Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCC([O:6][C:7]1([CH2:21][CH2:22][N:23]([CH2:25][CH2:26][CH2:27][C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)[CH3:24])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[CH:8]1[CH:18]([CH3:20])[CH3:19])=O.[F:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH:44]([CH:48]([CH3:50])[CH3:49])[C:43]([CH2:52][C:53]([OH:55])=[O:54])([OH:51])[CH2:42][CH2:41]2>>[F:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH:44]([CH:48]([CH3:50])[CH3:49])[C:43]([CH2:52][C:53]([OH:55])=[O:54])([OH:51])[CH2:42][CH2:41]2.[NH:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH2:27][CH2:26][CH2:25][NH:23][CH3:22].[NH:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH2:27][CH2:26][CH2:25][N:23]([CH3:24])[C:22](=[O:51])[CH2:21][C:7]1([OH:6])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[CH:8]1[CH:18]([CH3:20])[CH3:19]
Reactant: COCC(=O)OC1(CCN(C)CCCc2nc3ccccc3[nH]2)CCc2cc(F)ccc2C1C(C)C
Agent: CC(C)C1c2ccc(F)cc2CCC1(O)CC(=O)O
Product: CC(C)C1c2ccc(F)cc2CCC1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1
Product: CNCCCc1nc2ccccc2[nH]1

Procedure:
A method of preparing 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid or an activated derivative of (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid with [3-(1H-benzimidazol-2-yl)propyl]methylamine to form N-[3-(1H-benzimidazol-2-yl) propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3 ,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, reducing this to 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-ol, and treating the 2-[2-{[3-(1H-benzimidazol-2-yl) propyl]-methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}-ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N-[3-(1H-benzimidazol-2yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide is new.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.COC(C)(C)C>[CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH2:11][C@H:10]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(Cc2ccccc2)C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(Cc2ccccc2)C1
Yield: 33.6 %

Procedure:
To a solution of 1.8 g (5.6 mmol) (3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol in 50 ml THF were consecutively added 0.75 g (6.2 mmol) benzoic acid, 1.1 g (6.2 mmol) diethyl azodicarboxylate and 1.6 g (6.2 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixture was diluted with tert-butyl methyl ether washed with a 2N aqueous solution of sodium carbonate. The aqueous layer was extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with a 2N aqueous solution of sodium carbonate and brine and dried over sodium sulfate. Flash chromatography gave 0.80 g (3S,5R)-benzoic acid 1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-yl ester as a light brown oil. The ester was dissolved in a mixture of 50 ml dioxane and 18 ml 1N aqueous sodium hydroxide solution. The reaction mixture was heated at 70° C. for 5 h. After cooling to room temperature the mixture was extracted with tert-butyl methyl ether. The organic extract was washed with a 2N aqueous solution of sodium carbonate. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic extracts were washed with brine and dried over sodium sulfate. Flash chromatography gave 0.10 g (17%) of the title compound as a light brown oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][S:34][C:35]#[N:36])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.N1C=CC=CC=1.[C:44]([O:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:72]([NH2:73])[C:71](=[O:74])[N:53]2[C:54]=1[C:55]([O:57][CH:58]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])(=[O:46])[CH3:45].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:44]([O:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:72]([NH:73][C:27](=[O:28])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][CH2:33][S:34][C:35]#[N:36])[C:71](=[O:74])[N:53]2[C:54]=1[C:55]([O:57][CH:58]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])(=[O:46])[CH3:45]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: N#CSCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: I
