Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>CS(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=2)=[N:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Nc1cccc(N)n1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Solvent: CS(C)=O
Product: Nc1cccc(Nc2ccc([N+](=O)[O-])cn2)n1
Temperature: 80 °C
Yield: 19.7 %

Procedure:
2,6-Diaminopyridine (9.2 mmol, 1.0 g) and 2-fluoro-5-nitropyridine (4.6 mmol, 0.65 g) were dissolved in 6 mL of DMSO. The solution was heated to 80° C. for 18 h. The solution eventually turned dark red. The reaction mixture was cooled to room temperature and purified directly by flash column chromatography (silica, EtOAc:Hexanes=1:3) to give N2-(5-nitropyridin-2-yl)pyridine-2,6-diamine as a reddish crystalline solid (0.21 g, 20% yield): 1H NMR (500 MHz, CDCl3) δ 9.13 (d, 1H, J=3.0 Hz), 8.36 (dd, 1H, J=3.0 Hz, J2=9.5 Hz), 7.94 (d, 1H, J=9.5 Hz), 7.66 (s, 1H), 7.46 (t, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0 Hz), 6.23 (d, 1H, J=8.0 Hz), 4.46 (s, 2H); Ms m/z (relative intensity) 232 (M+1, 100), 186 (57). The nitro compound (0.78 mmol, 0.18 g) and 10% Pd/C (20 mg) were added to a 20 mL test tube equipped with a stir bar, dry ice (0.5 g) was added to the mixture just before MeOH (7 mL) was added. The suspension was then put into a pressure vessel under 80 psi of H2. The reaction mixture was stirred for 2 hours. The solution turned from yellow to colorless. The reaction mixture was transferred into a 10 mL syringe and was then filtered through an Acrodisc syringe Filter into a 100 mL round bottom flask containing 37% aqueous HCl (4 mL). The solvent was then evaporated and azeotroped to dryness with toluene and absolute ethanol (3×30 mL of 1:1 mixture). The product was obtained as a grayish yellow powder in quantitative yield.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:27]=C1CNCCN1>>[O:27]=[C:23]1[NH:22][CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:24]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: O=C1CNCCN1
Product: O=C1CN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3n2)CCN1

Procedure:
The title compound was prepared following the procedure described for 6a using 2-oxopiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.08 (2H, m), 3.90 (2H, dd, J=5.67, 4.94), 4.19 (2H, s), 7.15 (1H, dd, J=7.42, 1.09 Hz), 7.20 (1H, d, J=9.34 Hz), 7.40 (2H, dd, J=8.51, 7.42 Hz), 7.85 (1H, d, J=9.06 Hz), 8.16 (1H, br), 8.22 (1H, dd, J=7.70, 1.09 Hz), 8.57 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>C1COCC1>[CH3:23][N:24]([CH3:28])[C:25](=[O:26])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cn2cc(N)ccc2n1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2cc(NC(=O)N(C)C)ccc2n1
Temperature: 0 °C
Yield: 24.5 %

