Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]2[CH2:13][C:12]([CH3:22])([CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:29](I)[CH3:30]>O1CCOCC1.CN(C)C=O>[C:23]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:13][C:12]([CH3:22])([CH2:14][N:15]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:29][CH3:30])[CH2:11]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCI
Reactant: CC1(CNC(=O)C(F)(F)F)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCN(CC1(C)CN(C(c2ccccc2)c2ccccc2)C1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
0.16 g (3.6 mmol) of 55% strength sodium hydride is added to a solution of 1.3 g (3.6 mmol) of 1-diphenylmethyl-3-methyl-3-trifluoroacetylaminomethylazetidine in 40 ml of dioxane and 10 ml of dimethylformamide, and the mixture is stirred for two hours at 60°-70° C. The solution is cooled to room temperature, 0.73 g (4.6 mmol) of ethyl iodide is added, the mixture is stirred for 4 hours at 70° C. and evaporated to dryness, the residue is dissolved with chloroform, the organic phase is washed with water, dried with anhydrous sodium sulphate and evaporated and 1.1 g (79%) of 1-diphenylmethyl-3-methyl-3-[N-(ethyl)trifluoroacetylaminomethyl]azetidine are obtained. This compound is dissolved in ethanol, and ethyl ether saturated with hydrochloric acid is added. The product is allowed to crystallize and is filtered off, and 1-diphenylmethyl-3-methyl-3-[N-(ethyl)trifluoroacetylaminomethyl]azetidine hydrochloride, melting point 191°-4° C., is obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[S:7][CH:8]=[C:9]([Br:11])[CH:10]=1.Cl[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>ClCCl>[Br:11][C:9]1[CH:10]=[C:6]([Br:5])[S:7][C:8]=1[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Brc1csc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1sc(Br)cc1Br
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Aluminium chloride (0.26 g, 1.98 mmol) was added to a solution of 2,4-dibromothiophene (0.30 g, 1.24 mmol) and ethyl chlorooxoacetate (0.19 g, 1.36 mmol) in dichloromethane (10 mL) previously cooled with an ice bath. The reaction mixture was stirred at room temperature for 45 minutes, poured into ice water and extracted with dichloromethane (2×20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide ethyl 2-(3,5-dibromothiophen-2-yl)-2-oxoacetate (0.42 g, 1.24 mmol, 100%) as a yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][N:12]=2)=[O:10])[CH2:4][CH2:3]1.[BH4-].[Na+].Cl>CCOCC.C(O)C>[OH:10][CH:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][N:12]=1)[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]1
Reactant: O=C(CN1CCC(O)CC1)c1cc(-c2ccccc2)on1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: OC1CCN(CC(O)c2cc(-c3ccccc3)on2)CC1

Procedure:
To a solution of 3-(4-hydroxypiperidino)acetyl-5-phenylisoxazole (25 mg) in ether (10 ml) is added a solution of sodium borohydride (15 mg) in ethanol (1.0 ml) with stirring and then the mixture is stirred for 1 hour. After being cooled, the mixture is acidified with a dilute hydrochloric acid and evaporated under reduced pressure. To the residue is added water and the solution is made alkaline with an aqueous solution of potassium hydroxide, then extracted with chloroform. After removal of the solvent, the residue is subjected to a chromatography using silica gel to give crystalline 3-[1-hydroxy-2-(4-hydroxypiperidino) ethyl]-5-phenylisoxazole. Recrystallization from a mixture of ethyl acetate and hexane gives colorless prisms (20 mg) melting at 117-119°C.
Reaction SMILES: [Si]([N:8]1[CH:11]([CH2:12][CH:13]([O:15][C:16](=[O:18])[CH3:17])[CH3:14])[CH2:10][C:9]1=[O:19])(C(C)(C)C)(C)C>Cl.CO>[C:16]([O:15][CH:13]([CH3:14])[CH2:12][CH:11]1[NH:8][C:9](=[O:19])[CH2:10]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(=O)OC(C)CC1CC(=O)N1
Reaction time: 2.5 h

Procedure:
1-(t-butyldimethylsilyl)-4-(2-acetoxypropyl)-2-azetidinone (2.4 g) is dissolved in a solution of HCl in MeOH (0.25 N, 10 ml) and allowed to stand 2.5 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel to give 4-(2-acetoxypropyl)-2-azetidinone.
Reaction SMILES: O=[C:2]1[O:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCOCC1>[CH:12]1([N:17]2[C:2](=[O:7])[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(=O)oc1
Reactant: NC1CCCC1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(=O)n(C2CCCC2)c1
Reaction time: 0.08 h

