Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH:24]([OH:33])[C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[CH2:22][C@@H:21]([OH:34])[CH2:20]1)=[O:18])[CH:14]=[CH2:15].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH:24]([OH:33])[C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[CH2:22][C@@H:21]([O:34][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:20]1)=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(O)c1csc2cncn12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(O)c1csc2cncn12
Reaction time: 0.5 h

Procedure:
Triethylamine (0.25 ml) and 0.12 ml of methanesulfonyl chloride are successively added to a solution of 457 mg of crude (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (stereoisomer A) in 12 ml of dry THF in an argon atmosphere at 3° C., and the mixture is stirred in this state for 30 min. A 5% aqueous sodium hydrogencarbonate solution (30 ml) is added thereto, and the mixture is extracted with 100 ml of ethyl acetate. The organic layer is washed with saturated saline, dried over magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a slightly cloudy orange brown oil. This oil is purified by flash column chromatography on silica gel (ethyl acetate:methanol=92:8) to give 344 mg of crude (3R,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]-3-methanesulfonyloxypyrrolidine (stereoisomer A) as a milky white amorphous material.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:31]([Cl:33])=[O:32].O>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:31]([Cl:33])=[O:32])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccccc3C(=O)Cl)CC2)cc1
Temperature: 0 °C

Procedure:
Solution prepared by dissolving 47.2 g of (2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)benzene in 500 ml of methylene chloride was cooled down to 0° C., and 34.7 g of aluminum chloride was added thereto and stirred. Oxalyl chloride in an amount of 33 g was added dropwise little by little thereto, it was raised up to room temperature, and stirred for 2 hours. After finishing of the reaction, it was added to 500 ml of water and extracted with 500 ml of methylene chloride. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 33.2 g of (2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)benzoyl chloride.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[CH:19]1[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.O>CCCCCC.C1(C)C=CC=CC=1>[F:28][C:27]([F:29])([F:30])[C:21]1[CH:20]=[CH:19][C:24]([CH:25]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]3=[CH:9][C:8]=2[CH3:18])[OH:26])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c(nc1C(O)c1ccc(C(F)(F)F)cc1)CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 ml) in toluene (20 ml) at -20° C., under nitrogen, was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyridine (6.0 g, 0.025 m) in toluen (30 ml). The reaction mixture was kept at -20° C. for 0.25 hours and then blown over into a solution of a,a,a-tri-fluoro-p-tolualdehyde (4.7 g) in toluene (30 ml) at -20° C. The solution was allowed to warm up to room temperature and water added. The organic phase was separated with 2N hydrochloric acid. This was basified with solid potassium carbonate and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and evaporated. The residue was recrystallised from n-hexane to give the title compound, (5.05 g) m.p. 131°-3° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[Br:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[C:13]([Br:18])[CH:12]=1.N1C(C)=CC(C)=CC=1C.[H][H].N>C(OCC)(=O)C.O>[Br:10][C:11]1[CH:16]=[C:15]([CH:14]=[C:13]([Br:18])[CH:12]=1)[O:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccnc1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: [H][H]
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: Brc1cc(Br)cc(Oc2cccnc2)c1
Yield: 34.8 %

Procedure:
Sodium hydride (3.24 g of a 60% dispersion in mineral oil) was added portionwise to a stirred mixture of 3-hydroxypyridine (15.4 g), 1,3,5-tribromobenzene (76.4 g), cuprous oxide (11.6 g) and collidine (400 ml). When evolution of hydrogen had ceased, the mixture was heated at 200° for 8 hours and then cooled. The cool mixture was diluted with ethyl acetate and water, basified with aqueous ammonia (SG 0.880) and then filtered. The filtered residue was washed with ethyl acetate, then the washings and organic phase of the filtrate combined, washed with saturated brine and dried (MgSO4). The ethyl acetate was evaporated under vacuum, the collidine removed by distillation under vacuum and the residue chromatographed on silica gel using ether:hexane (1:4) as eluent. The earlier fractions gave, after evaporation under vacuum, recovered tribromobenzene (42.5 g). The later fractions were evaporated under vacuum to afford the title compound as an oil (18.55 g); δ (CDCl3): 7.07(2H,s), 7.22-7.26(2H,m), 7.42(1H,s), 8.42(1H,s), 8.47(1H,d). Found: C, 40.49; H, 2.17; N, 4.19. C11H7Br2NO requires C, 40.16; H, 2.14; N, 4.26%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.O>CN(C=O)C.C(OCC)(=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[CH3:3])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.4 %

