Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([Cl:3])=[O:22])=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(C(=O)Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (12 ml) and dimethylformamide (1 drop) were added to a solution of 4-benzyloxycarbonylaminomethylbenzoic acid (2.85 g) in dichloromethane (12 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure to give 4-benzyloxycarbonylaminomethylbenzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (5 ml), and the solution was dropwise added to a mixed solution of 4-amino-1H-pyrazolo[3,4-b]pyridine 2 trifluoroacetate (1.09 g) and diisopropylethylamine (1.7 g) in acetonitrile (10 ml)-dimethylformamide (5 ml). The mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and acetonitrile was evaporated under reduced pressure. The residue was extracted with ethyl acetate, dried and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 ml) and sodium methoxide (80 mg) was added, which was followed by stirring at room temperature for 4 hours. After the completion of the reaction, insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue and the mixture was extracted with chloroform:methanol=10:1. The extract was dried and the solvent was evaporated under reduced pressure. The obtained crystals were washed with ethyl acetate to give 540 mg of N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-benzyloxycarbonylaminomethylbenzamide
Reaction SMILES: Cl.[C:2]1([C@H:8]2[C@@H:13]([O:14][CH2:15][C:16]3[C:24]4[O:23][CH:22]=[CH:21][C:20]=4[CH:19]=[C:18]([C:25]4[N:29]([CH3:30])[N:28]=[N:27][CH:26]=4)[CH:17]=3)[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][CH2:32][C:33]#[C:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:31][CH2:32][C:33]#[C:34][CH2:35][N:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([C:25]3[N:29]([CH3:30])[N:28]=[N:27][CH:26]=3)[CH:17]=2)[C@@H:8]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nncc1-c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)c2occc2c1
Reactant: ClCC#CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)c2occc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [2S,3S]-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine hydrochloride (230 mg) in N,N-dimethylformamiide (2 ml) was slowly added to a solution of 1,4-dichlorobut-2-yne (106 ml) and potassium carbonate (224 mg) in N,N-dimethylformamide (2.0 ml). The solution was stirred for 18 hours at room temperature and the solvent removed under reduced pressure. To the residue was added water (40 ml) and the product was extracted with ethyl acetate (3×10 ml). The combined organic fractions were washed with water, saturated brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by MPLC (10% ethyl acetate/hexane) to give [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine as a yellow oil (205 mg). 1H NMR (360 MHz,CDCl3) δ1.57 (2H, m), 2.22 (2H, m), 2.98 (1H, m), 3.27 (2H, d, J=3.0 Hz), 3.43 (1H, br s), 3.62 (1H, br s), 3.95 (3H, s), 4.13 (2H, s), 4.46 (1H, d, J=11.0 Hz), 4.82 (2H, d, J=11.0 Hz), 6.77 (1H, d, J=1.0 Hz), 6.87 (1H, s), 7.15 (3H, m), 7.38 (2H, m), 7.43 (1H, s), 7.62 (2H, br s); MS m/z (CI+) 475 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:24](OC(C)(C)C)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][N:6]1[C:24](=[O:29])[CH2:25][C:26](=[O:27])[CH3:28])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 18) was reacted with tert-butyl acetoacetate to give the title compound as brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][CH3:16])=[O:14])([O-])=O.[BH4-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)n1ncc2c([N+](=O)[O-])cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)n1ncc2c(N)cccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
The product of Example 90A (1.66 g, 7.5 mmol) in ethanol (20 mL) was treated with BiCl3 (8.2 g, 2.6 mmol) followed by the addition of NaBH4 (1.13 g, 30.5 mmol). The reaction mixture was stirred at room temperature for 20 minutes, filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was partitioned between ethyl acetate/dilute NaHCO3 solution. The organic phase was separated, dried over MgSO4, filtered and the filtrate concentrated under reduced pressure to provide the title compound (1.2 g). 1H NMR (300 MHz, DMSO-d6) δ 6.1 (s, 2H), 6.41 (dd, 1H), 7.21 (m, 2H), 8.42 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:10])[C:6]2[C:8]([CH:9]=1)=[N:19][C:18]1[C:17](=[CH:16][CH:15]=[CH:14][C:13]=1[O:12][CH3:11])[N:7]=2
Reactant: COc1ccc(N)c(C)c1
Reactant: COc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc(C)c2nc3cccc(OC)c3nc2c1
Temperature: 25 °C

Procedure:
