Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20].S(=O)(=O)(O)O.[CH3:33]O>>[CH3:33][O:26][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][NH:21][C:19]([C:3]1[N:4]=[CH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:7]=2)=[O:20]
Reactant: O=C(O)CCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C

Procedure:
To a solution of 4-[(4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-butyric acid (1.32 g, 3.6 mmol) in MeOH (7.2 mL) was added 10% sulfuric acid. The reaction mixture was stirred at reflux for 20 hours. After cooled to rt, the solvent was concentrated in vacuo as a oil and purified by silica gel chromatography over silica gel, eluting with 15-75% EtOAc/hexanes to give product (900 mg) as a colorless oil: MS (m/z) 381.0 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[B:15]([OH:22])[O:16][CH:17]([CH2:18][N+:19]([O-:21])=[O:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C.[OH-].[Na+]>CO.O>[OH:22][B:15]1[C:14]2[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=[CH:12][C:13]=2[CH:17]([CH2:18][N+:19]([O-:21])=[O:20])[O:16]1
Reactant: CCOC(=O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester (2.51 g, 7.78 mmol), 10% NaOH (17 mL), and 1:1 MeOH/H2O (70 mL) was stirred at rt for 5 h. The MeOH was removed in vacuo and the remaining aqueous layer was acidified to pH 1 using 2 M HCl. The aqueous layer was then extracted with EtOAc. The organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound as a pale yellow foam: yield 1.85 g (81%).
Reaction SMILES: [Br-].[CH2:2]([O:9]CCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1C=CC=C[CH:4]=1.[H-].[Na+].[CH2:34]1[CH2:44][C:42](=O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1.O>O1CCCC1>[OH:9][CH2:2][CH2:3][CH2:4][CH:42]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:44]1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCCc2ccccc21
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-Benzyloxypropyl)triphenylphosphoniumbromide (1.00 g) was dissolved in tetrahydrofuran (10 ml), sodium hydride (162 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. α-Tetralone (1.36 ml) was added to the reaction mixture, and the mixture was stirred at 75° C. for 48 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in ethyl acetate (10 ml) was added 10% palladium carbon (200 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to give the object product (140 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[C:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>[Pd].CN(C)C=O>[CH2:1]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCCCCCCCNC(=O)c1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
150 mg (0.35 mmol) of N-octyl-4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-carboxamide, 20 ml of dimethylformamide and 150 mg of palladium-on-charcoal (10%) are introduced into a reactor under a stream of nitrogen. The medium is heated at 80° C. and hydrogenated under a pressure of 3 atm for 5 hours. The reaction medium is filtered through Celite. The filtrate is placed in water, extracted with ethyl acetate and washed thoroughly with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on a column of silica, eluted with a mixture of heptane and ethyl acetate (30/70). 100 mg (65%) of the expected product, with a melting point of 137-138° C., are obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][NH:23][CH3:24]>>[OH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][N:23]([CH3:24])[S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CNCC(O)c1ccccc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C)CC(O)c3ccccc3)s2)c(C)[nH]c1=O
Yield: 58 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (2-hydroxy-2-phenylethyl)methylamine as described in Step 5, Example 24 to give the title compound as a solid (58% yield). LC/MS: RT 2.93 min; m/e 433 (M+H); 1H NMR (δ, ppm): 11.81 (1H, s), 7.59 (1H, d), 7.34 (6H, m); 7.19 (1H, d), 5.61 (1H, d), 4.78 (1H, q), 3.12 (2H), 2.78 (3H, s), 2.38 (2H), 2.31 (3H, s), 1.09 (3H, t).
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][NH2:20]>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][N:20]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Reactant: NCc1ccc(F)c(F)c1
Product: Fc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1F