Procedure:
Sodium hydride (4.87 g, 122.0 mmol, 60% dispersion in oil) was added to a solution of 2-methylimidazole (10 g, 122.0 mmol) in DMF (100 ml) and stirred at room temperature for 0.25 h. 1-fluoro-4-nitrobenzene (17.18 g, 122.0 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. Water (150 ml) and ethyl acetate (250 ml) were added, the aqueous separated and extracted with ethyl acetate (3×150 ml). The combined extracts were washed with water (3×150 ml), dried (Na2SO4) and evaporated to give the desired product (11.5 g, 47%); δ (360 MHz, CDCl3) 2.24 (3H, s, Me); 7.06 (1H, d, J =1.5 Hz, Ar--H); 7.10 (1H, d, J=1.5 Hz, Ar--H); 7.50 (2H, d, J=9.5 Hz, Ar--H); 8.38 (2H, d, J=9.5 Hz, Ar--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH:14]=O)=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.C([O-])(=O)C.[NH4+].[CH3:21][N+:22]([O-:24])=[O:23]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH:14]=[CH:21][N+:22]([O-:24])=[O:23])=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)c2c(c1OC)CCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])c2c(c1OC)CCC2
Temperature: 112 °C
Yield: 9.1 %

Procedure:
To a 100 ml 3-necked round bottom flask fitted with a condenser and thermometer and magnetically stirred, was added 12.97 g (0.063 mole) of 4,5-dimethoxy-7-indanaldehyde, 3.00 g (0.039 mole) of ammonium acetate, 13.0 ml (0.292 mole) of CH3NO2 and 40 ml of glacial acetic acid. This mixture was heated for 1 to 2 hours at 112° C. As the reaction solution began to cool the entire solution solidified. After cooling in an ice bath and removing the solvent by filtration, the solid 4,5-dimethoxy-7-nitrovinylindane was washed with a small volume of acetic acid giving fine yellow needles (9.55 g) after thorough drying. The filtrate was poured into 300 ml of ice and water from which precipitated a slightly gummy, yellow-brown solid. This gave an additional 1.43 g of crystalline solid after drying and crystallizing from methanol giving a total yeild of 10.98 g (70%). An analytical sample melted at 128°-130° C. Anal. Calcd. for C13H15NO4 : C, 62.64; H, 6.06; N, 5.62. Found: C, 62.79; H, 6.12; N, 5.53
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=1)(=[O:3])[CH3:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(=O)N1CCCC1c1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 47.4 %

Procedure:
4-(1-Acetyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.32 g, 1.5 mmol) and methyl thiosalicylate (1.02 g, 6.0 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (8:1, v/v) were collected, concentrated and recrystallized from diethyl ether-methanol to give the titled compound (0.25 g, 48%) as white crystals.
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][C:12]=2[C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1.O.C(OCC)(=O)C>[C:3]1([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:23][C:12]=2[C:13]([OH:15])=[O:14])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(N2CCCCC2)ccc1OCc1ccccc1

Procedure:
LiOH (1.25 mL, 3.74 mmol) was added to a stirred solution of phenylmethyl 2-[(phenylmethyl)oxy]-5-(1-piperidinyl)benzoate (may be prepared as described in Description 41; 150 mg, 0.37 mmol) in a mixture of THF:water (3:1, 10 ml). The mixture was heated to reflux for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over magnesium sulphate, and concentrated to give a yellow oil. The crude product was purified using Comflash to yield the title compound. 80 mg.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:31]([NH2:36])[CH2:32][CH2:33][CH2:34][NH2:35]>C(O)CCC>[NH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:36][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCCCN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCCCN)nc3ccccc23)cc1
Temperature: 105 °C
Yield: 39.3 %

