Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=O)[C:24]=2[CH:23]=[CH:22][CH:21]=1.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[OH:42].[Br-:43].[K+]>ClCCl.C(OCC)(=O)C.O>[Br-:43].[OH:42][C:36]1[C:37]([CH3:41])=[CH:38][C:39]([S+:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:28]=3[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]2=3)=[CH:40][C:35]=1[CH3:34]
Reactant: Cc1cccc(C)c1O
Reactant: O=S1c2ccccc2-c2ccccc21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-[s+]2c3ccccc3c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 17474.8 %

Procedure:
Eaton's Reagent (100 mL) was added dropwise to a solution of dibenzothiophene oxide (15.0 g, 74.9 mmol) and 2,6-dimethylphenol (9.15 g, 74.9 mmol) in dichloromethane (200 mL) at 0° C. The reaction was warmed to r.t. and stirred for 4 h, then cooled to 0° C. and quenched with the slow addition of water (200 mL) keeping the reaction temperature below 20° C. The aqueous phase was extracted with ethyl acetate (3×100 mL) and potassium bromide (17.9 g, 0.150 mmol) in water (50 mL) was added to the aqueous layer under vigorous stirring. The slurry was stirred at r.t. for 1 h, filtered and washed with water (3×200 mL), MTBE (3×200 mL) and the residue dried in vacuo to afford the title compound (10.1 g, 35%) as an off-white solid. 1H NMR (300 MHz, (CD3)2CO) δ: 9.77 (brs, 10H), 8.52 (d, J=8.1 Hz, 2H), 8.27 (8.1 Hz, 2H), 7.95 (t, J=7.8 Hz, 2H), 7.74 (t, J=7.8 Hz, 2H), 7.20 (s, 2H), 2.12 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[C:6]([F:13])[C:5]=1[F:14])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)=[C:6]([F:13])[C:5]=1[F:14])[CH3:2]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Temperature: 25 °C
Yield: 94 %

Procedure:
4-Ethoxy-2,3-difluorophenylboronic acid (7) (14.4 g), 4-bromoiodobenzene (8) (20.0 g), potassium carbonate (29.3 g), Pd(Ph3P)2Cl2 (1.49 g), toluene (100 ml), Solmix A-11 (100 ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. Then, the solution was concentrated under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel; toluene). The product was further purified by means of recrystallization (Solmix A-11), giving 20.8 g of 4-ethoxy-4′-bromo-2,3-difluoro-1,1′-biphenyl (9). The yield based on the compound (8) was 94.0%.
Reaction SMILES: [Se](=O)=[O:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1>O.O1CCOCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:2])[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: O=[Se]=O
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(C(=O)c1ccc(F)cc1)c1ccncc1

Procedure:
A solution of selenium dioxide (4.82 g, 43.4 mmol) in H2O (20 mL) was added to a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)-2-ethanone (9.33 g, 43.4 mmol) in dioxane (100 mL) and the resulting mixture was heated at reflux for 2 h. This mixture was concentrated in vacuo, triturated with ethyl acetate and filtered. The residue was purified by column chromatography using ethyl acetate/hexane (1:1) as an eluent to give 1-(4-fluorophenyl)-2-(4-pyridyl)-1,2-ethandione. A mixture of ammonium acetate (25.25 g, 0.328 mol) and hexamethylenetetraamine (9.18 g, 65.5 mmol) was added to a solution of the isolated dione dissolved in acetic acid (150 mL). This mixture was stirred at 80° C. for 2 h, poured into concentrated ammonium hydroxide (200 mL) and the resulting precipitate was filtered, washed with H2O and dried to give the title compound as a solid: mp 242-44.3° C.; MS 240 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1
Reaction time: 1 h

