Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C1C(=O)N([I:20])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]2[N:6]([C:8]([I:20])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CSc1nc(Br)cn2ccnc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CSc1nc(Br)cn2c(I)cnc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To a stirred solution of 6-bromo-8-methylsulfanyl-imidazo[1,2-a]pyrazine (210.0 g, 860.3 mmol) in DMF (4200 mL) was added NIS (212.9 g, 946.3 mmol, 1.1 eq) in one portion at rt. After 18 h stirring at 60° C. the dark solution was evaporated and the brown residue was dissolved in DCM (7 L), washed with water (2×5 L) and sole (2×5 L) and dried over sodium sulphate. Crystallization by careful removal of solvent yielded 255 g (80.1%) 6-bromo-3-iodo-8-methylsulfanyl-imidazo[1,2-a]pyrazine: 1H-NMR (300 MHz, d6-DMSO): δ=8.24 (1H, s), 7.79 (1H, s), 2.46 (3H, s) ppm.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.[OH-].[Na+]>CN(C=O)C.CO>[O:24]1[CH2:25][CH2:26][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH:35]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:32]=2)[CH2:28][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc(CN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-morpholinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]([O:17][CH2:18][CH3:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:7]=[CH:8][CH:9]=1.[Br:21]C1C(OCC)=NC=C(C)N=1.B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.[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>[Br:21][CH2:16][C:14]1[N:15]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:20])[CH:5]=2)[C:11]([O:17][CH2:18][CH3:19])=[N:12][CH:13]=1
Reactant: CCOc1ncc(C)nc1-c1cccc(OC(F)F)c1
Reactant: CCOc1ncc(C)nc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ncc(CBr)nc1-c1cccc(OC(F)F)c1
Yield: 90 %

Procedure:
3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine. A solution of 3-bromo-2-ethoxy-5-methylpyrazine (1.80 g, 8.29 mmol), 3-(difluoromethoxy)phenyl)boronic acid (2.03 g, 10.78 mmol), tetrakis(triphenylphosphine) palladium(0) (958.25 mg, 0.83 mmol), sodium carbonate (21.63 mL, 1.15 mol/L, 24.88 mmol), in EtOH (22 mL) and toluene (118 mL), under nitrogen, was heated at 88° C. for 1 h. The reaction mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound as a colorless oil (2.09 g, 90%). [M+H]=281.19.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH:9]([C:28]1[CH:49]=[CH:48][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:33])=[CH:30][CH:29]=1)[CH2:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[C:14]2[N:13]=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].CO>Cl.O>[OH:7][CH2:8][CH:9]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:33])=[CH:48][CH:49]=1)[CH2:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[N:20]=[C:14]2[N:13]=[CH:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(COC2CCCCO2)Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(CO)Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OCC

Procedure:
The solution of 0.94 g of diethyl N-[4-(1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6-pivaloylaminopyrrolo-[2,3-d]pyrimidin-3-yl)prop-2-yl)benzoyl]glutamate in 40 ml of 0.1N methanolic hydrogen chloride is stirred at ambient temperatures for 2 hours. The reaction mixture is neutralized with a solution of 205 mg of sodium carbonate in 10 ml of water and most of methanol removed by evaporation under reduced pressure. One hundred milliliters of methylene chloride are added and the solution is washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated. The residue is triturated with 1:2 ethyl acetate and ether, filtered, and dried to give diethyl N-[4-{1-hydroxy-3-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]-pyrimidin-3-yl)prop-2-yl}benzoyl]glutamate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[OH:23]>Cl>[NH2:1][C:2]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:23])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CO
Reactant: CN(C)c1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Agent: Cl
Product: CN(C)c1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 91 %

Procedure:
6-Amino-9-benzyl-2-dimethylamino-8-bromopurine (51 mg, 0.15 mmol) in concentrated hydrochloric acid (30 ml) and methanol (10 ml) were refluxed for 5 hours under heating. After removal of methanol, the reaction mixture was made basic with 28% aqueous ammonia. The resulting crystals were filtered, washed with water and dried to give the subject compound (38 mg, yield 91%).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)([O-:3])=[O:2].C(O)(=O)C.[B-].[Na+].O>CS(C)=O>[N+:1]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccccc2)nc1
Agent: [B-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-((E)-2-nitro-vinyl)-2-phenoxy-pyridine described in Manufacturing Example 232-1-3 (5.97 g, 24.6 mmol) and acetic acid (3.2 mL) in dimethyl sulfoxide (52 mL) was added sodium borohydrate (1.4 g, 36.9 mmol), at room temperature while cooling appropriately. This mixture was stirred for 30 minutes at room temperature. This mixture was cooled appropriately, then, water was added, which was stirred for 30 minutes at room temperature. This mixture was liquid-separated, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (5.72 g) as a crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:21]([NH2:23])=[O:22])=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:21]([NH2:23])=[O:22])=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[NH:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: CCNC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Yield: 53.8 %

