Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:53]1([N:59]=[C:60]=[O:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:38][CH3:39])[CH2:40][CH3:41])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][C:60](=[O:61])[NH:59][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: O=C=Nc1ccccc1
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(OC(=O)Nc1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OC(=O)Nc1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 25.5 h

Procedure:
(8E,12E,14E)-7-acetoxy-6,21-dihydroxy-6,10,12,16,20-pentamethyl-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (100 mg, 154 μmol) was dissolved in methylene chloride (2 mL). Triethylamine (64.2 μL, 461 μmol) and phenyl isocyanate (34.0 μL, 312 μmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 25.5 hours. Then, triethylamine (200 μL, 1.43 μmol) and phenyl isocyanate (98.0 μL, 900 μmol) were further added to the reaction solution, and the reaction solution was stirred at room temperature for six hours. The reaction solution was diluted with ethyl acetate (30 mL), and the dilution was washed with saturated aqueous solution of sodium hydrogencarbonate (6 mL) twice, purified water (6 mL) twice, and brine (6 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (MERCK Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=4:1→3:1) and thin-layer chromatography (MERCK 60 F254, 0.5 mm, toluene:acetone=5:1) to obtain the title compound (54.0 mg, 70.1 μmol, 45.6%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.37 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. 2-Methoxyethylamine (1.71 g, 0.023 mole) was added and the reaction mixture was allowed to stir at room temperature overnight.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21](=[NH:25])OCC)(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.O.[NH2:34][NH2:35]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21]2[NH:25][C:1]([CH3:2])=[N:35][N:34]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: NN
Reactant: CCOC(=N)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nnc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)[nH]1
Reaction time: 18 h

Procedure:
Acetyl chloride (91 ml) was added to a stirred solution of ethyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboximidate (288 mg) [see Preparation 41] and triethylamine (178 ml) in toluene (5 ml). The reaction mixture was stirred at room temperature for 1 hr after which time hydrazine hydrate (62 ml) was added. The mixture was stirred for 18 hrs and then poured into a column containing silica gel, and the product eluted with a solvent gradient of 1:1, by volume, ethyl acetate: hexane followed by 95:5 ethyl acetate:methanol. The fractions containing the product were combined and the solvent removed under reduced pressure, the remaining residue was dissolved in toluene (10 ml) and the reaction mixture was heated to reflux for 1 hr. Tosic acid (5 mg) was then added and the mixture was heated to reflux for a further 18 hrs. The cooled reaction mixture was then purified by column chromatography on silica gel eluting with a solvent gradient of 1:1, changing to 0:100, by volume, hexane:ethyl acetate, in 10% increments, to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(5-methyl-4H-1,2,4-triazol-3-yl)piperidine (60 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[C:16]([OH:30])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:32]([O-])([O-])=O.[K+].[K+].CI>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])=[C:16]([O:30][CH3:32])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(O)c1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-hydroxy-L-phenylalanine methyl ester (0.45 g), K2CO3 (0.199 g), and n-Bu4NI (0.035 g) in DMF (4.0 mL) was added CH3I (0.072 mL) and the mixture was stirred overnight at room temperature. DMF was removed and the residue was partitioned between water and EtOAc. The organic layer was separated and the aqueous solution was extracted with EtOAc. The combined extract was dried (MgSO4) and evaporated. The residue was purified by preparative TLC (silica gel; eluent: hexanes/CH2Cl2/EtOAc, 3:3:1) to yield 0.396 g of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-methoxy-L-phenylalanine methyl ester. ESMS: m/z 484 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].NC1C=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33]CNCC2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:20][C:17]1[CH:18]=[CH:11][C:12]([NH:8][C:1]([N:3]2[CH2:4][CH2:33][CH:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:6][CH2:7]2)=[O:2])=[CH:15][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(O)cc1)N1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 0.17 h

Procedure:
Carbonyldiimidazole (1.48 g) was added to a solution of 4-aminophenol (1.0 g) in DMF (10 ml) at 0° C. After 10 minutes, a mixture of 4-(4-chlorophenyl)piperidine (hydrochloride; 2.13 g), Hünig's base (1.18 g) and DMF (10 ml) was added. After two hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 330.82 (C18H19ClN2O2); MS (ESI): 331 (M+H+) was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[H][H].[ClH:26].CCOCC>[Pt].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.CO>[OH2:16].[ClH:26].[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:18][CH:19]=1
Reactant: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pt]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(C(CC2CCNCC2)c2ccc(F)cc2)cc1
Product: O

