Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH:9](=O)[CH2:10][CH2:11]CC.[OH-].C(C([NH+](C(CCCC)(CCCC)C)CCCCCC[NH3+])(CCCC)C)CCC.[OH-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>O>[CH3:9][CH2:10][CH2:11][CH2:8][CH:7]1[O:6][C:1](=[O:5])[CH2:2][CH:3]1[CH3:4]
Reactant: CCCCC=O
Reactant: C/C=C/C(=O)OCC
Agent: CCCCC(C)(CCCC)[NH+](CCCCCC[NH3+])C(C)(CCCC)CCCC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [OH-]
Solvent: O
Product: CCCCC1OC(=O)CC1C

Procedure:
Ethyl crotonate (6.9% by weight) and pentanal (5.2% by weight) were emulsified in an aqueous electrolyte (0.16% by weight of bis(dibutylethyl)hexamethylenediammonium hydroxide (bisquat), 0.38% by weight of EDTA, 0.14% by weight of TEA, 1.45% by weight of Na2B4O7 and 5.84% by weight of Na2HPO4 in water at a pH of 10) (all % by weight based on the total aqueous reaction electrolyte) and subjected to galvanostatic electrolysis at a current density of 2.23 A/dm2 and a temperature of 25° C. in a frame electrolysis cell. The current throughput was 2 F/mol of ester. A steel anode and a lead cathode were used as electrodes (electrode area of 0.1 dm2 and spacing of 1 cm). To monitor the reaction, the MTBE extract of a sample of the electrolysis output is analyzed by gas chromatography. A yield of 3-methyl-4-butylbutyrolactone (whiskey lactone) of 68.5% and a yield of the corresponding ethyl γ-hydroxycarboxylate of 24.2% were achieved. This corresponded to a total yield of target products of 92.7% of the theoretical yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([N:21]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.Cl.C(OCC)C>>[N:21]1([C:16]2[C:15]([CH:13]3[CH2:12][N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:14]3)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Agent: Cl
Solvent: CCOCC
Product: c1ccc2nc(N3CC(c4nccnc4N4CCCNCC4)C3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a round bottomed flask was added tert-butyl 4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate (0.5340 g, 1.159 mmol, SCHEME 6, Example 6.15) and HCl, (1.0 M solution in diethyl ether (1.159 ml, 1.159 mmol)) and the reaction was allowed to stir at RT. After 1 h, the reaction mixture was concentrated, then diluted with saturated Na2CO3 and extracted with CH2Cl2. The organic extract was washed with saturated Na2CO3, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo to give 2-(3-(3-(1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline (0.3627 g, 1.006 mmol, 87% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.S(Cl)([Cl:12])=O>>[CH3:1][N:2]1[C:6]([C:7]([Cl:12])=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cn1nccc1C(=O)O
Product: Cn1nccc1C(=O)Cl
Yield: 51 %

Procedure:
To a stirred solution of 1-methyl-1H-pyrazole (77.0 g 0.916 mol) in absolute ether (960 mL) under an atmosphere of argon was added a 1.6 M solution of n-BuLi in hexane (600 mL, 0.96 mol) dropwise at −40° C. over a period of 2 h. The reaction mixture was stirred at this temperature for a further 1 h, then siphoned into a mixture of solid carbon dioxide with ether. After heating to room temperature, the resulting mass was treated with water (1.5 L), the aqueous layer was separated, washed with ether (500 mL), concentrated to half volume under reduced pressure on a rotary evaporator, cooled to 2–3° C., and acidified while stirring with concentrated HCl to pH=3. The resulting precipitate was separated by filtration, washed with ice-cold water (25 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to give 86.5 g (76%) of 1-methyl-1H-pyrazole-5-carboxylic acid as a white powder. To thionyl chloride (650 mL) was added 1-methyl-1H-pyrazole-5-carboxylic acid (86.5 g, 0.67 mol) in portions over a 35 min period, such that each portion was consumed before addition of the next. After this, the reaction mixture was refluxed for 4.5 h. The excess thionyl chloride was removed under vacuum at a bath temperature below 35° C. The residue was subjected to vacuum fractional distillation through a 15-cm Vigreux column. A fraction boiling at 71–72° C. at 15–16 mm Hg was collected to obtain the title product (49.0 g, 51%) as a colorless liquid.
