Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C2CCCC(=[O:10])C=2C=C1.[Li]C1C=CC=CC=1.C1([C:24]2[CH:35]=[C:34]3[CH:26]([CH2:27][CH2:28][C:29]4[S:30][CH:31]=[CH:32][C:33]=43)[CH:25]=2)C=CC=CC=1.C1(C2CC3C4C=CSC=4CCC=3C=2)C=CC=CC=1>CCOCC>[CH:32]1[C:33]2[C:34]3[CH:26]([CH2:25][C:24](=[O:10])[CH:35]=3)[CH2:27][CH2:28][C:29]=2[S:30][CH:31]=1
Reactant: C1=C(c2ccccc2)C=C2c3ccsc3CCC12
Reactant: O=C1CCCc2sccc21
Agent: C1=C(c2ccccc2)CC2=C1CCc1sccc12
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: O=C1C=C2c3ccsc3CCC2C1
Yield: 30 %

Procedure:
6,7-dihydro-1-benzothiophen-4(5H)-one was obtained with an overall yield of 43% via the acylation of thiophene by succinic anhydride followed by reduction of the ketone formed and by the cyclisation of 4-(2-thienyl)butanoic acid in the presence of the laton's reagent. Next, 4,5,5a,6-tetrahydro-7H-indeno[5,4-b]thiophen-7-one was synthesised from 6,7-dihydro-1-benzothiophen-4(5H)-one with an overall yield of 30%. The latter product was further reacted with one equivalent of PhLi in ether followed by acidification of the reaction medium to give a mixture of 7-phenyl-5,5a-dihydro-4H-indeno[5,4-b]thiophene and 7-phenyl-5,8-dihydro-4H-indeno[5,4-b]thiophene as shown in the scheme below
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([OH:22])=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1C=CC=CC=1>[CH3:24][S:25]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([O:22][S:25]([CH3:24])(=[O:27])=[O:26])=[C:8]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(-c2oc3cc(N)ccc3c(=O)c2O)cc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(-c2oc3cc(NS(C)(=O)=O)ccc3c(=O)c2OS(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
2.5 g of methyl 7-amino-3-hydroxy-4'-flavonecarboxylate are put in suspension in 25 cc of anhydrous benzene. The mixture is cooled to 0° C., and 10 cc of methanesulfonic acid chloride are added drop by drop. The mixture is stirred at ambient temperature until the reaction is complete. The reaction is checked by thin-layer chromatography (benzene (90)-dioxane (25)-acetic acid (4) elution solvent). The mixture is poured into 300 cc of ice water. The precipitate is filtered, washed with water and dried. The resulting product is purified by open silica column chromatography. MP=250° C. NMR in DMSO(D6): δ=3.3 ppm, 3H, singlet, CH3 methanesulfonamido; δ=3.6 ppm, 3H, singlet, CH3L methanesulfonyloxy; δ=3.9 ppm, 3H singlet, CH3 methyl ester; δ=7.1-8.4 ppm, 7H, complex multiplet, aromatic protons; δ=10.7 ppm, 1H, dome, NH; (interchangeable with D2O).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C([NH:11][C:12]1[CH:21]=[CH:20][C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][CH:13]=1)(=O)C.Cl.C([O-])(O)=O.[Na+]>CO.O>[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([S:16]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])(=[O:18])=[O:17])=[CH:14][CH:13]=1
Reactant: NCCOCCO
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(S(=O)(=O)NCCOCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H) 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methyl iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCl solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8ethoxymethylene-6,8-dihydro-I-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (brt, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H,4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25](O)=[O:26].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl.C(=O)([O-])O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:25]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][N:19]=2)=[O:26])=[N:2]1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1cnccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.2 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (60 mg, 0.26 mmol) was dissolved in THF (5 mL) and the solution was added with 2-pyrazinecarboxylic acid (38 mg, 0.31 mmol), 1-hydroxybenzotriazole monohydrate (51 mg, 0.33 mmol), 4-methylmorpholine (47 μL, 0.51 mmol) and EDC (68 mg, 0.36 mmol), followed by stirring at room temperature for 3 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 28 (25 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:1]([C:2]1[S:3][C:4]([C:10]2[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=2[F:16])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccccc3)s2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.480 mmol) and iodobenzene (98 mg, 0.480 mmol), Pd2(dba)3 (44 mg, 0.048 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (114 mg, 0.240 mmol), and potassium carbonate (73 mg, 0.528 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (1.6 mL) was added to the mixture via syringe. The solution was sealed and stirred overnight in an oil bath at 100° C. The following day, the reaction was allowed to cool to room temperature, taken up in ethyl acetate, and washed with aqueous sodium bicarbonate and brine. The organic layers were collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was conducted via silica gel chromatography (0-3% methanol in ethyl acetate). Fractions containing product were concentrated under reduced pressure, taken up in ethyl acetate and methanol, and recrystallized out using hexanes to yield the title product.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)([F:4])[CH3:3]>CC(O)=O.CCOC(C)=O.[Zn]>[F:1][C:2]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(F)(F)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1,1-difluoroethyl)-3-nitrobenzene (2.75 g, 14.7 mmol) in AcOH (30 mL) was added zinc (10.0 g, 153 mmol). The reaction mixture was allowed to stir at rt overnight. The mixture was diluted with EtOAc (40 mL) and filtered through Celite. The filtrate was concentrated. The residue was diluted with DCM (20 mL), washed with saturated NaHCO3 (20 mL) and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-(1,1-difluoroethyl)benzenamine as light brown oil. 1H NMR (300 MHz, DMSO) δ 7.21 (dd, 1H), 6.89 (s, 1H), 6.80 (d, 1H), 6.79 (d, 1H), 186 (t, 3H); LCMS: ES+ 158.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]#N)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:14]([NH2:17])(=[S:16])C.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([CH2:12][C:14](=[S:16])[NH2:17])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: CC(N)=S
Reactant: Cc1cnc2c(c1)CCCC2C#N
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)CCCC2CC(N)=S
Yield: 59.8 %

