Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.22-7.26 (m, 1H), 7.05-7.09 (m, 2H), 6.73-6.78 (m, 2H), 5.17 (s, 2H), 2.84 (t, J=7.2 Hz, 2H), 2.59 (t, J=7.8 Hz, 2H), 2.44 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H15F6NO3S, 476.1 (M+H). found 476.1.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][CH:15]=2)[NH:5][CH:6]=1
Reactant: Ic1nc(CCc2ccc(-c3ccccn3)cc2)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Ic1c[nH]c(CCc2ccc(-c3ccccn3)cc2)n1

Procedure:
A solution of 2-{4-[2-(4,5-diiodo-1H-imidazol-2-yl)ethyl]phenyl}pyridine (11.2 g, 22.4 mmol) and sodium sulfite (3.1 g, 24.7 mmol) in ethanol (200 mL) and water (200 mL) was heated at 100° C. for 2 days. The reaction mixture was concentrated to half its original volume and partitioned between ethyl acetate and water. The organic phase was separated and concentrated in vacuo to afford 2-{4-[2-(4-iodo-1H-imidazol-2-yl)ethyl]phenyl}pyridine, which was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][C:14]([C:22](OCC)=[O:23])([C:17](OCC)=[O:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>C1COCC1>[O:7]1[C:11]2([CH2:12][CH2:13][C:14]([CH2:17][OH:18])([CH2:22][OH:23])[CH2:15][CH2:16]2)[O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(CO)CCC2(CC1)OCCO2
Temperature: 12.5 °C
Reaction time: 8 h

Procedure:
A 3-neck 1-L round bottom flask was equipped with a thermometer, dropping funnel and nitrogen inlet. Under an atmosphere of N2, a solution of 1M lithium aluminum hydride in THF (900 mL, 900 mmol) was added and cooled using a dry ice/acetone bath. To this was added drop-wise a solution of diethyl 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate, Intermediate 3, (128.7 g, 450 mmol) in THF (75 mL) over a period of 1 h while maintaining the internal temperature at 10-15° C. The mixture was left in the cooling bath and allowed to regain room temperature while stirring overnight. The mixture was then cooled to −5° C. and quenched by the slow addition of water (40 mL) under vigorous stirring over 1.5 hours being careful to maintain the internal temperature below 30° C. To this was added drop-wise 15% NaOH (40 mL) and water (40 mL). The resulting precipitate was filtered over Celite, and washed with THF (300 mL). The filtrate was concentrated in vacuo to dryness to provide the title compound (63.3 g) as a white solid. Further extraction of the white cake with 10% MeOH/CH2Cl2 (2×500 mL) gave an additional amount (15.6 g) of the title compound. This constitutes total combined yield of 78.9 g (0.39 mol, Y. 87%). LCMS: m/z 203 (M+H), 225 (M+Na). 1HNMR (500 MHz, CD3OD) δ ppm 1.49-1.55 (4H, m, 3,5-CH2), 1.59-1.66 (4H, m, 2,6-CH2), 3.49 (4H, s, 9,10-OCH2), 3.94 (4H, s, 7,8-OCH2). 13C NMR (126 MHz, CD3OD) δ ppm 26.7 (3,5-CH2), 30.3 (2,6-CH2), 38.3 (4-C), 64.2 (7,8-OCH2), 65.4 (9,10-OCH2), 109.2 (1-OCO).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]([N:17](CC)C(C)C)(C)C.N#CBr>ClCCl.O>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)#[N:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: N#CBr
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
To a cooled (0° C.) solution of tert-butyl piperazine-1-carboxylate (1.517 g, 8.14 mmol) in dichloromethane (10 mL) were added N,N-diisopropylethylamine (1.54 mL, 9.00 mmol) and cyanogen bromide (911 mg, 8.60 mmol) and the reaction was stirred for 45 min at 0° C. The reaction mixture was warmed to room temperature, poured in water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was washed twice with heptane and dried in vacuo, yielding 1.24 g (5.87 mmol, 72%) of a white solid that was used directly in the next step.
Reaction SMILES: C=O.[CH2:3]([NH:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH3-][C:27]#N.[Na+].CC(O)=O>CC#N>[CH2:3]([N:10]([CH3:27])[C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(NCc2ccccc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)c1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 100.9 %

