Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].C([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)(C)C.Cl.[Al+3].[Cl-].[Cl-].[Cl-]>CCCCCC>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[C:7]([C:12](=[O:13])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C(=O)O)c(C(=O)c2ccccc2)c1
Temperature: 70 °C
Yield: 54 %

Procedure:
4-t-Butyl-phthalic anhydride (36.0 g, 176 mmol) and t-butyl benzene were placed under nitrogen in a 3-neck round-bottom flask equipped with a condenser. The condenser was attached to a water-gas trap for HCl released during the reaction. AlCl3 (56.0 g, 420 mmol) was added in portions during which time the mixture turned dark brown. Stirring became difficult in the thick mixture. The reaction was heated at 70° C. for 1 h and then cooled to room temperature. Ice was added slowly to the flask followed by concentrated HCl solution. A large clump of solid stuck to the bottom of the flask. This was washed multiple times with water and then dissolved in CH2Cl2, washed with water, dried over Na2SO4 and concentrated to give an oily solid. Hexane was added and after sonication, a blue-white solid was collected by filtration. Drying gave product as white solid 32.0 g (54% yield). 1H NMR (CDCl3) δ(ppm): 1.33 (s, 18 H), 7.30 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.63-7.70 (m, 3H), 8.08 (s, 1H); 13C NMR (CDCl3): 30.98, 34.92, 125.36, 125.41, 127.78, 127.84, 128.02, 129.51, 129.60, 129.81, 134.56, 139.83, 152.94, 156.80, 170.80, 196.89.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]1[CH:34]=[CH:33][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]3=[N:24][N:25]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:26]=[C:16]3[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]1[CH:34]=[CH:33][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]3=[N:24][N:25]([CH2:27][C:28]([OH:30])=[O:29])[CH:26]=[C:16]3[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
To a stirred slurry of 0.477 g of 6-[4-[(2,4-dichlorobenzoyl)amino]benzoyl]-5,6-dihydropyrazolo-(4,3-d][1]benzazepine-2(4H)-acetic acid, ethyl ester in 15 ml of ethyl alcohol is added 5 ml of tetrahydro-furan followed by 1.30 ml of 1M NaOH. The reaction mixture is stirred at room temperature for 6 hours followed by the addition of 0.750 ml of 2M HCl. The acidic reaction mixture is evaporated in vacuo, triturated with CHCl3, combined, treated with activated carbon, filtered through MgSO4 and evaporated in vacuo to give 0.380 mg of the desired product as a clear foam.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:18])=[C:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30](Cl)(=[O:32])=[O:31])#[N:20]>N1C=CC=CC=1.C(Cl)Cl.C(Cl)Cl.CCOC(C)=O>[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:18])=[C:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)(=[O:32])=[O:31])#[N:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: COC(=O)Cc1c(C)c2ccc(N)cc2oc1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)Cc1c(C)c2ccc(NS(=O)(=O)c3ccc([N+](=O)[O-])cc3C#N)cc2oc1=O

Procedure:
Methyl 7-amino-4-methylcoumarin-3-acetate (compound 1 in FIG. 2) (34.0 mg, 0.14 mmol) synthesized in Example 1(1) was dissolved in pyridine/CH2Cl2 (1.4 ml, 1:1), 2-cyano-4-nitrobenzenesulfonyl chloride (CNS chloride; 63.8 mg, 0.26 mmol, 1.9 equivalents) dissolved in CH2Cl2 (0.5 ml) was added under cooling on ice, and the mixture was stirred. The next day, the disappearance of the starting materials was confirmed by TLC and the reaction mixture was diluted with EtOAc, and partitioned between saturated aqueous NaHCO3 solution and H2O. The organic layer was washed with saturated brine and dried over Na2SO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluate: 1% acetic acid-containing hexane:EtOAc=1:1) (compound 2a: 32.0 mg, 0.07 mmol, 51%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:36]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:34])[N:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH3:26])=[O:17])=[CH:11][C:10]=1[F:35].CO.Cl.[OH-].[Na+]>CC(OC)(C)C.O>[NH2:36][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:34])[N:20]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[O:24][CH2:25][CH3:26])=[O:17])=[CH:11][C:10]=2[F:35])[CH:6]=[CH:5][N:4]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: COC(C)(C)C
