Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[C:11]=2[CH:10]=[CH:9][N:8]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:17]([C:12]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:19]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: NCCCCN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 62 %

Procedure:
In 200 ml of chloroform was dissolved 8.8 g of 1,4-diaminobutane, and to the solution was added dropwise 100 ml of a chloroform solution containing 4.55 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and then the reaction solution was extracted with a 10% aqueous hydrochloric acid solution. The pH of the aqueous layer was adjusted to 10 with a 10% aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The chloroform layer extracted was washed with water and dried with anhydrous potassium carbonate. Then the chloroform was distilled from the chloroform layer, and the residue obtained was subjected to a column chromatography [silica gel: 200 g; developing solvent: 2% methanol/chloroform (volume ratio)] to give 3.46 g of N-(4-aminobutyl)-5-isoquinolinesulfonamide, i.e., Compound (3) as an oily substance in a yield of 62%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[F:30])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-])=O)[CH:17]=2)[CH:10]=1)=[O:8])([O-])=O.Cl.O.[Cl-].[Na+]>C(O)C.COCCO.[Fe]>[NH2:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([F:30])=[C:4]([NH2:1])[CH:5]=2)[CH:10]=1)=[O:26]
Reactant: O=C(c1cccc(C(=O)c2ccc(F)c([N+](=O)[O-])c2)c1)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: COCCO
Solvent: CCO
Product: Nc1cc(C(=O)c2cccc(C(=O)c3ccc(F)c(N)c3)c2)ccc1F
Temperature: 65 °C
Yield: 82.9 %

Procedure:
Next, a glass reaction vessel equipped with a stirrer, reflux condenser and a thermometer was charged with 82.4 g (0.2 mole) of the above 1,3-bis(3-nitro-4-fluorobenzoyl) benzene, 820 ml of a 80% aqueous ethanol solution and 82.0 g (1.46 mole) of iron powder were charged and the internal temperature was raised to 65° C. Successively, a solution containing 6.08 g of 36% hydrochloric acid in 80 ml of 80% ethanol was added dropwise over 2 hours and the reaction was continued further for an hour with stirring. The reaction mixture was cooled to room temperature and filtered. The residue obtained was dissolved in 280 g of hot 2-methoxyethanol and hot filtered to remove iron powder. The filtrate was poured into 2 l of water. The precipitated crystals were filtered, washed with water and dried to obtain 63.5 g of crude crystals of 1,3-bis(3-amino-4-fluorobenzoyl) benzene. The crude crystals were mixed with 120 ml of water, 36% hydrochloric acid and activated carbon, and dissolved by heating. The solution was hot filtered. To the filtrate, 12 g of sodium chloride was added and dissolved. The solution thus obtained was gradually cooled to precipitate 1,3-bis(3-amino-4-fluorobenzoyl)benzene hydrochloride. The hydrochloride was filtered and neutralized in water with a 28% aqueous ammonia solution to obtain 58.4 g (83.0% yield) of 1,3-bis(3-amino-4-fluorobenzoyl)benzene. The purified product had purity of 99.1% by high performance liquid chromatography and a melting point of 169.7°-170.7° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Methyl 5-methyl-2-furoate (3.68 g, 26.29 mmol) in methanol (30 ml) was treated with a solution of potassium hydroxide (2.80 g, 50.0 mmol) in water (15 ml) and the mixture stirred for 2 h at room temperature. The methanol was evaporated in vacuo, the residue dissolved in water and washed with ethyl acetate. The aqueous phase was acidified with 5N hydrochloric acid, and the product extracted with ethyl acetate (×3). The combined organic solutions were dried and concentrated to yield the title compound as a yellow solid (3.12 g, 94%); m.p. 110-112° C.; (Found: M+, 126.0312. C6H6O3 requires M+ 126.0317); νmax (CH2Cl2) 3300-2700, 1688, 1524, 1424, 1305, 1210 and 1167 cm-1 ; δH (CDCl3, 90 MHz) 2.40 (3H, s), 6.15 (1H, d, J 4 Hz) and 7.22 (1H, d, J 4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([C:15]3[S:16][CH2:17][CH:18]([C:20]([OH:22])=[O:21])[N:19]=3)=[N:8][C:7]=1[CH:6]=[CH:5]2.[C:23](O)(C(F)(F)F)=O.[N+](=C)=[N-].CC(O)=O>CC#N.CO.CCOCC>[CH3:23][O:21][C:20]([CH:18]1[CH2:17][S:16][C:15]([C:9]2[S:10][C:11]3[C:12]4[C:4](=[CH:3][C:2]([OH:1])=[CH:14][CH:13]=4)[CH:5]=[CH:6][C:7]=3[N:8]=2)=[N:19]1)=[O:22]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)C1CSC(c2nc3ccc4cc(O)ccc4c3s2)=N1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: CC#N
