Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][OH:24])[C:16](=[O:26])[CH:15]2[CH3:27])[CH:10]=[CH:11][C:12]=1[Cl:13].CC1C=C(C)C=C(C)N=1>CC(N(C)C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[C:16](=[O:26])[CH:15]2[CH3:27])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC1C(=O)N(CC[C@@H](O)CO)CCN1c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: Cc1cc(C)nc(C)c1
Product: CC1C(=O)N(CC[C@@H](O)COS(C)(=O)=O)CCN1c1ccc(Cl)c(Cl)c1
Yield: 129.8 %

Procedure:
A solution of methanesulfonyl chloride (53 mg, 0.46 mmol) in DMA (0.5 mL) was added at 0° C. to a solution of 4-(3,4-dichloro-phenyl)-1-((R)-3,4-dihydroxy-butyl)-3-methyl-piperazin-2-one (160 mg, 0.46 mmol) and 2,4,6-trimethylpyridine (279 mg, 2.30 mmol) in DMA (2 mL), then after 2½ h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford crude methanesulfonic acid (R)-4-[4-(3,4-dichloro-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-2-hydroxy-butyl ester (254 mg) as a light yellow gum. This was dissolved in DMA (2 mL), cooled to 0° C., and treated with NaH (55% dispersion in mineral oil, 41 mg, 0.94 mmol). After 15 min, as the methanesulfonate intermediate had disappeared, with mass spectrometry confirming the formation of the epoxide intermediate, 4-(3,4-dichloro-phenyl)-3-methyl-1-((R)-2-oxiranyl-ethyl)-piperazin-2-one [m/e=329, (M+H)+)], cesium carbonate (184 mg, 0.56 mmol) and a solution of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 77 mg, 0.47 mmol) and N,N-diisopropylethylamine (152 mg, 1.2 mmol) in DMA (1 mL) were added. The reaction mixture was heated at 80° C. for 20 h, then diluted with EtOAc/MeOH 4:1 and filtered through diatomaceous earth. The filtrate was chromatographed (IST Isolute® Flash NH2; EtOAc/MeOH gradient) to produce the title compound (101 mg, 47%). Light yellow foam, MS: 456.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=O)[CH:10](C([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl[C:32](=[CH2:35])[C:33]#[N:34].C(N(CC)CC)C>ClCCl.O>[C:33]([C:32]1[CH:35]=[CH:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)#[N:34]
Reactant: C=C(Cl)C#N
Reactant: CC(C)(C)OC(=O)N1CCN(C=O)C(C(=O)[O-])C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCn2ccc(C#N)c2C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.4 %

Procedure:
To a solution under nitrogen of 28.7 g (102 mmol) of sodium 4-(tert-butyloxycarbonyl)-1-formylpiperazine-2-carboxylate (CAS 1108698-36-7) in 1 l of dichloromethane are added 21.5 g (113 mmol) of p-toluenesulfonyl chloride. After stirring for 40 minutes, 8.2 ml (102 mmol) of 2-chloroacrylonitrile are added. After stirring for 40 minutes, 32.8 ml (235 mmol) of triethylamine are added dropwise and the mixture is stirred overnight at room temperature, and then refluxed for 1 hour. The solution is then cooled to room temperature. 150 ml of water are added. The organic phase is separated out by settling, washed twice with 100 ml of water, dried over sodium sulfate and filtered, and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 0 to 10% ethyl acetate in dichloromethane, to give 17.5 g of tert-butyl 8-cyano-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after dissolving in a mixture of cyclohexane and dichloromethane and then precipitating by slow concentration and drying under reduced pressure.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:19]([NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Reaction time: 0.5 h
Yield: 41 %

Procedure:
In a biphasic solution consisting of 150 ml of dichloromethane and 100 ml of 50% aqueous NaOH were added 4.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one, and 0.96 g of tetrabutylammonium hydrogensulfate catalyst. The mixture was stirred mechanically for 0.5 hour and thereafter 2.47 ml (1.1 eq) of benzyl bromide was added in one portion. After 4 hours of vigorous stirring, the reaction appeared complete based on thin layer chromatography analysis. The reaction mixture was poured into water/ice and the dichloromethane layer separated, dried over MgSO4 and evaporated to a solid. The solid was recrystallized three times from dichloromethane/hexanes to yield 2.35 g (41%) of product, melting point 162°-163° C.
Reaction SMILES: [C@@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[OH:7].F[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]>>[F:16][C:14]1[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([CH:15]=1)[O:7][C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[OH:8]
Reactant: O[C@@H]1CCCC[C@@H]1O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CCCC[C@H]1O