A mechanically stirred mixture of 66.0 ml (0.51 mol) of freshly distilled 4-methoxy-2-methylaniline, 50.5 ml (0.41 mol) of freshly distilled o-nitroanisole, 189 g (3.37 mol) of finely powdered potassium hydroxide, and 945 ml of toluene was heated to reflux (initially exothermic) for 1 hour. The mixture was then cooled to room temperature, filtered, and the filter cake washed with toluene, 1% methanol/dichloromethane, and dichloromethane. The solvent from the combined filtrate and washings was removed in vacuo to yield 86 g of black solid. The black material was then flash filtered through silica gel eluting with ether and the fractions containing the desired phenazine (Rf =0.22 on silica gel, dichloromethane) were combined, concentrated in vacuo and purified by flash chromatography, eluting with dichloromethane. A final chromatography on a Waters Prep-500 chromatograph (6:1 hexane-acetone) followed by recrystallization from a hexane/toluene mixture afforded 12.3 g of the title compound as yellow needles, melting point 201°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:15]([OH:17])=[O:16])[CH2:8][C:7]2=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C.O>[CH2:24]([O:16][C:15]([CH:9]1[CH2:8][C:7]2[C:6]3[C:14](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[NH:13][C:12]=2[CH2:11][CH2:10]1)=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C1CCc2[nH]c3c(Cl)cccc3c2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)C1CCc2[nH]c3c(Cl)cccc3c2C1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A stirred mixture of crude 8-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (4.45 g, 17.8 mmol) and cesium carbonate (2.90 g, 8.92 mmol) in ethanol (150 ml) and water (25 ml) is refluxed until a clear solution is obtained (15 min). Then the solvents are evaporated and the dried residue is dissolved in dry DMF. This solution is treated with benzylbromide (2.27 ml, 18.7 mmol) and stirred at 45° C. for 15 min. The resulting precipitate is filtered off and the filtrate is concentrated. The residue is purified by flash chromatography on silica gel (heptane/EtOAc 3:1) to deliver pure title compound as a yellowish solid (4.2 g) in 69% yield. tR (LC-5) 1.09 min; ESI-MS (positive ion): m/z 340.19 [M+H]+ (calcd 339.82 for C20H18NO2Cl). 1H-NMR (DMSO-d6): 1.90 (m, 1H); 2.19 (m, 1H); 2.86 (m, 5H); 5.13 (s, 2H); 6.91 (t, J=7.6 Hz, 1H); 7.04 (d, J=7.6 Hz, 1H); 7.32 (m, 6H); 11.0 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[F:26][CH:27]1[CH2:33][CH:32]2[NH:34][CH:28]1[CH2:29][O:30][CH2:31]2>>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:34]2[CH:28]3[CH:27]([F:26])[CH2:33][CH:32]2[CH2:31][O:30][CH2:29]3)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: FC1CC2COCC1N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2C3COCC2C(F)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in analogy to compound 1a in Example 1 starting from compound C and compound 6-fluoro-3-oxa-8-azabicyclo[3.2.1]octane 51a. Preparation of 6-fluoro-3-oxa-8-azabicyclo[3.2.1]octane 51a:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O.[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of tert-butyl (4-bromopyridin-2-yl)carbamate (1.5 g), cesium carbonate (2.7 g) and DMF (15 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mL). The reaction mixture was stirred at room temperature for 15 hr, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.0 g).
Reaction SMILES: C1([C@@H]([NH:9][C@@H:10]([CH3:22])[CH2:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])C)C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[C+4].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[NH2:9][C@@H:10]([CH3:22])[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cccc(C[C@H](C)N[C@@H](C)c2ccccc2)c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [C+4]
Solvent: CCO
Product: COC(=O)c1cccc(C[C@H](C)N)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 280 mg of methyl 3-[(2S)-2-{[(1S)-1-phenylethyl]amino}propyl]benzoate in 6.8 ml of ethanol were added 30 mg of 20% palladium-carbon hydroxide (wet) and 320 mg of ammonium formate, followed by stirring at 80° C. for 4 hours. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation, followed by drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 180 mg of methyl 3-[(2S)-2-aminopropyl]benzoate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:19].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.CNC>CN(C=O)C.O>[CH3:17][N:18]([CH3:19])[C:10]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11]
Reactant: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
2-(tert-butoxycarbonylamino)-2-ethylbutanoic acid ((200 mg, 0.87 mmol), HATU (CAN 148893-10-1, 660 mg, 1.74 mmol) and triethylamine (CAN 121-44-8, 260 mg, 2.61 mmol) was added to a solution of dimethylamine hydrochloride (CAN 506-59-2, 117 mg, 1.74 mmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. The mixture was added to water (20 mL) and extracted with ethyl acetate (30 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (eluting with 30% ethyl acetate in petroleum ether) to give the product (120 mg, 53.7%); MS (EI): m/e=259.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.OC1C=C(C(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Cl)cc1)c1cccc(O)c1
Agent: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Product: O=C1CC(c2ccc(Cl)cc2)c2ccc(O)cc21
Reaction time: 96 h
Yield: 48 %

Procedure:
The procedure of Step 2 of Example 1 was repeated except for using (E)-3-(4-chlorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one obtained in Step 1 as a starting material instead of (E)-1-(3-hydroxyphenyl)-3-phenylprop-2-en-1-one and being stirred for 4 d to obtain the title compound (48%).
