Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[CH:22][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](C(=O)C)=[CH:14][C:13]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=[C:30]([C:35]([O:37]O)=[O:36])C=1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[C:35]([O:37][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:22]=[CH:23][C:24]([CH2:26][CH3:27])=[CH:25][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:21])[CH:14]=1)(=[O:36])[CH3:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(OC(C)=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
To a solution of 1-{4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl}ethanone (3 g, 8.24 mmol) in dry dichloromethane (30 ml), was added PTSA (0.047 g, 0.247 mmol). The reaction mixture was cooled in an ice bath and mCPBA (50% H2O)(2.84 g, 8.24 mmol) was added portionwise. The resulting mixture was stirred at RT for 3 days, then concentrated at 35-40 C. The residue was purified by column chromatography, (pet ether:EtOAC). The resulting solid was dissolved in pet ether, filtered then concentrated the yield the title compound (1.6 g; 51%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]3[S:19][C:20]([S:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=O)[CH:25]=4)=[CH:21][N:22]=3)[CH:11]=2)[CH2:6][CH2:5]1.[NH2:33][CH2:34][C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[OH:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[OH:36][C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:34][NH:33][C:30](=[O:32])[C:26]1[CH:25]=[C:24]([S:23][C:20]2[S:19][C:18]([NH:17][C:12]3[CH:11]=[C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[N:15]=[C:14]([CH3:16])[N:13]=3)=[N:22][CH:21]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Cc1nc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)cc(N2CCN(CCO)CC2)n1
Reactant: NCC(O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc(Nc2ncc(Sc3ccnc(C(=O)NCC(O)(c4ccccc4)c4ccccc4)c3)s2)cc(N2CCN(CCO)CC2)n1
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of 4-(2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazol-5-ylthio)picolinic acid (43.2 mg, 0.0912 mmol) and 2-amino-1,1-diphenylethanol (30.8 mg, 0.144 mmol, described in Synthesis of amines, Example D) in NMP (3 mL) was added HOBT (12.3 mg, 0.0910 mmol), EDAC (27.4 mg, 0.143 mmol) and diisopropylethylamine (0.05 mL, 0.281 mmol). The reaction was stiffed at 23° C. overnight and was purified on Prep HPLC (water/acetonitrile/ammonium acetate) to give the title material (26.7 mgs, 44%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.51 (1H, s), 8.35-8.42 (2H, m), 7.75 (s, 1H), 7.62 (1H, d, J=1.26 Hz), 7.43 (5H, d, J=7.07 Hz), 7.34 (1H, dd, J=5.31, 2.02 Hz), 7.27 (5H, t, J=7.71 Hz), 7.16 2H, t, J=7.33 Hz), 6.30 (1H, s), 6.03 (1H, s), 4.45 (1H, t, J=5.18 Hz), 4.09 (2H, d, J=5.56 Hz), 3.50 (7H, s), 2.41 (3H, t, J=6.32 Hz), 2.33 (3H, s). LC/MS (M+H)+: 669. HPLC ret. time (Condition E): 1.84 min. HRMS calcd: 669.2430; found: 669.2434.
Reaction SMILES: [C:1]12([C:8]3[C:13](Cl)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:24][N:25]1[C:29]([CH2:30][OH:31])=[N:28][CH:27]=[N:26]1.[H-].[Na+].O>CN(C)C=O>[C:1]12([C:8]3[C:13]([O:31][CH2:30][C:29]4[N:25]([CH3:24])[N:26]=[CH:27][N:28]=4)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: Cn1ncnc1CO
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (0.125 g, 0.39 mM) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.08 g, 0.47 mM; prepared using the conditions described in EP-A-421210) in N,N-dimethylformamide (20 ml) was added sodium hydride (0.015 g of a 60% dispersion in oil, 0.47 mM eq) and the reaction mixture was stirred at room temperature for 3 hours. Water was added until the solution became cloudy and after stirring for a further 15 minutes a solid was collected by filtration. This solid was recrystallised from ethyl acetate-dichloromethane to give the required product (0.048 g, m.p.=244-246° C.). 1H NMR (360 MHz, DMSO) δ1.39 (2H, m), 1.67-1.84 (8H, m), 2.30 (1H, m), 3.93 (3H, s), 5.70 (2H, s), 7.52-7.62 (3H, m), 8.00 (1H, s), 8.35 (1H, s), 8.38 (2H, m); (Regiochemistry was established using nOe data). MS (ES+) m/e 402 [MH]+. Anal. Found C, 65.71; H, 5.65; N, 24.07. C22H23N7O requires C, 65.82; H, 5.77; N, 24.42%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.BrC1C=CC([C@H]2C[C@@H]2C[OH:24])=CC=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][CH2:12][OH:24])=[CH:4][CH:3]=1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCC[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The alkene intermediate from Example 29F (1.64 g, 7.35 mmol) was converted to the alcohol by the method of Example 26F, followed by chromatography (7.3 hexane/ethyl acetate) provided the title compound. 1H NMR (300 MHz, CDCl3): δ 0.96-0.79 (m, 2H), 1.00-1.14 (m, 1H), 1.54-1.76 (m, 3H), 4.91-4.97 (m, 1H), 3.76 (t, J=6 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 7.35 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 258 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][C:5]([Cl:12])=[CH:4][N:3]=1.[C:13](OC(=O)C)(=O)[CH3:14]>>[Cl:12][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:13]([CH3:14])=[N:11][S:8](=[O:9])(=[O:10])[C:7]=2[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(Cl)cc1S(N)(=O)=O
Product: CC1=NS(=O)(=O)c2cc(Cl)cnc2N1