Procedure:
Methyl 6-oxo-6H-pyran-3-carboxylate (Aldrich, 4.00 g, 26.0 mmol) was placed in a 500 mL rbf before 1,4-dioxane (40.0 mL) was added via syringe. After 5 min, cyclopentyl amine (13.0 mL) was added via syringe and the reaction was allowed to stir for 14 h before the volatiles were removed by rotary evaporation. The solid residue was dissolved in diethyl ether (100 mL) and then washed with HCl (10%, 1×100 mL), NaHCO3 (sat, 1×100 mL), brine (sat 100 mL), and dried with magnesium sulfate. The dried solution was filtered and concentrated to provide 4.95 g of crude oil which was purified by a 120 g normal phase Isco column chromatography (50% EtOAc-100% EtOAc in hexanes) to give 2.38 g of methyl 1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate. MS m/z: 222 (M+1). This methyl ester was dissolved in THF (30 mL) and water was added (10 mL) before the addition of LiOH monohydrate (1.20 g) and then reaction was placed in a 70° C. oil bath for 2 h. The reaction was cooled and the bulk of the THF was removed by rotary evaporation. The reaction was then poured into a separatory funnel and HCl (10%, 75 mL) was added before extracting with diethyl ether (3×100 mL). The combined organics were washed with brine (sat, 200 mL) and dried with magnesium sulfate. The solution was filtered and concentrated to provide an off white solid (920 mg). MS m/z: 208 (M+1).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[C:3]1=[O:9].[CH3:10][C:11]1[O:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)(=O)C>[CH3:15][C:14]1[O:17][C:11]([CH:10]=[N:1][N:2]2[CH2:7][CH2:6][NH:5][C:4](=[O:8])[C:3]2=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(C=O)o1
Reactant: NN1CCNC(=O)C1=O
Solvent: CC(=O)O
Product: Cc1ccc(C=NN2CCNC(=O)C2=O)o1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
1.3 pts. by wt. of 1-amino-2,3-dioxo-piperazine, 1.3 pts. by wt. of 5-methyl-furfural and 7 pts. by vol. of glacial acetic acid are warmed to 90° C. for 10 minutes and then left for 30 minutes at RT. The precipitate is filtered off, washed first with 3 pts. by vol. of glacial acetic acid and then three times with 10 pts. by vol. of ethyl acetate and dried in air. 1.7 pts. by wt. (76.6%) of 1-(5-methyl-furfurylideneamino)-2,3-dioxo-piperazine of decomp. pt. 245°-8° C. are obtained.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]2[CH3:31])[N:20]=[C:19]([Cl:32])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl.CCOCC>C(Cl)Cl>[Cl:32][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]2[CH3:31])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: C[C@@H]1CN(C)CCN1c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CN(C)CCN1c1nc(Cl)nc(NN)c1F
Reaction time: 64 h

Procedure:
To a solution of tris(1,1-dimethylethyl)2-{2-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (215.28 g, 374.3 mmol) in DCM (1870 mL) was added 2 N HCl in Et2O (1870 mL, 3740 mmol). The solution was mechanically stirred for 64 h, and the resulting suspension was allowed to settle. Most of the solvent was then decanted, and the remaining solid was triturated with DCM (1000 mL) and collected by vacuum filtration. The solid was washed with DCM and dried under high vacuum to provide 2-chloro-4-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazinopyrimidine, assumed trihydrochloride (138.22 g, 96% yield) as a light yellow powder. LCMS: (M+H)+: 275.1.
Reaction SMILES: [OH-].[Na+].CO.[SH2:5].Br[CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]>O>[CH3:16][C:9]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:8][CH2:7][SH:5]
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)=CCCC(C)=CCS

