Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:27]C)[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.CO>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:46])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2CC)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 85 %

Procedure:
Prepared analogously to Example 25d from 1-ethyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 85% of theory, C28H31N7O3 (513.6); Rf value: 0.21 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=514; (M+H+Na)++=268.6; (M+2H)++=257.7.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)=[O:24])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(NC(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
Into a suspension of methyl 4-{[(4-{[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]carbonyl)benzoate (546 mg, 0.96 mmol) in THF/H2O (2/1) (20 mL) was added NaOH (1.0 N, 4.8 mL). The resulting solution was stirred at rt for 2 hr and quenched with HCl (5 N, 4 mL). A yellow solid precipitated out. Filtration, washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrs gave the title compound as a yellow powder (451 mg, 86%) in 97.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=3)=[CH:9][C:10]1=2
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol), tetrakis(triphenylphosphine) palladium (0) (0.17 g, 0.24 mmol), and cuprous (I) iodide (0.05 g, 0.28 mmol) in triethyl amine (20 mL) was heated under nitrogen at 80° C. for 3 hours. The reaction mixture was cooled to rt and the solvent was removed. The residue was taken up in ethyl acetate (50 mL) and washed with 1N aqueous HCl (3×20 mL) and brine ( 20 mL). The organic layer was separated and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.77 g, 92%): mp 240-242° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96 (d, 1H, J=7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H); MS (EI) m/z 349([M+], 50%); Anal. Calc. For C21H23NO2Si.0.2 EtOAc: C, 71.32, H, 6.75, N, 3.82. Found: C, 71.08, H, 6.64, N, 3.82.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[O:10][N:9]=2)=[CH:4][CH:3]=1.[N:18]1C=CC=CC=1.[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>CN(C=O)C>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=4)[C:32]([NH2:18])=[O:33])=[CH:3][CH:4]=3)[C:16]=12
Reactant: c1ccncc1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(-c2noc3ncnc(N)c23)cc1
Solvent: CN(C)C=O
Product: Cc1cccc(N(C(N)=O)c2ccc(-c3noc4ncnc(N)c34)cc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A 0° C. solution of Example 30 (126 mg, 0.3 mmol) in DMF (2 mL) at room temperature was treated with pyridine (0.121 mL, 1.5 mmol) and 3-methylphenylisocyanate (0.038 mL, 0.3 mmol) and stirred overnight. The reaction mixture was poured into ice water and filtered. The filter cake was recrystallized from ethyl acetate/hexanes to provide 87 mg (80% yield) of the desired product. MS (ESI(+)) m/e 361 (M+H)+; 1H NMR (DMSO-d6) δ 9.00 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.68 (q, J=15, 8.7 Hz, 4H), 7.10-7.40 (m, 3H), 6.82 (d, J=7.2 Hz, 1H), 2.28 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH:9]3[CH2:17][NH:16][CH2:15][CH2:14][N:10]3[CH2:11][C:12]=2[CH:13]=1)([O-])=O.[ClH:18].[H][H]>CO.O>[ClH:18].[ClH:18].[ClH:18].[CH2:17]1[CH:9]2[N:10]([CH2:11][C:12]3[CH:13]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[CH2:8]2)[CH2:14][CH2:15][NH:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCNCC1C2
Reactant: [H][H]
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)CN1CCNCC1C2

Procedure:
To 8-nitro-2,3,4,6,11,11a-hexahydro-1H-pyrazino[1,2-b]isoquinoline (2.98 g) in methanol (150 ml) and water (10 ml) was added concentrated hydrochloric acid (3.26 ml) and 5% Pd--C (300 mg). The mixture was treated with hydrogen at 50 psi on a Parr Hydrogenator. Hydrogen uptake was complete in 1.0 hour. The catalyst was filtered off and the solvent removed under reduced pressure to yield the title product as a solid (3.69 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][O:16][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCOC1CCCCO1
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Product: COC(=O)c1cc(COCCCOC2CCCCO2)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate (3.5 g) was reacted with 2-(3-bromopropoxy)-tetrahydropyran analogously to O5.063 to give methyl 3-tert-butyl-5-[3-(tetrahydropyran-2-yloxy)propoxymethyl]benzoate, and the latter was subsequently converted to the title compound according to the sequence O4.059 to O2.059. 1.75 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([PH:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:31]=[CH2:32])[CH:22]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([O:14][P:13]([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[C:23]([CH:31]=[CH2:32])[CH:22]=1)=[O:17])[CH3:16]
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Reactant: CCO[PH](=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1cc(P(=O)(OCC)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1OC(C)C
Temperature: 70 °C
Yield: 2.8 %

