Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[C:28]=2[CH:27]=[CH:26]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:25]1[C:33]2[C:28](=[C:29]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 120 °C
Yield: 19 %

Procedure:
A mixture of 2-chloro-6-(4-methyl-piperazin-1-yl methyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (72) (100 mg, 0.27 mmol), indole-4-boronic acid (1.1 eq., 48 mg), sodium hydrogen carbonate (3 eq., 69 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 eq., 10 mg) in toluene (2.5 mL), ethanol (1.5 mL) and water (0.7 mL) was flushed with argon and heated under microwave irradiation at 120° C. for 1 hour. The reaction mixture was partitioned between dichloromethane and water, organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography to yield the title compound 61 (23 mg, 19%).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:3].[CH2:14](I)[CH3:15]>>[CH2:14]([C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([OH:3])[C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH3:15]
Reactant: CCI
Reactant: CCOC(=O)CC(O)C(=O)OCC
Product: CCOC(=O)CC(O)(CC)C(=O)OCC
Yield: 84 %

Procedure:
Diethyl malate was alkylated with ethyl iodide by following the alkylation method described by Example 12A to provide in 84% yield diethyl ethylmalate as an oil. The product was obtained as a mixture (87:13) of the diastereoisomers represented by the formulas ##STR93##
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:13]=1[C:14]([NH2:16])=[O:15].Cl>CN(C=O)C>[CH2:1]([O:8][C:17]1[CH:18]=[CH:19][CH:20]=[C:12]([F:11])[C:13]=1[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1c(F)cccc1F
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (24 ml, 0.229 mol) is added portionwise to a suspension of sodium hydride (9.16 g, 0.229 mol) in DMF (300 ml) and stirred at room temperature for 1 h. 2,6-Difluorobenzamide (30 g, 0.190 mol) is added in one portion and stirring is continued overnight at room temperature. The reaction mixture is poured into 1N HCl (1.5 l) and extracted with dichloromethane. The extract is washed with water and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (39.6 g, 85%); MS for C14H12FNO2 m/z 246 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([O:43][CH3:44])[CH:34]=1)=[O:32]>O>[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=[CH:17][C:12]=3[N:11]([S:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]([O:30][CH3:29])=[O:32])=[CH:34][C:35]=3[O:43][CH3:44])(=[O:41])=[O:40])[C:10]2=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: COCCOc1ccc2[nH]c(=O)n(C3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
0.095 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 0.7 g of 3-cyclohexyl-1,3-dihydro-5-(2-methoxyethoxy)-2H-benzimidazol-2-one and 50 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for two hours at RT. The reaction mixture is poured into a mixture of water and ice, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 0.8 g of the expected product, which is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl([F:20])(=O)(=O)=O.O>CCCCCC>[F:20][C:9]1[S:8][C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:10]=1
Reactant: Cc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Cc1cccc2cc(F)sc12