Procedure:
200 mg of 3-(5-hydroxy-3-indolyl)quinuclidine are dissolved in 10 ml of pyridine and 5 ml of acetic anhydride are added with cooling. After one hour, the mixture is worked up as is customary. 3-(5-acetoxy-3-indolyl)quinuclidine is obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[N:32]=[C:31]([CH3:33])[C:30]([O:34][CH3:35])=[CH:29][CH:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([CH3:33])[N:32]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(I)nc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)nc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 164 mg (0.66 mmol) of 6-iodo-3-methoxy-2-methyl-pyridine in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 60 mg of a white powder. LC-MSD, m/z for C23H18BrN3O3 [M+H]+=464.0, 466.0; HPLC retention time: 1.9 min.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:27]=[C:26]([C:28]3[C:29]([N:46](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[CH:36][CH:35]=4)[N:33]=3)[O:25][N:24]=2)=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH:43]([S:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:33]=[C:28]([C:26]3[O:25][N:24]=[C:23]([C:20]4[CH:19]=[CH:18][C:17]([NH:16][CH2:1][CH:3]5[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]5)=[CH:22][CH:21]=4)[CH:27]=3)[C:29]([NH2:46])=[N:30][CH:31]=2)=[CH:39][CH:38]=1)(=[O:41])=[O:42])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C=O
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(N)cc4)no3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc(-c4ccc(NCC5CCCCN5)cc4)no3)n2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 2-formylpiperidine-l-carboxylate (18.45 mg, 0.08652 mmol) and tert-butyl N-[3-[3-(4-aminophenyl)isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (50 mg, 0.07865 mmol) in CH2Cl2 (5.0 mL) at 0° C. was added acetic acid (5.196 mg, 4.920 μL, 0.08652 mmol) and sodium triacetoxyborohydride (28.34 mg, 0.1337 mmol) and the resulting solution stirred at 0-10° C. for 2 h. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (5 mL) and dichloromethane (10 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (2×5 mL) and the combined organic extracts were then dried over MgSO 4 and concentrated in vacuo. The residue was taken up in CH2Cl2 (3.0 mL) and TFA (44.83 mg, 30.29 μL, 0.3932 mmol) was added and the resulting solution stirred at rt overnight. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 100 Å column, 5 M, 19 mm×150 mm, (solvent A: 0.05% TFA in water; solvent B: 0.05% TFA in CH3CN) over 16 minutes at 20 mL/min] The product fractions were collected and lyopholised to leave the title compound as a yellow solid (30.5 mg, 58% yield); 1H NMR (400 MHz, DMSO) δ 1.19 (d, 6H), 1.40-1.59 (m, 3H), 1.79 (m, 2H), 1.96 (m, 1H), 2.88 (m, 1H), 3.24 masked signal, 3.47 (m, 1H), 6.37 (t, 1H), 6.79 (m, 2H), 7.16 (br s, 2H), 7.64 (s, 1H), 7.78 (m, 2H), 7.94 (m, 2H), 8.28 (br s, 1H), 8.38 (m, 2H), 8.52 (br s, 1H) and 8.94 (s, 1H) ppm; MS (ES+) 533.3 (M+H), (ES−) 531.2 (M−H)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[Si:15]([O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCNCC1

Procedure:
To a methanol (28 mL) solution of 1-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}piperidine (2.80 g, 9.18 mmol) was added palladium hydroxide on carbon (20 weight %, 280 mg. 0.40 mmol) and stirred under an atmospheric pressure of hydrogen for 16 hours. The reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated in vacuo to afford the title compound. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 3.77-3.70 (m, 1H), 3.09-3.02 (m, 2H), 2.61 (ddd, J=12.5, 9.5, 3.0 Hz, 2H), 1.82-1.72 (m, 2H), 1.42 (dtd, J=13.0, 9.0, 3.7 Hz, 2H), 0.89 (s, 9H), 0.05 (s, 6H); LC-MS: m/z 216.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].O.[C:24](#[N:26])[CH3:25]>>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:25][C:24]#[N:26])[CH:10]=2)[O:3]1
Reactant: CC#N
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC1(C)OB(c2cnn(CC#N)c2)OC1(C)C
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.50 g, 2.58 mmol), sodium iodide (39 mg, 0.26 mmol) bromoacetonitrile (1.3 g, 10.8 mmol) and potassium carbonate (1.0 g, 7.8 mmol) in acetonitrile (10 mL) was heated at 70° C. overnight. Water was added and the solution was extracted with EtOAc (3×). The organic was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (10% to 100% EtOAc/hexane) to obtain 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile (0.38 g, 63% yield). MS (ESI) m/z: 234.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]([O:24]CC)=[CH2:23])CCC>[Cl-].C([N+](CC)(CC)CC)C.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.C(#N)C>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22](=[O:24])[CH3:23])=[CH:7][C:6]=1[CH:8]([OH:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC(c1ccccc1)c1cc(Br)ccc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: CC(=O)c1ccc(F)c(C(O)c2ccccc2)c1
Temperature: 150 °C

