Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[S:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=O.[NH2:17][C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+].FC(F)(F)C(O)=O>[Ti](Cl)(Cl)(Cl)Cl.C(O)C.O1CCCC1.C(O)(=O)C.ClCCl.C(N(CC)CC)C>[CH3:1][CH:2]([CH3:16])[CH2:3][CH:4]([NH:17][C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)[C:6]1[S:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1c(C(=O)CC(C)C)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(CC(C)C)c2sc3ccccc3c2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a mixture of 3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butan-1-one (1.00 g) synthesized in Example A32(1), methyl 6-aminopyridine-3-carboxylate (654 mg), triethylamine (4.79 mL) and dichloromethane (20 mL) was added titanium (IV) chloride (566 μL) at 0° C., and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a mixture of the obtained solid, acetic acid (2 mL) and tetrahydrofuran (20 mL) was added sodium cyanoborohydride (540 mg), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give a pale-brown solid. To a mixture of the obtained solid, trifluoroacetic acid (1.00 mL) and ethanol (10 mL) was added sodium cyanoborohydride (251 mg), and the mixture was stirred at room temperature for 1 hr. In addition, sodium cyanoborohydride (251 mg) was added, and the mixture was stirred at room temperature for 30 min then at 50° C. for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (743 mg, 47%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(O)C.S(Cl)(Cl)=O>[Br:1][C:2]1[S:6][C:5]([CH:7]=[C:11]([C:10](=[O:15])[CH3:9])[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(Br)s1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(=O)C(=Cc1ccc(Br)s1)C(C)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution containing 5.73 g 5-bromothiophene-2-carboxaldehyde and 5.0 g 2,4-pentanedione in 25 ml of 2-propanol, 2.9 ml thionylchloride was gradually added. The mixture was stirred for 2 h at 20° C. 120 ml of conc. Na2SO4 -solution was then added and the mixture was extracted with ether. The solvent was evaporated in vacuo and the crystalline residue was washed with cold ether. Yield 3.9 g, mp 70°-74° C.
Reaction SMILES: [C:1]12([N:6]3[C:29]4[CH:28]=[CH:27][C:11]5([CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[O:18])[CH2:13][CH2:12]5)[CH2:10][C:9]=4[CH:8]=[N:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.BrN1C(=[O:36])CCC1=O.C[N+]1([O-])CCOCC1.[Cl-].[NH4+]>C(OCC)(=O)C.C(#N)C.O1CCCC1.O.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.[Zn]>[C:1]12([N:6]3[C:29]4[C:28](=[O:36])[CH2:27][C:11]5([CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[O:18])[CH2:15][CH2:16]5)[CH2:10][C:9]=4[CH:8]=[N:7]3)[CH2:4][CH:3]([CH2:2]1)[CH2:5]2
Reactant: O=C(OCc1ccccc1)N1CCC2(C=Cc3c(cnn3C34CC(C3)C4)C2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Cc2cnn(C34CC(C3)C4)c21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
To a solution of benzyl 1-(bicyclo[1.1.1]pentan-1-yl)-1,4-dihydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (340 mg, 0.87 mmol) in 3:1 tetrahydrofuran:water (10 mL) was added N-bromosuccinimide (155 mg, 0.87 mmol). The reaction was stirred at room temperature for 45 minutes. The reaction was diluted with ethyl acetate (50 mL), washed with 0.5 N aqueous sodium hydroxide (25 mL) and saturated aqueous sodium thiosulfate (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting oil was taken up in dichloromethane (5 mL) and treated with activated 4 A molecular sieves (500 mg) and tetrapropylammonium perruthenate (16 mg, 0.04 mmol). The slurry was treated with N-methylmorpholine-N-oxide (243 mg, 1.75 mmol) in acetonitrile (5 mL). The reaction was stirred at room temperature for 2 hours. The reaction was filtered through Celite and the filtrate was concentrated. The residue was purified by flash column chromatography (7-60% ethyl acetate/heptanes) to yield a clear oil. The oil was taken up in tetrahydrofuran (5 mL) and treated with saturated aqueous ammonium chloride (5 mL) and zinc dust (171 mg, 2.62 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (7-60% ethyl acetate/heptanes) gave the title compound (148 mg, 42%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 7.34 (m, 6 H), 5.13 (s, 2 H), 3.51 (m, 4 H), 2.75 (s, 2 H), 2.59 (s, 1 H), 2.54 (s, 2 H), 2.41 (s, 6 H), 1.56 (m, 4 H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Li+].[H-].[CH:13]([OH:16])([CH3:15])[CH3:14].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(OCC)C>[CH2:19]([C@@H:20]1[CH2:21][CH2:22][CH2:15][C@H:13]([OH:16])[CH2:14]1)[CH:18]=[CH2:17]
Reactant: CC(C)O