Reaction SMILES: [CH:1]([C:18]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[C:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]=1[OH:32])([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[OH:17])[CH3:2].P(Cl)(Cl)Cl.Cl.C(C1C=CC=CC=1O)(C1C=CC=CC=1O)C.P1(Cl)OC2C(C(C)(C)C)=CC(C(C)(C)C)=CC=2C(C)C2C=C(C(C)(C)C)C=C(C(C)(C)C)C=2O1.P(Cl)([O-])[O-].[P:92]([F:95])([O-])[O-].N>C(Cl)Cl.N1C=CC=CC=1>[P:92]1([F:95])[O:17][C:4]2[C:5]([C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:6][C:7]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:8][C:3]=2[CH:1]([CH3:2])[C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[C:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]=2[O:32]1
Reactant: CC(c1cc(C(C)(C)C)cc(C(C)(C)C)c1O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: [O-]P([O-])F
Agent: CC(c1ccccc1O)c1ccccc1O
Agent: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(Cl)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(F)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 45 °C
Yield: 80.5 %

Procedure:
To a reaction vessel equipped with a turbine agitator and a reflux condenser was charged 375 g of methylene chloride, 250 g 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 5 g pyridine and 83 g PCl3. The stirred solution was heated to reflux (45° C.) and held at reflux for 22 hours. Byproduct HCl was vented to a scrubber. About 350 g of additional methylene chloride was added during the reaction to replace that lost through the vent and further dilute the reaction. GC analysis showed conversion of the above ethylidenebisphenol to 2,2'-ethylidenebis(4,6-di-tert-butylphenyl) chlorophosphite. While still at reflux, 13.1 g of anhydrous gaseous HF was fed to the reaction mixture through a dip leg. HF feed required 101/2 hours. Byproduct HCl was vented to a scrubber. GC analysis showed conversion of the above chlorophosphite to the corresponding fluorophosphite to be complete. Gaseous ammonia was immediately fed to the reaction to neutralize the mixture. The reaction mass was filtered to remove ammonium chloride. The filtrate was heated to distill out methylene chloride which was replaced by adding isopropanol. The temperature reached 81° C. at the end of the methylene chloride removal. The mixture was cooled to 30° C. giving a 50 weight percent solids slurry in isopropanol. The solids were removed and the wet cake was washed with isopropanol and dried under vacuum yield 223 g (80.5 percent yield) of 2,2'-ethylidenebis(4,6-di-tert-butylphenyl) fluorophosphite.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.[N:12]1[C:20]2[C:15]3[C:16](=[CH:21][CH:22]=[CH:23][C:14]=3[C:13]=1S)[CH:17]=[CH:18][CH:19]=2.C(O)C.C(Cl)(Cl)Cl>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:11])[CH2:8][CH2:9][NH:10][C:13]2[C:14]3[CH:23]=[CH:22][CH:21]=[C:16]4[C:15]=3[C:20](=[CH:19][CH:18]=[CH:17]4)[N:12]=2)=[CH:3][CH:2]=1
Reactant: CC(CCN)c1ccncc1
Reactant: SC1=Nc2cccc3cccc1c23
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: CC(CCNC1=Nc2cccc3cccc1c23)c1ccncc1

Procedure:
The title compound was prepared by the procedure of Example 55, utilizing 3.1 grams of 3-(4-pyridinyl)butanamine, 3.9 grams of benz(cd)indol-2-thiol, 6.4 grams of mercuric acetate, and 300 ml of ethanol. Chloroform (200 ml) was utilized as the partitioning solvent in place of dichloromethane. When the chloroform was being removed in vacuo, crystallization of the title compound suddenly occurred. The precipitate was collected, washed with a little chloroform, and dried. The yield was 3.9 grams; mp 220° C.-221° C. with decomposition.