Procedure:
To a solution of 7 g of 7-methylbenzo[b]thiophene in abs. tetryhydrofuran are added dropwise at -78°, 30 ml of a 1.6M solution of n-butyllithium in hexane. After 20 minutes 5.5 g of perchloryl fluoride are introduced whereby the reaction temperature is maintained below -60°. After 30 minutes at -78° the temperature is slowly raised to 0°. The mixture is then mixed with water and the organic phase separated, washed, dried and concentrated under vacuum. The residue is chromatographed (eluant: n-hexane) to obtain the title compound as an oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][CH2:12][O:13]C(C)=O.[C:17]([C:20]1[C:21]([NH:28][C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)(=O)[CH3:18]>C1COCC1>[CH3:18][C:17]1[C:20]2[CH:25]=[N:24][C:23]([S:26][CH3:27])=[N:22][C:21]=2[N:28]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[C:12](=[O:13])[CH:11]=1
Reactant: CCOC(C)=O
Reactant: CSc1ncc(C(C)=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc2c(C)cc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
LiHMDS (1.0 M in THF, 27.3 mL, 27.3 mmol) was added to THF (100 mL) at −78° C. and treated with EtOAc (2.50 mL, 25.6 mmol) and stirred 15 min. tert-Butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (53) (3.19 g, 8.52 mmol) was added in one portion at −78° C. and the solution warmed to RT and stirred for 3 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc (150 mL), washed with brine and dried over MgSO4, filtered and concentrated. Purification of the crude residue on silica gel column (10-90% EtOAc in hexanes) afforded the title compound (54) (2.49 g, 6.25 mmol, 73% yield) as a light yellow amorphous solid. m/z (ESI, +ve ion) 398.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (1H, s), 7.46 (1H, br. s.), 7.42 (1H, t, J=8.0 Hz), 7.31 (1H, dd, J=8.2, 1.4 Hz), 6.87-6.94 (1H, m), 6.50-6.59 (2H, m), 2.50 (3H, d, J=1.0 Hz), 2.17 (3H, s), 1.50 (9H, s).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:7]1=[NH:19].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C1(OC)C=CC=CC=1.O>[N+:16]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH2:19])=[N:6][CH:15]=[CH:14]2)([O-:18])=[O:17]
Reactant: COc1ccc(Cn2ccc3cc([N+](=O)[O-])ccc3c2=N)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nccc2cc([N+](=O)[O-])ccc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a solution of Intermediate 1B (11.9 g, 35 mmol) in anisole (24 mL) was added TFA (24 mL). The reaction mixture was stirred at 90° C. for 6 h and the solvent was removed under reduced pressure. The residue was suspended in MeOH (50 mL) and then treated with NaHCO3 (3.3 g, 39 mmol) in water (200 mL). The mixture was stirred at rt for 15 min and the pH was checked to be 9-10. The precipitate was collected by filtration and washed with water to afford Intermediate 1C (6.0 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J=5.7 Hz, 1H), 7.36 (s, 2H), 7.95 (d, J=5.7 Hz, 1H), 8.15 (dd, J=9.2, 2.6 Hz, 1H), 8.43 (d, J=9.2 Hz, 1H), 8.67 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].F[C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1>O1CCCC1>[CH2:1]([NH:5][C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: NS(=O)(=O)c1ncccc1F
Solvent: C1CCOC1
Product: CCCCNc1cccnc1S(N)(=O)=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
49.6 ml of n-butylamine are added to a mixture of 8.81 g of 3-fluoropyridin-2-ylsulfonamide in 10 ml of tetrahydrofuran (THF). After the reaction mixture has been stirred for 18 hours at a temperature of 60° C., the reaction mixture is evaporated, the oily residue is triturated with 100 ml of ice/water, the mixture is filtered, and the filtrate is washed first with a little cold water and subsequently with n-hexane. After drying at a temperature of 45° C. in vacuo, 8.8 g of 3-n-butylaminopyridin-2-ylsulfonamide (intermediate No. 2.001) of a melting point of 100°-101° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:4]([F:27])[CH:3]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(N)cc3F)cc2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl 7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E274, Step 2) (250 mg, 0.67 mmol) in dichloromethane (10 ml) was added triethylamine (0.19 ml, 1.34 mmol) and acetyl chloride (50 μL, 0.74 ml) and the reaction stirred at room temperature for 16 hours. The reaction was then diluted with dichloromethane and washed with a 3N aqueous solution of citric acid, then saturated sodium bicarbonate then water and the dichloromethane dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:1) to afford the title compound. MS (ES+) m/e 413 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9](OCC)(OCC)(OCC)[CH3:10].[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)(=O)C>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[N:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH3:10]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1ccccc1N
Reactant: NC1CCCCC1
Solvent: CC(=O)O
Product: CC(=NC1CCCCC1)Nc1ccccc1C
Temperature: 120 °C
Yield: 27.6 %

Procedure:
Glacial acetic acid (catalytic amount, 5 drops) was added to a mixture of o-toluidine (1.07 g, 10 mmol) and triethyl orthoacetate (1.94 g, 12 mmol) and was heated at 120° C. for 60 min. The reflux condenser was replaced by a distillation condenser and the low volatiles were distilled off at 74°-76° C. (head temperature). The undistilled residue was dried under manifold vacuum to give a light yellow liquid. Now cyclohexyl amine (0.99 g, 10 mmol) followed by catalytic amount (0.1 ml) of glacial acetic acid was added and the resulting suspension was heated on oil bath at 140° C. for 12 hr. The reflux condenser was replaced by a distillation condenser and the low volatiles including unreacted cyclohexyl amine were removed under manifold vacuum (0.5 mm Hg). After it cooled to room temperature, dichloromethane (30 ml) was added and then it was washed with dil. sodium bicarbonate solution. The organic phase was dried over Na2SO4, filtered and concentrated to give an off-white solid. It was crystallized twice from 95 EtOH-H2O to give the title compound (0.636 g, 24%) as bright white needles. Mp 130-31° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8](C(C)=C)[C:7]1=[O:18].Cl>C(O)C.O.ClCCl>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:18]
Reactant: C=C(C)n1c(=O)n(CCC(=O)OC)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: COC(=O)CCn1c(=O)[nH]c2ccccc21
Temperature: 60 °C
Yield: 86.4 %