Procedure:
CH2O (aq, 37%) (0.112 ml, 0.12 g, 1.51 mmol, 2 eq) was added to a stirred solution of tert-butyl 3-(benzylamino)benzylcarbamate (0.2353 g, 0.753 mmol, 1 eq) in 5 ml CH3CN. After 10 min NaBH3CN (0.0615 g, 0.98 mmol, 1.3 eq) was added. The reaction was adjusted to pH {tilde over ( )} 7 with HOAc. After 2 h the solvent was removed in vacuo. The residue was diluted with saturated aqueous NaHCO3/EtOAc, and the layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo to yield 0.2482 g (0.76 mmol, 100% yield) of tert-butyl 3-(benzyl(methyl)amino)benzylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NC(C)C)(C)C.[CH2:28]([O:35][C:36](=[O:49])[C@@H:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C.C(#N)C>[CH2:28]([O:35][C:36](=[O:49])[C@@H:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:17][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:14][CH:13]=2)=[CH:41][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCO[C@@H](Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-tert-butoxycarbonylamino-phenyl)-acetic acid (100 mg, 0.39 mmol), N,N′-diisopropylcarbodiimide (60 mg, 0.47 mmol) and DMAP (15 mg, 0.12 mmol) in dry acetonitrile (15 mL) was added (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (120 mg, 0.39 mmol). The mixture was stirred for 3 h at r.t. before the solvent was evaporated and the remaining crude product directly purified by HPLC. The title compound was obtained as a solid (48 mg, 22.6%). 1H NMR (400 MHz, CDCl3): δ 7.25-7.36 (m, 9H), 7.16-7.18 (d, 2H), 6.91-6.93 (d, 2H), 5.12 (s, 2H), 4.00-4.03 (dd, 1H), 3.77 (s, 2H), 3.55-3.29 (m, 1H), 3.30-3.36 (m, 1H), 2.97-2.99 (m, 2H), 1.51 (s, 9H), 1.11-1.14 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=3)[NH2:14])[CH:9]=2)[NH:4][CH:3]=1.C(NCC)C.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:36][N:37]([CH3:44])[CH2:38]/[CH:39]=[CH:40]/[C:41](O)=[O:42]>C1COCC1.CN(C=O)C.O>[CH3:36][N:37]([CH3:44])[CH2:38]/[CH:39]=[CH:40]/[C:41]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:11]([C:8]2[CH:9]=[C:10]3[C:2]([CH3:1])=[CH:3][NH:4][C:5]3=[N:6][CH:7]=2)[CH:12]=1)=[O:42]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Cc1c[nH]c2ncc(-c3cccc(N)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cc1c[nH]c2ncc(-c3cccc(NC(=O)/C=C/CN(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)aniline 24 (100 mg 0.449 mmol) was dissolved in THF/DMF was added diethyl amine (71.46 mg, 0.89 mmol). EDC.HCl (139.19 mg, 0.89 mmol) was added to the reaction then (E)-4-(dimethylamino)but-2-enoic acid 131 (103.8 mg, 0.6292 mmol) was added to the reaction and stirred at RT for overnight. After completion the reaction was diluted with water and the aqueous was extracted with 10% methanol in chloroform for two times. The organic layer was dried over sodium sulphate and concentrated to get the crude. The crude was purified through flash chromatography by using neutral alumina. The compound was eluted in 2% methanol in chloroform as half white solid (E)-4-(dimethylamino)-N-(3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide 152. MS-ES+334.9, 1H NMR (400 MHz, DMSO): 11.35 (s, 1H), 10.14 (s, 1H), 8.42 (d, 1H), 8.07 (d, 1H), 7.98 (s, 1H), 7.63 (m, 1H), 7.39 (d, 1H), 7.27 (s, 1H), 6.73 (m, 1H), 6.29, (d, 1H), 3.27 (m, 1H), 3.05 (d, 2H), 2.29 (s, 3H), 2.17 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:41][CH2:42][O:43][CH3:44])(=O)=O)=CC=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:41][CH2:42][O:43][CH3:44])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Temperature: 60 °C
Reaction time: 7 h
Yield: 78.3 %