Procedure:
3-Methyl-8-cyano-5,6,7,8-tetrahydroquinoline (1.7 g., 0.01 m.) and thioacetamide (1.5 g., 0.02 m.) were dissolved in dimethylformamide (50 ml.), and the solution saturated with dry hydrogen chloride gas and then heated on a steam bath for 4 hours. The cooled reaction mixture was poured onto water (200 ml.), washed with ethyl acetate (2 × ml) and the extracts discarded. The aqueous solution was adjusted to pH 10.0 with 46% sodium hydroxide and extracted into methylene chloride (2 × 200 ml.). The combined extracts were dried (sodium sulphate), evaporated i vacuo and the residual oil triturated with isopropanol and filtered. Recrystallization from benzene gave the title compound as pale yellow needles (1.3 g., 63%) m.p. 149°.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].C[O:14][C:15]([C:17]1[CH2:18][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21][CH:22]=1)=O>ClCCl>[C:26]([O:25][C:23]([N:19]1[CH2:18][C:17]([C:15](=[O:14])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[Br:5])=[CH:22][CH2:21][CH2:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1ccccc1Br
Reactant: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC=C(C(=O)Nc2ccccc2Br)C1
Temperature: 0 °C
Yield: 63.3 %

Procedure:
Trimethylaluminium (2M in heptane, 3 ml) was added dropwise to a solution of 2-bromoaniline (860 mg) in dichloromethane (15 ml). After gas evolution ceased, 5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Chem. Commun. 1999, 1757-1758, 1.2 g) dissolved in dichloromethane (10 ml) was added and the resulting mixture was refluxed for 5 hrs. The solution was cooled to 0° C., quenched by careful addition of saturated aqueous sodium bicarbonate (10 ml) and extracted with dichloromethane. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 85:15) to afford 5-(2-bromo-phenylcarbamoyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.2 g), which was characterised by its mass and NMR spectra.
Reaction SMILES: C(OOC(C)(C)C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:18]OC(C)(C)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH:2]1[CH2:3][CH2:4][CH2:5][CH:6]=[CH:7]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OOC(C)(C)C
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Product: CC(=O)OC1C=CCCC1

