Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:3]=1>CC(O)C>[CH:8]([O:12][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:3]=1)([CH3:9])[CH3:7]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1C
Solvent: CC(C)O
Product: COc1ccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1C

Procedure:
Similar procedure as described in the example 10 was used, starting from (1-Chloro-6-methoxy-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-propanol to give 5 mg of (1-Isopropoxy-6-methoxy-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 327 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])[N:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(NCC(F)(F)F)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 29.8 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenyl-pyrrolo[3,2-d]pyrimidine (Example-1(e)) (55.9 mg, 0.23 mmol) and 2,2,2-trifluoroethylamine (Aldrich Chemical Company) (95 μL, 1.15 mmol) was added a solution of K2CO3 (0.13 g, 0.92 mmol) in H2O (1.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution was washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated aqueous NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was washed with CH2Cl2 until all the color was removed. The remaining solid was recrystallized from hot MeOH to provide 21 mg (29%) of the title compound as a white solid. Mp: >310° C. MS m/z 307 (M+1), 294, 281, 226. 1H NMR (DMSO-d6; 400 MHz): δ 2.31 (s, 3), 2.52 (s, 2), 6.74 (s, 1), 7.33 (t, 1, J=7.3), 7.43 (t, 2, J=7.8), 7.92 (d, 2, J=7.3), 11.74 (s, 1), 12.22 (s, 1). HRMS: Calcd for M+H, C15H13F3N4: 307.1168. Found: 307.1160.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:21]=[C:20]([CH2:22][N:23]([CH3:42])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH:19]=[CH:18][CH:17]=3)=[O:15])=[C:9]([C:43](=[O:60])[NH:44][C:45]3[CH:49]=[CH:48][N:47]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=4)[N:46]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH3:42][N:23]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[C:43](=[O:60])[NH:44][C:45]2[CH:49]=[CH:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:57])([F:58])[F:59])[CH:51]=3)[N:46]=2)[N:21]=1
Reactant: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCOCCOCCOCCC(=O)O)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(2-(2-(2-(((6-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)-phenyl)carbamoyl)pyridin-2-yl)methyl)(methyl)amino)ethoxy)ethoxy)ethoxy)propanoate (210 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (4 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 32.9 mg (13%) of a brown solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.81-8.78(d, J=9.3 Hz, 1H), 8.48-8.47(d, J=2.7 Hz, 1H), 8.33-8.31(d, J=7.5 Hz, 1H), 8.21-8.16(d, J=7.5 Hz, 2H), 7.87-7.86(d, J=2.4 Hz, 1H), 7.79-7.72(m, 2H), 7.64-7.62(d, J=6.9 Hz, 2H), 6.98-6.97(d, J=2.4 Hz, 1H), 4.75(s, 2H), 3.80-3.77(t, J=4.5 Hz, 2H), 3.66-3.47(m, 16H), 3.11-3.09(d, J=6.3 Hz, 3H), 2.49-2.45(d, J=6 Hz, 2H), 1.94-1.75(m, 6H). MS (ES, m/z): 782 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:15])=[O:4].[OH:16][CH:17]([CH:19](O)[CH3:20])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:12]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:15])[C:6]=2[NH:5][C:3](=[O:4])[CH2:2][Cl:1])[O:16][CH:17]([CH3:18])[CH:19]([CH3:20])[O:14]1
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCl
Reactant: CC(O)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cccc(C2(C)OC(C)C(C)O2)c1NC(=O)CCl

Procedure:
The product from Example 1 (10.6 g), 2,3-dihydroxy-butane (8.5 g) and p-toluene sulfonic acid (1.5 g) in 200 ml benzene were refluxed to 2 hours, removing water with a Dean-Stark trap. The solution wash washed with 10% NaOH, dried (MgSO4) and stripped. The product was chromatographed on a silica gel column, eluting with 30% ether-hexane. Yield: 3.8 g of the title product, mp 55°-57° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.[CH:14](N1CCCCC1)=[O:15]>C(OCC)C>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([CH:14]=[O:15])=[CH:7][N:6]=1
Reactant: O=CN1CCCCC1
Reactant: Clc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Cl)nc1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 63.5 %

