Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].Cl.[C:47]([N:49]=[C:50]([NH2:52])[NH2:51])#N.C(=O)([O-])O.[Na+]>O>[NH:49]([C:47]1[NH:1][C:2]2[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])=[CH:41][CH:42]=[CH:43][C:44]=2[N:45]=1)[C:50]([NH2:52])=[NH:51]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: N#CN=C(N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2nc(NC(=N)N)[nH]c12
Yield: 45.1 %

Procedure:
To a suspension of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in water (5 ml) was added 1N hydrochloric acid (1.3 ml) and then dicyandiamide (545 mg) was added to the stirred reaction mixture. The solution was heated under reflux for 24 hours. After cooling, aqueous sodium hydrogen carbonate was added to the mixture and extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (SiO2, 30 g, 15% methanol in chloroform) to give 4-[2-guanidinobenzimidazol-4-yl]carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) as yellow amorphous.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH2:16](I)[CH2:17][CH2:18][CH3:19].Cl>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1>[CH2:16]([C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: O=C(O)C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of LDA (30 mL, 2.0M, 60 mmol) in THF/heptane/ethylbenzene and anhydrous THF (30 mL) at 0° C. was added cyclobutane carboxylic acid (3.0 g, 30 mmol) dropwise. After addition was complete, the cold bath was removed, the reaction mixture was stirred at room temperature for 2 hr. Neat n-BuI (3.41 mL, 30 mmol) was added dropwise at room temperature. The mixture was stirred over night. To the mixture was added 2N HCl and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water and brine to afford the title compound as a light yellow oil (quantitative), which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([O:17]C)=[O:16])=[C:7]([CH3:9])[N:8]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([OH:17])=[O:16])=[C:7]([CH3:9])[N:8]=1
Reactant: COCc1nc(C)c(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1nc(C)c(-c2cc(C(=O)O)c(C)cc2C)[nH]1
Temperature: 40 °C
Reaction time: 15 h
Yield: 98.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 2.1, 150 mg, 0.52 mmol) in methanol (15 mL) and H2O (5 mL). Sodium hydroxide (280 mg, 7.00 mmol) was added and the resulting solution was stirred at 40° C. for 15 h. After cooled to room temperature, the solution was adjusted to pH 5 with aqueous HCl (2 M) and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and the solids were filtered off. The filtrate was concentrated under reduced pressure to yield the title compound as a light yellow solid (140 mg, crude), which was used in the next step without further purification.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].[S:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>>[I-:1].[CH3:35][O:34][CH:10]([CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][CH:37]1[NH+:38]=[CH:39][CH2:40][S:36]1)(=[O:7])=[O:6])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCI)OC
Reactant: c1cscn1
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCC1[NH+]=CCS1)OC
Product: [I-]
Yield: 37 %

Procedure:
A solution of 76 mg of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIa6 in 1 ml of thiazole is heated at 60° C. for 6 hours. After the solvent is evaporated, the residue is washed with ether and subsequently with acetonitrile to give 32 mg of 2-methoxy-1-octadecylcarbamoylthio-3-(3-thiazoliniopropylsulfonylamino)propane iodide Ia26 in 37% yield.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)CS1
Yield: 52.2 %