Procedure:
0.115 g (0.362 mmol) of 4-(4-nitrophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.067 g (0.0636 mmol) of 10% palladium on carbon in 15 cm3 of methanol. After hydrogenating for 2.5 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.056 g of 4-(4-aminophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide, in the form of an orange solid; ES+: m/z=289 (MH+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][C:14]2=[O:21])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:24][O:19][C:18]([CH:16]1[CH2:17][N:13]([C:5]2[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=2)[C:14](=[O:21])[CH2:15]1)=[O:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 20 °C
Reaction time: 17 h
Yield: 1357.3 %

Procedure:
8.8 g (0.025 mole) of the 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid produced according to Example 1 is refluxed together with 0.3 g of p-toluenesulphonic acid in 130 ml of absolute methanol, and the reaction mixture is kept at this temperature during 17 hours. It is subsequently cooled to 20° C and 0.1 g of sodium carbonate is added. Excess methanol is evaporated off. The residue is dissolved in diethyl ether, extracted three times with water, dried, and concentrated by evaporation. By recrystallisation from n-hexane there is obtained 8.4 g (91% of theory) of 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid methyl ester; m.p. 68°-70° C. Analysis for C14H11F6NO3 (molar weight 355.17):
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>C1COCC1.C(O)C>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.5 %

Procedure:
To a solution of 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (143 mg, 0.214 mmol) in THF (5 mL) and ethanol (5 mL) was added aqueous 1.0 N sodium hydroxide (5 mL) at room temperature. The mixture was stirred for 7 h at room temperature. Then, the reaction mixture was concentrated, the residue was diluted with water (20 mL) and extracted with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1 N hydrochloric acid and the organic compound was extracted into ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under vacuum gave 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (125 mg, 95%) as a white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Cl[CH:31]([O:33][CH2:34][CH3:35])[CH3:32]>O1CCCC1>[CH2:31]([O:33][CH:34]([N:3]1[C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1])[CH3:35])[CH3:32]
Reactant: CCOC(C)Cl
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(C(C)OCC)C(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
In 50 ml. of anhydrous tetrahydrofuran was dissolved 5 g. of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine 3,5-dicarboxylate in a nitrogen gas stream and after adding to the solution 1 g. of a 50% oil dispersion of sodium hydride, the mixture was maintained at room temperature for 10 minutes. Then, 3 ml. of 1-chloro-1-ethoxyethane was added to the mixture under cooling to -40° C. and after removing the cooling bath, the resultant mixture was stirred for 30 minutes. After the reaction was over, 1 ml. of glacial acetic acid was added to the product and then the product was diluted with ethyl acetate. The reaction product was washed with water, saturated aqueous sodium bicarbonate solution, and then water, dried over anhydrous magnesium sulfate, and then the solvent was distilled away under a reduced pressure to provide crude diethyl N-(1-ethoxyethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. By purifying the product by means of a silica gel column chromatography and by using a 20:1 benzeneethyl acetate mixed solvent, 1 g. of faint-yellow oily diethyl N-(1-ethoxyethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained. The product was confirmed in the infrared absorption spectra, the nuclear magnetic responance spectra, and the mass analysis spectra to completely coincide with the presumed structure.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[O:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:39]1[CH:43]=[CH:42][C:41]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:9]=3)[NH:4][N:3]=2)=[CH:40]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccoc3)c2c1
Yield: 35.7 %

Procedure:
N-(3-Furan-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 47 from of 2 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 660 mg of 3-furanboronic acid, 80 ml of dimethylformamide, 6.4 ml of a saturated aqueous sodium hydrogencarbonate solution and 85.4 mg of tetrakis(triphenylphosphine)palladium[0]. 440 mg of N-(3-furan-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 249° C. (analysis C18H15N3O5S2 % calculated C, 51.79; H, 3.62; N, 10.07; O, 19.16; S, 15.36. % found C, 51.63; H, 3.55; N, 10.00; S, 15.13).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH:8]([CH3:15])[N:7]([CH:16]3[CH2:18][CH2:17]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31].C(O)C>Cl.O>[CH:16]1([N:7]2[CH:8]([CH3:15])[CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CC2)C1C
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC1)C(C)C(C)C(=O)N2C
Yield: 70.5 %

Procedure:
A mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-cyclopropyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-46), 0.10 g (0.0006 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.145 g of (rac)-4-(9-cyclopropyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-46a) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][N:35]=[CH:36][CH:37]=2)[N:32]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C>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]>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][N:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc2ccncc2n1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N)ccc2C(C)(C)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3Nc3ccc4ccncc4n3)ccc2C(C)(C)C1
Temperature: 80 °C

