Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
To a solution of 2-benzylacrylic acid (1.02 g, 6.3 mmol) in dimethylformamide (10 ml) was added potassium carbonate (1.04 g, 7.6 mmol) and water (0.25 ml) with stirring. After 10 minutes, benzyl bromide (0.9 ml, 7.6 mmol) was added. After 3 hours, water was added and the resulting mixture was extracted with ether. The ether layer was washed 3 times with water, dried over magnesium sulfate, filtered over silica gel, and concentrated under reduced pressure. The resulting oil was distilled (70° C., 0.2 torr) to remove any unreacted starting material, then distilled (125° C., 0.2 torr) to yield 1.38 g (87%) of clear oil. 1H NMR (CDCl3): δ 3.7 (s, 2H), 5.2 (s, 2H), 5.5 (s, 1H), 6.3 (s, 1H), 7.2-7.6 (m, 10H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[C:1]([CH2:3][CH2:4][N:5]1[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:20][N:19]=[N:18]1)#[N:2]
Reactant: COC(=O)c1cccc(C(=O)NCCC#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Yield: 41.2 %

Procedure:
Preparation H7, Step 2: To a soultion of methyl 3-((2-cyanoethyl)carbamoyl)benzoate (400 mg, 1.7 mmol) in MeCN (15 mL) at 0° C. was added NaN3 (111 mg, 1.7 mmol), and Tf2O (0.3 mL, 1.7 mmol). The mixture was stirred at rt for 16 h before aq NaHCO3 and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate as an oil (180 mg, 41% yield). MS found: (M+H)+=258.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](OCC)(OCC)OCC>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:12]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: CCOC(OCC)OCC
Product: Brc1ccc(-c2nnco2)cc1
Reaction time: 8 h

Procedure:
12.3 mmol of 4-bromo-benzoic acid hydrazide were dissolved in 26 ml of triethyl orthoformate. The reaction mixture was stirred overnight at 140°, evaporated and the residue crystallized from ethanol to give the title compound as a colorless solid. MS (m/e): 225.0 (MH+, 100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]nc(I)c2c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.1 g (about 39.65 mmol) of the compound from Example 6A were initially charged in DMF (217 ml), and 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of caesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then added to water (1.17 l) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase:petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the title compound as a solid. The solid was taken up in ethyl acetate and washed with 10% strength aqueous sodium thiosulphate solution and then with saturated aqueous sodium chloride solution, dried and concentrated.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[C:6]([O:5][C:1]([NH:2][N:3]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of t-butyl carbazate (2.0 g, 15.1 mmol) in 99% ethanol (20 ml) was added benzaldehyde (1.6 g, 15.1 mmol) and the mixture was stirred for 30 min. Then the mixture was cooled to 0° C. and the precipitate was separated and washed with cold ethanol and dried in vacuo to give 2.7 g (81%) of N′-benzylidenehydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26][CH3:27])(=[O:4])[CH2:2][CH3:3].C([O-])(O)=[O:29].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26]([CH3:27])=[O:29])(=[O:4])[CH2:2][CH3:3]
Reactant: O=C([O-])O
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: 4 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
3-Propanoyl-4-(2-methylphenylamino)-8-(2-methylthioethyloxy)quinoline (0.10 g, 0.26 mmol) was dissolved in methylene chloride (5 ml). NaHCO3 (45 mg) in H2O (5 ml) was added. The mixture was cooled to 4° C. A solution of 71% m-CPBA (0.062 g, 0.25 mmol) in methylene chloride (5 ml) was added dropwise. After stirring for 1 h at 2°-4° C., the organic layer was washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; CH2Cl2 :EtOH 90:10) gave 50 mg (48%) of the desired product.
Reaction SMILES: ON1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]O)=[O:17])[CH:11]=1>C(Cl)Cl.CCOCC>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C1CCC(=O)N1O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In still another alternative synthesis of (10), N-hydroxysuccinimide (230 mg, 2 mmol) was added to a solution of compound (8) (248 mg, 1 mmol) in CH2Cl2 (10 mL) was added and the reaction mixture cooled to 0° C. m-Chloroperbenzoic acid (670 mg, 3 mmol, commercial grade: 77% in water) was added over a period of 10 min and the mixture allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ether (50 mL) and washed with water (2×10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (10) together with m-chlorobenzoic acid. The crude product mixture was purified by column chromatography on silica gel, eluting with 4:6 EtOAc:hexane. Residual m-chlorobenzoic acid was removed by repeated crystallizations from a mixture of tert-butyl methyl ether and hexane which resulted in analytically pure product (30 mg, 11%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Br-].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl.[H-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH2:10][O:9]1
Reactant: CN(C)CCCCl
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 62.5 °C
Reaction time: 7 h
Yield: 66.1 %

