Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]3[CH2:18][CH2:17][CH2:16][C@H:15](O)[C:10]=3[CH:11]=2)[CH2:6]1)=[O:4].C1C=CC(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[N:36]([C@H:15]1[C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][C:9]=2[CH2:18][CH2:17][CH2:16]1)[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])[CH2:14][CH2:13]3)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(N1CCc2cc3c(cc2C1)CCC[C@@H]3O)C(F)(F)F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=N[C@@H]1CCCc2cc3c(cc21)CCN(C(=O)C(F)(F)F)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2,2,2-trifluoro-1-(6-hydroxy-3,4,6,7,8,9-hexahydrobenzo[g]isoquinolin-2(1H)-yl)ethanone (3.0 g, 10 mmol) in 30 mL of toluene at −10° C. was added DPPA (2.6 mL, 12 mmol). To this stirred solution was then added DBU (1.8 mL, 12 mmol) dropwise while keeping the temperature below 0° C. After stirring at room temperature overnight, 7 mL of 10% HCl was added and the resulting solution was evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/EtOAc=100:10 to 100:15 to 100:20) to afford (R)-1-(6-azido-3,4,6,7,8,9-hexahydrobenzo[g]-isoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone as a colorless oil which was directly used in the next step.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][NH:20][C:22](=[O:24])[CH3:23])[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(CN)cc3C2)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2

Procedure:
14.5 g of g of 2-(p-toluenesulfonyl)-5-aminomethylisoindoline was dissolved in 200 ml of chloroform. 6.13 g of acetic anhydride was added dropwise to the solution under ice cooling while stirring. The mixture was stirred at room temperature for 1 hour and concentrated. The residue was recrystallized from n-hexane to give 16.3 g of 2-(p-toluenesulfonyl)-5-acetamidomethylisoindoline.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][S:26][C:22]=4[C:21](=[O:27])[N:20]4[CH2:28][CH2:29][C@H:19]4[C:18]=23)[N:10]=1>CN(C)C=O>[N:1]1([CH2:8][C:9]2[O:13][N:12]=[C:11]([C:14]3[N:15]=[CH:16][N:17]4[C:23]5[CH:24]=[CH:25][S:26][C:22]=5[C:21](=[O:27])[N:20]5[CH2:28][CH2:29][C@H:19]5[C:18]=34)[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2sccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C1c2sccc2-n2cnc(-c3noc(CN4CCCCC4)n3)c2[C@@H]2CCN12
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
0.34 ml (3.45 mmol) of piperidine was added to a suspension of 400 mg (1.15 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]-imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 10 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 12 hours. The solution was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution was extracted with methylene chloride and the organic phases were dried, filtered and evaporated. The residue was chromatographed (silica gel, methyl acetate/methanol 15:1). There were obtained 375 mg (82%) of (S)-1-(5-piperidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e]-[1,4]diazepin-8-one as a colourless foam, Rf=0.22 (silica gel, methyl acetate/methanol 15:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
A suspension of 10% palladium-on-carbon (100 mg) in ethanol was added to a solution of (R)-(1-(4-amino-5-nitropyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (200 mg, 0.62 mmol) in ethanol (10 mL) at room temperature under a nitrogen atmosphere. The mixture was hydrogenated using a balloon filled with hydrogen gas at room temperature for 2 h. The suspension was filtered through a pad of Celite under a nitrogen atmosphere and the filtrate was used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9](=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=c1nc(-c2ccccc2)c2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccccc2)c2ccccc2n1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with 4-phenylquinazolin-2(1H)-one (110 g, 0.51 mol) and phosphorus oxychloride (300 mL), and the mixture was stirred at 105° C. for 30 min. The reaction mixture was cooled to rt and slowly poured over an ice/water mixture. The solid was collected by filtration, washed with water (50 mL) and dried under reduced pressure. The product, 2-chloro-4-phenylquinazoline, was isolated as an off-white solid (110 g, 91%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:48])[CH:6]([O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][N:26]([CH3:46])[C:27]([C:29]3[O:30][C:31]4[CH:45]=[CH:44][CH:43]=[CH:42][C:32]=4[C:33]=3[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:28])[CH:21]=2)[C:16]=1[Br:47])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CO>[Br:47][C:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:25][N:26]([CH3:46])[C:27]([C:29]3[O:30][C:31]4[CH:45]=[CH:44][CH:43]=[CH:42][C:32]=4[C:33]=3[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:28])=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:48])=[O:4]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CN(C)C(=O)c3oc4ccccc4c3CCc3ccccc3)ccc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(Cc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1)C(=O)c1oc2ccccc2c1CCc1ccccc1
Yield: 72.7 %

