Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:23]([O:22][C:20](=[O:21])[C:19]([O:17][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][C:13]=1[CH:14]=[O:15])([CH3:26])[CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Yield: 82.8 %

Procedure:
5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339-346) (169 g, 741 mmol), ethyl bromoisobutyrate (164 mL, 1.11 mol), and cesium carbonate (240 g, 741 mmol) in dry DMF (600 mL) were heated at 80° C. for 15 h. Additional cesium carbonate (5 g) and ethyl bromoisobutyrate (20 mL) were added, and the reaction mixture was heated for 6 h. The reaction mixture was cooled, diluted with EtOAc (4 L), and washed with water (3×2 L). The organic layer was dried (Na2SO4) and concentrated to a brown oil. The crude product was recrystallized from EtOAc (150 mL) with hexanes until turbid to give the title compound as a pale yellow solid (210 g, 83%): mp 65° C.; 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d, 1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30-7.43 (m, 6H); MS (ES) m/e 343.1 [M+1].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+]([O-])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:4][N:3]=1.[ClH:24]>O.[Fe]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:24])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: Cl
Reactant: Nc1ncc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c(N)n1
Agent: [Fe]
Solvent: O
Product: Nc1ncc(C2CCN(c3ccc(Cl)cc3)CC2)c(N)n1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
1 g of 2,4-diamino-5-[1-(p-nitrophenyl)-4-piperidinyl]pyrimidine was dissolved in 50 ml of water and 10 ml of conc. hydrochloric acid, treated with 700 mg of iron powder and stirred at 80° C. for 45 minutes. The mixture was filtered over a filter aid, the filtrate was cooled to 0°-5° C., diazotized with 210 mg of sodium nitrite in 2 ml of water and the resulting diazonium solution was added dropwise at 0°-5° C. to a solution of copper (I) chloride (prepared from 250 mg of copper (II) sulfate pentahydrate, 80 mg of sodium chloride and 70 mg of sodium bisulfite) in 0.8 ml of hydrochloric acid. Thereafter, the reaction mixture was heated at 90° C. for 1 hour, treated with active carbon, filtered and concentrated to 50 ml. The residue was neutralized with ammonium hydroxide, filtered off and the product obtained after distilling off the water was chromatographed on silica gel with CHCl3 /EtOH (9:1). Recrystallization from ethanol yielded 2,4-diamino-5-[1-(p-chlorophenyl)-4-piperidinyl]pyrimidine of melting point 254°-255° C.
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:19])[C:9]([CH3:18])([CH3:17])[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.C(O)(C(F)(F)F)=O>C(OCC)(=O)C>[CH:1]1([O:7][C:8](=[O:19])[C:9]([CH3:17])([CH3:18])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)OC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C(=O)O)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a mixture of 2,2-dimethylmalonic acid t-butyl ester cyclohexyl ester (817 mg) and dichloromethane (7.5 mL), TFA (1.5 mL) was added, and the resulting mixture was stirred at room temperature for 2.5 hours. To the resulting mixture, ethyl acetate (100 mL) was added. The resulting mixture was sequentially washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and toluene (10 mL) was added to the filtrate obtained, after which the filtrate was concentrated under reduced pressure to obtain the captioned compound (571 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](Cl)[C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:30]([NH:33][CH2:34][CH:35]=[CH2:36])[CH:31]=[CH2:32]>C(OC(O)C)C>[CH2:30]([N:33]([CH2:34][CH:35]=[CH2:36])[C:11]1[C:10]([N+:18]([O-:20])=[O:19])=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=1)[CH:31]=[CH2:32]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2ccccc2)c1C
Reactant: C=CCNCC=C
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(CC=C)c1nc(C)c(C)c(NCc2ccccc2)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 64.9 %

Procedure:
Benzyl-(2-chloro-5,6-dimethyl-3-nitro-pyridin-4-yl)-amine (1.2 g, 4.1 mmol) was dissolved in ethoxyethanol (60 mL) and diisopropylethylamine (1.1 mL, 6.2 mmol) and diallylamine (0.76 mL, 6.2 mmol) added in one portion. The reaction mixture was heated in a sealed vessel at 100° C. overnight, and then concentrated in vacuo to an orange residue. This residue was purified directly by column chromatography on silica gel, using a gradient of 8:1→1:1 pentane:EtOAc as eluant to provide the title compound as a bright orange oil (938 mg, 65%).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].[CH2:6]([CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH:7]=[C:8]([CH3:10])[CH3:9]>C(O)C>[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][CH:11]1[C:12](=[O:13])[NH:5][C:3](=[O:4])[NH:2][C:17]1=[O:18]
Reactant: CCOC(=O)C(CC=C(C)C)C(=O)OCC
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: CC(C)=CCC1C(=O)NC(=O)NC1=O

