Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[CH2:12](O)[CH3:13]>C(O)(=O)C>[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCO
Reactant: CC1CCNCC1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1CNCCC1C

Procedure:
Hydrogen chloride gas was bubbled into a solution of 4-methylpiperidine-3-carboxylic acid (6.0 g, 41.90 mmol) in ethanol (150 mL) and acetic acid (30 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was heated at reflux for 48 h, then was cooled and was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 4-methylpiperidine-3-carboxylate (5.0 g). The material was used without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH3:10])=[O:7]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 89.5 %

Procedure:
The title compound (D32) (70 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D14) (50 mg, 0.18 mmol) and 3-(trifluoromethyl)benzyl bromide (0.055 ml, 0.36 mmol). (Na2CO3: 2.5 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[C:20]([CH3:28])[CH:19]=3)[C:9]=2[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[C:20]([CH3:28])[CH:19]=3)[C:9]=2[CH3:29])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2c(C(=O)O)sc(-c3ccc(Cl)cc3)c2C)ccc1S(N)(=O)=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Ethyl 5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylate (41c, 0.6 g, 1.33 mmol) was suspended in ethanol (20 ml) and a solution of sodiumhydroxide (0.1 g, 2.66 mmol) in water (2 ml] was added to it at 25° C. The reaction mixture was then heated at 75° C. under stirring for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was then diluted with water (5 ml) and the mixture was cooled using ice bath. To the cooled mixture was added 10% aqueous HCl to bring the pH of the mixture between about 5 and 6. The mixture was then extracted with ethyl acetate (2×35 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (0.53 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:22][C@@H:23]1[CH2:27][N:26]([C:19](=[O:20])[CH2:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[O:10][C:11]=3[CH:17]=2)[C@H:25]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:24]1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1C(=O)Cc1ccc2nc(Nc3ccccc3C)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 167.5 %

Procedure:
In DMF (5 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (357 mg, 1.26 mmol), methyl 5-((2S,4S)-4-fluoro-2-pyrrolidinylmethoxy)pentanoate (295 mg, 1.26 mmol), EDC•HCl (362 mg, 1.89 mmol), HOBt (255 mg, 1.89 mmol) and triethylamine (0.88 ml, 6.30 mmol) was stirred at room temperature for 1 hour. The reaction mixture was poured in ice water (50 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 70 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (1.05 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(OCC)C>[Cl:1][CH2:2][C:3]([O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: OC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CCl)OC1CCCCC1
Yield: 98 %

Procedure:
Chloroacetyl chloride (40 mL, 500 mmol) was added dropwise to a solution of cyclohexanol (52 mL, 500 mmol) and triethylamine (77 mL, 550 mmol) in diethyl ether cooled to below 5° C. Upon completion of the addition, the mixture was filtered to remove triethylamine hydrochloride. The filtrate was washed twice with 1M HCl and twice with brine, and was then dried over MgSO4, filtered and evaporated to afford cyclohexyl chloroacetate (86.5 g, 490 mmol, 98%) as a colorless liquid, bp 100° C./5 mm. The chloroacetate (79.5 g, 450 mmol) was added dropwise to a suspension of sodium azide (36.6 g, 563 mmol) in dimethylformamide (60 mL) maintained below 20° C. The mixture was stirred at room temperature overnight, and then was poured into water (200 mL), and the solution was extracted with ether (4×200 mL). The combined organic extracts were washed with brine, then dried, filtered and evaporated to yield cyclohexyl azidoacetate (78.4 g, 428 mmol, 95%) as a colorless liquid, b.p. 85°-90° C. (0.1 mm). Catalytic reduction of the azide with hydrogen over 10% palladium on carbon in ethanol afforded cyclohexyl glycinate, treatment of which with dry HCl afforded glycine cyclohexyl ester HCl, m.p. 144°-145° C., in quantitative yield after crystallization from diethyl ether.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][CH:11]1[CH2:16][O:15][CH2:14][CH:13]([CH3:17])[NH:12]1>>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[CH:13]([CH3:17])[CH2:14][O:15][CH2:16][CH:11]2[CH3:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1COCC(C)N1
Product: CC1COCC(C)N1c1nc(Cl)nc(Cl)n1
Yield: 35 %