Procedure:
To a suspension of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (300 mg, 1.0 mmol) in n-butanol (3 mL) and diisopropylethylamine (323 mg, 2.5 mmol) was added 1,4-butanediamine (132 mg, 1.5 mmol). The reaction was heated to 105° C. for 18 h, cooled to room temperature and concentrated. The crude product was purified by chromatography (amine column, i-PrOH/CHCl3, 0-100%) to give 138 mg (39%) of the title compound. 1H NMR (CDCl3) δ 7.5 (d, 1H), 7.4 (t, 1H), 7.15 (d, 2H), 6.95 (d, 2H), 6.7 (m, 2H), 3.8 (s, 3H), 3.6 (s, 3H), 3.55 (t, 2H), 2.8 (t, 2H), 2.1 (s, 3H), 1.75 (pentet, 2H), 1.63 (pentet, 2H); LC-MS (ESI+; 352 ([M+H]+)).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=[O:4].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[CH3:13]>C1COCC1>[CH2:12]([O:14][C:15](=[O:30])[CH:16]([C:3](=[O:4])[C:2]([F:9])([F:8])[F:1])[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[CH3:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C

Procedure:
THF (3.0 mL) and ethyl trifluoroacetate (1.32 mL, 1.58 g, 11.1 mmol) were added to sodium hydride (442 mg of 60% oil dispersion, 11.1 mmol) in a flask fitted with a mechanical stirrer and a reflux condenser. 1-(tert-butoxycarbonyl)-4-piperidineacetic acid ethyl ester (1.50 g, 5.52 mmol) dissolved in THF (2.0 mL) was added over 30 min, with additional THF (2×1 mL) to complete the transfer. The mixture was warmed to 45° C. overnight. An additional portion of ethyl trifluoroacetate (1.0 mL, 1.19 g, 8.4 mmol) was added the temperature was increased to 70° C. for 17 h. After cooling to RT, the mixture was partitioned between EtOAc (50 mL) and a mixture of saturated aq. NaCl (25 mL) and 2 N aq. HCl (10 mL). The aqueous layer was extracted with EtOAc (25 mL). The organic layers were washed in succession with saturated aq. NaCl (2×10 mL), dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 90:10 to 85:15 v/v hexanes/EtOAc to give the title compound as a colorless oil. For the title compound: 1H NMR (500 MHz, CDCl3) showed an apparent mixture of tautomers; ESI-MS 268.2 (M+H−100); HPLC A: 3.3 min.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1c(OCC2CCNC2)cccc1[N+](=O)[O-]
Agent: Cl
Product: CCCC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Yield: 100 %