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:1]([O:9][CH2:10][CH:11]([CH3:14])[CH2:12][O:13][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(CO)COC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(COC(=O)c1ccccc1)COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 3-benzoyloxy-2-methylpropanol (369 mg; 1.9 mmol), dihydropyran (273 mg; 3.25 mmol) and pyridinium p-toluenesulfonate (50 mg; 0.2 mmol) in anhydrous dichloromethane (10 ml) was stirred at room temperature for 2 hours. Dihydropyran (200 mg; 2.38 mmol) and pyridinium p-toluenesulfonate (50 mg; 0.2 mmol) were further added thereto, and the resultant mixture was stirred for 3 hours. Ether (50 ml) was added to the reaction mixture, which was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was purified by TLC using a mixture of ethyl acetate and benzene (1:4) to give 1-benzoyloxy-2-methyl-3-tetrahydropyranyloxypropane (466.3 mg; yield, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[C:9]2[CH2:18][CH2:19][CH3:20])=[CH:6][CH:7]=1
Reactant: CCCc1nc(C(=O)OCC)cn1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc(C(=O)O)cn1-c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
To a solution of ethyl 1-(4-chlorophenyl)-2-propyl-1H-imidazole-4-carboxylate (compound 5, 1.28 g, 4.37 mmol) in THF/water (20/20 mL) was added lithium hydroxide monohydrate at room temperature. The reaction mixture was stirred at 55° C. for 12 hrs. The mixture was washed with CH2Cl2, the aqueous layer was acidified with 1N-HCl solution (pH≈6), extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The obtained product was washed with hexane to provide the title compound (740 mg, 64%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(C2(O)C(=O)Nc3cc(Cl)ccc32)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C2C(=O)Nc3cc(Cl)ccc32)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
rac-6-Chloro-3-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-indol-2-one (0.22 g, 0.84 mmol) (from Example 14a supra) was suspended in a mixture of triethylsilane (0.40 mL, 2.52 mmol) (Aldrich) and trifluoroacetic acid (1.2 mL, 12.5 mmol) (Aldrich) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (10 mL) and treated with solid sodium carbonate (1.0 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was triturated with dichloromethane-hexanes to give rac-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-indol-2-one as a white solid. (Yield 0.1 g, 50%).
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([S:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:37])[C@@H:5]1[C@H:38]([OH:40])[CH3:39])C.[Cl:41]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:41][C@H:4]1[N:7]([C:8](=[C:22]([S:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:37])[C@@H:5]1[C@H:38]([OH:40])[CH3:39]
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Sc1ccc(C)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(SC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2Cl)cc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a stirred solution of 1 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-{1(R)-hydroxyethyl}-azetidin-2-on-1-yl]-3-(4-methylthiophenoxy)-3-trimethylacetylthio-propenate in dichloromethane at -40° was added a solution of 1.6 mmol of chlorine in carbon tetrachloride. After 30 minutes the reaction was warmed to room temperature and evaporated to dryness. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded the title compound as a pale yellow foam (0.66 g, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH:9]=[C:10]2[O:12][Si](C(C)(C)C)(C)C)=[O:5])[CH3:2].C([O-])(O)=[O:21].[Na+].[Mg].C1C=C(C(O)=O)C(C(O[O-])=O)=CC=1.C1C=C(C(O)=O)C(C(O[O-])=O)=CC=1.O.O.O.O.O.O.[Mg+2]>CO>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH:9]([OH:21])[C:10]2=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C2CC=C(O[Si](C)(C)C(C)(C)C)C21
Reactant: O=C([O-])O
