). LC-MS: tR=7.35 min, MS (EI) m/z 417.2 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.C1C(=O)N([Br:16])C(=O)C1>CN(C=O)C.O>[Br:16][C:6]1[S:5][C:4]([CH2:7][OH:8])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1csc(CO)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CO)sc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of (4-methyl-thiazol-2-yl)-methanol (7.0 g, 54.3 mmol) in DMF (80 mL) was added NBS (10.6 mg, 59.6 mmol), and the mixture was stirred at 50° C. overnight. TLC (petroleum ether:EtOAc 2:1) indicated the reaction was completed. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column (petroleum ether:EtOAc 10:1) to give the title compound (11.2 g, 99%) as a brown solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2cn[nH]c2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (15.4 g, 52.5 mmol) and 2-bromo-5-fluoropyridine (8.4 g, 47.7 mmol) in 1,4-dioxane (100 mL), Pd(PPh3)4 (5.5 g, 4.77 mmol) and a 2M aqueous solution of Na2CO3 (71.6 mL, 0.14 mol) were added, then the resulting mixture was stirred at 100° C. for 3 hours and then at room temperature for 72 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. A small amount of EtOAc was added to the obtained residue and the resulting mixture was filtered out and dried to obtain the title compound (4.9 g) (colorless solid).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)(=[O:20])=[O:19]>Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)(=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3cccc(C)c3)c(C)o2)cc1
Agent: Cl
Product: Cc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Yield: 83.2 %

Procedure:
Reaction of benzoate 31 (217 mg, 0.56 mmol) and 6 M HCl (10 mL) gave acid 32 (173 mg, 83%) as a white solid: mp (H2O) 287-290° C.; 1H NMR δ 13.16 (br s, 1H, CO2H), 8.05 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.92 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.63 (br s, 1H, H-2′), 7.54-7.59 (m, 2H, H-4′, H-6′), 7.50 (t, J=7.6 Hz, 1H, H-5′), 4.65 (s, 2H, CH2SO2), 2.37 (s, 3H, CH3), 2.16 (s, 3H, CH3); MS m/z 372.6 (MH+, 100%). Anal. calcd for C19H17NO5S: C, 61.74; H, 4.61; N, 3.77. Found: C, 61.51; H, 4.56; N, 3.80%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[N:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:27].[K+].[K+].OO>CS(C)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:27])[NH2:24])[N:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C#N)n2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 158784064 %

Procedure:
Dissolve {2-[4-(6-cyanopyridin-2-yloxy)phenyl]ethyl}carbamic acid tert-butyl ester (0.814 g, 0.240 mmol) in DMSO (4.8 mL). Add K2CO3 (0.166 g, 0.120 μmol) and then 30% H2O2 (0.071 mL 0.624 mmol). Stir at room temperature for 3 hours. Quench the reaction mixture with water (30 mL). Extract with ethyl acetate (1× 60 mL). Wash the organic layer with water (1× 30 mL), dry over MgSO4, filter and concentrate to give the title compound (68.1 g, 79.5%): MS ES+ 357.9 (M+H)+, base peak ES+ 301.9 (M+2H—C(CH3)3), MS ES− 356.1 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=18.5 min, 94.5% purity.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl[C:56]1[S:57][CH:58]=[CH:59][N:60]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]2[S:57][CH:58]=[CH:59][N:60]=2)[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Clc1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(c2nccs2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 12 %

Procedure:
The desired compound was prepared according to the procedure of Example A157, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-chloro-1,3-thiazole as starting materials in 12% yield. LCMS for C27H28ClN8OS (M+H)+: m/z=547.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>C1C=CC=CC=1>[C:23]([NH:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
In 5 ml of benzene was dissolved 2.00 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, and 0.61 ml of anhydrous acetic acid was added thereto and the mixture was refluxed for one hour. Benzene was removed by distillation to obtain a crude product. This was washed with hexane to obtain 2.20 g of the desired compound as white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36][N:35]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(-c3ccc(C(=O)O)nc3)c2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(-c3ccc(C(=O)O)nc3)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 5-{3-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-pyridine-2-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white solid, MS (ESI+): m/z=452.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[C:36]1([CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:47]1[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:49][CH2:48]1)=[O:19]
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)=C(C)C1=O
Reactant: c1ccc(CCN2CCNCC2)cc1
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)N2CCN(CCc3ccccc3)CC2)c2ccccc2)=C(C)C1=O
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A solution of p-nitrophenyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenyl-heptanoate (0.50 g, 1.05 mmoles) and 4-(2-phenylethyl)piperazine (0.20 g, 1.05 mmoles) in dichloromethane was allowed to stand at room temperature under stirring for 18 hours. After the solvent was evaporated in a reduced pressure, the residue was dissolved in ethylacetate and the solution was washed with aqueous potassium carbonate and water, and dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel column with ethylacetate followed by chloroform-methanol (10:1) as eluant to give 4-[7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoyl]-(2-phenylethyl)piperazine (0.51 g, 92%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=O)[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18]>C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=2[C:5]2[CH2:14][CH2:13][C:12](=[N:19][C:16]#[C:17][CH3:18])[C:6]1=2
Reactant: C#CCN
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC#N
Product: CC#CN=C1CCc2c1n(C)c1ccc(O)cc21
Reaction time: 16 h

Procedure:
To a stirred suspension of 7-hydroxy-4-methyl-1,4-dihydrocyclopent[b]indol-3(2H)-one (5.5 g) in acetonitrile (100 ml) was added propargyl amine (3.0 g), the solution was stirred at room temperature under a nitrogen atmosphere while titanium (IV) isopropoxide (15.6 g) was added in a dropwise manner. The mixture was stirred for 16 hours before quenching with ice water. The mixture was filtered, the solids were washed with CH2Cl2, the layers were separated and the organic portion was dried (Na2SO4). After concentration, the crude product was purified via flash chromatography eluting with hexane/acetone (2:1) to give 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-ol.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.CC([O-])(C)C.[K+].[H][H]>CC(O)C>[CH3:1][CH:2]1[CH2:11][CH:9]([OH:10])[C:5](=[C:6]([CH3:7])[CH3:8])[CH2:4][CH2:3]1
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)=C1CCC(C)CC1O
Temperature: 30 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
A 200 ml capacity autoclave was charged with 30.4 g (200 mmol) of pulegone, 19.1 mg (0.02 mmol) of RuCl2(PPh3)3(propanediamine), 44.9 mg (0.4 mmol) of t-BuOK and 2-propanol (15 ml), and the mixture was stirred at 30° C. for 18 hours while forcing 3 Mpa of hydrogen. After completion of the reaction, hydrogen was purged and the reaction solution was concentrated and distilled under a reduced pressure to obtain 30.2 g of pulegol. The yield was 98%.