Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:11]1)=[O:9].[CH3:22][O:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:31][CH:32]=1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH2:25][CH2:24][O:23][CH3:22])[CH:28]=3)=[CH:17][N:16]=2)[CH2:11]1)=[O:9]
Reactant: O=C(Nc1cnccn1)N1CC(Oc2ccc(Br)cn2)C1
Reactant: COCCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: COCCOc1cccc(-c2ccc(OC3CN(C(=O)Nc4cnccn4)C3)nc2)c1
Yield: 58.3 %

Procedure:
This compound was prepared by the method outlined for example 5 step 6. Thus 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyrazin-2-ylamide (100 mg, 0.285 mmol) was reacted with 2-[3-(2-Methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example 5 step 5, 118 mg, 0.855 mmol) to afford title compound (70 mg, 58%) as a colourless powder.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].CS(CCO)(=O)=[O:22].[H-].[Na+]>CN(C=O)C>[OH:22][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(O)c(S(=O)(=O)N2CCOCC2)c1
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
4-Fluoro-3-(morpholine-4-sulfonyl)-benzoic acid (Example 6, 5.36 g, 19 mmol) was dissolved in DMF and commercially available 2-methylsulfonyl ethanol (4.8 g, 39 mmol) was added. After five minutes of stirring, sodium hydride (2.4 g of 60% dispersion in mineral oil, 61 mmol) was added. The solution immediately turned black. After 15 min, the reaction was complete. The DMF solution was partitioned between ethyl acetate (150 mL) and brine/HCl (200 mL). The brine solution was discarded, and this was repeated two additional times. All ethyl acetate was dried with magnesium sulfate, and removed under reduced pressure to provide the title compound as a white solid (4.0 g, 74%): 1HNMR (DMSO-d6) δ8.23 (d, J=2 Hz, 1H), 8.02 (dd , J=9 Hz, 2 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 3.62 (m, 4H), 3.12 (m, 4H); MS (−APCI):[M−H]−286; Anal.Calc. for C11H13NO6S: C, 44.99; H, 4.56; N, 4.88. Found: C, 45.45; H, 4.41; N, 4.74.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]1[S:13][C:14]([C:17]2[CH2:24][S:23][CH:22]3[N:19]([C:20](=[O:33])[CH:21]3[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:18]=2[C:34]([O:36][CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[CH:15][N:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[CH:37]([O:36][C:34]([C:18]1[N:19]2[CH:22]([S:23][CH2:24][C:17]=1[C:14]1[S:13][C:12]([NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)=[N:16][CH:15]=1)[CH:21]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:20]2=[O:33])=[O:35])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4cccnc4)s3)CSC12
Temperature: 3 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
Nicotinoyl chloride hydrochloride (7.12 g) is added to a solution of 3-(2-aminothiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (11.3 g) in tetrahydrofuran (300 cc), cooled to 3° C., and triethylamine (11.12 cc) is then added in the course of 10 minutes. The mixture is stirred for 1 hour at 3° C. and then for 2 hours while allowing the temperature to ri$e to 20° C. The reaction mixture is poured into ethyl acetate (400 cc) and washed with distilled water (3×120 cc) and a saturated solution of sodium chloride (100 cc). The organic phase is dried and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is crystallised from ethyl acetate (20 cc) to give 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-nicotinoylaminothiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (7.4 g) in the form of a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Cl.C(OCC)(=O)C>CCCCCC.C(OCC)(=O)C>[C:7]1([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
