Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:13][C@H:14]1[CH2:19][O:18][CH2:17][CH2:16][NH:15]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][C@@H:14]2[CH3:13])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C[C@H]1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Methyl 2,6-dichloropyrimidine-4-carboxylate (5.00 g) was dissolved in DCM (120 mL). (3S)-3-Methylmorpholine (2.49 g) dissolved in triethylamine (3.70 mL) and DCM (10 mL) was added dropwise to the solution over 10 minutes. The reaction was left to stir at room temperature for 1 hour then the mixture concentrated in vacuo and dissolved in DCM (300 mL). The organics were washed with water (150 mL) and dried (MgSO4). The crude material was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (3.15 g) as a white solid.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[C:12]([C:13]2[N:18]3[N:19]=[CH:20][N:21]=[C:17]3[C:16]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[N:15][CH:14]=2)=[CH:11][N:10](C2CCCOC2)[N:9]=1)(C)(C)C.C([SiH2]OC(C)(C)C1N(C2CCCOC2)N=CC=1C1N2N=CN=C2C(NC2C=CC(N3CCOCC3)=CC=2)=NC=1)(C)(C)C.Cl>CO>[O:32]1[CH2:31][CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:16]3[C:17]4[N:18]([N:19]=[CH:20][N:21]=4)[C:13]([C:12]4[CH:11]=[N:10][NH:9][C:8]=4[CH2:7][OH:6])=[CH:14][N:15]=3)=[CH:28][CH:27]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nn(C2CCCOC2)cc1-c1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Agent: CC(C)(C)[SiH2]OC(C)(C)c1c(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3ncnn23)cnn1C1CCCOC1
Agent: Cl
Solvent: CO
Product: OCc1[nH]ncc1-c1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12

Procedure:
A solution of {5-[3-(tert-butyl-dimethyl-silanyloxymethyl)-1-(tetrahydro-pyran-3-yl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-(4-morpholin-4-yl-phenyl)-amine and {5-[5-(tert-butyl-dimethyl-silanyloxymethyl)-1-(tetrahydro-pyran-3-yl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-(4-morpholin-4-yl-phenyl)-amine (53.6 mg, 0.077 mmol) and conc. HCl (0.27 mL) in MeOH (5 mL) is stirred at room temperature for 2 hours. After removing the solvent, the residue is partitioned between ethyl acetate and water. The aqueous layer is washed with ethyl acetate (3×) and the combined organic layers are dried over MgSO4, filtered and concentrated. The residue is dissolved in 4M HCl in dioxane, concentrated in vacuo and then partitioned between ethyl acetate and sat. NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to afford a crude compound purified by silica gel column chromatography. The title compound is isolated eluting with EtOAc and a 95:5 mixture DCM:MeOH (5.4 mg, 18%).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].FC(F)(F)C(O)=O.O.O.O.C([O-])(=O)C.[Na+]>ClCCl>[CH3:1][C:2]([CH3:30])([CH3:29])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Oc3ccccc3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Oc3ccccc3)nc12
Reaction time: 2 h

Procedure:
A solution of impure 2,2-dimethyl-1-[2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one, prepared according to general procedures as described in these Examples, (0.032 g, “0.075 mmol”) in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 13 h, then concentrated to a yellow-green oil, which was partitioned between 5 mL of a sat. aq. NaHCO3 solution and 5 mL of dichloromethane. The aqueous layer was extracted with 5 mL of dichloromethane, and the combined organic layers were dried over MgSO4, filtered and concentrated to a pale yellow oil. The oil was dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.103 g, 0.756 mmol). The mixture was stirred for 2 h, then concentrated. The residue was partitioned between 5 mL of water and 5 mL of dichloromethane. The aqueous layer was extracted with 5 mL of dichloromethane, and the combined organic layers were dried over MgSO4, filtered and concentrated to a pale yellow oil. The oil was again dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.101 g, 0.745 mmol). The mixture was stirred for 4 h, then concentrated. The residue was partitioned between 5 mL of water and 5 mL of dichloromethane. The aqueous layer was extracted with 5 mL of dichloromethane, and the combined organic layers were dried over MgSO4, filtered and concentrated to an off-white solid. Column chromatography (0→33% EtOAc/hexanes) afforded 0.014 g (65% from impure; 40% 2-step) of 2,2-dimethyl-1-(2-phenoxy-5H-pyrrolo[2,3-b]pyrazin-7-yl)-propan-1-one as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH:13]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCCCC2)cc1
Reaction time: 22 h

