Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.[F:14][C:15]1[C:20]2[NH:21]C(=O)[O:23][C:24](=O)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>C1(C)C=CC=CC=1>[NH2:21][C:20]1[C:15]([F:14])=[CH:16][CH:17]=[CH:18][C:19]=1[C:24]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[C:3]=1[Cl:9])=[O:23]
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Reactant: Nc1cccc(Br)c1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Nc1c(F)cccc1C(=O)Nc1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A mixture of 3-bromo-2-chloroaniline [prepared according to the procedure described in U.S. Pat. No. 8,242,260] (600 mg, 2.91 mmol) and toluene (10 mL) was cooled to 0° C. and slowly treated with 2 M trimethylaluminum in toluene (2.47 mL, 4.94 mmol). The mixture was allowed to warm to room temperature and stirred for 15 min. The mixture was treated with 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (684 mg, 3.78 mmol) and heated at 50° C. for 16 h. The mixture was cooled to 0° C. and treated dropwise with 1M aqueous HCl until gas evolution stopped, and stirred for 2 h while allowing to warm to room temperature. The mixture was extracted three times with EtOAc. The combined organic phases were washed sequentially with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-30%), to provide 2-amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide as a pale yellow solid (350 mg, 35% yield). Mass spectrum m/z 343, 345 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.46 (dd, J=8.4, 1.3 Hz, 1H), 8.42 (br. s., 1H), 7.43 (dd, J=8.0, 1.4 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 7.15 (ddd, J=11.0, 8.0, 1.2 Hz, 1H), 6.69 (td, J=8.0, 5.1 Hz, 1H), 5.72 (br. s., 2H).
Reaction SMILES: [C:1]([C:4]([CH:12]([F:14])[F:13])([CH2:8][CH2:9][CH:10]=[CH2:11])C(O)=O)([OH:3])=[O:2]>C(O)(=O)C>[F:13][CH:12]([F:14])[CH:4]([CH2:8][CH2:9][CH:10]=[CH2:11])[C:1]([OH:3])=[O:2]
Reactant: C=CCCC(C(=O)O)(C(=O)O)C(F)F
Solvent: CC(=O)O
Product: C=CCCC(C(=O)O)C(F)F
Temperature: 110 °C
Yield: 71 %

Procedure:
2-Carboxy 2-difluoromethyl 5-hexenoic acid, prepared as in Step C (1.040 g, 5 mM) is dissolved in glacial acetic acid (5 ml) and the mixture is heated at 110° C. for 16 hours. The solvent is evaporated in vacuo yielding a colorless oil. The acid is isolated by distillation under reduced pressure. 0.585 g (yield 71%). Bp: 67° C./0.01 mm Hg.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33].Cl.O1CCCC1>CC(C)=O.CCOCC>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH:1]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[C@H](N)C(=O)CCl
Agent: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)CCl

