Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:29])[CH3:28]>CO>[CH3:28][C:3]1([CH3:29])[CH:2]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccccc3)C(C)(C)O4)CC2)cc1
Solvent: CO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccccc3)C(C)(C)O4)CC2)cc1
Yield: 84 %

Procedure:
Using 1-(3-hydroxy-2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 39, the title compound was synthesized in the same manner as in Example 46. Yield 84%. mp. 126–128° C. (methanol).
Reaction SMILES: CS(O[C@@H:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][C@@H:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[C:33]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>CC1CCCO1.Cl>[C:33]([C:37]1[CH:38]=[CH:39][C:40]([N:41]2[C@H:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH2:8][CH2:7][C@H:6]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:42][CH:43]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CS(=O)(=O)O[C@H](CC[C@@H](OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Solvent: CC1CCCO1
Product: CC(C)(C)c1ccc(N2[C@H](c3ccc([N+](=O)[O-])cc3)CC[C@H]2c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To the crude product solution (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate (7.35 g, 13.39 mmol) was added 4-tert-butylaniline (13.4 g, 90 mmol) at 23° C. over 1 minute. The reaction was heated to 65° C. for 2 h. After completion, the reaction mixture was cooled to 23° C. and diluted with 2-methyltetrahydrofuran (100 mL) and 1 M HCl (150 mL). After partitioning the phases, the organic phase was treated with 1 M HCl (140 mL), 2-methyltetrahydrofuran (50 mL), and 25 wt % aq. NaCl (100 mL), and the phases were partitioned. The organic phase was washed with 25 wt % aq. NaCl (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2-methyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 2-methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspended in MeOH (46 mL) for 3 h, filtered, and the wet solid was washed with additional MeOH (18 mL). The solid was dried at 45° C. in a vacuum oven for 16 h to provide (2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine (3.08 g, 51% 2-step yield).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:7][N:6]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:4]=1>C(OCC)(=O)C>[ClH:1].[NH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[C:3]([NH2:2])[NH:7][N:6]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N)[nH]n2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cc(C2CCNCC2)n[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Hydrochloric acid (4 M solution in dioxane, 31.7 mL, 127 mmol) was added dropwise to a solution of tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate (compound described in the pamphlet of WO2011/045344, 13.5 g, 50.7 mmol) in ethyl acetate (60 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (40 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. Then, the obtained precipitate was collected by filtration to obtain the title compound (12.5 g, yield: 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:13][CH2:14][CH2:15][O:12][C:4]1[CH:5]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Temperature: 120 °C
Yield: 72.7 %

Procedure:
A mixture of 3-fluoro-5-methylsulfonyl-phenol (4.2 g, 22.08 mmol), 1.2-dibromoethane (24 ml, 27.7 mmol) and potassium carbonate (6.1 g, 44.2 mmol) in acetonitrile (36 ml) was divided into 6 aliquots which were each heated under microwave radiation at 120° C. for 30 min. The reaction mixtures were cooled to room temperature, filtrated and pooled. The volatiles were evaporated, aqueous sodium carbonate (100 ml, 10%) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic phase was washed with brine (75 ml), dried (Na2SO4) and evaporated. Purification by flash column chromatography (ethyl acetate/isooctane, 0:1 to 1:0) gave the title compound (4.77 g, 73%). MS m/z (relative intensity, 70 eV 298 (M+, 18), 296 (M+, 18), 109 (bp), 107 (99), 82 (15).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N([O-])=O.[Na+].[BrH:18]>O.C(OCC)C.[Cu]Br>[Br:18][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(N)ccc1C
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(Br)ccc1C
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
A mixture of ethyl 5-amino-2-methylbenzoate (1.50 g, 8.3 mmol) in 48% HBr (12 mL) and water (24 mL) was cooled with an ice-bath for 15 min. Sodium nitrite (0.59 g, 8.6 mmol) was then added dropwise as a solution in water (2 mL), and the resulting mixture stirred for 5 min. After this time, the mixture was added to an ice-cold mixture of copper (I) bromide (1.40 g, 9.90 mmol) in 48% HBr (5 mL) and water (12 mL). The resulting mixture was heated to 70° C. for 1 h. After this time, the reaction mixture was cooled to room temperature and diluted with diethyl ether (150 mL). The organic layer was washed with 1 N hydrochloric acid (50 mL), water (50 mL), and brine (50 mL) then dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, gradient 1-10%, hexanes/ethyl acetate) afforded 1.4 g (69%) of ethyl 5-bromo-2-methylbenzoate as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J=2.2 Hz, 1H), 7.50 (dd, J=8.2, 2.2 Hz, 1H), 7.12 (dd, J=8.2 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.40 (t, J=7.2 Hz, 3H); ESI MS m/z 404 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][OH:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O.O>ClCCl>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][OH:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[O:21][Si:28]([CH3:31])([CH3:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CO)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC1(CO)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of 0.59 g of 4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 48 and 1.17 ml of 2,6-luthidine in 5 ml of dichloromethane was cooled to 0° C. under nitrogen, combined with 1.25 ml of trimethylsilyl trifluoromethanesulfonate and stirred. After 30 minutes, the reaction solution was poured into water and extracted with ether, and the combined organic layers were concentrated. The residue was dissolved in 10 ml of THF, 5% hydrochloric acid was added and the solution was stirred for 1 hour, after which the reaction solution was concentrated and extracted with water and ether. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 9% ethyl acetate to give 0.62 g of 4,6-di-t-butyl-2-hydroxymethyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran as a colorless oil (yield 84%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].CO.[BH4-].[Na+]>O>[CH3:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)[OH:11]
Reactant: CNc1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1ccc(C(C)O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 89 %

