Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:36].O>CN(C=O)C>[C:1]([CH2:4][NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:36])[C:18]([N:20]3[CH2:21][CH2:22][CH:23]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[CH2:24][CH2:25]3)=[O:19])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(F)cc4)CC3)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CN[C@@H]1CCN(c2ccc(N(C)C(=O)N3CCC(c4ccc(F)cc4)CC3)cc2)C1
Reaction time: 2 h

Procedure:
(R)-4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethyl -amino)pyrrolidin-1-yl]phenyl}amide (22 mg) was added to a suspension of sodium hydride (95% in oil; 0.005 g) in DMF (1 ml). After evolution of gas ceased, iodomethane (0.02 ml) was added. After two hours, the reaction mixture was cautiously hydrolyzed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated, and the residue was crystallized from pentane. This resulted in the product with the molecular weight of 452,58 (C26H33FN4O2); MS (ESI): 453 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([OH:32])[CH2:18][O:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[NH:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.CN(C=O)C.B(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][C:23]1[C:24]([O:26][CH3:27])=[CH:25][C:20]([O:19][CH2:18][C@@H:17]([OH:32])[CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)=[C:21]([NH:28][C:29](=[O:31])[CH3:30])[CH:22]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(NC(C)=O)c(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c(NC(C)=O)cc1Br
Reaction time: 8 h
Yield: 45 %

Procedure:
To a stirred suspension of N-[2-({(2S)-3-[4-(5-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-methoxyphenyl]acetamide (Example 32 iii)) (0.17 g, 0.36 mmol) in CH2Cl2 (5 ml) with some drops of DMF a solution of boron tribromide (BBr3) in dichloromethane (CH2Cl2) (1M, 1.08 mmol, 1.08 ml) was added dropwise under nitrogen. The stirring was continued overnight art room temperature. Then the reaction mixture was quenched with methanol, diluted with water and extracted with dichloromethane (CH2Cl2) (2×10 ml) and ethyl acetate (2×10 ml). The combined organic extracts were dried with sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography of silica gel (CH2Cl2/MeOH, 9:1) to give a colourless solid (89 mg, 0.16 mmol, 45%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:45])[C@@H:24]([NH:25][C:26](=[O:44])/[C:27](/[C:31]4[N:32]=[C:33]([NH:36]C(OC(C)(C)C)=O)[S:34][CH:35]=4)=[CH:28]\[CH2:29][CH3:30])[C@H:21]3[S:20][CH2:19][C:18]=2[S:46][CH2:47][S:48][C:49]2[N:50]=[N:51][NH:52][CH:53]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.O>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.C(O)C>[NH2:36][C:33]1[S:34][CH:35]=[C:31](/[C:27](=[CH:28]/[CH2:29][CH3:30])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:45])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:46][CH2:47][S:48][C:49]4[N:50]=[N:51][NH:52][CH:53]=4)[CH2:19][S:20][C@H:21]23)=[O:44])[N:32]=1
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(N)n1
Reaction time: 1 h
Yield: 43.6 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (537 mg: 0.68 mMol.) in a mixture of anisole (2 ml) and nitromethane (8 ml) at -30° C. is added a solution of aluminum chloride (0.54 g: 4 mMol. ) in anisole (2 ml), and the mixture is stirred for 1 hour. The reaction mixture is diluted with ethanol (3 ml), stirred for 5 minutes, mixed with 1N-hydrochloric acid (8 ml) and water (200 ml), washed with ethyl acetate, and concentrated under reduced pressure to remove remaining organic solvents. The resulting aqueous solution is subjected to chromatography over styrene-divinylbenzene copolymer (methanol: water=4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (156 mg) as white solid. Yield: 44%.
Reaction SMILES: [N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3][C:2]=1N.[BrH:15].N([O-])=O.[Na+]>[Cu]Br>[Br:15][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:1]=1
Reactant: Nc1ncc2[nH]c3ccccc3c2n1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1ncc2[nH]c3ccccc3c2n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution is prepared from 2 g of 2-amino-5H-pyrimido[5,4-b]indole (Example 7) in 25 ml of 48% strength hydrobromic acid and combined at 0° C. with 6 ml of a 2N sodium nitrite solution. The mixture is stirred into a solution of 2.1 g of copper(I) bromide in 20 ml of 24% strength hydrobromic acid. The mixture is then stirred for 20 minutes at 0° C., then briefly heated on a steam bath. The cooled-off reaction mixture is extracted with a mixture of 9 parts of ethyl acetate and one part of ethanol. The residue is evaporated and chromatographed on silica gel with a mixture of 20 parts of methylene chloride and one part of methanol, thus obtaining 0.2 g of 2-bromo-5H-pyrimido[5,4-b]indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:10]=1)[C:5]([N:22]([O:23][CH3:24])[CH3:21])=[O:7]
Reactant: CNOC
Reactant: O=C(O)c1cc(Cl)cc(OC(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Cl)cc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
3-Chloro-5-difluoromethoxybenzoic acid (1.8 g, 8 mmol; see step (iii) above) and oxalyl chloride (1.5 g, 11.8 mmol) were dissolved in methylene chloride (50 mL). DMF (2 drops) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. Then, N,O-dimethylhydroxylamine (1 g, 10.2 mmol) and triethylamine (3 g, 30 mmol) were added and after another 10 minutes stirring at ambient temperature, the reaction mixture was concentrated at reduced pressure. The residue was taken up in ether (100 mL) and water (50 mL). After separation, the organic phase washed with brine, dried over sodium sulphate, filtered and concentrated. This residue was chromatographed on silica (hexane/ethyl acetate 2:1) which gave 2 g, 7.5 mmol (93%) of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].[CH3:42]N(C)P(=O)(N(C)C)N(C)C.C([Li])(CC)C.CI>O1CCCC1.C(OCC)C.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:6]([O:13][CH3:14])=[C:7]([CH3:42])[C:8]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(C)c(OC)c2OCOC)c1OC
Reaction time: 1 h