Procedure:
Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (0.975 mmol, 0.2 g) was dissolved in THF (10 ml). Triethylamine (2.92 mmol, 0.296 g) was added and the reaction mixture was cooled to 0° C. Dimethylcarbamyl chloride (1.462 mmol, 0.135 ml) was added carefully and the mixture was allowed to warm to ambient temperature with stirring. More of dimethylcarbamyl chloride (1.462 mmol, 0.135 ml) was added and the stirring continued for another hour. The solvent was evaporated, DCM was added and the resulting mixture was washed with NaHCO3 solution and water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.066 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3H), 2.95 (s, 6H), 4.29 (q, 2H), 7.39-7.44 (m, 1H), 7.50-7.54 (m, 1H), 8.41 (s, 1H), 8.54 (s, 1H), 8.89-8.93 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[CH2:9]O.S(Cl)([Cl:22])=O>C1COCC1>[Cl:22][CH2:9][CH:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=S(Cl)Cl
Reactant: OCC(c1ccccc1Cl)N1CCc2sccc2C1
Solvent: C1CCOC1
Product: ClCC(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
To a solution of 2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl)ethanol (9.7 g, 33.1 mmol) in THF (280 mL) was added thionyl chloride (7.9 g, 66.2 mmol) drop-wise. The solution was stirred at room temperature for 1.5 h (monitored by TLC). The excess thionyl chloride was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (200 mL), washed with saturated NaHCO3 solution (to pH=7), dried over Na2SO4, and concentrated under vacuum to provide 5-[2-chloro-1-(2-chlorophenyl)ethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10.1 g, 98.1%) as a light yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.63 (d, J=6.3 Hz, 1H), 7.36-7.22 (m, 3H), 7.05 (d, J=5.1 Hz, 1H), 6.70 (d, J=5.1 Hz, 1H), 5.62 (t, J=6.3, 1H), 3.71 (s, 2H), 3.10-3.07 (m, 2H), 2.95-2.91 (m, 2H), 2.86-2.84 (m, 2H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 137.72, 133.43, 132.79, 129.56, 129.47, 129.00, 127.43, 125.31, 122.70, 64.37, 56.60, 53.24, 50.98, 25.24. MS (HR, GC-CI): Calculated for C15H15Cl2NS (MH)+: 312.0375, found 312.0349.
Reaction SMILES: N1C=CN=C1.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].Cl[Si:15]([CH3:18])([CH3:17])[CH3:16].CCOCC>CN(C)C=O.CCCCCC>[CH3:16][Si:15]([CH3:18])([CH3:17])[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH2:6]
Reactant: Nc1ccccc1O
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)Oc1ccccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
Imidazole (3.73 g) was added in one portion to a solution of 2-aminophenol (2.0 g) in dry dimethylformamide (10 ml) stirred at 25° C. under nitrogen. Chlorotrimethylsilane (2.98 g) was added dropwise over 5 minutes and stirring continued for a further 18 hours. The mixture was poured onto water (30 ml) and extracted with diethyl ether (2×60 ml). The organic solution was separated and washed with 2N sodium hydroxide (2×40 ml), brine and dried over magnesium sulphate. Evaporation of the filtrate under reduced pressure gave an oil. Column chromatography on silica eluting with 10% ether:hexane gave 2-trimethylsilyloxyaniline (0.85 g). NMR 1H: 0.2(9H,s), 3.5(2H,s), 6.4(4H,m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](SCC)[N:11]3[CH:17]=[CH:18][N:19]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.C[OH:21].[OH-].[K+].Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:21])[N:11]3[CH:17]=[CH:18][N:19]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCSc1nc(-c2ccc(Br)cc2)cc2nccn12
Reactant: CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2nccn12
Reaction time: 48 h
Yield: 94.71 %

Procedure:
To a flask charged with 7-(4-bromophenyl)-5-(ethylthio)imidazo[1,2-c]pyrimidine (62.34 g, 186.5 mmol), methanol (250 mL), and potassium hydroxide (52.32 g, 932.6 mmol) was added water (250 mL) and the reaction was fitted with a condenser and heated to reflux for 4 hours. The reaction mixture was diluted with water (500 mL) and acidified with concentrated hydrochloric acid to a pH=5. The solids were collected by vacuum filtration and then washed with water (3×500 mL) and the cake was dried. The semi dry solids were placed in a vacuum desiccator under high vacuum for two days to afford 7-(4-bromophenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (51.25 g, 176.7 mmol, 94.71% yield). MS (apci) m/z=290.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([N:28]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]4)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: O=C(O)C1CCNC1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCC(C(=O)O)C4)cc3)cc12

Procedure:
1-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)pyrrolidine-3-carboxylic acid was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and pyrrolidine-3-carboxylic acid (commercially available) following the procedures described for Example 187, except that in this case, acetic acid was used instead of triethylamine (30%). 1H NMR (Acetone-d6) TFA Salt: δ 8.81 (s, 1H), 8.75 (s, 1H), 8.70 (s, 1H), 8.28 (d, 1H), 7.59 (d, 2H), 7.37 (m, 3H), 4.46 (m, 1H), 4.21 (m 1H), 3.45 (m, 2H), 3.32 (m, 2H), 3.21 (m, 2H), 3.17 (m, 2H), 2.27 (m, 2H), 2.07 (s, 3H) 1.77 (d, 3H). LRMS [M+H]=455.2
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[N:18]2)=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:23][CH2:22][C:19]2[CH:20]=[CH:21][N:17]([C:14]3[CH:15]=[CH:16][C:11]([I:10])=[CH:12][CH:13]=3)[N:18]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccn(-c2ccc(I)cc2)n1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccn(-c2ccc(I)cc2)n1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid (51 mg, 0.31 mmol), (1-(4-iodophenyl)-1H-pyrazol-3-yl)methanamine (78 mg, 0.26 mmol) and TEA (0.100 mL, 0.72 mmol) in DMF (3 mL), BOP (170 mg, 0.38 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a preparative TLC plate (developed in EtOAc/hexane (35/65)) to give 5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH2:5][CH2:6][C:7]2=[O:15].O1CCOCC1>[Pd].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[C:7](=[O:15])[CH2:6][CH2:5][CH:4]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)c2c(Cl)ccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1ccc(Cl)c2c1C(=O)CCC2N1C(=O)c2ccccc2C1=O

