Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[C@@H:5]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1.C(Cl)Cl.Cl[C:31]([O:33][CH3:34])=[O:32]>CN(C)C1C=CN=CC=1>[CH3:1][O:2][C@@H:3]1[CH2:8][N:7]([C:31]([O:33][CH3:34])=[O:32])[C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[C@@H:5]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl (2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate (0.0233 g, 0.0000645 mol) and 4-dimethylaminopyridine (0.0118 g, 0.0000967 mol) in methylene chloride (1.00 mL, 0.0156 mol) was added methyl chloroformate (0.00648 mL, 0.0000838 mol). The reaction was stirred at rt overnight. After quenched with aq. sodium bicaronate, the reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, concentrated to dry. The resulting residue was used directly in next step. MS (ESI): (M+H)+=420.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][OH:12]>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]=[O:12]
Reactant: OCc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Reaction time: 5 h
Yield: 89.5 %

Procedure:
To a suspension of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-methanol (see Example 1) (2.02 g, 7.88 mmol) in CH2Cl2 (10 mL) at ambient temperature was added MnO2 (6.78 g, 78.0 mmol). The mixture was stirred for 5 h then filtered through a diatomaceous earth pad. Removal of the solvent in vacuo provided 1-(3,5-dichloro-benzyl)-1H-imidazole-2-carbaldehyde (1.80 g, 90%) as a white solid: ESI MS m/z 225 [C11H8Cl2N2O+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([C:23](=[O:25])[CH3:24])[CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:25][CH:23]([C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[N:16]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:24]
Reactant: CC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 62 (0.96 g) was dissolved in methanol (30 mL) and treated with 0.5 g of sodium borohydride. The solvent was removed and the residue partitioned between ethyl acetate and water. The residue was purified by HPLC. LC-MS showed the product had the expected M+H+ of 336. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.31 (m, 1H) 8.05 (s, 1H) 7.4-7.6 (m, 3H) 7.09 (d, 2H) 6.99 (d, 1H) 6.72 (d, 2H) 5.29 (t, 1H) δ 5.0 (q, 1H) 3.73 (q, 2H) 2.9 (t, 2H) 1.52 (d, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2>C(O)(=O)C.[Pt]>[F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(-n3ccnc3)c(F)ccc2n1
Agent: [Pt]
Solvent: CC(=O)O
Product: CC1CCc2c(ccc(F)c2-n2ccnc2)N1

Procedure:
To a solution of 4.2 g (18 mmole) of 6-fluoro-5-(imidazol-1-yl)-2-methylquinoline in 75 ml of acetic acid was added 0.5 g of platinum on carbon, and the mixture was reduced on a Paar apparatus. After one day the mixture was filtered, the filtrate was evaporated and the residue was diluted with water. The aqueous mixture was basified with 10% aqueous sodium hydroxide solution. The off-white solid was separated by filtration to provide 6-fluoro-5-(imidazol-1-yl)-2-methyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[NH3:16]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:10]1([CH2:9][O:8][C:4]2[CH:3]=[C:2]([NH2:16])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Nc1cncc(OCc2ccccc2)c1
Temperature: 180 °C

Procedure:
A thick-walled glass pressure tube was charged with copper(II) sulfate pentahydrate (1.96 g, 7.85 mmol), 5-bromo-3-(phenylmethoxy)pyridine (4.00 g, 15.15 mmol) and concentrated aqueous ammonia (29.7%, 14.8 M, 37 mL). The tube was sealed and the dark blue suspension was stirred and heated at ˜180° C. (oil bath temperature) for 24 h. The mixture was allowed to cool to ambient temperature. After further cooling in an ice-water bath, the mixture was concentrated on a rotary evaporator to a small volume (˜20 mL) of a dark-blue solution. The solution was diluted with water (40 mL) and saturated K2CO3 solution (40 mL) and extracted with CHCl3 (4×40 mL). The combined, turbid-brown CHCl3 extracts were washed with saturated NaCl solution (2×100 ml), dried (Na2SO4), filtered and concentrated (rotary evaporator). The resulting dark-brown oil, was briefly dried on the vacuum pump to give a dark-brown solid (2.06 g). The product was purified by column chromatography on silica gel (100 g) eluting with CHCl3—MeOH (3:1,v/v). Selected fractions, based on TLC (Rf 0.65) analysis, were combined and concentrated to give a 1.64 g(54.1%) of a tan-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.Br[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.3 %