Procedure:
To a solution of 2 g. of sodium hydroxide in 40 ml. of methanol saturated with hydrogen sulfide is added 14 g. of 1-bromo-3,7-dimethylocta-2,6-diene. The mixture is stirred at about 25° for about five hours with continued introduction of hydrogen sulfide. The mixture is diluted with water and then extracted with petroleum ether. The organic phase is washed well with water, dried over sodium sulfate and evaporated under reduced pressure to yield 3,7-dimethylocta-2,6-dienylmercaptan which is purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:26](O)(=[O:32])[CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:26](=[O:32])[CH2:27][CH2:28][C:29](=[O:30])[NH2:31])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: NC(=O)CCC(=O)O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)CCC(N)=O)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-1-(3-carbamoyl-propionyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using succinamic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a colorless oil. MS m/e: 465.1 [M]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41]>C1COCC1>[ClH:31].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:33]4[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=4[Cl:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)Nc1ccc(Cl)cc1Cl
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 40.2 mg (0.21 mmol) of 2,4-dichlorophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 25 mg (44.5% of theory) of the title compound are obtained.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C@@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[C@H:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]=3[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:5]2)[O:3]C1.Cl>O1CCCC1>[CH2:29]([O:28][C:15]1[CH:16]=[C:17]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:19][C:14]=1[C@H:6]1[C@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OCCC[C@@H]1CCC2(C[C@H]1c1ccc(OCc3ccccc3)cc1OCc1ccccc1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CC[C@@H](CCCO)[C@H](c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Yield: 92 %

Procedure:
A mixture of 5.17 g. (10.6 mmole) of trans-3-(2,4-dibenzyloxyphenyl)-4-(3-hydroxypropyl)cyclohexanone ethylene ketal, 50 ml. 1 N hydrochloric acid and 100 ml. tetrahydrofuran was heated at reflux for one hour. The reaction was cooled, partially evaporated on a rotovapor and the residue diluted with 300 ml. saturated sodium chloride-300 ml. ether. The ether extract was washed with 300 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue was crystallized from diisopropyl ether to yield 4.32 g. (92%) of the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2cccc(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 59% overall yield. FDMS m/e=426 (M+ of free base). α[D]589 =-11.39 (c=0.56, methanol).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[C:21]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:21])[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c(Br)cccc1-n1c(=O)c2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A suspension of 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (23.02 g, 69.5 mmol) and Cs2CO3 (34.0 g, 104 mmol) in DMF (70 mL) cooled in an ice-water bath was treated portionwise with iodomethane (5.22 mL, 83 mmol). The mixture was warmed to room temperature and stirred for 30 min. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc and water. A precipitate which formed was collected by filtration. The collected solid was washed with water and dried overnight under vacuum to give a white solid. The organic phase of the filtrate was separated, washed 3 times with 10% aqueous LiCl, then was washed twice with water, dried and concentrated to give additional solid. The two solids were combined to give 3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione as a white solid (15.56 g, 92% yield). Mass spectrum m/z 345, 347 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:12](=[CH2:22])[O:11][C@H:10]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:33][CH2:34][O:35][P:36]([O:40][CH2:41][CH3:42])([CH2:38][OH:39])=[O:37].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClC(Cl)C>[NH2:32][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[C:29]=1[N:30]=[CH:31][N:23]2[C@@H:10]1[O:11][C@:12]([CH3:22])([O:39][CH2:38][P:36](=[O:37])([O:40][CH2:41][CH3:42])[O:35][CH2:34][CH3:33])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@H:9]1[O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCOP(=O)(CO)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(Cl)Cl
Product: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C)OCC
Temperature: 60 °C
Yield: 26.8 %

Procedure:
To a solution of compound 31.2 (280 mg, 0.59 mmol) in dichloroethane (5 mL) was added diethyl (hydroxymethyl) phosphonate (0.22 mL, 1.47 mmol) and pyridinium p-toluene sulfonate (56 mg, 0.29 mmol). The mixture was heated to 60° C. for 1 h and then concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to give compound 31.3 (102 mg, 16% yield). 1H NMR (300 MHz, CDCl3): δ −0.45 (s, 3H), −0.08 (s, 3H), 0.05 (s, 3H), 0.71 (s, 9H), 0.98 (s, 9H), 1.35 (m, 6H), 1.61 (s, 3H), 3.78 (t, 1H), 3.95 (t, 1H), 4.04 (s, 1H), 4.21 (m, 4H), 4.96 (m, 1H), 6.24 (d, 1H, J=6.7), 8.10 (s, 1H), 8.70 (s, 1H). LRMS (ESI) MH+ C27H52N5O7PSi2 requires 646.9. Found 645.9.
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.Cl.Cl[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([CH3:25])=[CH:19][N:18]=1.[OH-].[Na+]>O>[CH3:24][O:23][C:21]1[C:20]([CH3:25])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[CH:22]=1
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Reactant: COc1cc(CCl)ncc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CSc2nc3cc4c(cc3[nH]2)OCO4)ncc1C