Procedure:
To a solution of 7.8 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine in 40 ml of dimethylformamide are added 4.9 g of potassium carbonate and 7.2 g of 2-methoxyethyl p-toluenesulfonate, and the mixture is stirred at 60° C. for 7 hours. The resulting mixture is poured into ice-cold water and the precipitate is extracted with toluene. The extract is washed with water, dried and concentrated. The residue is recrystallized from hexane to give 7.2 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 111°-113° C.
Reaction SMILES: C([O:8][C:9](=[O:22])[CH:10]=[CH:11][C:12]1[CH:13]=[N:14][C:15]([C:18](=[O:21])[NH:19][CH3:20])=N[CH:17]=1)C1C=CC=CC=1.[CH2:23](O)C>[Pd]>[CH3:20][NH:19][C:18]([C:15]1[CH:23]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([OH:8])=[O:22])=[CH:13][N:14]=1)=[O:21]
Reactant: CNC(=O)c1ncc(C=CC(=O)OCc2ccccc2)cn1
Reactant: CCO
Agent: [Pd]
Product: CNC(=O)c1ccc(CCC(=O)O)cn1

Procedure:
3-(2-methylcarbamoyl-pyrimidin 5-yl)acrylic acid benzyl ester in ethanol (20 mL) in presence of 15 mg of Pd/C, 10%, and stirred under hydrogen balloon overnight to give 3-(2-methylcarbamoyl-pyridine-5-yl)-propionic acid which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[N:3]1.[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[CH2:15][NH:16][C:17]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[N:3][N:2]2[CH3:1])=[O:18]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: Cn1ncc2c(N)cccc21
Solvent: Cc1ccccc1
Product: Cn1ncc2c(NC(=O)NCc3ccc(Cl)cc3Cl)cccc21
Temperature: 80 °C

Procedure:
1-Methyl-1H-indazol-4-amine (310 mg, 2.1 mmol) and 2,4-dichlorobenzyl isocyanate (0.3 mL, 2.06 mmol) were combined in toluene (10 mL) and heated for 2 hours at 80° C. The mixture was then allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 9.22 (s, 1H), 8.21 (d, J=1.0 Hz, 1H), 7.62-7.67 (m, 2H), 7.43-7.46 (m, 2H), 7.21-7.27 (m, 2H), 7.12 (m, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37CI)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1)=[O:4].[CH2:13]([OH:17])[CH2:14][CH2:15][OH:16].CO.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:16]1[CH2:15][CH2:14][CH2:13][O:17][CH:11]1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(C2OCCCO2)cc1
Temperature: 111 °C
Reaction time: 3.5 h
Yield: 92.4 %

