Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(O)cc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
Methyl iodide (36 ml) was added to a mixture of methyl 3,5-dihydroxybenzoate (104 g), potassium carbonate (79 g) and dimethylformamide (1200 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between water (2.5 liter) and petrol (b.p. 60°-80° C., 600 ml). The aqueous layer was washed with petrol (b.p. 60°-80° C., 600 ml) and then extracted with toluene (2×1 liter). The toluene extracts were combined, washed with water (4×800 ml), dried (MgSO4) and evaporated to give methyl 3-hydroxy-5-methoxybenzoate as an oil (33 g, 30%).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>ClCCl>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([SH:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CCO
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S)cc1

Procedure:
Ethyl-4-mercaptobenzoate was prepared by treating 4-mercaptobenzoic acid (1.50 g, 9.73 mmol) with ethanol (97 mL) in the presence of catalytic concentrated sulfuric acid under a nitrogen atmosphere. The reaction was heated at reflux for three hours. The volume of the reaction was reduced to 10 mL under reduced pressure and then partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic solutions were washed with water (75 mL) and saturated aqueous sodium bicarbonate (2×75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The oil was dissolved in dichloromethane (100 mL), and the resulting solution was extracted with saturated aqueous sodium carbonate (3×100 mL). The combined extracts were washed with dichloromethane (3×50 mL) and then treated with concentrated hydrochloric acid to adjust to pH 7. The solution was then extracted with dichloromethane (3×100 mL), and the combined extracts were washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.23 g of ethyl-4-mercaptobenzoate as a colorless oil.
Reaction SMILES: [N:1]1([C:8](OC(C)(C)C)=O)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:16][CH:17]=C>ClCCl>[CH2:8]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH:16]=[CH2:17]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: ClCCl
Product: C=CCN1CCCNCC1
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of tert-butyl 1-homopiperazinecarboxylate (9.73 mL, 50 mmol) in dichloromethane (250 mL) was added PS-TBD resin (40 g, 100 mmol) and 3-bromoprop-1-ene (4.33 mL, 50 mmol) dropwise at 25° C. The mixture was stirred for 2 h. The PS-TBD was filtered off and the filtrate evaporated to dryness, redissolved in MeOH/EtOAc (1:9) and then filtered through a short silica column. The filtrate obtained was evaporated to dryness, treated with TFA (20 ml) and then stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (50 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford 1-prop-2-enyl-1,4-diazepane (4.07 g, 58.0%) as a pale yellow oil.
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[C:10]([CH3:17])[C:11]([OH:16])=[C:12]([CH3:15])[CH:13]=2)[CH:8]([CH3:18])[CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[C:1]([N:6]1[C:14]2[C:9](=[C:10]([CH3:17])[C:11]([O:16][C:25](=[O:27])[CH3:26])=[C:12]([CH3:15])[CH:13]=2)[CH:8]([CH3:18])[CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc2c(c1C)C(C)CN2C(=O)C(C)C
Temperature: 0 °C
Reaction time: 17 h
Yield: 77.8 %

Procedure:
To an ice-cold solution of N-isobutyryl-5-hydroxy-3,4,6-trimethylindoline (11b, 49 mg, 0.2 mmol) dissolved in methylene chloride (2 mL) were added sequentially pyridine (0.16 mL, 2 mmol) and acetic anhydride (0.1 mL, 1 mmol). The mixture was stirred over the range of 0° C. to room temperature for 17 h. The mixture was diluted with methylene chloride, transferred to a separatory funnel and washed sequentially with 10% hydrochloric acid, saturated aq. sodium bicarbonate and brine. Removal of solvents after drying (MgSO4) gave a viscous liquid, which was purified by flash column chromatography, using 1:4 ethyl acetate:hexanes as eluent, to afford the N-isobutyryl-5-acetoxy-3,4,6-trimethylindoline (12b, 45 mg, 77% yield) as a colorless solid, mp 118°-120° C. Spectral data: 1H NMR: δ 2.0 (s, 3H), 2.06 (s, 3H), 2.26 (s, 3H), 2.7 (quintet, 1H, J=6.7 Hz), 3.3 (t, 1H, J=6.7 Hz), 3.7 (dd, 1H, J=10.2, 1.2 Hz), 4.1 (t, 1H, J=9.3 Hz), 8.0 (s, 1H); CI-HRMS: calcd. for C17H24NO3 (M+H+) 290.1756, fnd. 290.1756.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(OCC)(=O)C.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:12](=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)Cl
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)NCCOC
Reaction time: 1 h

