Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:18][C:10]([F:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][C:5]1[C:4]([F:20])=[C:3]([CH2:21][CH2:22][OH:23])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution N-[4-chloro-2-fluor-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamide (1.05 g, 3.06 mmol), as prepared according to the procedure in the preceding step, in THF (12 mL) at 0° C. under argon was added a solution of borane-THF complex in THF (12.3 mL, 12.3 mmol, 1.0 M) over a period of 10 minutes, and the reaction mixture continued to stir until the ice-bath expired. The reaction mixture was heated at reflux for 20 hours, and allowed to cool to room temperature. A solution of K2CO3 (1.7 g, 12 mmol) in H2O (12 mL) was added, the THF was removed in vacuo, and the mixture was extracted with DCM (3 times). The extracts were combined, washed with brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAC/DCM (0 and 2.5%) to give the title compound (815 mg, 81% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.52-7.43 (m, 5H), 6.97 (dd, J=8.8, 1.7 Hz, 1H), 6.51 (t, J=8.9 Hz, 1H), 4.17 (bs, 1H), 3.83 (t, J=6.9 Hz, 2H), 3.74 (dt, J=13.4, 6.6 Hz, 2H), 3.04 (dt, J=6.9, 2.4 Hz, 2H), 1.43 (s, 1H). Mass spectrum (LCMS, ESI) calc'd for C16H16ClF3NO (M+H): 330.1. Found: 330.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5/[CH:29]=[N:30]\O)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(OC(=O)C)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:26])([CH3:28])[CH3:27])=[C:19]5[C:29]#[N:30])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1/C=N\O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C#N

Procedure:
Z-1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-((hydroxyimino)-methyl)-1H-indol-5-yl)cyclopropanecarboxamide (39 mg, 0.090 mmol) was dissolved in acetic anhydride (1 mL) and heated at reflux for 3 h. The mixture was cooled in an ice bath and the precipitate was collected and washed with water. The solid was further dried under high vacuum to yield 1-(benzo[d][1,3]-dioxol-5-yl)-N-(2-tert-butyl-3-cyano-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.5, found 402.5(M+1)+1; retention time 3.70 minutes, 1 H NMR (400 MHz, DMSO-d6) δ 11.72(s, 1H), 8.79(s, 1H), 7.79(s, 1H), 7.32(m, 2H), 7.03-7.02(m, 1H), 6.95-6,89(m, 2H), 6.03(s, 2H), 1.47(s, 9H), 1.43-1.41(m, 2H), 1.06-1.04(m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:8]1.[CH:22](OCC)=[O:23]>O>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:11][CH:10]([CH2:17]3)[N:9]3[C:5](=[N:6][C:7]([C:18]([O:20][CH3:21])=[O:19])=[C:8]3[CH:22]=[O:23])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: CCOC=O
Solvent: O
Product: COC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxylate (4 g) was reacted with ethyl formate similar to as described in Example 8 or Example 9 to give (2.3 g) of methyl 9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxylate following triteration from water.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1([CH:16]=[C:17]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C([O-])(=O)CCCCCCCCCCC.C([Sn+](CCCC)CCCC)CCC.CCOCC>[CH:10]1([CH:16]=[C:17]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:18]([O:23][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: CCOCC
Product: CC(C)(C)C(OC(=O)Nc1ccccc1)C(=CC1CCCCC1)n1cncn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 25.1 %

