Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20]1([NH2:30])[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[C:3](=[O:19])[C:2]([NH:30][C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1cccc2c1CCCC2
Product: COCCN1C(=O)C(Nc2cccc3c2CCCC3)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 5,6,7,8-tetrahydronaphthalen-1-amine in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 7.37 (bs, 1H), 7.20-7.15 (m, 1H), 7.11-7.01 (m, 4H), 6.75 (d, 1H), 6.70 (t, 1H), 6.63-6.60 (m, 1H), 3.90 (t, 2H), 3.72 (t, 2H), 3.38 (s, 3H), 2.60-2.54 (m, 4H), 1.76-1.69 (m, 2H), 1.66-1.59 (m, 2H); Mass Spectrum: M+H+ 413.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:13][C:6]1([F:14])[C:5]2[C:9](=[CH:10][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:3]([OH:15])[CH:4]=2)[C:8]([F:11])([F:12])[O:7]1
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
A mixture of 2.0 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 1.1 g of isonicotinic acid, 2.23 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture. Precipitated solid was filtered and washed with water and dried under reduced pressure to give 1.34 g of N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C)C=O.[H-].[Na+].Br[CH:34]([CH2:36][CH3:37])[CH3:35]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH:34]([CH2:36][CH3:37])[CH3:35])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(C)Br
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(C(C)CC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.00 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.60 g), and the mixture was stirred at room temperature for 30 min. To the mixture was added 2-bromobutane (1.64 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water 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 column chromatography to give the title compound as a colorless solid (0.61 g, 53%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1-n1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Product: Cc1ccncc1-n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 85 %

Procedure:
3-tert-Butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-amine (844 mg, 3.66 mmol) was treated with phenyl chloroformate (1.90 mL, 15.0 mmol) according to the procedure in Example 118A to afford phenyl 3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (1.09 g, 3.11 mmol, 85%). 1H NMR (300 MHz, DMSO-d6) δ 10.09 (br s, 1H), 8.53 (d, 1H), 8.43 (s, 1H), 7.44 (d, 1H), 7.39-7.34 (m, 2H), 7.22 (t, 1H), 6.98 (br s, 2H), 6.35 (s, 1H), 2.09 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1c[nH]c2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of (7-(benzyloxy)-1H-indol-3-yl)acetic acid (7.21 g, 27.4 mmol) in tetrahydrofuran (150 mL) is added a 1M solution of borane.tetrahydrofuran complex in tetrahydrofuran (55 ml, 55 mmol) under nitrogen atmosphere, and the mixture is stirred at room temperature for 17 hours. To the reaction solution is added methanol (100 mL), and the mixture is stirred at room temperature for one hour. The solvent is evaporated, and the resulting crude product is purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1) to give 2-(7-(benzyloxy)-1H-indol-3-yl)ethanol (6.37 g, 23.8 mmol, yield: 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH3:2].[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:24][C:9]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[N:11][C:12]2[C:7]([C:8]=1[C:25]([O:27][CH3:28])=[O:26])=[CH:6][C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(=O)(=O)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(=O)(=O)CC
Temperature: 100 °C

Procedure:
A mixture of methyl 7-(ethyloxy)-6-(ethylsulfonyl)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.11 g, 18.92 mmol), N-bromosuccinimide (4.38 g, 24.60 mmol) and diphenylperoxyanhydride (0.458 g, 1.892 mmol) in carbon tetrachloride (100 mL) was heated to 100° C. overnight. The mixture was cooled to room temperature and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-7-(ethyloxy)-6-(ethylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 562.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([NH:13][C:14]2[N:15](C(=O)C3C=CC=CC=3)[CH2:16][CH2:17][N:18]=2)[C:4]([CH3:27])=[N:3]1>CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([NH:13][C:14]2[NH:15][CH2:16][CH2:17][N:18]=2)[C:4]([CH3:27])=[N:3]1
Reactant: Cc1nn(C)c(-c2ccccc2)c1NC1=NCCN1C(=O)c1ccccc1
Solvent: CO
Product: Cc1nn(C)c(-c2ccccc2)c1NC1=NCCN1
Yield: 80.2 %