Procedure:
5-Bromo-2-chloropyridine (T-9) (15.0 g) and diethyl ether (450 ml) were put in a reaction vessel and cooled to −50° C. under an atmosphere of nitrogen. n-Butyllithium (1.57 M in n-hexane; 54.6 ml) was added dropwise in the temperature range of −50° C. to −45° C., and the stirring was continued for another 90 minutes. After the reaction vessel had been cooled to −70° C., formylpiperidine (9.70 g) was added dropwise in the temperature range of −70° C. to −65° C., and the stirring was continued for another 60 minutes while the mixture was allowed to return to room temperature. The resulting reaction mixture was poured into ice-water (500 ml) and mixed with it. Diethyl ether (200 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from heptane. The solvent was distilled off and the product was dried, giving 2-chloro-5-formylpyridine (T-10) (7.01 g). The yield based on the compound (T-9) was 68%.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11]([O:13][CH2:14]Cl)[CH3:12]>C(#N)C>[CH2:11]([O:13][CH2:14][O:10][C:6]1[CH:5]=[C:4]([NH2:3])[CH:9]=[CH:8][CH:7]=1)[CH3:12]
Reactant: Nc1cccc(O)c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOCOc1cccc(N)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
12 g (274.9 mmol) of a dispersion of sodium hydride (55% in oil) was added portionwise at 0° C. to a solution of 20.0 g (183.3 mmol) of 3-aminophenol in 450 mL of dried acetonitrile. The mixture was then allowed to agitate at 0° C. for 3 hours. A solution of 25 g (210.8 mmol) of chloromethyl ethyl ether in 30 mL of acetonitrile was added dropwise, and the mixture was allowed to agitate overnight at room temperature. The reaction mixture was then filtered and the filter cake was washed with a small amount of acetone and the filtrate was evaporated. This gave 32.3 g of 3-ethoxymethoxyphenylamine. The resulting product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@:4]([NH2:28])([C@@H:13]([CH2:21][C:22](=[O:27])[CH:23]=[CH:24][CH2:25][CH3:26])[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C@:4]([NH2:28])([C@@H:13]([CH2:21][C:22](=[O:27])[CH:23]=[CH:24][CH2:25][CH3:26])[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[NH:5][C:6]([O:8][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[O:7]
Reactant: CCC=CC(=O)C[C@@H](OC1CCCCO1)[C@](N)(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCC=CC(=O)C[C@@H](OC1CCCCO1)[C@](N)(NC(=O)O[Si](C)(C)C(C)(C)C)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-(t-butoxycarbonyl)-2-amino-4-pentenoyl-O-(tetrahydropyranyl)threonine methyl ester (37 mg, 0.09 mmol) and 2,6-lutidine (0.021 ml, 0.18 mmol) was added dropwise t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.031 ml, 0.14 mmol) at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 45.8 mg.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8][OH:9].[C:10]([SiH:14]([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: Cc1oc(=O)oc1CO
Reactant: C[SiH](C)C(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene (1 mmole) in DMF was treated with tert-butyldimethylsilane (1.2 mmole) and imidazole (2.2 mmole) at 25° C. for 24 h. Extraction and chromatography gave 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N+:40]([O-:44])=[C:39]([CH3:45])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:42]=[C:41]([CH3:43])[N+:40]([O-:44])=[C:39]([CH3:45])[CH:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.185, m/z=459.1; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.57 (d, 3H), 2.20 (s, 2H), 2.22-2.35 (m, 2H), 2.38-2.49 (m, 1H), 2.72 (s, 6H), 2.91 (m, 1H), 5.70 (m, 1H), 7.08 (d, 2H), 7.31 (m, 3H), 7.37 (m, 4H), 7.43 (s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[C:9]([C:11]#[N:12])[N:10]=1)=[O:5])C.[OH-:21].[Na+].[OH-].[K+].Cl>CCO.O>[C:11]([C:9]1[N:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=1)(=[O:21])[NH2:12]
Reactant: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(C(N)=O)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (prepared in Example 11, step (c))(2.0 g, 6.8 mmol) in 15 mL of EtOH was added 5 N NaOH (2.0 mL, 10 mmol) and the reaction stirred for 8 h at RT. The mixture was concentrated, then water (20 mL) and 2 N KOH (3.4 mL, 6.8 mmol) was added and the mixture heated to 90° C. for 1 h. The mixture was cooled in an ice bath and the pH adjusted to 4 with 3 N HCl and a white ppt collected by filtration and dried under vacuum to give 1.5 g (77%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C1, H19N3O4Si, 286.1 (M+H), found 285.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[H-].[Na+].[CH3:17]N(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:17])[C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Brc1ccc2[nH]c3cnccc3c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cn1c2ccc(Br)cc2c2ccncc21
Reaction time: 1 h

Procedure:
A solution of 6-bromo-β-carboline (1.0 g, 4.05 mmol) in 12 mL of DMF was stirred in an ice bath and 186 mg (4.65 mmol, 1.15 equiv.) of 60% sodium hydride in mineral oil dispersion was added. Gas evolution was observed and stirring was continued for 1 h at ambient temperature. The homogenous reaction was partitioned between EtOAc and H2O. The organic layer was washed again with H2O followed by brine. After drying (MgSO4), evaporation gave a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: OCCCCCCCl
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(C=O)ccc1OCCCCCCO
Yield: 88 %

Procedure:
4-[(6-hydroxyhexyl)oxy]-3-methoxybenzaldehyde is prepared starting from 4-hydroxy-3-methoxybenzaldehyde and 6-chlorohexan-1-ol according the same procedure following for example 7 in 88% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[Cl:6][C:7]1[C:8]2[CH:15]=[CH:14][NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([CH2:2][CH:3]3[CH2:5][CH2:4]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: BrCC1CC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
(Bromomethyl)cyclopropane (7.6 mL, 78 mmol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 65 mmol) and cesium carbonate (25.4 g, 78 mmol) in DMF (100 mL). The reaction mixture was stirred at room temperature 12 h, filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 1:9→2:8 EtOAc:hexanes) provided the title compound as a white solid (12.9 g, 95%). MS: 208.5 (MH+); HPLC Rf: 5.21 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: Nc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(Nc2ccc(Cl)nc2)c(C(=O)O)c1
Temperature: 130 °C
Yield: 46 %