Procedure:
To a solution of 70 mg sodium (3.03 mmol) in 1.0 mL absolute ethanol was added 61 mg urea (1.01 mmol), followed by 200 mg of the diethyl prenylmalonate (0.88 mmol) prepared in the previous experiment. The solution was refluxed gently for 12 hours. Most of the ethanol was removed by rotary evaporation, and the residue was diluted in water. The solution was acidified to pH 3 and extracted 2×10 mL with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to 214 mg of an off-white solid.
Reaction SMILES: C([C:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[CH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)#N.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O>[S:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:4]1[NH:25][N:24]=[N:23][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2nccs2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nn[nH]c2-c2nccs2)CC1
Temperature: 110 °C

Procedure:
To a stirred solution of tert-butyl 4-(1-cyano-2-(thiazol-2-yl)vinyl)piperazine-1-carboxylate (2.25 g), sodium azide (0.4 g) were taken in dry DMSO (4 ml) and heated to 110° C. overnight. The reaction mixture was carefully quenched with water (10 ml) and the reaction mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using methanol:chloroform (1:9) as an eluent to afford tert-butyl 4-(5-(thiazol-2-yl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate as white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([O:23]C)=[O:22])=[N:14][C:13]=23)[S:3]1.[OH-].[Na+]>CCO>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([OH:23])=[O:22])=[N:14][C:13]=23)[S:3]1
Reactant: COC(=O)c1cccc(-c2ccn3ncc(C=C4SC(=O)NC4=O)c3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(-c4cccc(C(=O)O)c4)nc23)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 3-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate (25 mg, 0.066 mmol) in EtOH was added 1 mL of 6M NaOH. The mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure. Water was added and the mixture was neutralized with 1M HCl. The resulting solid was isolated by filtration and air dried to yield 3-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid. LCMS (M+1=367)
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][C:13](=[CH2:30])[C:14]([O:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].O.NN>C(Cl)Cl.C(O)C>[NH2:3][O:12][C:13](=[CH2:30])[C:14]([O:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)OC(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: C=C(ON)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-[(1,3-dioxo-2H-isoindol-2-yl)oxy]-2-propenoic acid, diphenylmethyl ester (6.07 g, 15.2 mmole) in 375 ml of methylene chloride under argon at 0° C. was added hydrazine hydrate (0.76 g, 15.2 mmole) in 4 ml absolute ethanol. After one hour at 0° C., the mixture was evaporated to dryness at +10° C. and triturated with ethyl ether. Filtration and concentration of the filtrates gave 2-aminooxy-2-propenoic acid, diphenylmethyl ester as a residue. This compound was then treated at 20° C. with a solution of 2-amino-4-thiazoleglyoxylic acid (2.61 g, 15.2 mmole) in dimethylformamide (50 ml), followed by 5 ml of water. The reaction was stirred at 20° C. for 20 hours, and was then chilled and diluted with 250 ml of water. Stirring of the resulting gum gave a granular solid which was filtered, washed with water, and then azeotroped with acetonitrile to dryness. The dry solid was slurried with 100 ml of acetonitrile, filtered, and finally washed sequentially with acetonitrile, ethyl ether, and hexane. Drying in air gave 1.97 g of the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].C([O:9][C:10](=[O:13])[CH2:11][SH:12])C.Cl[CH:15]=[C:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17](=O)[CH3:18].CC[O-].[Na+]>C1COCC1.C(O)C>[CH2:20]([C:16]1[C:17]([CH3:18])=[C:11]([C:10]([OH:9])=[O:13])[S:12][CH:15]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(=O)C(=CCl)CC(C)C
Reactant: CCOC(=O)CS
Agent: CC(C)(C)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(CC(C)C)csc1C(=O)O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
KOtBu (44.2 g, 394 mmol) is added portionwise to ethanol (200 mL). The mixture is stirred for 30 min at 20° C. to dissolve all KOtBu. Mercapto-acetic acid ethyl ester (47.3 g, 394 mmol) is added and the temperature is maintained at 20° C. This solution is slowly added at 20° C. to a solution of the crude 4-chloro-3-isobutyl-but-3-en-2-one (31.6 g, 197 mmol) in THF (350 mL). The mixture is stirred at rt for 15 h before sodium ethylate (13.4 g, 197 mmol) is added and stirring is continued at reflux for 1 h. The mixture is cooled to rt, and the solvents are evaporated on a rotavap. The residue is diluted with diethyl ether (500 mL), washed with 1 M aq. NaH2PO4 (200 mL), 1 N aq. NaOH (2×100 mL), sat. aq. NaHCO3 (35 mL) containing 10% aq. NaOCl (15 mL) and brine (100 mL), dried over Na2SO4, filtered and evaporated. The resulting residue (36.3 g) is dissolved in EtOH (250 mL), 2 N aq. LiOH (100 mL) is added, and the mixture is stirred at rt for 48 h before it is extracted with diethyl ether (1×400 mL, 2×150 mL). The organic extracts are washed with 1 N aq. NaOH (3×100 mL). The aq. extracts are carefully acidified with 25% aq. HCl and then extracted with DCM (3×150 mL). The combined DCM extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by crystallisation from acetonitrile (150 mL) at 4° C. to give 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (16.0 g) as a beige-brown crystalline powder; LC-MS: tR=0.95 min; 1H NMR (CD3OD): δ 7.21 (s, 1H), 2.43 (s, 3H), 2.42 (d, J=7.0 Hz, 2H), 1.83 (m, J=7.0 Hz, 1H), 0.92 (d, J=7.0 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH2:9].[CH3:10][O:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[F:1][C:2]1[CH:7]=[C:6]([O:14][CH2:13][CH2:12][O:11][CH3:10])[CH:5]=[CH:4][C:3]=1[NH2:9]
Reactant: COCCO
Reactant: Nc1ccc(I)cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCOc1ccc(N)c(F)c1
Temperature: 110 °C
Reaction time: 17 h
Yield: 41.1 %