Procedure:
Boc-Phe-Gly-Ala-LeuCH2Cl was prepared by coupling Boc-Phe-Gly-Ala-OH (11.8 g, 30 mmol) to H-LeuCH2Cl.HCl (6.06 g, 30 mmol) using a mixed anhydride procedure. A mixed anhydride of Boc-Phe-Gly-Ala-OH was prepared in a solution of 300 mL of tetrahydrofuran and 25 mL of acetone, and then H-LeuCH2Cl HCl was added in acetone. The resulting crude product, 17.6 g, was dissolved in ether, treated with carbon, and filtered. Product Boc-Phe-Gly-Ala-LeuCH2Cl crystallized from ether (10.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][O:29][CH3:30])=[N:11][C:12](N)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.C(Cl)[Cl:39]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][O:29][CH3:30])=[N:11][C:12]([Cl:39])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: COCOCCCCCCCCCCc1nc(N)nc(C)c1OCc1ccccc1
Agent: CC(C)(C)ON=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: COCOCCCCCCCCCCc1nc(Cl)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
To a stirred solution containing 240 mg (0.58 mmol) of 5-(benzyloxy)-4-(10-(methoxymethoxy)decyl)-6-methylpyrimidin-2-amine in 10 mL of anhydrous DCM were added 1.10 g (5.80 mmol) of benzyltrimethylammonium chloride followed by 696 μL (5.80 mmol) of t-butyl nitrite. The reaction mixture was stirred at 23° C. protected from light for 15 h. The mixture was filtered and the filtrate was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (3×10 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as a colorless oil: yield 44 mg (16%); silica gel TLC Rf 0.45 (4:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.24 (br s, 12H), 1.55 (quint, 2H, J=7.2 Hz), 1.65 (quint, 2H, J=6.8 Hz), 2.42 (s, 3H), 2.67 (dd, 2H, J=8.0, 8.0 Hz), 3.33 (s, 3H), 3.47 (t, 2H, J=6.8 Hz), 4.59 (s, 2H), 4.83 (s, 2H) and 7.37 (m, 5H); 13C NMR (CDCl3) δ 19.32, 26.16, 28.14, 29.25, 29.35, 29.35, 29.47, 29.51, 29.71, 31.92, 55.04, 67.85, 76.03, 96.36, 128.08, 128.73, 128.73, 128.77, 128.77, 135.73, 149.01, 154.24, 163.79 and 167.41; mass spectrum (APCI), m/z (M+H)+435.2411 (C24H36N2O3Cl requires 435.2415)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:24]([OH:27])[C:25]#[CH:26].Cl>O1CCCC1.CCOCC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][OH:27])=[CH:3][CH:4]=1)([F:12])[F:11]
Reactant: C#CCO
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: OCC#Cc1ccc(SC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a degassed solution of 1-bromo-4-(trifluoromethylsulfanyl)benzene (4.8 g, 18.7 mmol) in tetrahydrofuran (40 mL) was added in the following order: copper(I) iodide (106 mg, 0.56 mmol), tetrakis(triphenylphosphine)palladium (647 mg, 0.56 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.36 mL, 22.3 mmol). The resulting mixture was degassed one more time and a solution of propargyl alcohol (1.30 mL, 22.3 mmol) in tetrahydrofuran (5 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 50° C. and then stirred at this temperature for 6 h and then left to stand at ambient temperature over night. The mixture was diluted with ether (50 mL) and acidified with 5% hydrochloric acid to pH 2. Ethereal solution was washed with water (2×15 mL), saturated solution of sodium hydrogen carbonate (15 mL) and brine (15 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 85:15) affording 3-[4-(trifluoromethylsulfanyl)phenyl]prop-2-yn-1-ol.
Reaction SMILES: [Br-].[CH3:2][CH:3]([CH3:26])[CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([CH:47]=O)=[CH:41]2>C1COCC1>[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([CH:47]=[CH:6][CH2:5][CH2:4][CH:3]([CH3:26])[CH3:2])=[CH:41]2
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCC=Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To the cold suspension of (4-methyl-pentyl)-triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes and then the solution of 5-chloro-1H-indole-2-carbaldehyde was added to the reaction mixture and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-(5-methyl-hex-1-enyl)-1H-indole was purified by column chromatography.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[OH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])[C:3]([OH:5])=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C(O)C1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
To a solution of 1.002 g (6.9 mmoles) of 2-hydroxy-2-(pyrrolidin-2-yl)acetic acid in a solution of 550 mg (2 equivalents) of sodium hydroxide in 10 ml of water is added 1.18 ml (1.2 equivalents) of benzyloxycarbonyl chloride, and the mixture is stirred at room temperature for 1.5 hours, washed twice with ether, adjusted to pH 2 with 10% hydrochloric acid, and then extracted thrice with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield 1.288 g of α-hydroxy-α-(1-benzyloxycarbonylpyrrolidin-2-yl)acetic acid in 70.3% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[C:6]([N+:19]([O-:21])=[O:20])[CH:5]=[CH:4][C:3]=1[CH2:22]C(O)=O>C(#N)C.[Cu-]=O>[F:1][C:2]1[C:3]([CH3:22])=[CH:4][CH:5]=[C:6]([N+:19]([O-:21])=[O:20])[C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(Oc2cccc3ccccc23)c1F
Agent: O=[Cu-]
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(Oc2cccc3ccccc23)c1F
Temperature: 90 °C
Yield: 46.1 %

Procedure:
Copper(I) oxide (1.258 g, 8.79 mmol) was added to a solution of [2-fluoro-3-(1-naphthalenyloxy)-4-nitrophenyl]acetic acid (15.70 g, 46 mmol) in acetonitrile (200 mL). The mixture was heated at 90° C. for 4 hrs. The reaction mixture was concentrated and the residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (6.30 g, 36%). ES MS: m/z 298 (M+1), ˜80% pure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([N:13](CC)CC)[CH3:12].BrCC#N.O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:11]#[N:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: N#CCBr
Solvent: C1CCOC1
Solvent: O
Product: N#CCSc1ccc([N+](=O)[O-])cc1

