Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH3:16])=[C:12]([CH2:14]Cl)[N:13]=2)=[CH:5][CH:4]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)C.O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:14][C:12]3[N:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=4)[NH:10][C:11]=3[CH3:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1ccc(-c2nc(CCl)c(C)[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)c(C)[nH]2)cc1

Procedure:
50 Grams (0.2 mol) of 2-(4-methylphenyl)-4-chloromethyl-5-methyl-1H-imidazole hydrochloride dissolved in 200 ml of a mixture of ethanol:water 6:4 were added dropwise to a refluxing solution of 55 grams (0.2 mol) of N-(diphenylmethyl)piperazine and 24 grams (0.6 mol) sodium hydroxide in 200 ml of a mixture of ethanol:water 6:4. After 2 to 3 hours 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine precipitated from the reaction mixture. After having left the crystals standing at room temperature, they were removed by filtration and recrystallized from methanol to give the free base which melted at 220°-222° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH2:27])[CH3:20].O>C(O)COCCO>[CH2:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH:27][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH3:20]
Reactant: CCN1CCCC1CN
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Solvent: OCCOCCO
Solvent: O
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 10 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 7.0 g of 1-ethyl-2-aminomethylpyrrolidine in 50 ml of diethylene glycol is heated at 120°-130° C. and stirred for 18 hours. The reactant solution is cooled to room temperature and added slowly with stirring to 300-400 ml of water. Under ice-cooling crystals are thoroughly deposited. The crude crystals are collected by suction filtration and washed with cold water. The crude crystals obtained are dried and recrystallized from about 220-230 ml of ethyl acetate by the use of decolorizing charcoal to give crystals of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 167°-169° C.
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[N:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[N:6][N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(F)(F)F)c2)C(N)C1
Product: NC(=O)c1cccc2c(NC3CNCCC3c3cccc(C(F)(F)F)c3)nnnc12

Procedure:
Compound 21 was prepared following general synthesis scheme 9 wherein 4-hydroxybenzo[d][1,2,3]triazine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [417 (M+H)], 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.98 (d, 1H), 8.84 (t, 1H), 8.54 (d, 1H), 8.50 (d, 1H), 8.30 (d, 1H), 8.04-7.89 (m, 2H), 7.67 (s, 1H), 7.59 (t, 1H), 7.45 (d, 2H), 5.42-5.26 (m, 1H), 3.64 (d, 1H), 3.49 (d, 1H), 3.35 (td, 1H), 3.23-2.90 (m, 2H), 2.52-2.00 (m, 2H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(N1CCCN2CCCN=C12)C1C=CC=CC=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Agent: c1ccc(CN2CCCN3CCCN=C32)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(Cc3ccc(C#N)cc3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 150 °C
Yield: 30.4 %

Procedure:
A mixture of 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) (0.100 g, 0.275 mmol), 4-(bromomethyl)benzonitrile (0.054 g, 0.275 mmol), 1-benzyl-1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine on polystyrene (0.055 g, 0.413 mmol) in DMF (2 ml) was heated in a microwave reactor at 150° C. for 7 mins. The reaction mixture was filtered, evaporated to dryness and the residue was purified by preparative HPLC to give the title compound (0.040 g, 30%); 1H NMR (500 MHz CDCl3): δ 7.59 (d, 2H), 7.52-7.49 (m, 2H), 7.48-7.42 (m, 3H), 7.37 (d, 2H), 5.21 (d, 1H), 3.41 (s, 2H), 3.01-2.90 (m, 1H), 2.65-2.56 (m, 2H), 1.74 (s, 9H), 1.69-1.60 (m, 4H), 1.44-1.34 (m, 2H); 13C NMR (125 MHz CDCl3): δ 159.9, 144.5, 134.2, 132.3, 131.9, 129.9, 129.4, 128.9, 125.4, 119.1, 111.1, 106.9, 62.3, 61.8, 51.9, 50.1, 32.5, 27.8; Mass Spectrum M+H+ 479.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:13]([CH3:26])[CH:12]=1>ClCCl>[CH3:8][O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:13]([CH3:26])[CH:12]=1
Reactant: COC(=O)c1ccc(CCC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CCC(=O)O)c(C)c1
Reaction time: 2 h
Yield: 71 %