Procedure:
A mixture of 6-chloropyridin-3-amine (11.67 mmol, 1.5 g) and 2-bromo-5-methylbenzoic acid (23.34 mmol, 5.02 g), Cu (1.17 mmol, 0.1 g), Cu2O (0.58 mmol, 0.1 g) and K2CO3 (23.34 mmol, 3.2 g) in 1,2-dimethoxyethane (15 ml) was heated at 130° C. for 16 hours, under argon atmosphere. Water was added and the mixture was filtered through celite. HCl 2N aqueous solution was added until pH 6 and the solid formed was filtered off. The crude was purified by chromatography eluting with DCM/MeOH mixtures affording 1.40 g (yield 46%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:15]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccc1-c1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1ccccc1-c1ccccc1
Yield: 70.1 %

Procedure:
Under an atmosphere of argon, 2,2′-dibromobiphenyl (9.5 g, 30 mmole), phenylboronic acid (3.7 g, 30 mmole) and tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.87 mmole, 3% Pd) were dissolved into toluene (75 ml). To the obtained solution, an aqueous solution of sodium carbonate (9.7 g, 92 mmole, 3 eq/46 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a dark yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and a colorless oil (6.5 g, 70%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]=[CH:11]\[CH2:12][CH3:13].Br[CH2:15][CH2:16][CH2:17]Cl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]=[CH:15]\[CH2:16][CH3:17]
Reactant: CC/C=C/C=C\CC/C=C\CCCl
Reactant: ClCCCBr
Product: CC/C=C/C=C\CC/C=C\CCCCCCl

Procedure:
The (Z,Z,E)-1-chloro-3,7,9-dodecatriene (2) is converted into a corresponding Grignard reagent and then the Grignard reagent is reacted with 1-bromo-3-chloropropane to obtain (Z,Z,E)-1-chloro-6,10,12-pentadecatriene (3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:41][CH:42]=[C:43]([CH3:44])[C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][C:10]([NH:13]C(=O)OC(C)(C)C)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:13][C:10]([CH3:12])([CH3:11])[CH2:9][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[C:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:33][N:32]=[C:31]3[NH:41][CH:42]=[C:43]([CH3:44])[C:30]=23)[CH2:27][CH2:28]1)=[O:22]
Reactant: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CC(C)(C)NC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CC(C)(C)N)c4ccc(Cl)cc4)CC3)c12
Reaction time: 1 h
Yield: 101.4 %

Procedure:
(R)-tert-Butyl 4-(4-chlorophenyl)-2-methyl-5-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-5-oxopentan-2-ylcarbamate (0.040 g, 0.065 mmol) was placed in DCM (3 mL). TFA (0.3 mL) was then added. The reaction was stirred for 1 hour and then concentrated to dryness. The resulting oil was dissolved in minimal DCM, and added to a stirring solution of 1M HCl in ether. The resulting solid was collected by filtration, washed with ether, and dried to give (R)-4-amino-2-(4-chlorophenyl)-4-methyl-1-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)pentan-1-one (0.034 g, 89% yield) as the dihydrochloride salt. MS ESI (+) m/z 517 detected.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C.[Si:27](OS(C(F)(F)F)(=O)=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:27]([O:17][C:15]([C:14]1[C:9]([C:8]#[C:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH2:16])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(=O)c1cccnc1C#Cc1ccccn1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccnc1C#Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
455 mg 1-(2-(pyridin-2-ylethynyl)pyridin-3-yl)ethanone was dissolved in 10 mL DCM, 1.069 mL of DIPEA was added, the solution was cooled 0° C. and 1.42 mL of tert-butyldimethylsilyltrifluormethansulfonate added slowly. The mixture was stirred 30 min at 0° C., warmed to 25° C. and filtrated over a plug of silica (cyclohexane/ethylacetate 1:1+small amount of TEA) to yield 1.025 g 3-(1-(tert-butyldimethylsilyloxy)vinyl)-2-(pyridin-2-ylethynyl)pyridine as oil. Analysis: HPLC-MS: Rt=1.59 min (method E) m+H=337.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:17][C@H:16]([N:18]=[N+]=[N-])[CH2:15][NH:14]1)=[O:12])[CH3:9].COC([C@@H]1C[C@H](N)CN1[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=O>>[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:17][C@H:16]([NH2:18])[CH2:15][N:14]1[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:12])[CH3:9]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Reactant: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1

Procedure:
(2S,4S)-4-Amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid ethyl ester trifluoroacetate salt in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C14H27N2O2 [(M+H)+] 255, obsd. 255.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:28][C:6]1[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:21])[N:11]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1,3-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.081 mmol), β-alanine (431 mg, 4.84 mmol) and NaOMe solution (8 mL, 4.03 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 30 mg of the title compound as a light yellow solid. MS: (+) m/z 430.27 (M+1).