Reactant: CCCCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CC[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0° C. After the evolution of gas has ceased, 12.4 g of cis-3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1M HCl and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N NaOH and dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=15:1=>5:1. This gives 6.8 g of cis-3-allylcyclohexanol as an oil. C9H160 (140.23), MS(ESI): 141 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.22.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].[Br:35][C:36]1[C:37](=[O:44])[N:38]([CH3:43])[CH:39]=[C:40](I)[CH:41]=1.C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.C(#N)C>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[N:8][CH:9]=[CH:10][C:11]=1[C:40]1[CH:41]=[C:36]([Br:35])[C:37](=[O:44])[N:38]([CH3:43])[CH:39]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(I)cc(Br)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.6 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (766 mg, 2.0 mmol), 3-bromo-5-iodo-1-methylpyridin-2(1H)-one 214b (626 mg, 2.0 mmol), Pd(dppf)Cl2 (164 mg, 0.20 mmol), sodium acetate (328 mg, 4.0 mmol), K3PO4 (848 mg, 4.0 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was stirred at room temperature for 5 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 217a (700 mg, 67%) as a yellow solid. MS-ESI: [M+H]+ 525.2
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:22][NH2:23])[CH2:3]1.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>CO>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([C:18]([CH3:19])([CH3:20])[CH3:21])[CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:22][NH:23][CH2:26][CH2:25][C:24]([O:28][CH3:29])=[O:27])[CH2:3]1
Reactant: CN1C[C@H](CN)C[C@@H]2c3cc(C(C)(C)C)cc4[nH]cc(c34)C[C@H]21
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNC[C@@H]1C[C@@H]2c3cc(C(C)(C)C)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
A mixture of 5.1 g of 6-methyl-8β-aminomethyl-13-t-butyl-ergoline and 1.8 ml methyl acrylate in 100 ml of methanol was refluxed for 4 hours. The solvent was evaporated off and the residue was crystallized from ethylacetate to afford 6 g of 6-methyl-8β-N-(2-methoxycarbonylethyl)aminomethyl-13-t-butyl-ergoline, melting at 153°-157° C., (I, R1 =R2 =H, R3 =CH3, A=NHC2H4CO2CH3, n=1).
Reaction SMILES: C([Cl:4])C=C.[CH3:5][SiH:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:5][Si:6]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[Cl:4]
Reactant: C=CCCl
Reactant: C[SiH](C)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C[Si](C)(Cl)c1ccccc1
Temperature: 42.5 °C
Yield: 96 %

Procedure:
To a 500 ml glass flask equipped with a stirring machine, a thermometer, a reflux condenser and a dropping funnel, there were added 91.8 g (1.2 mole) of allyl chloride and 0.03 g of palladium acetate, the temperature of the mixture was raised up to 40 to 45° C., then 136.3 g (1.0 mole) of dimethylphenylsilane was dropwise added to the mixture over 3 hours through the dropping funnel to carry out the reaction of the allyl chloride and the dimethylphenylsilane and the reaction mixture was aged at 50° C. for 3 hours. The reaction solution obtained after the aging was distilled to give a distillate having a boiling point range of from 80 to 84° C./16 mmHg. Thus, 163.9 g of dimethylphenylchlorosilane having a purity of 99.9% was obtained. The yield of the product was found to be 96.0%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:24]3[CH:23]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:27]=[CH:26][CH:25]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (520 mg, 2.0 mmol), 3-acetamidophenol (320 mg, 2.1 mmol, Aldrich) and K2CO3 (368 mg, 2.7 mmol) in DMF (10 mL) was heated at 80° C. for 8 h. The mixture was allowed to cool to room temperature, poured into H2O, extracted with EtOAc and the combined organic layers were evaporated onto SiO2. Purification by flash silica gel chromatography with EtOAc/hexanes (0:1→2:3) as eluant gave the title compound as a white amorphous solid. Mp: 202–205° C. MS (ESI, pos ion.) m/z: 374 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.C(OC([NH:34][C@H:35]([C:39](O)=[O:40])[C@@H:36]([CH3:38])[OH:37])=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>C1COCC1>[NH2:34][C@@H:35]([CH:36]([OH:37])[CH3:38])[C:39]([N:23]1[CH2:22][CH2:21][N:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)[N:19]=2)[CH2:25][CH2:24]1)=[O:40]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCNCC4)n3)ccc21
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)[C@H](N)C(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
200 mg (0.57 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pyridin-2-yl]piperazine, 138 mg (0.629 mmol) of N-(tert-butoxycarbonyl)-L-threonine, 105 mg (0.69 mmol) of HOBt, 132 mg (0.69 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 291 μl (1.72 mmol) of DIPEA are dissolved in 5 ml of THF and stirred at room temperature for 18 h. The crude product was purified by column chromatography and silica gel, dissolved in dioxane, and an excess of 4N HCl in dioxane was added. The reaction mixture is stirred at room temperature for 12 h, evaporated and purified by means of preparative HPLC. The product is converted into the hydrochloride using methanolic HCl.