Procedure:
140 Milligrams of 2,2'-pentamethylene-bis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in 5 ml of anhydrous tetrahydrofuran under argon gas stream conditions, then 0.5 ml of hexamethylphosphoric triamide was added to this solution and the mixture was cooled in a dry ice-acetone bath. Next, 0.23 ml of sec-butyllithium (1.4M, cyclohexane solution) was added dropwise to the reaction mixture and stirred for 1 hour. Then, 0.06 ml of methyl iodide was added dropwise thereto under cooling in a dry ice-acetone bath for 12 hours with stirring. The solvent was removed by evaporation under reduced pressure, to the residue obtained was added 100 ml of a mixed solvent of diethyl ether-benzene (1:1), and the organic layer was washed with water then with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to obtain 100 mg of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-methyl-6-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl}benzene. Colorless needles crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:20]1([C:23]([NH2:31])([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH3:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]([NH:31][C:10]([C:7]2[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)C2CC2)no1

Procedure:
The mixture of epimers was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (135 mg, 58%) as a light yellow oil. The mixture of epimers was separated into its epimers by preparative chiral HPLC (Chiralpak AD, ethanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH3:21][NH:22][C:23](SC)=[CH:24][N+:25]([O-:27])=[O:26]>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[CH:24][N+:25]([O-:27])=[O:26])[N:8]=1
Reactant: NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CNC(=C[N+](=O)[O-])NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine (0.31 g.) 1-methylamino-1-methylthio-2-nitroethylene (0.15 g.) and acetonitrile (5 ml.) was heated under reflux for 6 hours and then left at room temperature for 18 hours. The yellow crystalline precipitate was collected to give 1-(2-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]ethylamino)-1-methylamino-2-nitroethylene (0.26 g.), m.p. 154°-157° after recrystallisation from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:3]=1[CH:4]=[O:5].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:3]=1[C:4]([OH:24])=[O:5]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzaldehyde (4.5 g, 13.2 mmole) in 40 ml of acetone was added 13 ml (26 mmole) of Jones' reagent. The solution was stirred at ambient temperature for 2 hours and poured into 400 ml of water. The resulting solid was filtered and air dried overnight to afford 4.5 g (96%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluoro-benzoic acid as a white solid. An analytical sample was recrystallized from ether/hexanes; mp 179°-181° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[C:12](=[O:18])[CH2:11]1)[C:5]#[N:6].[CH:19]([Mg]Br)=[CH2:20]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[C@@:12]([OH:18])([CH:19]=[CH2:20])[CH2:11]1)[C:5]#[N:6]
Reactant: C=C[Mg]Br
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Solvent: C1CCOC1
Product: C=C[C@@]1(O)C[C@H](c2ccc(C#N)cc2F)n2cncc21
Temperature: 25 °C