Procedure:
(a-2) To a stirred mixture of 19.4 parts of 1-[4-(methylamino)-3-nitrophenyl]ethanone and 160 parts of methanol were added dropwise 4 parts of sodium tetrahydroborate. Upon complete addition, stirring was continued for 1 hour at room temperature. The reaction mixture was poured into 1000 parts of water and the product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 17 parts (89%) of α-methyl-4-(methylamino)-3-nitrobenzenemethanol as a residue (int. 88).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:12][CH3:13])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>ClCCl>[C:16]1([NH:15][C:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH2:12][CH3:13])=[NH:11])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCc1cccc(N(C#N)CC)c1
Reactant: Nc1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(N(CC)C(=N)Nc2cccc3ccccc23)c1
Temperature: 160 °C
Yield: 67.2 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-ethylcyanamide (500 mg, 2.86 mmol) and 1-aminonaphthalene hydrochloride (520 mg, 2.86 mmol) was heated in a preheated oil bath at 160° C. for 2 hours and then allowed to cool to room temperature. The resulting solid was taken in dichloromethane and washed with 10% NAOH solution. The organic layer was concentrated and the resulting residue was flash chromatographed on silica gel to give N-(1-naphthyl)-N'-(m-ethylphenyl)-N'-ethylguanidine (610 mg, 67%) as a light brown liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccc(F)cc3)nc2n1
Temperature: 115 °C
Yield: 59.8 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.9 g), 4-fluorophenol (44.8 g) and potassium hydroxide pellets (13.2 g; 85% purity). After 2 hours' heating at 115° C. and treatment as described above in Example 4, 2-amino-7-(4-fluorophenoxy)-1,8-naphthyridine (15.2 g) is produced, m.p. 210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]([NH:26][C:27]([CH3:31])([CH3:30])[CH:28]=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C=O)NC(=O)OCc1ccccc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Product: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)NC(=O)OCc2ccccc2)cc1

Procedure:
By treating 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 2-(benzyloxycarbonylamino)-2-methylpropanal obtained in 2-a above in the same way as in Example 1, (1-c), 6-[4-(2-benzyloxycarbonylamino-2-methylpropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone was obtained.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[N+:36]([O-:38])=[O:37])[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][C:32]=5[N+:36]([O-:38])=[O:37])[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5c([N+](=O)[O-])cccc5n4)cc3CC[C@@H]12
Yield: 55.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.12 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-5-nitroquinoline (30 mg, 0.14 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 29 mg (56%) of the title compound as an amorphous foam. mp 149°-154°. FDMS: m/e=433. α[D]589 =+60.00 (c=0.10, chloroform).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:51]([O:55][P:56]([O:63][CH2:64][C:65]([CH3:71])([CH3:70])[CH2:66][C:67](O)=[O:68])([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])([CH3:54])([CH3:53])[CH3:52].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:51]([O:55][P:56]([O:63][CH2:64][C:65]([CH3:71])([CH3:70])[CH2:66][C:67]([O:29][C@H:10]([C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C@@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:68])([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Reactant: CC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](OC(=O)CC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 68 h
Yield: 80.7 %

Procedure:
To a solution containing the compound of Example 1 (0.10 g, 0.14 mmol), the product from Example 10D (0.045 g), and 4-(dimethylamino)pyridine (0.017 g) in DMF (1.4 mL) was added EDAC (0.027 g), and the mixture was stirred at room temperature for 68 hours. Additional product from Example 10D (0.045 g) and EDAC (0.027 g) were added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the concentrate was partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with ethyl acetate and ending with 5% methanol in ethyl acetate, to give the title compound (0.115 g, 81% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([I:19])=[C:13]([CH:18]=1)[C:14]([NH:16][OH:17])=[NH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=O)[CH3:23]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([I:19])=[C:13]([C:14]2[N:15]=[C:22]([CH3:23])[O:17][N:16]=2)[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(I)c(C(=N)NO)cc1OCc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(I)c(-c2noc(C)n2)cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-benzyloxy-N-hydroxy-2-iodo-4-methoxy-benzamidine (reference example 3-3) (20 g) and pyridine (115 mL) was added acetyl chloride (3.8 mL) under ice-bath cooling. After stirring at the same temperature for 3 hours, the mixture was stirred and heated at 120° C. for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and 2 mol/L hydrochloric acid. The separated organic layer was washed with 2 mol/L hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 15%-50% ethyl acetate/hexane, gradient elution) to give the title compound (17.0 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: c1ccc(CN2CCNCC2)cc1
Product: O=c1[nH]nc(N2CCN(Cc3ccccc3)CC2)c2ccccc12