Procedure:
Trifluoroacetic acid (40 ml) was added slowly to a stirred solution of 4-(2-tert-butoxycarbonyl-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.2 (4.9 g, 17.6 mmol) in dichloromethane (80 ml) at room temperature. The mixture was stirred for 2 h then concentrated in vacuo and azeotroped with dichloromethane. The residue was recrystallised in EtOAc to yield the title compound (2.77 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9].[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[C:27]([NH:1][C:2]1[C:3]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2NC(C)=O)c1

Procedure:
3-{5-Amino-6-[(2,2-dimethyl-propyl)-methyl-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (16 mg), acetyl chloride (3.5 mg), triethylamine (0.02 ml) were stirred in methylene chloride (0.2 mL) at room temperature for overnight. The product (2.8 mg) was purified by preparative thin layer chromatography. MS (m/z): 399 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CC#N.[C:13](=[S:22])(Cl)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:13](=[S:22])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:9])[N:3]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Nc1nc(O)ncc1F
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc(=O)n(C(=S)Oc2ccccc2)cc1F
Temperature: 65 °C
Reaction time: 1.33 h
Yield: 29.6 %

Procedure:
A 25 mL screw-top vial was charged with 4-amino-5-fluoropyrimidin-2-ol (99.7 mg, 0.772 mmol) and CH3CN (3 mL). BSA (0.284 mL, 1.16 mmol) was added, the vial was capped and the resulting heterogenous mixture was agitated on a rotary shaker at 65° C. for 80 min. The resulting clear and colorless solution was cooled to room temperature. O-Phenyl carbonochloridothioate (0.118 mL, 0.853 mmol) was added, and the reaction was agitated on a rotary shaker at 65° C. for 15 h. After cooling to room temperature, the crude material was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous sodium chloride (satd aq NaCl) solution (50 mL×2). The organic solution was then dried over Na2SO4, filtered, and concentrated in vacuo. The green/brown residue was then purified by normal phase chromatography (gradient, 0 to 35% methyl alcohol (MeOH)/CH2Cl2) to afford O-phenyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carbothioate (60.7 mg, 30%) as an 85% pure brown solid: mp 113-116° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.44 (d, J=7.2 Hz, 1H), 8.28 (s, 1H), 7.56-7.48 (m, 2H), 7.40-7.33 (m, 1H), 7.27-7.21 (m, 2H); ESIMS m/z 266 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH2:28][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.O>CN(C=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([CH2:29][CH2:28][C:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=2)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(CCBr)cc1
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCc1ccc(C#N)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
6.70 g (0.17 mol) of sodium hydride are added in portions to a solution of 55.71 g (0.17 mol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate from Example 12A in 34 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 1 hour. The reaction solution is then cooled to 0° C., 42.98 g (0.20 mol) of 4-(2-bromoethyl)benzonitrile from Example 8A in 21 ml of DMF are added, and the mixture is stirred at this temperature for 30 min. The mixture is subsequently stirred at room temperature overnight. Water is added dropwise to the reaction mixture, which is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 3:1; 3 kg of silica gel). 36 g (0.078 mol, 46% yield) of a colorless solid are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(C)c(N4CCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 120 °C