Procedure:
822 mg (4.95 mmol) of ethyl 4-hydroxybenzoate was dissolved in 20 ml of tetrahydrofuran. 545 mg (5.45 mmol) of cyclohexanol, 1.56 g (5.94 mmol) of triphenylphosphine and 202 mg (1.50 mmol) of diethyl azodicarboxylate were added to the solution, and they were stirred for 22 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with 1 N sodium hydroxide and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][C:23]([OH:25])=[O:24])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Li].CI.[CH3:29]N(C=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][C:23]([O:25][CH3:29])=[O:24])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(CC(=O)O)sc2-c2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Agent: [Li]
Solvent: O
Solvent: CI
Product: COC(=O)Cc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Yield: 37 %

Procedure:
A solution of 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, lithium salt (8.82 g.; 0.024 mole), methyl iodide (17.4 g.; 0.122 mole) and DMF (100 ml.) was stirred at ambient temperature for 16 hours. The mixture was poured into water (1.5 l.) and extracted with methylene chloride (500 ml.). The organic layer was washed with water (3×1.5 l.), saturated sodium bicarbonate (1.0 l.), water (1.5 l.), dried (sodium sulfate), and concentrated in vacuo. The oily residue was dissolved in acetone and applied directly to a Florisil-packed (340 ml.) gravity column (Florisil previously equilibrated with solvent mixture; 500 ml. packing: 100 ml. solvent). The sample was eluted with 5% acetone in hexane. The recovered product was recrystallized from diethyl ether-pentane to afford 3.32 g. (37% yield) of 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, methyl ester; m.p. 79°-81.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[NH:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24].NC1C=C(C=CC=1NCC1C=CC=CC=1Cl)C(O)=O.C([NH-])(=O)CCCC>C(O)(=O)C>[CH2:21]([C:20]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[N:19]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=O)Nc1cc(C(=O)O)ccc1NCc1ccccc1Cl
Agent: CCCCC([NH-])=O
Agent: Nc1cc(C(=O)O)ccc1NCc1ccccc1Cl
Solvent: CC(=O)O
Product: CCCCc1nc2cc(C(=O)O)ccc2n1Cc1ccccc1Cl
Yield: 81 %

Procedure:
The procedure of example 2(iii) was followed to prepare the amide, 4-[(2-chlorophenyl)methyl]amino-3-(valeryl)aminobenzoic acid, from 3-amino-4-[(2-chlorophenyl)methyl]aminobenzoic acid. The valeryl amide melted at 207°-209° C. (from ethyl acetate/hexane). This amide (0.39 g, 1.08 mmol) was refluxed in acetic acid (2.5 mL) for 3 hours, the acetic acid was evaporated, water was added and the resulting solid was filtered and washed with water. Crystallization from methanol provided 0.3 g (81%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-5-carboxylic acid; mp 238°-239° C.
Reaction SMILES: C(O[C:4](=[O:28])[C:5](=[O:27])[N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][NH:12]2)C>O1CCCC1.[Ni]>[C:21]1([CH2:20][N:6]2[C:7]3[C:8]4[CH2:9][CH2:10][CH2:11][NH:12][C:13]=4[CH:14]=[CH:15][C:16]=3[NH:17][C:4](=[O:28])[C:5]2=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)c1c([N+](=O)[O-])ccc2c1CCCN2
Agent: [Ni]
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc3c(c2n(Cc2ccccc2)c1=O)CCCN3
Reaction time: 48 h
Yield: 57.4 %

Procedure:
A solution of the product from Example 92 (0.67 g, 1.7 mmol) in 20 ml tetrahydrofuran was treated with Raney nickel (0.1 g) and stirred under a hydrogen atmosphere (1 atm) for 48 hours. The Raney nickel was removed with a magnet and washed with methanol. The remaining solid was collected by filtration, washed with methanol and then dissolved in 2 N HCl and filtered. The filtrate was neutralized with saturated sodium bicarbonate and the precipitate collected by filtration and dried to give the title compound (0.30 g, 57% yield) mp>300° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7]3)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Product: Cc1cc(NC(=O)Nc2ccccc2)c2[nH]c(-c3ccccn3)cc2c1

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole prepared in Step A of Example 1 and phenylisocyanate were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6][O:5]1.[CH3:11][O:12][CH2:13]Cl>O1CCCC1>[CH3:11][O:12][CH2:13][N:8]1[CH2:9][C@@H:4]([CH3:3])[O:5][CH2:6][C:7]1=[O:10]
Reactant: C[C@@H]1CNC(=O)CO1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN1C[C@@H](C)OCC1=O
Reaction time: 0.5 h