Procedure:
A mixture of 1 N NaOH (5 mL, 5 mmol) and 2-(1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (1.68 g, 2.49 mmol), prepared in the previous step, in 110 mL of methanol plus 5 mL of water was stirred under nitrogen at room temperature overnight. 1 N HCl (50 mL, 50 mmol) was added and the reaction was concentrated under reduced pressure to remove the methanol. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (1.20 g, 73%) as a white solid, mp 87-90° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9](=[O:17])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:18][CH2:19][CH:20]([OH:36])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=1[CH2:33][CH:34]=[CH2:35])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+:41]>O>[Na+:41].[CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]([O-:16])=[O:15])=[CH:10][C:9](=[O:17])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:18][CH2:19][CH:20]([OH:36])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=1[CH2:33][CH:34]=[CH2:35])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OCC(O)COc2ccc3c(=O)cc(C(=O)O)oc3c2CC=C)ccc(C(C)=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCc1c(OCC(O)COc2ccc3c(=O)cc(C(=O)[O-])oc3c2CC=C)ccc(C(C)=O)c1O

Procedure:
A solution of 3.5 parts of 8-allyl-7-[3-(4-acetyl-2-allyl-3-hydroxyphenoxy)-2-hydroxypropoxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid and 0.584 parts of sodium bicarbonate in 500 parts of water was freeze dried to yield 3.5 parts of 8-allyl-7-[3-(4-acetyl-2-allyl-3-hydroxyphenoxy)-2-hydroxypropoxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt as a white solid, melting point 249°-251° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[CH2:24]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Nc1cccc(CC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-amino-phenylacetic acid benzyl ester p-toluene sulphonic acid was prepared by adding 3-aminophenylacetic acid (10 g) and p-toluene sulphonic acid monohydrate (13.2 g) to benzyl alcohol (27.2 ml) in toluene (30 ml). The mixture was heated under reflux and the water formed collected in a Dean-Stark receiver. When all the water had been distilled off the mixture was allowed to cool to 25° C. before diluting with diethyl ether and placing in an ice-bath for 1 hr. The crystalline p-toluene sulphonate was filtered off and dried in a dissicator (23.5 g) NMR δ2.31(s)3H, 3.82(s)2H, 5.11(s)2H, 7.11(d)2H, 7.25-7.45(m)8H, 7.52(d)2H.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:43][CH2:44][CH2:45][CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:13](=[O:15])[NH:43][CH2:44][CH2:45][CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])[CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCN)OCC
Reactant: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)C(NC(=O)OCc1ccccc1)C(O)C(C)C)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-methylpentanoic acid (368 mg, 1.31 mmol) in anhydrous tetrahydrofuran (5 ml) was added hydroxybenzotriazole (177 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 1.31 mmol). The resulting solution was stirred at room temperature under nitrogen for 30 minutes. A solution of 1-amino-3,3-diethoxypropane (183 mg, 1.25 mmol) in tetrahydrofuran (2 ml) and N,N-diisopropylethylamine (0.228 ml, 169 mg, 1.31 mmol) were added and stirred at room temperature for 15 hours. The reaction mixture was partitioned between ethyl acetate (75 ml) and water (40 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×75 ml). The combined extracts were washed with 2% cold hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to provide [1-(3,3-diethoxy-propylcarbamoyl)-2-hydroxy-3-methyl-butyl]-carbamic acid benzyl ester (407 mg, 79%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([NH:21][C:22]([NH2:24])=[NH:23])([OH:20])[C@@H:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:7][CH2:8][N+:9]([O-:11])=[O:10].[OH-].[Li+]>CO.O>[N+:9]([CH2:8][CH2:7][CH2:6][C@H:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:4]([NH:21][C:22]([NH2:24])=[NH:23])([OH:20])[C:3]([OH:25])=[O:2])([O-:11])=[O:10]
Reactant: COC(=O)C(O)(NC(=N)N)[C@H](CCC[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCC[N+](=O)[O-])C(O)(NC(=N)N)C(=O)O
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A solution of the compound of Example 3 (5.0 g, 13.8 mmole) in 100 mL of methanol was treated with 17 mL of 1M lithium hydroxide. This solution was allowed to stir overnight and then treated with 20 mL of Dowex-50 resin X8 400 (H+ form) in 50 mL of deionized water. This solution was swirled for 15 minutes then passed through a 4×4 cm. column of the same resin, the column was washed with 1:1 methanol:water and the combined filtrates were concentrated to dryness under vacuum. The residue was dissolved in 100 mL acetonitrile and concentrated to dryness, this process was repeated two more times to give 4.2 g (87 % yield) of the above-identified compound as an off-white foam. 1H NMR (CD3OD) d 1.42 and 1.42 (s, 9H), 1.7 (m, 4H), 3.3 (m, 2H), 3.95 (m, 1H), 4.19 (bs, 0.65H), 4.33 (bs, 0.35H), 4.15 (d, J=1 Hz, 0.65H), 4.38 (d, J=4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[N:12]O)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH2:12])[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=NO)CO2
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1C(N)CO2
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A mixture of the above described 4-methoxy-benzofuran-3-one oxime (6.15 g, 34.3 mmol) in ethanol (500 ml) with 10% palladium on charcoal (6.15 g) was hydrogenated at 23° C. and atmospheric pressure for 18 h. Filtered the catalyst off, washed with ethanol, evaporated the filtrate totally and dried in high vacuum to give rac-4-methoxy-2,3-dihydro-benzofuran-3-ylamine as a light yellow oil (3.65 g, 64%); MS: m/e=166.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:5]([NH:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:11][CH2:10][C:9]1[O:12][C:5]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:15]=[C:14]([Cl:16])[CH:13]=2)=[N:7][N:8]=1
Reactant: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: ClCc1nnc(-c2cc(Cl)cc(Cl)c2)o1
Yield: 88.1 %