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCCSC#N)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 16 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1.69 g of the product of Step A, 0.685 g of pyridine hydroiodide, 1.16 g of benzhydryl 3-acetoxymethyl-7-amino-ceph-3-eme-4-carboxylate and 1.36 g of dicyclohexylcarbodiimide was admixed with 17 ml of dimethylformamide and the mixture was cooled to 16° C. for 30 minutes and was then vacuum filtered. 400 ml of ether were added to the filtrate and the mixture was stirred for 5 minutes and allowed to stand for one hour. The mixture was decanted and the gum was washed with ether and was added to 50 ml of ether. The mixture was kneaded until concretization and was vacuum filtered. The product was washed with ether and dried to obtain 1.92 of raw product which was chromatographed over silica gel. Elution with a 91-9 chloroform-acetonitrile mixture yielded 790 mg of amorphous syn isomer of benzhydryl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-thiocyanatoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CS[C:9]1[S:10][CH2:11][CH2:12][N:13]=1.C[O-].[Na+]>C(O)C>[OH:2][CH:3]1[CH2:6][N:5]([C:9]2[S:10][CH2:11][CH2:12][N:13]=2)[CH2:4]1
Reactant: CSC1=NCCS1
Reactant: OC1CNC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: OC1CN(C2=NCCS2)C1
Yield: 75.6 %

Procedure:
To a solution of 109 mg of 3-hydroxyazetidine HCl [Compound (15)] in 5 ml of ethanol was added a mixture of 133 mg of 2-methylthiothiazoline [Compound (16)] and sodium methoxide (0.9 equivalent mole), and the reaction mixture was refluxed for 8 hours. After removal of the solvent under reduced pressure, the resulting residue was dissolved in chloroform and washed with saturated saline solution. After removal of the solvent under reduced pressure, the resulting residue was washed with diethylether to give 119 mg (81.5%) of 3-hydroxy-1-(thiazolin-2-yl)azetidine [Compound (17)] as crystals.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1.C(OCC)(=O)C.O>[C:1]([NH:9][S:19]([C:16]1[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
To a solution of benzamide (1.42 g) in tetrahydrofuran (50 ml) were added sodium hydride (611 mg) and 4-bromobenzenesulfonyl chloride (3.0 g), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give N-benzoyl-4-bromobenzenesulfonamide (2.1 g) as a colorless powder.
Reaction SMILES: Br[C:2]([P:5](=[O:10])([O-:9])[O:6][CH2:7][CH3:8])([F:4])[F:3].[CH:11]([Mg]Cl)(C)[CH3:12].[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1.CC(C)=O.C(Cl)Cl>[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)[CH:22]=[CH:21][C:18]=1[CH:19]([OH:20])[C:2]([P:5](=[O:10])([O:9][CH2:11][CH3:12])[O:6][CH2:7][CH3:8])([F:4])[F:3]
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(-c2ccc(F)cn2)c(F)c1F
Reactant: CCOP(=O)([O-])C(F)(F)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(F)(F)C(O)c1ccc(-c2ccc(F)cn2)c(F)c1F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of ethyl bromodifluoromethylphosphonate (3.2 g, 12.1 mmol) in tetrahydrofuran (20 mL) was added dropwise to a solution of isopropylmagnesium chloride (2 M in tetrahydrofuran) (6.1 mL, 12.1 mmol) in tetrahydrofuran (20 mL) at −78° C. After stirring at −78° C. for 5 min, a solution of 2,3-difluoro-4-(5-fluoropyridin-2-yl)benzaldehyde (1.92 g, 8.1 mmol) in tetrahydrofuran (20 mL) was added dropwise. After stirring for a further 5 min at −78° C. then a further 1 h between −78 and 0 then a further 1 h between 0 and ambient temperature. The reaction mixture was poured into saturated ammonium chloride and extracted with methylene chloride. Combined extracts were washed with saturated aqueous sodium bicarbonate, dried (sodium sulfate) and concentrated in vacuo to afford a slightly yellow oil. Chromatography over silica eluting with 0-40% acetone/methylene chloride afforded diethyl {2-[2,3-difluoro-4-(5-fluoropyridin-2-yl)phenyl]-1,1-difluoro-2-hydroxyethyl}phosphonate as an off-white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O1CCOCC1.O>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1CCNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
The 3(S)-hydroxy-pyrrolidine (1.0 g, 11.5 mmol), triethylamine (2.32 g, 22.9 mmol, 2.0 equiv) in 1,4-dioxane (30 mL) and water (10 mL) is stirred at room temperature and then 4-methoxyphenylsulfonyl chloride (2.61 g, 12.6 mmol, 1.10 equiv) is added. The resulting solution is stirred at room temperature for 3 h. and then the solution is acidified to pH~1 with 1 N HCl. The solution is poured into water and then extracted with CH2Cl2. The organic extracts are dried (Na2SO4) and concentrated o an oil. The oil is purified by chromatography using 1/1 hexane/EtOAc as the eluent to afford 2.62 g (81%) of the desired product as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1.BrC1C=CC=CC=1.COC(C)(C)C>CCCCCC>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:10]([C:4]2[C:3](=[O:15])[N:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[OH:9])=[O:12])=[N:18][CH:19]=1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Cc1ccc(N)nc1