Procedure:
To sodium hydride (63%, 4.4 g, 116 mmol) suspended in tetrahydrofuran (100 mL), a solution of (6R)-6-methylmorpholin-3-one (EP350002) (12.1 g) in tetrahydrofuran (50 mL) was added dropwise over 30 minutes under ice cooling. The mixture was stirred at the same temperature for 30 minutes and then further stirred at room temperature for 30 minutes. A solution of chloromethyl methyl ether (10 mL) in tetrahydrofuran (50 mL) was added dropwise thereto over 30 minutes under ice cooling. The mixture was stirred for 30 minutes under ice cooling and then stirred overnight at room temperature. An appropriate amount of water for partition was added thereto, followed by several extractions with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane-hexane/ethyl acetate=40/60) to obtain the title compound (7.86 g).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].C([O-])([O-])=O.[Na+].[Na+].[Cl:23][C:24]1[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(OCC)(=O)C.CC(C)=O.O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:26]([C:25]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([O:33][CH3:34])[C:24]=1[Cl:23])=[O:27]
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OC
Reactant: CC(C)CCNCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3[nH]2)c(Cl)c1OC
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of 3.0 g (13.8 mmole) of (benzimidazol-2-ylmethyl) (3-methylbutyl)amine in 150 mL of 1:1:1 ethyl acetate, acetone, water is treated with 3.66 g (34.5 mmole) Na2CO3 and a solution of 3.22 g (13.7 mmole) of 2-chloro-3,4-dimethoxybenzoyl chloride in 50 mL of acetone at 0° C. The resulting mixture is allowed to warm to room temperature for 1 hour. The reaction solution is diluted with 300 mL of ethyl acetate and then washed with 2×60 mL water, 1×60 mL sat. NaHCO3, and 1×60 mL of brine. The resulting organic layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo. The residue is treated with 150 mL of methanol and 1.1 g of NaOH at reflux for 2 hours and then allow to cool to room temperature for 2 hours. The resulting solution is evaporated under reduced pressure and partioned between ethyl acetate 200 mL and water 100 mL. The ethyl acetate extracts are dried over anhydrous Na2SO4 and the solvent removed in vacuo. The resulting residue is flash chromatographed (1:1 ethyl acetate/hexanes) to afford 2.82 g (49%) of N-(benzimidazol-2-ylmethyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.
Reaction SMILES: [C:1]12(Br)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br-].C12CC3CC(CC(C3)C1)C2.C[Si](C)(C)[O:25][CH:26]=[C:27]([O:33][Si](C)(C)C)[O:28][Si](C)(C)C.[NH4+].[Cl-]>C(Cl)Cl.[Cl-].[Zn+2].[Cl-].CCCCCCC.C(OCC)(=O)C>[OH:25][CH:26]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)[C:27]([OH:33])=[O:28]
Reactant: C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: C1C2CC3CC1CC(C2)C3
Agent: [Br-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(O)C(O)C12CC3CC(CC(C3)C1)C2
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A dry vessel was charged with 7.5 kg adamantyl bromide. Methylene chloride (22.5 liters) was then added at room temperature to dissolve the solid adamantane bromide. Dissolving is endothermic so before the next step, the temperature of the reaction mixture was allowed to return to 20° C. The reaction mixture was then charged with zinc chloride (1.05 kg) and stirred for approximately 5 minutes at 20° C. The reaction mixture was then charged with tris(trimethylsiloxy)-ethylene (15.3 kg) while maintaining the reaction temperature between 20 to 25° C. and the resulting mixture was stirred for 2 hours. Following this mixing, tris(trimethylsiloxy)-ethylene (5.10 kg) was added. During this addition, the temperature was maintained below 30° C. The reaction was maintained for another 12 to 15 hours at 20 to 25° C., at which time the reaction mixture was diluted with methylene chloride (15 liters) and cooled to 0 to 5° C. The reaction mixture was then treated, beginning in dropwise fashion, with half-saturated NH4Cl solution. During addition, the temperature was kept below 30° C. A thick suspension was obtained. To this suspension was added ethyl acetate (93.75 liters). The mixture was stirred vigorously for 15 minutes and the organic and aqueous phases were split. The organic layer was stored and the aqueous layer was washed twice with ethyl acetate (18.75 liters in each wash). The ethyl acetate washes and organic layer were then combined and washed with water (37.5 liters) followed by water half saturated with brine (37.5 liters). The organic layer was separated again and evaporated to form crystals. A solvent exchange to heptane was then performed at a final volume of 22.5 liters. The resulting suspension was cooled to 5 to 10° C. for 1 hour and the product α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B) was obtained via filtration. Yield of α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B) was 6.96 kg (33.11 mol, 95%).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][P:8]([CH3:12])(=[O:11])[O:9][CH3:10].C([O:15][C:16](=O)[CH:17]([CH3:23])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])C.C(O)(=O)C>CCCCCC.O1CCCC1>[CH3:6][O:7][P:8]([CH2:12][C:16]([CH:17]([CH3:23])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[O:15])(=[O:11])[O:9][CH3:10]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)C(C)CC=C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)C(C)CC=C(C)C)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
Under argon at -60° C., 274.7 ml of a 1.61-molar butyllithium solution in hexane was added dropwise to a solution of 59 g of methanephosphonic acid dimethyl ester in 400 ml of absolute tetrahydrofuran. After 15 minutes of agitation, a solution of 34.05 g of 2,5-dimethyl-4-hexenoic acid ethyl ester in 100 ml of absolute tetrahydrofuran was added dropwise thereto. The reaction mixture was allowed to warm up to room temperature within 4 hours and thereafter stirred for another 3 hours. Then the mixture was combined with 26.5 ml of glacial acetic acid and concentrated under vacuum. The residue was taken up in ether/water, the aqueous phase was combined with solid sodium chloride, and shaken out with ether. The combined organic phases were dried over magnesium sulfate and concentrated on a forced circulation evaporator. The evaporation residue was purified by column chromatography on silica gel with hexane/50-100% ethyl acetate as the mobile phase, thus producing 32 g of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:33]3[O:32][C:36]4=[CH:37][CH:38]=[CH:39][C:40]4=[CH:35][CH:34]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3-c3ccc4cccc-4o3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 2-benzofuryl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH2:13][S:14][C:15](=N)N)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.ClC[CH2:23][C:24]#[N:25].[OH-].[Na+]>O.C(O)C>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH2:13][S:14][CH2:15][CH2:23][C:24]#[N:25])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#CCCCl
Reactant: N=C(N)SCc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CCCSCc1cccc(CN2CCCCC2)c1
Temperature: 20 °C