Procedure:
To a mixture of 3,5-dichlorobenzohydrazide 5 (0.5 g, 2.4 mmol) and K2CO3 (0.61 g, 4.4 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.41 g, 3.66 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford 3,5-dichloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 92%) which was used for the next step without further purification. A mixture of 3,5-dichloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 2.24 mmol) and phosphorous oxychloride (0.51 g, 3.36 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 7 (0.52 g). Yield: 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27](O)=[O:28].Cl.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH2:39][NH:38][CH2:37][CH2:36]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27]([N:38]1[CH2:37][CH2:36][C:35]2[C:40](=[CH:41][CH:42]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH2:39]1)=[O:28]
Reactant: COc1ccc2c(c1)CCNC2
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3cc(OC)c(OC)cc13)C2
Yield: 32.7 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 117 (32.7% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.89 and 3.05 (2t, 2H), 3.48-4.05 (m, 20H), 4.40 and 4.92 (2s, 2H), 6.65-7.26 (m, 4H), 7.47 and 7.50 (2s, 1H), 7.78 and 7.83 (2s, 2H); MS (ESI) m/z 546 ([M+H]+).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].O1CCCC1.[CH3:10][O:11][CH2:12][C:13]1[N:18]2[N:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:17]2[C:16]([CH:26]=[O:27])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[OH:27][CH:26]([C:16]1[C:17]2[N:18]([N:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)[C:13]([CH2:12][O:11][CH3:10])=[CH:14][CH:15]=1)[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: COCc1ccc(C=O)c2cc(C(F)(F)F)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(COC)n2nc(C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
In an argon atmosphere, a 0.97 mol/L ethyl magnesium bromide-tetrahydrofuran solution (12.0 mL) was added dropwise to a solution of the compound of Example 327 (2.00 g) in tetrahydrofuran (50 mL) at −78° C. The mixture was allowed to gradually warm to room temperature. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The extract was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=7:1→2:1) to afford the title compound as a colorless powder (1.68 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN1CCCC1=O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: Clc1ccnc2ccc(Br)cc12
Solvent: CN1CCCC1=O
Product: Brc1ccc2nccc(N3CCCCC3)c2c1
Temperature: 150 °C
Yield: 100.4 %