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(N)c2Cl)c(F)c1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 40.7 %

Procedure:
To a 250 mL vessel, N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (100.0 g, 147.7 mmoles, 1.0 eq) and methanol (900 mL) were charged. The white slurry was cooled to 10° C. and concentrated HCl (16.3 g, 163.3 mmoles, 1.105 eq) was added, maintaining the reaction temperature below 10° C. The reaction mixture was held at 10° C. for approximately 2.5 h, until HPLC indicated 0.5 relative area percent of starting material. Water (500 mL) and MTBE (500 mL) were added and the reaction mixture was warmed to 20° C. Next, 1N NaOH (184.08 g, 177.0 mL, 177 mmoles, 1.20 eq), was added dropwise over 20 minutes while maintaining the temperature between 15 and 20° C. The resulting slurry was cooled to 10° C. and aged for at least 10 minutes. The precipitate was filtered off, and the cake washed with water (2×350 mL), followed by a mixture of methanol:MTBE (10:90) (1×300 mL). Next, the cake was dried in a vacuum oven at 50-60° C. until LOD analysis indicated less than 1 wt % of volatiles. N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl )-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide: 79.5 g (95% yield with 98.1 AP and 99.4 wt % potency). The resulting product (35.0 g) was subsequently re-crystallized from THF (367.2 mL)/EtOH (200 proof, 244.8 mL)/n-heptane (350 mL) to obtain N-(4-(2-amino-3-chloropyridin-4-yloxy )-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30.8 g) in 88% yield with >99.9 AP and 99.7 wt % potency.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:3])[CH3:2].CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:21](=[O:22])[CH2:20][Br:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)NCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1ccccc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
To a solution of N-isopropylbenzylamine (40 mL, 240 mmol) in CHCl3 (300 mL) was added Et3N (36.8 mL). The reaction was cooled to 0° C. and bromoacetyl bromide (21.8 mL, 251 mmol) was added. The mixture was stirred at room temperature for 24 hours and was diluted with CH2Cl2. The organic solution was washed consecutively with 5% aqueous HCl (1×) and aqueous NaHCO3 (1×). The organic solution was dried (Na2SO4), filtered and concentrated. The residue was dissolved in 40% EtOAc in hexanes and was filtered through a silica gel pad to provide 52.2 g of N-benzyl-2-bromo-N-isopropyl-acetamide. 1H NMR (CD2Cl2) δ 7.20-7.40 (m, 5H), 4.53 (d, 2H), 4.22 (m) and 4.74 (m, total 1H), 4.01 (s, 1H), 3.72 (s, 1H), 1.20 (d, 3H), 1.12 (d, 3H).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:7]([O:17][CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:6][CH:5]=1.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[C:7]([O:17][CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:25])=[O:2])=[CH:11][CH:12]=1
Reactant: COC(=O)c1cnc(OCc2nccn2C)c(-c2ccc(Cl)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccnc1COc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5-(4-Chloro-phenyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)-nicotinic acid methyl ester (0.28 g, 0.8 mmol) was dissolved in tetrahydrofuran (4.5 mL). Water (1.5 mL) and lithium hydroxide (99 mg, 2.3 mmol) was added and the mixture was stirred for 1 h at 80° C. The mixture was cooled to room temperature; citric acid (4 mL, 10%) was added and the mixture was extracted with ethyl acetate. Organic phases were pooled dried with Na2SO4 and the solvent evaporated to give a quantitative yield of the title compound as beige solid, MS (ISP) 342.0 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:24]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(O)cc2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
A mixture of 4-{[4-(2-tert-Butylphenyl)piperazin-1-yl]carbonyl}phenol obtained in Example 20 (1.0 g), methyl bromoacetate (542 mg), potassium carbonate (1.38 g), and N,N-dimethylformamide (30 mL) was stirred at 50° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (430 mg, 59%) as white crystals.