Procedure:
To a degassed solution of ethyl 3,5-bis(trifluoromethyl)phenylphosphinate (3.33 g, 15.24 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (3.33 mg, 13.8 mmol) in DMF (25 mL) were added the triethylamine (3.85 mL, 27.6 mmol) and tris(dibenzylideneacetone)dipalladium (2.53 g, 2.76 mmol). The mixture was heated in an oil bath at 70° C. overnight. The volatiles were removed in vacuo and the mixture was purified by column chromatography with 20 to 70% ethyl acetate in petroleum ether to afford compound BA3 (185 mg) as an oil in 2.8% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.38 (dd, J=6.1 and 1.4 Hz, 6H) overlapping 1.41 (t, J=7.1 Hz, 3H), 4.11-4.21 (m, 2H), 4.65 (sept., J=6.1 Hz, 1H), 5.33 (dd, J=11.2 Hz and 1.4 Hz, 1H), 5.80 (dd, J=17.9 and 1.2 Hz, 1H), 6.96 (dd, J=8.6 and 3.0 Hz, 1H) overlapping 7.00 (dd, J=18.0 and 11.4 Hz, 1H), 7.63 (ddd, J=11.9, 11.9 and 2.0 Hz, 1H), 7.90 (dd, J=12.7 and 2.1 Hz, 1H), 7.99 (s, 1H), 8.22 (s, 1H), 8.25 (s, 1H); 31P NMR (CDCl3, 161.8 MHz): δ (ppm) 28.59.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Br[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[OH:16][CH2:15][CH2:14][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: OCCBr
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCO)c(C)c1
Temperature: 60 °C
Yield: 25.6 %

Procedure:
To a solution of methyl 4-hydroxy-3-methyl-benzoate (5.77 g, 34.7 mmol) in DMF (17 mL) was added 2-bromoethanol (6.51 g, 3.7 mL, 52.1 mmol) and cesium carbonate (33.95 g, 104.2 mmol) and the reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and then pardoned between water (250 mL) and ethyl acetate (2×100 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to yield a crude oil that was purified by silica gel column chromatography using EtOAc/hexanes (10 to 100%) as eluent to give methyl 4-(2-hydroxyethoxy)-3-methyl-benzoate (1.87 g, 26%) as a white solid. ESI-MS m/z calc. 210.1. found 211.1 (M+1)+; Retention time: 1.08 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.94-7.79 (m, 2H), 6.84 (d, J=8.5 Hz, 1H), 4.23-4.08 (m, 2H), 4.08-3.96 (m, 2H), 3.88 (s, 3H), 2.34-2.18 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 76 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 76%). 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 6H), 3.18-3.21 (m, 4H), 3.69-3.72 (m, 4H), 4.15 (s, 3H), 6.97-7.04 (m, 3H), 7.22-7.42 (m, 4H), 7.82-7.87 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10](F)[C:7]=1[CH:8]=O.O.[NH2:21][NH2:22]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]2[C:7]=1[CH:8]=[N:21][NH:22]2
Reactant: NN
Reactant: O=Cc1c(F)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Solvent: O
Solvent: CCO
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Temperature: 25 °C