Procedure:
The product from step (ii) (6.55 g) was dissolved in DMF (50 ml) and triethylamine (7.9 ml) was added. tert-Butyl 2-bromoethylcarbamate (4.3 g) in DMF (5 ml) was added and the solution stirred at room temperature for 3 days. Ethyl acetate and water were added, the organic phase separated, dried and evaporated to a gum. Purification by chromatography (dichloromethane:methanol 95:5) gave the sub-titled product as a gum (5.7 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([CH:11]1[C:27]2([CH3:28])[CH:14]([CH:15]3[CH:24]([CH2:25][CH2:26]2)[C:23]2([CH3:29])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:10].[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O>[N:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([CH:11]1[C:27]2([CH3:28])[CH:14]([CH:15]3[CH:24]([CH2:25][CH2:26]2)[C:23]2([CH3:29])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:10])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COCCCCCBr)CCC12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COCCCCCN=[N+]=[N-])CCC12
Temperature: 65 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 7 (125 mg, 0.261 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added sodium azide (169 mg, 2.61 mmol). The reaction mixture was heated to 65° C. and stirred overnight. Excess sodium azide was filtered off and the solvent was removed by rotary evaporation. The crude residue was dissolved in ethyl acetate and washed with water three times. The organic layer was dried over sodium sulfate and concentrated followed by flash chromatography in hexanes/ethyl acetate (2:1) to give 9 (78 mg, 68%). 1H NMR (500 MHz, CD3OD) δ 5.61 (d, J=4.9 Hz, 1H), 3.39 (t, J=6.4 Hz, 2H), 3.25-3.17 (m, 4H), 2.60 (t, J=9.1 Hz, 1H), 2.45-2.33 (m, 2H), 2.25-2.15 (m, 2H), 2.12-2.03 (m, 1H), 1.99 (m, 1H), 1.89-1.76 (m, 2H), 1.70-1.29 (m, 15H), 1.29-1.15 (m, 2H), 1.13 (d, J=11.0 Hz, 4H), 1.04-0.87 (m, 2H), 0.60 (s, 3H). 13C NMR (125 MHz, CD3OD) δ 210.81, 202.29, 174.92, 124.24, 78.00, 72.34, 62.71, 59.71, 57.39, 55.16, 52.43, 45.67, 39.99, 39.72, 36.81, 34.72, 33.90, 33.20, 30.15, 29.75, 25.52, 24.46, 24.17, 23.76, 22.15, 17.67, 13.96. ESI-MS m/z [M+Na]+ observed: 464.2, calculated: 464.3.
Reaction SMILES: CN1[C@@H]2CC3C=CC(O)=C4O[C@H]5C(OC)=CC=C2[C@]5(C=34)CC1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:34][N:35]1[C@H:45]2[CH2:46][C:47]3[CH:52]=[CH:51][C:50]([OH:53])=[C:49]4[O:54][C@H:39]5[C:40]([CH:42]=[CH:43][C@:44]2([OH:55])[C@:38]5([C:48]=34)[CH2:37][CH2:36]1)=[O:41].[H][H]>[Pd].C(O)(=O)C>[CH3:34][N:35]1[C@@H:45]2[CH2:46][C:47]3=[CH:52][CH:51]=[C:50]([OH:53])[C:49]4[O:54][C@H:39]5[C:40]([CH2:42][CH2:43][C@:44]2([OH:55])[C@:38]5([C:48]=43)[CH2:37][CH2:36]1)=[O:41]
Reactant: [H][H]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Agent: [Pd]
Agent: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of CPS-0 (6.92 g contains 76% (5.26 g, 17.7 m mol) of oripavine), meta-chloroperoxybenzoic acid (MCPBA, 4.30 g) and glacial acetic acid (52 ml) is stirred at room temperature for 5 hours. The amount of oripavine is then expected to be not more than 1% by HPLC analysis. To the resulting 14-hydroxymorphinone mixture is added 5% Pd/C (0.55 g) and hydrogenation proceeds at room temperature at 48 psig of hydrogen for about 18 hours. The amount of unreacted 14-hydroxymorphinone is expected to be not more than 0.5% by HPLC analysis. The mixture is filtered to remove the catalyst and the filtrate is evaporated to almost dryness. The residue is dissolved in water and basified to pH 9 by ammonium hydroxide. The solids are collected by filtration and dried at 90° C. and under 25-inch Hg of vacuum for 3 hours to give crude oxymorphone (approximately 95% yield expected).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH:30]=[CH:31][C:32]3[CH:33]=[C:34]([C@@H:38]([O:57][Si](C)(C)C(C)(C)C)[CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([O:50][CH:51]4[CH2:56][CH2:55][CH2:54][CH2:53][O:52]4)([CH3:49])[CH3:48])[CH:35]=[CH:36][CH:37]=3)=[N:27]2)=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH:30]=[CH:31][C:32]3[CH:33]=[C:34]([C@@H:38]([OH:57])[CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([O:50][CH:51]4[CH2:56][CH2:55][CH2:54][CH2:53][O:52]4)([CH3:49])[CH3:48])[CH:35]=[CH:36][CH:37]=3)=[N:27]2)=[CH:22][CH:21]=1
Reactant: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 4 h