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:8]([O:10]C)=[O:9].CO.O>C1COCC1.C(OCC)C>[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(CCCCl)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
A 5 N sodium hydroxide solution (2.5 ml) was added to a solution of methyl 5-chloro-2-cyclohexyl-valerate (1.00 g) in THF (3 ml)-methanol (6 ml). The reaction solution was stirred at room temperature for six hours and at 60° C. for further two hours. After allowing the reaction solution to cool, water and diethyl ether were added to the reaction solution, and the aqueous layer was separated. 5 N hydrochloric acid (2.6 ml) and ethyl acetate were added to the aqueous layer, and the organic layer was separated. The ethyl acetate extraction layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5-chloro-2-cyclohexyl-valeric acid (287 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[F:10][C:11]1[C:12]([NH2:19])=[C:13]([NH2:18])[CH:14]=[C:15]([F:17])[CH:16]=1>>[NH2:19][C:12]1[C:11]([F:10])=[CH:16][C:15]([F:17])=[CH:14][C:13]=1[NH:18][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Nc1cc(F)cc(F)c1N
Reactant: Cc1cscc1N=C=S
Product: Cc1cscc1NC(=S)Nc1cc(F)cc(F)c1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3,5-difluoro-1,2-diaminobenzene. Crystalline solid, 1st melting point: 178-182° C., another crystallization with 2nd m.p.: 299-301° C.
Reaction SMILES: [C:1]([C:5]1([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]([CH3:11])[O:6]1)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:12][C:5]12[CH2:1][O:2][C:7]([CH3:11])([O:6]1)[CH2:8][CH2:9][CH2:10]2
Reactant: COC(=O)C1(C)CCC=C(C)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC12CCCC(C)(OC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 2-carbomethoxy-2,6-dimethyl-3,4-dihydro-2 H-pyran (11.2 gm, 0.066 mol) in dry ether was added dropwise with stirring to lithium aluminum hydride (3 gm, 0.079 mol) in dry ether. The reaction mixture was heated under reflux for 4 hours, cooled and decomposed with water (3 ml), aqueous 15% NaOH solution (3 ml) and finally water (9 ml). It was stirred at room temperature for 2 hours and filtered. The ether solution containing the resulting alcohol was treated with a catalytic amount of p-toluenesulfonic acid, stirred at room temperature for 2 hours and neutralized with K2CO3. The solvent was removed using a 40 cm Vigreux column and the residue was distilled to give 7.6 gm (75.6%) of frontalin.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([O:14]CC)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OC1C=C2C(CCC2=O)=CC=1OC>>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:12](=[O:14])[CH2:11][CH2:10]2
Reactant: CCOC(=O)C=Cc1ccc(OC)c(O)c1
Agent: COc1cc2c(cc1O)C(=O)CC2
Product: COc1cc2c(cc1O)CCC2=O

Procedure:
5-Hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-one 18b was prepared from 35b V according to the protocol described for the preparation of compound 18a in Example 33 (Scheme 11). Isolated as light brown powder in 67% overall yield (3.55 g). 1H NMR (300 MHz, CDCl3): δ 2.69 (2H, m); 3.03 (2H, m); 3.92 (3H, s); 4.28 (1H, broad s); 6.92 (1H, s); 7.17 (1H, s). 13C NMR (75 Hz, CDCl3): δ 24.65; 35.86; 55.05; 103.68; 111.00; 127.98; 147.67; 151.32; 153.72; 206.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].N#N.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: N#Cc1ccccc1N
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: C1COCCO1
Product: N#Cc1ccccc1Nc1cc(Cl)ncc1Cl
Yield: 78.9 %

Procedure:
