Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:4]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:31].C([Li])(C)(C)C.C[Si]([N:41]=[C:42]=[O:43])(C)C.CC(O)=O>C1COCC1.C([O-])(O)=O.[Na+].O.CCO>[C:27]([O:26][C@@H:20]([C:4]1[C:3]([CH3:31])=[C:2]([C:42](=[O:43])[NH2:41])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:29])([CH3:30])[CH3:28]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(N)=O)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 23 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A solution of (S)-ethyl 2-(4-bromo-3-methyl-1 (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (200 mg, 0.380 mmol) in dry THF (7.6 mL) was cooled to −78° C. tert-butyllithium (1.7 M in pentane, 446 μL, 0.759 mmol) was added dropwise under N2 over 3 min. 10 min later, trimethylsilylisocyanate (62.0 μL, 0.456 mmol) was quickly added. The reaction was warmed to 23° C. After 1 h, the system was treated with glacial AcOH (87.0 μL, 1.52 mmol) followed by EtOH (absolute, 1.9 mL). The reaction was stirred for 30 min then diluted with saturated NaHCO3 (20 mL) and H2O (10 mL). The system was extracted with DCM (3×15 mL). Combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (75 mg, 40% yield.) 1H NMR (400 MHz, CDCl3) δ 8.10-8.05 (m, 1H), 7.96-7.86 (m, 1H), 7.64-7.58 (m, 2H), 6.19 (s, broad, 1H), 6.06 (s, broad, 1H), 5.75 (s, 1H), 4.30-4.07 (m, 2H), 2.53 (s, 3H), 1.21 (s, 9H), 1.20 (t, J=7.0 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−73.2 (s).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][C:35]([F:39])([F:38])[CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][C:35]([F:38])([F:39])[CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CCC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CCC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Reaction time: 1 h
Yield: 43.3 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (91.4 mg, 135 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo. 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added, and the reaction mixture stirred for 1 h then concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-{5-Difluoromethoxy-1-[3-(3,3-difluoro-pyrrolidin-1-yl)-propyl]-1H-indazol-3-yl}-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (32 mg, 43%). MS (M+H)+=548; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.38 (s, 1H), 8.21 (d, J=2.3 Hz, 2H), 7.88 (s, 2H), 7.86 (s, 1H), 7.36-7.43 (m, 1H), 6.92-7.49 (m, 1H), 4.59 (t, J=6.8 Hz, 2H), 2.84 (t, J=13.6 Hz, 2H), 2.64 (t, J=7.0 Hz, 2H), 2.43 (t, J=6.7 Hz, 1H), 2.15-2.29 (m, 2H), 2.08 (t, J=7.0 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:8][C:7]1[C:2]2[N:1]=[C:20]([CH3:21])[C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:24][CH:23]=3)=[C:17]([CH3:18])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: CC(=O)C(Oc1ccc(Cl)cc1)C(C)=O
Reactant: Nc1cc(O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Oc1ccc(Cl)cc1
Temperature: 125 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (0.36 g), 3-(4-chlorophenoxy)pentane-2,4-dione (0.57 g) and p-toluenesulfonic acid monohydrate (0.020 g) was heated at 125° C. for 3 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) to afford title compound as a brown oil, 0.16 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[NH:20][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of methyl (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinate (D33, 2.5 g, 7.6 mmol), and diisopropylethyl amine (2 ml, 11.4 mmol) in dry DCM (25 ml) at 0° C. was added dropwise benzyl chloroformate (1.3 ml, 9.1 mmol) and the mixture was stirred for 1 h from 0° C. to r.t. The mixture was washed with a 20% solution of citric acid and after with brine. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (85:15) to afford the title compound (3.4 g, 97%) as a white solid; Rt (HPLC) 6.56 min; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.42-7.60 (m, 3H); 7.29-7.42 (m, 3H); 7.15-7.25 (m, 3H); 7.06-7.15 (m, 1H); 6.86-7.03 (m, 3H); 5.10 and 5.15 (s, s, 2H); 4.84-5.04 (m, 3H); 4.48 and 4.55 (m, m, 1H); 3.69 and 3.84 (s, s, 3H); 2.27-2.39 (m, 1H); 2.16-2.27 (m, 1H); 2.03-2.16 (m, 1H); 1.91-2.03 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1)#[N:12].C(=O)(O)[O-].[Na+].NC(N)=S>O.C(COC)OC>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[S:21])[O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:17][CH:18]=1)#[N:12]