Procedure:
To a stirred solution of 3-(3-Isopropenyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (4.8 g, 18.4 mmol) in ethanol (30 ml) and water (30 ml) was added 37% hydrochloric acid (24 ml). The resulting solution was warmed to 60° C. for twenty minutes and cooled. The reaction was diluted with dichloromethane and water. The layers were separated and the organic phase was dried (Na2SO4), filtered and concentrated to give 3.5 g (86%) of the desired product as an oil which solidified on standing. Used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@@H:11]([CH2:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14].Cl[C:19]1[C:20]2[S:36][C:35]([NH2:37])=[N:34][C:21]=2[N:22]=[C:23]([S:25][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])[N:24]=1.O>CN1C(=O)CCC1>[NH2:37][C:35]1[S:36][C:20]2[C:19]([NH:10][CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][OH:17])=[N:24][C:23]([S:25][C@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])=[N:22][C:21]=2[N:34]=1
Reactant: CC(C)C[C@@H](N)CO
Reactant: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)CC(CO)Nc1nc(S[C@@H](C)c2ccccc2)nc2nc(N)sc12
Temperature: 120 °C
Yield: 55.1 %

Procedure:
DIPEA (400 mg, 3 mmol) and D-leucinol (400 mg, 3.4 mmol) were added to 7-chloro-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (300 mg, 0.9 mmol) in NMP (6 mL) and the mixture was heated to 120° C. for 24 h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4), evaporated and the residue was purified by flash column chromatography (EtOAc) to give the title compound (200 mg, 54% yield).
Reaction SMILES: [CH:1]1([C@@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26]C(=O)[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.[OH-].[Li+]>O>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:10][CH2:11][C@@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]3)[C:14]=2[C:30]([F:32])([F:33])[F:31])[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@@H](C5CCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](C4CCCC4)CC3)ccc2c1
Temperature: 80 °C
Yield: 72.6 %

Procedure:
(R)-4-[6-(cis-4-Cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol) was dissolved in ethanol (2.2 g, 0.049 mol) and treated with 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol). The mixture was then heated to 80° C. overnight. The reaction was then cooled to room temperature and diluted with water. Solid formed. Solid was removed via filtration and dried on the filter for 4 hours to give 158 mg the desired product as a white solid (58%). ESI-MS: 419 (M-16)+. 1H NMR (400 MHz, MeOD) δ=8.64-8.50 (m, 1 H), 8.17-7.98 (m, 2 H), 7.98-7.87 (m, 1 H), 7.73-7.62 (m, 1 H), 7.50-7.40 (m, 1 H), 4.21-4.09 (m, 2 H), 3.80-3.58 (m, 2 H), 2.12-1.96 (m, 2 H), 1.85-1.42 (m, 18 H), 1.21-1.05 (m, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:46]=[CH:45][C:12]([O:13][CH2:14][C@@H:15]([OH:44])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:43]=[CH:42][C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].[CH2:49]([OH:51])[CH3:50]>[Pd]>[CH2:34]([NH:33][C:31]([N:28]1[CH2:27][CH2:26][CH:25]([N:24]([C:49](=[O:51])[CH3:50])[C:23]2[CH:42]=[CH:43][C:20]([CH2:19][CH2:18][NH:17][CH2:16][C@H:15]([OH:44])[CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:46][CH:45]=3)=[CH:21][CH:22]=2)[CH2:30][CH2:29]1)=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)cc3)cc2)CC1
Reactant: [H][H]
Reactant: CCO
Agent: [Pd]
Product: CCCCCCCCNC(=O)N1CCC(N(C(C)=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Temperature: 25 °C