Reaction SMILES: N1(CC(O)=O)CCNCC1.[CH2:11]([NH:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC.Br[CH2:37]/[CH:38]=[CH:39]/[C:40]([O:42][CH3:43])=[O:41]>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:37][CH:38]1[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: COC(=O)/C=C/CBr
Agent: O=C(O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
The piperazineacetic acid compound of formula (XXIV) employed in the synthesis above and many others in this application was synthesized as follows: Twelve milliliters (50 mmol) of N,N′-dibenzylethylene-diamine, 14 mL (100 mmol) of Et3N and 250 mL toluene were combined at 0° C., and 7 mL (50 mmol) of methyl 4-bromocrotonate (7 mL, 50 mmol) was added. The reaction was slowly warmed to room temperature, stirred for 24 hours, filtered, concentrated in vacuo to a residue and treated with 10% aqueous HCl (300 mL). The mixture was filtered again and the filtrate washed with ethyl acetate (2×100 mL). The filtrate was made basic with K2CO3 and extracted with ethyl acetate (3×150 mL). The combined extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 13.7 g of methyl 1,4-dibenzylpiperazine-2-acetate. 1H NMR (CDCl3) δ 2.28-2.50 (m,4), 2.5-2.75 (m,4), 3.1 (bs, 1), 3.42 (d,2), 3.52 (d,1), 3.6 (s,3), 3.75 (d,1), 7.15-7.35 (m,1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.CN(C)C=O>C(#N)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:29][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Reactant: NC(c1ccncc1)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cccc2c(NC(c3ccncc3)c3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 19, method 19.2. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and C-(4-chlorophenyl)-C-pyridin-4-yl-methylamine. Acetonitrile was used as solvent instead of dimethylformamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:30][O:31][C:32]1[N:33]=[CH:34][C:35]([O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: COc1ccc(Oc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cn1

Procedure:
The title compound was prepared from [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone and 2-Methoxy-5-pyridineboronic acid, following the procedure of Example 519: MS m/z 501.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C@H:23]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([CH3:26])[CH3:25])[C@@H:10]([OH:21])CC(=C)C(NCCCC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40]C(N[C@@H](C[C@H](COCC1C=CC=CC=1)C(C)C)[C@H](O)CC(=C)C(NCCCC)=O)=O)(C)(C)C>>[CH3:36][O:40][C:10](=[O:21])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:22][C@@H:23]([CH2:27][O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:24]([CH3:25])[CH3:26]
Reactant: C=C(C[C@@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Reactant: C=C(C[C@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Product: COC(=O)[C@H](C[C@@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
(2S,3S,5R)-2-[3-(tert-Butoxycarbonyl)amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptyl]-N-(butyl)acrylamide (A) and (2R,3S,5R)-2-[3-(tert-butoxycarbonyl)amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptyl]-N-(butyl)acrylamide (B): In a manner analogous to that described in Example 1g), there is obtained first, by reduction of (2S,4R)-2-(tert-butoxycarbonyl)amino-4-(benzyloxymethyl)-5-methyl-hexanoic acid methyl ester (8.0 g), dissolved in anhydrous toluene (120 ml), with a 1.2M diisobutylaluminium hydride solution in toluene (34.9 ml), (2S,4R)-2-(tert-butoxycarbonyl)amino-4-(benzyloxymethyl)-5-methyl-hexanal in the form of a pale-yellow oil (Rf (N)=0.6). The crude aldehyde is reacted in a manner analogous to that described in Example 1g) without being purified further. The crude product (14.8 g) obtained after aqueous working-up is chromatographed over 1.0 kg of silica gel using an eluant gradient from B to E, with separation of the two (2S,3S,5R)- and (2R,3S,5R)-diastereoisomers. There are obtained title compound A (2.52 g, 24%) in the form of a light-yellow oil, Rf (E)=0.55, HPLC Rt =19.8 min, MS(FAB) m/e 491 (M+ +1), and title compound B (3.76 g, 35%) in the form of a light-yellow oil, Rf (E)=0.42, HPLC Rt =19.6 min. MS(FAB) m/e 491 (M+ +1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=C)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:14]=[O+][O-].CSC>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=Cc1cccc(F)c1C(=O)OC
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1c(F)cccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Into a solution of methyl 2-fluoro-6-vinylbenzoate (31 g, 0.172 mol) in dry dichloromethane (300 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until it turned colorless. Dimethylsulfane (84.13 g, 1.36 mol) was added dropwise to the solution, which was subsequently warmed to RT and stirred for 2 hours. The mixture was then washed with water (30 mL) and extracted with DCM (3×300 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (10-100%) and PE to give the title compound (21 g, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 10.01 (s, 1H), 7.65-7.63 (d, J=7.6 Hz, 1H), 7.56-7.53 (dd, J1=5.2 Hz, J2=8.0 Hz, 1H), 7.35-7.30 (t, J=8.4 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [CH2:1](OC(=O)C)C.Cl.C[N:9]([CH2:17][CH2:18][N:19]([CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1)[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:40]=[CH:39][C:27]2[N:28]([CH3:38])[C:29](=[O:37])[C:30]([CH3:36])([CH3:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]=2[CH:25]=1)C(=O)OC(C)(C)C>C(OCC)(=O)C>[CH3:38][N:28]1[C:29](=[O:37])[C:30]([CH3:35])([CH3:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]2[CH:25]=[C:24]([O:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:18][CH:17]([NH2:9])[CH3:1])[CH2:41][C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)[CH:40]=[CH:39][C:27]1=2
Reactant: CCOC(C)=O
Reactant: CN(CCN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(N)CN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4N-hydrogen chloride ethyl acetate solution (3.2 ml) was added to an ethyl acetate solution (30 ml) of tert-butyl methyl-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)carbamate (1.43 g, 2.5 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and trifluoroacetic acid (3 ml) was added thereto. Stirring was conducted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a dichloromethane-methanol mixture solvent. Polymer-bonded quaternary ammonium carbonate (PL-HcO3MP) was added thereto to neutralize the mixture. The resulting reaction mixture was filtered. The filtrate was concentrated under reduced pressure to thereby obtain 1.44 g (yield: quantitative) of 1,3,3,5-tetramethyl-7-{3-[(2-methyl aminoethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a pale brown oil.