Procedure:
10.0 g of 1,3-dimethyl-5-phenyl-4-(1-benzoyl-2-imidazolin-2-yl)aminopyrazole are heated to boiling in methanol under reflux for 6 hours. The solvent (methanol) is distilled off in vacuo, and the residue is twice recrystallized from isopropyl alcohol to yield 5.7 g (80.2% of theory) of 1,3-dimethyl-5-phenyl-4-(2-imidazolin-2-yl)aminopyrazole, mp 232° to 234°. The mixed melting point with the product obtained in accordance with Example 8 shows no depression.
Reaction SMILES: [NH2:1][N:2]1[C:6]2[N:7]=[C:8]([CH:16]3[CH2:18][CH2:17]3)[CH:9]=[C:10]([C:11]([O:13]CC)=[O:12])[C:5]=2[CH:4]=[N:3]1.[OH-].[Na+]>C(O)C>[NH2:1][N:2]1[C:6]2[N:7]=[C:8]([CH:16]3[CH2:17][CH2:18]3)[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1cnn2N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nn1ncc2c(C(=O)O)cc(C3CC3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 1-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (100 mg, 0.406 mmol) in ethanol (10 mL) was added sodium hydroxide (1 ml, 0.406 mmol), and the mixture stirred at room temperature for 2 h. The solvent was removed in vacuo, and the residue diluted with EtOAc (30 mL) and water (20 mL). The reaction mixture was acidified to pH 3 with citric acid. The phases were separated and the aq. phase extracted with EtOAc (4×20 mL). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The final product was collected as 0.075 g (84%). LCMS E-S (M+H)=219.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.13 (m, 4H), 2.27-2.45 (m, 1H), 6.36 (s, 2H), 7.60 (s, 1H), 8.06 (s, 1H), 13.81 (br. s., 1H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.CS(O)(=O)=O>C1COCC1>[NH2:8][C@@H:9]([CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CCSc1ccccn1)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)CCSc1ccccn1
Reaction time: 16 h

Procedure:
To methyl 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyrate (0.75 g, 2.4 mmol) in THF (5 mL) was added methanesulfonic acid (6.9 g, 7.2 mmol) in one portion. The solution was stirred for 16 h and the crude reaction mixture was concentrated to give methyl 2(S)-amino-4-(pyridin-2-ylsulfanyl)butyrate as the mesylate salt which was used directly in the next step.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:7])[CH2:15][CH2:14]1)[CH3:12]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2ccc(I)cc2)CC1

Procedure:
Into a 100 mL round bottom flask was placed 4-iodobenzoyl chloride (2.67 g, 0.01 mmol) and dichloromethane (25 mL). The flask was placed in an ice water bath. Then N-ethylpiperazine (2.6 mL, 0.021 mmol) was added dropwise with stirring. The reaction was allowed to stir for 10 days at room temperature. Saturated aqueous potassium carbonate (50 mL) was added, and the product was extracted with ethyl acetate (3×100 mL). The organic layers were dried over sodium sulfate, filtered through a silica plug, and concentrated under reduced pressure to afford the title compound as a yellow oil. Mass found by LC-MS(+): 345 M+H+); calc. for C19H29BN2O3: 344.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].ON1C2C=CC=CC=2N=N1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][NH:33][CH2:32][CH2:31]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][N:33]([C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=1)[CH2:32][CH2:31]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(C(=O)Cc1ccc(OC)c([N+](=O)[O-])c1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A mixture of 4-methoxy-3-nitrophenylacetic acid (1.2 g) and 1-hydroxybenzotriazole (0.95 g) in DMF (30 ml) was stirred at room temperature for 10 min. 1,2,3,4-Tetrahydro-6,7-dimethoxy-isoquinoline (1.1 g) in DMF (20 ml) was then added, followed by dicyclohexylcarbodiimide (1.2 g) and the mixture was stirred at room temperature for 6 h and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxyde and extracted with ethyl acetate. The dried organic extract was evaporated to give the title compound (1.6 g) as an oil which crystallised from ethanol as a white solid, MP 175°. IR: Freq CO: 1650 cm-1.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][C:21]=1[F:22].S(Cl)(Cl)=O>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([CH3:28])([CH3:27])[C:24]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:25])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccc(F)c(Cl)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Diethyl malonate (5.68 mL, 37.6 mmol) was dissolved in ACN (75 mL) at 0° C. MgCl2 (3.93 g, 41.3 mmol) was added to the reaction mixture in one portion and TEA (10.5 mL, 75.1 mmol) was added dropwise. 2-(3-chloro-4-fluorophenyl)-2-methylpropanoic acid (7.73 g, 35.7 mmol) was converted to the acid chloride by reaction with thionyl chloride at 65° C. for 1 hour, and the resulting acid chloride was concentrated under reduced pressure. The acid chloride was then dissolved in ACN and added dropwise via addition funnel to the initial reaction mixture. The resulting mixture was stirred at ambient temperature for 2 hours and then quenched with water, acidified with 5N HCl, diluted with 100 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed with water (2×50 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (7.17 g) as a light yellow oil after flash chromatography. MS m/e=359 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:20]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (0.26 g, 0.51 mmol) in dichloromethane (5 mL) at ambient temperature was added trifluoroacetic acid (5 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The solution was concentrated and the residual glassy solid was redissolved in ethyl acetate (2 mL). Hexanes (10 mL) were added, and after mixing for a few minutes, the product solidified. The mixture was concentrated to afford the desired compound as a light brown powder (0.23 g, 99% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[C:13]([O:17]CC3C=CC=CC=3)=[CH:12][N:11]=2)=[O:9])[CH2:4][CH2:3]1>CO.[C].[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[C:13]([OH:17])=[CH:12][N:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)c2cc(O)c(OCc3ccccc3)cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2cc(O)c(O)cn2)CC1
Reaction time: 0.33 h
Yield: 38.7 %