Procedure:
To 320 mg of the compound prepared in (1) above were added 9 ml of dioxane and 15 ml of ethanol. The mixture was catalytically hydrogenated with 200 mg of 10% palladium-on-carbon. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 176 mg of the title compound.
Reaction SMILES: [Br-].[Li+].B.[Na].C([O:12][C:13]([C@@H:15]([NH:29][C:30]([N:32]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=O)C1C=CC=CC=1.[Cl-].[NH4+]>C(O)C>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][C@H:15]([NH:29][C:30]([N:32]([CH2:38][CH2:39][N:40]([CH3:41])[CH3:42])[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:13][OH:12])=[CH:22][CH:21]=1
Reactant: CC(C)CCN(CCN(C)C)C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: B
Agent: [Br-]
Agent: [Cl-]
Solvent: CCO
Product: CC(C)CCN(CCN(C)C)C(=O)N[C@H](CO)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Lithium bromide (179 mg) and sodium boron hydride (52 mg) were suspended in anhydrous ethanol (1 ml) in the nitrogen gas atmosphere and the resulting suspension was stirred at room temperature for one hour. To the suspension, there was dropwise added a solution of 1-[(1S)-1-(benzyloxycarbonyl)-2-(4-biphenylyl) ethyl]-3-[2-(dimethylamino)ethyl]-3-isopentyl urea (Compound 4-1, 310 mg) in anhydrous ethanol (5.8 ml) with ice cooling. The resulting mixture was stirred at room temperature for 24 hours. Saturated ammonium chloride aqueous solution was added to the reaction liquid with ice cooling and then the resulting mixture was extracted with ether. The resulting organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting oily product was purified through the silica gel column chromatography to give the title compound (Compound 5-1, 138 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([O:41][CH3:40])=[CH:43][CH:44]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: COc1ccc(N)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added p-anisidine (54 mg, 0.44 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (191 mg) as a yellow solid. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4].C(=O)C1[C:15](=CC=CC=1)[OH:16]>>[OH:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]([OH:12])[C:9](=[CH:10][CH:11]=1)[CH:15]=[O:16])([CH3:5])[CH3:4]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(CO)c1cccc(O)c1
Product: CC(C)(CO)c1ccc(C=O)c(O)c1

Procedure:
The phenol (Step 5) was converted to the salicylaldehyde via a method similar to that described in Example 2, Step 1: mp 80.4–81.9° C. 1H NMR (CDCl3/300 MHz) 11.00 (s, 1H), 9.87 (s, 1H), 7.51 (d, 1H, J=8.3 Hz), 7.08 (dd, 1H, J=8.3 Hz, 1.4 Hz), 7.02 (d, 1H, J=1.4 Hz), 3.66 (s, 2H), 1.34 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 34.4 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.1 g, 0.25 mmol), 4-methylphenylboronic acid (0.04 g, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in dioxane (2.0 mL) at 20° C. was added K2CO3 (0.04 g, 0.28 mmol) in water (0.6 mL). The resulting reaction mixture was stirred at 100° C. for 15 h under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 31 mg of the title compound as a yellow oil. MS: [M+H]+=360.
Reaction SMILES: Br[CH:2]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:8]2[C:9](=[O:12])[C:10]=1[I:11])[CH2:3][CH3:4].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:18]([CH:2]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:8]2[C:9](=[O:12])[C:10]=1[I:11])[CH2:3][CH3:4])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(Br)c1nc2cccc(C)n2c(=O)c1I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(1-bromopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (4.50 g, 11.0 mmol) and sodium azide (3.59 g, 55.3 mmol) in DMF was stirred at room temperature for 2 h. After diluting with ethyl acetate, the mixture was washed with water, brine, dried over sodium sulfate, and evaporated under reduced pressure to provide the crude product, which was used directly in next step (3.35 g, 82.1%). LCMS calculated for C12H13IN5O (M+H)+: m/z=370.0. Found: 370.2.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([O-:19])=[CH:17][CH:16]=1.[Na+].C(=O)([O-])[O-].[K+].[K+]>[Cu]=O>[Cl:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([O:19][C:18]3[CH:20]=[CH:21][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[N:3]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc([O-])cc1
Reactant: Clc1ccc2cc(Cl)ncc2c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Temperature: 180 °C
Yield: 45.9 %