Procedure:
A 5 mL microwave tube was charged with (5-bromo-2-fluorophenyl)-(phenyl)methanol (1 eq), tributyl-(1-ethoxyvinyl)tin (1 eq), tetraethylammonium chloride (3 eq), bis(triphenylphosphine)palladium(II) chloride (10 mol %) and acetonitrile (3.5 mL). The reaction was heated to 150° C. for one hour using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and then concentrated to an oil. Purification by silica gel chromatography provided 1-{4-fluoro-3-[hydroxy(phenyl)methyl]phenyl}ethanone as an oil. H1 NMR (d6-dmso): 8.16 (dd, 1H), 7.89 (m, 1H), 7.18-7.34 (m, 6H), 6.14 (d, 1H), 5.93 (d, 1H), 2.53 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1)=C>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:30][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: C=Cc1cnccn1
Product: CC(C)(Cc1c[nH]c2c(C=Cc3cnccn3)cccc12)NC(=O)OC(C)(C)C

Procedure:
{1,1-Dimethyl-2-[7-(2-pyrazin-2-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 2-vinylpyrazine as described for the preparation of Amine 23 (99%). FDMS m/e=393.2 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:18][CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:40][NH:41][CH3:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([C:7]1[CH:8]=[CH:9][C:10]([C:11](=[O:13])[N:41]([CH3:42])[CH3:40])=[CH:14][CH:15]=1)[CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:18][CH2:17]1
Reactant: CNC
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)O)cc2)CC1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)N(C)C)cc2)CC1
Yield: 73.9 %

Procedure:
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and dimethylamine (2.0M in THF, 56 μL, 0.11 mmol) afforded COMPOUND 87 as a white solid (31 mg, 71%). 1H NMR (CDCl3) δ 0.89-1.20 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.54 (m, 1H), 1.70-1.83 (m, 3H), 2.16 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.56 (t, 1H, J=12.0 Hz), 2.74-2.90 (m, 3H), 3.03 (s, 6H), 3.24-3.31 (m, 1H), 3.62-3.69 (m, 1H), 3.81 (s, 2H), 3.84-3.91 (m, 1H), 6.52 (d, 2H, J=8.4 Hz), 6.96 (d, 2H, J=7.5 Hz), 7.02-7.12 (m, 3H), 7.21-7.28 (m, 4H), 8.39 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.32, 30.67, 31.31, 40.24, 43.98, 48.67, 52.54, 56.18, 60.96, 112.31, 124.37, 124.68, 126.63, 127.30, 127.77, 128.88, 129.70, 130.16, 134.41, 134.83, 138.96, 142.53, 149.98, 170.32, 172.18. ES-MS m/z 575 (M+H). Anal. Calcd. for C34H43N4ClO2.0.5CH2Cl2: C, 67.09; H, 7.18; N, 9.07. Found. C, 66.75; H, 7.12; N, 8.94.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][C:11](=[O:13])[NH:10][N:9]=2)=[C:4]([NH:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1.[Si:18]([O:25][CH2:26][CH2:27][CH2:28][NH2:29])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(O)C>[Si:18]([O:25][CH2:26][CH2:27][CH2:28][NH:29][C:11]([NH:10][NH:9][C:8](=[O:12])[C:5]1[C:4]([NH:14][CH:15]([CH3:17])[CH3:16])=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)=[O:13])([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCCN
Reactant: CC(C)Nc1cc(Cl)ncc1-c1n[nH]c(=O)o1
Solvent: CCO
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)NCCCO[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one (49) (1.2 g, 4 mmol) and 3-((tert-butyldimethylsilyl)oxy)propan-1-amine (48) (7 mmol, 1.5 equiv.) were dissolved in ethanol (5 mL). Refluxed the reaction mixture at 90° C., overnight. The reaction mass was concentrated under reduced pressure to remove excess of solvent. The crude material obtained was taken to next step as such, without purification. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 1.02 min; LCMS (ES-API), m/z 444.9 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]2[O:10][C:11]3[C:16]([C@@:17]4([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]4)[C:4]=2[CH:3]=1)=[CH:15][C:14]([NH2:24])=[CH:13][CH:12]=3.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]3[O:10][C:11]4[C:16]([C@@:17]5([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]5)[C:4]=3[CH:3]=2)=[CH:15][C:14]([NH2:24])=[CH:13][CH:12]=4)[CH2:29][CH2:30]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1nc(Cl)cc2c1Oc1ccc(N)cc1[C@@]21CCOC(N)=N1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(C2=CCOCC2)cc2c1Oc1ccc(N)cc1[C@@]21CCOC(N)=N1
Yield: 79.7 %

