Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.O>CCO.[O-2].[Mn+4].[O-2]>[N:1]1[C:2]([CH:10]=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: OCc1cn2ccccc2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: CCO
Product: O=Cc1cn2ccccc2n1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
To a solution of imidazo[1,2-a]pyridin-2-ylmethanol (3.0 g, 20 mmol) in EtOH (50 mL) was added manganese (IV) oxide (8.8 g, 100 mmol). The mixture was refluxed for 2 days. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by reverse phase column chromatography (eluting with acetonitrile in water 25% v/v, with 0.01% NH3. H2O) to afford the title compound (0.45 g, 15% yield) as a yellow solid. ESI MS: m/z 147 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:13]O)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:13][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(-c2ccc(Cl)cc2)s1
Solvent: ClCCl
Product: ClCc1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a suspension of [2-(4-chlorophenyl)thiazol-5-yl]methanol (3.24 g, 14.3 mmol) in dichloromethane (40 ml) is added dropwise the thionyl chloride (1.3 ml, 18 mmol) at room temperature under nitrogen. The reaction mixture is stirred at room temperature for 4 hours. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 5-chloromethyl-2-(4-chlorophenyl)thiazole (3.24 g)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:13]1[N:14]=[C:15]([Cl:22])[C:16]2[CH:21]=[CH:20][NH:19][C:17]=2[N:18]=1.[OH-].[Na+]>CC(C)=O>[Cl:22][C:15]1[C:16]2[CH:21]=[CH:20][N:19]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:17]=2[N:18]=[CH:13][N:14]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.9 %

Procedure:
4-Methylbenzene-1-sulfonyl chloride (3.7 g, 19.32 mmol, 1.20 equiv.) was added to a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine 1 (3 g, 16.1 mmol, 1.00 equiv.) in acetone (20 mL). At about 0° C., an aqueous sodium hydroxide solution (2 mol/L, 12 mL) was added dropwise to the solution. The solution was then stirred at ambient temperature for about 3 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (5.2 g; yield=95%). LC-MS: m/z=342 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]3[CH2:14][CH2:13][CH2:12][CH:7]3[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]3[CH2:14][CH2:13][CH2:12][CH:7]3[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:27])=[O:26]
Reactant: Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A stirred solution of 7-amino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide (150 mg; 0.5 mmol) and triethylamine (70 μl; 0.5 mmol) in THF (1 ml) was added a solution of CH3SO2Cl (40 μl; 0.5 mmol) in THF (1 ml) and stirred at rt. over night. The reaction mixture was evaporated to dryness, suspended in H2O and extracted by EtOAc. The combined organic fractions were evaporated to dryness. Column chromatography gave 40 mg product. M.p. 177–180° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15](Cl)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:20])[N:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:20])[N:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Yield: 78.6 %

Procedure:
Following the procedure of Example X-2, the reaction of 1-benzyl-3-benzyloxy-7-chloro-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example P-2, 142 mg, 0.345 mmol) with pyrrolidine (0.070 mL, 0.828 mmol) in dichloromethane (3 mL) afforded 121 mg of the title compound as a solid. mp 171-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:14]S(O)(=O)=O>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH:11]=[O:14]
Reactant: O=S(=O)(O)O
Reactant: COc1c(C)ccc([N+](=O)[O-])c1Cl
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1c(C=O)ccc([N+](=O)[O-])c1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2-methoxy-4-nitrotoluene (1.0 g, 5.0 mmol) in acetic acid (10 mL) and acetic anhydride (10 mL) was cooled to 50° C. and treated with 1 mL conc. H2SO4. Chromium trioxide (1.4 g, 14 mmol) was added in portions over 10 minutes while the reaction temperature was maintained at 0-5° C. After 30 minutes at this temperature, the mixture was poured onto ice-water (20 g) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine, dried (sodium sulfate) and concentrated. The crude bis-acetate was combined with water (10 mL), ethanol (10 mL) and concentrated sulfuric acid (1 mL) and heated to reflux for 40 minutes. Upon cooling, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The crude mixture was chromatographed (10% ethyl acetate/hexanes) to give 3-chloro-2-methoxy-4-nitrobenzaldehyde (400 mg, 1.9 mmol): LC/MS (m/z=215).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27](=[O:29])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][Mg+].[Br-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27]([CH3:30])([OH:29])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(O)CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Temperature: -78 °C