53 mg of L-Nα -[(2RS)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine methyl ester was dissolved in 0.8 ml of methanol/water (10/1), and 0.387 ml of a solution of 1N potassium hydroxide in methanol/water (10/1) was added thereto. The mixture was stirred at room temperature for 50 minutes. The mixture was neutralized with 1N hydrochloric acid under cooling with ice, and 20 ml of ethyl acetate was added thereto. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography (chloroform/methanol/acetic acid=15/1/0.15). The fractions containing the desired product were collected, and the organic layer was washed with a 4% sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 49 mg of L-Nα -[(2RS)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:4][CH:3]=1.CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:34][C:35]1[S:36][C:37]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:38]=2[N:39]=1>>[F:44][C:42]1[CH:41]=[CH:40][C:38]2[N:39]=[C:35]([NH:34][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[S:36][C:37]=2[CH:43]=1
Reactant: O=C(O)c1cccnc1Nc1ccc(Cl)cc1
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(F)cc2s1)c1cccnc1Nc1ccc(Cl)cc1
Temperature: 27 °C
Reaction time: 9 h

Procedure:
Compound 13 (185 mg, 1 mmol) and, 4-chloro aniline (17, 128 mg, 1 mmol) was taken in ethylene glycol and refluxed at 160° C. for 5 h. Then the reaction mixture was cooled and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain ethyl 2-(4-chloro anilino) nicotinate (24) as pure product. Ethyl 2-(4-chloro anilino) nicotinate (24, 276 mg, 1 mmol) were refluxed with 2N NaOH in ethanol for 2 h. The reaction mixture was cooled and left acidified with 2N HCl white solids obtained, filtered and washed with water to give pure compound of 2-(4-chlorophenylamino)nicotinic acid (31). To a stirred solution of 2-(4-chlorophenylamino) nicotinic acid (31, 249 mg, 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino 6-fluoro benzothiazole (36, 118 mg, 0.7 mmol) were added Then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (9) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][C:3]2[CH:10]=[CH:11][C:12]3[C:17]([C:2]1=2)=[CH:16][CH:15]=[C:14]([C:18](=[O:21])[CH2:19]Br)[CH:13]=3.[C:22]([O:26][C:27]([N:29]1[C@H:34]([C:35]([OH:37])=[O:36])[C@@H:33]2[CH2:38][C@H:30]1[CH2:31][CH2:32]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C@H:30]12[CH2:38][C@H:33]([CH2:32][CH2:31]1)[C@@H:34]([C:35]([O:37][CH2:19][C:18]([C:14]1[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=1)[C:2]1[S:1][C:5]([C:6](=[O:9])[CH2:7][O:37][C:35]([C@@H:34]4[C@@H:33]5[CH2:38][C@@H:30]([CH2:31][CH2:32]5)[N:29]4[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[O:36])=[CH:4][C:3]=1[CH:10]=[CH:11]3)=[O:21])=[O:36])[N:29]2[C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28]
Reactant: O=C(CBr)c1ccc2c(ccc3cc(C(=O)CBr)sc32)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C(=O)OCC(=O)c1ccc2c(ccc3cc(C(=O)COC(=O)[C@@H]4[C@H]5CC[C@H](C5)N4C(=O)OC(C)(C)C)sc32)c1

Procedure:
was synthesized from 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2-bromoethanone) (10c) and (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (see, e.g., WO 2012/041227) by following an analogous procedure described in Step 5, Example 1. m/z 746.3 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[NH:27]1[CH2:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:27]1([C:23]([C:17]2([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]4)=[CH:16][CH:15]=3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:24])[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(Oc2ccc(C3(C(=O)N4CCC4)CCOCC3)cc2)CC1
Yield: 43.3 %

Procedure:
4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 0.58 mmol), azetidine hydrochloride (81 mg, 0.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol), 1-hydroxybenzotriazole hydrate (97 mg, 0.63 mmol) and triethylamine (210 μL, 1.51 mmol) were stirred in dichloromethane (8 mL) at room temperature for 18 hours. The reaction was diluted with dichloromethane (60 mL) and washed with aqueous sodium bicarbonate. The aqueous were extracted again with dichloromethane. The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.5, by volume) to provide the title compound (97 mg, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 1.11 (d, 6H), 1.77-1.82 (m, 2H), 1.88-1.95 (m, 2H), 2.01-2.08 (m, 4H), 2.26-2.29 (m, 2H), 2.47-2.52 (m, 2H), 2.76-2.86 (m, 3H), 3.66-3.74 (m, 4H), 3.79-3.82 (m, 2H), 3.92-3.96 (m, 2H), 4.40 (m, 1H), 6.95 (d, 2H), 7.22 (d, 2H). HRMS ESI+ m/z 387.2634 [MH]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:15][CH2:16][C:17](=O)[CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:18][C:17]1[CH2:16][CH2:15][C@@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1