Procedure:
A stirred solution of the above isothiourea (1.2 g) and 3-chloropropionitrile (0.4 ml) in a mixture of water (7 ml) and ethanol (5 ml) was treated at 0°-5° C. with 2.5N sodium hydroxide (5.3 ml). The reaction mixture was stirred at 0°-5° C. for a further hour and then allowed to warm to 20° C. The reaction mixture was extracted with ethyl acetate and the extracts washed with water, dried and evaporated to provide 3-(3-piperidinomethylbenzylthio)propionitrile as an oil.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([O:34][CH3:35])[CH:27]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:30][C:29]3[C:31]([CH3:33])=[CH:32][C:26]([Cl:25])=[CH:27][C:28]=3[O:34][CH3:35])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: COc1cc(Cl)cc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2c(C)cc(Cl)cc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 22.8 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 470 mg, 1.27 mmol), 4-chloro-2-methoxy-6-methylaniline (650 mg, 3.81 mmol) and p-toluenesulfonic acid (241 mg, 1.27 mmol) and xylene (5.0 mL) was irradiated by microwave at 150° C. for 4 hr. After cooling, the reaction mixture was extracted with ethyl acetate (×3). The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (120 mg, 0.289 mmol, 18.7%) as a brown amorphous.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].Br[CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(OC(C)C)(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH2:22]([O:21][C:19]([CH2:18][CH2:17][CH2:24][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13])=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(C)Br
Reactant: O=C1Nc2cccc3c2C1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCC12CCCc3cccc(c31)NC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
(RS)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (8.65 g, 50 mmol) was dissolved in anhydrous N,N,-dimethylformamide (70 ml). Then, 60% sodium hydride (2.0 g, 50 mmol) was added thereto and the resulting mixture was stirred at room temperature for 1 hour. Successively the reaction mixture obtained was cooled to −20° C., and ethyl 3-bromobutyrate (7.15 ml, 50 mmol) was added thereto. The resulting mixture was stirred at room temperature for further 18 hours. Ethyl acetate and water were added thereto to extract a reaction product. The ethyl acetate solution was washed with saturated saline solution and then dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain a reaction product. Thereafter, diisopropyl ether was added to the resulting reaction product to crystallized the same. Thus, the above-described object compound was obtained in an amount of 8.01 g (yield 56%).