Procedure:
Prepared as in Example 165b from 2-nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrile hydrochloride (Example 181d) and butyryl chloride in 100% yield as an orange solid. MS 318 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].Cl>C(Cl)Cl>[C:38]([O:31][CH2:30][CH2:29][NH:28][C:26]([C:15]1[N:14]=[N:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:27])(=[O:40])[CH3:39]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(F)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCOC(C)=O)c2COc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-fluorophenoxy)methyl]-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 498 in methylene chloride (10 ml) were added pyridine (0.2 ml) and acetic anhydride (0.17 ml), and the mixture was stirred at room temperature for 10 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/2 to 1/1) and recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (480 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C[O-].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:13][C:14]([F:21])([F:20])[C:15](=[O:16])[CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH3:1])[CH:3]=1)=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(C(C)=O)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To stirred solution of 1-(3-methyl-4-methoxyphenyl)ethanone (3.29 g, 20 mmol) in DME was added ethyl trifluoroacetate (5.68 g, 40 mmol) and sodium methoxide (4.32 g, 80 mmol), and the resulting reaction mixture was stirred at room temperature overnight. EtOAc (200 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 1 N HCl solution. The organic layer was washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuo to give the crude product which was recrystallized from isooctane to give the title compound (3.2 g, 62%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:56])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:48][CH3:49])[C@H:43]([C:45](O)=[O:46])[CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:82][CH:83]([CH:88]1[CH2:95][C:94]2[C:89]1=[CH:90][CH:91]=[CH:92][CH:93]=2)[C:84]([O:86][CH3:87])=[O:85].C(NC(C)C)(C)C>ClCCl.CN(C)C=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:20])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:48][CH3:49])[C@@H:43]([CH3:44])[C:45]([NH:82][CH:83]([CH:88]3[CH2:95][C:94]4[C:89]3=[CH:90][CH:91]=[CH:92][CH:93]=4)[C:84]([O:86][CH3:87])=[O:85])=[O:46])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:56])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(N)C1Cc2ccccc21
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NC(C(=O)OC)C1Cc2ccccc21)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To a mixture of #105 (225 mg, 0.289 mmol, 1 eq.) in dichloromethane (15 mL, 0.02 M) and N,N-dimethylformamide (1 mL) was added HATU (136 mg, 0.347 mmol, 1.2 eq.). After five minutes, a solution of amine #102 (72.4 mg, 0.318 mmol, 1 eq.) and diisopropylamine (203 mL, 1.16 mmol, 3 eq.) in dichloromethane (5 mL) was added. After 24 hours, the reaction mixture was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo onto silica gel, and purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) to give the single enantiomer #106 (210 mg, 76%) as a clear oil. LC-MS: m/z 953.1 [M+H+], retention time=3.99 minutes; 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers, characteristic signals: 7.76 (d, J=7.5 Hz, 2H), 7.57-7.64 (m, 2H), 7.40 (dd, J=7.5, 7.4 Hz, 2H), 7.28-7.34 (m, 2H), 4.82-4.88 (m, 1H), 3.95-4.01 (m, 1H), 3.76 and 3.82 (2 s, total 3H), 3.30, 3.31, 3.34 and 3.35 (4 s, total 6H), [1.20 (d, J=7.0 Hz) and 1.20 (d, J=7.0 Hz), total 3H].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C(Cl)=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[S:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[CH2:48][NH2:49]>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH:33]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C@H:9]([C:24]([NH:49][CH2:48][C:44]2[S:43][CH:47]=[CH:46][CH:45]=2)=[O:26])[CH2:10]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NCc1cccs1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: O=C(NCc1cccs1)[C@@H]1CC(=NOCc2ccc(Cl)c(Cl)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 2-thienylmethylamine the title compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=592.6.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=N[C:13](Cl)=[N:14][CH:15]=1.[CH2:17]1COCC1>>[Br:9][C:10]1[CH:11]=[CH:17][C:13]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:14][CH:15]=1
Reactant: CN(C)CCO
Reactant: Clc1ncc(Br)cn1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N,N-dimethylethanolamine (0.36 mL) in THF (15 mL) was added sodium hydride (145 mg). After stirring at room temperature for 10 minutes, 5-bromo-2-chloropyrimidine (500 mg) was added and the mixture heated at reflux for 16 h. After cooling to room temperature, the mixture was extracted into 2 M aqueous HCl solution (30 mL) and washed with ethyl acetate (30 mL). The aqueous layer was made basic with sodium carbonate and the produt extracted into ethylacetate (3×30 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give [2-(5-bromo-pyridin-2-yloxy)-ethyl]-dimethylamine as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[OH:17]>O>[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[C:11]=1[OH:17]
Reactant: Cc1ccc(O)c(F)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
70% Nitric acid (d=1.42) (5.5 ml, 87.4 mmol) was dropwise added to an acetic acid (105 ml) solution of 2-fluoro-4-methyl-phenol (10.5 g, 83.2 mmol), taking 20 minutes, followed by stirring at room temperature for 30 minutes. Water was added to the reaction liquid, followed by extraction three times with diethyl ether, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (10:1) was concentrated under reduced pressure to obtain the entitled compound (5.47 g, 31%) as a yellow solid.