Procedure:
6.5 g (0.055 mol) of phenyl isocyanate and three drops of tributyl-tin laurate, as the catalyst, were added to a solution of 13.15 g (0.05 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol (Example 2) in 100 ml of ether. The mixture was stirred at room temperature for 5 days. After distilling off the solvent in vacuo, the residue was recrystallised from ethyl acetate/ligroin. 4.8 g (25.1% of theory) of 1-cyclohexyl-4,4-dimethyl-3-phenylcarbamoyloxy-2-(1,2,4-triazol-1-yl)-pent-1-ene of melting point 156° C. were obtained.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:16][CH2:17]Br.Cl>O.[Cl-].C([N+](CC)(CC)CC)C.C(Cl)Cl>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: BrCCBr
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
NaOH (5.0 N, 80 ml) was added to a mixture of 4-nitrophenylacetonitrile (10.0 g, 61.7 mmol), 1,2-dibromoethane (8.0 ml, 92.5 mmol), and tetraethylammonium chloride hydrate (10.2 g, 61.7 mmol) in 200 ml of CH2Cl2 at RT. The resulting mixture was stirred at RT for 24 h, diluted with CH2Cl2, and acidified with HCl (10%, aq). The organic layer was separated, washed with brine, condensed, and the crude was purified by flash column chromatography. The titled compound was obtained as a light yellowish solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:50][NH:51][CH2:52][C:53]1[CH:64]=[CH:63][C:56]([CH2:57][N:58]2[CH2:61][CH:60]([OH:62])[CH2:59]2)=[CH:55][CH:54]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:51]([CH2:52][C:53]3[CH:54]=[CH:55][C:56]([CH2:57][N:58]4[CH2:61][CH:60]([OH:62])[CH2:59]4)=[CH:63][CH:64]=3)[CH3:50])=[O:26])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3ccc(CN4CC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol) DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}azetidin-3-ol dihydrochloride (35 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [C:1]([NH2:9])(=O)[C:2]1C=CC=CC=1.[C:10]([O:14][C:15](=[O:42])[C@@H:16]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:17][C:18](=[O:34])[NH:19][N:20]=[C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:13])([CH3:12])[CH3:11].C(O)(C(F)(F)F)=O.[CH:50]([NH2:53])(C)C.[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:60][C:61](=[O:77])[NH:62][N:63]=[C:64]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([CH3:56])[CH3:55]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:42])[C@@H:16]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:17][C:18](=[O:34])[NH:19][N:20]=[C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:13])([CH3:11])[CH3:12].[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:60][C:61](=[O:77])[NH:62][N:63]=[C:64]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([CH3:56])[CH3:55].[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:60][C:61](=[O:77])[C:50](=[C:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:53][NH:9][C:1]#[CH:2])([CH3:55])[CH3:56]
Reactant: NC(=O)c1ccccc1
Reactant: CC(C)N
Agent: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)NN=C(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CNNC(C(=O)N[C@H](Cc1ccccc1)C(=O)NC(C)C)=C(c1ccccc1)c1ccccc1

Procedure:
With these cyclization conditions in hand, N-acyl amino imidazolin-2-one amide 14 was synthesized to study the conformation of this model system in the solid state and in solution, using X-ray crystallography and NMR spectroscopy, respectively (Scheme 2). Benzhydrylidene aza-glycinyl-D-phenylalanine isopropyl amide 9 was prepared from benzhydrylidene aza-glycinyl-D-phenylalanine tert-butyl ester 7 by tertbutyl ester cleavage in a 1:1 v/v mixture of TFA: DCM, followed by coupling to iso-propylamine using a mixed anhydride approach.xx Employment of amide 9 in the alkylation and cyclization steps minimized racemization, likely due to preferential amide nitrogen deprotonation inhibiting removal of the α-hydrogen. Indeed, in comparison to the alkylation of aza-glycinyl-D-phenylalanine tert-butyl ester 7, the chemoselective alkylation of semicarbazone 9 gave aza-propargyl glycinamide 10 in 71% yield with no detectable racemization (see above). Subsequent NaH-promoted 5-exo-dig cyclization gave imidazolin-2-one 11, possessing an exocyclic double bond, in a 57% yield. However, olefin migration occurred upon hydrazone removal, using hydroxylamine hydrochloride in pyridine 11 to afford N-amino imidazalone 12, which without further purification was treated with 4-methoxybenzoyl chloride to provide N-acyl dipeptide amide 14 in 56% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:26][CH:27]1CC1.[C-]#N.[K+]>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 10.37 g (0.03 mol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 35 ml of hydroxymethyl-cyclopropane and 0.5 g of potassium cyanide is stirred at 125° for 12 hours, during this time three 2-3 ml portions of the solvent being distilled off by the application of a slight vacuum. The mixture is subsequently evaporated in vacuo, the residue is partitioned between chloroform and water, the chloroform solution is washed successively with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is recrystallized from ethyl acetate, there being obtained cyclopropylmethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 195°-196 °.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([CH3:11])=[CH:7][C:8]=1[C:9]#[N:10].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16](F)=[CH:15][C:14]=1[F:23].Cl>C1COCC1>[F:12][C:13]1[C:14]([F:23])=[CH:15][C:16]([NH:3][C:4]2[S:5][C:6]([CH3:11])=[CH:7][C:8]=2[C:9]#[N:10])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Cc1cc(C#N)c(N)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)c(Nc2cc(F)c(F)cc2[N+](=O)[O-])s1
Temperature: 2.5 °C
Yield: 43.9 %