Procedure:
To a stirred solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (0.6 g, 2.5 mmol), in THF (20 mL) cooled in a dry ice acetone bath under nitrogen was added via syringe a solution of vinyl magnesium bromide (0.7 M) in THF (4.3 mL, 3.0 mmol). The crude was warmed to room temperature in 3 hrs. The crude was quenched with NH4Cl aq. The crude was diluted in EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The crude was purified via preparation plate using 5% (2M NH3 in MeOH)/CH2Cl2 two times followed by purification using RPHPLC using 10% to 40% MeCN/H2O to give 142 mg of the entitled product as the major diastereomer. MS 270.2 (M+H); LCMS condition A, retention time 0.99 min. 1H NMR (400 MHz, CDCl3-d) ppm 2.56 (br. s., 1H), 2.68 (dd, 1H), 3.22 (dd, 1H), 5.24 (d, 1H), 5.41 (d, 1H), 5.59-5.73 (m, 1H), 6.10 (dd, 1H), 6.91 (br. s., 1H), 7.10 (t, 1H), 7.35 (d, 2H), 7.39 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[C:19](=[O:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[C:32]([F:35])([F:34])[F:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:33][C:32]([F:35])([F:34])[C:19]([CH3:20])([OH:21])[C:18]([CH3:22])([CH3:23])[CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of the compound of Example 120, 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-4-phenylbutan-2-one (12 mg, 0.031 mmol) in THF (1 ml) at 0° C. was added trimethyl(trifluoromethyl)silane (22 mg, 0.155 mmol) and tetrabutylammonium fluoride in THF (0.031 ml, 0.031 mmol, 1M THF solution). The reaction mixture was stirred at 0° C. for 10 minutes, and then at room temperature for 45 minutes. Additional trimethyl(trifluoromethyl)silane (22 mg, 0.155 mmol) was added to the reaction mixture, after which stirring was continued for 2 hours. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to give the crude product. The crude material was purified via chromatography on silica gel eluting with 10% ethyl acetate in hexane to afford the compound of Example 135 as a white solid (10 mg, 71% yield). It is a mixture of diastereomers in 1:1 ratio. 1H NMR (400 MHz, MeOD) δ ppm 8.17 (1 H, s) 7.98 (1 H, d, J=16.79 Hz) 7.68 (3 H, dd, J=8.90, 4.83 Hz) 7.58 (2 H, d, J=8.14 Hz) 7.54 (1 H, d, J=7.63 Hz) 7.20-7.33 (4 H, m) 7.12 (1 H, t, J=7.12 Hz) 4.55 (1 H, d, J=5.09 Hz) 1.31 (3 H, 2 singlets) 1.22 (3 H, 2 singlets) 1.13 (3 H, 2 singlets). LC/MS (m/z) 387.20 [(M+H)+]; HPLC Rt: 3.758 min.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:23])[S:13][C:14]=2[CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=1.[C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH3:26].[Li]>>[C:29]([O:28][C:25](=[O:27])[CH2:26][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:23])[S:13][C:14]=2[CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1cccc(-c2nc(C)sc2COC2CCCCO2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: Cc1nc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(COC2CCCCO2)s1

Procedure:
3-[2-Methyl-5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-[3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-phenyl]-propionic acid tert-butyl ester (5.45 g) as a pale-yellow oil.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[OH:7][C:6]1[CH:8]=[C:9]2[C:11]([C:3](=[O:4])[CH2:2][O:10]2)=[CH:12][CH:13]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2cc(O)ccc21