Procedure:
Under nitrogen atmosphere, to a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (3.0 g) in N,N-dimethylformamide (15 ml) were added tetra n-butfylammonium bromide (0.12 g) and N,N,N′,N′-tetramethylethylened amine (2.92 g). Thereto was added dropwise a solution of 3-(dimethyiamino)propyl chloride (2.0 g) in toluene (12 ml), and then a suspension of 60% sodium hydride (0.58 g) and liquid paraffin (1.5 ml) over 1.5 hr. The mixture was stirred at 61-64° C. for 7 hr. The reaction mixture was treated in the same manner as in Example 22 to give 1-(3-(dimethylamino)propyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (2.69 9, yield 66.1%). Hydrobromide thereof showed the same HPLC retention time and melting point as obtained in Example 22.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[O:5]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Cl:3])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ccccc2)cc1
Product: ClCc1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 97.2 %

Procedure:
Thionyl chloride (13.34 g) was added to 4.06 g of 4-phenoxybenzyl alcohol, and the mixture was stirred at 80° C. for 3.5 hours. After the completion of the concentration, the reaction mixture was extracted with ethyl acetate and with water. The organic layer was concentrated to give 4.31 g of 4-phenoxybenzyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:20][C:21]([C:23]3([NH:29]C(=O)OC(C)(C)C)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:18]#[N:19])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[F:37])(=[O:3])[NH2:2]>C(O)=O>[NH2:29][C:23]1([C:21]([NH:20][C@H:17]([C:18]#[N:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH2:2])=[C:5]([F:37])[CH:6]=3)=[CH:15][CH:14]=2)=[O:22])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C(N)=O)c(F)c3)cc2)CCOCC1
Solvent: O=CO
Product: N#C[C@H](Cc1ccc(-c2ccc(C(N)=O)c(F)c2)cc1)NC(=O)C1(N)CCOCC1
Yield: 61 %

Procedure:
(S)-tert-Butyl 4-(2-(4′-carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 25, step (i), 108 mg) in formic acid (2 mL) was heated at 50° C. for 20 mins. Volatiles were removed under reduced pressure and the residue azeotroped with methanol. The residue was purified by reversed phase HPLC using methanol in 0.1% aqueous TFA solution as eluent. The residue was converted to the free base by elution through a PL-HCO3 MP cartridge in dichloromethane/methanol to afford the titled compound (53 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1CCOCC1

