Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].[CH:10]([OH:13])=[CH:11][CH3:12].C([O-])(O)=O.[Na+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:9][C:3]1[CH:4]=[C:5]([CH2:12][CH2:11][CH:10]=[O:13])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(I)cc1Cl
Reactant: CC=CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=CCCc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 49.5 %

Procedure:
To a solution of 1,2-dichloro-4-iodobenzene (5.44 g, 20 mmol) in DMF (60 ml) was added Bu4NCl (5.56 g, 20 mmol), propenol (4.64 g, 80 mmol), Pd(OAc)2 (224 mg, 1 mmol) and NaHCO3 (10.0 g, 120 mmol) successively at room temperature. The mixture was heated at 50° C. for 12 hour. After cooling to the room temperature, the mixture was poured into ice-water, extracted with DCM three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using PE/EA (20/1) as eluent to afford the title compound (2.01 g, yield 49.8%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[OH:14][C@@H:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:25][CH2:24][C:23]3([CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[C:22]2=[O:31])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([N:27]2[CH2:28][CH2:29][CH2:30][C:23]3([C:22](=[O:31])[N:21]([C@H:18]4[CH2:17][CH2:16][C@@H:15]([OH:14])[CH2:20][CH2:19]4)[CH2:25][CH2:24]3)[CH2:26]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCCNC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Reaction time: 1 h

Procedure:
A solution of 3-chloro-2-methylbenzenesulfonyl chloride (0.050 g, 0.22 mmol) in CH2Cl2 (110 mL) was slowly added to a mixture of 2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (0.060 g, 0.2 mmol) and DIPEA (0.10 mL, 0.6 mmol) in CH2Cl2 (110 mL) at 0° C. and the reaction was stirred for 1 h. The mixture was diluted with ethyl acetate and then washed with diluted HCl, water and brine, dried and concentrated. The product was purified by CombiFlash eluted with CH2Cl2/EtOAc. LC-MS: 441.2/443.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH2:23])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:19].[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].O>C1COCC1>[O:19]=[C:7]1[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][C:22]3[NH:23][C:24](=[O:25])[NH:1][C:2]=3[CH:3]=2)[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8]1
Reactant: COC(=O)c1ccc2oc(=O)n(Cc3ccc(N)c(N)c3)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1

Procedure:
1.1 g (3.5 mmol) of methyl 3-(3,4-diaminobenzyl)-2-oxo-2,3-dihydrobenzoxazole-5-carboxylate and 626 mg (3.9 mmol) of 1,1′-carbonyldiimidazole are stirred at room temperature for 24 h in 10 ml of THF. The reaction mixture is added to 150 ml of water, and the resultant precipitate is filtered off with suction and dried in vacuo; product: 1.1 g; ESI: 340 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]=[CH:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1.[OH-].[Na+]>>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][O:11][CH:6]([CH:5]=[CH:4][C:3]([OH:22])=[O:2])[CH2:7]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C=CC1CN(C(=O)OCc2ccccc2)CCO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C=CC1CN(C(=O)OCc2ccccc2)CCO1
Yield: 96.2 %

Procedure:
Benzyl 2-(3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate (0.86 g, 2.82 mmol) was reacted with NaOH (1.12 g, 28.2 mmol) according to the procedure as described in Example 21, Step A to give the title compound as colorless oil (0.79 g, 96%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=S)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[NH:27])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C(Nc1ccc(Cl)c(Cl)c1)Nc1ncccc1OCc1ccccc1
Product: N=C(Nc1ccc(Cl)c(Cl)c1)Nc1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-(3-benzyloxypyrid-2-yl)-N'-(3,4-dichlorophenyl)thiourea (3.59 g, 0.009 mol), yellow mercuric oxide (2.34 g, 0.011 mol) and methanolic ammonia (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 2.44 g (70%), m.p. 161°-162 ° C.
Reaction SMILES: C([O:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[O:5]1)C.C(#N)C.Cl.[OH-].[Na+]>O>[OH:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[O:5]1
Reactant: CCOC1CCc2ccc(OC)cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1ccc2c(c1)OC(O)CC2
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
A 500-milliliter egg plant type flask was charged with 5.14 g of 2-ethoxy-7-methoxychroman, 74 ml of acetonitrile and 25 ml of water, and 4.8 ml of a 35% hydrochloric acid aqueous solution was slowly added thereto dropwise at room temperature. The solution was stirred at 60° C. for 20 minutes, and then cooled to 20° C. The reaction solution was neutralized with 39 ml of a 5% sodium hydroxide aqueous solution, and the acetonitrile was removed by distillation in vacuo therefrom. The residue was extracted three times with 50 ml of ethyl acetate, and the organic layer was washed with water. Then, the ethyl acetate was removed by distillation in vacuo therefrom. The resulting residue was purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate 5:1) to obtain 3.60 g of a colorless liquid (yield 81%). Further, 0.77 g of 2-ethoxy-7-methoxychroman was recovered.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][CH3:15])[N:13]=1)(C)(C)C.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32]>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH:22][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][CH3:15])[N:13]=1
Reactant: CC[C@@]1(c2cc(N)ccc2F)CCOC(NC(=O)OC(C)(C)C)=N1
Reactant: O=C(O)c1ccccn1
Product: CC[C@@]1(c2cc(NC(=O)c3ccccn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-ethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F2 (R3=Et) and pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH2:7][CH2:8]1)(=[O:26])=[O:25]
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)[C@H]1CC[C@@H](COS(C)(=O)=O)CC1
Reaction time: 18 h