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: Brc1ccccc1
Product: Cc1ccc(NC(=O)c2c(O)cc(C)n(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
214 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 101 mg of 2-amino-5-methylpyridine were added to 2.5 ml of bromobenzene and the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, and t-butyl methyl ether and n-hexane were added to the mixture. The resulting solid was collected by filtration, washed with t-butyl methyl ether and n-hexane, and dried to obtain N-(5-methyl-2-pyridyl)-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:22].[OH-].[K+].CO>O>[CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:22]
Reactant: CCOC(=O)COc1ccc2ncc3nc(C)n(C)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2cnc3ccc(OCC(=O)O)cc3c2n1C
Yield: 86.1 %

Procedure:
Ethyl 2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetate (1.6 g, 5.35 mmol) was added to a solution of potassium hydroxide (0.90 g, 0.16 mol) in a 50:50 mixture of methanol:water (30 mL). The solution was stirred under a nitrogen atmosphere until it was complete as evidenced by HPLC analysis. The methanol was removed under reduced pressure, and 6 N aqueous hydrochloric acid was added until the solution exhibited a neutral pH. A precipitate formed and was isolated by filtration to provide 1.25 g of 2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetic acid as a white solid, mp 290° C. (decomposition).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:18][CH3:19])[C:15]([NH2:17])=[O:16].F[B-](F)(F)F>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:4][Si:3]([C:1]#[C:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:18][CH3:19])[C:15]([NH2:17])=[O:16])([CH3:6])[CH3:5]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(C(N)=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCC(C(N)=O)c1ccccc1C#C[Si](C)(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Ethynyltrimethylsilane (0.11 mL, 0.80 mmol) and dry DMF (9.0 mL) was added to a mixture of 2-(2-iodophenyl)butanamide (I2) (193 mg, 0.668 mmol), PdCl2(PPh3)2 (23 mg, 0.033 mmol), t-Bu3PH.BF4 (10 mg, 0.033 mmol) and CuI (6 mg, 0.033 mmol) under nitrogen. The resulting solution was degassed with a stream of nitrogen for 10 minutes before the addition of Et3N (3.0 mL). The resulting mixture was stirred at 60° C. under nitrogen for 16 hours then adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound I3 as a tan coloured solid (151 mg, 87); 1H NMR (400 MHz, d6-DMSO) δ 7.46-7.39 (m, 2H), 7.34 (td, J=7.7, 1.4 Hz, 1H), 7.26 (br, 1H), 7.21 (td, J=7.5, 1.4 Hz, 1H), 6.97 (br, 1H), 3.80 (dd, J=8.9, 5.7 Hz, 1H), 1.95-1.80 (m, 1H), 1.69-1.55 (m, 1H), 0.85 (t, J=7.3 Hz, 3H), 0.25 (s, 9H). LCMS-A: rt 6.267 min; m/z 260 [M+H]+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=2)[CH2:2]1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:22][CH:21]=1.N12CCN(CC1)CC2>CN(C)C=O.C(OCC)(=O)C>[Si:30]([O:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=2)=[CH:21][CH:22]=1)([C:43]([CH3:45])([CH3:46])[CH3:44])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)c1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(OCC(O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Temperature: 70 °C
Yield: 58.7 %

Procedure:
A mixture of 1,2-epoxy-3-[4-(tert-butoxycarbonyl)phenoxy]propane (5.11 g, 20.4 mmol) [S. P. Connors, et al., J. Med. Chem., 1991, 34, 1570] and 3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (7.97 g, 20.4 mmol) in N,N-dimethylformamide (50 ml) was treated with 1,4-diazabicyclo[2,2,2]octane (0.45 g) and the resulting mixture was heated at 70° C. for 48 hours. The cooled mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 95:5) gave 7.67 g (58%) of the title material as oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[N:18]=[C:17]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:16]=[C:15]2[N:34]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:35]=[C:36]([CH2:37][CH:38]([C:40]#[N:41])[OH:39])[C:14]=12.ClCCl.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:39][CH:38]([C:40]#[N:41])[CH2:37][C:36]2[C:14]3[C:15](=[N:16][C:17]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[N:18][C:13]=3[Cl:12])[N:34]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:35]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1c(C)cnc(Cn2nc(CC(O)C#N)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc(CC(C#N)OS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