Yield: 50.5 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (115 mg, 0.227 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 148, step D) (67 mg, 0.204 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (82 mg, 0.103 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.73 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.49 (s, 1H), 7.40-7.45 (m, 1H), 7.32-7.39 (m, 1H), 7.25 (d, J=8.61 Hz, 1H), 7.18 (t, J=8.15 Hz, 2H), 6.94 (t, J=6.87 Hz, 1H), 6.75 (s, 1H), 6.54 (d, J=5.31 Hz, 1H), 4.25 (q, J=6.78 Hz, 2H), 3.79 (s, 3H), 3.31-3.34 (m, 2H), 3.05 (s, 3H), 2.82-2.89 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.52-2.63 (m, 4H), 2.13 (s, 3H), 1.41 (t, J=6.87 Hz, 3H). MS (ESI): 797 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:17])([C:13]#[C:14][CH2:15][CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:26][C:27](Br)=[O:28]>CCOCC>[C:13]([C:8]1([C:9]([F:10])([F:11])[F:12])[C:7]2[CH:6]=[C:5]([Cl:18])[CH:4]=[CH:3][C:2]=2[NH:1][C:27](=[O:28])[CH2:26][O:17]1)#[C:14][CH2:15][CH3:16]
Reactant: O=C(Br)CBr
Reactant: CCC#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC#CC1(C(F)(F)F)OCC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solition of 167 mg of 6-amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 0.066 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF and was treated at room temperature with 25 mg of 100% sodium hydride for 1.5 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product wes purified by preparative silica gel TLC. (elution with ethel acetate/hexanes 1:2) affording after crystallization from ethyl acetate/hexanes 106 mg of the title compound as colorless crystals: mp 167 -168°; Anal. Calcd. for C14H11NO2ClF3 : C, 52.93; H, 3.49; N, 4.42. Found: C, 52.73; H, 3.64; N, 4.13.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH2:35]([N:42]1[C:46]([CH2:47]Br)=[CH:45][C:44]([CH3:49])=[N:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:35]([N:42]1[C:46]([CH2:47][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[CH:45][C:44]([CH3:49])=[N:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cc(CBr)n(Cc2ccccc2)n1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc(C)nn3Cc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 5 mL of DMF at 0° C. is added 1.57 mL (0.79 mmol, 1.2 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 5 min, and a solution of 190 mg (0.72 mmol, 1.1 equiv.) of 1-Benzyl-5-bromomethyl-3-methyl-1H-pyrazole, prepared as in Intermediate 56, in 2 mL of DMF is added. The resulting solution is stirred for 18 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/2 as eluent afforded 254 mg of the title compound as a white solid: mp 117°-120° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-7.02 (m, 15H), 6.94 (m, 2H), 6.85 (d, 1H, J=7.4), 5.80(s, 1H), 5.30 (dd, 2H, J=16.1, 30.9), 4.98 (m, 1H), 4.19 (dd, 2H, J=15.6, 76.0), 3.83 (s, 3H), 3.43 (t, 1H, J=6.7), 3.25 (ddd, 1H, J=7.1, 16.0, 40.5), 2.20 (s, 3H), 1.06 (m, 6H); low resolution MS (FAB)m/e 642 (MH+), 641 (M+); Anal. (C39H39N5O4) Calcd. C, 72.99; H, 6.13; N, 10.91 Found C, 72.86; H, 6.11; N, 10.96.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([O:34][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:36]=1
Reactant: O=C(Cl)c1cccc(OCc2ccccc2)c1
Reactant: COC(=O)CCCCCCCNc1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1cccc(OCc2ccccc2)c1)c1ccc(OCc2ccccc2)cc1

