Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[N:20]1[NH:21][C:22](=[O:29])[N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:21]2[C:22](=[O:29])[N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[N:20]2)=[CH:14][CH:15]=1
Reactant: O=c1[nH]nc2ccccn12
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: O=c1n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)nc2ccccn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. M/e+ 376 for C20H15 ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.68 (d, J=6.9 Hz, 1H), 8.18 (d, J=8.4 Hz, 2H), 7.80 (d, J=7.3 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.25 (m, 1H), 7.09 (dd, J=4.0, 2.9 Hz, 2H), 6.89 (m, 1H), 6.52 (m, 1H), 5.54 (s, 2H) ppm.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[N:31]=[C:32]=[O:33]>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:32]([NH:31][C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)=[O:33])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1cccs1
Product: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccs1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (60 mg, 0.17 mmoles) and 2-thienyl isocyanate (18 mg, 0.14 mmoles), the title compound was isolated as a grey solid after Silica gel column chromatography by eluting with 5% ethyl acetate: methanol. Yield: 12 mg (14%); (M+H)=470.
Reaction SMILES: Cl.C[O:3][C:4]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]3[CH2:12][NH:11][CH2:10][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[O:23]C.B(Br)(Br)Br.CO.[CH:31]([OH:33])=[O:32]>C(Cl)Cl.O>[CH:31]([OH:33])=[O:32].[OH:3][C:4]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]3[CH2:12][NH:11][CH2:10][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:23]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C1=C2CNC1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O=CO
Solvent: O
Product: Oc1ccc2c(c1O)CC(c1ccccc1)C1=C2CNC1
Temperature: 25 °C
Yield: 58 %

Procedure:
A suspension of 54.5 mg (0.159 mmol) of 6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindole hydrochloride, from Step 6, in 2 mL of methylene chloride was cooled to -78° C. and 0.64 mL of a 1M solution of boron tribromide in methylene chloride was added. The reaction mixture was warmed to ambient temperature for 1 h and recooled to 78° C. before 1 mL of methanol was added. After warming to ambient temperature for 1 h, the solvents were removed in vacuo. Additional methanol (5 mL) was added and removed in vacuo. The product was purified on silica gel eluted with 18:1:1 ethyl acetate:formic acid:water to give 29.8 mg (58% yield) of 6,7-dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindole formic acid salt as an off white powder, m.p. 144° C. MS DCI: M+ 279. 1H NMR (d6 -DMSO) delta 2.95-3.15 (m, 2H), 3.6-3.9 (m, 3H), 4.1-4.3 (m, 2H), 6.43 (d, 1H, J=7.5 Hz), 6.62 (d, 1H, J=7.5 Hz), 7.1-7.3 (m, 5H), 8.3 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)=[O:5])[CH3:2].[C:19](P(=O)(OCC)OCC)#[N:20].[C-]#N.[Li+].O>C1COCC1.CN(C=O)C>[C:19]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][C:8]=1[CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])#[N:20]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCOC(=O)CCC1CCc2ccccc2C1=O
Agent: [C-]#N
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC1=C(C#N)c2ccccc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
2-(2-Ethoxycarbonylethyl)-3,4-dihydro-1(2H)-naphthalenone (19.7 g, 80 mmol), from Step 1, was dissolved in 200 mL of dry THF and diethyl cyanophosphonate (23.6 mL, 160 mmol), commercially available from Aldrich Chemical Company, was added, followed by 160 mL of a 0.5M solution of lithium cyanide in DMF. The reaction mixture was stirred at ambient temperature overnight and then poured into water. The aqueous mixture was extracted with three portions of diethyl ether. The ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 400 mL of toluene and 20 g of p-toluenesulfonic acid was added. The reaction mixture was heated at reflux for 3 h and allowed to cool to ambient temperature. The toluene solution was washed with 5% aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 10% ethyl acetate in hexane to give 13.1 g (64.2% yield) of the title compound; MS DCI-NH3 M/Z: 273 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=2)[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>C1C=CC=CC=1>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH2:12])=[O:11])=[CH:13][CH:14]=2)[CH2:2]1)=[O:18]
Reactant: NC(=O)c1ccc(OC2CNC2)cc1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccc(C(N)=O)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirring solution of 5.0 g. (0.026 mole) of 4-(3-azetidinyloxy)benzamide in 75 ml. of dry benzene was added dropwise 1.5 g. (0.026 mole) of methylisocyanate. Stirring was continued for 1.5 hours. The white solid which separated was filtered and recrystallized using 95% ethanol. The solid was triturated with acetonitrile (due to solvation effects of the ethanol). The product weighed 4.0 g. (58%) and melted at 208°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: COc1cccc(C2(O)c3ccccc3-c3ccccc32)c1
Product: COc1cccc(C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)c1