Procedure:
A mixture of 10.0 g (0.30 mole) α,α-bis(4-fluoropheny)-4-pyridineethanol of 1.2 g of 5% platinum on carbon catalyst in 200 ml of acetic and was shaken under an atomsphere of hydrogen (49 psi)for 16 hr. The solution was filtered through Celite®, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give an oil. This was dissolved in methanol, an excess of ethereal hydrogen chloride was added and ether was added. A precipitate was collected to give 7.58 g (72.4%)as a white, crystalline solid, m.p. 171°-173° C.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH3:15][C:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][NH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.COCCOC>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:20]3[CH:19]=[N:18][NH:17][C:16]=3[CH3:15])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2C
Temperature: 25 °C
Yield: 38.1 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. After cooling to room temperature, 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.208 g, 1.00 mmol), Cs2CO3 (0.489 g, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) were added. The mixture was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.041 g, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 6 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (100 mL), and the extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc). The obtained yellow solid was triturated with EtOAc and collected by filtration to afford the title compound (52.7 mg, 38%) as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:23]C)=[CH:4][C:5]2[CH:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[CH2:17][CH2:16][CH2:15]4)[CH2:10][N:9]([CH3:21])[CH2:8][CH2:7][C:6]=2[CH:22]=1.B(Br)(Br)[Br:26]>ClCCl>[BrH:26].[Cl:1][C:2]1[C:3]([OH:23])=[CH:4][C:5]2[CH:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[CH2:17][CH2:16][CH2:15]4)[CH2:10][N:9]([CH3:21])[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: BrB(Br)Br
Reactant: COc1cc2c(cc1Cl)CCN(C)CC2c1ccc2c(c1)CCC2
Solvent: ClCCl
Product: Br
Product: CN1CCc2cc(Cl)c(O)cc2C(c2ccc3c(c2)CCC3)C1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
1.1 g of 8-chloro-7-methoxy-3-methyl-5-(5-indanyl)-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 10 ml of dichloromethane. The solution was cooled to -10° C. and 5 ml of boron tribromide was added. The reaction mixture was stirred while warming up to room temperature. After standing for 4 hours, the volatile components were removed by evaporation in vacuo and the residue was diluted with methanol at -10° C. Stripping with methanol gave 8-chloro-7-hydroxy-3-methyl-5-(5-indanyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 190°-200° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7](=O)[CH3:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:13][C:12]1[C:2]([N:1]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][C:4]2[O:5][CH:6]=[C:7]([CH3:8])[C:10]=2[CH:11]=1
Reactant: BrCCCCCBr
Reactant: CC(=O)COc1ccc(Cl)c(N)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1coc2cc(N3CCCCC3)c(Cl)cc12

Procedure:
A mixture of 9.98 g (50 mmole) of 1-(3-amino-4-chlorophenoxy)-2-propanone, 22.9 g (0.10 mole) of 1,5-dibromopentane, 12.9 g (0.10 mole) of N-ethyldiisopropylamine and 60 ml of ethanol is boiled under reflux for 18 hours. The residue obtained after concentration by evaporation in vacuo is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the crude product is taken up in 250 ml of ethanol, 40 ml of concentrated hydrochloric acid are added and the whole is boiled under reflux for 30 hours. The ethanol is concentrated in a vacuum rotary evaporator and the residue is diluted with ice-water, rendered alkaline with 6N sodium hydroxide solution and extracted with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Chromatography over silica gel using chloroform as eluant yields 5-chloro-3-methyl-6-(piperidin-1-yl)-benzofuran which, after recrystallisation from petroleum ether, melts at 82°-84°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:22][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH3:21])=[N:3][C:2]=1[F:1]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)nc1F
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of 2,3,6-trifluoro-5-nitropyridine (Method 56, 2.0 g, 11.2 mmol) in THF (50 ml) was cooled to 0° C., to which was added (S)-1-(4-fluorophenyl)ethanamine (1.56 g, 11.2 mmol). The reaction was stirred at 0° C. for 30 min., then quenched with water (50 ml) and extracted with DCM (2×75 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (hexanes-DCM=1:1) to give the title compound (2.3 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[NH2:17])=[N:6][CH:7]=1.[CH3:19][S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[NH:17][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([S:20][CH3:19])=[CH:22][C:23]=2[O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][CH2:32]2)=[N:6][CH:7]=1
Reactant: Nc1cc(I)ccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: CSc1ccc(C(=O)Nc2cc(I)ccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 84 %