Procedure:
2-Methoxyethylamine (44.6 g), ethyl acetate (100 mL) and triethylamine (50.6 g) were introduced into a 300 mL flask equipped with a dropping funnel and a magnetic stirrer. The flask was immersed in an ice bath and the contents of the flask were stirred as nitrogen gas was being introduced. Acryloyl chloride (45.3 g) was introduced into the dropping funnel and was added dropwise over a period of approximately one hour. After the dropwise addition was completed, stirring was continued for 1 hour at room temperature. The salt, which was separated out by suction filtration using celite, was separated by filtration, after which low boiling point components were removed with a rotary vacuum evaporator. Purification was performed by distillation under reduced pressure and N-(2-methoxyethyl)acrylamide was obtained as a colorless transparent liquid.
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[CH:10]=[CH:11][CH2:12]Cl)=O)C.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][NH:18]1>CO>[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[CH:10]=[CH:11][CH2:12][N:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17]1
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)Oc1cccc(C=CCCl)c1
Solvent: CO
Product: Oc1cccc(C=CCN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. 4.8 grams of m-ethoxycarbonyloxycinnamyl chloride and 7.15 grams of isoindoline are dissolved in 70 milliliters of methanol, and the resulting solution is stirred for 2 hours at room temperature. After completion of the reaction, the methanol is distilled off, and the residue is extracted with benzene. The resulting extract is then purified by silica gel column chromatography and recrystallized from methanol to obtain 1.2 grams (yield 23.9%) of N-(m-hydroxycinnamyl)-isoindoline as crystals having a melting point of 164.5°-165.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2)cc1
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinyl methoxy]benzoate (529 mg, 1.15 mmol) in CH2Cl2 (5 ml) was added TFA (5 ml). The mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was made basic by the addition of sat. NaHCO3. The mixture was extracted with CHCl3 (2×100 ml). The extracts were dried over K2CO3 and evaporated to give methyl 4-[4-(2,4-difluorophenoxy)-2-pyrrolidinyl methoxy]benzoate (385 mg, 92%) as a yellow oil. 1H-NMR (CDCl3) δ 1.89–1.95 (m, 1 H), 2.28–2.35 (m, 1 H), 3.09 (dd, J=12.5, 4.9 Hz, 1 H), 3.33 (d, J=12.5 Hz, 1 H), 3.60 (m, 1 H), 3.86 (s, 3 H), 4.10 (d, J=5.6 Hz, 2H), 4.84(m, 1H), 6.73–6.89(m, 3 H), 6.91 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 2 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(/[CH:18]=[CH:19]/OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=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>[C:12]1(/[CH:18]=[CH:19]/[C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: OB(O)O/C=C/c1ccccc1
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: C1COCCO1
Solvent: O
Product: COC(=O)c1ccnc(/C=C/c2ccccc2)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl 2-chloroisonicotinate, Pd(PPh3)4, and [(E)-2-phenylvinyl]boric acid in dioxane was added a 2 M aqueous Na2CO3 solution, followed by stirring at 90° C. for 5 hours. To the reaction mixture was added water, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4, and the filtrate was then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 2-[(E)-2-phenylvinyl]isonicotinate as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCOCC1>O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(Br)cnc1NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)cnc1NC
Yield: 44 %

