Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)C.[CH3:6][C:7]([CH:14]=[CH:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:8][C:9](OCC)=[O:10].C(Cl)(=O)OCC.[NH3:36]>C(N(CC)CC)C>[CH3:6][C:7]([CH:14]=[CH:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:8][C:9]([NH2:36])=[O:10]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)CCC=C(C)CCC=C(C)C
Reactant: N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(N)=O
Reaction time: 0.17 h

Procedure:
In 20 ml. of diethyl ether was dissolved 3.0 g. of the above-obtained 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid. To this solution was added 1 g. of triethylamine, and further added 1.1 g. of ethyl chlorocarbonate under stirring at room temperature. After 10 minutes, gaseous ammonia was introduced into the solution. The reaction liquid was washed with three 10 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was purified by alumina column chromatography and crystallized from a mixture of acetone and n-hexane (1:2). There was obtained 1.7 g. of the desired product as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[Zn+2].[Br-].[Br-]>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: c1ccc(COc2ccc(OCCC3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous ZnBr2 (1.10 g, 4.88 mmol, 2.0 equiv.) was added to a solution of tert-butyl 4-[2-[4-(benzyloxy)phenoxy]ethyl]piperidine-1-carboxylate (1.00 g, 2.43 mmol) in CH2Cl2 (20 mL) under N2. The mixture was stirred overnight at room temperature, diluted with CH2Cl2 (300 mL), and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by preparative HPLC (column: SunFire Prep C18, 100×19 mm, 5 μm particle size; UV detection at 220 nm; flow 18 mL/min; mobile phase: CH3CN in water with 0.05% CF3COOH; 5-30% CH3CN in 6 min.) The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was basified with aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried. After concentration in vacuo, the free base was obtained as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.46-7.31 (m, 5H), 6.93 (d, 2H, J=9.0 Hz), 6.83 (d, 2H, J=9.0 Hz), 5.03 (s, 2H), 3.97 (t, 2H, J=6.0 Hz), 3.12 (d, 2H, J=11.7 Hz), 2.64 (t, 2H, J=12 Hz), 2.27 (br s, 1H), 1.78-1.69 (m, 5H), 1.25-1.17 (m, 2H). LC-MS (ESI) m/z 312 (M+H+).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([C@H:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])C.[Al+3].[Cl-].[Cl-].[Cl-]>O>[OH:3][C:4]1[CH:5]=[C:6]([C@H:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)N([C@H](CS(C)(=O)=O)c1ccc(O)c(O)c1)C2=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)—N-{2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (0.55 mmol) in anhydrous CH2C2 at room temperature, is added AlCl3 (1.10 mmol). After stirring for 1 hour, water is added. The product is extracted with CH2Cl2, and the organic extract is dried over MgSO4. The solvent is removed to give crude (S)—N-{2-[1-(3,4-dihydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide. The product is purified by column chromatography or recrystallization.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])(=[O:3])[CH3:2].OC(COC1C2C(=CC=CC=2)C=CC=1)CN[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2>>[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH:11][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(OCC(O)CN)c1
Reactant: OC(CNc1ncnc2[nH]cnc12)COc1cccc2ccccc12
Product: CC(=O)c1cccc(OCC(O)CNc2ncnc3[nH]cnc23)c1

Procedure:
By substituting 3-(3-acetylphenoxy)-2-hydroxypropylamine (3.65 g, 0.0174 moles) for the starting material of Example 2 and following the method of Example 2, the desired compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.[NH2:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:18][CH2:19][CH2:20][CH2:21][S:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCCCSc1ccncc1
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)s1
Yield: 64.5 %