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 3,4-difluorobenzylamine (0.5 ml) as described above; yield: 0.049 g (15.8%); MS m/z: 312.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 5.36 (s, 2H); 6.81-6.84 (m, 1H); 7.13-7.19 (m, 1H); 7.29-7.36 (m, 1H); 7.59 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.82 (d, 1H, 3J=8.7 Hz); 7.88 (d, 1H, 4J=1.7 Hz); 8.77 (s, 1H); 9.03 (s, 1H); HPLC (METHOD [A]): it 8.82 min (95.6%)
Reaction SMILES: [CH2:1]1[C:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[O:19]1[C@@:10]23[C@H:5]([CH2:4][CH2:3][O:2][CH2:1]2)[CH2:6][CH2:7][CH2:8][CH:9]13
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=C2COCCC2CCC1
Solvent: ClCCl
Product: C1CC2O[C@@]23COCC[C@@H]3C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3,4,4a,5,6,7-hexahydro-1H-isochromene (0.410 g, 2.97 mmol) in CH2Cl2 (10 mL) at 0° C. was added MCPBA (˜77%, 1.24 g, 445 mmol). The mixture was stirred at rt for 3 hr. It was quenched with sat'd aq. sodium sulfite. The mixture was diluted with CH2Cl2 and sat'd. aq. NaHCO3 then extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 4.03-4.10 (m, 1H), 3.86 (d, 1H, J=12.0 Hz), 3.54-3.62 (m, 1H), 3.34 (d, 1H, J=12.0 Hz), 3.03 (d, 1H, J=4.4 Hz), 1.70-1.98 (m, 3H), 1.52-1.65 (m, 3H), 1.17-1.34 (m, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16]/[CH:17]=[CH:18]/[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[C:31]([Cl:32])=[C:30]([Cl:33])[CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[O:14])=[CH:11][CH:12]=2)[CH:6]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[Cl:32][C:31]1[C:30]([Cl:33])=[CH:29][CH:28]=[CH:27][C:26]=1[N:23]1[CH2:24][CH2:25][N+:20]([O-:42])([CH2:19]/[CH:18]=[CH:17]/[CH2:16][NH:15][C:13](=[O:14])[C:10]2[CH:11]=[CH:12][C:7]([C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=3)=[CH:8][CH:9]=2)[CH2:21][CH2:22]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC/C=C/CN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(-c2ccccn2)cc1
Solvent: ClCCl
Product: O=C(NC/C=C/C[N+]1([O-])CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of PG01037, see U.S. 2006/0106030 (288 mg, 0.60 mmol) in 10 mL dichloromethane was treated at 0° C. with meta-chloroperbenzoic acid (0.16 g, 77%, 0.72 mmol). After stirring for 16 h at room temperature, the reaction mixture was successively washed with saturated sodium bicarbonate solution, H2O and brine and dried with sodium sulphate. The volatiles were removed in vacuo and the residue was purified by preparative thin layer chromatography. Yield: 93 mg (32%). Mp. (hydrochloride): foam. 1H NMR (CD3OD): δ 3.23-3.29 (m, 4H), 3.50-3.61 (m, 4H), 3.99 (d, J 6.5, 1H), 4.13 (d, J 4.6, 1H), 6.04-6.18 (m, 2H), 7.18 (dd, J 7.8, 3.9, 1H), 7.24-7.28 (m, 2H), 7.40 (m, 1H), 7.91-7.93 (m, 2H), 7.99 (d, J 8.4, 2H), 8.06 (d, J 8.7, 2H), 8.64 (dt, J 4.8, 1.2, 1H). 13C NMR (CDCl3): δ 41.0, 45.5, 63.5, 72.0, 119.3, 120.0, 121.6, 123.1, 125.4, 127.0, 127.3, 127.7, 128.0, 133.8, 134.6, 137.8, 137.9, 142.2, 149.3, 150.1, 156.4, 168.3. Anal. (C26H26Cl2N4O2:2HCl.0.5H2O) C, H, N.
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>>[O:28]=[C:19]1[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:23])[N:18]1[O:17][C:8](=[S:9])[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C(Cl)N(C1CCCCC1)C1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1c2ccccc2C(=O)N1OC(=S)N(C1CCCCC1)C1CCCCC1

Procedure:
This compound was prepared in analogy to example 8 starting from 24.94 g (0.096 mol) of dicyclohexyl-thiocarbamoyl chloride (prepared as described in (Chem. Ber., 101, (1968), 113) and N-hydroxyphthalimide. Yield 9.65 g of white crystals after recrystallization from hexane, mp. 148-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:14]=3[N:15]=2)=[C:5]([O:29]COC)[CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:14]=3[N:15]=2)=[C:5]([OH:29])[CH:4]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of 7 (100 mg, 0.23 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1 mmol) in methanol (20 mL) was stirred overnight at room temperature. After the solvent was evaporated, ethyl acetate (20 mL) was added to the resulting residue which was neutralized by Na2CO3, washed with brine and water, dried over MgSO4, and concentrated in vacuo to give a pale yellow solid that was purified by silica gel column chromatography (ethyl acetate) and crystallized from ethanol to afford a white solid of Zinbo-5 (80 mg, 89%): 1H-NMR (500 MHz, CDCl3) δ3.95 (s, 3H), 3.96 (s, 3H), 4.01 (s, 2H), 4.21 (s, 2H), 6.66 (s, 1H), 7.17 (dd, 1H, J=7.5, 5.0 Hz), 7.31 (t, 1H, J=8.0 Hz), 7.37–7.40 (m, 2H), 7.41 (s, 1H), 7.48 (d, 1H, J=8.0 Hz),7.67 (t, 1H, J=7.5 Hz), 8.66 (d, 2H, J=5.0 Hz), 11.27 (s, 1H); Anal. Calcd for C22H21N3O4: C, 67.51; H, 5.41; N, 10.74. Found: C, 67.12; H, 5.25; N, 10.57.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1
Reactant: NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCN1CCN(c2csc3cc(F)ccc23)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 64.8 %