Procedure:
Under nitrogen atmosphere, to a solution of methyl terephthalaldehydate (10.0 g) in toluene (200 mL) were added p-toluenesulfonic acid monohydrate (130 mg) and 1,3-propanediol (5.56 g), and the mixture was stirred at 111° C. for 3.5 hours. The mixture was cooled to room temperature, washed twice with a NaHCO3 solution, and dried over MgSO4. The solvent was evaporated under reduced pressure to give crude methyl 4-(1,3-dioxan-2-yl)benzoate (14.2 g). To a solution of this compound (14.2 g) in THF (150 mL)-MeOH (150 mL) was added a 6N NaOH solution (50.8 mL), and the mixture was stirred at room temperature for 78 hours. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, and thereto was added a 6N aqueous hydrochloric acid to adjust the pH value thereof to pH=2. The precipitated solid was collected by filtration to give 4-(1,3-dioxan-2-yl)benzoic acid (11.725 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[F:41][C:42]([F:48])([F:47])[CH2:43][CH2:44][CH2:45]I>CN(C=O)C>[F:41][C:42]([F:48])([F:47])[CH2:43][CH2:44][CH2:45][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:5][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Reactant: FC(F)(F)CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CCCC(F)(F)F)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a cooled (−15° C.) solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.100 g; 0.295 mmol) in dry DMF (1.5 mL) was wadded a 1N solution of LHMDS in THF (0.324 mL; 0.324 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of 1,1,1-trifluoro-4-iodo-butane (0.076 mL; 0.589 mmol). After stirring for 2 h at (−15° C.) the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.102 g (66%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26](O)([CH3:29])([CH3:28])[CH3:27].N12CCCN=C1CCCCC2>CN(C=O)C>[C:26]([O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc2ncccc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a suspension of 6-quinolinecarboxylic acid (12 g, 69 mmol) in DMF (100 mL) was added 1,1′-Carbonyldiimidazole (11.2 g, 69.3 mmol) and the mixture stirred at 40° C. for 1 hour. tert-Butanol (13 mL, 139 mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (10.4 mL, 69.3 mmol) were added and the mixture was stirred at 80° C. for 4 h. After cooling to room temperature the reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate/heptane (1:3, 2×400 mL). The organic layer was dried over MgSO4 and concentrated to give quinoline-6-carboxylic acid t-butyl ester (14.54 g, 92%). 1H NMR (400 MHz, CDCl3) δ 1.63 (9H, s), 7.42-7.46 (1H, m), 8.10 (1H, d), 8.23 (1H, d), 8.26 (1H, d), 8.50 (1H, d), 8.96-8.98 (1H, m). LCMS: Retention time: 1.42 min. MS (ESI) m/z 230 (M+H)+
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)C.[NH3:17]>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]([NH2:17])=[O:3])[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: CCOC(=O)CCNc1cc(C)cc(C)c1
Reactant: N
Solvent: CO
Product: Cc1cc(C)cc(NCCC(N)=O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
3-(3,5-dimethyl-phenylamino)-propionic acid ethyl ester (0.0026 mol) in a 7N solution of NH3 in CH3OH was stirred at 80° C. in a sealed vessel. The reaction was cooled down to room temperature and the solvent was evaporated until dryness, yielding 0.5 g of 3-(3,5-dimethyl-phenylamino)-propionamide (100%).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[C:7]1[N:16]=[C:15]2[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]2[CH:17]2[CH2:19][CH2:18]2)=[CH:9][C:8]=1[F:24]>C(#N)C>[CH:17]1([N:14]2[C:15]3[C:10](=[CH:9][C:8]([F:24])=[C:7]([N:1]4[CH2:5][CH:4]=[CH:3][CH2:2]4)[N:16]=3)[C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13]2)[CH2:18][CH2:19]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: C1=CCNC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2nc(N3CC=CC3)c(F)cc2c1=O

Procedure:
3-Pyrroline (1.0 g; 14.5 mmol) and acid 51 (2.0 g; 7.1 mmol) in acetonitrile (50 mL) were heated at reflux temperature overnight. The volatiles were evaporated and water added to the residue. The resulting solid was filtered, washed with water and ether to yield 109 as a beige solid.
Reaction SMILES: [CH2:1]1[C:10]2=[CH:11][CH:12]=[CH:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]3)[CH:3]=[CH:2]1.N1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Zn].C(O)(=O)C>[CH:6]1[CH:5]=[C:4]2[CH:3]=[CH:2][C:1]3[C:1]4[CH:10]=[CH:9][C:4]5=[CH:5][CH:6]=[CH:19][C:18]6=[C:3]5[C:2]=4[C:15]([CH:16]=[CH:17]6)=[C:11]4[CH:12]=[CH:13][C:8](=[C:9]2[C:10]=34)[CH:7]=1
Reactant: C1=Cc2cccc3cccc(c23)C1
Reactant: c1ccncc1
Agent: [Zn]
Solvent: CC(=O)O
Product: c1cc2ccc3c4ccc5cccc6ccc(c7ccc(c1)c2c37)c4c56