Procedure:
A mixture of 5-bromo-2-methylamino-nicotinic acid ethyl ester (100 mg, 0.39 mmol), potassium carbonate (160 mg, 1.16 mmol), dichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium(II); (28 mg, 39 μmol) and phenylboronic acid (146 mg, 1.16 mmol), 1,4-dioxane (0.9 mL), and water (0.11 mL) was heated at reflux for 3 h, then partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (44 mg, 44%). Yellow liquid, MS (EI): 256.2 (M+).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH2:13])=[C:11]([F:17])[CH:10]=1.O.Cl>N1C=CC=CC=1>[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH:13][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:11]([F:17])[CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(Br)cc(F)c1N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(F)c1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
Pivaloyl chloride (4 mL, 38.4 mmol) was added slowly (caution—exothermic reaction) to an ice cold solution of the crude 4-bromo-2-fluoro-6-methylaniline from step 4 (about 32 mmol) in pyridine (20 mL). After the addition, the ice bath was removed and the warm reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a water solution of 1 N HCl and extracted with EtOAc. The organic layer was washed with 1N HCl three times, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 9:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide N-(4-bromo-2-fluoro-6-methylphenyl)-2,2-dimethylpropanamide (4.3 g, 49% for 3 steps) as a yellow solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[N:26]=[CH:27][NH:28][C:29]=1[C:30]([NH2:32])=[O:31])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[C@@H:6]1([O:24][C:25]2[N:26]=[CH:27][NH:28][C:29]=2[C:30]([NH2:32])=[O:31])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nc[nH]c2C(N)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1[nH]cnc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of 457 mg of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)oxy-1H-imidazole-5-carboxamide in 30 ml of dry methanol was added 270 mg of 95% sodium methoxide. The reaction mixture was stirred for 20 minutes at room temperature and 0.33 ml of acetic acid was added. Chromatographical purification on LH-20 (product of Pharmacia A/S) in methanol of the residue which was obtained after evaporation of the reaction mixture under reduced pressure, gave 260 mg of 4-β-D-glucopyranosyloxy-1H-imidazole-5-carboxamide which was crystallized with acetone. m.p. 167° C. (dec.)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[OH-:13].[K+]>C(O)C>[CH3:1][C:2]([CH3:11])([CH2:3][OH:13])[CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[OH:12]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(CO)C(O)c1ccc2ccccc2c1
Reaction time: 0.17 h
Yield: 181.3 %

Procedure:
2-Naphthoaldehyde (26.0 g, 0.167 mol) and isobutylaldehyde (24.0 g, 0.33 mol) were dissolved in ethanol (50 ml) with heating. 85% Potassium hydroxide (11.0 g, 0.167 mol) dissolved in ethanol (150 ml) was added dropwise to the above solution with stirring. Exothermic reaction started immediately, and the temperature reached to 51° C. and then decreased. After the dropping was completed for about 10 min, the solution was stirred at 55 to 60° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and water (150 ml) was added thereto and the mixture was extracted with chloroform (100 ml) twice. The extract was washed with saturated brine, dehydrated with anhydrous sodium sulfate and concentrated to give the title compound as a brown oil (34.86 g, yield 91.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C@H:11]12[CH2:17][C@H:14]([NH:15][CH2:16]1)[CH2:13][N:12]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:15]2[CH2:16][C@@H:11]3[CH2:17][C@H:14]2[CH2:13][N:12]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc([N+](=O)[O-])nc1

Procedure:
5-Bromo-2-nitropyridine, prepared as described in (J. Am. Chem. Soc., (1945) 67, 668), and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were coupled according to the procedure of Example 2A to provide the title compound.
Reaction SMILES: C([Br:4])(=O)C.[N+]([C:8]1[CH:13]=[CH:12][N:11]([OH:14])[CH2:10][C:9]=1[CH3:15])([O-])=O>>[Br:4][C:8]1[CH:13]=[CH:12][N:11]([OH:14])[CH2:10][C:9]=1[CH3:15]
Reactant: CC(=O)Br
Reactant: CC1=C([N+](=O)[O-])C=CN(O)C1
Product: CC1=C(Br)C=CN(O)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Acetyl bromide (5 mL) was cooled to 0° C. To this was added 4-Nitro-3-methyl-pyridin-1-ol (1000 mg, 6.48 mmol) portionwise while maintaining temperature. After the addition was complete, the reaction was heated to 50° C. and stirred for 2 hours. The reaction was then cooled to 0° C., quenched with ice and neutralized with solid Na2CO3 (pH=8). The neutral aqueous reaction mixture was extracted into DCM. The organic layer was dried (MgSO4), the solvents were removed in vacuo resulting in the title compound as a yellow solid (1.05 mg, 86%). ESI-MS (m/z): Calcd. for C6H6BrNO: 188.0 (M+1); found: 188.0.
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])=[O:5].Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:19]([C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[C:10]([F:14])=[CH:9][C:8]=1[F:15])=[O:5]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(O)c(F)cc3F)c2Cl)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A suspension of 2-chloro-3-(1-cyanocyclopropyl)-N-(2,4-difluoro-5-hydroxyphenyl)benzamide (4.20 g, 12 mmol), 2-chloro-5-nitropyridine (1.9 g, 12 mmol) and potassium carbonate (1.66 g, 12 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (5.20 g, 92%) as a yellow powder.
Reaction SMILES: [Si]([N:5]=[C:6]=[S:7])(C)(C)C.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1>O1CCCC1.C(OCC)(=O)C>[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[S:7])[NH2:5]
Reactant: C[Si](C)(C)N=C=S
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(N)=S)CC1
Yield: 20.3 %