Product: COC(=O)C1CSC(c2nc3ccc4cc(O)ccc4c3s2)=N1

Procedure:
2-(7-Hydroxynaphtho[2,1-d]thiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (8 mg, 24 umol) was suspended in a mixture of MeCN and MeOH and acidified to pH<3 by the addition of TFA. The solution was treated with a solution of diazomethane in ether until the yellow color persisted. Excess diazomethane was neutralized by the addition of AcOH, the ether removed under reduced pressure, and the desired product (3.3 mg) isolated as a yellow solid by preparative HPLC eluting with 5→100% MeCN in NH4OAc, followed by lyophilization. Calcd for C16H13N2O3S2 (M+H): 345.0. found 345.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[C:18]([O:24][CH2:25][CH3:26])[C:19]([C:21](O)=[O:22])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:25]([O:24][C:18]1[C:19]([C:21]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:22])=[CH:20][C:14]2[N:13]=[C:12]([C:8]3[C:7]([NH:6][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:30][CH:29]=[CH:28][C:27]=4[F:31])=[CH:11][NH:10][N:9]=3)[NH:16][C:15]=2[CH:17]=1)[CH3:26]
Reactant: C1COCCN1
Reactant: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2cc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.7 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-6-ethoxy-1H-benzimidazole-5-carboxylic acid (50 mg, 0.12 mmol), morpholine (13 μl, 0.14 mmol), EDC (29 mg, 0.15 mmol) and HOBt (21 mg, 0.15 mmol) in DMF (5 mL) was stirred at r.t. for 48 h. The reaction mixture was reduced in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried (MgSO4) and reduced in vacuo to give the title compound (29 mg) as a gray solid. (LC/MS: Rt 2.56, [M+H]+ 497.03).
Reaction SMILES: [I:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH3:17])[CH:15]=[CH:16][C:3]=12.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+]>ClCCl>[I:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH3:17])[CH:15]=[CH:16][C:3]=12
Reactant: CCOC(=O)c1c(C)nc2c(ccn2C)c1I
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(ccn2C)c(I)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A −78° C. solution of ethyl 4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate in dichloromethane (DCM) (150 mL) was treated dropwise with DIBAL-H (128 mL, 128 mmol) and warmed to ambient temperature. After 30 min, the reaction mixture was cooled to 0° C. and treated sequentially with water (5.1 mL), 15% NaOH (5.1 mL) and finally water (12.8 mL) with a 10 minute delay in between each addition. The fine suspension was then filtered through a pad of celite and washed with ethyl acetate 3×. The filtrate was concentrated in vacuo to afford (4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (12.4 g, 41.0 mmol, 96% yield) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:6]([CH3:20])[CH:5]=1.[Li+].[OH-]>C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:16]([O:15][C:13]([CH2:12][CH2:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][C:6]=1[CH3:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(C)c(CCC(=O)OC(C)(C)C)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid methyl ester (10.8 g, 37.0 mmol) in ethanol (100 mL) a 2 M aq. solution of LiOH (50 mL) is added at 0° C. The turbid mixture is stirred at 0° C. for 30 min, then at rt for 4 h. The mixture is diluted with 10% aq. citric acid solution and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and concentrated. The solid residue is suspended in diethyl ether/heptane, stirred at rt, and filtered. The slurry procedure in diethyl ether/heptane is repeated. The solid material is collected and dried under HV to give 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid (5.09 g) as a white crystalline powder; LC-MS: tR=0.95 min, [M+1]+=279.14; 1H NMR (CDCl3): δ 1.47 (s, 9H), 2.30-2.40 (m, 2H), 2.39 (s, 6H), 2.94-3.03 (m, 2H), 7.75 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26]([C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:29]=[N:30][C:31]([O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[N:32][CH:33]=1)=[O:27]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)nc1
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 101 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) and methyl-2-chloropyrimidine-5-carboxylate [CAS Reg. No. 287714-35-6]. MS (m/e)=502.1 [MH+].