Procedure:
Add sodium hydride, 60% dispersion in mineral oil (55.0 g×60%=33.0 g, 1.38 mol) to THF (950 mL) with stirring at 0-5° C. under nitrogen. Add a solution of 2-amino-5-methyl-thiophene-3-carbonitrile (95.0 g, 0.687 mol) and 1,2,4-trifluoro-5-nitro-benzene (121.7 g, 0.687 mol) in THF (1325 mL) dropwise over ˜1 hour, keeping the temperature below 10° C. Allow the reaction to warm to ambient temperature and stir for 8-20 hours. Cool to 10-15° C. and add aqueous 1N HCl (550 mL) dropwise over 10-15 minutes to adjust the pH to 7.0-7.2, keeping the pot temperature below 15° C. Remove most of the organic portion under reduced pressure, and then filter and rinse with water. Dry at 50-60° C. to obtain the crude product. Purify by flash chromatography, eluting with 1:1/methylene chloride:heptane to give 89.1 g (44%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (bs, 1H), 8.33 (m, 1H), 7.09 (s, 1H), 7.07 (m, 1H), 2.47 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H7F2N3O2S 318.0125; found 318.0133.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[N:16]2)[O:11][C:10]([CH3:24])([CH3:23])[O:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]2)[O:11][C:10]([CH3:24])([CH3:23])[O:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](Cn2ccc([N+](=O)[O-])n2)OC(C)(C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](Cn2ccc(N)n2)OC(C)(C)O1
Reaction time: 3 h
Yield: 117 %

Procedure:
A solution of [(4R,6S)-2,2-dimethyl-6-(3-nitro-pyrazol-1-ylmethyl)-[1,3]dioxan-4-yl]-acetic acid t-butyl ester (1.56 g 3.52 mmol) in ethanol (25 mL) was hydrogenated in a Parr hydrogenator at 50 psi hydrogen pressure, using 10% palladium on carbon (0.2 g, 0.19 mmol), for 3 h. The reaction mixture was filtered through a celite plug, and the filtrate concentrated which afforded [(4R,6S)-6-(3-amino-pyrazol-1-ylmethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid t-butyl ester (1.34 g, 94%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Cl:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][Cl:9])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(Cl)nn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc(Cl)nn1
Yield: 43.9 %

Procedure:
A suspension of 3-chloro-6-methylpyridazine (3 g), benzoyl peroxide (150 mg) and N-chlorosuccinimide (3.12 g) in CCl4 (30 ml) was refluxed 16 hours, cooled, filtered and evaporated. Chromatography (EtOAc/hexane) gave title compound (1.67 g). NMR δ(CDCl3) 4.87 (2H, s), 7.58 (1H, d), 7.71 (1H, d).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][C:12]=1[O:19][CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:4]([CH3:9])([CH3:5])[CH:3]=[O:1])=[CH:13][C:12]=1[O:19][CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(CCl)ccc1OCc1ccccc1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(CC(C)(C)C=O)ccc1OCc1ccccc1
Temperature: 70 °C

Procedure:
Under argon, a mixture of sodium hydroxide (1.43 g, 35.85 mmol) and tetrabutylammonium iodide (0.30 g, 0.82 mmol) in 8 ml benzene and 2.8 ml H2O was heated at 70° C. to form a homogeneous mixture. A mixture of the product of Step 1 (8.05 g, 30.64 mmol) and isobutraaldehyde (2.95 g, 40.85 mmol) in 20 ml benzene was added to the above solution dropwise. The resulting reaction mixture was heated at 70-75° C. for 6 h. The product was extracted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/9) to yield a colorless oil in 8.32 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[H-].[Na+].ClC[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.[I-].[Na+]>CN(C=O)C.C(OCC)C>[CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:33][CH2:32][CH2:31][O:30][CH:29]1[CH2:34][CH2:26][CH2:27][O:28]1
Reactant: ClCCCOC1CCCCO1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCOC1CCCO1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of compound 11a (950 mg, 3.20 mmol) in anhydrous DMF (10 mL) under argon at room temperature was carefully added sodium hydride (60% suspension in oil) (140 mg, 3.50 mmol). The solution was stirred for 30 min and 2-(3-chloropropoxy)-tetrahydro-2H-pyran (656 mg, 3.66 mmol) was dropwise added. Finally, sodium iodide (480 mg, 3.20 mmol) was added and the solution was heated at 50° C. for 36 hrs. The resulting solution was diluted with diethyl ether (75 mL), washed successively with a 10% potassium phosphate and brine solution, and finally dried with magnesium sulphate. The crude compound was purified by flash chromatography using EtOAc/Hexane (3:7) as an eluant to give pure compound 12a (1.03 g, 73%). 1H NMR (300 MHz, Acetone-d6) δ: 1.51 (m, 4H), 1.57 (s, 6H), 1.6-1.9 (m, 2H), 2.04 (m, 2H), 3.50 (m, 4H), 3.80 (m, 2H), 4.59 (t, 1H, J=3.42 Hz), 8.18 (m, 2H), 8.27 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([OH:6])=[O:5].Cl.ClC(N(C)C)=C(C)C.[F:23][C:24]([F:32])([F:31])[C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27].N1C=CC=CC=1.ClCl.CC1C2=C(C3C=CC=CC=3)NN(CC3C=CC=CC=3)C(=O)C2=NN=1>CC#N>[Cl:1][C:2]1[C:10]([CH2:11][NH:12][C:26]([C:25]([CH3:30])([CH3:29])[C:24]([F:32])([F:31])[F:23])=[O:27])=[CH:9][CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: NCc1ccc(Cl)c(C(=O)O)c1Cl
Agent: CC(C)=C(Cl)N(C)C
Agent: Cc1nnc2c(=O)n(Cc3ccccc3)[nH]c(-c3ccccc3)c1-2
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C(=O)NCc1ccc(Cl)c(C(=O)O)c1Cl)C(F)(F)F