Procedure:
In Example 5, the t-butyl peroxybenzoate was replaced by 5 ml of t-butyl peroxyacetate (30% solution), whereby 0.60 g of 2-cyclohexenyl acetate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38]>>[C:37]([NH:36][CH2:35][CH2:34][NH:33][C:27]([C:10]1[C:9](=[O:32])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:17]2[C:12]([C:11]=1[OH:26])=[N:13][CH:14]=[C:15]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH:16]=2)=[O:28])(=[O:39])[CH3:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 56.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.043 mmol) and N-(2-aminoethyl)acetamide (60 mg, 0.595 mmol), was prepared N-[2-(acetylamino)ethyl]-1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (12 mg, 57% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.17 (br s, 1 H), 8.54 (s, 1 H), 7.32-7.27 (m, 2 H), 7.22-7.18 (m, 2 H), 7.03-6.93 (m, 4 H), 6.74 (s, 1 H), 6.03 (br s, 1 H), 3.96 (s, 2 H), 3.58 (m, 2 H), 3.46 (m, 2 H), 1.97 (s, 3 H); MS m/z 493 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)=[N:6][CH:7]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].N1C(C)=CC=CC=1C.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: OC[C@H]1CC[C@H](CCNc2ncc(Br)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)OC[C@H]1CC[C@H](CCNc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 481 mg (1.53 mmol) of trans-{4-[2-(5-Bromo-pyrimidin-2-ylamino)-ethyl]-cyclohexyl}-methanol in 14 ml CH2Cl2 was treated at 0 C with 0.13 ml (1.68 mmol) methanesulfonylchloride and 0.27 ml (2.30 mmol) 2,6-lutidine. The reaction was stirred for 20 h at room temperature, water (2 ml) was added and stirred for 5 min. After extraction with aqueous saturated NaHCO3/Et2O(3×), the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 970 mg of crude trans-Methanesulfonic acid 4-[2-(5-bromo-pyrimidin-2-ylamino)-ethyl]-cyclohexylmethyl ester, MS: 392 (MH+, 1Br).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[C:16]([C:24](=[N:26][OH:27])[NH2:25])[C:17](=[O:23])[NH:18]3)[CH:10]=[CH:11][CH:12]=1>CN(C=O)C>[CH3:1][C:2]1[O:27][N:26]=[C:24]([C:16]2[C:17](=[O:23])[NH:18][C:19]3[C:14]([CH:15]=2)=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=2)[N:22]=[CH:21][CH:20]=3)[N:25]=1
Reactant: COc1cccc(-c2nccc3[nH]c(=O)c(C(N)=NO)cc23)c1
Reactant: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cccc(-c2nccc3[nH]c(=O)c(-c4noc(C)n4)cc23)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a solution of acetic acid (0.90 g) in DMF (100 ml) was added N,N′-carbonyldiimidazole (2.43 g) and the mixture was stirred at 70° C. for 3 hours. To the solution was added 1,2-dihydro-5-(3-methoxyphenyl)-2-oxo-1,6-naphthyridin-3-amidoxime (3.10 g) prepared in the same manner as described in Example 1(1), and the mixture was stirred at 70° C. for 2 hours and further at 130° C. for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the residue, and the precipitated crystals were separated by filtration and washed with water, isopropanol and diisopropyl ether in this order and then dried. The resulting crystals were subjected to silica gel column chromatography and eluted with chloroform-methanol (50:1). The resulting crystals were recrystallized from chloroform-ethanol to give the title compound (2.22 g) as colorless crystals. M.p. 286-288° C. Hydrochloride of the title compound, M.p. 281-282° C. (recrystallized from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([CH3:21])=[N:10][S:11][C:12]=2[NH:13]C(=O)OC(C)(C)C)=[O:7])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[NH2:13][C:12]1[S:11][N:10]=[C:9]([CH3:21])[C:8]=1[C:6]([C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: Cc1nsc(NC(=O)OC(C)(C)C)c1C(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nsc(N)c1C(=O)c1ccc(Cl)cc1
Yield: 74.8 %

