Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:6][C:5]=2[S:4][C:3]=1[C:19]([O:21]CC)=[O:20].Cl>[OH-].[Na+]>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:6][C:5]=2[S:4][C:3]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1sc2nc(CN3CCCCC3)[nH]c(=O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)O)sc2nc(CN3CCCCC3)[nH]c(=O)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
671 Milligrams of ethyl 5-methyl-4-oxo-2-piperidinomethyl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate was suspended in 8 mL of 0.5N sodium hydroxide, stirred at 80° C. for 2 hours, and allowed to cool off. The reaction liquid was neutralized with 2N hydrochloric acid, and the precipitate was recovered by filtration and dried, to provide 565 mg (92%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH:15]([C:17](=[O:19])[CH3:18])[CH3:16])[CH:11]=[C:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH:15]([C:17]([OH:19])([CH3:24])[CH3:18])[CH3:16])[CH:11]=[C:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(=O)n(C(C)C(C)=O)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(=O)n(C(C)C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 5-(4-fluorophenyl)-6-oxo-1-(3-oxobutan-2-yl)-1,6-dihydropyridine-3-carboxylate (11.1 g, 35.0 mmol) in tetrahydrofuran (175 mL) at 0° C. was added methylmagnesium bromide (3.0 M in THF; 14.0 mL, 42.0 mmol). After 20 min, the mixture was quenched with saturated aqueous sodium bicarbonate. The mixture was cooled to ambient temperature and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→80% dichloromethane/ethyl acetate) gave the title compound. MS 334.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:8])[C:4]1([CH3:18])[CH3:17].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.O>[C:12]([O:11][C:10]([NH:9][C@:5]1([CH3:8])[CH2:6][CH2:7][C@H:3]([CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])[C:4]1([CH3:18])[CH3:17])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CC[C@H](CO)C1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@]1(C)CC[C@H](COS(C)(=O)=O)C1(C)C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of t-butyl [(1R,3S)-3-(hydroxymethyl)-1,2,2-trimethyl cyclopentyl]carbamate (2.0 g, 7.78 mmol) in 30 mL of dichloromethane maintained at 0° C., triethylamine (5.4 mL, 38.9 mmol) was added. To this reaction mixture, methanesulphonyl chloride (1.91 mL, 23.3 mmol) was added dropwise over a period of 30 minutes and the stirring continued for two hours. Subsequently, the reaction mixture was diluted with dichloromethane and water. The layers were separated and the organic layer was dried over anhydrous Na2SO4, concentrated and dried to give a light yellow colored crude sticky mass, which was purified by column chromatography to furnish methanesulfonic acid (1S,3R)-3-t-butoxycarbonylamino-2,2,3-trimethyl-cyclopentylmethyl ester (2.01 g) in 76% yield as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (s, 3H), 1.05 (s, 3H), 1.32 (s, 3H), 1.43 (s, 9H), 1.49 (m, 1H), 1.85-2.04 (m, 3H), 2.20-2.24 (m, 1H), 3.01 (s, 3H), 4.10-4.15 (dd, J=8 & 9.24 Hz, 1H), 4.24-4.29 (dd, J=6.44 & 9.52 Hz, 1H), 4.47 (s, 1H); m/z (M−55): 280.1; [α]D +36.3° (C., 1.0, methanol).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[Br:14][CH2:15][CH2:16]Br>O>[Br:14][CH2:15][CH2:16][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1cccc(OCCBr)c1
Reaction time: 7 h

Procedure:
A solution of NaOH at 33% (17 cc) is added dropwise to a solution of 3-trifluoromethylphenol (2.5) and 1,2-dibromoethane (30.0 g) in deionized water (30 cc). The resulting mixture is kept under refluxing conditions for 7 hours. The reaction mixture is then cooled, the oil formed is separated from the aqueous phase and distilled under a pressure of 15 mm Hg. The fraction within the range of from 118° to ° C. is collected. 26 g of the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]=1.[ClH:21].O1CCOCC1>CO>[ClH:21].[ClH:21].[CH3:13][NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN(CCCNc1ccnc(N)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNCCCNc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.6 %