Procedure:
The title compound was prepared by following the procedure of Example 462 step 3 using cyanuric chloride and 3,5-dimethylmorpholine. Yield 5 g, 35% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1)[CH3:2].[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:18]>O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1)[CH3:2].[Ag:18]
Reactant: [Ag+]
Agent: CCc1ccc2[nH]nnc2c1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [Ag]
Reaction time: 0.08 h

Procedure:
The mixture thus obtained was stirred for 5 minutes, and then mixed with a solution of 4.2 g of 5-ethylbenzotriazole and 1.2 g of sodium hydroxide in 150 ml of water and a solution of 5 g of silver nitrate in 150 ml of water simultaneously over 6 minutes, to prepare an emulsion.
Reaction SMILES: [N:1]1([C:7]2[CH2:8][CH2:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)(=O)C.C(Cl)Cl>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH2:8][CH2:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCNCC1)CC2
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(CN2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
(Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 125 mg, 0.510 mmol) was added to 6-(piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.365 mmol) and 4-fluorobenzaldehyde (63 mg, 0.510 mmol) in 10% acetic acid in DCM (2.2 mL). The resulting mixture was stirred at ambient temperature for 16 hours, then the resin removed by filtration and the solvents evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[4-(4-fluorobenzyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (85 mg, 61%) as a solid. 1H NMR (399.9 MHz, DMSO-d6) δ 2.44 (4H, m), 2.88 (2H, t), 3.13 (2H, t), 3.52 (6H, m), 7.16 (2H, m), 7.36 (2H, m); m/z=383 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:26]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:28]2)=[CH:25][C:9]2[N:10]([CH3:24])[C:11]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH2:21][NH2:22])[C:15]=3[Cl:23])=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO>[Cl:23][C:15]1[C:16]([CH2:21][NH2:22])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[NH:13][C:11]1[N:10]([CH3:24])[C:9]2[CH:25]=[C:26]([N:27]3[CH2:32][CH2:31][CH:30]([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:28]3)[C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[N:12]=1
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CN)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[aminomethyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid ethyl ester (5.83 g, 10 mmol), 50% aq NaOH-solution (25 ml) and MeOH (100 ml) is stirred for 2.5 h at rt. The mixture is concentrated and slowly added to ice-cooled 12 M aq HCl (39.5 mL). Then aq NaHCO3 solution is added (to pH 8) and the resulting precipitate is collected by filtration and dried.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[C:5]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[C:7](=[O:19])[C:6]=12.C(O)C.C(O)(=O)C.CCCCCC>Cl.[Zn].C(Cl)(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[C:7](=[O:19])[C:6]=12
Reactant: CCCCC(CC)CN1C(=O)c2c(Br)sc(Br)c2C1=O
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCC(CC)CN1C(=O)c2csc(Br)c2C1=O

Procedure:
1,3-Dibromo-5-(2-ethylhexyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (2.6 g, 5 mmol) was placed in a three neck round-bottom flask equipped with a water condenser with ethanol (35 mL), acetic acid (10 mL) and three drops of 1 M HCl. The mixture was heated until the starting material was fully dissolved. At this point, zinc (310 mg, 5 mmol) was added in one portion. Mixture was refluxed for one hour after which an aliquot was taken for GC analysis and NMR, indicating reaction completion. After cooling, the solution was filtered through fitted glass to eliminate remaining Zn particles and solvent was evaporated under vacuum. Product was obtained by silica chromatography (1.1 g, 52%), using a 100% hexane to 100% CHCl3 gradient.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1.Cl>C(O)(C)C>[F:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[N:7][C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)=[N:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(Nc2ncc(F)c(Nc3ccccc3C(=O)NC(C)C)n2)cc1
Temperature: 95 °C
Yield: 77.4 %