Procedure:
To a solution of 1.27 g (8.91 mmol) of 5-methyl-2-thiophenecarboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of t-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.68 g of the desired compound (yield: 64.5%, colorless powder).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:19]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH2:20][CH3:21].O>C(Cl)Cl>[CH2:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][C:25](=[O:26])[CH2:24][O:23][C:19](=[O:22])[CH2:20][CH3:21])[C:3]=1[C:4]#[N:5])[CH3:12]
Reactant: CCC(=O)OCC(=O)Cl
Reactant: CCNc1cccc(N)c1C#N
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCNc1cccc(NC(=O)COC(=O)CC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzonitrile (2.3 g) in methylene chloride (50 ml) is added pyridine (1.6 ml), and thereto is added dropwise propionyloxyacetyl chloride (3.0 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol to give the title compound (1.6 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:9][CH2:10][N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[CH:4][CH:3]=1.[C:26]([NH:28][C:29](=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)OC1C=CC=CC=1)#[N:27]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:29]([NH:28][C:26]#[N:27])=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]2[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.5 g (1.4 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,6-hexanediamine and 0.52 g (1.4 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=641 ([M+H]+, 5), 230 (47), 154 (100); IR (KBr): 2161 cm-1 (C≡N).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][N:12]2[CH2:17][CH:16]([CH3:18])[NH:15][CH2:14][CH:13]2[CH3:19])=[CH:9][CH:8]=1.[OH-].[K+].CS(C)=O>O>[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH2:2][CH2:3][CH2:4][Cl:5])[CH2:14][CH:13]2[CH3:19])=[CH:9][CH:8]=1
Reactant: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1CCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
22.0 g g of 1-bromo-3-chloropropane were added to a mixture of 33.0 g of 4-chlorobenzyl-2,5-dimethylpiperazine, 25.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide. After stirring the solution for 3 hours at room temperature, water was added, the product was extracted with ether, and the extract was dried (magnesium sulfate) and concentrated to give 25.8 g (58% of theory) of 1-(4-chlorobenzyl)-2,5-dimethyl-4-(3-chloropropyl)piperazine as an oil, suitable for use in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[CH2:37]([O:39][C:40](=[O:48])[C:41]1[CH:46]=[C:45](Br)[CH:44]=[N:43][CH:42]=1)[CH3:38].C([O-])(O)=O.[Na+]>C(#N)C>[CH2:37]([O:39][C:40](=[O:48])[C:41]1[CH:46]=[C:45]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)[CH:44]=[N:43][CH:42]=1)[CH3:38]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cncc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)c1
Yield: 69 %

Procedure:
Into a 20 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.995 g, 2.18 mmol), 5-Bromo-nicotinic acid ethyl ester (0.645 g, 2.33 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (95.5 mg, 0.117 mmol), acetonitrile (10 mL) and saturated aqueous NaHCO3 (10 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 15 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 5-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester as a white powder (0.794 g, 69%). MS: m/z 528.1 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([NH2:17])=[O:16])=[C:6]2[C:11]=1[O:10][CH2:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7]2.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([NH2:17])=[O:16])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([N+:12]([O-:14])=[O:13])[CH2:7]2
Reactant: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(F)c2c1CC([N+](=O)[O-])CO2
Reaction time: 0.33 h

Procedure:
8-Fluoro-3-nitro-2H-1-benzopyran-5-carboxamide (730 mg, 3.1 mmol) was slurried in chloroform (75 mL) and isopropyl alcohol (25 mL). To the stirred mixture, silica gel (2.2 g, 230-400 mesh ASTM) was added followed by powdered sodium borohydride (255 mg, 6.2 mmol) portionwise over a period of 15 min. After the addition was complete, the reaction was stirred for 20 min. and the reaction was then quenched by the addition of acetic acid (2 mL) and stirred for an additional 30 min. The insoluble material was filtered off and the solvent removed in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined ethyl acetate phases were treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give 0.67 g (91% yield) of an off-white solid as the title compound (mp 191.0-191.5° C.). EIMS (70 eV) m/z (relative intensity) 240 (1, M+), 195 (17), 194 (100), 193 (17), 177 (26), 151 (44), 149 (27), 148 (18), 123 (23), 103 (48), 102 (11), 101 (29), 96 (13), 95 (15), 94 (11), 88 (41), 83 (14), 77 (25), 76 (11), 75 (39), 74(23), 70 (10), 63 (11), 60 (11), 51 (17), 50 (10).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:23]#[N:24])=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Reactant: C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Temperature: 40 °C
Reaction time: 96 h
Yield: 28 %