Agent: O=C(O)c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1C2CC(O)C(=O)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of (1RS,5SR,6RS)-2-(tert-butyl-dimethyl-silanyloxy)-bicyclo[3.1.0]hex-2-ene-6-carboxylic acid ethyl ester (172 mmole) in MeOH (900 ml) was subsequently added NaHCO3 (33.25 g) and magnesium-monoperoxyphthalate (104.5 g) and stirring was continued at ambient temperature for 1 h. The mixture was filtered, the filtrate evaporated and the residue partitioned between saturated NaHCO3 (until gas evolution ceased) and dichloromethane. The organic layer was dried, evaporated and the residue dissolved in MeOH (750 ml). To the solution was subsequently added water (65 ml) and p-toluenesulfonic acid hydrate (3.44 g) and the mixture was stirred at 22° C. for 18 h. The mixture was evaporated, the residue partitioned between saturated NaHCO3 and dichloromethane, the organic layer was dried, evaporated and the residue dissolved in diethylether (350 ml) at reflux temperature. The solution was treated with n-pentane until the solution became cloudy, the mixture was slowly cooled to 0° C. and stirring was continued at 0° C. for 2 h. The suspension was filtered, and the residue dried to give the title compound (15.0 g) as white crystals.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[C:15]2([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.F[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]>C1COCC1>[F:29][C:27]1[CH:26]=[CH:25][C:24]([N+:30]([O-:32])=[O:31])=[C:23]([CH:28]=1)[O:21][CH:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OC1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
63 ml LiHMDS (1 M in THF) were added dropwise to a stirred solution of 10 g 1,4-dioxa-spiro[4.5]decan-8-ol in THF (60 ml) at 0° C. and the reaction stirred for 30 min. A solution of 2,4-difluor-1-nitro-benzene in THF (20 ml) was than added over 5 min and the reaction warmed to rt and stirred for 16 h. The reaction was quenched with sat. ammonium chloride solution and adjusted to pH 7 with 2N HCl. The solvent was removed under vacuum and the residue portioned between EtOAc (200 ml) and water (100 ml). The organic layer was separated and the aqueous phase washed with EtOAc (2×50 ml). The combined organic phases were washed with brine (50 ml) and separated. The organic phase was evaporated to give a solid that was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[CH:12]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:28]2[CH2:29][CH2:30][N:25]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A mixture of 2-acetamido-4-chloromethylthiazole (7.6 g), 1-benzhydrylpiperazine (10.0 g) and potassium carbonate (5.5 g) in N,N-dimethylformamide (80 ml) was stirred at 80° C. for 2 hours. After the reaction mixture was poured into ice-water, the precipitated crystals were collected by filtration, washed with water and then crystallized twice from methanol to give white crystals (8.4 g) of 2-acetamido-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole, mp 178°-179° C.
Reaction SMILES: [O:1]=[C:2]([N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:3][CH3:4].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C(OCC)(=O)C>[O:1]=[C:2]([N:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]1[CH2:7][CH2:8][N:9]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:11]1)[CH2:3][CH3:4]
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)C1CCN(CC(=O)OC)CC1
Yield: 53 %

Procedure:
A mixture of 4-[(1-oxopropyl)phenylamino]-piperidine (500 mg, 2.15 mmol), prepared according to the procedure of P. A. J. Janssen et al, U.S. Pat. No. 3,164,600, methyl bromoacetate (0.25 ml, 2.58 mmol), and potassium carbonate (594 mg, 4.3 mmol), in acetonitrile (2.5 ml) is stirred at room temperature for five hours. The reaction mixture is diluted with 1:1 water and ethyl acetate (20 ml total). The phases are separated and the aqueous phase extracted with ethyl acetate (2×) and the combined organics washed with brine, dried over sodium sulfate and then concentrated. The residue is chromatographed on silica gel (95/5 CHCl3 /MeOH) to give 4-[(1-oxopropyl)phenylamino]-1-piperidineacetic acid, methyl ester, as an oil: 348 mg, 53% yield. An equimolar amount of maleic acid in ether is added to a solution of the free base in ethyl acetate to give the maleate salt as a white solid; maleate salt: m.p. 130°-133° C.
