Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=O)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl-].[NH4+].C[N:20](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH2:20])[CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.4 %

Procedure:
In a round-bottomed flask, (1R,3R)—N-Boc-1-aminocyclopentane-3-carboxylic acid (300 mg, 1.31 mmol) and ammonium chloride (210 mg, 3.93 mmol) were suspended in DMF (6 ml). HATU (547 mg, 1.44 mmol) and N,N-diisopropylethylamine (0.80 ml, 4.58 mmol) were added and the yellow suspension was stirred at room temperature for 72 h. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 97 mg (33%) of ((1R,3R)-3-carbamoyl-cyclopentyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.O>C(Cl)Cl>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:19][C:14]([C:13]([NH:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:9][CH3:10])=[O:11])=[C:2]([F:1])[CH:3]=2)([CH3:18])[CH3:17])=[O:16])=[CH:21][C:22]=1[C:28]([F:29])([F:30])[F:31])#[N:25]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(NC(C)(C)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
The title compound was made in accordance with General Method 1. 2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionic acid (1.27 g) was dissolved in DCM. EDC1-HCl (1.91 g) was added to it and the reaction mixture was stirred for 5 min at RT. 4-Amino-2-(trifluoromethyl)benzonitrile (1.00 g) was added portionwise and stirring was continued for 5 h at RT. Water was added to the reaction mixture, and the product was extracted with DCM. The combined organic layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel) eluting with 5% MeOH-DCM to obtain 650 mg of 4-[1-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-1-methyl-ethylamino]-2-fluoro-N-methyl-benzamide, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 11.174 min, M+1: 423.
Reaction SMILES: [H-].[K+].[H-].[Na+].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]3[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[N:19][C:13]=3[N:14]([CH2:17][CH3:18])[C:15]=2[N:16]=1.[N+]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=1)([O-])=O>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]3[CH:22]=[C:21]([CH2:23][O:24][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:20]=[N:19][C:13]=3[N:14]([CH2:17][CH3:18])[C:15]=2[N:16]=1
Reactant: CCN1c2ncc(CO)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Cc1cc([N+](=O)[O-])ccn1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Product: CCN1c2ncc(COc3ccnc(C)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 69 %

Procedure:
Using a procedure analogous to that described in Example 91, except potassium hydride was employed as the base instead of sodium hydride, the title compound, m.p. 163°-164° C., was prepared from 2-chloro-5,11-dihydro-11-ethyl-8-hydroxymethyl-5-methyl-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-nitro-2-picoline. The yield was 69% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22].CN(C)C=O>C(Cl)(Cl)Cl>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2)[CH:21]=[CH2:20]
Reactant: C=CCI
Reactant: Cc1cc(O)cc2ccc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C=CCOc1cc(C)c2[nH]c(=O)ccc2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
A mixture of 6-hydroxy-8-methylcarbostyril (15.0 g, 85.7 mmol), potassium carbonate (23.4 g, 169.5 mmol), allyl iodide (15.6 g, 90.0 mmol), and N,N-dimethylformamide (120 ml) was stirred in a bath of 70° C. for 1.5 hours. The mixture was condensed, and the residue was dissolved in chloroform, followed by washing with water and 2N-NaOH. The washed material was dried and condensed. The resultant residue was recrystallized (chloroform--n-hexane) to obtain 10.11 g of 6-allyloxy-8-methylcarbostyril as pale brown prisms (54.8%).
Reaction SMILES: [CH2:1]([N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:24]N1C(=O)CCC1=O>ClCCl>[Br:24][C:16]1[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCCCCCCn1c2ccccc2c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCCCCCCCn1c2ccccc2c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 9-decylcarbazole 15 (3.0 g, 10 mmol) in dichloromethane (90 mL) was added N-bromosuccinimide (1.80 g, 10.1 mmol) at 0° C. in portions. The mixture was warmed to room temperature and stirred overnight. After removal of the solvent, the residue was purified by silica gel column chromatography using petroleum ether/dichloromethane as eluent affording the desired product (3.35 g, 87%). 1H NMR (400 MHz, CDCl3, δ) 8.19 (d, J=1.6 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.53-7.45 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.24-7.20 (m, 2H), 4.26 (t, J=7.2 Hz, 2H), 1.86-1.79 (m, 2H), 1.30-1.22 (m, 2H), 0.88 (t, J=6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ) 140.7, 139.0, 128.2, 126.3, 124.5, 123.0, 121.8, 120.5, 119.1, 111.5, 110.1, 108.9, 43.2, 31.8, 29.5, 29.4, 29.3, 29.2, 28.9, 27.2, 22.6, 14.1. MS (MALDI-TOF): m/z 387.0912 (M+).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)[CH2:37][CH2:36]1.[OH-].[Na+]>O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:1][C@@H:2]([C:10](=[O:12])[NH:49][CH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH:38]2[CH2:37][CH2:36][O:35][CH2:40][CH2:39]2)[CH2:47][CH2:46]1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC1CCN(CC2CCOCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of tetrahydrofuran and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of tetrahydrofuran cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 0.5 hours. A solution consisting of 8.0 g of (11) in 20 ml of tetrahydrofuran is then dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. 100 ml of 1M NaOH is added to the mixture, and the tetrahydrofuran is evaporated at low pressure. The residue is taken up with dichloromethane and water; the organic phase is washed with water (2×), and after a solvent change with ethyl acetate at low pressure, compound (12) is crystallised from ethyl acetate to obtain 15 g of white solid. Yield 87%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Br:16])[CH:8]=1)[CH3:2].[Cl-].[NH4+]>C1COCC1.C(O)C.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2=[CH:11][N:10]=[C:9]([Br:16])[CH:8]=[C:7]2[CH:6]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Br)ncc2[nH]1