Procedure:
A mixture of 7-(2-amino-benzoylamino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Step A, 303 mg, 0.77 mmol), 2-chloro-[1,7]naphthyridine (126 mg, 0.77 mmol), Pd2(dba)3 (7.1 mg, 0.008 mmol), 2-dicyclohexyl phosphino-2′-(N-N-dimethyamino)biphenyl (8 mg, 0.02 mmol), and LiN(TMS)2 (1 M solution in THF, 2.3 mL) was heated at 80° C. for 12 h. The mixture was concentrated in vacuo and the crude material was purified with flash chromatography (SiO2, 5% MeOH/CH2Cl2) to obtain the titled compound. MS (ES+): 524.0 (M+H)+. Calc'd for C31H33N5O3-523.63.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1nc2cc(Cl)ccc2[nH]c1=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a solution of methyl 7-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylate (106 mg, 444 μmol) in acetic acid (1 ml) was added a solution of fuming nitric acid (39.5 μl, 888 μmol) in acetic acid (0.2 ml), and the mixture was stirred for 1 hour at 60° C. Water (10 ml) was added to the reaction mixture. The precidpitate was collected by filtration, washed with water, and then air-dried to obtain 66.6 mg of the title compound as yellow powder. Yield 53%.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:17][C@H:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:30][CH3:31])[O:7]1)=O)C>C(#N)C>[CH3:29][O:28][C:26](=[O:27])[C@@H:18]([N:17]1[CH2:16][C:15]2=[CH:14][C:13]3[C:12]([O:30][CH3:31])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][CH:6]2[C:4]1=[O:3])[CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)C1Oc2cccc(OC)c2C=C1CN[C@@H](CC1CCCCC1)C(=O)OC
Solvent: CC#N
Product: COC(=O)[C@H](CC1CCCCC1)N1CC2=Cc3c(OC)cccc3OC2C1=O
Yield: 28 %

Procedure:
A solution of 5-methoxy-3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (1.0 g, 2.32 mmol) and N,N′-diisopropylethyl amine (1.60 mL, 9.27 mmol) in acetonitrile (2 mL) was heated in a sealed tube at 140° C. for 48 h. The reaction mixture, after aqueous work-up, was extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified over neutral alumina using hexanes-ethyl acetate as eluents to afford (S)-2-(8-methoxy-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid methyl ester (0.25 g, 87.3%) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8](S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: COc1ccnc2c1CCCC2NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: COc1ccnc2c1CCCC2NCc1ccc(CNCc2ccccn2)cc1
Yield: 81.3 %

Procedure:
Using general procedure C: N-(2-pyridinylmethyl)-N-(2-nitrobenzenesulfonyl)-N′-(4-methoxy-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.269 g, 0.50 mmol) was treated with thiophenol (0.35 mL, 3.41 mmol) and K2CO3 (0.757 g, 5.48 mmol) in CH3CN (10 mL). Purification of the crude material by radial chromatography on silica gel (2 mm plate, 20:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.158 g (82%) of the title compound as a yellow oil. 1H NMR (CDCl3) □ 1.61–1.80 (m, 2H), 1.98–2.17 (m, 2H), 2.56–2.70 (m, 2H), 3.79–3.83 (m, 6H), 3.88–3.98 (m, 4H), 6.60 (d, 1H, J=5.7 Hz). 7.15 (dd, 1H, J=5.1, 6.9 Hz), 7.23–7.41 (m, 5H) 7.63 (ddd, 1H, J=7.8, 7.8, 1.8 Hz), 8.30 (d, 1H, J=5.7 Hz); 8.55 (d, 1H, J=3.9 Hz);
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:18][N:17]=[CH:16][C:7]=3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)O1>CN(C=O)C.CCOC(C)=O.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][CH:12]([N:9]1[C:10]2[CH:11]=[C:2]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[CH:3]=[CH:4][C:5]=2[C:6]2[NH:18][N:17]=[CH:16][C:7]=2[C:8]1=[O:15])[CH3:14]
Reactant: CC(C)n1c(=O)c2cn[nH]c2c2ccc(Br)cc21
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(=O)c2cn[nH]c2c2ccc(-c3ccncc3)cc21
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 19 %

Procedure:
To a solution of 7-bromo-5-(propan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.25 g, 0.82 mmol) in 8 mL of DMF placed in a microwave reactor are added caesium carbonate (0.8 g 2.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.25 g 1.22 mmol) and the catalyst PdCl2(dppf) (60 mg, 0.08 mmol). The reactor is sealed and the mixture is stirred for 20 minutes at 150° C. under microwave irradiation. The reaction medium is diluted with an EtOAc/THF mixture (50/50) and washed with water and then with saturated aqueous NaCl solution. The organic phase is dried over Na2SO4 and concentrated to dryness. After purification by flash chromatography (DCM/MeOH: 100/0 to 90/10), 45 mg of a white solid are obtained (yield: 19%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl.C(N(CC)CC)C>O1CCCC1>[CH3:7][Si:8]([CH3:11])([CH3:10])[N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6]
Reactant: S=C1NCCN1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)N1CCNC1=S

Procedure:
30.6 parts by weight of imidazolidine-2-thione were boiled overnight with 54.4 parts by weight of trimethylchlorosilane and 51.5 parts by weight of triethylamine in absolute tetrahydrofurane. The warm suspension was freed of the precipitated triethylamine hydrochloride by filtration, and the filtrate was evaporated and dried in a vacuum desiccator.