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15].C(OCC)(=O)C.[ClH:22]>O.[Cu]Cl>[Cl:22][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A saturated solution of sodium nitrite (1.8 g, 26.0 mmol) in water (12 mL) was added dropwise to a suspension of 2-amino-5-nitro-phenol (2.0 g, 13.0 mmol) in concentrated hydrochloric acid (10 mL) at 0° C. and stirred for 30 min. A solution of Copper (I) chloride (5.15 g, 52.0 mmol) and concentrated hydrochloric acid (20 mL) heated to between 60 and 70° C. was added dropwise over a period of 30 min. The resultant reaction mixture was heated to 80° C. and stirred for 15 min and then allowed to cool to ambient temperature. Ethyl acetate (50 mL) was added and after stirring for 5 min the organic phase was separated and the aqueous phase was re-extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with water (4×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent to afford 2-chloro-5-nitro-phenol (2.08 g, 92%) as a crystalline yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCc1ccc(I)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Brc1ccc(COCc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
1-Bromo-4-[(4-iodobenzyloxy)methyl]benzene (3v) was prepared using an non-optimized procedure as follows. To a stirred solution of 4-iodobenzyl alcohol (1.33 g, 5.5 mmol, 1.1 equiv) in DMF (40 mL) at 0° C. was added NaH (240 mg, 60% in mineral oil, 6.0 mmol, 1.2 equiv), and the mixture was warmed to room temperature and stirred for 30 min. The mixture was cooled to 0° C., and 4-bromobenzyl bromide (1.25 g, 5.0 mmol, 1.0 equiv) and tetra-n-butylammonium iodide (92.3 mg, 0.25 mmol, 0.050 equiv) were added. The reaction mixture was warmed to room temperature, stirred for 2 h and quenched with saturated aqueous NH4Cl solution. The mixture was extracted with Et2O, and the organic layer was washed with 1 M aqueous HCl solution and brine and dried over Na2SO4. After evaporation of the solvent, the crude mixture was purified by flash silica gel column chromatography (hexane/Et2O=400/1 to 20/1) to give 1-bromo-4-[(4-iodobenzyloxy)methyl]benzene (3v) as a white solid (1.02 g, 51% yield). 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J=8.4 Hz, 2 H), 7.48 (d, J=8.4 Hz, 2 H), 7.22 (d, J=8.4 Hz, 2 H), 7.10 (d, J=8.4 Hz, 2 H), 4.49 (s, 4 H). 13C{1H} NMR (125 MHz, CDCl3): δ 137.9, 137.8, 137.2, 131.8, 129.8, 129.6, 121.9, 93.4, 71.8, 71.7. Anal. calcd. for C14H12BrIO: C, 41.72; H, 3.00; found: C, 41.71; H, 2.77.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:17]([NH:24][C:25]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(CC)CC>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:16])[CH:6]([NH:7][C:30]([C:25]1([NH:24][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:31])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (12.2 mmol) of tyrosine ethyl ester hydrochloride and 2.8 g (12.2 mmol) of N-Boc-cycloleucine are suspended in 10 mL of CH2Cl2. 1.65 g (12.2 mmol) of HOBT, 3.02 g (14.6 mmol) of DCC, and 1.7 mL (12.2 mmol) of Et3N are added, and the solution is stirred at room temperature overnight. The reaction mixture is filtered, and CH2Cl2 is removed in vacuo. The residue is taken up in EtOAc, filtered, and washed successively with 1N HCl, water, saturated aqueous NaHCO3 solution, and brine, then dried over MgSO4, filtered, and concentrated. The residue is purified by chromatography on silica gel (50% EtOAc/hexane) to yield 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester; 1H NMR (250 MHz, CDCl3) δ7.97 (d, 2 H), 6.7 (d, 2 H), 7.51 (d, 1 H), 5.58 (s, 1 H), 4.70-4.80 (m, 2 H), 4.12 (q, 2 H), 3.02 (d, 2 H), 2.07-2.35 (m, 2 H), 1.60-2.00 (m, 6 H), 1.40 (s, 9 H), 1.20 (t, 3H).