Procedure:
A mixture of 1 g of 2-amino-5-chloropyridine-3- sulfonamide (Preparation 20) and 10 cm3 of acetic anhydride is brought to reflux for 6 hours. After cooling, the crystals are filtered off, washed with a small amount of acetic anhydride and then with diethyl ether and dried. The crystals are redissolved in 50 cm3 of 0.1N NaOH. The possible insoluble material is removed by filtration. The filtrate, adjusted to a pH of 4 using formic acid, allows crystals to precipitate. They are collected on a filter, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:19][CH:18]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:33])[C:7]=2[CH:34]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:22]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:33])[C:7]=2[CH:34]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(CC(C)C)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl]amino}propanoate (266 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (216 mg, 86%) as a white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4].[OH2:25]>N1C=CC=CC=1.C(O)(=O)C>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][C:15]([O:14][CH2:13][CH3:6])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCCCNc1cc(CNC(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine (1.05 g; prepared as described in Example 289) in pyridine (7 ml) ethyl chloroformate (0.3 ml) is dropwise added at 22°-25° C., and the mixture is stirred for a further 1.5 hours. The mixture is then diluted with water (30 ml) and acetic acid (10 ml) to precipitate crude N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)urethan. After filtration and recrystallization from ethanol it is obtained with a melting point of 105°-107° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CC(C)=O>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Br:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
A solution of 2-bromo-4-chlorophenol (Aldrich; 13.11 g; 63.2 mmol) in acetone (100 mL) was treated with potassium carbonate (9.61 g; 69.5 mmol), stirred for 10 minutes then treated with tert-butyl bromoacetate (Aldrich; 9.34 mL; 63.2 mmol). The reaction mixture was stirred at 65° C. for 18 hours, then the mixture was filtered, the solid was washed with acetone and the filtrate was concentrated to dryness under vacuum to give the title compound as a yellow sticky solid (19.4 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]([O:15]C)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CO>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Yield: 97.5 %

Procedure:
A 29.4 g (0.10 mole) quantity of methyl 3-methylflavone-8-carboxylate was added to 200 ml of a solution of 0.5N--KOH in methanol. The mixture was refluxed with heating for 3 hours and the solvent was removed by distillation. To the residue was added 300 ml of water to dissolve the residue in water and the solution was subjected to filtration. The filtrate was neutralized with dilute hydrochloric acid to give 27.3 g (97.5%) of 3-methylflavone-8-carboxylic acid, M.P. 229° to 231.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:54][CH2:55][C:56]([CH3:59])([OH:58])[CH3:57]>CN(C)C=O.O>[OH:58][C:56]([CH3:59])([CH3:57])[CH2:55][NH:54][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CC(C)(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NCC(C)(C)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min. A solution of 1-amino-2-methylpropan-2-ol (77 mg) in N,N-dimethylformamide (1 mL) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (150 mg, 65%) as colorless prisms. MS 533 (Me). mp 200-201° C.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[NH:5][C:4]1=[O:20].O1CCCC1.C([Li])CCC.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>O>[CH3:31][N:32]([CH2:33][CH2:34][N:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH2:8][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]([O:2][CH3:1])[C:4]1=[O:20])[CH3:36]
Reactant: CN(C)CCCl
Reactant: CON1C(=O)Nc2ccccc2CC1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CON1C(=O)N(CCN(C)C)c2ccccc2CC1c1ccccc1
Temperature: 25 °C
Yield: 162 %