Procedure:
from 9-(3-methoxyphenyl)-9H-fluoren-9-ol (Example 3f) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[S:19][C:20]3[CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][C:25]=3[N:26]=2)[C:3]1=[O:28].Cl[C:30]1[C:35]([CH:36]=[O:37])=[C:34]([N:38]2[CH2:51][CH2:50][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[C:48]([F:49])=[C:40]3[C:39]2=[O:52])[N:33]=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[F:49][C:48]1[C:47]2[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=2[N:41]2[CH2:50][CH2:51][N:38]([C:34]3[N:33]=[CH:32][CH:31]=[C:30]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[S:19][C:20]6[CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][C:25]=6[N:26]=5)[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=4)[C:35]=3[CH:36]=[O:37])[C:39](=[O:52])[C:40]=12
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Reactant: CN1CCc2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)sc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCc2nc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4C=O)cn(C)c3=O)sc2C1
Temperature: 100 °C

Procedure:
A 50-mL round-bottomed flush equipped with a reflux condenser was charged with 1-methyl-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylamino)-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 216a (200 mg, 0.50 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (174 mg, 0.50 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (21 mg, 0.025 mmol), and acetonitrile/water (15/1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. for 1 h under N2 protection. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (70/1 to 30/1) to afford 223a (167 mg, 57%) as yellow solid. MS-ESI: [M+H]+ 588.1
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]1)C.[OH-].[K+].CO>CO.O>[CH3:16][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][CH2:5][C:4]([OH:17])=[O:3])[CH2:12][CH2:11]1)([CH3:14])[CH3:15]
Reactant: CCOC(=O)CC[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring solution of trans-4-(1,1-dimethylethyl)cyclohexanepropanoic acid ethyl ester (3.58 g, 14.9 mmol) in CH3OH (198 mL) at 0° C. were added 10% KOH/MeOH (46 mL), followed by H2O (30 mL). The mixture was stirred at room temperature 5 h, then diluted with H2O (20 mL) and concentrated. The residue was diluted with H2O (20 mL) and ice chips and the mixture was acidified to pH 2 with 3N HCl. The aqueous solution was extracted with ethyl ether (4×150 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4) and concentrated to give crystalline trans-4-(1,1-dimethylethyl)cyclohexanepropanoic acid (3.09 g, 14.5 mmol) in 98% yield mp 105°-107° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>CN(C=O)C>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCCCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Triethylamine (31 g, 0.31 mol) was added to a solution of 2,4-dichloro-3-nitroquinoline (50 g of 90% pure material) in anhydrous DMF (400 mL). 4-Amino-1-butanol (21 mL, 0.23 mol) was added in portions over a period of ten minutes, and the reaction was stirred at room temperature overnight and then partitioned between deionized water (1.5 L) and ethyl acetate (800 mL). The organic layer was separated, and a precipitate formed. The precipitate was collected by filtration, and the filtrate was concentrated under reduced pressure to provide a solid. The two solids were dried under vacuum to provide 44.34 g of 4-(2-chloro-3-nitroquinolin-4-ylamino)butan-1-ol.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].CS(O[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=O)=O>CN(C)C=O.O>[NH2:1][C@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Temperature: 25 °C

Procedure:
Sodium azide (7.65 g, 118 mmol) was added to a solution of 1,1-dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-piperidine-1-carboxylate (21.9 g, 78.5 mmol) in dry dimethylformamide (120 mL) and the resultant suspension heated at 70° C. for 48 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted into ethyl acetate. The organic phase was washed two further times with water, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (10:90 to 50:50), to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.Cl[CH2:12][CH:13]=O.C(=O)([O-])O.[Na+]>C(O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]2[N:3]([CH:12]=[CH:13][N:1]=2)[CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1ccc(N)nc1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc2nccn2c1
Yield: 29.8 %