Procedure:
1.0M Tetrabutylammonium fluoride in THF (85 mL) was added slowly to a solution of the product of Step 5 (33.31 g, 47 mmol) in 250 mL of anhydrous THF at 0° C. and the mixture was left in a refrigerator overnight and at r.t. for 4 h. 25% Aq. NH4OAc was then added and the product was extracted in EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with EtOAc:toluene 10:90 and 15:85, to afford the title product. Yield of Steps 4-6: 81%.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22](=[O:39])[N:23]([CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38])[C:24]([CH3:30])=[N:25]2>C(OCC)C.O1CCCC1>[O:38]=[C:32]1[CH:31]([N:23]2[C:22](=[O:39])[C:21]3[C:26](=[CH:27][CH:28]=[CH:29][C:20]=3[NH:19][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[N:25]=[C:24]2[CH3:30])[CH2:36][CH2:35][C:34](=[O:37])[NH:33]1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCOCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOCC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
To a stirred solution of ethoxyacetic acid (0.39 mL, 4.2 mmol), oxalyl chloride (0.34 mL, 3.9 mmol) in diethylether (3 mL) was added DMF (0.02 mL). The mixture was stirred at room temp for two hours, followed by addition of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.60 g, 2.0 mmol) and tetrahydrofuran (20 mL). The mixture was refluxed overnight and then cooled and quenched by methanol (˜5 mL). The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-2-ethoxy-acetamide as a white solid (90 mg, 12% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.75 min (99.6%); mp, 291-293° C.; 1HNMR (DMSO-d6) δ 1.23 (t, J=6 Hz, 3H, CH2CH3), 2.18-2.25 (m, 1H, CHH), 2.58-2.92 (m, 6H, CHCH2, CH3), 3.57 (q, J=7 Hz, 2H, CH2CH3), 4.01-4.12 (dd, J=16 Hz, 2H, CH2O), 5.30 (dd, J=6, 11 Hz, 1H, CH), 7.30-8.64 (m, 3H, Ar), 11.07 (s, 1H, NH), 12.52 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.61, 20.81, 23.25, 30.52, 56.64, 67.05, 70.09, 107.95, 115.13, 120.83, 135.55, 138.97, 147.90, 154.80, 162.61, 169.38, 169.54, 172.51. LCMS MH=373; Anal Calcd For C18H20N4O5: C, 58.06; H, 5.41; N, 15.05. Found: C, 57.83; H, 5.37; N, 14.92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([N:7]=[C:8]1[N:12]([CH2:13][CH2:14][C:15](=[S:17](=[O:19])=[O:18])C)[C:11]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:23][C:10]=2[S:9]1)=[O:6].Cl[C:33]1C=CC=C(C(OO)=O)C=1.N=C1N(CCCSC)C2C=CC(OC(F)(F)F)=CC=2S1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([N:7]=[C:8]1[N:12]([CH2:13][CH2:14][CH2:15][S:17]([CH3:33])(=[O:19])=[O:18])[C:11]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:23][C:10]=2[S:9]1)=[O:6]
Reactant: CC(CCn1c(=NC(=O)c2cccc(Cl)c2)sc2cc(OC(F)(F)F)ccc21)=S(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CSCCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Solvent: ClCCl
Product: CS(=O)(=O)CCCn1c(=NC(=O)c2cccc(Cl)c2)sc2cc(OC(F)(F)F)ccc21
Reaction time: 18 h