Procedure:
3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone (100 mg, 248 mols) was dissolved in dry THF (1.0 mL) under inert atmosphere and cooled to −78° C. A solution of MeMgBr (40 μL, 322 mols) in toluene: THF (75:25) was added slowly to the cooled solution. After 24 h of reaction at rt the reaction was cooled to 0° C. and quenched with NH4Cl sat. aq. solution and the aqueous layer was washed with EtOAc (2×). The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by silica gel column chromatography [Jones Flashmaster, 10 g/70 mL cartridge, eluting with 2-5% ((7N NH3) in MeOH):CH2Cl2], yielding 3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([NH:14][C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])=[O:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([NH:14][C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])=[O:16])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(O)cc2)nsc1NC(=O)[C@@H]1C[C@H]1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1
Temperature: 45 °C
Yield: 33.4 %

Procedure:
To a dry flask containing (R,R)—N-[3-(4-hydroxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide (100 mg, 0.347 mmol) is added dry acetone (2 mL), K2CO3 (50 mg, 0.347 mmol), and methyl iodide (19 μL, 0.313 mmol). The reaction mixture is heated 16 h at 45° C. and treated with additional methyl iodide (19 μL, 0.313 mmol). After heating for another 6 h, the solvent is evaporated, and the residue is partitioned between ethyl acetate and water. The ethyl acetate solution is washed (satd aqueous K2CO3 (twice) and brine), dried (MgSO4), and the solvent evaporated. Chromatography over silica gel, eluting with EtOAc/hexanes, affords (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropane-carboxamide (35 mg, 33%) as a white solid. 1H NMR; ES-MS: m/e 303 (m+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[O:26])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].CNC.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Agent: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CO)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound. LCMS: 491.25 (M+1)+; HPLC: 99.58% (@ 254 nm) (Rt; 3.984; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.75 (s, 1H), 8.19 (t, 1H), 8.05 (d, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.41 (s, 1H), 7.24 (s, 1H), 5.86 (s, 1H), 5.44 (t, 1H, J=5.6 Hz), 4.59 (d, 2H, J=5.6 Hz), 4.28 (d, 2H, J=4 Hz), 3.85 (d, 2H, J=10.4 Hz), 3.32 (2H merged in solvent peak), 3.03 (m, 1H), 2.64 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.61 (bs, 4H).
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:19]([O:21][C:22](=[O:48])[CH2:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:48])[CH2:23][C:24]1([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:2]4[CH:6]=[N:5][N:4]([CH3:7])[C:3]=4[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[CH2:25][CH2:26]1)[CH3:20]
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: Cn1ncc(Br)c1C(O)CCCc1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4cnn(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-phenyl-butan-1-ol and {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[C:15]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.O>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc2scnc2c1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2nc3ccccc3s2)CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.5 %