Procedure:
To a solution of butyl cis-4-(hydroxymethyl)cyclohexanecarboxylate (25.06 g, 117 mmol) and triethylamine (24.3 ml, 17.8 g, 176 mmol) in methylene chloride (600 ml) under nitrogen, cooled in an ice-bath, was added dropwise over 20 minutes methane-sulfonyl-chloride (13.6 ml, 16.1 g, 140 mmol). The solution was stirred 18 hours while warming from 0° C. to ambient temperature. Additional triethylamine (2 ml, 1.5 g, 14 mmol) and methane-sulfonyl-chloride (1 ml, 1.5 g, 13 mmol) were added and the mixture was stirred four hours at ambient temperature. The mixture was diluted with methylene chloride (300 ml), washed with IN hydrochloric acid (300 ml), water (300 ml), and half-saturated sodium carbonate solution (300 ml), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give crude butyl cis-4-{[(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate (35.31 g) as an orange oil: 1H NMR (CDCl3) 4.08 (4H, m), 3.00 (3H, s), 2.59 (1H, m), 2.05 (2H, m), 1.86 (1H, m) 1.52-1.69 (6H, m), 1.31-1.43 (4H, m), 0.94 (3H, m). MS.: 293.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.[CH3:28][CH:29]1[CH2:34][NH:33][C:32](=[O:35])[CH2:31][NH:30]1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:30]4[CH:29]([CH3:28])[CH2:34][NH:33][C:32](=[O:35])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC1CNC(=O)CN1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CC(=O)NCC3C)nn12
Temperature: 180 °C
Reaction time: 16 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 5-methylpiperazin-2-one hydrochloride salt (65.5 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 16 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 0.9 min (conditions 4), MH+=423).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[N:50]1([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C)C=O>[F:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:58]5[CH2:59][CH2:60][CH:55]([N:50]6[CH2:54][CH2:53][CH2:52][CH2:51]6)[CH2:56][CH2:57]5)=[O:7])[CH:24]=4)=[C:27]([F:48])[CH:28]=3)=[O:34])[CH2:37][CH2:36]2)=[O:47])=[CH:41][CH:42]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC(N2CCCC2)CC1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added 4-(pyrrolidin-1-yl)piperidine (61.3 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (48.0 mg, 80%).
Reaction SMILES: C[Al](C)C.[C:5]([C:9]1[CH:13]=[C:12]([NH2:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:7])[CH3:6].[O:21]=[C:22]1[NH:41][C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=3)[C:34](OC)=[O:35])=[C:24]2[NH:23]1>C1COCC1>[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:34](=[O:35])[C:33]2[CH:38]=[CH:39][CH:40]=[C:31]([O:30][C:29]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:41][C:22](=[O:21])[NH:23][C:24]=34)[CH:32]=2)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: COC(=O)c1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Method L2: A solution of AlMe3 (solution in toluene 2M, 260 μL, 0.527 mmol,) was added dropwise to a cooled (0° C.) solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (113 mg, 0.527 mmol) in THF (2.5 mL). When the addition was complete, the mixture was allowed to warm to room temperature and stirring was continued for 30 minutes. Then methyl 3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)benzoate (100 mg, 0.351 mmol) was added and the mixture was heated under reflux for 19 hours. The mixture was cooled to room temperature and carefully quenched with 5% aq HCl (1 mL). After evaporation of solvent, the residue was retaken in CH2Cl2, washed with saturated solution of NaHCO3 then with brine, dried over MgSO4 and evaporated under vacuum. The obtained residue was chromatographied (eluent: EtOAc) and the title compound was obtained as a light yellow solid (54 mg, 33%). 1H-NMR (δ, ppm, DMSO-d6): 1.30 (s, 9H, tBu), 6.39 (s, 1H, Hpyrrazole) 6.51 (d, 1H, HPy,5, J=5.9 Hz), 7.31 (t, 1H, Harom, J=7.4 Hz), 7.37 (dd, 1H, Harom, J=8.0 Hz, J=2.3 Hz), 7.41-7.44 (m, 2H, Harom), 7.49-7.51 (m, 2H, Harom), 7.55-7.62 (m, 2H, Harom), 7.71 (d, 1H, Harom, J=8.1 Hz), 7.82 (d, 1H, HPy,6, J=5.9 Hz), 10.34 (s, 1H, NHamide), 11.18 (s, 1H, NHurea), 11.42 (s, 1H, NHurea). LC-MS (m/z): 469 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([O-:24])=[O:23]>CO.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:29][C:28]3[CH:30]=[CH:31][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Nc1ccc([N+](=O)[O-])cc1
Yield: 23 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 4-nitroaniline (25 mg, 0.18 mmol) as the coupling partner. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 13 mg (23%) of the titled compound. ESI-MS m/z 412 (MH+), 410 (M−H−).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[C:16]=1[NH2:17]>C(O)(C)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[C:16]=3[NH2:17])=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: Cc1ccc(CCl)c(N)c1C
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2[nH]c(SCc3ccc(C)c(C)c3N)nc2c1

