Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:4].[O-]CC.[Na+].C(O)C.O=[C:20]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C([BH3-])#N.[Na+]>CCOCC.C(O)C>[CH2:24]([O:23][C:21]([C@@H:20]([NH:2][C@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:4])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:22])[CH3:25]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of L-alanine, t-butyl ester, hydrochloride (4.86 g., 26.7 mmole) in 35 ml. of absolute ethanol, there is added 4.2 ml. (6.72 mmole) of 1.6 N sodium ethoxide/ethanol. To the resulting milky solution which is approximately pH 7.5, is added a solution of ethyl 2-oxo-4-phenylbutyrate [prepared by treating ethyl 2-hydroxy-4-phenylbutyrate with oxalyl chloride] (27.6 g.,0.135 mmole) in 25 ml. of ethanol followed by 22 g. of powdered 3A° molecular sieves. The resulting mixture is stirred at room temperature and during the next 30 minutes a total of 4.8 ml. (7.68 mmole) of 1.6 N sodium ethoxide/ethanol is added to maintain a pH of between 6 and 7. After stirring for an additional 30 minutes, a solution of sodium cyanoborohydride (3.35 g., 53.5 mmole) in 20 ml. of ethanol is added over a period of six hours. After stirring for 40 hours, the mixture is filtered through celite and then evaporated at reduced pressure. The residue is dissolved in 350 ml. of ether and the resulting solution is washed with water (3×100 ml.) and then extracted with 1N hydrochloric acid (3×100 ml.). The hydrochloric acid extracts are combined and washed with ether and basified with 4N sodium hydroxide (70 ml.) followed by 1N sodium bicarbonate. The resulting mixture is extracted with ether (2×350 ml.). The ether fractions are combined, washed with water and brine, and dried (MgSO4). The solvent is removed at reduced pressure to give crude product as a mixture of diastereomers Rf =0.46 (undesired isomer) and 0.36 (desired isomer), silica gel, petroleum ether: ether, 1:1). The crude material is then filtered through a column of silica gel (petroleum ether:ether, 3:1). Chromatography (silica gel, hexane:ethyl acetate, 92:8) yields N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine, t-butyl ester as a colorless oil. Rf =0.36 (silica gel, petroleum ether:ether, 1:1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32]>CN(C=O)C>[OH:32][CH2:31][CH2:30][CH2:29][C:28]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:34])[CH3:33]
Reactant: CC(C)(N)CCCO
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCCO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) was suspended in DMF (3 mL). Mukaiyama Reagent (CAN 878-23-9, 233.8 mg, 0.85 mmol), DIEA (0.31 mL, 2.24 mmol) and 4-amino-4-methyl-pentan-1-ol (CAN 85054-53-1, 101.33 mg, 0.64 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xterra-RP18, 10 μ, 19×250 mm/acetonitrile/10 mM ammonium acetate in water) to give the desired product (100 mg, 70.26%) as colorless sticky liquid; LC-MS (UV peak area, ESI) 96.12%, 334.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([O:28][Si](C)(C)C(C)(C)C(C)C)[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[OH-].[Na+].Cl.[C:52](=[NH:57])(OCC)[CH3:53].Cl>>[OH:28][C:27]1[C:12]2[CH2:11][S:10][CH2:9][C@@H:8]([C:6]3[O:5][N:4]=[C:3]([CH2:2][NH:1][C:52](=[NH:57])[CH3:53])[N:7]=3)[NH:21][C:20](=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]=2[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=1
Reactant: CCOC(C)=N
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=S)N[C@H](c1nc(CN)no1)CSC2
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=S)N[C@H](c1nc(CNC(C)=N)no1)CSC2
Reaction time: 3 h
Yield: 24 %

Procedure:
The pH of a suspension of 20 mg of the product of Example 130 in 3 ml of 0.05M pH7 sodium phosphate buffer was adjusted to 8.5 by the addition of 0.1N sodium hydroxide. Over 3 h, 74 mg of ethyl acetimidate hydrochloride were added in small portions, the pH of the reaction mixture being maintained at 8.5. The mixture was set to pH 7 by addition of 1N hydrochloric acid and then extracted with ethyl acetate. The aqueous phase was concentrated in vacuo and chromatographed on MCI-Gel CHP20P (Mitsubishi Chemical Industries, Ltd.) using at first 1% aqueous acetic acid and then mixtures of 1% aqueous acetic acid with acetonitrile (10:1 to 2:1, v/v). The product-containing fractions were lyophilized to yield 4 mg of (4R)-N-[5-(16-hydroxy-14-methoxy-13-methyl-12-oxo -6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-4-yl)-1,2,4-oxadiazol-3-ylmethyl]-acetimidamide hydroacetate.
Reaction SMILES: [CH3:1][S:2](F)(=[O:4])=[O:3].[NH:6]([CH2:9][CH3:10])[CH2:7][CH3:8]>>[CH3:1][S:2]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)F
Reactant: CCNCC
Product: CCN(CC)S(C)(=O)=O
Yield: 96.5 %