Procedure:
2-(3-Chlorobenzoylimino)-3-(3-methyl-sulphonylpropyl)-6-trifluoromethoxybenzothiazoline may be prepared in the following way: 75% m-chloro-perbenzoic acid (5.2 g) is added in the course of about 10 minutes, to 2-imino-3-(3-methylthiopropyl)-6-trifluoromethoxybenzothiazoline (3.9 g) in solution in dichloromethane (100 cc) stirred at a temperature close to 20° C. The reaction mixture is brought to the boil for 18 hours. After cooling to a temperature close to 20° C., the precipitate is filtered off and washed with dichloromethane (50 cc) and the filtrate is concentrated to dryness under reduced pressure after washing with 1N sodium hydroxide solution. The oil obtained is crystallised from ethyl acetate. 2-(3-Chlorobenzoylimino)-3-(3-methylsulphonylpropyl)-6-trifluoromethoxybenzothiazoline (0.6 g) melting at 188° C. is obtained.
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 6 h
Yield: 89.2 %

Procedure:
2.4 Liters of ethyl acetate and 200 g (2.3 mol, 15 eq) of manganese dioxide were added to 80 g (0.15 mol) of 6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide. The mixture was stirred at 40˜45° C. for 6 hours, filtered with Celite, and the filtered material was washed with 300 mL of ethyl acetate two times. After the filtrate was concentrated under reduced pressure, 200 mL of ethyl acetate and 400 mL of IPE were added to the concentration residue, followed by stirring at 0° C. for 2 hours. Crystals were filtered, and washed with 200 mL of IPE. Vacuum drying (50° C.) to a constant weight afforded 69.8 g of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (yield 88%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[F:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11]Br>CN(C)C=O>[F:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
In a 10 ml flask, under a nitrogen atmosphere, 2-methoxyethanol (0.125 ml, 1.60 mmol) was dissolved in N,N-dimethylformamide (2 ml). Sodium hydride (60%, 72 mg, 1.81 mmol) was added and the mixture was stirred at ambient temperature for about thirty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (285 mg, 1.06 mmol) as a solution in N,N-dimethylformamide (2 ml). The resulting mixture was stirred at ambient temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed with brine (7×) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:8]=1)[CH3:2].[I-].[Na+].C(#N)C.Cl[Si](C)(C)C>O>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:10]=[CH:11][CH:12]=[CH:13]2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-n2cccc2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(-n2cccc2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 17 h
Yield: 92.6 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-pyrrol-1-yl-pyridine (68 mg, 0.315 mmol) and sodium iodide (141 mg, 0.94 mmol) under a N2 atmosphere is added anhydrous acetonitrile (4 mL) followed by dropwise addition of chlorotrimethylsilane (118 μL, 0.940 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 17 hr. The reaction mixture is allowed to cool, diluted with water and extracted with three portions of dichloromethane. The combined extracts are dried over magnesium sulfate and evaporated to leave an orange residue. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). Clean fractions containing the product are combined and evaporated to give 3-ethyl-6-methyl-5-(pyrrol-1-yl)-1H-pyridin-2-one (59 mg, 93% yield) as a white solid. This material (49 mg) is dissolved in dichloromethane (2 mL) and treated with ethereal hydrochloric acid (2.0M, 0.49 mL). The solution is stirred for 1.5 hr and then evaporated to give 3-ethyl-6-methyl-5-pyrrol-1-yl-1H-pyridin-2-one hydrochloride (54 mg) as an off-white solid. LC/MS: RT: 2.70 min, MS: m/e=203 (M+H); 1H NMR (δ ppm): 11.75 (1H, s), 7.16 (1H, s), 6.80 (2H, t), 6.16 (2H, t), 2.38 (2H, q), 1.97 (3H, s), 1.08 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>O1CCOCC1.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]>[Br:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])=[CH:17][CH:18]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cc(I)c2nccn2c1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(Nc2cc(Br)cn3ccnc23)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 44 %