Procedure:
The title compound was prepared by the method of Example 1 using 207 mg of 2-mercapto-5-methylbenzimidazole instead of 2-mercaptobenzimidazole and 260 mg of 2-(chloromethyl)-5,6-dimethylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 10% sodium hydroxide instead of sodium carbonate. The dichloromethane extract was dried over sodium sulfate, filtered, and concentrated in vacuo to 274 mg of the title compound as a gum. The compound was used in subsequent reactions without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].Br[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[N:4]1([CH2:3][CH:2]([O:1][CH2:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CCCCCOCC(O)Cn1ccnc1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOCC(Cn1ccnc1)OCc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[2-hydroxy-3-(pentoxy)propyl]1H-imidazole (Example 29b, 2.12 g, 0.010 mol) in anhydrous tetrahydrofuran (15 ml) was treated with sodium hydride (0.44 g of a 60% dispersion in oil, 0.011 mol) and stirred at room temperature for 1 hour. Ethyl 4-(bromomethyl)benzoate (2.67 g, 0.011 mol) was then added and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate, washed with water and dried (MgSO4). The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, chloroform) to give ethyl 4-[[1-(1H-imidazol-1ylmethyl)-2-(pentoxy)ethoxy]methyl]benzoate as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Fc1ccccc1F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1ccccc1-n1ccnc1
Temperature: 110 °C
Yield: 1.2 %

Procedure:
1,2-Difluorobenzene (25 mL, 254.0 mmol), imidazole (15.6 g, 228.6 mmol), and potassium carbonate (70.2 g, 508.0 mmol) were suspended in dimethyl sulfoxide (15 mL). The reaction mixture was heated at 110° C. for 72 hours. The reaction mixture was then partitioned between ethyl acetate and was water and washed several times with a saturated aqueous solution of ammonium chloride to remove a small amount of di-imidazole material. The organic layer was then dried over sodium sulfate and evaporated to dryness to yield 1-(2-fluorophenyl)imidazole (430 mg, 1%) that was used without further purification. ESI-MS m/z calc. 162.1, found 163.3 (M+1)+. Retention time 0.26 minutes (3 min run). NMR (400 MHz, DMSO) δ 8.04 (s, 1H), 7.69-7.62 (m, 1H), 7.57 (s, 1H), 7.54-7.45 (m, 2H), 7.41-7.33 (m, 1H), 7.13 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:54]1[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:54]2[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[CH:17][CH:18]=2)[O:10][N:9]=1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3F)cc2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3F)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (4-ethyl-5-{5-[4-(2-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.17 g, 0.43 mmol) that was obtained in Example 10 (10f), carbon tetrabromide (0.17 g, 0.51 mmol), triphenylphosphine (0.13 g, 0.51 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.10 g, 0.65 mmol), N,N-diisopropylethylamine (0.23 mL, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography using a mixed solvent of ethyl acetate and hexane (5:5) to afford the title compound (0.19 g) in a yield of 90% as a white crystalline solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][N:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[CH3:25])=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4]>C(O)C>[CH2:3]([O:5][CH:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][N:23]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:30][CH:31]=2)[CH3:25])=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.5 %

Procedure:
1.30 ml of a 1N aqueous sodium hydroxide solution was added to a solution of 310 mg of ethyl 2-ethoxy-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 1 in 5 ml of ethanol, and the mixture was stirred at room temperature for 1.5 hours. After the reaction, the ethanol was evaporated under reduced pressure, and the pH of the mixture was adjusted to a value of 3 with 1N hydrochloric acid. The reaction mixture thus obtained was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline crude product thus obtained was washed with isopropyl ether and hexane to obtain 232 mg of the desired compound.