Procedure:
A mixture of 3,7-dichloroisoquinoline (5.59 g), sodium 4-methoxyphenoxide (4.55 g), potassium carbonate (3.86 g) copper powder (50 mg) and trace of copper oxide were heated at 180° C. for 14 hrs. the mixture was then cooled and extracted with ethyl acetate, which in turn was washed with water, dried (MgSO4) and evaporated to give a crude brown solid. Purification by column chromatography over silica gel gave 7-chloro-3-(4-methoxyphenoxy)isoquinoline (3.70 g) as a tan solid, mp 77° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C@@H:15]([NH2:24])[C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=1[F:14].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:39][CH:38]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:25]([O:29][C:30](=[O:31])[NH:32][C@H:33]([C:37]1[CH:38]=[CH:39][C:40]([O:43][CH2:44][CH2:45][O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:41][CH:42]=1)[C:34](=[O:35])[NH:24][C@H:15]([C:4]1[NH:5][C:6]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=2[F:14])=[C:2]([Cl:1])[N:3]=1)[C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])([CH3:27])([CH3:28])[CH3:26]
Reactant: C[C@@H](c1ccccc1)[C@H](N)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Reactant: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOC(C)(C)C)cc1)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of (1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propylamine (550 mg, 1.21 mmol) in N,N-dimethylformamide (12 mL) was added (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid (532 mg, 1.45 mmol) (prepared as described below), N,N-diisopropylethylamine (841 μL, 4.83 mmol), N-hydroxybenzotriazole (212 mg, 1.57 mmol) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (595 mg, 1.57 mmol). The mixture was stirred under an atmosphere of nitrogen at room temperature for 3 hours. The reaction was poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 20 to 50% v/v ethyl acetate/hexanes to give ((R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-{(1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propylcarbamoyl}-methyl)-carbamic acid tert-butyl ester (440 mg, 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[C:22](Br)([CH3:25])([CH3:24])[CH3:23]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O>[C:22]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 22.2 %

Procedure:
To a mixture of 6-nitroindole (1 g, 6.2 mmol), zinc triflate (2.06 g, 5.7 mmol) and TBAI (1.7 g, 5.16 mmol) in anhydrous toluene (11 mL) was added DIEA (1.47 g, 11.4 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 10 min at 120° C., followed by addition of t-butyl bromide (0.707 g, 5.16 mmol). The resulting mixture was stirred for 45 min at 120° C. The solid was filtered off and the filtrate was concentrated to dryness and purified by column chromatography on silica gel (Pet.Ether./EtOAc 20:1) to give 3-tert-butyl-6-nitro-1H-indole as a yellow solid (0.25 g, 19%). 1H NMR (CDCl3) δ 8.32 (d, J=2.1 Hz, 1H), 8.00 (dd, J=2.1, 14.4 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.25 (s, 1H), 1.46 (s, 9H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])[C:12]1=[O:26].O>C(O)(=O)C>[Cl:4][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:9]1[CH:27]=[CH:28][C:29]([Cl:30])=[C:7]([Cl:6])[CH:8]=1)[C:12](=[O:26])[C:13]12[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]
Reactant: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
Sulphuryl chloride (2.74 g.) was added to a stirred suspension of 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (3.0 g.) in acetic acid (50 ml.). The mixture was stirred at 60° C. for 5 hours, cooled to ambient temperature and then stirred at this temperature for 16 hours. The mixture was then poured into water (250 ml.). The white solid which formed was collected by filtration, washed with water, air dried and recrystallised from 2-propanol to give 5'-chloro-1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (1.9 g.), m.p. 268°-270° C.