Procedure:
With reference to the following scheme, perinaphthene and zinc powder were added to pyridine (I in the following synthesis scheme), 50 ml of 80% acetic acid was added dropwise thereto with stirring under reflux in nitrogen flow over five hours, the resulting precipitate (II in the following synthesis scheme I) was filtrated, was dehydrated and sublimated using a vacuum sublimation apparatus and thereby yielded unsubstituted peropyrene (III in the following synthesis scheme).
Reaction SMILES: [N:1]#[C:2]Br.O.[CH2:5]([O:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:11]([NH2:22])[CH:10]=1)[CH3:6].C(O)C>C(#N)C>[NH2:1][C:2]1[N:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:12]2[CH:13]=[CH:14][C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:23])=[CH:10][C:11]=2[N:22]=1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Reactant: N#CBr
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)nc(N)n2C1CCCCC1

Procedure:
5 M cyanogen bromide in acetonitrile (2.25 mL) was added to water (25 mL, 1.4 mol) in a 250 mL round bottom flask at room temperature with stirring. To this was added dropwise a solution of 3-amino-4-cyclohexylaminobenzoic acid ethyl ester (2.25 g, 0.00858 mol) in ethanol (25 mL, 0.43 mol) via an additon funnel over 45 minutes. After 3 hours the reaction was concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution then brine. The organic phase was dried over sodium sulfate and concentrated to a dark solid. The solid was triturated with ethanol, filtered and washed with ethanol to give 1.747 g of the title compound as a grayish solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:29])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]3[O:25][C:24]([C:26](O)=[O:27])=[CH:23][C:21]3=2)[CH:16]=[N:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N.O1CCOCC1.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH3:29])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]3[O:25][C:24]([C:26](=[O:27])[NH2:32])=[CH:23][C:21]3=2)[CH:16]=[N:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(=O)O)cc3c21)NC(=O)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)cc3c21)NC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 169.9 %

Procedure:
To a stirred solution of the product from Step A (0.17 g, 0.43 mmol) in DMF (5 mL) was added 1-hydroxy-benzotriazole hydrate (0.029 g, 0.21 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.65 mmol) followed by a solution of ammonia in dioxane (0.5 M, 1.72 mL, 0.86 mmol). After 18 h, a saturated aqueous solution of ammonium chloride (20 mL) added and the mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried and evaporated. The residue was purified by chromatography (silica, dichloromethane, 5% methanol in dichloromethane) to give an oil (0.14 g, 83%): MS (ES) m/z 393 (M+); 1H NMR (CDCl3) δ 8.20 (brs, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.69 (d, 1H, J=8.0 Hz), 7.32-7.23 (m, 6H), 6.76 (brs, 2H), 5.03 (m, 2H), 4.63 (m, 2H), 4.40 (m, 1H), 1.16 (d, 3H, J=8.0 Hz).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:16]2[C:11](=[C:12]([S:19][C:20]([F:23])([F:22])[F:21])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6].Cl>COCCO.O>[CH3:18][O:17][C:13]1[C:12]([S:19][C:20]([F:23])([F:21])[F:22])=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([C:5]([OH:6])=[O:4])=[CH:8][CH:9]=[CH:10]2
Reactant: COC(=O)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: COc1ccc2c(C(=O)O)cccc2c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
Aqueous NaOH solution (1 N, 15.5 ml) was added to a solution of 6-methoxy-5-(trifluoromethylthio)-1-naphthalenecarboxylic acid methyl ester (2.45 g, 7.7 mmoles) in 2-methoxyethanol (60 ml). The resulting solution was stirred at room temperature for 24 hr, cooled in an ice-bath, made acidic (pH=3) by the addition of 1 N aqueous HCl and diluted with water. The resulting solid was collected, washed with water and recrystallized from ethanol to give the title compound (1.7 g); mp 204°-205° C.; NMR (DMSO-d6) δ 4.00 (s, 3H), 8.20 (m, 5H), 10.30 (broad, 1H).