Procedure:
A solution of 4-(2-hydroxylethyl)-morpholine (Aldrich, 5.1 mL, 42 mmol), triethylamine (17 mL, 124 mmol), and methanesulfonyl chloride (4.8 mL, 62 mmol) in 100 mL THF were processed as described in Example 1C to give the crude material which was used directly in the next reaction.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH2:11])([CH3:3])[CH3:2].[Br:12]Br>C(O)(=O)C.C(Cl)Cl>[Br:12][C:8]1[CH:7]=[C:6]([CH3:10])[C:5]([NH2:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: BrBr
Reactant: Cc1cccc(C(C)C)c1N
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Isopropyl-6-methyl-phenylamine (5 g, 33.5 mmol) was dissolved in acetic acid (20 mL). To this solution was added a solution of bromine (1.8 mL, 35.14 mmol) in acetic acid (5 mL) dropwise over 10 min. After stirring for 1 h at room temperature, the reaction mixture was diluted with methylene chloride, washed with water (2×), saturated sodium thiosulfate (2×), saturated sodium bicarbonate (2×), and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel afforded 7.6 g (quantitative) of the desired product. LC/MS: tR=1.37 min, 230.07 (MH)+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:4]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Sodium hydride (3.78 g, 80% suspension in oil) was added to a solution of 3-pyridinol (10 g) in THF (150 ml) at 0°. The mixture was stirred under nitrogen for 30 min, treated dropwise with methyl bromoacetate (19.3 g), heated under reflux for 24 h, poured into ice-water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried and concentrated to give an oil which was purified by FCC, eluting with System G (98:2:1) to give the title compound (4 g), as an oil. T.l.c. (System E 80:20:1) Rf 0.46
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].C(OCC)(=O)C.[ClH:25]>C(O)(=O)C.[Cu](Cl)Cl>[Cl:25][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To 3-amino-4-methoxycarbonylbenzoic acid (0.98 g, 5 mmol) suspended in 12 M hydrochloric acid (25 mL) and acetic acid (25 mL), an aqueous solution (10 mL) sodium nitrite (0.35 g, 5 mmol) was added at −10° C., and the resulting solution was stirred for 30 minutes. The solution was added to copper chloride (I) (0.99 g, 10 mmol) in 12 M hydrochloric acid (25 mL) at −10° C., and the resulting reaction mixture was stirred at room temperature for 1 hour. After addition of ethyl acetate, the reaction mixture was washed with water, dried over magnesium sulfate, filtered through celite and purified by silica gel column chromatography to give 0.44 g of the desired product as a colorless solid (yield 39%).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH:19][C:20]3[S:21][C:22]([C:25]([O:27]C)=[O:26])=[CH:23][N:24]=3)[CH:13]=2)[CH2:8][CH2:7]1.Cl>O>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH:19][C:20]3[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=3)[CH:13]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(Nc2ncc(C(=O)O)s2)cc(N2CCN(CCO)CC2)n1
Yield: 81.2 %

Procedure:
NaOH (8.0 g, 0.2 mol) was added in a reaction flask with water (190 mL) and dissolved by stirring. Then methyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate (Compound 6) (37.8 g, 0.1 mol) was added and stirred for reaction at room temperature overnight. The pH value of the reactant was adjusted to 6-6.5 with hydrochloric acid (6 mol/L) when the temperature is controlled between 20° C. and 25° C., and the crystal was grown by heat preservation for 2 h, and then filtrated and dried to give Compound 7 (29.6 g, yield: 81.4%).
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.Br.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)CBr
Agent: Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 89 %

Procedure:
80 g (0.31 mol) of ethyl 2,3-dibromopropionate diluted in 300 ml of benzene are added dropwise, but fairly rapidly, to a warm solution of 72 g (0.3 mol) of N,N'-dibenzylethylenediamine, 700 ml of benzene and 50 ml (0.36 mol) of triethylamine. After the addition, reflux is maintained for 3 hours (triethylamine hydrobromide precipitates in the reaction mixture). The mixture is cooled and filtered through fritted glass, and the solid is washed with ether. The filtrate is washed with 200 ml of saturated sodium hydrogen carbonate solution and then twice with 100 ml of water. The organic phases are dried over magnesium sulfate and the solvents are evaporated off in vacuo. Approximately 100 ml of toluene are added, and evaporation is continued. The resulting residue is diluted in 400 ml of absolute ethanol and saturated with gaseous hydrogen chloride. The salt precipitates by the addition of ether. Filtering, washing with ether and drying yield from 100 to 110 g of white crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13](=O)([O-])[O-].[Na+].[Na+].IC>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
4-Fluoro-2-methyl-5-nitro-phenol (1.08 g, 6.3 mmol) was dissolved in acetone (100 ml). To this was added solid sodium carbonate (2 eq, 1.34 g) and iodomethane (10 eq, 3.75 ml). The mixture was allowed to stir at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give 1-fluoro-4-methoxy-5-methyl-2-nitro-benzene (1.18 g, quantitative) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH:5]=[O:6].[Br:9]Br>O1CCOCC1>[Br:9][CH:4]([CH2:3][C:2]([F:8])([F:7])[F:1])[CH:5]=[O:6]
Reactant: BrBr
Reactant: O=CCCC(F)(F)F
Solvent: C1COCCO1
Product: O=CC(Br)CC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a mixture of 4,4,4-trifluorobutyraldehyde (5 g, 39.68 mmol) in 1,4-dioxane (5 ml) cooled to 0° C., bromine (2.24 ml, 43.65 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h. The resulting reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (MgSO4) and evaporated in vacuo to yield compound D4 (6.2 g, 76%) that was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[F:3][C:4]1[CH:12]=[C:11]([NH:2][CH3:1])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Solvent: O
Product: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylamine (13.5 mL, 40% in water) is added to an ice-cooled mixture of 2,4-difluoro-5-nitro-benzoic acid (10.0 g, 49 mmol) in water (100 mL) and it is stirred for 30 min at rt. The mixture is acidified with 6N aq. HCl-solution and the precipitate is filtered, washed with water and dried at 60° C. The crude material was recrystallized from MeOH. The final product was slightly contaminated by its regioisomer 4-fluoro-2-methylamino-5-nitro-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1C(=O)N1CCOCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cc(F)ccc1CBr)N1CCOCC1
Yield: 38.3 %