Procedure:
To the solution of 2-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (1.0 g, 3.25 mmol) in isopropanol (30 mL) was added ethyl 4-aminobenzoate (0.59 g, 3.57 mmol, 1.1 eq) followed 0.2 mL of 12N HCl. The reaction mixture was sealed in vessel and heated in a 95° C. oil bath for 16 h. The reaction was cooled to room temperature then white solid was precipitated. The white solid was collected by filtration and washed with cooled isopropyl alcohol (3×5 mL) to give the titled compound (1.1 g, 77% yield). MS: M(C23H23FN5O3)=437.47, (M+H)+=438
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:13][CH2:14][C:15]3[NH:22][C:20](=[O:21])[C:19]4[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccccc1NC(=O)CCCl
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(CCn2cnc(-c3ccccc3)c2)nc2ccccc12
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A solution of 4-phenyl-1H-imidazole (500 mg, 3.47 mmol), 2-(3-chloropropanamido)benzamide (1.17 g, 5.21 mmol) and K2CO3 (717 mg, 5.20 mmol) in DMF (50 mL) was stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting product was washed with EtOAc and filtered to give the desired product (60 mg). LC-MS: m/z 317 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[O:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]2=[O:20]>C(O)(=O)C.[C].[Pd]>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[O:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]2=[O:20]
Reactant: COC(=O)c1cc(=O)c2cc(OC)cc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc(=O)c2cc(OC)cc(N)c2o1
Yield: 86.9 %