Reactant: OCc1cccnc1
Reactant: N#Cc1ccc(N=C=S)cc1
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [H-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(NC(=S)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 3-pyridylcarbinol (2.18 g., 0.02 mole) in 50 ml. of glyme there is added sodium hydride (0.87 g. of a 57% oil dispersion, 0.02 mole). The solution is allowed to stand 2 hrs. and then p-cyanophenyl isothiocyanate (3.2 g., 0.02 mole) in 50 ml. of glyme is added dropwise. The reaction mixture is stirred at room temperature for 18 hrs. It is then saturated with sodium bicarbonate and poured into an excess of water. The resulting suspension is filtered to give a solid residue which is recrystallized from toluene to give 2.3 g. of solid melting at 153°-154° C., with decomposition. The thiourea structure is confirmed by infra-red spectroscopy. The product is obtained in a 43.5% yield.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([NH:7][C@@H:8]([CH2:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=1)=[O:6]>C1COCC1>[I:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][C@H:8]1[NH:7][C:5](=[O:6])[CH2:4][O:18][CH2:17]1
Reactant: O=C(CCl)N[C@@H](CO)Cc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COC[C@@H](Cc2cccc(I)c2)N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH 60% Dispersion in mineral oil (0.93 g, 23.2 mmol) was added portionwise to a 0° C. solution of 2-chloro-N—[(R)-1-hydroxymethyl-2-(3-iodo-phenyl)-ethyl]-acetamide A-9 (3.72 g, 10.5 mmol) in THF (100 mL) under argon and the resulting suspension was warmed to RT and stirred for 1 h. The reaction mixture was cooled back to 0° C. before being quenched with water and concentrated in vacuo. The remaining aqueous phase was extracted with DCM (3×) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 50% to 100% EtOAc in hexane) to give the title compound as a white solid. LC-MS B: tR=0.72 min; [M+H+MeCN]+=359.01; 1H NMR (CDCl3) δH: 7.64 (d, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.18 (m, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.25 (s, 1H), 4.20 (s, 2H), 3.91 (dd, J1=11.7 Hz, J2=3.7 Hz, 1H), 3.76 (m, 1H), 3.60 (dd, J1=11.7 Hz, J2=6.1 Hz, 1H), 2.87 (dd, J1=13.6 Hz, J2=6.0 Hz, 1H), 2.72 (dd, J1=13.6 Hz, J2=8.5 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:26](=[O:29])[NH:27][CH3:28])=[N:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:13][CH:12]=1.[OH-].[Na+].Cl.CCOC(C)=O>CO.O1CCCC1.O>[CH3:28][NH:27][C:26]([C:15]1[C:14]2[C:18](=[CH:19][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:30])=[O:2])=[CH:12][CH:13]=2)[N:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:16]=1)=[O:29]
Reactant: CNC(=O)c1nn(C2CCCCO2)c2cc(Nc3ccccc3C(=O)OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1nn(C2CCCCO2)c2cc(Nc3ccccc3C(=O)O)ccc12
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 2-[3-Methylcarbamoyl-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid methyl ester (0.20 g, 0.49 mmol) in methanol (1.4 mL) and tetrahydrofuran (0.6 mL) was added a solution of sodium hydroxide (59 mg, 1.47 mmol) in water (0.3 mL). The reaction was heated to 60 degrees Celsius for 1 hour and then was cooled to room temperature. The pH was adjusted with 2 N HCl to a pH of 2. EtOAc (30 mL) and water (30 mL) was added and the layers were separated. The aqueous was extracted with EtOAc (3×20 mL) and the organic layers were combined. After washing with water (15 mL), the organic layer was dried over Na2SO4. The solids were filtered away, and the organic was evaporated to yield a yellow solid (193 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1>CCO.C(O)(=O)C.[Fe]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:5]2[C:4]3[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([Br:1])[C:3]=3[CH3:23])[O:8][C:7](=[O:13])[CH:6]=2)=[CH:19][CH:18]=1
Reactant: Cc1cc2oc(=O)cc(-c3ccc([N+](=O)[O-])cc3)c2c(C)c1Br
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2oc(=O)cc(-c3ccc(N)cc3)c2c(C)c1Br
Temperature: 110 °C
Yield: 0.8 %