Procedure:
To tert-butyl 4-(4-chlorobenzoyl)-3-methylisothiazol-5-ylcarbamate (2.80 g, 7.94 mmol) was added an excess of TFA (20 mL). After a period of 15 min at reflux, the reaction mixture was evaporated under reduced pressure to give (5-amino-3-methylisothiazol-4-yl)(4-chlorophenyl)methanone as a white solid (1.50 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Cl-].[C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([N:25]1[CH2:30][CH2:29][NH2+:28][CH2:27][CH2:26]1)[CH2:19]2)#[N:15].C(N(C(C)C)C(C)C)C>C(#N)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([CH:20]3[CH2:19][C:18]4[C:22](=[CH:23][CH:24]=[C:16]([C:14]#[N:15])[CH:17]=4)[CH2:21]3)[CH2:30][CH2:29]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: N#Cc1ccc2c(c1)CC(N1CC[NH2+]CC1)C2
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc2c(c1)CC(N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)C2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a 12 mL reaction vial was added 1-(2-bromoethyl)-4-nitrobenzene (42 mg, 0.18 mmol), 4-(5-cyano-2,3-dihydro-1H-inden-2-yl)piperazin-1-ium chloride (33 mg, 0.12 mmol) and acetonitrile (2 mL). To a stirred solution of above mixture was added N-ethyl-N-(propan-2-yl)propan-2-amine (32 mg, 0.24 mmol). The reaction was stirred at 60° C. for 5 hr, then concentrated and purified by preparative TLC to give the desired product. LC-MS (IE, m/z): 377 [M+1]+. (0.73 μm)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[N:21]=1)([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[CH3:15][C:13]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:21]=1)([CH3:14])[CH:12]=[O:11]
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C=O)Nc1nc(-c2ccc(C#N)cc2)cs1
Temperature: 25 °C
Yield: 61 %

Procedure:
A 1M solution of oxalyl chloride in methylene chloride (20 mL, 20 mmol) was cooled to −78° C., dimethyl sulfoxide was added dropwise (1.77 mL, 25 mmol) and the mixture was stirred. This solution (5.5 mL, 5.5 mmol of activated dimethyl sulfoxide) was added via syringe to a solution of 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (1.5 g, 5.5 mmol), prepared in step 1 of Example 7, in 60 mL of 5:1 methylene chloride:tetrahydrofuran that had been cooled to −78° C. The reaction was stirred for 30 min, triethylamine (1.6 mL, 11 mmol) was added, the mixture was stirred for 20 min, and then allowed to warm to 25° C. The mixture was then diluted with methylene chloride and washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10%-20% acetone in hexane) afforded 4-{2-[(1,1-dimethyl-2-oxoethyl)amino]-1,3-thiazol-4-yl}benzonitrile (0.91 g, 61%) of as a white solid. HRMS: calcd for C14H13N3OS+H+, 272.08521; found (ESI, [M+H]+), 272.0853; Analytical HPLC: HPLC purity 100% at 210-370 nm, 9.1 min.; 100% at 328 nm, 9.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:29]=[CH:28][C:16]2[NH:17][C:18]([NH:20]C(OC(C)(C)C)=O)=[N:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>ClCCl.CCCCC>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([O:12][C:13]1[CH:29]=[CH:28][C:16]2[NH:17][C:18]([NH2:20])=[N:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCC
Product: Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1
Reaction time: 24 h
Yield: 40.9 %

Procedure:
To a solution of 250 mg of 2-[(tert-butoxycarbonyl)amino]-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate in 20 cm3 of dichloromethane are added 746 mg of trifluoroacetic acid. After stirring overnight at a temperature in the region of 20° C., 746 mg of trifluoroacetic acid are added. After stirring for 24 hours, the reaction medium is concentrated to dryness under reduced pressure (2 kPa) and then taken up in 40 cm3 of saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is extracted with five times 60 cm3 of dichloromethane and the combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (90/10 by volume)], the resin obtained is solidified in 5 cm3 of pentane and the solid obtained is filtered off by suction and then washed with three times 2 cm3 of pentane and dried under reduced pressure over phosphorus pentoxide. 80 mg of 2-amino-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(Cl)Cl>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
4-Amino-N-(1-(3-aminopropyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (0.70 g) was dissolved in dimethylformamide (10 ml). Triethylamine (0.30 ml) was added, and a solution of benzoyl chloride (0.25 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.15 g of 4-amino-N-(1-(3-benzoylaminopropyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.