Procedure:
A mixture of 2-fluoro-4-iodo-phenylamine (2.3672 g, 10 mmol), 2-methoxyethanol (13 ml, 164 mmol), copper(I)iodide (190 mg, 1 mmol), 1,10-phenanthridine (360 mg, 2 mmol), and cesium carbonate (4.55 g mg, 14 mmol) was sealed and heated at 110° C. After 17 hours, the crude mixture was extracted with CH2Cl2 and brine. Organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (1:1 v/v) twice to give 2-fluoro-4-(2-methoxy-ethoxy)-phenylamine as an oil (761 mg, 41%). Exact mass calculated for C9H12FNO2 185.09. found 186.0 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[I-].[Na+].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.Cl.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:11][C:4]1[CH:3]=[C:2]([O:1][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: CC(=O)c1ccc(OCCN2CCOCC2)cc1C
Temperature: 25 °C

Procedure:
A mixture of 1-(4-hydroxy-2-methyl-phenyl)-ethanone (15.0 g, 0.10 mole), sodium iodide (15.0 g, 0.10 mole), 4-(2-chloro-ethyl)-morpholine; hydrochloride (18.6 g, 0.10 mole), anhydrous powdered potassium carbonate (67.0 g, 0.50 mole) and 2-butanone (500 mL) is stirred and heated at a gentle reflux overnight. The mixture is cooled to room temperature, filtered, the solids washed with acetone. The combined filtrates were evaporated in-vacuo, the residue treated with water and extracted with ether. The ether layer is washed with 1N sodium hydroxide, water, brine, dried over anhydrous sodium sulfate, filtered and evaporated to give an oil, 19.2 g. (73%) used as is for the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H-].[Na+].[C:12]1([CH:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH2:20][O:21][C:22](=[O:28])[CH2:23][C:24]([CH2:26]Cl)=[O:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>C1COCC1>[C:12]1([CH:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH2:20][O:21][C:22](=[O:28])[CH2:23][C:24](=[O:25])[CH2:26][O:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: OCCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(COCCc1ccccn1)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
503 mg (4.08 mmol) of 2-(pyridine-2-yl)ethanol was added dropwise to a suspension of 326 mg (8.16 mmol) of sodium hydride (60% oily) in 10 ml of THF at 0° C., and they were stirred for 30 minutes. A solution of 0.90 mg (2.72 mmol) of (3,3-diphenylpropane-1-yl)4-chloroacetoacetate in 3 ml of THF was added dropwise to the reaction mixture, and they were stirred at room temperature overnight. After the addition of methanol, the reaction mixture was concentrated and fractionated with ethyl acetate and water. After the drying over sodium sulfate followed by the purification by the silica gel chromatography (methylene chloride/methanol=100/1), the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([C:19]4[N:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28](C(OCCCC)=O)[CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH:16]=[CH:17][CH:18]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.Cl>C(#N)C.O1CCOCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[N:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH:14]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)N1CCN(c2cnc(-c3cccc(Cn4c(=O)oc5ccc(C)nc54)c3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCNCC5)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.16 mmol) of tart-butyl 4-{2-[3-(5-methyl-2-oxooxazolo[4,5-b]pyridin-3-ylmethyl)phenyl]pyrimidin-5-yl}piperazine-1-carboxylate are dissolved in 6 ml of acetonitrile, and 6 ml of 4 M HCl in dioxane are added. The reaction mixture is stirred at room temperature for 1 h and evaporated. The residue is taken up in water and ethyl acetate, and the water phase is adjusted to pH 12 using NaOH and extracted with ethyl acetate and dichloromethane. The organic phases are combined, dried over sodium sulfate and purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])=[C:4]([CH:9]=[C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].[N-:31]=[N+:32]=[N-:33]>>[N:31]([C:11]1[C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C:2]=1[F:1])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F