Procedure:
To a solution of (1R,2R)-2-aminocyclohexanol (1.00 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.17 g), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (971 mg).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I:14][C:15]1[CH:22]=[C:19]([CH:20]=O)[C:18]([OH:23])=[CH:17][CH:16]=1>>[OH:23][C:18]1[CH:17]=[CH:16][C:15]([I:14])=[CH:22][C:19]=1[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(I)ccc1O
Product: O=c1cc(N2CCN(Cc3cc(I)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(2-Hydroxy-5-iodo-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-iodosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, DMSO-d6) δ 2.42-2.47 (m, 4H), 3.28-3.55 (m, 6H), 5.26 (s, 1H), 6.61-6.63 (m, 1H), 7.38-7.46 (m, 2H), 7.84 (s, 1H), 10.30 (br s, 1H), 11.63 (br s, 1H). Mass spectrum (ES) MH+=413.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:22])[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][C:20]1[C:15]([NH:14][C:10]2[CH:9]=[C:8]([CH3:22])[CH:13]=[CH:12][CH:11]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:35])([CH3:24])([CH3:25])[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cccc(Nc2ncccc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Nc2ncccc2NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (1.7 mL, 12.0 mmol) was added to a mixture of N2-m-tolylpyridine-2,3-diamine (600 mg, 3.01 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.03 g, 5.42 mmol), HOAt (740 mg, 5.42 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.04 g, 5.42 mmol) in anhydrous DCM (25 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 min then slowly warmed to RT. Stirring at RT was continued for 16 h. After re-cooling the mixture to 0° C., additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (220 mg, 1.20 mmol), HOAt (160 mg, 1.20 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol) and triethylamine (0.41 mL, 3.01 mmol) were added. The reaction mixture was stirred at 0° C. for 15 min then slowly warmed to RT. Stirring at RT was continued for 72 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an off-white foam. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method C): RT 2.70 min [M+H]+ 371.3.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([Cl:13])([Cl:12])[Cl:11])=[N:8][CH:9]=1)[CH3:3].[CH3:14][S-:15].[Na+]>C(O)C>[CH3:14][S:15][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([Cl:13])([Cl:12])[Cl:11])=[N:8][CH:9]=1)[CH3:3]
Reactant: CC(Br)c1ccc(C(Cl)(Cl)Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSC(C)c1ccc(C(Cl)(Cl)Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(1-bromoethyl)-2-(trichloromethyl)pyridine (A) (0.95 g, 3.14 mmol) in ethanol (15 mL) was treated with sodium thiomethoxide (0.44 g, 6.29 mmol) portionwise at 0° C. The mixture was stirred at room temperature overnight. The solvent ethanol was then removed under a reduced pressure and the residue was re-taken into CH2Cl2 and brine. The two phases were separated and the organic layer was dried over anhydrous Na2SO4, filtered, concentrated. The residue was purified on silica gel using 5 percent EtOAc in hexane to give 0.57 g of the partially pure 5-[1-(methylthio)ethyl]-2-(trichloromethyl)pyridine (B) in 67 percent crude yield. GC-MS: mass calcd for C9H10Cl3NS [M]+ 269. Found 269.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](NCC)=[CH:4][CH:3]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.[CH3:18][CH2:19][N:20](C(C)C)C(C)C>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH2:19][NH:20][C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CCNc1ccc(O)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1CSC(=S)N1
Solvent: CCO
Product: O=C1CSC(NCCc2ccc(O)cc2)=N1
Temperature: 0 °C
Reaction time: 15 h
Yield: 19.1 %

Procedure:
To a suspension of (4-hydroxy-phenyl)-ethylamine (3.14 g, 22.2 mmol) and Rhodanine (2.96 g, 22.2 mmol) in ethanol (314 mL) was added DIPEA (4.76 mL, 26.64 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (6.05 g, 22.2 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 15 h. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (200 mL) and methanol (500 mL). The combined solvents were removed under the vacuum and the crude residue was diluted with water (150 mL) and ethyl acetate (150 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using Biotage silica gel column chromatography to afford 1.0 g (19% yield) of 2-[2-(4-hydroxy-phenyl)-ethylamino]-thiazol-4-one as a white amorphous solid: HRES(+) m/e calcd for C10H8ClFN2OS (M+H)+237.0692, found 237.0693.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[CH:33]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2/[CH:33]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 70 °C
Yield: 40.9 %