Procedure:
A stirred solution of tert-butyl 3-(2-aminopyrimidin-4-ylamino)propyl(methyl)carbamate (Example 7A, 40 mg, 0.1422 mmol) in methanol (0.5 mL) was treated with a 4M solution of HCl in dioxane (0.5 mL, 2.0000 mmol). After stirring at ambient temperature for 18 hours, volatiles were removed under reduced pressure to give a white solid that was crystallized methanol/ether. White crystals were collected by filtration to provide N4-(3-(methylamino)propyl)pyrimidine-2,4-diamine dihydrochloride (6.0 mg, 16.6% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.01 (pentet, J=7 Hz, 2H), 2.72 (s, 3H), 3.07 (t, J=7 Hz, 2H), 3.58 (t, J=7 Hz, 2H), 6.13 (d, J=7 Hz, 1H), 7.58 (d, J=7 Hz, 1H). MS (DCl—NH3) m/z=182 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH:13]1[O:15]C1>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH:13]=[O:15]
Reactant: COc1cccc(C2CO2)c1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Product: COc1cccc(C=O)c1

Procedure:
Following the procedure of Example 7 and employing 2.42 g. of sodium hydride, 9.46 g. of trimethylsulfonium iodide and 6.33 g. (0.046 mol) of m-methoxybenzaldehyde there is obtained m-methoxystyrene oxide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]3[NH:33][CH2:34][C:35]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:30]3=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:33]1[C:31]3[C:30](=[CH:29][CH:28]=[C:27]([N:24]4[CH2:23][CH2:22][O:21][CH2:26][CH2:25]4)[CH:32]=3)[C:35]3([CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:34]1)=[C:3]([CH3:20])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:5]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 22 h

Procedure:
A mixture of 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (60.7 mg, 0.21 mmol) (described herein), 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (68.7 mg, 0.25 mmol) (described herein), Pd2dba3 (28.7 mg, 0.031 mmol), 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (29.9 mg, 0.063 mmol), and sodium tert-butoxide (60.2 mg, 0.626 mmol) in toluene (3 mL) was stirred at 100° C. for 22 h, then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with saturated aqueous sodium bicarbonate solution, 1 M NaOH, and brine, and the organic layer dried (MgSO4) and concentrated. Chromatography afforded 1-(5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.71-8.79 (1H, m), 7.85-7.97 (2H, m), 7.65-7.74 (1H, m), 7.42 (1H, ddd, J=7.0, 5.0, 1.7 Hz), 7.09 (1H, d, J=8.2 Hz), 6.97 (1H, ddd, J=11.6, 8.9, 2.5 Hz), 6.25-6.34 (1H, m), 5.45-5.57 (1H, m), 3.98-4.09 (2H, m), 3.86-3.96 (2H, m), 3.69-3.82 (4H, m), 3.46-3.62 (2H, m), 2.91-3.05 (4H, m), 2.39 (3H, s), 2.06-2.24 (2H, m), 1.83-1.93 (1H, m), 1.72-1.83 (1H, m). Mass Spectrum (ESI) m/e=529 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[N:8][C:7]([NH:19][C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[NH:26]C(=O)OC(C)(C)C)=[N:6][C:5]=2[CH2:4][NH:3]1.Cl>CC(O)=O>[NH2:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:7]1[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[C:10]2[C:2](=[O:1])[NH:3][CH2:4][C:5]=2[N:6]=1
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc3c2C(=O)NC3)c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)nc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(5-oxo-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-ylamino)cyclohexylcarbamate (50.4 mg, 0.111 mmol) in HOAc (2 mL) was added hydrochloric acid (0.5 mL, 16.46 mmol). The mixture was stirred at RT for 30 min and then concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 and extracted with EtOAc. The organic layers were washed with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, EtOAc/MeOH=20/1) to give the title compound as a white powder (11.3 mg, 29%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48-1.80 (m, 10H), 2.37 (s, 3H), 3.24 (br s, 1H), 4.07 (br s, 1H), 4.20 (s, 2H), 5.55 (br s, 1H), 5.89 (br s, 1H), 6.89-6.91 (m, 1H), 7.22-7.24 (m, 1H), 7.53-7.63 (m, 2H), 8.49 (br s, 1H). [M+H] calc'd for C19H25N6O, 353. found, 353.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]4)=[CH:21][CH:22]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)NC4CC4)cc3)cc2)CC1
Yield: 14.9 %