Procedure:
The crude product from Example 112D, the mono-(L)-tartaric acid salt of (2R)-2-methylpyrrolidine (306 mg, 1.3 mmol), and Cs2CO3 (652 mg, 2.0 mmol) were stirred in an approximately 0.2 M MeCN solution of (2R)-2-methylpyrrolidine (1.6 mL, 0.3 mmol). The mixture was heated at 40° C. overnight. More Cs2CO3 (326 mg, 1.0 mmol) and acetonitrile (0.5 mL) were added and the reaction was stirred at 40° C. for four days. The mixture was cooled to room temperature, diluted with CH2Cl2, filtered, and concentrated. The residue was chromatographed twice through a short column of silica with a 0 to 5% gradient of MeOH/CH2Cl2 to provide the title compound as an orange-tan gum (28% yield). 1HNMR (300 MHz, CD3OD) δ 1.18 (d, 3 H), 1.39-1.54 (m, 1 H), 1.75-1.87 (m, 2H), 1.96-2.09 (m, 1H), 2.27-2.39 (m, 1 H), 2.46-2.63 (m, 2 H), 2.95-3.15 (m, 2 H), 3.20-3.35 (m, 2 H), 6.63 (s, 1H), 7.49-7.52 (m, 2 H), 7.62 (dd, 1 H), 7.67 (ddd, 1 H), 7.78 (dd, 1 H), 7.90 (ddd, 1 H), 7.98 (dd, 1 H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][NH:16][C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:21]=1)(=[O:3])[CH3:2].Cl[C:27]1[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>C(Cl)Cl.CC(O)C>[C:1]([O:4][CH2:5][C:6]1[C:7]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:27]4[N:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[C:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:29][N:28]=4)[C@H:17]([CH:18]([CH3:19])[CH3:20])[C:12]3=[N:11][C:10]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(=O)OCc1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CCn3c(nc4cc(COC(C)=O)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
The mixture of (R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methyl acetate (284 mg, 0.8 mmol), ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (296 mg, 1.2 mmol, 1.5 eq.) and DIEA (310 mg, 2.4 mmol, 3 eq.) in CH2Cl2/i-PrOH (3 mL/3 mL) was stirred at 80° C. for 16 h. TLC showed compound was consumed completely PE:EtOAc=1:1. The solvents were removed under vacuum and the residue was dissolved in EtOAc (10 mL). Water (10 mL) was added to the mixture. The mixture was extracted with EtOAc (10 mL×3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with PE:EtOAc 5:1 to give (R)-ethyl 2-(8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (0.41 g, 87% yield) as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].N12CCCN=C1CCCCC2.Cl[CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[N:35][C:36]([Cl:42])=[CH:37][CH:38]=2)[N:33]=1.O>CN(C)C=O.ClCCl>[CH3:2][N:3]([CH3:9])[CH2:4][CH2:5][C:6]([O:8][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[N:35][C:36]([Cl:42])=[CH:37][CH:38]=2)[N:33]=1)=[O:7]
Reactant: CN(C)CCC(=O)O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 14.1 %