Procedure:
Chem. Abstracts 56:7116f, abstracting Sokolsku et al., Izvest. Akad Nauk S.S.S.R., Otdel Khem Nauk 1606 (1968), describes the reaction of CH3SO2F with (C2H5)2NH after one day to give 96.5% CH3SO2N(C2H5)2.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].Cl.[CH3:21][C:22]1[C:23]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[CH3:21][C:22]1[C:23]([N:29]2[CH2:30][CH2:31][N:32]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])([CH3:8])[CH3:9])=[CH:18][CH:17]=3)=[O:16])[CH2:33][CH2:34]2)=[N:24][CH:25]=[C:26]([CH3:28])[N:27]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)n1
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(C(C)(C)N4CCCS4(=O)=O)cc3)CC2)c(C)n1
Yield: 53.9 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (100 mg) described in Preparation Example 39 and (3,5-dimethylpyrazin-2-yl)piperazine hydrochloride (81 mg) described in Preparation Example 104 and by the reaction and treatment in the same manner as in Example 86, the title compound (87 mg) was obtained.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[CH2:20][C:21]([OH:23])=O)([O-])=O.[OH-].[Na+]>C(O)C>[NH2:17][C:15]1[CH:16]=[C:11]2[C:12]([CH2:20][C:21](=[O:23])[NH:8]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C2
Temperature: 90 °C
Yield: 101.3 %

Procedure:
Tin chloride dihydrate (225 g) was added to a solution of 2,4-dinitrophenylacetic acid (22.6 g) in ethanol (450mL). The mixture was heated at 90° C. for 10 hours. The reaction mixture was cooled and basified to pH 11 with 12M sodium hydroxide. The solids were removed by filtration and the filtrate was concentrated. The residue was treated with ethanol (300 mL). The insolubles were filtered and washed with ethanol (5×60 mL). The combined ethanol washes were evaporated and dried under vacuum to give 15 g of 6-amino-2-oxindole as a brown powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Nc1nccs1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
3-Cyano-4-fluorobenzenesulfonyl chloride (10 g, 45.53 mmol) was added portion wise to a solution of 2-aminothiazole (5 g, 50.13 mmol) in dichloromethane (50 mL) and pyridine (18.4 mL, 228 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 1 hour a precipitate was observed. The mixture was stirred for 18 hours at room temperature. The mixture was sonicated for 2.5 hours until the solid had dissolved, then left to stir at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and azeotropically dried with toluene (2×100 mL). The residue was diluted carefully with a 1M aqueous solution of hydrogen chloride and stirred for 1 hour at room temperature whereupon a precipitate formed. The brown solid was collected by filtration and triturated with dichloromethane to afford the title compound as a brown solid (7.8 g, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](OB(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: COc1cccc(OB(O)O)c1
Reactant: COc1ccc2cc(Br)cnc2c1
Product: COc1cccc(-c2cnc3cc(OC)ccc3c2)c1
Reaction time: 4.5 h
Yield: 76 %

Procedure:
The compound is prepared by the reaction of 3-bromo-7-methoxyquinoline (255 mg, 1.07 mmol, 1.06 eq) and 3-methoxyphenylboric acid (154 mg, 1.01 mmol, 1 eq) according to method A in 4.5 h. Purification by column chromatography with a mixture of hexane/ethyl acetate 9/1 yields the desired product in a yield of 76% (215 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([O:19]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:14]=1)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:12](=[O:30])[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc2ccccn2c1C(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc2ccccn2c1C(=O)c1ccc(O)cc1