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([CH:22]=[C:23]([CH2:25][O:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19](O)=[O:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:37][S:38]([NH:41][C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:10]2[N:9]3[CH:22]=[C:23]([CH2:25][O:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:24]=[C:8]3[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[N:12][CH:11]=2)=[CH:18][N:17]=1)=[O:20])(=[O:40])=[O:39]
Reactant: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Reactant: CS(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 15c (400 mg, 0.790 mmol) in DCM (20 mL) was added methanesulfonamide (78.8 mg, 0.830 mmol), DCC (256 mg, 1.24 mmol) and 4-dimethylaminopyridine (152 mg, 1.24 mmol). The reaction mixture was stirred at rt overnight, and was quenched with H2O (40 mL). The resulting mixture was extracted with DCM (3×40 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (10:1 v/v). The title compound 76 was obtained as a yellow solid (307 mg, 69% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.99 (s, 1H), 8.27-8.19 (m, 3H), 8.08 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.68 (t, J=6.9 Hz, 1H), 7.56 (s, 1H), 7.47 (t, J=6.9 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 5.58 (s, 2H), 4.41-4.20 (m, 4H), 3.88-3.71 (m, 4H), 3.05 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H25N7O5S: 560.2 (M+H). Found 560.0.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N)(=O)C1C=CC=CC=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([F:33])[CH:32]=1)[C:27](Cl)=O>>[F:23][C:24]1[CH:25]=[C:26]([C:27]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[C:10]([CH3:11])[C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[N:1]=2)[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Agent: NC(=O)c1ccccc1
Product: COc1ccc2c(O)nc(-c3cc(F)cc(F)c3)nc2c1C
Yield: 85 %

Procedure:
The general procedure described in Example 10 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and 3,5-difluoro-benzoyl chloride as acid chloride [B], which gave the title compound (2.1 g, 85%), [M+H]=303.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[CH:11]=[C:12]1[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15][NH:14][CH2:13]1.[C:31](Cl)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:31]([N:14]1[CH2:13][C:12](=[CH:11][C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=2[F:8])[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15]1)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
Triethylamine (0.4 ml, 2.85 mmol) was added to a solution of compound 1 (300 mg, 0.96 mmol) in ice-cold 1,2 dichloroethane. A solution of stearoyl chloride (450 mg, 1.49 mmol) in 1,2-dichloroethane was added drop-wise to the ice-cold solution of compound 1. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, 10% potassium carbonate solution (10 ml) was added, and stirred for 30 min. The organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain a shiny solid of 25 (373 mg, 67% yield). 