Procedure:
To a stirred solution of the crude material (22 mg) containing 6-bromo-5,7-dimethyl-4-(4-nitrophenyl)-2H-chromen-2-one (7-2) in EtOH (0.75 mL) and acetic acid (0.15 mL) was added iron (16 mg, 0.29 mmol) at room temperature. The mixture was heated at 110° C. for 2.5 h. The reaction mixture was then cooled at room temperature and filtrated. To the filtrate was added EtOAc and saturated NaHCO3 solution, and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The residues was purified by silica gel column chromatography (hexane:EtOAc=5:1˜2:1) to give the title compound 7-3 (4.0 mg, 0.8% yield, 2 steps) as an orange solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[O:6][C:7]=1[NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)#[N:2].S(=O)(=O)(O)[OH:27]>>[C:1]([C:3]1[N:4]=[C:5]([C:18]2[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=2[F:24])[O:6][C:7]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)(=[O:27])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)O)cc1
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 57 %

Procedure:
A solution of 4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.962 g, 2.819 mmol) in concentrated sulfuric acid (5 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was added to ice water and a precipitate formed. The precipitate was isolated by filtration and the remaining aqueous layer extracted with ethyl acetate. The organic layer was combined with the precipitate and reduced in vacuo to yield 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.580 g, 1.614 mmol, 57%) as a yellow solid. 1H NMR (DMSO) δ 7.35 (2H, t), 7.46 (4H, m), 7.65 (1H, m), 7.87 (2H, d), 9.71 (1H, s), 12.64 (1H, br s). LCMS (2) Rt: 1.37 min; m/z (ES+) 360.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: Oc1ccc(F)cc1Cl
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Cl
Yield: 125.6 %

Procedure:
2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69°-71° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[CH3:9][C:10]([CH3:12])=O.N1CCCCC1>>[C:10](=[C:5]([C:6]#[N:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])([CH3:12])[CH3:9]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)=O
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A mixture of 152 g (1.34 mole) of ethylcyanoacetate (3) in 152 g (2.62 mole) of acetone (2) containing 4 mL of piperidine was stirred at 20-30° C. for 16 hours then heated to reflux for 24 hours. Removing the volatile portion, the residue was distilled at 30-50μ of Hg. The fractions boiling at 56-67° C. were collected to give 169 g (82%) of a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:19])[C@H:6]([OH:7])[CH2:5][C@@H:4]([C@@:8]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:3]1.C(OC([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1)=O)(C)(C)C>>[F:1][C:2]1([F:19])[C@H:6]([OH:7])[CH2:5][C@@H:4]([C@@:8]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([O:11][CH2:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1C[C@@H](O)C(F)(F)C1
Product: O=C(OCC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1C[C@@H](O)C(F)(F)C1

Procedure:
Using (2R)-2-((1R,4R)-3,3-difluoro-4-hydroxycyclopentyl)-2-hydroxy-2-phenylacetic acid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compound was prepared by a method similar to steps 2 and 3 of Referential Example 12.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH2:15][O:16][CH3:17])=[CH:9][C:8]=1[O:18][CH3:19].C[O:21][B:22]([O:25]C)[O:23]C.[Cl-].[NH4+]>O1CCCC1>[CH3:19][O:18][C:8]1[CH:9]=[C:10]([CH2:15][O:16][CH3:17])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[O:21][B:22]([OH:25])[OH:23]
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (2.64M hexane solution; 182 mL) was added dropwise to a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (121.3 g) in tetrahydrofuran (730 mL) at −78° C., and the mixture was stirred for 20 minutes. A solution of trimethoxyborane (61.7 mL) in tetrahydrofuran (20 mL) was then added to the reaction mixture at −78° C. When internal temperature was raised to −10° C., to the reaction mixture was added saturated aqueous ammonium chloride (730 mL), and stirring was continued for 15 minutes. The obtained reaction mixture was extracted with ethyl acetate, the extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (90.4 g) was obtained as a white solid from the n-hexane:ethyl acetate (2:3) fraction.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]3[C:22](=[O:23])[NH:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O>[CH3:30][N:21]1[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[S:18][CH:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)[C:22]1=[O:23]
Reactant: CI
Reactant: O=C1Nc2ccccc2SC1CCCCN1CC=C(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(CCCCN2CC=C(c3ccccc3)CC2)Sc2ccccc21
Temperature: 25 °C
Yield: 32.7 %