Reactant: CCOC(=O)[C@H](CCC(C)=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC(C)=N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-ethyl 2-(tert-butoxycarbonylamino)-5-oxohexanoate in a 1 L flask was treated with a trifluoro acetic acid/dichloromethane solution (1:1 mixture, 100 mL). Effervescence was observed and the mixture was allowed to stir for 4 hours at room temperature. After which time the volatiles were removed in vacuo to yield (S)-ethyl 5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate as an oil, and used directly in the following step.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[O:27][CH:31]=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: c1ccoc1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and furane
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:15]([CH2:14][N:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]1=[O:12])#[N:16]
Reactant: Oc1ncc(C(F)(F)F)cc1Cl
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCn1cc(C(F)(F)F)cc(Cl)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4.0 g (0.02 mole) of 3-chloro-5-(trifluoromethyl)-2-pyridinol, 2.6 g (0.022 mole) of monobromoacetonitrile, and 4.0 g of potassium carbonate in 40 ml of dimethyl sulfoxide was prepared and stirred at ambient temperature for 3 hours. Water was then added and the light brown solid that formed was separated by filtration and dried to obtain 2.3 g (45 percent of theory) of the title compound: melting point, 84°-85° C. This product had infrared and nmr spectra compatible with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[CH:53]=[CH:52][C:8]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=4)=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[C:13]([NH:15][C@H:16]([CH3:24])[C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:37]=[CH:36][C:35]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:42][CH:43]=4)=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[C:13]([NH:15][C@H:16]([CH3:24])[C:17]([OH:19])=[O:18])=[O:14])=[O:10])=[CH:52][CH:53]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)N[C@H](C)C(=O)O)cc3)nc2)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
Prepared using General Procedure 8. To a stirred solution of (R)-tert-butyl 2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate (120 mg, 0.166 mmol) in DCM (4 mL) was added TFA (3 mL) and stirred for 2 h. The reaction mixture was diluted with toluene (15 mL) and solvent removed. DMSO (3 mL) was added and the solution was sonicated. This solution was added to vigorously stirring water (30 mL) and the white solid was isolated by filtration and washed with additional ACN (10 mL). The material was dried under high vacuum for 24 h to afford 75 mg (66%) of (R)-2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoic acid Compound 398 as a white powder. LCMS-ESI (m/z) calculated for C40H48N4O5: 664.4. found 665.0 [M+H]+, tR=12.33 min (Method 10). The chiral purity was calculated at >99% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 9.15 (s, 2H), 8.52 (d, J=8.7 Hz, 1H), 8.45 (d, J=7.4 Hz, 1H), 8.35-8.20 (m, 2H), 7.85-7.68 (m, 4H), 7.56-7.50 (m, 2H), 7.49-7.39 (m, 2H), 7.14-7.03 (m, 2H), 4.93-4.80 (m, 1H), 4.38-4.17 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.22-3.12 (m, 1H), 3.12-3.02 (m, 1H), 1.81-1.67 (m, 2H), 1.53-1.24 (m, 20H), 0.95-0.80 (m, 3H).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.Br[CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.613 mmol, Example 11b) and 4-(bromomethyl)benzoic acid (198 mg, 0.919 mmol) in acetonitrile (6 mL) was added potassium carbonate (254 mg, 1.838 mmol). The reaction mixture was stirred for 3 hours at the 90° C. The reaction mixture was then filtered and evaporated. The crude oil was mixed with 10 mL of 10% acetic acid and 10 mL of ethyl acetate. Layers were separated, and the organic layer was discharged. Aqueous layer was neutralized with 1 M Na2CO3, and the product was extracted into 10 mL of ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 min, and then it was concentrated. The solution was then partioned between 2 ml of water and 5 mL of ethyl acetate. The organic layer was separated and evaporated. The oil was purified on preparatory HPLC (2 to 10% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. To each fraction was added 1 ml of 1 M HCl, and the fractions were evaporated to dryness. 