Procedure:
Prepared analogously to III.1 from cis-1,2-cyclohexandiol (1.0 g) and 0.94 ml 2,4-difluoronitrobenzene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[N:11]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C@H:5]([OH:6])[C:10]#[N:11]
Reactant: O=Cc1cccc(O)c1
Reactant: C#N
Product: N#C[C@@H](O)c1cccc(O)c1
Reaction time: 0.58 h

Procedure:
61 mg (0.5 mmol) of meta-hydroxybenzaldehyde were reacted at pH 3.25 with 450 μl of 4.2M aqueous HCN solution in accordance with Example 14. The reaction was complete after 30 to 40 minutes. The (S)-3-hydroxymandelonitrile was isolated as described in Example 14.
Reaction SMILES: [H-].[Na+].C([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16](O)[CH:15]=[CH:14]2)C1C=CC=CC=1.FC(F)(F)S([O:27][CH2:28][C:29]([F:41])([F:40])[C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[CH2:32][O:33][CH2:34][CH3:35])(=O)=O>COCCOC>[CH2:34]([O:33][CH2:32][C:31]([F:36])([F:37])[C:30]([F:38])([F:39])[C:29]([F:40])([F:41])[CH2:28][O:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:10])[CH:20]=[CH:19]2)[CH3:35]
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Reactant: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc2cc(O)ccc2c1
Reaction time: 18 h
Yield: 42.9 %

Procedure:
0.7 g of 60% sodium hydride in mineral oil was added to 25 ml of dry 1,2-dimethoxyethane. The contents were stirred, and 2.5 g (0.010 moles) of 6-benzyloxy-2napthol was slowly added. After stirring the resulting solution for 20 minutes at room temperature, it was cooled with an ice bath. 4.1 g (0.011 moles) of 5-ethoxy-2,2,3,3,4,4-hexafluoropentyl trifluoromethanesulfonate (prepared essentially as in Example 3) was then added slowly. When this addition was complete, the ice bath was removed, and the product-containing mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure, and 30 ml of water, followed by 30 ml of diethyl ether, were added sequentially. Once all of the solids had dissolved, two homogeneous liquid layers formed. The layers were separated, and the aqueous layer was extracted twice with 25 ml aliquots of diethyl ether. The resulting ether layers were combined, washed three times with 20 ml aliquots of deionized water, dried with anhydrous magnesium sulfate, and stripped to dryness using a rotary evaporator. The resulting solid was dissolved in tetrahydrofuran and was hydrogenated at 60 psi in the presence of catalytic 10% palladium on carbon for 18 hours. When the hydrogenation was complete, the catalyst was removed by filtration, and the solvent was removed on a rotary evaporator. The resulting brown semisolid material was then purified by using chromatography on silica gel (2.5% methanol in chloroform) to yield 1.64 g of 6-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)-2-hydroxynapthalene product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[Li]C.C([Li])CCC.CN([CH:32]=[O:33])C.C(=O)(O)[O-].[Na+]>C1COCC1.CC(O)=O>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[C:4]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:3][C:2]([CH:32]=[O:33])=[CH:7][N:6]=2)[S:10][CH:11]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1csc(Nc2ncc(C=O)cc2Oc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
N-(5-bromo-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine (724 mg, 2.00 mmol) was dissolved in THF (20 mL) and cooled to −78° C. MeLi (1.30 mL, 2.20 mmol) is added slowly, and stirred for 10 minutes. n-Butyllithium (0.88 mL, 2.20 mmol) was added and the reaction mixture was stirred for 15 minutes. DMF (0.31 mL, 4.00 mmol) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was warmed to room temperature and AcOH (2 mL) is added. The reaction mixture was stirred at room temperature for 1 hour, poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel (10-20% EtOAc in hexanes) to afford 6-(4-methylthiazol-2-ylamino)-5-phenoxynicotinaldehyd.
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].OO>O.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+]>[OH:17][C:8]1[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][C:9]=1[C:9]1[CH:8]=[C:7]([C:3]([CH3:5])([CH3:4])[CH3:6])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[OH:1]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: [OH-]
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Yield: 97.9 %