Reaction SMILES: Cl[C:2]([F:18])([F:17])[C:3](Cl)([F:15])[CH2:4][CH:5]([Cl:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CC(O)C.[Zn]>[Cl:14][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:3]([F:15])=[C:2]([F:17])[F:18]
Reactant: CCCCCCCCC(Cl)CC(F)(Cl)C(F)(F)Cl
Agent: [Zn]
Solvent: CC(C)O
Product: CCCCCCCCC(Cl)CC(F)=C(F)F
Temperature: 100 °C
Yield: 51.9 %

Procedure:
A stirred suspension of 2.1 grams (0.033 mole) of zinc dust in 100 ml of 1-methylethanol is heated to 100° C. and a solution of 10.0 grams (0.030 mole) of 1,2,4-trichloro-1,1,2-trifluorododecane in 50 ml of 1-methylethanol is added dropwise. Upon completion of addition, the reaction mixture is heated at 100° C. for 60 hours. The reaction mixture is cooled to ambient temperature and filtered. The filtrate is concentrated under reduced pressure to a residual oil. The oil is fractionally distilled under reduced pressure through a Vigreux column. The appropriate fractions are combined to yield 4.0 grams of 4-chloro-1,1,2-trifluoro-1-dodecene; b.p. 70°-73° C./0.5mm. The nmr spectrum is consistent with the proposed structure.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42]>>[OH:42][CH2:41][CH:40]([NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:28])=[O:29])=[CH:38][CH:37]=1)[CH2:43][OH:44]
Reactant: NC(CO)CO
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: O=C(NC(CO)CO)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 66.3 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 40 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 604 [M+H]+.
Reaction SMILES: C(O[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=3[CH3:36])[CH:20]=[C:21]([C:26](=[O:28])[CH:27]=2)[C:22]([O:24]C)=[O:23])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[CH3:37]O>[C].[Pd]>[CH3:9][N:11]([CH3:37])[CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=3[CH3:36])[CH:20]=[C:21]([C:26](=[O:28])[CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:14][CH2:13]1
Reactant: CO
Reactant: COC(=O)c1cn(-c2ccc(O)cc2C)c(C2CCC(NC(=O)OCc3ccccc3)CC2)cc1=O
Agent: [Pd]
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCC(N(C)C)CC1

Procedure:
In 15 ml of methanol was dissolved 0.2 g of methyl 6-(4-benzyloxycarbonylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate, and 0.05 g of 5% by weight palladium carbon was added to the resulting solution, and the above ester was hydrogenated under atmospheric pressure for 1.5 hours. Then, the catalyst was removed by filtration, and the solvent was removed by distillation under reduced pressure. To the residue was added 0.4 g of 37% by weight formalin and 0.1 g of formic acid, and they were reacted at 100° C. for 7.5 hours. After completion of this reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (3:1 by volume) mixture) to obtain 0.04 g of 6-(4-dimethylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 207°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](N3CCN(CCCS(C)(=O)=O)CC3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:57]1([CH2:63][C:64]([NH2:66])=[O:65])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>>[C:46]([NH:45][S:42]([C:40]1[C:39]([Cl:50])=[CH:38][C:37]([O:51][CH2:52][CH3:53])=[C:36]([C:10]2[N:11]([C:21]([N:60]3[CH2:61][CH2:62][N:57]([CH2:63][C:64]([NH2:66])=[O:65])[CH2:58][CH2:59]3)=[O:22])[C@@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[C@@:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:54])[N:9]=2)[CH:41]=1)(=[O:43])=[O:44])([CH3:47])([CH3:48])[CH3:49]
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% of 1:1 acetonitrile/ethanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H44N6O5SCl3 [(M+H)+] 777.2154, observed 777.2146.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[NH:20][CH:21]=[CH:22][C:10]=12.[H-].[Na+].Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31].O>CN(C)C=O.CCOC(C)=O>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[CH:22][C:10]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1N[C@H]1CCCC[C@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1N[C@H]1CCCC[C@H]1C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3.8 g) in N,N-dimethylformamide (76 mL) was added 60% sodium hydride (580 mg) at 4° C. The mixture was stirred at the same temperature for 1 hour. To the mixture was added [2-(chloromethoxy)ethyl](trimethyl)silane (2.55 mL) and the solution was stirred at ambient temperature for 1 hour. To the solution was added water and EtOAc. The mixture was extracted with EtOAc and washed with brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane (1:3 to 1:1) to give ethyl 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5.4 g) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:9][CH:10]=1)=[O:4].O1CCCC1.[OH-].[Li+].[NH4+].[Cl-]>O>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:7]2[C:8]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cnc2OCC(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
In a 25 mL round-bottomed flask, the above prepared 2-(2,2,2-trifluoro-ethoxy)-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-5,1′-dicarboxylic acid 1′-tert-butyl ester 5-methyl ester (1.266 g, 2.42 mmol, Eq: 1.00) was combined with tetrahydrofuran (7 mL) and water (3.5 mL) to give a colorless solution. Lithium hydroxide (145 mg, 6.05 mmol, Eq: 2.5) was added and the reaction mixture was stirred at 40° C. for 3 h when TLC indicated the absence of starting material. Work up: 10 mL H2O and 10 mL sat NH4Cl were added and the reaction mixture was extracted with AcOEt (2×50 ml). The organic layers were washed with H2O/NaCl solution, combined, dried over Na2SO4 and concentrated in vacuo. Crystallization from EtOAc and heptane afforded 800 mg of the title compound as white solid; MS (EI) 403.6 (M−H)−.