Procedure:
4-{4-[2-({(2S)-3-[4-(Benzyloxy)phenoxy]-2-hydroxypropyl}amino)-ethyl]anilino}-N-octyl-1-piperidinecarboxamide (0.1 g, 0.15 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.1 g) added. The mixture was shaken on a Parr apparatus overnight under 50 psi hydrogen. The mixture was cooled to ambient temperature, filtered through a Celite pad, and the solvent removed in vacuo to yield the title compound (eluant: 5:1 chloroform-methanol) (0.033 g, 0.05 mmol)
Reaction SMILES: C(OC(CNC1C=C(OC)C=CC=1[C@@H]1CCC2C=C(OC(=O)C(C)(C)C)C=CC=2C1)=O)C.C(OC(CC1C=CC(C(O)=O)=CC=1)=O)C1C=CC=CC=1.C([O:60][C:61]([CH2:63][C:64]1[CH:103]=[CH:102][C:67]([C:68]([CH2:70][CH2:71][O:72][C:73]([CH2:75][NH:76][C:77]2[CH:82]=[C:81]([O:83][CH3:84])[CH:80]=[CH:79][C:78]=2[C@@H:85]2[CH2:94][CH2:93][C:92]3[CH:91]=[C:90]([O:95][C:96](=[O:101])[C:97]([CH3:100])([CH3:99])[CH3:98])[CH:89]=[CH:88][C:87]=3[CH2:86]2)=[O:74])=[O:69])=[CH:66][CH:65]=1)=[O:62])C1C=CC=CC=1>CO.[Pd]>[C:61]([CH2:63][C:64]1[CH:65]=[CH:66][C:67]([C:68]([CH2:70][CH2:71][O:72][C:73]([CH2:75][NH:76][C:77]2[CH:82]=[C:81]([O:83][CH3:84])[CH:80]=[CH:79][C:78]=2[C@@H:85]2[CH2:94][CH2:93][C:92]3[CH:91]=[C:90]([O:95][C:96](=[O:101])[C:97]([CH3:98])([CH3:100])[CH3:99])[CH:89]=[CH:88][C:87]=3[CH2:86]2)=[O:74])=[O:69])=[CH:102][CH:103]=1)([OH:62])=[O:60]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)OCCC(=O)c2ccc(CC(=O)OCc3ccccc3)cc2)c1
Agent: [Pd]
Agent: CCOC(=O)CNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: O=C(Cc1ccc(C(=O)O)cc1)OCc1ccccc1
Solvent: CO
Product: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)OCCC(=O)c2ccc(CC(=O)O)cc2)c1
Yield: 97.7 %

Procedure:
From pivalic acid (R)-6-[2-(ethoxycarbonylmethylamino)-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (150 mg) and 4-benzyloxycarbonylmethylbenzoic acid (138 mg), according to an analogous synthetic method to Preparation Example 154, obtained was pivalic acid (R)-6-{2-[(4-benzyloxycarbonylmethylbenzoyl)ethoxycarbonylmethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (200 mg). A solution thereof in methanol (5 ml) was subjected to a catalytic reduction in the presence of 10% palladium-activated charcoal (40 mg) for 2 hours at room temperature under hydrogen atmosphere at ambient pressure. After filtration through celite pad, the solution was concentrated in vacuo to provide the title compound (170 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19](O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].[C:34]1([CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:40]([S:41]([NH:44][C:19]([CH:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:20])(=[O:43])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NS(=O)(=O)Cc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
To a solution of 700 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, 351 mg of 1-phenylmethanesulfonamide, and 334 mg of DMAP in 10.5 ml of DMF was added 525 mg of WSC/hydrochloride, followed by stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were then added thereto for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added thereto, and the precipitated solid was collected by filtration to obtain 33 mg of (3RS,4RS)—N-(benzylsulfonyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[N:21]([C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)[C@H](CCCCN)N(C(=O)OC(C)(C)C)C(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and N,-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=119-121° C.). The reaction was monitored by tlc (Rf=0.46 in 90:10:1 CH2Cl2MeOHNH4OH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[CH3:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH-].[Na+]>CN(C=O)C>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[C:14]([CH3:13])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1c(F)cc([N+](=O)[O-])cc1F
Yield: 76.9 %

Procedure:
A solution of commercially available 3,4,5-trifluoro-nitrobenzene (25b) (5.0 mL, 42.8 mmol), diethyl methylmalonate (6.1 mL, 35.7 mmol), and sodium hydroxide (1.54 g, 38.5 mmol) in DMF (55 mL) was allowed to react in the same manner as in (a) in Production Example 1. The crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (10:1) solution to give 9.1 g (63%) of compound (26b) of interest as clear brown oil.