Procedure:
4-Chlorophthalazin-1-one and 1-benzylpiperazine were processed using a method similar to that described in Example 1A to afford the title compound. MS (APCI+) M/Z 321 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH2:11]>>[CH3:9][CH:4]1[C:5](=[O:8])[C:6]([O:7][CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])=[C:2]([CH3:1])[O:3]1
Reactant: C=COCCCC
Reactant: CC1=C(O)C(=O)C(C)O1
Product: CCCCOC(C)OC1=C(C)OC(C)C1=O
Yield: 38.7 %

Procedure:
2,5-Dimethyl-4-hydroxy-3(2H)-furanone (13.3 g, 0.1 mole) and butyl vinyl ether (20.0 g, 0.2 mole) are reacted as in Example 1 to give a 37.8% yield (8.83 g) of 2,5-dimethyl-4-[(1'-butoxy)ethoxy]-3(2H)-furanone, b.p. 68.8° C. (0.75 torr) IR (neat, film) 1200, 1625, 1700, 2865, 2930, 2958, 2978 cm-1, 1H NMR (CDCl3) δ0.95 (m, 3), 1.35 (d, J=5 Hz, 3), 1.38 (d, J=8 Hz, 3), 2.18 (S, 3), 3.70 (m, 2), 4.48 (q, J=7 Hz, 1) 5.31 (q, J=5 Hz, 1).
Reaction SMILES: [N+](C1C=CC(S(O[CH:14]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:15]2)(=O)=O)=CC=1)([O-])=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C)C=O>[CH3:32][N:30]1[CH:31]=[C:27]([C:25]2[CH:24]=[CH:23][C:21]3[N:22]=[C:18]([N:16]4[CH2:17][CH:14]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:15]4)[S:19][C:20]=3[CH:26]=2)[CH:28]=[N:29]1
Reactant: Cn1cc(-c2ccc3nc(N4CC(OS(=O)(=O)c5ccc([N+](=O)[O-])cc5)C4)sc3c2)cn1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nc(N4CC(N5CCCCC5)C4)sc3c2)cn1
Temperature: 25 °C

Procedure:
A stirred solution of 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-yl 4-nitrobenzenesulfonate (Reference Example 3, 38 mg, 0.08 mmol), and piperidine (0.024 mL, 0.24 mmol) in N,N-dimethylformamide (0.5 mL) was heated at 160° C. under microwave irradiation for 15 minutes. The mixture was cooled to room temperature then purified by silica gel chromatography (60:30:10 hexane/dichloromethane/2 M NH3 in isopropanol). These product fractions were purified by silica gel chromatography again (79:20:1 to 70:25:5 hexane/dichloromethane/2 M NH3 in isopropanol). A final silica gel chromatographic purification was performed by first eluting the column with 100% dichloromethane to 80:20 dichloromethane/ethyl acetate followed by elution with 99:1 to 96:4 dichloromethane/methanol to provide 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-(piperidin-1-yl)azetidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.57 (m, 1H), 1.65 (pentet, J=5 Hz, 4H), 2.37-2.45 (m, 4H), 3.36-3.46 (m, 1H), 3.92 (s, 3H), 4.02-4.09 (m, 2H), 4.25 (t, J=8 Hz, 2H), 7.45 (d, J=8 Hz, 1H), 7.50 (dd, J=2, 8 Hz, 1H), 7,79 (s, 1H), 7.85 (d, J=2 Hz, 1H), 7.92 (s, 1H); MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](Cl)=[O:9])(=[O:4])=[O:3].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16]1=[CH:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)=[O:26]>O1CCOCC1>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16]1=[C:24]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)=[O:26])[C:8]([C:7]1[CH:11]=[CH:12][C:13]([F:14])=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=1)=[O:9]
Reactant: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: O=C(C=C1Nc2ccccc2N1)c1cccc(F)c1
Solvent: C1COCCO1
Product: O=C(C(C(=O)c1ccc(F)c(S(=O)(=O)Cl)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
At room temperature, 3-(chlorosulfonyl)-4-fluorobenzoyl chloride (3.19 g) was added to a dioxane (75 mL) suspension of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)ethanone (1.50 g), followed by heating up to 110° C. and stirring for 1 hour. The reaction mixture was cooled to room temperature, the insoluble matter was separated by filtration, and then this was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorobenzenesulfonyl chloride (2.10 g).