Procedure:
A mixture of (S)-3-chloro-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.183 g, 0.528 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.222 g, 1.055 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.019 g, 0.026 mmol) and potassium phosphate tribasic (0.336 g, 1.583 mmol) in dioxane/water (21 mL) was heated in microwave at 130° C. for 40 min. The mixture was poured into water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-5% 2M NH3 MeOH/DCM to afford a yellow solid as (S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.166 g, 0.421 mmol, 80% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3C(OC(C)(C)C)=O)=[CH:18][C:17]=2[C:36]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:37])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>ClCCl>[C:8]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]3[CH2:28][CH2:27][CH2:26][NH:25]3)=[CH:18][C:17]=2[C:36]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:37])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnc1)c1cc(OC[C@H]2CCCN2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.5 ml, 19.47 mmol) was added dropwise to an ice-cooled solution of 1,1-dimethylethyl (2R)-2-[({4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)methyl]-1-pyrrolidinecarboxylate (may be prepared as described in Description 73; 500 mg, 0.99 mmol) in dichloromethane (15 ml). After stirring at 25° C. for 2 h, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. Half of the crude product was purified by pre-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*19 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-7 min, 35%-50%; 7-14 min, 95%; RT=6.5 min) to yield the title compound as a light yellow solid. 70 mg.
Reaction SMILES: [O:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH:6]1[CH2:10]C=[CH:8][CH:7]=1.O>ClCCl.C(N(CC)CC)C>[CH:5]12[CH2:8][CH:7]([CH:6]=[CH:10]1)[CH2:4][CH:3]2[CH:2]=[O:1]
Reactant: C=C(C)C=O
Reactant: C1=CCC=C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=CC1CC2C=CC1C2
Yield: 95 %

Procedure:
Diels-Alder reaction was conducted to a methacrolein wherein the scandium (III) pentafluorophenylbis(triflyl)methide obtained from Examples 13 and 14 was used as a Lewis acid catalyst (Chemical formula 39). Methacrolein (0.21 mL, 2.6 mmol) and cyclopentadiene (0.56 mL, 6.8 mmol) were reacted while stirring in 3 mL dichloromethane at −40° C. for 4 hours, under the presence of scandium (III) pentafluorophenylbis(triflyl)methide as 1 mol % of Lewis acid catalyst. Two to 3 drops of triethylamine was added to stop the reaction, 5 mL of water was added and the 5-norbornene-2-aldehyde produced was extracted with pentane. After concentration and drying, the crude product was analyzed with 1HNMR and it was found that the 5-norbornene-2-aldehyde showed a high yield of 95% (88% exo). The same reaction as mentioned above was conducted, except for the use of scandium (III) triflate [Sc(OTf)3] as a conventionally known Lewis acid catalyst, instead of the scandium (III) pentafluorophenylbis(triflyl)methide mentioned above. The 5-norbornene-2-aldehyde was hardly synthesized. Subsequently, 2 mol % of this scandium (III) triflate was used, and the yield of the 5-norbornene-2-aldehyde was 97% (89% exo). Based on these results, it was found out that the catalytic activity of the scandium (III) pentafluorophenylbis(triflyl)methide of the present invention is much more higher compared to that of the existing Lewis acid catalysts.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: Brc1ncccn1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2ncccn2)CCN1
Reaction time: 15 h
Yield: 33.7 %

Procedure:
To a solution of (R)-2-methyl piperazine (4.0 g, 40 mmol) in xylene (100 mL) at 140° C. under nitrogen was added 2-bromo pyrimidine (6.36 g, 40 mmol) slowly over a period of 30 min. The heating was continued for additional 15 h and cooled. The solid precipitate was filtered and dried under suction and neutralized with a saturated aqueous solution of sodium bicarbonate. The product was extracted with DCM (2×50 mL), dried and evaporated to afford the title compound as a liquid (2.4 g, 34%). TLC-Chloroform/MeOH (8/2); Rf: 0.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)c1cccc(F)c1
Product: O=C1CCCc2cc(-c3cccc(F)c3)ccc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-fluorophenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 241.