Procedure:
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-iodo-2-aminobenzamide and 4-methylthio-2-(1-t-butoxycarbonylpiperidin-4-yloxy)benzoic acid gave the title compound as a white solid (3.03 g, 84%).
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:8]2[C:32]([CH3:39])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:31](=[O:40])[NH:30][C:9]=2[N:10]=[C:11]([NH:13]/[N:14]=[C:15](/[C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2Br)\[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:12]=1.CNCCNC>CCOC(C)=O.[Cu]I>[NH2:6][C:7]1[C:8]2[C:32]([CH3:39])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:31](=[O:40])[NH:30][C:9]=2[N:10]=[C:11]([N:13]2[C:23]3[C:22](=[CH:27][C:26]([Cl:28])=[CH:25][CH:24]=3)[C:15]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:14]2)[N:12]=1
Reactant: CC1(c2ccccc2)C(=O)Nc2nc(N/N=C(\CCC(F)(F)F)c3cc(Cl)ccc3Br)nc(N)c21
Agent: [Cu]I
Agent: CNCCNC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)Nc2nc(-n3nc(CCC(F)(F)F)c4cc(Cl)ccc43)nc(N)c21

Procedure:
A DMF (3 mL) solution of the crude intermediate from Step C (77 mg, 0.135 mmol), copper (I) iodide (25.7 mg, 0.135 mmol), and N,N′-dimethylethylenediamine (14.3 mg, 0.162 mmol) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with 10% aqueous NH4OH solution (2×), water (3×), and brine. The organic phase was JO dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC using a water/acetonitrile (with 0.1% TFA) gradient. The isolated material was converted to the free base by suspending in EtOAc, washing with aqueous saturated NaHCO3 solution (2×) and brine. The solution was dried over anhydrous MgSO4, filtered, concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound as a racemic mixture. The enantiomers were separated on a ChiralPak IB column using 7% EtOH/heptane as eluent to give the indicated compound. Data is given for the faster eluting enantiomer. 1H NMR (500 MHz, DMSO-d6): δ (ppm) 11.23 (1H, s), 8.86 (1H, d, J=9.1 Hz), 8.07 (1H, d, J=2.1 Hz), 7.52 (1H, dd, J=9.0, 2.1 Hz), 7.37-7.25 (5H, m), 6.75 (2H, s), 3.30-3.20 (2H, m), 2.88-2.76 (2H, m), 1.79 (3H, s). m/z=487.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)c2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3-Trifluoromethyl-benzoic acid. LC-MS (basic): tR=0.98 min; [M+H]+=520.3.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[CH:14][C:13]1=[O:20].N12CCCN=C1CCCCC2.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.C([O-])(O)=O.[Na+]>CN(C)C=O>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][O:19][C:15]1[CH:16]=[C:17]([CH3:18])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[F:1])[C:6]([O:8][CH3:9])=[O:7])[C:13](=[O:20])[CH:14]=1
Reactant: COC(=O)c1ccc(F)c(-n2c(C)cc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reaction time: 18 h

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 3 (14.4 g, 51.9 mmol) and N,N-dimethyl formamide (40 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (10.9 mL, 72.8 mmol) was added followed by 2,4-difluorobenzyl bromide (9.3 mL, 72.8 mmol). The reaction mixture was stirred at 65 C for 18 h, was poured into saturated aqueous NaHCO3 and was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to give the title product, as an orange oil (21.59), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.20 (dddd, J=2.2, 4.8, 7.2 and 8.8 Hz, 1H), 8.00 (dd, J=2.2 and 7.2 Hz, 1H), 7.56 (td, J=2.4, 6.4 and 9.2 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J=0.8 and 2.6 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 1.98 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.34 (1F), −116.00 (1F), −117.35 (1F) ppm. ES-HRMS m/z 404.1104 (M+H calcd for C21H17F3NO4 requires 404.1104).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])(=O)C.CO.C[O-].[Na+].Cl>O.C(Cl)(Cl)Cl>[C@@H:6]1([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)CCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
1.5 g (3.4 mmol) of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-butyric acid (see Stage 1.1) are taken up in 13 ml f chloroform and, at -10°, 22 ml of methanol containing 17.3 mmol of sodium methoxide (obtained by dissolving 400 mg of sodium) are added thereto. Stirring is carried out for 1 1/2 hours at 0° and for 1 hour at 22°. The mixture is cooled to 0°, 2 ml of water are added and the whole is adjusted to pH 3.0 with 1 molar hydrochloric acid. Concentration is carried out by evaporation in vacuo and the residue is taken up in warm ethanol and the resulting sodium chloride is filtered off. After concentrating the filtrate by evaporation, 4-(β-D-glucopyranosyloxy)butyric acid is obtained.