Procedure:
To a 0° C. solution of 4-(6-fluorobenzo[b]thien-3-yl)-1-piperazine-butanamine (2.45 g, 7.97 mmol), triethylamine (1.23 g, 12.2 mmol), and dichloromethane (30 mL) under a nitrogen atmosphere was added 4-fluorobenzoyl chloride (1.61 g, 10.2 mmol) in one portion. The reaction was stirred at 0° C. for 70 minutes and then at room temperature for 3 hours. The reaction was diluted with dichloromethane (50 mL) and the mixture was washed successively with 5% aqueous NaOH (50 mL) and water (50 mL), dried (Na2SO4), and concentrated in vacuo to a tan solid. The crude product was chromatographed on silica gel with 10% ethanol/dichloromethane as eluent to afford an 2.22 g of an off-white solid. Recrystallization from ethyl acetate/heptane gave 1.60 g (46%) of the title compound as beige needles, m.p. 161°-163° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][N:9]1[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([Cl:1])[C:3]=2[CH:11]=[CH:10]1)[CH3:19]
Reactant: Cc1nc(Cl)c2cc[nH]c2n1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1ccc2c(Cl)nc(C)nc21
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
0.5 g (3 mmol) of 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to West and Beauchamp, J. Org. Chem. 26 (1961) 3809) was dissolved in 3 ml DMF and 2.06 g (15 mmol) of potassium carbonate was added to this solution. 0.431 ml (3 mmol) of 4-bromobutyric acid ethyl ester was added and the mixture was stirred at 50° C. for 45 minutes. The reaction mixture was diluted with 50 ml EE and washed three times with water, dried over MgSO4, filtered and the solvent was removed in vacuo. Yield: 0.8 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[S:8][N:7]=1.Cl.CCCCCC>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[S:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccs3)ns2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1csc(-c2nsc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxylate (4.30 g, 12.2 mmol) in ethyl acetate (70 ml) was added a solution of 4 N hydrochloric acid in ethyl acetate (35 ml), and the mixture was stirred at room temperature for 18 hours and half. Hexane (150 ml) was poured to the reaction mixture, and a solid was separated by filtration. The obtained solid was dissolved in an aqueous saturated sodium hydrogen carbonate solution, followed by stirring at room temperature for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with a mixed solution of ethyl acetate/tetrahydrofuran (1:1). The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 2.31 g (75.0%) of the desired product as a solid was separated by filtration.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:35][CH2:36][N:37]([CH2:40][CH2:41][OH:42])[CH2:38][CH2:39]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO)CC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(1-(2-hydroxyethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate (0.085 g) in ethyl acetate (1.0 mL) and methanol (1.0 mL), 10% palladium-carbon (0.040 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (0.040 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 4 hours. The insoluble substance was removed from the reaction mixture by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.035 g of methyl 2-(2-hydroxy-5-(1-(2-hydroxyethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH3:12]>CO>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[NH:12])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: N=Cc1ccccc1[N+](=O)[O-]
Yield: 75.3 %

Procedure:
To a solution of 15.1 g (0.1 mole) of 2-nitrobenzaldehyde and 40 ml of methanol a methanolic solution of 1.7 g (0.1 mole) of ammonia is added dropwise under stirring. The reaction mixture is stirred at room temperature for 20 hours, then cooled, the precipitated product is filtered, washed with methanol and dried. Thus 11.3 g of trimeric 2-nitro-benzaldehyde-imine are obtained, yield 75.3%, m. p.: 117°-119° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][OH:17])[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[C:9]1[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17]1
Reactant: Cc1c(Br)cccc1C#Cc1ccccc1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1C=C1OCc2ccccc21
Yield: 72 %