Procedure:
1.77 g (=0.004 m) of 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-2H-1,4-benzothiazine-3(4H)one (see Example 10) prepared analogously to Example were dissolved in 20 ml of anhydrous dimethylformamide with stirring. 0.121 g of sodium hydride was added under a nitrogen atmosphere, and the resulting suspension was maintained at room temperature for 10 minutes. 0.70 g of methyl iodide was then added all at once, and the reaction mixture was stirred for 2.5 hours at room temperature. The reaction mixture was worked up by distilling off the solvent, adding 100 ml of water to the residue, and extracting the mixture with 100 ml of ethyl acetate. The organic phase was concentrated by evaporating the solvent, and the crude title compound which remained as a residue was purified by column chromatography. 0.6 g of 4-methyl-2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-2H-1,4-benzothiazine-3(4H)-one was obtained as beige-colored powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1ccccc1
Yield: 39 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (20 mg) with benzoyl chloride (10 uL) provided 10 mg (39%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: C([O:8][C:9](=[O:22])[CH:10]=[CH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[CH2:12][CH2:11][CH2:10][C:9]([OH:22])=[O:8]
Reactant: O=C(C=CCC1Cc2ccccc2C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCCC1Cc2ccccc2C1
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
Dissovled in 120 ml of methanol were 6.45 g (22.1 mmol) of benzyl-4-(indan-2-yl)-2-butenoate, and 0.6 g of 10% palladium-carbon was added to the solution, followed by vigorous stirring for 2.5 hours under a hydrogen atmosphere. The catalyst was separated by filtration, and the filtrate was concentrated to obtain 3.84 g of 4-(indan-2-yl)butanoic acid as a crystal. Yield: 85%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CC(C)=O>[CH:27]1([CH2:26][O:16][C:13]2[CH:14]=[C:15]3[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:8][N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]3=[N:11][CH:12]=2)[CH2:29][CH2:28]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(OCC4CC4)cc23)cn1
Yield: 59.1 %

Procedure:
According to the general procedure using: 27 (60 mg, 0.174 mmol), (bromomethyl)cyclopropane (101 μL, 1.05 mmol), K2CO3 (241 mg, 1.74 mmol) and n-Bu4NI (6.4 mg, 17 μmol) in acetone (4.0 mL) were heated at reflux overnight. Standard workup and purification by PTLC using 5% MeOH in CH2Cl2 gave 28s as a clear oil (41 mg, 59%); 1H NMR (400 MHz, CDCl3) δ-0.066 (s, 9H), 0.38 (q, J=4.68 Hz, 2H), 0.68 (m, 2H), 0.91 (m, 2H), 1.31 (m, 1H), 3.55 (t, J=8.3 Hz, 2H), 3.89 (d, J=7.0 Hz, 2H), 3.98 (s, 3H), 5.64 (s, 2H), 7.36 (s, 1H), 7.51 (d, J=2.6 Hz, 1H), 7.58 (s, 1H), 7.74 (d, J=0.3 Hz, 1H), 8.16 (d, J=2.6 Hz, 1H).
Reaction SMILES: [N:1]#[N:2].C([O:10][C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@H:35]([OH:49])[CH2:36][C@@:37]1([C:46]([NH2:48])=[O:47])[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[CH:17]=[CH:16]2)=[O:12])C1C=CC=CC=1>C(O)(C)C.[Pd]>[N:1]#[N:2].[C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@H:35]([OH:49])[CH2:36][C@@:37]1([C:46]([NH2:48])=[O:47])[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([CH3:43])([CH3:44])[CH3:45])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[CH:17]=[CH:16]2)([OH:12])=[O:10]
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2cc(C(=O)OCc3ccccc3)ccc2c1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CC(C)O
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2cc(C(=O)O)ccc2c1)C(N)=O
Yield: 55.9 %

Procedure:
294 mg of N2 -[3(S)-[[N-[6-(benzyloxycarbonyl)-2-naphthoyl]-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 100 ml of isopropanol was hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 145 mg of N2 -[3(S)-[[N-(6-carboxy-2-naphthoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a white solid from methanol/ethyl acetate; MS: m/e 646 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(OC)c(OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(OC)c(OC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,6-dimethoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.