Procedure:
4-nitrobenzenethiol (10 g) was dissolved in THF (100 ml), and to this solution was added triethylamine (12.6 ml) and then, bromoacetonitrile (5.4 ml), and the mixture was stirred for 30 minutes. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-[(4-nitrophenyl)sulfanyl]acetonitrile (10.3 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([F:20])=[CH:9][C:10]([NH:12][CH2:13][C@@H:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:6]=2[O:5][C:4]1=[O:21])[CH3:2].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>>[CH2:1]([N:3]1[C:7]2[C:8]([F:20])=[CH:9][C:10]([N:12]3[CH2:13][C@H:14]([C:15]([O:17][CH3:18])=[O:16])[O:19][C:22]3=[O:23])=[CH:11][C:6]=2[O:5][C:4]1=[O:21])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCn1c(=O)oc2cc(NC[C@@H](O)C(=O)OC)cc(F)c21
Product: CCn1c(=O)oc2cc(N3C[C@H](C(=O)OC)OC3=O)cc(F)c21

Procedure:
Prepared from methyl (2R)-3-[(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate (Step 3, 1.01 g, 3.39 mmol) and 1,1′-carbonyldiimidazole (0.549 g, 3.39 mmol) according to the method of EXAMPLE 86, Step 9 (1.10 g, 99%); MS for C14H13FN2O6 m/z 325 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:25][C:26]1(OCCC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:23][CH3:24]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:26]3([O:25][CH2:22][CH2:23][CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCOC1(OCCC)CCCCCC1
Product: CCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCC1
Yield: 37.6 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-propoxycycloheptane (2.14 g, 10 mmol) in the same manner as the example 20 to give the compound 27 (188 mg, 39.8%). PMR (CDCl3 -0.1% d5 -Py): δH0.87 (3 H, t, J 7.4 Hz, Pr) 1.24 (6 H, d, J 7 Hz, (CH3)2C), 3.00 (2 H, t, J 6 Hz, CH2 -Im), 3.05 (2 H, t, J 7 Hz, OCH2CH3), 3.09 (1 H, m, (CH3)2CH), 3.51 (3 H, s, NCH3), 3.71 (2 H, t, J 6 Hz, OCH2), 6.82 (2 H, d, J 1.6 Hz, arom-H), 7.11 (t-like, arom-H). IR(KBr)cm-1 : 3435, 3063, 1563, 1459, 1119, 1096, 1068, 1015. Elementary analysis (for C25H36N2O2Cl2S) Cacld.: C, 60.11% H, 7.26% N, 5.61% S, 6.42% Cl, 14.19% Found: C, 60.18% H, 7.30% N, 5.84% S, 6.55% Cl, 13.52%
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17])[CH3:5])[CH3:2].C(N(CC)CC)C.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:25]1([C:31]([N:9]2[C@@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[C:8]2=[O:17])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(C)OC1C(=O)NC1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)O[C@H]1C(=O)N(C(=O)N2CCOCC2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 30 mg (0.13 mmol) of 3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone 6 in 2 mL of CH2Cl2, 2 mg of DMAP and 0.05 mL of triethylamine was added at room temperature. After 5 min. 22.9 mg (0.15 mmol) of morpholinecarbonyl chloride was added. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with 20 mL of CH2Cl2 and the organic layer was washed two times with brine, dried over Na2CO3 and concentrated. The crude solid product was purified by chromatography on silica gel to yield pure 7f: 87%; pale yellow oil; 1H NMR (250 MHz, CDCl3) δ [0.90 (d, J=5.3 Hz), 1.01 (d, J=5.3 Hz) (3H)], [1.04 (t, J=7.1 Hz), 1.18 (t, J=7.1 Hz)] (3H), 3.20 (m, 4H), [3.28 (m), 3.53 (m), 3.67 (m) (2H)], 3.60 (m, 4H), [4.41 (g, J=5.3 Hz), 4.63 (q, J=5.3 Hz) (1H)], [5.07 (d, J=5.8 Hz), 5.08 (d, J=5.8 Hz) (1H], [5.29 (d, J=5.8 Hz), 5.32 (d, J=5.8 hz) (1H], 7.23-7.27 (m, 5H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([O:17][S:33]([CH3:32])(=[O:35])=[O:34])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e7) (100 mg) was treated with methanesulphonyl chloride and triethylamine in dichloromethane as described in Example 1. After work-up, evaporation of the dichloromethane solution afforded p-nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e8) (112 mg) as a foam; νmax (CH2Cl2) 1785, 1700 sh, 1680, 1525, 1350, 1335 and 1175 cm-1.
Reaction SMILES: C(Cl)(=O)C.C([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[C:17]([F:22])[C:16]=2[F:23])[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[Cl:28])(=O)C>CO>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[C:17]([F:22])[C:16]=2[F:23])[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[Cl:28]
Reactant: COC(=O)c1nc(-c2ccc(I)c(F)c2F)cc(NC(C)=O)c1Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(I)c(F)c2F)cc(N)c1Cl
Temperature: 23 °C
Yield: 94.2 %