Procedure:
In a 20-liter flask, a suspension of 1050 g (2.5 mols) of 2-ethyl-3-(4-tosyloxy-benzoyl)-indolizine in a solution of 420 g (10.5 mols) of sodium hydroxide dissolved in 8 l of ethanol and 4 l of water was refluxed for 6 hours. At the end of the reaction, the mixture was cooled, diluted with 2.5 l of water, neutralized with hydrochloric acid and the desired product was allowed to crystallize while being stirred. The product was then suction-filtered and dried under vacuum in a drying-oven maintained at 70° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=O)OC(C)(C)C)[CH2:10][CH2:9]2)[CH2:3]1.Cl.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][C:28]([C:34]([CH:36]1[CH2:38][CH2:37]1)=[O:35])=C2Cl.C([O-])([O-])=O.[K+].[K+].C(N(CC)C(C)C)(C)C>C1COCC1.O1CCOCC1.O>[Br:23][C:24]1[CH:33]=[C:32]2[C:31](=[CH:26][CH:25]=1)[N:30]=[CH:29][C:28]([C:34]([CH:36]1[CH2:38][CH2:37]1)=[O:35])=[C:15]2[NH:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([CH2:7][N:4]2[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN2CC[C@@H](F)C2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CC[C@@H](F)C2)CC1)C1CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl (trans-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclohexyl)carbamate (265 mg, 0.88 mmol) in THF (6 mL) was added aqueous 6N HCl (6 mL) and water (6 mL) and the reaction mixture was heated at 65° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with satd. aq. sodium bicarbonate (50 mL) and 1 M aqueous sodium hydroxide (50 mL) and extracted with a mixture of CHCl3/isopropanol (3:1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford a white semisolid. The residue was dissolved in dioxane followed by the addition of (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (225 mg, 0.724 mmol), K2CO3 (415 mg, 3.0 mmol), and N,N-diisopropylethylamine (0.39 mL, 3.0 mmol) and the resultant suspension was heated at 80° C. for 16 h. The reaction was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (180 mg, 52%) as an off-white solid. ESI MS m/z 474 [C24H29BrFN3O+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([CH3:13])[CH:11]=[O:12])=[CH:5][CH:4]=1.[CH2:14]([Mg]Br)[CH3:15]>C(OCC)C>[OH:12][CH:11]([CH2:14][CH3:15])[C:10]([CH3:13])=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(C=C(C)C=O)cc1
Solvent: CCOCC
Product: CCC(O)C(C)=Cc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-methoxyphenyl)-2-methylpropenaldehyde (10.3 g, 0.058 mol) in dried diethyl ether (150 ml) cooled to −15° C. and stirred under an atmosphere of nitrogen was added a solution of ethylmagnesium bromide in diethylether (3M, 21.4 ml). The reaction mixture was allowed to warm to room temperature and after ½ hour poured onto ice cold aqueous hydrochloric acid (2M, 50 ml). The organic phase was separated, washed with water, a saturated solution of sodium bicarbonate and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to give 3-hydroxy-1-(4-methoxyphenyl)-2-methylpent-1-ene as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:24][C:21]2[CH:20]=[CH:19][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:9])[CH3:8])[CH:13]=3)=[CH:23][CH:22]=2)[S:26]1
Reactant: CCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C
Reactant: O=C1CSC(=O)N1
Product: CCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 91.2 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 1.35 g (4 mmol) of tert-butyl ethyl(4′-formylbiphenyl-3-ylmethyl)carbamate with 470 mg (4 mmol) of 2,4-thiazolidine dione, 1.6 g (92%) of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl.C(N(CC)CC)C.O>[CH:32]1([C:35]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 60.2 %

Procedure:
To a suspension of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (500 mg, 1.2 mmol) in DCM (5 mL) and triethylamine (1 mL) was added cyclopropanecarbonyl chloride (377 mg, 3.6 mmol) at 0° C. slowly. The mixture was warmed up to rt and stirred for 4.5 hours, then diluted with DCM (10 mL) and water (10 mL). The organic phase was separated and concentrated in vacuo. The residue was dissolved in MeOH (30 mL), and saturated solution of Na2CO3 (30 mL). The resulted mixture was stirred at rt for 2 hours, then filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as an off-white solid (350 mg, 60%).
Reaction SMILES: [CH2:1]([C@H:8]1[C:12](=[O:13])[O:11][C@@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:9]1[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:34](Br)[CH:35]=[CH2:36].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:36]([C@:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12](=[O:13])[O:11][C@@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:9]1[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH:35]=[CH2:34]
Reactant: C=CCOC(=O)N1[C@H](C(C)(C)C)OC(=O)[C@@H]1Cc1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1[C@H](C(C)(C)C)OC(=O)[C@]1(CC=C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.16 g of allyl (2S,4S)-4-benzyl-2-tert-butyl-5-oxooxazolidine-3-carboxylate in 20 ml of tetrahydrofuran are cooled in a dry ice bath to −65° C. under argon, and 20.9 ml of a 0.5 molar solution of potassium bistrimethylsilylamide in toluene are added dropwise, and the mixture is stirred at this temperature for 30 minutes. Then 0.861 ml of allyl bromide are added dropwise, and the mixture is stirred while gradually warming to room temperature. After being left to stand overnight, 15 ml of saturated ammonium chloride solution were added, and the product was extracted with ethyl acetate. Washing of the ethyl acetate solution with saturated brine was followed by evaporation in vacuo and purification of the product by column chromatography (silica gel, mobile phase: ethyl acetate:heptane=5:45).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:10].[CH2:20]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:20]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:18][CH3:19])[CH3:10])=[CH:16][CH:15]=2)=[O:34])=[CH:36][CH:37]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC[C@H](C)CCCCCOC(C)c1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(C)OCCCCC[C@@H](C)CC)cc2)cc1