Procedure:
To a solution of 4-choro-6-bromoquinoline (726 mg, 3 mmol) in 3 mL of 1-methyl-2-pyrrolidinone was added piperidine (510 mg, 6 mmol). The reaction was heated to 150° C. for 5 h. The solvents were removed in vacuo at 100° C. and the residue dissolved in methylene chloride and washed with water. The methylene chloride was dried with sodium sulfate and concentrated. The residue was triturated with hexane and the solid filtered off to give 6-bromo-4-(1-piperidinyl)quinoline (877 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[Br:21][C:22]1[CH:23]=[C:24]([NH2:29])[C:25]([NH2:28])=[CH:26][CH:27]=1>C(O)(=O)C>[Br:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:26][CH:27]=1)[N:28]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[N:29]2
Reactant: Nc1ccc(Br)cc1N
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ccc(Br)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 47.5 %

Procedure:
A solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (540 mg, 2.00 mmol, 1.00 equiv) and 4-bromobenzene-1,2-diamine (380 mg, 2.03 mmol, 1.10 equiv) in acetic acid (5 mL) was stirred for 3 h at 130° C. in an oil bath, then quenched by the addition of water (30 mL). The solids were collected by filtration and washed with water (20 mL). The solid was dried in an oven under reduced pressure, yielding 400 mg (48%) of 6-bromo-2,3-bis(4-methoxyphenyl)quinoxaline as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:4][C:3]=1[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]=1.CN(C)C=O.[H-].[Na+].Br[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:5]([C:9]([CH3:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][C:3]=1[C:18]1[N:19]=[C:20]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:23]=1
Reactant: CCCCCCCCBr
Reactant: CC(C)(c1ccccc1)c1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.5 %

Procedure:
To a 500 mL three-necked, round-bottomed flask equipped with a condenser, magnetic stirrer, thermometer, and a nitrogen atmosphere are charged 4.00 g (8.71 mmol) of the product of Example 9, 50 mL of N,N-dimethylformamide and 0.40 g (10 mmol) of sodium hydride (60% in mineral oil). The mixture is heated to an external temperature of 50° C. and 1.68 g (8.70 mmol) of 1-bromooctane are added. The mixture is stirred at this temperature for six hours and is allowed to cool to room temperature. The mixture is poured into a beaker of water which is extracted four times with chloroform. The combined chloroform layers are washed four times with water and dried over anhydrous magnesium sulfate and filtered. The solvent is removed under reduced pressure to afford a yellow oil. The crude product is purified with medium pressure chromatography with 10:1 heptane:ethyl acetate followed by recrystallization from acetone/water to yield 1.12 g of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]([OH:14])=[O:13].[C:15]1([S:21]([NH2:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:15]1([S:21]([NH:24][C:8]([C:6]2[CH:5]=[C:4]([CH3:11])[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH:7]=2)=[O:10])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1C(=O)O
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NS(=O)(=O)c2ccccc2)cc(C)c1C(=O)O
Temperature: 0 °C

Procedure:
2,6-Dimethyl-1,4-benzenedicarboxylic acid (from Preparation 7) (500 mg, 2.6 mmol) and benzene sulfonamide (486 mg, 3.1 mmol) were combined in dry DMF (25 mL), and EDCI (494 mg, 2.6 mmol) was then added with stirring at 0° C. The mixture was stirred for 2 hours at 0° C. and 2 days at room temperature, then 1N HCl (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with 1N HCl (1×), water (5×), and brine (3×); dried (Na2SO4); and rotary evaporated to give the crude product (used as such in the next step) as a white solid; NMR (acetone-d6) showed 8.0-7.4 ppm (multiplet with a singlet at 7.7 ppm, 7H) and 2.4 ppm (singlet, 6H).