Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[O:2].O[CH:4]1[CH:11]2[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:13][CH:5]1[CH2:6]3)[CH2:10]2.[ClH:14]>>[Cl:14][CH2:1][O:2][CH:4]1[CH:11]2[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:13][CH:5]1[CH2:6]3)[CH2:10]2
Reactant: Cl
Reactant: C=O
Reactant: OC1C2CC3CC(C2)CC1C3
Product: ClCOC1C2CC3CC(C2)CC1C3
Reaction time: 12 h

Procedure:
Paraformaldehyde was added to 2-hydroxyadamantane, and a hydrogen chloride gas was injected at 2.5 equivalent amounts per this 2-hydroxyadamantane. Then, the reaction was conducted at a temperature of 50° C. for 12 hours. After the completion of the reaction, the product was distillated under reduced pressure so as to obtain 2-adamantyl chloromethyl ether (compound 2) represented by the following chemical formula (59).
Reaction SMILES: [Al:1](Cl)([CH2:4][CH3:5])[CH2:2][CH3:3].[CH2:7]([O:9][C:10]1([Li])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH2:11]1)[CH3:8].C([Li])(C)(C)C.C(OC1C2C(=CC=CC=2)C=CC=1)C>CCCCCC.C(OCC)C>[CH2:7]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[C:18]([Al:1]([CH2:4][CH3:5])[CH2:2][CH3:3])=[CH:17][CH:16]=[CH:15]2)[CH3:8]
Reactant: [Li]C1(OCC)CC=Cc2ccccc21
Reactant: CC[Al](Cl)CC
Agent: CCOc1cccc2ccccc12
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOc1cccc2cccc([Al](CC)CC)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 ml (20 mmol) of Et2AlCl are added dropwise at −40° C. to a suspension of 50 ml of diethyl ether and 3.5 g (20 mmol) of (1-ethoxynaphth-1-yl)lithium, prepared from 33 ml (56 mmol) of t-butyllithium (1.7M solution in pentane) and 9.7 g (56 mmol) of 1-ethoxynaphthalene in 200 ml of hexane. The mixture is slowly brought to room temperature and stirred at room temperature for 24 h. The mixture is subsequently decanted off from the solid, the solvent is removed, the residue is taken up in 35 ml of toluene and filtered through a D4 frit. After removal of the toluene, fractional distillation gives (8-ethoxynaphth-1-yl)diethylaluminium as pale-yellow liquid having a boiling point of 146° C. at 0.01 mbar.
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:27]I.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[N:17]([CH3:27])[C:16]2=[O:26])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: C#CCn1c(=O)oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(=O)oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 22.2 %

Procedure:
To a solution of 1-[6-fluoro-3-propargyl-2(3H)benzoxazolon-5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (2.0 g) in dimethylformamide (10 g), methyl iodide (0.5 g) and sodium hydride (0.4 g) were added, and the resultant mixture was heated at 40° to 50° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography to give 1-[6-fluoro-3-propargyl-2(3H) -benzoxazolon-5-yl]-3-methyl -4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.3 g ).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.N12CCCNC1CCCC=[CH:13]2.IC>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: C1=CN2CCCNC2CCC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: CI
Solvent: CC#N
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
20 ml acetonitrile was added to 4-bromophenylacetic acid (2 g, 9.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-2-ene (1.7 g, 11.2 mmol) was added at 0° C. Iodomethane (1.98 g, 14.0 mmol) was slowly dropped to the mixture and stirred for 2 hours at room temperature. After the reaction is complete, the mixture was extracted using water (100 ml×2) and dichloromethane (100 ml). The title compound (1.7 g, 75%) was obtained by column chromatography (ethylacetate/n-hexane, 1/15).
Reaction SMILES: [Br-].[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].CC([O-])(C)C.[K+].[C:37]([C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)#[N:38].O>O1CCCC1>[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]=[CH:43][C:42]2[CH:45]=[CH:46][C:39]([C:37]#[N:38])=[CH:40][CH:41]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: CCC[C@H]1CC[C@H](C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C=Cc2ccc(C#N)cc2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a mixture of 25.0 g (0.11 mol) of trans-4-propylcyclohexylmethyltriphenylphosphonium bromide and 100 ml of tetrahydrofuran (THF) was added 12.2 g (0.10 mol) of t-BuOK while maintaining a temperature of lower than −20° C., and stirred for 1 hour. Subsequently, 70 ml of solution of 12.9 g (0.10 mol) of 4-cyanobenzaldehyde in THF was added dropwise to the solution while maintaining a temperature of lower than −20° C., and stirred at the same temperature for 2 hours to react. After finishing of the reaction, 50 ml of water was added to the reaction product and then extracted with 100 ml of toluene. The organic layer thus obtained was washed with water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: toluene) to obtain 12.1 g of a crude 4-(2-(trans-4-propylcyclohexyl)vinyl)benzonitrile.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NCCCSc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1cccnc1)c1cccs1
Yield: 85.4 %