Procedure:
A mixture of intermediate 41, (5-fluoro-2-methylphenyl)(morpholino)methanone, (2.1 g, 9.5 mmol) and N-bromosuccinimide (2.0 g, 11 mmol) in CCl4 (30 mL) was heated at reflux. To this mixture was added benzoylperoxide (242 mg, 1 mmol) and the mixture heated at reflux for 2 hrs. After cooling, the insoluble materials were filtered and the filtrate purified by column chromatography (SiO2, 0-10% ether in CH2Cl2) to give 1.1 g (Yield 38%) of the title compound as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm: 3.31 (2H, t, J=4.94 Hz) 3.55-4.02 (6H, m) 4.56 (2H, dd, J=128.81, 9.51 Hz) 6.89 (1H, dd, J=8.23, 2.74 Hz) 6.96-7.12 (1H, m) 7.33-7.49 (1H, m); LC/MS m/z 302 (M+H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].COC1C=CC(C[N:12]2[C:17]3[NH:18][N:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]=3[C:15](=[O:28])[N:14]([CH3:29])[C:13]2=[O:30])=CC=1.C1(OC)C=CC=CC=1>ClCCCl>[CH3:29][N:14]1[C:15](=[O:28])[C:16]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][NH:18][C:17]=2[NH:12][C:13]1=[O:30]
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n[nH]c32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: Cn1c(=O)[nH]c2[nH]nc(Nc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
AlCl3 (0.733 g, 5.50 mmol) is added to a solution of 7-(4-methoxybenzyl)-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.692 g, 1.83 mmol) and anisole (40 μL, 0.367 mmol) in 1,2-dichloroethane (10 mL) under argon. The reaction mixture is stirred at room temperature for 30 min, and then quenched with water with cooling. The resulting suspension is filtered through a layer of celite and the celite is washed with MeOH (20 mL). The product is eluted from the celite with a large amount of THF. The THF eluent is evaporated to afford 0.47 g of product (Yield: 99%). MS (FAB) m/z 258.2 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.O>O1CCOCC1>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:18][CH:19]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1

Procedure:
At room temperature, 31.60 g (281.48 mmol) of potassium tert-butoxide and 52.70 g (270.22 mmol) of tert-butyl bromoacetate are added to a solution of 27.50 g (225.18 mmol) of 4-hydroxybenzaldehyde in 200 ml of dioxane, and the mixture is heated at the boil overnight. 1 l of water is added, and the mixture is then extracted with diethyl ether, washed with 1 N sodium hydroxide solution, water and saturated sodium chloride solution and dried over magnesium sulphate, and the solvent is distilled off. Flash chromatography on silica gel (cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→5:1) gives, after recrystallization from pentane, the target compound.