Procedure:
To a solution of 1-methyl-4-(4-hydroxy-5-benzyloxy-2-pyridylcarbonyl)piperazine (4.71 g) in methanol (300 ml) was added 10% palladium-carbon (2.35 g) in a stream of nitrogen and the mixture was hydrogenated at atmospheric pressure for 20 minutes. After the catalyst was removed by filtration, the filtrate was evaporated to dryness. The residue was recrystallized from methanol to give 1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)piperazine (1.32 g).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=O)[C:11]=3[C:20]([O:22]CC)=[O:21])=[CH:4][C:3]=2[O:2]1>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[CH:11]2[C:20]([OH:22])=[O:21])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Yield: 100 %

Procedure:
Ethyl 3-(3,4-Methylenedioxyphenyl)-1-oxoindene-2-carboxylate. A solution containing diethyl 2-[2-(3,4-methylenedioxybenzoyl)benzoylmalonate (crude material prepared above) in 5% aqueous Na2CO3 (100 ml) was heated at reflux for 10 min. The reaction mixture was then allowed to cool, and the aqueous material was removed by decantation. The residue was placed in H2O (50 ml), and the mixture was heated at reflux, cooled and concentrated under reduced pressure. The residue was recrystallized from hexanes to afford the title compound as a yellow solid (5.0 g, 100% for two steps).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>C1COCC1.[C].[Pd]>[CH:20]([N:18]1[N:17]=[N:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:19]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1nnc(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1nnc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.4 %

Procedure:
To a solution of 5-(4-benzyloxyphenyl)-2-isopropyl-2H-tetrazole (521 mg) in THF (5 mL)-methanol (5 mL) was added 7.5% palladium-carbon (60 mg). The mixture was stirred at room temperature for 3.5 hours under hydrogen atmosphere. The catalyst was filtered off through a Celite pad. The filtrate was concentrated to give the title compound (352 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]#[N:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[N-:29]=[N+:30]=[N-:31].[Na+].[NH4+].[Cl-]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(C#N)cc3nc2-c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3ccc(-c4nnn[nH]4)cc3nc2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Into a 20-mL sealed tube, was placed a solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-carbonitrile (200 mg, 0.51 mmol, 1.00 equiv, 93%) in N,N-dimethylformamide (7 mL), NaN3 (500 mg, 7.69 mmol, 15.18 equiv), NH4Cl (147.9 mg, 2.79 mmol, 5.00 equiv). The resulting solution was stirred for 4 h at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 8×50 mL of dichloromethane/MeOH (10:1) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 47 mg (23%) of 2,3-bis(4-methoxyphenyl)-6-(1H-tetrazol-5-yl)quinoxaline as a yellow solid.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17]CO)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:2][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCCCOCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCOCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
179 g of tetrabromomethane is added in portions to the solution of 85 g of 5-benzyloxy-pentan-1-ol and 143 g of triphenylphosphine in 720 ml of methylene chloride that is cooled to −15° C., and after the addition has been completed, it is stirred for 3 hours at 0° C. After the reaction mixture was concentrated by evaporation in a vacuum, the purification is carried out by chromatography on silica gel with a hexane-methylene chloride gradient. 71 g of 5-benzyloxy-1-bromo-pentane is obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][N:18]1[CH2:23][C:22]([CH3:24])=[N:21][NH:20][C:19]1=[O:25].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[CH3:24][C:22]1[CH2:23][N:18]([NH:17][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[C:19](=[O:25])[NH:20][N:21]=1
Reactant: CC1=NNC(=O)N(N)C1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC1=NNC(=O)N(NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (0.317 g, 1.45 mmol) in anhydrous DMF (5 mL) is added 4-amino-6-methyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (0.206 g, 1.45 mmol) followed by the addition of DMTMM (0.421 g, 1.52 mmol). The mixture is stirred at rt overnight. The mixture is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The organic phase is separated, dried (MgSO4), filtered and concentrated in vacuo to afford 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (0.306 g) as a solid. MS: 329 (M+H).
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.[CH2:28]([NH2:33])[CH2:29][CH:30]([CH3:32])[CH3:31].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[CH2:28]([NH:33][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:4](=[O:22])[C:3]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]3[C:1]2=[O:27])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)CCN
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 3 g (8.4 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), by reaction with isopentylamine in the presence of HOBT and DIC, 3.2 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acid isopentylamide were obtained; m.p. 169° C. The product was dissolved in 100 ml of methanol and treated with 5 ml of hydrazine hydrate. After stirring at 40° C. for 1 h, the cooled reaction mixture was filtered. The filtrate was concentrated and the residue was taken up in methylene chloride. After washing with water, drying and concentrating, 1.8 g of 2′-amino-methylbiphenyl-2-carboxylic acid isopentylamide were obtained.