Procedure:
As described in example 3(b), the reaction is carried out with 4.7 g (13 mmol) of 8-(4-benzyloxyphenyl-amino)-caprylic acid methyl ester, 3.3 (13 mmol) of 3-benzyloxy- benzoic acid choride, 1.5 g (15 mmol) of triethylamine and 100 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([F:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2)(=O)C.ClC1C=CC=[C:19]([C:23]([O:25]O)=[O:24])C=1>C(Cl)(Cl)Cl>[C:23]([O:25][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([F:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2)(=[O:24])[CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(F)c2c(c1)CCC(=O)N2
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(F)c2c(c1)CCC(=O)N2
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a stirring solution of 6-acetyl-8-fluoro-3,4-dihydroquinolin-2(1H)-one (1.6 g, 7.72 mmol) in CHCl3 (100 mL) at room temperature was added in portions m-chloroperbenzoic acid (2.077 g, 9.27 mmol). The reaction mixture was stirred at reflux for 18 h, then cooled to room temperature and quenched with saturated sodium bicarbonate solution. The reaction was extracted with DCM (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to a yellow oil. This was purified by column chromatography on silica gel using 1% MeOH in DCM to give 8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl acetate as a white foam (1.3 g, 75%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 (s, 1H), 6.84-6.72 (m, 1H), 2.77-2.54 (m, 2H), 2.45-2.21 (m, 2H), 1.62 (s, 3H). LCMS: R.T.=1.382 min; [M+H]+=224.0.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[CH:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)=[CH2:21]
Reactant: C=COCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=COCCCCCOc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 128.6 %

Procedure:
Ethyl p-hydroxybenzoate (33.2 g), 5-bromopentylvinyl ether (58.0 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and dissolved in water (1 L). Concentrated hydrochloric acid (25.7 mL) was added thereto, and the precipitated crystal was collected through filtration under reduced pressure, and washed with water. This was dried to give 4-(5-vinyloxypentyloxy)benzoic acid (TP-29C) (64.3 g, 90%). Production of 2,3,6,7,10,11-hexa(4-(5-vinyloxypentyloxy)benzoyloxy)triphenylene (TP-29):
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[CH:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=C[C:21]1=[O:30]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([CH:21]=[O:30])[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(O)c2ccccc2n1Cc1ccccc1
Reactant: O=c1ccc2ccccc2[nH]1
Product: O=Cc1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
Following the Procedure set forth in Preparation B, 1-benzyl-4-hydroxy-2(1H)-quinolinone was converted to 1-benzyl-3-formyl-4-hydroxy-(2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS (FAB): m/e 370 (M·+ +1); NMR (DMSO): δ5.50 (s, 2H, CH2 --Ar), 10.18 (s, 1H, CHO) ppm.
Reaction SMILES: [N+]([C:4]1[CH:5]=C2C(=C[CH:13]=1)C(=O)NN=C2Br)([O-])=O.[N+:16]([C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Br:30])=[N:24][NH:25][C:26]2=[O:29])=[CH:21][CH:20]=1)([O-:18])=[O:17].[H-].[Na+].BrC(C)C>CN(C=O)C>[N+:16]([C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Br:30])=[N:24][N:25]([CH:4]([CH3:5])[CH3:13])[C:26]2=[O:29])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=c1[nH]nc(Br)c2ccc([N+](=O)[O-])cc12
Reactant: O=c1[nH]nc(Br)c2cc([N+](=O)[O-])ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc([N+](=O)[O-])cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A mixture of 6-nitro-4-bromo-2H-phthalazin-1-one and 7-nitro-4-bromo-2H-phthalazin-1-one (84 g, 0.31 mol) was dissolved in DMF (400 ml). To this was added NaH (60%, 7.5 g, 0.31 mol) as a DMF suspension (200 ml). The mixture was stirred at RT for 30 min then 2-bromo-propane (7.7 g, 62 mmol) was added in one portion as a solution in DMF (250 ml). The reaction mixture was stirred for 24 hours whereupon LC-MS showed 40% starting material remaining. To this was added NaH (3.75 g, 0.15 mol) and the reaction stirred for a further 24 hours. The DMF was removed under vacuum and the resulting crude material purified by successive column chromatography (elution: 92% heptane, 8% EtOAc) to give the title compound (38.8 g, 40% yield) as a light yellow solid. δH (400 MHz, DMSO), 8.88 (1H, d), 8.87 (1H, dd), 8.16 (1 H, d), 5.19 (1H, m), 1.13 (6H, d).