Procedure:
The procedure of Example 26 was followed except for use of (+)-4-(1-(6-(S)-methyloctyloxy)ethyl)phenol in place of (+)-4-(1-methoxyethyl)phenol and 4-octyloxybenzoic acid chloride in place of 4'-octyloxy-4-biphenylcarboxylic acid chloride to obtain (+)-4-(1-(6(S)-methyloctyloxy)ethyl)phenyl 4-octyloxy-benzoate. [α]D20 =+44.0° (c=1, CHCl3)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9]1>>[OH:13][C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1ccccn1
Reactant: O=C1CCCC1
Product: OC1(c2ccccn2)CCCC1

Procedure:
Prepared from 2-bromopyridine and cyclopentanone by the method described in Example 10.
Reaction SMILES: C(OC([N:8]([CH2:26][C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][CH:39]=3)[CH:33]=2)[O:28]1)[CH2:9][C@@H:10]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[O:11][SiH2]C(C)(C)C(C)(C)C)=O)(C)(C)C.[Li+].[OH-].CO.P(=O)(O)(O)O>O1CCCC1>[OH:11][C@H:10]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][NH:8][CH2:26][C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)[CH:33]=2)[O:28]1
Reactant: COC(=O)c1ccc(Cc2ccc3c(c2)CC[C@H](CN(C[C@H](O[SiH2]C(C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
To a solution of 77.2 mg (0.11 mmol) methyl 4-[((2R)-2-{[(tert-butoxycarbonyl)((2R)-2-(3-pyridinyl)-2-{[(1,1,2,2-tetramethylpropyl)silyl]oxy}ethyl)amino]-methyl}-3,4-dihydro-2H-chromen-6-yl)methyl]benzoate (Example 167) in 1 mL of tetrahydrofuran was added 0.54 mL of 1M LiOH and 0.27 mL methanol. The mixture was stirred at room temperature for 3 hours after which point 0.5 mL of 1N phosphoric acid was added to the solution. The mixture was partitioned between ethyl acetate (3×5 mL) and water (5 mL). The organic layer was washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated. To the residue was added 0.4 mL of hydrochloric acid in dioxane. This solution was stirred at room temperature for 0.5 hour. The solution was then washed with water and concentrated in vacuo, followed by purification by preparative HPLC (gradient of 100:0 0.1% TFA/H2O:acetonitrile to 30:70 0.1% TFA/H2O:acetonitrile) to obtain 16.4 mg of product as the TFA salt. MH+419.3. 1H NMR (DMSO d6, δ): 8.89 (br. s, 1H), 8.63 (s, 1H), 8.57 (d, 1H), 7.88 (dt, 1H), 7.85 (s, 1H), 7.82 (s, 1H), 7.50 (dd, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 6.96 (m, 2H), 6.73 (d, 1H), 6.38 (br. s, 1H), 5.08 (m, 1H), 4.38 (m, 1H), 2.76 (m, 1H), 2.71 (m, 1H), 1.99 (m, 1H), 1.67 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][N:24]([C:34]2[C:43]([F:44])=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][C:35]=2[F:45])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:25][N:24]([C:34]2[C:43]([F:44])=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=2[F:45])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C(=O)O)cc2F)CCC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To 122 mg of methyl 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-3,5-difluorobenzoate were added 2.0 mL of THF, 2.0 mL of methanol, and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 115 mg of 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-3,5-difluorobenzoic acid as a pale yellow oily substance. ESI+: 601