Procedure:
To a mixture of 6-chlorooxindole (0.84 g, 5 mmol) and 4-(4-chloro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 5 mmol) in methanol (10 mL) was added pyrrolidine (0.4 mL, 5 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[CH3:22])[S:11][CH:12]=1.[CH:23](OCC)=[O:24].Cl>C(O)=O.C(OCC)(=O)C>[CH3:22][C:14]1[CH:15]=[CH:16][C:17]([NH:19][CH:23]=[O:24])=[CH:18][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:9]=1
Reactant: CCOC=O
Reactant: Cc1ccncc1-c1csc(-c2cc([N+](=O)[O-])ccc2C)n1
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cc1ccncc1-c1csc(-c2cc(NC=O)ccc2C)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
4-Methyl-3-[2-(2-methyl-5-nitrophenyl)-1,3-thiazol-4-yl]pyridine (98 mg) and reduced iron (170 mg) were suspended in a mixture of formic acid (3 ml)-ethyl formate (3 ml). 1N Hydrochloric acid (0.2 ml) was added and the mixture was stirred at 80° C. for 12 hrs. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off. The organic layer was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was separated and concentrated by drying. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1–0:1) for purification. Recrystallization from ethyl acetate gave the title compound (15 mg) as pale-yellow columnar crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](OC)[CH:7]=[CH:6][C:5]=1[N:12]=[N:13][C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=[C:16]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:15]=1[OH:33])([O-])=O.C(N)(C)(C)C.[PH2](O)=O>[Pd].CO>[OH:33][C:15]1[C:16]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][C:14]=1[N:13]1[N:12]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CCCCCCCCCc1cc(N=Nc2ccc(OC)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=[PH2]O
Solvent: CC(C)(C)N
Solvent: CO
Product: CCCCCCCCCc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 500 mL capacity stainless steel autoclave equipped with a stirrer, external heating jacket and internal heating and cooling coils are added 5.0 g of (0.0082 mole) of 2-nitro-4-methoxy-2'-hydroxy-3'-t-butyl,5'-nonylazobenzene (nonyl group is an isomeric mixture)(purity 75%), 0.25 g (dry weight) of (4% Pd/C+1% Pt/C) catalyst, 3.2 g (about 4 equivalent) of tert-butylamine, 4.4 g (about 3 equivalent) of 50% aqueous hypophosphorous acid and 150 mL of methanol. The autoclave is purged with nitrogen gas and then hydrogen gas and then sealed and charged with hydrogen gas to a pressure of 53,000 Kg/m2. The reaction is stirred at room temperature and at 53,000 Kg/m2 pressure (recharging if necessary) for one hour. After one hour the temperature is raised to 50° C. and held at the same temperature and pressure for an additional 12 hours. Then the autoclave and its contents are cooled to 45°-47° C., removed and filtered through a Celite filter-aid pad to remove the catalyst. The catalyst and the residue on the filter pad are further washed with some tetrahydrofuran for complete recovery of the product. The organic solvents are removed on a rotary evaporator. The residue is diluted with about 500 mL of brine (saturated aqueous sodium chloride solution) and treated with hydrochloric acid dropwise until the Congo Red Indicator paper turns blue. The light purple insoluble liquid material (the desired product) is extracted with dichloromethane (200 mL), washed with brine (2×150 mL), dried (Na2SO4), filtered off and solvent is removed from the filtrate on a rotary evaporator to obtain 4.6 g of brown-purple colored viscous crude of 2-(2'-hydroxy-3'-t-butyl,5'-nonylphenyl)benzotriazole. After purifying by silica gel flash column eluting with heptane 2.93 g of nearly colorless liquid (yield 95%) is obtained. It shows a retention time of 27.3 min. in HPLC analysis and its FD-mass spectral analysis shows molecular ion peak at m/e 423.
Reaction SMILES: [NH2:1][C:2]([C@H:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:11][CH:10]=2)[N:5]1C(OC(C)(C)C)=O)=[O:3].C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>>[ClH:39].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:6]2[NH:5][C@@H:4]([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(N)=O)CC[C@H]1c1ccc(OCc2ccccc2F)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NC(=O)[C@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5S)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate (D40, 145 mg, 0.37 mmol) in DCM (6 ml) was added TFA (1.5 ml) dropwise at 0° C. The mixture was stirred for 1 h under these conditions. After evaporating the solvent, the resulting crude material was purified by SCX cartridge, to afford the title compound (100 mg, 92%) as a mixture of diastereoisomers. The diastereoisomers were separated via chiral semipreparative HPLC: Column: chiralpak AD-H; Mobile phase: n-Hexane:Ethanol=70/30; Flow rate: 13 ml/min; UV wavelength range: 225 nm; Analysis time: 25 min. Analytical chromatographic conditions: Chiral HPLC: Column: chiralpak AD-H 5 um, 250×4.6 mm; Mobile phase: A: n-Hexane; B: Ethanol; Gradient: isocratic 30% B; Flow rate: 0.8 ml/min; UV wavelength range: 200-400 nm; Analysis time: 30 min; Rt: 14.02 min (E21); Rt: 16.12 min (E20)
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11]N[C:9]1=[O:13])(=[O:4])=[O:3].O[CH2:15]CN1CCCC1=O>>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:15][C:9]1=[O:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OCCN1CCNC1=O
Reactant: O=C1CCCN1CCO
Product: CS(=O)(=O)OCCN1CCCC1=O
Yield: 50 %