4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (50 mg, 0.118 mmol, 19.33% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.16 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.34 Hz, 2H), 7.30-7.37 (m, 2H), 7.23-7.29 (m, 1H), 7.20 (d, J=7.33 Hz, 2H), 4.44 (br. s., 2H), 3.57 (d, J=11.62 Hz, 2H), 3.07-3.27 (m, 4H), 3.04 (dt, J=3.95, 7.52 Hz, 1H), 2.59 (ddd, J=3.54, 6.57, 10.11 Hz, 1H), 2.12 (d, J=13.89 Hz, 3H), 1.54-1.81 (m, 3H), 1.42 (q, 1H); LC-MS Rt=0.47 min; MS (ESI): 365.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[OH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][C:23]=1[CH2:32][OH:33].[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22](=[O:21])[C:23]([CH2:32][OH:33])=[CH:24]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: OCc1cnc2ccccc2c1O
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cc(CO)c(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C
Yield: 73.6 %

Procedure:
To a suspension of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (344 mg) and 4-hydroxy-3-hydroxymethylquinoline (412 mg) in anhydrous ethanol (2.5 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 439 μL). After heating at 85° C. for 17 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 80%-100% ethyl acetate-hexanes) to give the title compound as a white solid (405 mg), m.p. 183° C.-184° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:16])[CH2:7][CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)C.C1COCC1>O>[CH:10]1([NH:9][CH2:8][CH2:7][C:6]([OH:16])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCNC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCNC1CCCCC1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
22 g of cyclohexylamine were added to 40 mL of ethanol, 10 g of ethyl 3-bromopropionate were added, and the mixture was heated and refluxed for two hours. The reaction system was concentrated under reduced pressure, the resulting residue was extracted with 200 mL of ethyl acetate, the organic layer was desiccated over anhydrous magnesium sulfate, and the product was then filtered and concentrated. The residue was purified by distillation under reduced pressure, and 6.3 g of N-cyclohexylmethyl β-alanine ethyl ester (yield of 57%) were obtained. 1.26 g of sodium hydroxide were dissolved in 200 mL of water, 6.3 g of N-cyclohexyl-β-alanine ethyl ester were added, and THF was added for dissolution. After stirring for one hour, the product was neutralized using Dowex 50WX4-[H+] and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized and 3.2 g of the desired product were obtained (yield of 64%).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:25])([F:24])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:23])[CH2:14][C@@H:15](OS(C)(=O)=O)[CH2:16][CH3:17])=[CH:8][CH:7]=1.O>O1CCCC1>[CH2:16]([C@H:15]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([F:25])([F:24])[F:4])=[CH:7][CH:8]=2)[C:13](=[O:23])[CH2:14]1)[CH3:17]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
31.8 mg (0.589 mmol) of sodium methoxide was suspended in tetrahydrofuran (1 mL) and a tetrahydrofuran solution (1 mL) containing 200 mg (0.589 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide produced in Example 3 was added dropwise thereto at room temperature for 5 minutes. After stirring at room temperature for further 3.5 hours, water (5 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (141.6 mg). The reaction yield of the product was determined by HPLC analysis (column; NACALAI COSMO SEAL 5C18-AR packed column 4.6×250 mm: eluent; acetonitrile/5 mM phosphate buffer solution (pH=3)=1/1: flow rate; 1.0 mL/min: column temperature; 30° C: detector; UV 210 nm) to be 60%.