Procedure:
To a solution of 2.00 g (8.29 mmol) of 3-(3-aminopropylthio)pyridine dihydrochloride and 4.16 ml (29.9 mmol) of triethylamine in 80 ml of methylene chloride, 1.06 ml (9.95 mmol) of 2-thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.97 g of the desired compound (yield: 85.3%, yellow powder).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([C:57]3([NH2:63])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C>[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([C:57]3([NH:63][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][C:10]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])=[C:2]([CH3:1])[CH:3]=4)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC1(c2nc3cc(Cl)ccc3[nH]2)CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2(c3nc4cc(Cl)ccc4[nH]3)CCCCC2)ccc1C(=O)N1CCCC1
Yield: 78 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)cyclohexylamine in tetrahydrofuran. Yield: 78%; Rf value: 0.28 (silica gel; ethyl acetate); C26H29ClN4O2 (464.99); mass spectrum: (M+H)+=465/467 (chlorine isotope).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[I:15]CI.N(OCCC(C)C)=O>C(OCC)C>[I:15][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: CCOC(=O)CCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 42 %

Procedure:
To a solution of Part (2) compound (7.2 g, 32 mmol) in diiodomethane (10.3 mL, 128 mmol) under argon at RT was added isoamyl nitrite (6.5 mL, 64 mmol) over 10 min. The brownish solution was stirred at RT for 40 min and then heated to 80° C. for 2 h. Ethyl ether (300 mL) was added to the reaction and the organic layer was washed with 1N hydrochloric acid (70 mL×2), water (70 mL), saturated sodium bicarbonate (70 mL×2), 10% sodium bisulfite solution (30 mL) and dried over magnesium sulfate. Purification was performed by flash chromatography on 800 g silica gel, loaded and eluted with 7% ethyl acetate in hexane. Pure fractions were combined and evaporated to give the title compound (4.1 g, 42%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:5]([CH2:8][CH3:9])[C:6]=1Cl.[Li]CC[CH2:23][CH3:24].CCCCCC.[C:31](=O)([O:34]C)[O:32]C>C1COCC1.O>[CH2:23]([O:34][C:31]([C:6]1[N:5]([CH2:8][CH3:9])[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[N:3][C:2]=1[Cl:1])=[O:32])[CH3:24]
Reactant: CCn1c(-c2cccc3ccccc23)nc(Cl)c1Cl
Reactant: COC(=O)OC
Reactant: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1c(Cl)nc(-c2cccc3ccccc23)n1CC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4,5-dichloro-1-ethyl-2-naphthalen-1-yl-1H-imidazole (2.87 g, 9.86 mmol) in anhydrous THF (60 ml) at −78° C. under nitrogen is added a solution of n-BuLi in hexane (1.6 M, 6.78 ml, 10.84 mmol, 1.1 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 hr, followed by the addition of dimethyl carbonate (2.66 g, 29.6 mmol, 3.0 eq.). The resulting solution is stirred at −78° C. for 30 min, warmed to rt slowly, and stirred for an additional 60 min at rt. Water (30 ml) is added to quench the reaction, and THF is evaporated under reduced pressure. The residue is extracted with EtOAc (30 ml×2) and the combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified through silica gel chromatography (hexanes/EtOAc, from 20:1 to 10:1) to give 5-chloro-3-ethyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester. LCMS 315 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[C:22]([O-])([O-])=O.[K+].[K+].[Cl:28][C:29]([CH2:31]Cl)=[CH2:30]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:31][C:29]([Cl:28])=[CH2:30])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:22])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: C=C(Cl)CCl
Reactant: O=C([O-])[O-]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)cn1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.5 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-5-pyridylcarboxylate (reference example 7) (0.73 g, 2 mM) in DMF (12 ml) was treated with K2CO3 (0.83 g, 6 mM) and 2,3-dichloro-1-propene (0.490 g, 44 mM). The reaction was allowed to stir at ambient temperature for 48 hours. The reaction was evaporated at reduced pressure. The residue was subjected to chromatography (eluant: ethyl acetate/hexane) to give the title compound as a white solid (0.8 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][CH2:9][CH3:10]>>[CH2:7]([O:6][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)[CH2:8][CH2:9][CH3:10]
Reactant: O=CCCCO
Reactant: CCCCO
Product: CCCCOC1CCCO1
Temperature: 22 °C
Reaction time: 17 h
Yield: 87.6 %