Procedure:
The title compound (13 mg, 12%) was prepared from {4-[(cyclopropylamino)carbonyl]phenyl}boronic acid (41 mg, 0.2 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, 2H, J=8.4 Hz), 7.59 (d, 2H, J=8.6 Hz), 7.53 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.24 (s, 1H), 4.97-4.84 (m, 1H), 4.21 (bs, 2H), 3.84 (d, 2H, J=6.4 Hz), 2.96-2.86 (m, 1H), 2.83-2.73 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.36-1.26 (m, 2H), 1.24 (d, 6H, J=6.4 Hz), 0.93-0.84 (m, 2H), 0.66-0.60 (m, 2H); LRMS (ESI), m/z 437 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FC(F)(F)CCCI
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCCC(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.9 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.2 g of 1-iodo-4,4,4-trifluorobutane were dissolved in 5 ml of dimethyl sulfoxide, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(4,4,4-trifluorobutyl)malononitrile (hereinafter, referred to as the present compound (66)).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([O:27]C)=[O:26])[CH:21]=2)[CH:15]=1)=[O:8].C1COCC1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8]
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Temperature: 68 °C

Procedure:
To a stirred solution of methyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.30 g, 3.12 mmol) in a mixture of solvents THF/MeOH (10 ml/10 ml) was added 2 ml of 5M NaOH (10 mmol) solution. The mixture was heated in a 68° C. bath for 8 hours, cooled to room temperature and poured into 200 ml of water. 2M HCl was added until pH=3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid as white solid. Yield: 1.20 g, 95%.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[CH:20][CH:19]=[C:18]3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:13][CH:12]=2)[C:8]2[C:27]([C:31]([O:33]C)=[O:32])=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH:21]=[CH:20][CH:19]=[C:18]3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:15][CH:16]=2)[C:8]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-n2cccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-n2cccc2-c2nnn[nH]2)cc1

Procedure:
A solution of methyl 2-butyl-1-[[4-[2-(1H-tetrazol-5-yl)-1-pyrrolyl]phenyl]methyl]benzimidazole-7-carboxylate (0.85 g) in methanol (10 ml) containing 1N aqueous NaOH (5.7 ml) was heated under reflux for 2 hours. After evaporation of methanol, the residue was neutralized with 1N aqueous hydrochloric acid to precipitate crystals. Recrystallization from chloroform-methanol afforded colorless prisms (0.71 g, 78%), m.p. 165°-167° C.
Reaction SMILES: C(OC([NH:8][CH:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10]1[CH:11]=[CH:12][C:13]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[N:14][CH:15]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10]1[CH:11]=[CH:12][C:13]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[N:14][CH:15]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(NC(=O)OC(C)(C)C)c2ccccc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cn1
Yield: 58 %

Procedure:
A solution of compound 4-f in HCl/dioxane (100 ml) was stirred at room temperature overnight. The mixture was then concentrated under vacuum and the residue was diluted with water followed by extraction with ethyl acetate. The aqueous layer was basified with ammonia and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to provide the product, 4-g, (1.5 g, 58%). 1H NMR (CD3OD, 300 MHz,): δ 8.64 (s, 1H), 7.77 (m, 2H), 7.22 (m, 5H), 5.16 (s, 1H), 4.07 (m, 4H), 1.22 (m, 6H). (M+H)+=321.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=1[CH:11]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc(OCc2ccccc2)c(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc(OC)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a nitrogen stream, to a solution of 2-benzyloxy-5-methoxy-benzaldehyde (2.0 g, 8.25 mmol) in THF (50 mL), a solution of 4-methoxyphenylmagnesium bromide in THF (0.5 M, 19.8 mL) was added dropwise under cooling with ice. The mixture solution was stirred at room temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:1)] to obtain the title compound (2.9 g, 100%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][CH2:15][CH3:16])[CH:12]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl.[OH-].[Na+]>CCOC(C)=O>[C:13]([C:11]1[CH:12]=[C:7]([B:17]([OH:22])[OH:18])[CH:8]=[N:9][CH:10]=1)#[C:14][CH2:15][CH3:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCC#Cc1cncc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC#Cc1cncc(B(O)O)c1
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
n-BuLi (2.5 M in hexanes, 5.46 mL, 13.7 mmol) was added dropwise to a solution of 3-bromo-5-(but-1-ynyl)pyridine (Intermediate 48, 2.39 g, 11.4 mmol) and triisopropyl borate (3.15 mL, 13.65 mmol) in 2-Me THF (20 mL) at −50° C. The mixture was stirred for 1.5 h while the temperature was kept between −50 and −40° C. The mixture was lifted up from the cooling bath and 2 M aq. HCl (12 mL, 24 mmol) was added followed by stirring for 20 min. The mixture was diluted with EtOAc. Aq. NaOH (2 M) was added until pH about 12 was obtained in the aqueous phase. The phases were separated. The organic phase was extracted with dilute aq. NaOH and with water. The combined aqueous phases were washed with EtOAc, acidified to pH about 5 by the addition of conc. HCl and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated to give 1.522 g (76% yield) of the title compound: 1H NMR (500 MHz, CDCl3) δ ppm 1.11-1.37 (m, 3H), 2.26-2.58 (m, 2H), 7.46-10.34 (m, 3H); MS (ES+) m/z 176 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([N:24]([CH2:31][CH:32]=[CH2:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([N:14]([CH2:21][CH:22]=[CH2:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:35]>CO>[CH2:21]([N:14]([C:12]1[CH:13]=[C:4]2[C:3](=[O:2])[NH:35][C:6](=[O:7])[C:5]2=[CH:10][C:11]=1[N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:31][CH:32]=[CH2:33])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:22]=[CH2:23]
Reactant: N
Reactant: C=CCN(c1ccccc1)c1cc(C(=O)OC)c(C(=O)OC)cc1N(CC=C)c1ccccc1
Solvent: CO
Product: C=CCN(c1ccccc1)c1cc2c(cc1N(CC=C)c1ccccc1)C(=O)NC2=O
Temperature: 120 °C