Procedure:
5.82 g of 5H-1,3-dioxolo[4,5-f]benzimidazole-6-thiol were suspended in 200 ml of alcohol and the suspension was treated with 6.3 g of 2-chloromethyl-4-methoxy-5-methylpyridine hydrochloride while cooling. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×300 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel using ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 6-[[(4-methoxy-5-methyl-2-pyridyl)-methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting pont 191°-193°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.CC(C)([O-])C.[K+].[C:17]1(=[O:21])[O:20][CH2:19][CH2:18]1.Cl>O1CCCC1>[C:17]([CH2:18][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1)([OH:21])=[O:20]
Reactant: Cc1cc(O)ccc1C=O
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OCCC(=O)O)ccc1C=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-hydroxy-2-methylbenzaldehyde (5 g) and potassium tert-butoxide (4.12 g) in tetrahydrofuran (60 mL) was added β-propiolactone (4.6 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in ethyl acetate (20 mL)-n-hexane (100 mL). The insoluble material was collected by filtration, and washed with n-hexane and dried under reduced pressure to give the title compound (7.2 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CS(O[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=2)[CH2:24][CH2:23]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:35][CH:33]([C:30]1[N:29]=[C:28]([N:25]2[CH2:24][CH2:23][CH:22]([CH2:21][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=4)=[N:14][CH:13]=3)[CH2:27][CH2:26]2)[O:32][N:31]=1)[CH3:34]
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Reactant: CSc1ccc(-c2ccc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A mixture of 6-[4-(methylthio)phenyl]-3-pyridinol (53.2 g, 245 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, 74.3 g, 735 mmol), K2CO3 (101.5 g, 735 mmol) and DMF (500 mL) was stirred at 80° C. for 2 h. The mixture was charged with water, allowed to stand for 30 min, and the resulting precipitate was filtered, washed with water, heptane, and air dried to give 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylthio)phenyl]pyridine (93.7 g, 90%) as a tan solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 1H, J=2.8 Hz), 7.83 (d, 2H, J=8.5 Hz), 7.61 (d, 1H, J=8.7 Hz), 7.30 (d, 2H, J=8.5 Hz), 7.22 (d, 1H, J=3.0 Hz), 4.30-4.10 (m, 2H), 3.90 (d, 2H, J=6.2 Hz), 3.15-3.05 (m, 2H), 2.92-2.82 (m, 1H), 2.50 (s, 3H), 2.14-1.99 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.27 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 425 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH:13]=[N:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:27]([OH:30])(=[O:29])[CH3:28]>>[C:27]([O:30][CH:13]([NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:23])([F:24])[F:25])[CH2:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][N:4]=1)(=[O:29])[CH3:28]
Reactant: O=C(N=CCc1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(=O)O
Product: CC(=O)OC(Cc1ncc(C(F)(F)F)cc1Cl)NC(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 24 %

Procedure:
0.16 g of N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethylidene}-2-(trifluoromethyl)benzamide (Int-6) were diluted in 2 mL of acetic acid. The reaction mixture was stirred for two days at room temperature and then heated to 90° C. for one day and left at room temperature for four days. After concentration in vacuo, the crude product was purified by chromatography on silica gel to yield 0.045 g (24%) of desired product 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1-{[2-(trifluoromethyl)benzoyl]amino}ethyl acetate (Ia-112), [M+1]=455.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([SH:11])[CH:7]=[CH:8]2)=[CH:3][CH:2]=1.F[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[CH:5]1[C:4]2[C:9](=[CH:10][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:7][C:6]=1[S:11][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: O=Cc1ccccc1F
Reactant: Sc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: O=Cc1ccccc1Sc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-thionaphthol (5.29 g; 33 mmol), 2-fluorobenzaldehyde (3.73 g; 33 mmol) and potassium carbonate (4.57 g; 33 mmol) in 28 mL of iso-propanol was heated to reflux for 12 h. The mixture was cooled to r.t., diluted with water and filtered. The solution was diluted with EtOAc and washed with water, brine and dry over MgSO4. The crude product (7.9 g) was used as is for the next step.