Procedure:
6-Bromo-8-iodo-imidazo[1,2-a]pyridine (500 mg, 1.53 mmol), (4-aminophenyl)(morpholino)-methanone (348 mg, 1.69 mmol) and CsCO3 (998 mg, 3.06 mmol) were dissolved in dioxane (10 ml). Under N2 atmosphere, Pd2(dba)3 (70 mg, 0.077 mmol) and Xantphos (89 mg, 0.153 mmol) were added and the mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature, poured into water (100 mL) and extracted with DCM (100 ml). The organic extracts were washed with saturated aqueous solution of sodium chloride (100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate 1:2) to afford the desired product as a yellow solid (270 mg, yield 44%). LC-MS: 401[M+1]+, tR=1.257 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:13][N:14]([O:15][CH3:16])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc2nc[nH]c2c1
Reaction time: 24 h
Yield: 43.4 %

Procedure:
To a suspension of 5-benzimidazolecarboxylic acid (1.62 g, 10 mmol) in CH2Cl2 (30 mL) was added N,O-dimethylhydroxylamine (1.17 g, 12 mmol), N-methylmorpholine (1.65 mL, 15 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g, 12 mmol), respectively at room temperature. After stirring for 24 h, the reaction mixture was filtered to remove solid and rinsed thoroughly with CH2Cl2. The combined filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 5% MeOH/CH2Cl2 as an eluent to obtain 890 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.02 (s, 2H); 7.59 (d, J=7.6 Hz, 2H); 3.58 (s, 3H); 3.4 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]3)[NH:9][CH2:8][CH2:7][C:6]2=1.[CH:25]1(O)[CH2:29]CC[CH2:26]1>O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22][CH:23]4[CH2:29][CH2:25][CH2:26][CH2:24]4)=[O:21])[CH2:17][CH2:18][CH2:19]3)[NH:9][CH2:8][CH2:7][C:6]2=1
Reactant: OC1CCCC1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: O
Product: O=C(OC1CCCC1)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1

Procedure:
4.0 g of the compound of Example 1 are heated at the reflux of 80 ml of cyclopentanol in the presence of 1 ml of titanium tetraisopropoxide. After reaction for 24 hours, the reaction mixture is diluted with water and then filtered. After extraction with dichloromethane, drying and evaporation under reduced pressure, crystallisation of the residue from an ethanol-diethyl ether-hydrogen chloride mixture enables the expected product to be isolated.