Procedure:
Step 2 A solution of (2-((3-bromo-2-methylphenyl)ethynyl)phenyl)-methanol (50 mg, 0.166 mmol) and tetrabutylammonium fluoride, 1.0 M in THF (0.332 mL, 0.332 mmol) in THF (0.5 mL) was heated at 67° C. for 2 h. The mixture was diluted with EtOAc, washed twice with water and once with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 80:20 EtOAc-hexane) to provide 1-(3-bromo-2-methylbenzylidene)-1,3-dihydroisobenzofuran as a light yellow solid (36 mg, 72%). 1H NMR (400 MHz, chloroform-d) δ 8.00-8.06 (1H, m), 7.58-7.64 (1H, m), 7.32-7.41 (4H, m), 7.04 (1H, t, J=7.92 Hz), 6.07 (1H, s), 5.49 (2H, s), 2.51 (3H, s). Mass spectrum m/z 301, 303 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
3,5-dibromotoluene (78.92 g, 0.316 mole) was dissolved in 1.27 L of carbon tetrachloride; to this solution was added N-bromosuccinimide (61.65 g, 0.346 mole) at room temperature. A portion of dibenzoyl peroxide (0.6 g, 0.008 equivalents) was added and the solution heated to reflux temperature for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo to yield a solid. The solid was dissolved in 200 mL of warm hexane, filtered and cooled to room temperature. Crystallizations ensued; the crystals were filtered off and washed with cold hexane and air dried to give 45.15 g (44%) of 3,5-dibromobenzyl bromide. 1H-NMR(CDCl3); δ 7.6 (1H), 7.47 (2H), 4.36 (2H).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH:13][C:22](=[O:24])[CH3:23])=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CCN)c1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CCNC(C)=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 69.2 %

Procedure:
To a mixture of N-(4-bromophenyl)-N-ethylethane-1,2-diamine dihydrochloride (1.044 g, corresponding to 2.33 mmol), pyridine (4 ml) and anhydrous dichloromethane (8 ml) was added dropwise acetic anhydride (0.28 ml, 2.92 mmol) at 0° C. After stirring at room temperature for 70 mins, the reaction mixture was diluted with dichloromethane (50 ml), washed twice with diluted aqueous sodium hydrogen carbonate solution and with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→1:0) to give N-{2-[(4-bromophenyl)(ethyl)amino]ethyl}acetamide (460 mg, overall yield of 2 steps 92%) as a white solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[Li]CCCC.[CH3:12][O:13][CH2:14][CH2:15]Br>C1COCC1>[CH3:12][O:13][CH2:14][CH2:15][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: COCCBr
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCC1SCCCS1
Temperature: -78 °C
Yield: 96 %

Procedure:
A solution of 1,3-dithiane (15.12 g, 126.0 mmol) in dry THF (150 mL) was treated at 0° C. with BuLi (53.0 mL of a 2.5 M solution, 132.5 mmol, 1.05 eqiuv) for 1.5 h. The reaction mixture was cooled to −78° C., and 2-bromoethyl methyl ether was added (11.3 mL, 16.7 g, 120.2 mmol). The reaction mixture was allowed to warm overnight to room temperature. The reaction was quenched by addition of saturated aqueous NH Cl. The mixture was extracted with Et2O. The combined organic extracts were washed with water. The mixture was dried over Na2SO4. The mixture was filtered. The filtrate was concentrated at reduced pressure. The residue was chromatographed [silica, ethyl acetate/hexanes (1:19)] affording a viscous, colorless liquid (21.53 g, 96%): 1H NMR δ 1.84-1.93 (m, 1H), 1.96-2.03 (m, 2H), 2.07-2.15 (m, 1H), 2.78-2.93 (m, 4H), 3.34 (s, 3H), 3.51-3.55 (m, 4H), 4.19 (t, J=6.9 Hz, 1H); 13C NMR δ 26.16, 30.40, 35.58, 44.16, 58.84, 68.92; EI-MS: 178 (M+), 146, 133, 119/121, 71/73, 45.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][NH2:18])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:24])=O>C(O)(=O)C>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][N:18]=[C:22]([CH3:24])[CH3:21])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Reactant: CC(C)=O
Solvent: CC(=O)O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A solution of 0.5 g of 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 15 cc of absolute acetone, to which 4 drops of glacial acetic acid have been added, is heated on a water bath for 1 hour. The solution is concentrated in a vacuum, and the crude title compound, obtained as an oil, is crystallized with ether. The title compound has a M.P. of 188°-190° (decomp.).