p-Toluenesulfonyl chloride (511 mg) was added to a mixture composed of the above crude di-tert-butyl {4-chloro-3-(2-cyano-2-hydroxyethyl)-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (788 mg) and dehydrated dichloromethane (12 mL), followed by dropwise addition of triethylamine (0.56 mL). Then, 4-dimethylaminopyridine (16 mg) was added and the mixture was stirred at room temperature for three hours. The reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (450 mg, 45%) as a solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)#[N:4].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]=1[OH:28])([CH3:17])([CH3:16])[CH3:15].Cl>CS(C)=O>[C:24]([C:20]1[CH:21]=[C:22]([C:10]2[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[C:3]#[N:4])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[OH:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2C#N)cc(C(C)(C)C)c1O
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of 30 mg (0.75 mmol) of powdered sodium hydroxide, 87 mg (0.59 mmol) of 3-cyano-1-nitrobenzene, 155 mg (0.75 mmol) of 2,6-di-t-butylphenol, and 1.0 mL of dimethylsulfoxide was heated at 80° C. for 90 minutes and poured into 10 mL of 1N HCl, and the resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. The ether layers were combined, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative thin layer chromatography and crystallization afforded 98 mg (47% yield) of 2,6-di-t-butyl-4-(2'-cyano-4'-nitrophenyl)phenol.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[CH2:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:14][CH3:15])=[N:9]2)=[N:4][CH:3]=1.Cl.C1(C[N:24]([CH2:28][C@@H:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[C:25](=[O:27])[OH:26])C=CC=CC=1.C(N([CH:40]([CH3:42])[CH3:41])CC)(C)C>CN(C=O)C>[C:40]1([CH2:41][O:26][C:25](=[O:27])[NH:24][CH2:28][C@@H:29]2[CH2:33][CH2:32][N:31]([CH2:13][CH2:12][C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[N:9]=4)[N:4]=[CH:3][C:2]=3[Cl:1])[CH2:30]2)[CH:42]=[CH:10][CH:11]=[CH:2][CH:3]=1
Reactant: O=C(O)N(Cc1ccccc1)C[C@@H]1CCNC1
Reactant: CCN(C(C)C)C(C)C
Reactant: C=Cc1c(Cl)cnc2ccc(OC)nc12
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
To a solution of 7-chloro-8-ethenyl-2-(methyloxy)-1,5-naphthyridine (1.68 g, 7.6 mmol) in DMF (5 mL) was added phenylmethyl[(3R)-3-pyrrolidinylmethyl]carbamate hydrochloride (2.1 g, 7.6 mmol) and diisopropylethylamine (3.9 mL, 22.8 mmol)). The reaction was heated at 100° C. for 18 h. Upon cooling to room temperature, the crude reaction mixture was directly added to a silica gel column and purified to give a light brown oil (1.3 g): LC/MS (ES) m/e 455 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:12](B(O)O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:22][C:23]1[C:27]([C:28]2[CH:29]=[C:30](C3C(C)=CC=C4C=3C=CC=N4)[C:31]3[NH:35][C:34](=[O:36])[NH:33][C:32]=3[CH:37]=2)=[C:26]([CH3:49])[O:25][N:24]=1>>[CH3:22][C:23]1[C:27]([C:28]2[CH:29]=[C:30]([C:12]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][CH:9]=[CH:10][CH:11]=3)[C:31]3[NH:35][C:34](=[O:36])[NH:33][C:32]=3[CH:37]=2)=[C:26]([CH3:49])[O:25][N:24]=1
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Reactant: OB(O)c1cccnc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1-c1cc(-c2cccnc2-c2ccccc2)c2[nH]c(=O)[nH]c2c1

Procedure:
6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one was synthesized using 2-phenylpyridin-3-ylboronic acid and Cs2CO3 in a similar fashion as 6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example 2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH2:16][OH:17])[S:15][C:11]=2[C:10]([I:18])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH2:16][O:17][S:27]([CH3:26])(=[O:29])=[O:28])[S:15][C:11]=2[C:10]([I:18])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1nc(I)c2sc(CO)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(I)c2sc(COS(C)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
To 5-hydroxymethyl-3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [220 mg, 0.58 mmol, Intermediate (80)] in dichloromethane (5 mL) were added triethylamine (85 μL, 0.67 mmol), and methane sulfonyl chloride (50 μL, 0.67 mmol). The mixture was stirred at 0° C. for 15 minutes then at room temperature for 30 minutes. The solution was washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to afford 3-iodo-5-methanesulfonyloxymethyl-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [220 mg, 79%, Intermediate (81)] as a white foam. LC/MS: 458.97 (M+H), RT=3.39 minutes.