Procedure:
To a suspension of 2-(3-bromo-5-chlorophenoxy)-3-chloro-6-fluorobenzaldehyde (77.5 g, 213 mmol) in ethanol (120 mL) was added hydrazine hydrate (31 mL, 639 mmol). The resulting mixture was then heated at reflux for 4 days, after which the mixture was cooled to room temperature, diluted with water (100 mL) and the resulting solid was filtered. The solid was absorbed onto silica gel (300 g) and purified on a silica gel (1500 g) column (0-40% EtOAc/CH2Cl2) to give the title product as a white solid. LRMS (M+1)=358.8
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C:10]1[NH:11][CH:12]=[C:13]([CH3:15])[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH:12]=[C:13]([CH3:15])[N:14]=[C:10]2[CH3:9])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1c[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ncc(Br)cn2)c(C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (0.3 g, 1.55 mmol) in NMP (15 mL) were added 2,4-dimethyl-1H-imidazole (0.224 g, 2.2 mmol) and K2CO3 (0.43 g, 3.1 mmol). The resulting solution was stirred at 80° C. overnight. After water (50 mL) and EtOAc (50 mL) were added, the mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by pre-TLC to afford 5-bromo-2-(2,4-dimethyl-1H-imidazol-1-yl)-pyrimidine (0.2 g, 51%).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:32]([CH2:31][CH2:30][CH2:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCCCc1ccccc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CCCc1ccccc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 3-phenylpropylamine(0.19 mL, 1.4 mmol). Purification using silica gel, eluting with 9:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 114 as a white solid (m.p. 222-223° C.).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:7][C:6]=1[F:22])=[N+]=[N-].CO>C(OCC)(=O)C.[C].[Pd]>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:7][C:6]=1[F:22]
Reactant: CC(=O)Nc1nc(CCc2ccc(CN=[N+]=[N-])c(F)c2)cs1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(CN)c(F)c2)cs1
Yield: 85.3 %

Procedure:
To a solution of N-(4-{2-[4-(azidomethyl)-3-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (152.3 mg, 0.477 mmol) in ethyl acetate (21 ml) was added 10% palladium carbon (30.5 mg, containing 50% water), and the mixture was hydrogenated at room temperature under an atmospheric pressure. Ethyl acetate (5 ml) and methanol (5 ml) were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting solid was collected by filtration, washed with tert-butyl methyl ether (5 ml) and dried under reduced pressure to give N-(4-{2-[4-(aminomethyl)-3-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (119.3 mg, 0.407 mmol, yield 85.3%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][C:35]([NH:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27])=[O:36])=[CH:21][CH:20]=[CH:19]2
Reactant: O=C=Nc1ccccc1F
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4c(NC(=O)Nc5ccccc5F)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)naphthalen-1-amine (50 mg, 0.144 mmol) and 2-fluorophenylisocyanate (20 mg, 0.144 mmol) were dissolved in THF (1 mL) then stirred at RT for 16 h. A precipitate formed in the mixture and was collected on a glass frit, washing with minimal THF then CH2Cl2 to give N-(6-((6,7-bis(methoxy)-4-quinolinyl)oxy)-1-naphthalenyl)-N′-(2-fluorophenyl)urea as an off-white solid. MS (ESI, pos. ion) m/z: 484.2 (M+1). Mass Calc'd for C28H22FN3O4: 483.50
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([CH:26]=[CH2:27])[CH:23]=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[NH3:7].[C:29]1([C:28]2[N:21]3[CH:22]=[CH:23][C:24]([CH:26]=[CH2:27])=[CH:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:9][CH2:10][CH2:11]3)=[CH:17][CH:16]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.5 %