Procedure:
To a solution of 2 mL (18.3 mmol) of benzothiazole in 20 mL of tetrahydrofuran was added 11.4 mL (18.2 mmol) of 1.6 M n-BuLi at −78° C. After 45 min, 1.6 mL (18.1 mmol) of cyclopentanone was added at the same temperature. The reaction was let warm to room temperature over 1 h. Water was added to quench the reaction and the mixture was extracted with ether (3×). The ether layer was washed with brine (3×) and dried over magnesium sulfate. After removal of solvent, purification by silica gel column chromatography eluting with hexane:ethyl acetate (4:1) gave 2.8 g (71%) of 1-(1,3-benzothiazol-2-yl)cyclopentanol as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 2.25 (m, 4H), 2.00 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26].F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:18][N:17]=1
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added isopropylamine (18 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (0.096 g, 0.30 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4), filtered and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (51 mg, 65%) as a colorless oil. MS: m/e=369.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([NH2:6])=[O:5])[CH2:2]1.[C:10](OC([O-])=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:1]1[CH2:9][CH2:8][CH2:7][C@@H:3]([C:4]([NH2:6])=[O:5])[CH2:2]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NC(=O)C1CCCNC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To the reaction mixture obtained in Example 4, tert-butyl dicarbonate (16.1 g, 1.0 equivalent) was added. The pH of the reaction mixture was kept from 7.0 to 8.0. The reaction mixture was stirred for 3 hours at room temperature to obtain a solution containing (R)-1-(tert-butoxycarbonyl)nipecotamide (6.6 g, yield: 39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CCCCCC.C([Li])CCC.[C:24](=[O:26])=[O:25]>O1CCCC1>[Cl:8][C:7]1[C:2]([F:1])=[C:3]([C:4]([C:9]([F:12])([F:10])[F:11])=[CH:5][CH:6]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: Fc1cc(C(F)(F)F)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
77.0 g of 3-fluoro-4-chlorobenzotrifluoride was dissolved in 750 ml of dried tetrahydrofuran, and to the solution, 250 ml of hexane solution of n-butyl lithium (1.6 mol/l) was added dropwise over 15 minutes at -78° C. under a nitrogen atmosphere. After stirring the solution at -78° C. for 2 hours. 50 g of dry ice was gradually added to the solution at the same temperature. After elevating the temperature of the solution up to room temperature, 500 ml of ice water was added to the solution to separate the resulting solution. While cooling down the aqueous layer, the layer was adjusted to a pH value of 1 with concentrated hydrochloric acid. The aqueous layer was then extracted with ether, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the oily residue obtained was crystalized with n-hexane, followed by a filtration and then dried to obtain 88.4 g of the title compound(mp. 92-93° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 167 parts of p-nitrobenzoic acid and 93 parts of aniline is heated at 210° C. with the water formed during the reaction being distilled off. After heating for 3 hours, 18 parts of water have been collected, which shows that the reaction is ended. 242 parts of N-(4'-nitrobenzoyl)-aniline melting at 215° C. are obtained according to the instructions in the literature, i.e. a yield of 99% by weight. The infra-red spectrum confirms the formula of the product:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)O)cs1
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)NC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a round bottom flask with 50 mL methylene chloride was added 2-((tert-butoxycarbonylamino)methyl)thiazole-4-carboxylic acid (2.0 g, 7.74 mmole) and methyl 2-amino-2-methylpropanoate hydrochloride salt (1.25 g, 8.13 mmole). To the mixture, triethylamine (5.4 mL, 38.7 mmole) was then added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.97 g, 15.5 mmole) and hydroxybenzotriazole (2.09 g, 15.5 mmole). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with methylene chloride. The mixture was then washed with water and the aqueous layer was extracted with methylene chloride. The combined organic layer was then dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 1:1 EtOAc/hexane to provide the desired product (2.40 g, 87% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[Br:16]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Br:16])[C:11]([OH:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 4-hydroxyisophthalic acid dimethyl ester (10.51 g) in THF (100 mL) was added N-bromosuccinimide (9.34 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (200 mL) and saturated aqueous sodium bicarbonate (100 mL) were successively added to the reaction solution. The resulting precipitate was filtered, washed successively with saturated aqueous sodium bicarbonate and water, and dried to give the title compound (12.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=2[O:37][CH3:38])=[CH:22][CH:21]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:38][O:37][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:32]=[CH:33][C:28]=1[O:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(COc2ccc(B(O)O)cc2OC)cc1
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccc(O)nc5)c4c3)cc2OC)cc1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To the 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2-ol, 4-(4-methoxyphenylmethoxy)-3-methoxyphenylboronic acid (1.3 equiv.), and 6 mol % of dichlorobis(triiphenylphosphino)palladium (II) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water and a 2 M aqueous solution of sodium carbonate (0.10 M). The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture was extracted three times with ethyl acetate Purification on silica gel with a gradient or methanol/dichloromethane by flash chromatography afforded 5-{5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyridin-2-ol as a tan solid (46% yield). 1H NMR (DMSO-d6): δ 11.86 (broad s, 1H), 11.67 (broad s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.89 (dd, J=2.5, 9;5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.72 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.20 (dd, J=2.0, 8.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.44 (d, J=9.5 Hz, 1H), 5.03 (s, 2H), 3.85 (s, 3H), 3.75 (s, 3H); HPLC/MS m/z: 454.1 [MH]+.