Reaction SMILES: CC1C2N=C(C3C=NC(OCCCC4CCN(C)CC4)=CC=3)NC=2C=CC=1.[CH3:28][C:29]1[CH:34]=[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)[N:32]=[CH:31][C:30]=1[CH:46]=O.[Cl:48][C:49]1[CH:54]=[C:53]([NH2:55])[C:52]([NH2:56])=[C:51]([CH3:57])[CH:50]=1>>[Cl:48][C:49]1[CH:50]=[C:51]([CH3:57])[C:52]2[N:56]=[C:46]([C:30]3[CH:31]=[N:32][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[CH:34][C:29]=3[CH3:28])[NH:55][C:53]=2[CH:54]=1
Reactant: Cc1cc(Cl)cc(N)c1N
Reactant: Cc1cc(OCCCC2CCN(C)CC2)ncc1C=O
Agent: Cc1cccc2[nH]c(-c3ccc(OCCCC4CCN(C)CC4)nc3)nc12
Product: Cc1cc(OCCCC2CCN(C)CC2)ncc1-c1nc2c(C)cc(Cl)cc2[nH]1
Yield: 29.7 %

Procedure:
4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole. This compound was prepared by the method described in General Procedure 3 using 4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde (60 mg, 0.22 mmol, 1.0 equiv), 5-chloro-3-methyl-benzene-1,2-diamine (34 mg, 0.22 mmol, 1.0 equiv) and Na2S2O5 (54 mg, 0.29 mmol, 1.3 equiv). Purification by Method 2 afforded 27 mg (30%) of the title compound. MS (electrospray): mass calculated for C23H29ClN4O, 412.20; m/z found, 413.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.77 (s, 1H), 8.23 (dd, J=8.7, 2.3 Hz, 1H), 7.25 (m, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.04-6.98 (m, 1H), 6.74 (d, J=8.7 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.84-2.76 (m, 2H), 2.73-2.34 (br s, 3H), 2.23 (s, 3H), 1.92-1.83 (m, 2H), 1.81-1.62 (m, 4H), 1.39-1.17 (m, 4H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[CH3:15]I.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH3:15])[C:8]=2[CH:14]=1
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)COc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.10 g, 2.6 mmol) was added to a solution of 6-bromo-2H-1,4-benzoxazin-3(4H)-one (0.49 g, 2.1 mmol) in N,N-dimethylformamide (3 mL) under nitrogen. After the mixture was stirred at r.t. for 10 min, methyl iodide (0.27 mL, 4.3 mmol) was added. The reaction mixture was stirred at r.t. for 1 h. Then 10 mL of water was added to the mixture, and a white precipitate was removed by filtration, washed with water, and dried under vacuum to afford the product which was directly used in next step reaction without further purification. LCMS (M+H)+=242.2/244.2.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]([NH:14][CH3:15])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][NH:14][CH3:15])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CNC(=O)CCc1cnc2occc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCc1cnc2occc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
To a solution of 0.36 g of 3-furo[2,3-b]pyridin-5-yl-N-methyl-propionamide in 10 ml of THF was added dropwise 2.3 ml of a LiAlH4 (2.3M THF) solution at 0° C. The reaction mixture was slowly heated to 60° C. over 1 h and stirred for another 2 h at 60° C. The reaction was quenched by addition of 1M NaOH solution. The resulting mixture was filtrated over a pad of celite, washed with THF and the filtrate was concentrated in vacuo to yield 0.35 g of (3-furo[2,3-b]pyridin-5-yl-propyl)-methyl-amine as brown oil.