Procedure:
In 50 ml of acetic acid was dissolved 2.98 g (10.67 mmol) of 6-methoxy-2-methoxycarbonyl-8-nitrochromone, and the mixture was stirred at room temperature for 1.5 hour in the presence of 1.0 g of 5% palladium carbon while bubbling hydrogen gas thereinto. After completion of the reaction, the inorganic substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of chloroform, and washed with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was concentrated under reduced pressure to obtain 2.31 g (yield: 87%) of 8-amino-6-methoxy-2-methoxycarbonylchromone as brown crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:1][CH2:2][CH2:3][OH:4])=[CH:9][CH:8]=1
Reactant: NCCO
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNCCO)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 1 L round bottom flask is charged with 2-aminoethanol (29 g, 213 mmol), 4-methoxybenzaldehyde (39 g, 639 mmol), methanol (250 mL) and acetic acid (75 mL) under a nitrogen atmosphere. The contents were cooled to 0° C. and sodium triacetoxyborohydride (50 g, 234 mmol) was added over a 20 minute period. The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and partitioned between water (500 mL) and ethyl acetate (500 mL). The ethyl acetate layer was washed with 3N HCl (400 mL). The HCl layer is separated, cooled to 0° C., made basic using 6N NaOH and extracted with dichloromethane (2×100 mL). The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound a as an oil (20 g). 1H-NMR of the oil was consistent with the desired structure.
Reaction SMILES: C1(C(N2C3C(=CC(S(N)(=O)=O)=CC=3)CC2)=O)CCCCC1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[Cl:45])[C:39](Cl)=[O:40]>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[Cl:45])[C:39]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:40]
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)c1ccc(Cl)c(Cl)c1
Yield: 36.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 195 mg, 0.98 mmol) and 3,4-dichlorobenzoyl chloride (412 mg, 1.97 mmol) were converted to the title compound (132 mg, 36%) after purification using preparative HPLC. 1H NMR (DMSO-d6) δ 7.92 (d, J=1.1 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.71-7.61 (m, 3H), 7.26 (s, 2H), 4.07 (t, J=8.3 Hz, 2H), 3.16 (t, J=8.2 Hz, 2H); MS(ESI+) m/z 370.8 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:24])[C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:24])[C@@H:18]([OH:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CC(=O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a stirred solution of 2(S)-t-Butyloxycarbonylamino-1-cyclohexyl-3(R)-hydroxy-6-methylheptan-4-one (200 mg, 0.586 mmol) in THF (10 mL) was added NaBH4 (22 mg, 0.586 mmol). After 2 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The organic phase was washed (brine), dried (MgSO4), filtered and evaporated. The residue was recrystallized from methylcyclohexane to give 76 mg (38%) of the desired product. M.p. 130°-131° C. The mother liquor was chromatographed (silica gel, ether/hexane) to afford 43 mg (21%) more.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[OH:6][C@@:7]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:38]([NH:40][CH3:41])=[O:39])[CH:34]=2)[CH:29]=1)([C:14]1[N:15]=[CH:16][N:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=1)[CH2:8][C:9](OCC)=[O:10].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.O.C(OCC)(=O)C>[OH:6][C@@:7]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C:38]([NH:40][CH3:41])=[O:39])[CH:32]=[CH:31]2)([C:14]1[N:15]=[CH:16][N:17]([S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH:18]=1)[CH2:8][CH2:9][OH:10]
Reactant: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(S(=O)(=O)c2ccccc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(S(=O)(=O)c4ccccc4)cn3)ccc2c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of anhydrous calcium chloride (0.84 g, 7.4 mmol) in ethanol (9 mL) was added sodium borohydride (0.57 g, 14.8 mmol) at −15° C., and the mixture was stirred at −10° C. for 30 min. To the reaction mixture was added dropwise a solution of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-phenylsulfonyl-1H-imidazol-4-yl)propanoate (1.5 g, 3.0 mmol) in tetrahydrofuran (75 mL)/ethanol (15 mL) at −10° C. The obtained reaction mixture was stirred at 5° C. for 8 hr, and to the obtained reaction mixture were added dropwise water (12 mL), 1 mol/L hydrochloric acid (15 mL) and ethyl acetate (30 mL) at 10° C. or below, and the mixture was stirred. To the separated organic layer was added 0.2 mol/L hydrochloric acid (15 mL) at 5° C., and the mixture was stirred. The reaction mixture was adjusted to pH 7.5 with 0.5 mol/L aqueous sodium hydroxide solution at 5° C. To the separated organic layer was added again 0.2 mol/L hydrochloric acid (15 mL) at 5° C., and the mixture was stirred. The reaction mixture was adjusted to pH 7.5 with 0.5 mol/L aqueous sodium hydroxide solution at 5° C. To the separated organic layer was added water (15 mL), and the mixture was adjusted to pH 9.5 with 0.5 mol/L aqueous sodium hydroxide solution. The separated organic layer was washed with 10 w/v % brine (15 mL). To the separated organic layer was added water (18 mL), and the mixture was heated to 60° C., and stirred for 3 hr. The separated organic layer was concentrated under reduced pressure to give 6-[(1S)-1,3-dihydroxy-1-(1-phenylsulfonyl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (1.2 g, 2.5 mmol). yield 83%. enantiomeric excess: 62% ee.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
(R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (5.0 g, 26.7 mmol) and Et3N (8.0 g, 80.2 mmol) were dissolved in dichloromethane (50 mL). The mixture was stirred at 0° C. for 30 minutes, then methanesulfonyl chloride (4.5 g, 40.1 mmol) was added dropwise. It was stirred at room temperature for 2 h and concentrated under reduced pressure. DCM (50 mL) and water (50 mL) were added. The organic phase was washed with saturated NaHCO3 (30 mL) and H2O (2×30 mL), and concentrated to afford the title compound as oil (6 g, 100%).
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+]>CO>[C:29]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[O:10])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1.7 Grams of ethyl 3-(2-{(3,3,3-triphenylpropanoyl)amino}-acetylamino)propionate was dissolved in a mixed liquid consisting of 70 ml of tetrahydrofuran and 20 ml of methanol. To the solution 5.0 ml of 4N aqueous sodium hydroxide solution was added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was distilled off under reduced pressure, and the residue was rendered acidic by addition of 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated saline solution and dried over anhydrous magnesium sulfate. Upon distilling the solvent off under reduced pressure, 1.10 g of the title compound was obtained.