Procedure:
40 g (1 mole) of sodium hydroxide are dissolved in 170 ml of water which contains 1 g of sodium lauryl sulfate. With stirring, the solution is heated to 80° and then 103 g (0.5 mole) of 2,4-di-tert-butylphenol are added. Then 31 ml of a 30% solution of hydrogen peroxide are added dropwise in the course of 2 hours. After the reaction mixture has cooled, the product is isolated by filtration and washed with water and dried, affording 100.5 g (98% of theory) of 2,2'-dihydroxy-3,3',5,5'-tetra-tert-butyl-biphenyl with a melting point of 190°-195° C.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cn1ccnc1Br
Product: Cn1ccnc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 2-bromo-1-methyl-1H-imidazole (Aldrich), the title compound was obtained as an off-white solid after purification by preparative HPLC.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][C:7]1([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[S:13](=[O:15])=[O:14].C([N-]C(C)C)(C)C.[Li+].[I:31]N1C(=O)CCC1=O>>[CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][C:7]1([C:16]2[NH:20][C:19]([I:31])=[CH:18][N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[S:13](=[O:15])=[O:14]
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)CCOCC1(c2ncc[nH]2)C=CC=CC1=S(=O)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[Si](C)(C)CCOCC1(c2ncc(I)[nH]2)C=CC=CC1=S(=O)=O

Procedure:
According to the foregoing reaction scheme 1, 1-[[2-(trimethylsilyl)ethoxy]methyl]- imidazole (1) is treated with n-BuLi at -78° C. and reacted with phenyl disulfide to afford 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-thiophenyl-imidazole (2). 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-thiophenyl-imidazole (2) is oxidized with 2 equivalents of m-chloroperbenzoic acid to give 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-sulfonylphenyl-imidazole (3). 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-sulfonylphenyl-imidazole (3). is deprotonated with lithium diisopropylamide at -78° C. and treated with N-iodosuccinimide to afford 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-sulfonylphenyl-5-iodo-imidazole (4). The corresponding grignard reagent of (4) is prepared by treatment with 1 equivalent of t-butyl magnesium chloride at 0° C. in anhydrous CH2Cl2 for 30 minutes and then reacted with 1,4-cyclohexanedione mono-ethylene ketal (5) to provide alcohol (6). The sulfonylphenyl protecting group is removed by treatment of (6) in methanol at 0° C. in the presence of 4 equivalents of sodium phosphate buffer with excess 2-3% Na(Hg) to give alcohol (7). Alcohol (7) is dehydrated by heating in THF/2 drops of water in the presence of a catalytic amount of PPTS to give olefin (8). The SEM protecting group is removed by treatment of (8) with n-butyl ammonium flouride at 60° C. to provide olefin (9). Catalytic hydrogenation of (9) over Pd(C) affords cyclohexane (10). Ketal deprotection of (10) proceeds smoothly with 5% HCl in THF at room temperature to give (1H -4(5)-imidazoyl)-4-cyclohexanone (11). The N-methoxy oxime is prepared by treatment of ketone (11) with N-methoxyl amine and TEA in dichloromethane to give (12). Finally, TBAH reduction of oxime (12) affords the (1H-(4,5)-imidazoyl)-4-cyclohexyl-N-methoxylamine (13). ##STR12##
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[BH4-].[Na+].O>CO.C(O)(=O)C>[OH:12][CH2:3][CH:4]1[O:10][CH:8]2[CH2:7][CH:6]([CH2:11][CH:1]([OH:2])[CH2:9]2)[O:5]1
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: OCC1OC2CC(O)CC(C2)O1

Procedure:
To a solution of 340 mg (2mmols) of 2,5,11-trioxatricyclo[4,3,1,14,8 ]undecan-3-one in 10 ml of methanol are added all at once 150 mg of sodium borohydride while stirring and cooling to 12°-15°C(water bath). After 11/2 hours, during which time the bath temperature is allowed to rise to 20°C, a further 150 mg of sodium borohydride are added and the mixture is stirred for 21/2 hours at 20°C. The reaction mixture is then treated with 10 ml of water, the pH adjusted to 8 with a few drops of acetic acid, and concentrated under reduced pressure to about 3 ml. The concentrate is extracted three times with 25 ml of methylene chloride on each occasion, the combined extracts are dried over sodium sulphate and the solvent is distilled off (at the conclusion under reduced pressure) to give crystalline 3-hydroxymethyl-2,4-dioxabicyclo[ 3,3,1]nonan-7-ol of the formula IIa (m.p.146° -149°C).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1.O>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[N:9]([CH2:21][CH3:22])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:7][CH:6]=1)#[N:18]
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Yield: 67.7 %

Procedure:
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) is cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol) and methanesulfonylchloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%) of N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamide as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(=O)([O-])O.[Na+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 45 %

Procedure:
1,4-Diaminobenzene (1.081 g) was dissolved in tetrahydrofuran (50 ml) under a nitrogen atmosphere while stirring, and then triethylamine (2.01 ml) and benzyl chloroformate (1.71 ml) were added dropwise thereto while cooling in an ice-bath, followed by raising the temperature gradually up to room temperature. After 7 hrs, to the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extracting with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in hexane-ethyl acetate. The solid was filtered off, and dried under aeration to provide the titled compound (1.093 g, 45%) as pale yellow powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[C@H:11]2[CH2:17][C:18]#[CH:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C@H:11]2[CH2:17][C:18]#[CH:19])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccccc1