Procedure:
A solution of TMS-isothiocyanate (5.4 mL, 38 mmol) and ethyl piperidine-4-carboxylate (5.9 ml, 38 mmol) in tetrahydrofuran (127 ml) was stirred at room temperature for 3 days. The mixture was then diluted with 500 mL ethyl acetate and washed with 500 mL water and 500 mL brine. The aqueous fractions were further extracted with 500 mL ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by CombiFlash (40-100% ethyl acetate/hexanes) to provide 1.85 g (7.7 mmol, 20%) of ethyl 1-carbamothioylpiperidine-4-carboxylate as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[C@H:5]([CH3:32])[CH2:6][C@H:7]([NH:21][C:22]([C:24]1O[CH:26]=[C:27]([OH:31])[C:28](=[O:30])[CH:29]=1)=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[CH3:34][NH2:35]>O>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:22]([C:24]2[N:35]([CH3:34])[CH:26]=[C:27]([OH:31])[C:28](=[O:30])[CH:29]=2)=[O:23])[CH2:6][C@@H:5]([CH3:32])[C:4]([OH:3])=[O:33])=[CH:10][CH:11]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)co1
Reactant: CN
Solvent: O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)cn1C)C(=O)O

Procedure:
To a suspension of (2R,4S)-5-biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (Example 23-1) (50 mg) in water (1 mL) is added methylamine (1 mL of a 40% solution in water) and the resulting mixture is heated to reflux for 6 hours. The mixture is under reduced pressure and is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to elute the title compound; HPLC Retention time 1.21 minutes (condition C): MS 435.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (d, J=7.07 Hz, 3H) 1.45-1.65 (m, 1H) 1.82-1.98 (m, 1H) 2.25-2.38 (m, 1H) 2.63-2.78 (m, 1H) 2.79-2.97 (m, 1H) 4.14-4.32 (m, 1H) 6.45 (br. s., 1H) 7.26-7.39 (m, 2H) 7.45 (t, J=7.58 Hz, 2H) 7.55-7.68 (m, 4H) 8.79 (d, J=9.09 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[N:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.[F:25]C(F)(F)C(O)=O>ClCCl>[F:25][N:6]1[CH:7]=[CH:2][CH:3]=[C:4]2[N:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9](=[O:24])[NH:8][CH:5]12
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncc(F)cc32)CC1
Solvent: ClCCl
Product: O=C1NC2C(=CC=CN2F)N1C1CCNCC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (340 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added. After 2 h, the reation was concentrated, diluted with dichlormethane (5 mL) and a solution of 1N hydrochloric acid in 1,4-dioxane (2 mL) was added at room temperature. Concentration afforded the title compound (302 mg). MS 237.2 (M+1)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].Cl.Cl.[CH3:28][N:29]1[CH2:32][C:31]2([CH2:35][NH:34][CH2:33]2)[CH2:30]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:34]4[CH2:35][C:31]5([CH2:32][N:29]([CH3:28])[CH2:30]5)[CH2:33]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN1CC2(CNC2)C1
Agent: Cl
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC5(CN(C)C5)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (d, J=2.27 Hz, 3H) 2.80 (d, J=4.55 Hz, 3H) 3.94-4.67 (m, 8H) 7.61 (d, J=8.08 Hz, 1H) 7.69-7.78 (m, 1H) 8.16-8.29 (m, 2H) 8.42 (d, J=8.59 Hz, 1H) 8.69 (br. s., 1H). ESI-MS m/z [M+H]+ 433.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: NCCN1CCOCC1
Solvent: COCCOC
Product: Nc1nc(NCCN2CCOCC2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 4-(2-aminoethyl)morpholine in DME. ES-MS m/e (%): 335 (M+H+, 100).