Procedure:
Following the general method as outlined in Intermediate 31, starting from 1-(2-hydroxyethyl)pyrrolidin-2-one (500 mg; 3.87 mmol), 400 mg (50%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:22][O:23][CH2:24][O:25][CH2:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH2:18]([CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:39]([C:36]2[CH:35]=[CH:34][C:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][O:25][CH2:24][O:23][CH3:22])[CH:28]=3)=[CH:38][CH:37]=2)=[O:40])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Reactant: COCOCc1cccc(-c2ccc(C(=O)O)cc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(COCOC)c3)cc2)cc1)C(=O)OCC
Yield: 85.7 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (358 mg), which is the product of Reference example 6, 3′-methoxymethoxymethylbiphenyl-4-carboxylic acid (333 mg), which is the product of reference example 15(c), and carbonyldiimidazole (238 mg) and the reaction mixture was treated to afford the desired compound (573 mg) as a brown syrup.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:58])([F:57])[O:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([C:12]([N:54]2[CH2:53][CH2:52][N:51]([S:48]([C:45]3[CH:46]=[CH:47][C:42]([O:41][C:40]([F:57])([F:58])[F:39])=[CH:43][CH:44]=3)(=[O:49])=[O:50])[CH2:56][CH2:55]2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Reactant: Cc1c(C(=O)O)ccc2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)ccc2cccnc12
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To the solution of 8-methyl-7-quinolinecarboxylic acid (may be prepared as described in Intermediate 2; 90 mg, 0.483 mmol) in N,N-Dimethylformamide (DMF) (2 ml), HATU (193 mg, 0.508 mmol) was added at room temperature. The reaction was stirred for 20 min and then 1-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)piperazine (may be prepared as described in Intermediate 11; 150 mg, 0.483 mmol) was added followed by DIPEA (0.211 ml, 1.209 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into the separating funnel and partitioned between ethyl acetate (25 ml) and sodium hydroxide (15 ml). The organic phase was washed with sodium hydroxide (2×10 ml), water (2×10 ml) and brine (10 mL) before it was dried using phase separator and the solvent was removed under vacuum. The crude product was purified by MDAP to give the title compound as a white solid (115 mg).
Reaction SMILES: [CH2:1]([C@:3]1([OH:38])[C:35]2[CH:34]=[C:33]3[N:9]([CH2:10][C:11]4[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([CH3:31])=[C:18]5[CH2:23][CH2:22][CH:21]([NH:24]C(=O)C(F)(F)F)[C:20]=4[C:19]=35)[C:8](=[O:36])[C:7]=2[CH2:6][O:5][C:4]1=[O:37])[CH3:2].[ClH:39].CO>O>[ClH:39].[NH2:24][CH:21]1[C:20]2=[C:11]3[CH2:10][N:9]4[C:33](=[CH:34][C:35]5[C@:3]([CH2:1][CH3:2])([OH:38])[C:4](=[O:37])[O:5][CH2:6][C:7]=5[C:8]4=[O:36])[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([CH3:31])=[C:18]([C:19]=32)[CH2:23][CH2:22]1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(NC(=O)C(F)(F)F)CC3
Agent: Cl
Solvent: O
Solvent: CO
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(N)CC3
Temperature: 80 °C
Reaction time: 7 h

Procedure:
625 mg of the compound prepared in (10) above was added to a mixed solution of 7.5 ml-of concentrated hydrochloric acid, 18 ml of methanol and 12 ml of water, and stirred at 80° C. for 7 hours. Insoluble substances were removed by filtration and the filtrate was purified with HPLC (CAPCELL PAK C18) using a mixture of acetonitrile-water-1 N hydrochloric acid (20:80:1) to obtain 138 mg of Isomer A and 143 mg Isomer B of the title compound.