Procedure:
Acetyl chloride (1.3 mL, 18 mmol, 10 equiv) was slowly added to methanol (12 mL) and stirred at 23° C. for 30 m. Methyl 4-acetamido-3-chloro-6-(2,3-difluoro-4-iodophenyl)picolinate (830 mg, 1.8 mmol, 1.0 equiv) was added and the heterogeneous white mixture was stirred at 23° C. for 18 h. The reaction mixture was concentrated by rotary evaporation. The residue was diluted with saturated sodium bicarbonate (200 mL) and extracted with dichloromethane (3×75 mL). The organic layer was dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a white powder (720 mg, 95%).
Reaction SMILES: [CH2:1]([CH:4]([CH2:11][CH:12]=[CH2:13])[CH:5](O)[CH2:6][C:7](O)=O)[CH2:2][CH3:3].C([O-])(=O)C.[K+].[H-].[Na+].COP([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(OC)=O>C(OC(=O)C)(=O)C.O1CCCC1.CCCCC>[CH2:1]([C:4]1[CH2:11][C@@H:12]2[C@H:6]([CH:5]=1)[C:7](=[CH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:13]2)[CH2:2][CH3:3]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: C=CCC(CCC)C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Propyl-3-hydroxyhept-6-enoic acid (2.79 g, 15.0 mmol) was dissolved in acetic anhydride (13 mL). To the solution, potassium acetate (3.52 g, 36.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was heated to 120° C. and stirred for 3 hours. To the reaction solution, ice water and n-pentane were then added, and this mixture was stirred overnight at room temperature. Saturated saline was added thereto, and the mixture was separated into aqueous and organic layers by the addition of n-pentane. Then, the organic layer was washed with a 1 N aqueous sodium hydroxide solution and saturated saline in this order and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL). The solution was added to a reaction solution prepared in advance by adding sodium hydride (>65% oil, 761.9 mg, 20 mmol) to a tetrahydrofuran solution (50 mL) of tert-butyl dimethoxyphosphorylacetate (4.48 g, 20 mmol) under ice cooling, and the mixture was further stirred for 1 hour. The reaction solution was separated into aqueous and organic layers by the addition of a saturated aqueous solution of ammonium chloride and saturated saline. The aqueous layer was subjected to extraction with ethyl acetate. These organic layers were combined, then washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (1.81 g, 49%, E/Z mixture).
Reaction SMILES: [CH:1]([O:14][C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[N:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][CH:23]=1.C(#N)C.C(N(CC)CC)C>C(OCC)(=O)C>[CH:1]([O:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH2:21][C:22]2[N:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(O[C@@H]2CCNC2)c2ccccc2)cc1
Reactant: CCOC(=O)c1cccc(CCl)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cccc(CN2CC[C@@H](OC(c3ccccc3)c3ccccc3)C2)n1
Yield: 54 %

Procedure:
A mixture of 8.144 g of (R)-3-benzhydryloxypyrrolidine synthesized in Production Example 168, 7.701 g of a known compound ethyl 6-chloromethylpyridine-2-carboxylate, 69 mL of acetonitrile, and 9.0 mL of triethylamine was heated under reflux for 3 hours. After being allowed to cool down, the mixture was diluted with ethyl acetate. The diluted mixture was poured into a saturated saline solution, and the organic layer was collected by separation. The organic layer was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography (chloroform/acetone (volume ratio)=15:1 to 10:1) to give the title compound (7.22 g (54%)).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>C(Cl)Cl>[CH3:49][O:50][CH2:51][CH2:52][NH:53][C:13](=[O:15])[C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1)([CH3:17])[CH3:16]
Reactant: COCCN
Reactant: CC(C)(C(=O)O)c1ccc(-c2ccco2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid (reference example 28) (344 mg, 1.5 mmol) in CH2Cl2 (4 mL) is added TBTU (528 mg, 1.65 mmol) followed by diisopropylethylamine (280 mL, 1.6 mmol). The resulting mixture is stirred for 2 h then a further portion of DIEA added (280 mL) along with 2-methoxy-ethylamine (225 mL, 2.6 mmol). The resulting solution is stirred for 90 minutes then concentrated. The residue is purified by flash chromatography (eluting with 10% CH2Cl2/50% ethyl acetate in hexanes) to give 380 mg of product as a white solid. 1H NMR (CD3OD) d 1.58 (s, 6H), 3.24 (s, 3H), 3.36 (m, 4H), 5.58 (bs, 1H), 6.47 (dd, J=3, 2 Hz, 1H), 6.65 (d, J=3 Hz, 1H), 7.41 (m, 2H), 7.49 (d, J=2 Hz, 1H), 7.65 (m, 2H). MS (EI) m/z 287 (M+).