Procedure:
Aqueous 4-hydroxybutanal (502 g of 10.2 wt. % solution, 0.58 mol, 1.0 eq.), n-butanol (34.6 g, 0.47 mol, 0.80 eq.), hexanes (500 mL), and "Amberlyst-15" resin (product of Rohm and Haas Company, 2.3 g) are charged to a 2-L glass reaction vessel equipped with a magnetic stir bar. The two-phase mixture is stirred at ambient temperature (22° C.) for 17 h. The two liquid phases are separated from the ion-exchange resin. The hexane layer, which is separated from the aqueous phase and analyzed by gas chromatography (GC), contains 14.8 wt. % of 2-n-butoxytetrahydrofuran (59.4 g, 88.5% yield). Product identity is confirmed by infrared, 1H NMR, and 13C NMR spectroscopies. The aqueous phase contains 4.2% unreacted 4-hydroxybutanal.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:3]([OH:22])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1
Temperature: 47.5 °C
Yield: 59.6 %

Procedure:
A solution of 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (1.00 g, 3.08 mmol) in ethanol (15 mL) was treated with a 1N aqueous sodium hydroxide solution (6 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (20 mL) and extracted with diethyl ether (1×40 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (570 mg, 60%) as a white solid: mp 139-143° C.; EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1241.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.ClCCl.C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:18]=3[O:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(C(F)(F)F)ccc2N)C1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C
Temperature: 80 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (326 mg) and (S)-tert-butyl 3-(2-amino-5-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (485 mg) was dissolved in dioxane (4 ml), p-toluenesulfonic acid (26 mg) was added. The reaction mixture was heated at 80° C. for about 5 h. The mixture was diluted with dichloromethane and 10% aq. K2CO3 solution. The organic layer was separated, passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica gel; solvent:100% iso hexane→4:1 H:E).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12]([CH2:21]Cl)=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:23][S:24]C.[Na].C(N(CC)CC)C.O>O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12]([CH2:21][S:24][CH3:23])=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Fc1cccc(-c2nc(-c3cccnc3)c(CCl)[nH]2)c1
Reactant: CSC
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CSCc1[nH]c(-c2cccc(F)c2)nc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of a crude product of 2-(3-fluorophenyl)-5-chloromethyl-4-(3-pyridyl)imidazole dihydrochloride (268 mg) in tetrahydrofuran (10 ml) were added 15% aqueous sodium methyl sulfide solution (0.95 ml) and triethylamine (206 mg), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=19:1) to obtain 2-(3-fluorophenyl)-5-methylthiomethyl-4-(3-pyridyl)imidazole (198 mg) as colorless powder.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[OH-].[Na+].Cl.[CH3:8][N:9]([CH3:20])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[O:15][CH2:16][CH2:17][CH3:18]>O>[P:1]([O-:4])([O-:3])[O-:2].[CH3:20][NH+:9]([CH3:8])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:15][CH2:16][CH2:17][CH3:18])=[O:19].[CH3:8][NH+:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:15][CH2:16][CH2:17][CH3:18])=[O:19])[CH3:20].[CH3:8][NH+:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:15][CH2:16][CH2:17][CH3:18])=[O:19])[CH3:20]
Reactant: OP(O)O
Reactant: CCCOC(=O)NCCCN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCOC(=O)NCCC[NH+](C)C
Product: [O-]P([O-])[O-]
Reaction time: 0.5 h