The solution of 2,5-dichloro-4-iodopyridine (100 g, 365 mmol), 2-aminobenzonitrile (43.1 g, 365 mmol) and potassium triphosphate (233 g, 1095 mmol) in 1,4-dioxane (2.5 L) was degassed by N2 stream. To this solution was added DPEPhos (15.73 g, 29.2 mmol) and palladium acetate (3.28 g, 14.60 mmol). The reaction mixture was stirred at reflux for 18 hour. The solution was filtered through 0.5 in. celite and 0.2 inch of silica. The solution was evaporated. Solid was suspended in the diethyl ether and filtered. Diethyl ether was concentrated, and the resulting solid was filtered. 2-[(2,5-Dichloro-4-pyridinyl)amino]benzonitrile (80 g, 288 mmol, 79% yield) was isolated as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.49 (s, 1H) 7.50 (td, J=7.58, 1.01 Hz, 1H) 7.56 (d, J=7.58 Hz, 1H) 7.80 (td, J=7.83, 1.77 Hz, 1H) 7.95 (dd, J=7.83, 1.52 Hz, 1H) 8.26 (s, 1H) 9.05 (brs, 1H); HPLC Rt=2.88 min, MS (ESI): 263.9, 265.9 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([CH2:15][O:16][Si:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:5]=2[N:4]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C(#N)C>[CH2:24]([NH:27][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([CH2:15][O:16][Si:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:5]=2[N:4]=1)[CH2:25][CH3:26]
Reactant: CCCn1c(CCl)nc2cc(CO[Si](C)(C)C(C)(C)C)ccc21
Reactant: CCCN
Solvent: CC#N
Product: CCCNCc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2n1CCC
Yield: 99 %

Procedure:
A solution of 2.0 g (5.6 mmole) of 1-{[2-(chloromethyl)-1-propylbenzimidazol-5-yl]methoxy}-1,1,2,2-tetramethyl-1-silapropane in 20 mL of anhydrous acetonitrile is treated with 10 mL of propylamine for 16 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 2.1 g (99%) of propyl({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)amine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: O=C(O)c1cnc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOc1cccc(-c2ncc(C(=O)O)cn2)c1
Temperature: 140 °C
Yield: 6.5 %

Procedure:
To a solution of 2-chloro-5-pyrimidinecarboxylic acid (Anichem LLC; 100 mg, 0.631 mmol) in 1,2-dimethoxyethane (9 ml) was added [3-(ethyloxy)phenyl]boronic acid (Sigma-Aldrich; 314 mg, 1.892 mmol), sodium carbonate (401 mg, 3.78 mmol) pre-dissolved in water (1 ml) and bis(triphenylphosphine)palladium(II)chloride (66.4 mg, 0.095 mmol). The mixture was heated at 140° C. for 30 minutes in a microwave reactor (high absorbance). The catalyst was filtered and the mother liquor evaporated to dryness. Purification using MDAP gave the title compound as a white solid (10 mg);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][NH:29][N:28]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:29]3[CH:30]=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:27]([CH3:26])=[N:28]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Reactant: Cc1n[nH]cc1-c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cc(-c4ccccc4)c(C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.4 %

Procedure:
A mixture of 4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (200 mg, 0.55 mmol), 3-methyl-4-phenylpyrazole (87 mg, 0.55 mmol), Copper(II) acetate (120 mg, 0.66 mmol), triethylamine (0.23 mL, 1.65 mmol), molecular sieves 4A (200 mg), and dichloromethane (8 mL) was stirred at room temperature for 3 days. After filtration through a bed of celite, the filtrate was diluted with dichloromethane, and washed with water. The organic fraction was dried over MgSO4. After concentration under reduced pressure, the residue was purified by TLC with dichloromethane/ethylacetate (10:1) to afford 56 mg (21%) of the title compound as white solids: MS (ESI) m/z 476 [M+H]+, 474 [M−H]−, 1H-NMR (CDCl3) δ 7.88 (2H, d, J=8.5 Hz), 7.61-7.19 (11H, m), 4.31 (2H, t, J=6.6 Hz), 2.92 (2H, t, J=6.6 Hz), 2.49 (3H, s), 2.42 (3H, s).