Procedure:
Prepared analogously to example 8 with 2,6-dichloro-3-aminomethyl-benzoic acid×HCl (0.257 g; 1 mmol); 1-chloro-N,N,2-trimethylpropenylamine (0.2 mL; 1.51 mmol); 3,3,3-trifluoro-2,2-dimethyl-propionic acid (0.19 g; 1.22 mmol) and pyridine (0.4 mL; 4.96 mmol) in 10 mL MeCN. Yield: 117 mg (33%); MS: [m+H]+ 358 (Cl2 isotope pattern); HPLC: Rt=1.97 min (Method CC-4)
Reaction SMILES: [S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[O:15])[C:6](Cl)=[O:7])([OH:4])(=[O:3])=[O:2].[C:16]([O:19][CH2:20][C:21]1[CH2:28][S:27][CH:26]2[N:23]([C:24](=[O:30])[CH:25]2[NH2:29])[C:22]=1[C:31]([OH:33])=[O:32])(=[O:18])[CH3:17].C(=O)(O)[O-].[Na+]>CCOCC.O>[C:16]([O:19][CH2:20][C:21]1[CH2:28][S:27][CH:26]2[N:23]([C:24](=[O:30])[CH:25]2[NH:29][C:6](=[O:7])[CH:5]([S:1]([OH:4])(=[O:3])=[O:2])[N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]=[O:15])[C:22]=1[C:31]([OH:33])=[O:32])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=Cc1cccn1C(C(=O)Cl)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(n3cccc3C=O)S(=O)(=O)O)C2SC1

Procedure:
A solution of 2-sulfo-2-(2-formyl-1-pyrryl)acetyl chloride (0.01 m) in ether is added to 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.01 m) and sodium bicarbonate (0.03 m) in water. After 30 minutes the phases are separated, the pH adjusted to about 6.5 and the aqueous extracted with ethyl acetate. The ethyl acetate is separated from the aqueous phase, dried over magnesium sulfate and flash evaporated to give the title compound.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:5]=2[O:4]1.C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH:3]([CH2:2][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:7][C:6]=2[CH:8]=1
Reactant: FC(F)(F)c1ccc2c(c1)CC(CI)O2
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc2c(c1)CC(CN1CCNCC1)O2
Yield: 51.4 %

Procedure:
To a solution of 2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran (2.8 g, 8.5 mmol) in CH3CN (40 ml) was added potassium carbonate (2.36 g, 17.1 mmol, 2 eq) and piperazine (2.94 g, 34.1 mmol, 4 eq) at room temperature. The mixture was heated at reflux for 3 h, then solids were filtered out and the filtrate was concentrated under vacuum. The crude material was purified by silica gel chromatography using 1-2.5% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine as light yellow oil (1.25 g, 51%); (ES, m/z): [M+H]+ 287; 1H NMR (300 MHz, CDCl3): δ 7.37 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.00-5.10 (m, 1H), 3.26-3.35 (m, 1H), 2.96-3.04 (m, 1H), 2.88-2.95 (m, 4H), 2.78-2.80 (m, 1H), 2.54-2.69 (m, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[CH:23]1([CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[CH2:25][CH2:24]1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH:23]2[CH2:24][CH2:25]2)=[CH:36][CH:35]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)NC(=O)c1ccc(OCC2CC2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propanoyl}amino)ethyl acetate and 4-(cyclopropylmethoxy)benzoic acid prepared in Example 18 (18a) to give the title compound.