Procedure:
Chloroacetyl chloride (28.25 g) was added dropwise over 1.5 hours to a stirred mixture of resorcinol (Aldrich Chemical Company) (22 g), aluminum chloride (33.3 g) and nitrobenzene (250 cc), the temperature being kept at 50°-55° C. during the chloroacetyl chloride addition and for an additional 15 minutes thereafter. The solution was then cooled and poured into an excess of ice and dilute hydrochloric acid. The organic layer was retained and extracted with aqueous sodium hydroxide (300 ml, 1M). The alkaline extract was acidified with concentrated hydrochloric acid and filtered to give 6-hydroxycoumaran-3-one, m.p. --238°-240° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: Clc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Temperature: 80 °C
Yield: 80 %

Procedure:
To a 22 L, three-necked flask fitted with a thermometer, mechanical stirrer and a Vigreux column connected to an aqueous NaOH scrubbing tower, was added 1,4-dichlorobenzene (3 Kg, 26.4 mol) and benzoyl chloride (2.6 Kg, 18.55 mol). The mixture was heated to 80° C. to give a homogeneous solution. Aluminum chloride (5.5 Kg, 41.25 mol) was added over 12 min. with stirring. (The molar ratio of reactants was 2.2:1.4:1.0 (AlCl3 : Dichlorobenzene:Benzoyl Chloride)). The resulting mixture was heated to 140° C. over 60 min followed by heating to 175° C. over 30 min. Heating was stopped at 175° C. The mixture was allowed to cool to 80° C. over two hours and poured into a well stirred mixture of ice and water (ca. 25 L water and 15 Kg of ice) over 30 min. The organic solid was collected by filtration and dissolved in 7 L of toluene. The solution was washed with aqueous sodium bicarbonate and dried. Toluene was removed by distillation. Pure 2,5-dichlorobenzophenone was isolated in 80% yield after recrystallization from hexane and toluene. Gas chromatography indicated an absolute yield of 97%.
Reaction SMILES: ClC1C([N+]([O-])=O)=CC=C(Cl)N=1.NCC1C=NC=CC=1.Cl[C:21]1[N:26]=[C:25]([NH:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:24]([N+:35]([O-:37])=[O:36])=[CH:23][CH:22]=1.[N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[NH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(N(CC)CC)C>[N:38]1([C:21]2[N:26]=[C:25]([NH:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:24]([N+:35]([O-:37])=[O:36])=[CH:23][CH:22]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[CH:39]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccnc1
Agent: NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-n2cnc3ccccc32)nc1NCc1cccnc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 2,6-dichloro-3-nitropyridine (46) (0.5 g) in acetonitrile (20 mL) was cooled to 0° C. and treated with triethylamine (0.36 mL) followed by 3-(aminomethyl)pyridine (0.26 mL). The mixture was stirred for 30 minutes at 0° C. and eight hours at RT. The resulting solution, which contained the intermediate 6-chloro-3-nitro-N-(pyridin-3-ylmethyl)pyridin-2-amine (47), was transferred to a sealed tube containing benzimidazole (0.84 g) and potassium carbonate (3 g) and heated at 70° C. for 16 h. The mixture was cooled and filtered. The precipitated was washed with water and air-dried to provide 239 mg of the title compound (48).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:23]1([C@H:33]([N:35]([CH2:43][C@@H:44]2[C@@H:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:47][NH:46][CH2:45]2)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:55]([O:64][CH3:65])(=[O:63])[CH2:56][CH2:57][CH2:58][CH2:59][C:60]([O-])=[O:61]>ClCCl.C(N(CC)CC)C>[C:38]([O:37][C:36]([N:35]([CH2:43][C@@:44]1([C:60](=[O:61])[CH2:59][CH2:58][CH2:57][CH2:56][C:55]([O:64][CH3:65])=[O:63])[C@H:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:47][NH:46][CH2:45]1)[C@@H:33]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:34])=[O:42])([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)[C@@]1(CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)CNC[C@H]1c1ccccc1
Reaction time: 72 h
Yield: 94.4 %

Procedure:
At room temperature, 144 mg of WSC hydrochloride, 101 mg of HOBt, 215 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 0.08 ml of triethylamine were added in that order to a mixture of 80 mg of monomethyl adipate and 5 ml of dichloromethane and stirred for 3 days, and then the reaction was quenched by adding water, and this was extracted with chloroform and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 270 mg of methyl 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-3-yl)-6-oxohexanoate as a colorless amorphous substance. FP: 573.