Procedure:
To a stirred mixture of (R)-4-(benzenesulfonyl)-3-(Prop-2-ynyl)-3,4-dihydropyrazin-2(1H)-one (2.7 g, 9.77 mmol) and Et3SiH (16 mL, 97.7 mmol) in CH2Cl2 (30 mL) was added TFA (16.7 g, 147 mmol). The reaction mixture was refluxed for 24 h and cooled. The mixture was concentrated and triturated with ether. The solid was filtered and air-dried to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 2.02 (s, 1H), 2.45 (s, 3H), 2.85 (m, 1H), 2.97 (m, 1H), 3.24 (m, 2H), 3.81 (m, 2H), 4.48 (t, 4.7 Hz, 1H), 6.47 (s, 1H), 7.55 (m, 3H), 7.78 (d, 8.3 Hz, 2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:3]=1.[Li]CCCC.CON(C)[C:41]([C:43]1([CH3:46])[CH2:45][CH2:44]1)=[O:42]>O1CCCC1>[CH3:46][C:43]1([C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[N:4]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:3]=2)=[O:42])[CH2:45][CH2:44]1
Reactant: CON(C)C(=O)C1(C)CC1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(n2)c(C(=O)C2(C)CC2)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reaction time: 0.01 h
Yield: 19.1 %

Procedure:
A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (116 mg, 0.2 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to −78° C. and treated with nBuLi (2.13M in hexanes, 0.13 ml, 0.27 mmol) dropwise. The solution was stirred for 30 seconds and 1-methyl-cyclopropanecarboxylic acid methoxy-methyl-amide (88 mg, 0.61 mmol) was added in one portion. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was quenched with saturated aqueous NaHSO4 and then partitioned between EtOAc/brine. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellow oil. The oil was purified by silica gel chromatography using 2-30% EtOAc in hexanes as eluant to provide 20 mg (19%) of (1-methyl-cyclopropyl)-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.S(O[CH2:29][C@@H:30]1[O:35][C@H:31]1[CH2:32][CH2:33][CH3:34])(C)(=O)=O.C(Cl)Cl>CN(C)C=O.[K+].[Br-]>[CH2:16]([C:13]1[CH:14]=[N:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:29][C@H:30]3[C@H:31]([CH2:32][CH2:33][CH3:34])[O:35]3)=[CH:9][CH:8]=2)=[N:11][CH:12]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCC[C@@H]1O[C@H]1COS(C)(=O)=O
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(OC[C@@H]3O[C@H]3CCC)cc2)nc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
0.16 g of NaH (5 mmol), as an 80% strength dispersion in oil, is added to a solution of 1.42 g (5 mmol) of 2-(4-hydroxyphenyl)-5-n-octylpyrimidine in 50 ml of dimethylformamide at a temperature of 0° C. When the evolution of gas has subsided, 1.35 g (7 mmol) of (2S, 3S)-1-mesyloxy-2,3-epoxyhexane are added, and the mixture is stirred for 6 hours at 0° C. The mixture is subsequently hydrolized in 100 ml of ice water and extracted with dichloromethane. After three-fold column chromatography (silica gel, dichloromethane), 0.61 g (32% of theory) of colorless crystals are obtained. The IR spectrum (in KBr) and the 1H NMR spectrum (in CDCl3) support the structural formula indicated, and the optical rotation is (α) D25 : -18.8° (c=10, CH2Cl2).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21](Br)=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)[CH2:13]1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)[CH2:13]1)=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nc(Cl)ncc2Br)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2nc(Cl)ncc2-c2ccccc2)C1
Yield: 52.8 %

Procedure:
A solution of (1H-benzoimidazol-2-yl)-[3-(5-bromo-2-chloro-pyrimidin-4-yl)-azetidin-1-yl]-methanone (206 mg, 0.53 mmol) in dioxane (15 mL) was treated with Na2CO3 (112 mg, 1.1 mmol dissolved 1 mL of H2O), followed by additional of phenylboronic acid (78 mg 0.64 mmol) and Pd(dppf)Cl2 (37 mg, 0.05 mmol). The resulting mixture was heated at refluxing overnight under N2 atmosphere. TLC showed that most of the staring materials were consumed completely. The solution was filtered, and the filter was concentrated. And the residue was purified by silica gel chromatography to give the product (102 mg, 0.28 mmol, yield: 53%). ESI-MS (M+1): 362 calc. for C21H16ClN5O 361.