Procedure:
To 100 ml of ethanol are added 10 g of 6-aminonicotinamide, 11 g of 40% chloroacetaldehyde and 12.5 g of sodium hydrogen carbonate and the mixture is heated under reflux for 4 hours. Ethanol is evaporated off and 100 ml of water is added to the residue. The mixture is adjusted to pH 10 by adding 10% aqueous sodium hydroxide solution and then extracted four times with 50 ml portions of a mixture solvent of tetrahydrofuran-ethyl acetate (1:1). The extracts are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is recrystallized from a mixture solvent of methanol-diethyl ether to give 3.5 g of the above-identified compound as colorless needles.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][S:25][CH3:26])=[CH:17][CH:16]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:3][CH2:2]1.[OH:28]OS([O-])=O.[K+]>CO>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][S:25]([CH3:26])=[O:28])=[CH:19][CH:20]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:2][CH2:3]1
Reactant: O=S([O-])OO
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CCSC)cc1
Agent: [K+]
Solvent: CO
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CCS(C)=O)cc1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of N-cyclopropyl-1-(4-{[3-(methylthio)propanoyl]amino}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.10 g) obtained in Example 10 in methanol (6 ml) was added an aqueous solution (2 ml) of Oxone (0.10 g) at room temperature, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to give the title compound as a white powder (0.09 g, 82%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.B(Br)(Br)Br.[CH2:28](Cl)Cl>>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH2:20][CH3:28])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(OC)cc2OC)cc1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CCOC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of methyl 4-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)benzoate (55 g, 141.6 mmol) in DCM (600 ml) was added dropwise BBr3 (164 ml, 1.7 mol) at −10° C. When the addition was complete, the mixture was stirred at room temperature overnight and poured into crashed ice (700 g) with stirring. The volatiles were evaporated to afford a yellow solid, which was dried in high vacuo and dissolved in absolute ethanol (500 ml). To the solution was added dropwise thionyl chloride (80 ml) at 0-10° C. When the addition was complete, the resultant mixture was heated to reflux for 3 hours. The volatiles were evaporated and the residue was partitioned between EtOAc (600 ml) and saturated sodium carbonate (200 ml). The organic phase was separated, washed with brine (200 ml), dried with anhydrous sodium sulfate, filtered and concentrated to afford brown slurry, which was purified by column chromatography (PE/EtOAc=3/1) to afford product (24.5 g, 58%) as a yellow solid. 1H NMR (CDCl3 500 MHz TMS): δ 12.58 (s, 1H), 8.01 (d, J=8.5 Hz, 2H), 7.69 (d, J=9.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.05 (brs, 1H), 6.41 (d, J=8.0 Hz, 1H), 6.37 (s, 1H), 4.38 (q, J=7.0 Hz, 2H), 4.26 (s, 2H), 1.38 (t, J=7 Hz, 3H). MS (ESI): m/z 301.1 [M+1]+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:64])[C:7]([S:25][C@@H:26]1[CH2:30][N:29](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:28]([CH2:44][N:45]3[CH2:50][CH2:49][N:48](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:47][CH2:46]3)[CH2:27]1)=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].C([O-])(=O)C.[Na+].C(O)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:64])[C:7]([S:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:44][N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH2:27]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CN4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CN4CCNCC4)C3)[C@H](C)[C@H]12
Yield: 42.2 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-{4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl}methylpyrrolidin-4-yl]thio-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylate (1.20 g), 20% palladium hydroxide on carbon (0.6 g), 0.2 M sodium acetate-acetic acid buffer (pH=5.8, 50 ml) and tetrahydrofuran (50 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin, "Diaion HP-20" (trademark, made by Mitsubishi Chemical Industries) (30 ml) eluting in turn with water (80 ml) and 5% aqueous acetone (90 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(2S,4S)-2-(piperazin-1-yl)methylpyrrolidin-4-yl]thio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.23 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[CH2:43]Cl>>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[CH2:43][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: Fc1ccc(Br)c(CCl)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(F)ccc2Br)cc1

Procedure:
Analogously to Method D, 1.45 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.816 g of 1-bromo-2-chloromethyl-4-fluorobenzene are reacted. The title compound is obtained as a yellowish oil. Rf=0.35 (1:2 EtOAc-heptane); Rt=6.39.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.CC(O)(C)C>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([NH:1][C:2]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:33]=[CH:32][CH:31]=1)(=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: CC(=O)Nc1cccc(Br)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cccc(Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 2-methyl-2-propanol 2.5 mL solution of tert-butyl 2-amino-4-phenylbenzoate 0.12 g were added cesium carbonate 0.29 g, N-(3-bromophenyl)acetamide 0.14 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 11 mg, tris(dibenzylideneacetone)dipalladium(0) 4.0 mg and palladium acetate 2.0 mg at room temperature, and it was stirred at 80° C. for 4 hours. Tris(dibenzylideneacetone)dipalladium(0) 4.0 mg, palladium acetate 2.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 11 mg were added to it at room temperature, and it was stirred at 80° C. for 12 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=2:1] to give tert-butyl 2-((3-(acetamido)phenyl)amino)-4-phenylbenzoate.
Reaction SMILES: C(NC1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.FC1C=C(CC(O)=O)C=CC=1OCCN1CCCCC1.[CH2:43]([N:45]([CH2:64][CH2:65][C:66]1[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH2:74][N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[C:68]([F:81])[CH:67]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[C:57]([O:62]C)[CH:58]=2)[CH2:53]1)[CH3:44]>>[CH2:43]([N:45]([CH2:64][CH2:65][C:66]1[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH2:74][N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[C:68]([F:81])[CH:67]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH:52]1[CH2:61][CH2:60][C:59]2[CH:58]=[C:57]([OH:62])[CH:56]=[CH:55][C:54]=2[CH2:53]1)[CH3:44]
Reactant: CCN(CCc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1ccccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(O)Cc1ccc(OCCN2CCCCC2)c(F)c1
Product: CCN(CCc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 79.2 %

Procedure:
Synthesized from ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]acetic acid hydrochloride according to an analogous synthetic method to Example 337 described below, ethyl {2-[3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]ethyl}[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (302 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (233 mg).
Reaction SMILES: [N+:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Sc3ccccc3)cn12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cnc2ccc(Sc3ccccc3)cn12

Procedure:
A solution of 0.542 gm. (0.002 mole) of 3-nitro-6-phenylthioimidazo [1,2-a] pyridine in 20 ml. of dioxane is reduced at 40 psi. under a hydrogen atmosphere with 0.500 g. of 5% palladium on carbon as catalyst. When the uptake of hydrogen is complete, the catalyst is removed by filtration. The filtrate is evaporated in vacuo to yield 3-amino-6-phenylthioimidazo [1,2-a] pyridine.