Procedure:
To a solution of {1-[4-(3-phenyl-7-vinyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (77 mg, 0.17 mmol) in MeOH (0.7 mL) and CH2Cl2 (1.1 mL) was added a 4 molar solution of HCl in dioxane (0.8 mL, 3.3 mmol, 20 equiv) and the resulting solution was stirred at room temperature for 18 h with monitoring by UPLC-MS. The resulting material was concentrated under reduced pressure. The remaining material (82 mg) was purified using MPLC (Isolute Flash NH2 reverse phase column; 100% CH2Cl2 for 1 min., gradient to 95% CH2Cl2: 5% MeOH over 10 min.; 95% CH2Cl2: 5% MeOH for 5.2 min.) to give partially purified material, which was further purified using preparative HPLC (Waters Autopurification System equipped with pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424 and SQD 3001 using a XBridge C18 5 uM 100×30 mm column; 70% water with 0.2% NH3/30% acetonitrile 1 min., gradient to 30% water with 0.2% NH3/70% acetonitrile over 7 min.) to give 1-[4-(3-phenyl-7-vinyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (7 mg, 11%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Br:14]Br.OS([O-])=O.[Na+].O>C(O)(=O)C.C(Cl)Cl>[Br:14][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH3:13])=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: BrBr
Reactant: COc1ccc(NC(C)=O)c(C)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(NC(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of N-(4-methoxy-2-methylphenyl)acetamide (130 g, 0.73 mol) in acetic acid (800 mL) is added bromine (42 mL, 0.8 mol) dropwise at 0° C. After addition, the resulting mixture is stirred at RT overnight. Saturated aqueous NaHSO3 is added until a clear solution is obtained, and then a large amount of water (2.0 L) is added forming a precipitate. The precipitated solid is collected and washed with water to give the crude product (thin layer chromatography (TLC) solvent: DCM:EtOAc=10:1). The solid is dissolved in minimum amount of refluxing DCM, and then PE (about 10-20% volume of DCM used) is added. The resulting solution is cooled to RT. After 2 hours, the precipitated solid is collected and washed with PE to give a white product (108 g, 57% yield). MS (m/z): 260.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].[CH:14](O)([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C>[CH:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6])([CH3:16])[CH3:15]
Reactant: CC(C)O
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)O)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of methyl 3-hydroxy-4-methoxybenzoate (3.00 g, 16.5 mmol), isopropanol (1.9 mL, 24.8 mmol) and triphenylphosphine (5.40 g, 20.6 mmol) in ethyl acetate (70 mL) was added, dropwise, diethyl azodicarboxylate (3.9 mL, 25 mmol). The reaction was allowed to proceed overnight and then washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated. The resulting yellow oil was taken up in 1:1:1 tetrahydrofuran/methanol/1 N aqueous sodium hydroxide (120 mL) and heated at reflux. After 4 hours additional 1 N aqueous sodium hydroxide (10 mL) was added and the mixture was stirred at room temperature overnight. The reaction was then concentrated to remove organic solvents and diluted with water. After washing several times with ethyl acetate, the solution was stirred and acidified with 1 N aqueous hydrochloric acid (50 mL). The resulting precipitate was filtered off, rinsed with water and vacuum oven dried to afford 2.83 g (82%) of product as a white solid: 1H NMR (DMSO-d6) δ 12.64 (s, 1H), 7.53 (dd, J=8.4, 1.8 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.55 (sept, J=6.0 Hz, 1H), 3.71 (s, 3H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][CH:11]=[CH:10]2)=[O:4].[NH:21]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:13]1[C:14]2[C:9](=[N:8][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:21]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCNCCNCCN1
Reactant: O=C(CCl)NCc1nc2ccccc2c2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CN1CCNCCNCCNCC1)NCc1nc2ccccc2c2ccccc12
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A solution of the chloro 9 (20.0 mg, 70.2 μmol) in anhydrous CHCl3 (5 mL) was added to a solution of cyclen (48.4 mg, 0.281 mmol) and triethylamine (11.7 μL, 84.2 μmol) in anhydrous CHCl3 (15 mL) under N2 (g). The reaction mixture was heated to reflux under N2 (g) for 23 hours. The reaction mixture was then allowed to cool to room temperature and washed with NaOH (aq) (1.0 M, 3×5 mL) and H2O (3×5 mL). The organic phase was dried over MgSO4, and concentrated under reduced pressure yielding product 10 as a colorless oil (13.9 mg, 47.1%). This procedure follows closely that developed by Gunnlaugsson and coworkers. (Massue et al. Tetrahedron Lett., 2007, 48, 8052-8055).