Procedure:
Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be reacted with azide (such as NaN3, KN3) in appropriate solvent. The reaction is generally carried out at high temperature (60-120° C., prefer 80-100° C.) and normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[OH-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Reactant: NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCCCC(=O)O)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
14.0 g of 3-benzyloxy-4-methoxybenzoyl chloride are added in one portion at 26° C. to 15.6 g of 4-aminobutyric acid, 12.1 g of sodium hydroxide and 160 ml of ion-free water and subsequently 30 ml of tetrahydrofuran are added dropwise within 10 minutes. After 2 hours, the mixture is acidified with concentrated hydrochloric acid at a temperature below 10° C. The precipitate is separated and stirred with ethyl acetate. The mixture is filtered and the filter cake is washed with ethyl acetate. There is obtained 4-[(3-benzyloxy-4-methoxybenzoyl)amino]butyric acid which, after recrystallisation from ethyl acetate, melts at 156°-158° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]1=[O:17].Cl[C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:21][C:20]=1[F:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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:34][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:19]=1[C:6]1[CH:5]=[CH:4][C:3](=[O:17])[N:2]([CH3:1])[CH:7]=1)[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2F)ccc1=O
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 21-3 (78 mg, 0.33 mmol), tert-butyl 4-chloro-3-fluorobenzylcarbamate 21-5 (94 mg, 0.36 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol) and K3PO4 (140 mg, 0.66 mmol) in dioxane (1.2 mL) and water (0.1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography to give crude tert-butyl 3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzylcarbamate 21-6.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1)(OC(C)(C)C)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:38].Cl.Cl.CCOCC.CO>CCOCC>[ClH:38].[ClH:38].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1
Reactant: COC(=O)NCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: CO
Product: COC(=O)NCc1cncc(OC[C@@H]2CCN2)c1
Yield: 99 %

Procedure:
The product of step 159a (0.23 g, 0.70 mmol) was deprotected and isolated as the free base in 99% yield according to the procedure of Example 20b, followed by conversion to the dihydrochloride with excess HCl/Et2O. [α]D23 +12.46 (c 0.1, MeOH); 1H NMR (D2O, 300 MHz) δ2.65-2.75 (m, 2H), 3.66 (s, 3H), 4.08-4.19 (m, 2H), 4.43 (s, 2H), 4.53-4.69 (m, 2H), 4.90 (m, 1H), 8.22 (s, 1H), 8.44 (s, 1H), 8.63 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 252 (M+H)+. Anal. Calcd for C12H17N3O·2.5 HCl·1.5 H2O·0.4 Et2O: C, 40.93; H, 6.69; N, 10.53. Found: C, 40.96; H, 6.63; N, 10.46.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54]>C(OCC)(=O)C>[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54].[CH:1](/[C:9]1[N:10]([C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccnc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-chloro-4-trifluromethyl-pyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.