Procedure:
In an autoclave, 457 mg (1 mmol) of 4,5-bis(N-allylanilino)phthalic acid dimethyl ester are dissolved in 5 ml of methanol, and 15 ml of ammonia are Used for the purpose of amide formation. The autoclave is closed and then heated at 120° C. for 24 hours, then cooled and opened, and the ammonia is driven off with nitrogen. The residue is rinsed out with ethyl acetate and filtered, and the filtrate is chromatographed on silica gel with hexane/ethyl acetate 3:1. The product fractions are concentrated by evaporation and crystallized from hexane/ethyl acetate, yielding the title compound in the form of yellow crystals, FAB-MS: 410 [M+ +H], m.p. 122°-127° C. As byproduct of the reaction, 4,5-Bis-(N-allyl-N-phenylamino)phthalic acid monoamide was isolated and recrystallized from hexane/ethyl acetate to yield yellow crystals, FAB-MS: 428 [M+ +H], m.p. 114°-116° C.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1>C(OC(=O)C)(=O)C.C1(=O)OC(=O)C=C1>[CH2:6]=[CH:1][CH2:2][CH2:3][CH:14]1[C:15](=[O:16])[O:17][C:12](=[O:18])[CH2:13]1
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: C=CCCC1CC(=O)OC1=O
Temperature: 215 °C

Procedure:
Into a 5 liter/3 neck Pyrex flask equipped with a condenser, addition funnel, thermometer, gas inlet tube, mechanical stirrer, and heating mantle was weighed 2200 grams of polybutene having a molecular weight of about 432 and an unsaturation content of 99.6. Into the addition funnel was placed 3.3 grams of paratoluene sulfonic acid dissolved in 6.6 grams of acetic anhydride and 450.5 grams of maleic anhydride (4.24 moles) which was melted and kept in a liquid state with heat lamps. The polymer in the flask is stirred and heated to a temperature of about 215° C. under a nitrogen atmosphere. The melted maleic anhydride catalyst mixture was added dropwise to the stirred polymer at a rate such that the reaction mixture temperature could be maintained between 210° to 215° C. without flooding the condenser. The addition under these conditions required 4 hours. During the addition, two drops of anti-foam fluid was added to reduce foaming. After the addition of the maleic anhydride the reaction mixture was maintained at 215° C. for 21 hours. The reaction mixture at the end of this period was increased to 235° C. The condenser was replaced with a distillation head and air cooled condenser. The nitrogen flow through the gas inlet tube was increased to 4 SCFH and the unreacted maleic anhydride was thus stripped from the reaction mixture for 2 hours. The mixture was cooled and filtered. The product polybutenyl succinic anhydride obtained had an activity of 67%, the balance of the material being unreacted polybutene with a viscosity of 336 SUS at 100° C. The infrared spectrum displayed carbonyl absorptions at 1870 (medium), 1790 (strong), and 1710 (weak).