Procedure:
3-Dimethylaminopropionic acid hydrochloride 9.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (16.7 g) are added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (16.5 g) in anhydrous dimethylformamide (100 cc), and the suspension obtained is stirred for 24 hours at a temperature in the region of 20° C. Distilled water (200 cc) and dichloromethane (200 cc) are then added. The aqueous phase is separated after settling has occurred and then re-extracted with dichloromethane (3×50 cc). The organic phases are combined, washed with distilled water (2×50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 80° C. The residue obtained is dissolved in dichloromethane (100 cc) and the solution extracted with 1N aqueous hydrochloric acid solution (2×100 cc). The aqueous phases are combined, washed with dichloromethane (50 cc), alkalinized with 10 N sodium hydroxide solution to a pH in the region of 11 and extracted with dichloromethane (2×150 cc). The organic phases are combined, washed with distilled water (2×30 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After the product thereby obtained has been recrystallized twice successively in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 3-dimethylaminopropionate (2.9 g), m.p. 150° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.Cl>C1COCC1>[CH:20]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1)=[O:21]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)O
Reaction time: 3 h
Yield: 41.4 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (10.7 g, 50 mmol) in THF (250 mL) at −78° C. was added n-BuLi (60 mL, 2.5 M in hexane). The mixture was stirred for 3 h and to it was added DMF (9.6 mL, 125 mmol). The reaction mixture was stirred for 1.5 h, acidified with 1N HCl and extracted with EA (200 mL). The organic solution was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude yellow solid was washed with PE to afford 4-formyl-2-methylbenzoic acid (3.4 g; yield 41%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[C:14]([C:18]1[O:22][N:21]=[C:20]([OH:23])[CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:14]([C:18]1[O:22][N:21]([C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:20](=[O:23])[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(=O)n(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])o1
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
After mixing 3.7 g of 2,4-dinitrofluorobenzene, 20 ml of dimethylformamide, 2.9 g of 5-t-butyl-3-hydroxyisoxazole, and 2.8 g of potassium carbonate, the reaction was performed for 30 minutes at 80° C. and after cooling the reaction mixture, the product formed was extracted with a mixture of diethyl ether and ethyl acetate. The solvent was distilled off from the extract under reduced pressure and the residue obtained was crystallized from a mixture of diethyl ether and ethyl acetate to provide 1.9 g of the desired compound with a yield of 30.9%. The melting point thereof was 167° C. to 168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:12][NH2:13])=[O:11].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].Cl>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([NH:13][NH:12][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])=[O:28]
Reactant: NNC(=O)Cc1ccc(F)cc1Cl
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCCl)NNC(=O)Cc1ccc(F)cc1Cl
Reaction time: 1.5 h

Procedure:
A mixture of 2-(2-chloro-4-fluorophenyl)acetohydrazide (909 mg, 4.5 mmol) and DIPEA (0.817 ml, 4.7 mmol) in dry DCM (65 ml) was added over 20 min to 4-chlorobutyryl chloride (0.505 ml, 4.5 mmol) in dry DCM (5 ml). After 1.5 h, 2M HCl was added and the precipitated 4-chloro-N-[(2-chloro-4-fluorophenyl)acetyl]butanohydrazide was filtered off, washed with water and dried (1.24 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1cncc(Cl)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2cncc(Cl)n2)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a mixture of 2,6-dichloropyrazine (3 g, 20 mmol), sodium carbonate (5.55 g, 52 mmol) and 4-methylphenylboronic acid (2.74 g 20 mmol) in dimethoxyethane (90 mL) and water (45 mL) under nitrogen was added tetrakis(triphenylphosphine) palladium (0) (0.46 g). The resulting mixture was heated at reflux for 18 h under nitrogen. After cooling to room temperature, the reaction was diluted with water (100 mL) and extracted with chloroform (2×150 mL). The organic solution was dried MgSO4 and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) 9:1 cyclohexane:EtOAc afforded the title compound as a white solid (2.3 g).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1.[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[Br:5][C:6]1[CH:14]=[C:10]([C:11]([O:13][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Oc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Oc1ccccc1)c1cc(Br)ccc1O

Procedure:
80 ml of thionyl chloride was gradually added to a benzene suspension of 217 g of 5-bromosalicyclic acid and 113 g of phenol, followed by refluxing for ten hours under heating. After distilling off the benzene, ice-water was added to the residue, and the precipitate formed was collected by filtration, followed by drying. Yield: 210 g.