Procedure:
A solution of phosphorous acid (2.87 g in water (50 ml)) was stirred for 1 hour with a solution of sodium hydroxide (2.8 g in water (50 ml)). Propyl 3-(dimethyiamino)propylcarbamate hydrochloride (15.7 g) in water (50 ml) was added and the mixture stirred for 30 min, evaporated to dryness, dichloromethane (450 ml) added and re-evaporated. The residue was dissolved in dichloromethane (150 ml) allowed to stand for 1 hour and the insoluble white solid (sodium chloride) filtered off. The filtrate was evaporated to leave dimethyl-[3-(propoxycarbonylamino)propyl]ammonium phosphite, as a viscous colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[CH2:16](I)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2)[CH:17]=[CH2:16]
Reactant: C=CCI
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2[nH]c(C(=O)OCC)cc12
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 71.3 %

Procedure:
50 mg (0.24 mmol) of ethyl 4-hydroxyindole-2-carboxylate (U.S. Pat. No. 3,705,907), 48 mg (0.29 mmol) of allyl iodide, and 33 mg (0.24 mmol) of potassium carbonate were added to 0.5 ml of N,N-dimethylformamide, and the mixture was stirred for 1 hour and 45 minutes at 50° C. After the reaction, the solvent was evaporated. The residue was dissolved in chloroform, washed with saturated aqueous solution of sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 63 mg of a crude product, which was purified by separation thin layer chromatography (silica gel, chloroform: methanol=30:1) to obtain 42 mg (yield: 70.2%) of the target compound. This compound was recrystallized from a mixture of chloroform and n-hexane to obtain light brown needles of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([N+:14]([O-])=O)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1O)(=[O:3])[CH3:2].O.NN.[ClH:21]>C(O)C.[Pd]>[ClH:21].[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][C:13]=1[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(O)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of 107 (1.00 g, 4.46 mmol) and 10% Pd-C (1.0 g) in ethanol (10 mL) and 5% HCl (1.2 mL) was added dropwise hydrazine hydrate (55% hydrazine, 1.0 mL, 17 mmol). The mixture was stirred at room temperature for 1 hour, the catalyst was filtered, and the filtrate was concentrated under reduced pressure. Compound 108 (0.875 g, 100%) was obtained as a white solid residue: mp 220-223° C. (methanol/hexane). A literature reference (Ellis and Jones, 1974) did not report the mp.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[CH3:22][N:23]([CH3:32])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH2:33]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:33][N:29]4[CH2:28][CH2:27][N:26]([C:24]([N:23]([CH3:32])[CH3:22])=[O:25])[CH2:31][CH2:30]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Reactant: C=O
Solvent: CCO
Product: CN(C)C(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.050 g, 0.18 mmol) obtained in Example A1, Step 1 in ethanol (2.0 mL) was added with piperazine-1-carboxylic acid dimethylamide (0.035 g, 0.22 mmol), and 37% aqueous formaldehyde (0.020 g, 0.24 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)-N,N-dimethylpiperazine-1-carboxamide (0.044 g, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](I)[CH3:13].O[Li].O>CCO>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:13]
Reactant: CCI
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A 500 mL 3-neck flask fitted with a stir-bar, condenser, and an Ar inlet was charged with 4-amino-3-nitrophenol (12.0 g, 77.9 mmol), ethyl iodide (15.2 g, 8.00 mL, 97.3 mmol), LiOH.H2O (6.55 g, 156 mmol), and EtOH (120 mL). The resultant solution was heated at 60° C. overnight. Another 3 mL of ethyl iodide and 1 g of LiOH.H2O were added, and the mixture was stirred at 60° C. overnight again. The solution was cooled and partitioned with EtOAc (250 mL) and H2O (200 mL). The organic phase was washed with 1% aqueous LiOH (2×200 mL), H2O (200 mL), and brine (200 mL), filtered through phase separation paper, and concentrated in vacuo to a dark red solid. The crude solid was triturated with hexanes:EtOAc 8:1 (50 mL). The solid was filtered, pressed with rubber dam, and rinsed with hexanes (3×10 mL). The material was dried to give 10.7 g of 46a as a red solid (75%). 1H NMR (60 MHz, CDCl3): δ 7.5 (d, 1H), 7.0 (dd, 1H), 6.7 (d, 1H), 5.9 (bs, 2H), 4.0 (qt, 2H), 1.4 (t, 3H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 96% with a retention time of 4.2 min.