Reaction SMILES: O.C[O:3][C:4]([C:6]1[N:7]([CH3:34])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[N:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=4)[C:18]3=[O:31])[C:12]=2[CH2:32][OH:33])=[CH:9][CH:10]=1)=[O:5].[OH-].[Na+]>O1CCOCC1>[C:27]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:31])[N:17]([C:13]1[C:12]([CH2:32][OH:33])=[C:11]([C:8]3[N:7]([CH3:34])[C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)[CH:16]=[CH:15][CH:14]=1)[N:26]=[CH:25]2)([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(C(=O)O)ccc1-c1cccc(-n2ncc3cc(C(C)(C)C)ccc3c2=O)c1CO
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
Water (5 mL) was added to a solution of 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (150 mg, 0.337 mmol) in dioxane (5 mL). The mixture was stirred for 5 min and NaOH (40 mg) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was extracted with diethyl ether (5 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid (113 mg, yield 78%) as a yellow solid. LC-MS calcd for C25H25N3O4 (m/e) 431.18, obsd 885 [2M+23]+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]([OH:16])(C)[CH3:14].[CH2:17]([O:29][CH2:30][CH:31]1O[CH2:32]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CC.[ClH:34]>O>[ClH:34].[OH:16][CH:13]([CH:17]([O:29][CH2:30][CH2:31][CH2:32][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:14]
Reactant: CC(C)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: Cl
Solvent: O
Product: CCCCCCCCCC(OCCCN[C@@H](CCCNC(=N)N)C(=O)O)C(C)O
Yield: 36 %

Procedure:
L-arginine (17.4 g, 0.1 mols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 24.2 g (0.1 mols) of dodecylglycidyl ether (made by Sakamoto Yakuhin Kogyo Co., Ltd.) were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was determined through TLC and gas chromatography that dodecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60 made by Merck & Co., Inc., eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 15.0 g of N-(2-hydroxy-3-dodecyloxy)propyl-L-arginine hydrochloride (yield 36.0%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:10]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.C1COCC1.CO.Br[CH2:45][C:46]1[N:47]([CH3:71])[C:48]2[C:53]([N:54]=1)=[C:52]([N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)[N:51]=[C:50]([N:61]1[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=3[N:63]=[C:62]1[CH3:70])[N:49]=2>>[CH3:71][N:47]1[C:46]([CH2:45][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([NH2:10])([CH3:8])[CH3:9])[CH2:5][CH2:6]2)=[N:54][C:53]2[C:48]1=[N:49][C:50]([N:61]1[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=3[N:63]=[C:62]1[CH3:70])=[N:51][C:52]=2[N:55]1[CH2:56][CH2:57][O:58][CH2:59][CH2:60]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C1CCNCC1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)N)CC3)n(C)c2n1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
According to General Procedure E, [(9H-fluoren-9-yl)methyl 2-(piperidin-4-yl)propan-2-ylcarbamate (0.0923 g, 0.253 mmol) and N,N-diisopropylethylamine (0.265 mL, 0.00152 mol) were mixed in THF (0.7 mL, 0.008 mol) and Methanol (0.7 mL, 0.02 mol) at room temperature, and 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (0.112 g, 0.253 mmol) was added. The reaction was stirred overnight. The reaction mixture was concentrated to dryness. The crude residue was dissolved in N,N-Dimethylformamide (2.0 mL) and Piperidine (0.200 mL) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated. The crude was purified by reverse phase HPLC to give 383 (45.5 mg, 35.7%). [M+H]+=504.3.