1H NMR (300 MHz, CDCl3): δ 7.92, 7.89 (2s, 2H, C═CH), 7.50-7.35 (m, 4H, Ar—H), 7.30-7.14 (m, 4H, Ar—H), 4.79, 4.55 (2s, 4H), 2.44 (td, 2H, J=7.3, 2.3), 2.09 (t, 2H, J=7.6), 1.65 (t, 2H, J=7.0), 1.41 (t, 2H, J=7.3), 1.40-1.05 (m, 24H), 0.87 (t, 3H, J=6.7, CH3). 13C NMR (75 MHz, CDCl3): δ 172.05, 133.77, 133.40, 133.48, 130.76, 130.23, 124.29, 116.39, 116.09, 115.81, 46.45, 43.48, 35.26, 33.08, 31.92, 29.69, 29.37, 28.86, 25.06, 24.21, 22.69, 14.12. ESI Mass calculated for C37H50F2NO2(M+H)+578.38. found 578.40.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5]O[C:3]=1[CH3:9].[CH2:10]([NH2:12])[CH3:11].C>O>[CH2:10]([N:12]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:9])[CH3:11]
Reactant: CCN
Reactant: Cc1occc(=O)c1O
Solvent: O
Product: CCn1ccc(=O)c(O)c1C
Reaction time: 0.5 h

Procedure:
1-Ethyl-3-hydroxy-2-methylpyrid-4-one was prepared by dissolving 10.0 g of 3-hydroxy-2-methylpyr-4-one (Maltol) and 3 equivalents of ethylamine (70%) in 200 ml of water. The reaction mixture was refluxed for 10 hours at which time it was black in color. Decolorizing charcoal was then added to the mixture and it was stirred an additional 0.5 hours. The mixture was then filtered through a fine frit and the filtrate was concentrated in vacuo to remove the water and excess amine. The resulting brown crystals were recrystallized using hot methanol which yielded white needles of pure product. m.p. 204°-205 ° C.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]3[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][C:10]=3[N:11]3[CH:12]=[CH:13][C:4]([C:5]=23)=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH:30]1[CH2:32][CH2:31]1>CN(C)C=O>[CH:30]1([CH2:29][CH:14]2[C:10]3[N:11]4[CH:12]=[CH:13][C:4]5[C:5]4=[C:6]([CH2:1][CH2:2][CH:3]=5)[C:7]4[N:8]([CH:19]=[N:20][N:21]=4)[C:9]=3[CH:17]=[CH:16][C:15]2=[O:18])[CH2:32][CH2:31]1
Reactant: O=C1C=CC2=C(C1)n1ccc3c1=C(CCC=3)c1nncn12
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C=CC2=C(C1CC1CC1)n1ccc3c1=C(CCC=3)c1nncn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,2,4]triazolo[4,3-d][1,4]benzodiazepin-8(7H)-one (5.2 g) was dissolved in dimethylformamide (150 ml). Potassium carbonate (0.5 g) was added, followed by (chloromethyl)cyclopropane (2.1 ml). The mixture was stirred at 95° C. overnight, filtered, and evaporated under reduced presure. The residue was purified by high performance liquid chromatography (1% methanol/dichloromethane) to yield 3.4 g (54.8%) of product. Recrystallization from pentane/ether gave the analytical sample, mp 9920 C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18](Cl)=[O:19])=[CH:14][CH:13]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(Cl)Cl>[CH2:24]([N:26]([CH2:27][CH3:28])[C:18](=[O:19])[CH:17]([O:16][C:15]1[CH:22]=[CH:23][C:12]([O:11][C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:13][CH:14]=1)[CH3:21])[CH3:25]
Reactant: CCNCC
Reactant: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound can be prepared by interaction of 2-[4-(2-quinoxalinyloxy)phenoxy]propionic acid with thionyl chloride in a suitable solvent such as chlorobutane. Add a solution of 3.3 g (0.01 mole) 2-[4-(2-quinoxalinyloxy)phenoxy]propionyl chloride in 30 cc methylene chloride to a cold (5° C.) solution of 1.8 g (0.025 mole) diethylamine in 30 cc methylene chloride. Stir the mixture at room temperature overnight. Wash the methylene chloride solution with water and dry over magnesium sulfate. Remove the methylene chloride under vacuum to yield N,N-diethyl-2-[4-(quinoxalinyloxy)phenoxy]propanamide.