Procedure:
To a stirred, chilled (-78° C.) solution of (±) -3-methoxy-4-phenyl-1,3,4,5-tetrahydro-2H-1,3-benzodiazepine-2-one (5.0 g, 0.019 mol) of Example 1c and tetrahydrofuran (200 ml) was added n-butyllithium (9.1 ml of a 2.5 M solution in hexanes, 0.023 mol) (nitrogen atmosphere). The solution was stirred and cooled for 50 minutes, then 2-dimethylaminoethylchloride (10.22 .g, 0.095 mol) was added and the solution was allowed to warm to room temperature. The mixture was stirred and heated to 45° C. for 48 hours, with additional 2-dimethylaminoethylchloride added as follows: 16.5 hours, 14.0 g, 0.13 mol; 24 hours, 14.0 g, 0.13 mol. The mixture was then heated to reflux for 2 hours, allowed to cool, and water (400 ml) was added to quench the reaction. The tetrahydrofuran was removed in vacuo and the resulting oily aqueous phase was extracted twice with 250 ml portions of dichloromethane. The combined organic phase was washed twice with water (300 ml portions), once with saturated sodium chloride (200 ml), and was dried (Na2SO4), filtered, and concentrated to give a solid (10.45 g). The solid was purified by preparative HPLC (Waters Associates Prep LC/System 500, silica gel sample loaded in dichloromethane, eluted with 3:1 ethyl acetate:methanol). The appropriate fractions were combined, evaporated, dissolved in dichloromethane, filtered to remove all insoluble material, and concentrated to yield 1.70 g of a solid (26%). The products of several similar reactions were combined and repurified by preparative HPLC, as above, to yield 2.95 g of a solid, which was recrystallized from dichloromethane/ether to afford 2.39 g (26%) of (±) -1-[2-(N,N-dimethylamino)ethyl]-3-methoxy-4-phenyl-1,3,4,5-tetrahydro-2H-1,3-benzodiazepine-2-one,m.p.127°-128° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:16][CH:17]=[CH:18][C:5]=3[C:4](=[O:19])[N:3]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][NH2:29])[CH:8]=[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2.[C:30]1([C:47](O)=[O:48])[C:43]2[C:34](=[CH:35][C:36]3[C:41]([C:42]=2[C:44](O)=[O:45])=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:16][CH:17]=[CH:18][C:5]=3[C:4](=[O:19])[N:3]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][N:29]1[C:47](=[O:48])[C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:43]=3[C:42](=[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]3=[CH:35]4)[C:44]1=[O:45])[CH:8]=[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2
Reactant: NCCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Reactant: O=C(O)c1cccc2cc3ccccc3c(C(=O)O)c12
Solvent: Cc1ccccc1
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A mixture of 1.0 g (2,5 mmol) of N-[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-N'-(2-aminoethyl)-1,3-propanediamine in 50 ml of toluene was treated with 0.62 g (2,5 mmol) of anthracene-1,9-dicarboxylic acid anhyride in 10 ml of toluene, refluxed for 6 hours, and cooled to room temperature. The solid was collected, dried in vacuo, and crystallized from toluene to give 0.8 g 48% of N,N'-Bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine. M.p. 191° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]=O)=[C:6]2Cl)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]3[CH:14]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:6]2=3)[CH2:2][CH2:3]1
Reactant: COC(=O)CS
Reactant: O=Cc1c(Cl)n(CC2CC2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3ccccc3n(CC3CC3)c2s1

Procedure:
Prepared from (4) (6.5 g), K2CO3 (10 g) and methyl 2-mercaptoacetate (3.2 ml) yielding (7) (6 g), m.p. 110°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([SH:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:24][CH2:22][CH3:23])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCS
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(SCC)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Step2) (0.5 g, 1.54 mmole) and ethanethiol (0.1 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The solution was maintained at 90° C. for 48 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 10-40% ethyl acetate in hexane to give light yellow solid (0.24 g, 43%): GCMS 366.00 (M+). 1H NMR (CDCl3/400 MHz) 7.60 (s, 1H), 7.27 (s, 1H), 6.77 (s, 1H), 5.67 (q, 1H, J=7.0 Hz), 4.29 (m, 2H), 2.96 (m, 2H), 1.40 (m, 3H), 1.35 (m, 3H).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:27])[C:9]([O:11][CH:12]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10]>>[CH3:2][N:1]([C:17]([O:16][CH:12]([O:11][C:9](=[O:10])[CH:8]([CH3:27])[CH3:7])[CH:13]([CH3:15])[CH3:14])=[O:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: CNCC(=O)O
Product: CC(C)C(=O)OC(OC(=O)N(C)CC(=O)O)C(C)C
Yield: 55.8 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.108 g, 1.19 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanoate (0.3 g, 0.99 mmol) were reacted to provide 0.152 g (55% yield) of the title compound (37) as a colorless liquid after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=6.57 (dd, 1H), 4.19 (m, 2H), 3.03 (2s, 3H), 2.6 (m, 1H), 2.01 (br m, 1H), 1.18 (m, 6H), 1.0-0.98 (2m, 6H). MS (ESI) m/z 298.14 (M+Na)+, 274.13 (M−H)−.
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11](C)[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC([N+]([O-])=O)=C[C:36]=1[O:44]C>>[NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11]([O:44][CH3:36])[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Product: COc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Yield: 25 %

Procedure:
The experimental protocol used is the same as that described for the compound of Example 6, 2-chloro-5-nitroanisole replacing 2-fluoro-5-nitrotoluene. A pale yellow solid product is obtained (yield 25%). Melting point: 185.6-186.3° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([NH:40][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([N:3]2[C:2](=[O:1])[C:6]3[N:7]=[N:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]=3[NH:4]2)=[CH:23][CH:22]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)benzoic acid (52 mg, 0.17 mmol) was mixed with DMF (2 ml). Diisopropylethylamine (22 mg, 29 μl, 0.17 mmol) and benzylamine (18.2 mg, 18.6 μl, 0.17 mmol) were added followed by HBTU (64.5 mg, 0.17 mmol). The mixture was stirred at room temperature for 4 h. The product was purified by preparative HPLC. The title compound was isolated as a red solid (6.6 mg, 0.02 mmol, 10%). LCMS: m/z 396 [M+H]+.