Procedure:
Route A: To a solution of 3-(2-bromo-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester (Preparation 25, 3.38 g, 10.7 mmol) in THF (50 mL) and ethanol (100 mL) was added saturated ammonium chloride solution (50 mL) and iron powder (3.57 g, 64.0 mmol) and the reaction heated under reflux for 2 h. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The solvent was removed in vacuo and the remainder partitioned between saturated sodium hydrogen carbonate solution (100 mL) and ethyl acetate (3×150 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid. δH (CD3OD): 1.42 (3H, t), 4.43 (2H, q), 7.14 (1H, s), 7.85 (1H, s), 8.58 (1H, s); m/z (ES+)=269 [M+H]+. Route B: To a solution of 2-bromo-4-methyl-5-nitropyridine (Preparation 24, 5.7 g, 26.3 mmol) in diethyl oxalate (17.9 mL) under argon was added 1,8-diazabicyclo[5,4,0]undec-7-ene (4.5 mL, 30.2 mmol) to give a dark red precipitate. Reaction mixture was stirred at rt for 4.5 h and concentrated in vacuo. Acetic acid (140 mL) was added to the residue under argon and heated to 60° C. Iron (2.94 g, 52.6 mmol) was added in small portions over a period of 1 h. The reaction mixture was heated at 80° C. for 4 h. The reaction mixture was cooled to rt and poured into water (300 mL) which gave a beige precipitate. The precipitate was isolated and washed with water. The solid obtained was dissolved in ethyl acetate (700 ml) and filtered. The filtrate was concentrated in vacuo to give the title compound. m/z (ES+)=269 [M+H]+; RT=3.39 min.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH:11]([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)C[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
A solution of 4-bromobenzaldehyde (2 g, 10.8 mmol) in tetrahydrofuran (30 mL) in a two-necked round flask was cooled to −5° C. under nitrogen atmosphere. After 0.5 hour, isobutylmagnesium bromide (8 mL) was added dropwise. And then the mixture was warmed to room temperature. The resultant reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over sodium sulfate and concentrated to give a residue. The crude product was purified by silica gel column chromatography (silica gel, petroleum ether/ethyl acetate=8:1) to give 1-(4-bromophenyl)-3-methylbutan-1-ol (0.35 g, 13%). 1H NMR (300 MHz, CDCl3): δ 7.48-7.45 (m, 2H), 7.25-7.21 (m, 2H), 4.74-4.72 (m, 1H), 1.72-1.68 (m, 2H), 1.47-1.46 (m, 1H), 0.95 (d, J=6.0 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:29]=1)#[N:2].[SH2:30]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:29]=1)(=[S:30])[NH2:2]
Reactant: S
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)ccc3o2)cc1
Reaction time: 18 h

Procedure:
t-Butyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate (430 mg, 1.10 mmol) was dissolved in a mixed solution of pyridine (30 ml) and triethylamine (7 ml), and hydrogen sulfide gas was blown in for 10 minutes at room temperature, which was followed by stirring for 18 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with a 2N aqueous potassium hydrogensulfate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give t-butyl 4-[(5-thiocarbamoyl-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. The solid was dissolved in acetone (50 ml) and methyl iodide (2 ml) was added. The mixture was refluxed under heating for 40 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give t-butyl 4-[[5-[(1-methylthio)iminomethyl]-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. Thereto were added methanol (30 ml) and ammonium acetate (280 mg, 3.64 mmol), and the mixture was refluxed under heating for 3 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/3-3/1) to give 596 mg of hydriodide of compound (8) as a yellow solid (quantitatively in 3 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[N:26][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])=[N:26][N:27]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1-c1nnc(CBr)s1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2nnc(-c3ccccc3C(F)(F)F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 18, 33 mg (0.11 mmol) of the compound from Example 5A were reacted with 35 mg (0.11 mmol) of the compound from Example 85A. This gave 16 mg (27% of theory) of the target compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH2:17][C:18](O)=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46].O>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH2:17][C:18]([NH:45][OH:46])=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid (1.1 g, 2.6 mmol) in tetrahydrofurane was added carbonyldiimidazole (0.73 g, 4.5 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine HCl salt (0.4 g, 2.3 mmol). The resulted mixture was stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-hydroxy-propionamide as a white solid (700 mg, 61%): mp 129-131° C.; 1HNMR (DMSO-d6): δ 0.33-0.35 (m, 2H), 0.54-0.57 (m, 2H), 1.15-1.30 (m, 1H), 3.11 (d, J=5 Hz, 2H), 3.87 (d, J=7.5 Hz, 2H), 5.71 (t, J=7.5 Hz, 1H), 6.95-6.98 (m, 1H), 7.03 (t, JH-F=75 Hz, 1H), 7.11-7.17 (m, 2H), 7.85 (s, 4H), 8.80 (s, 1H), 10.60 (s, 1H). 13C NMR (CDCl3): δ 0.7, 3.9, 3.9, 10.8, 35.7, 52.0, 74.6, 112.6, 114.9, 116.7, 120.8, 120.9, 123.6, 124.2, 132.3, 135.00, 137.7, 140.9, 151.3, 169.0; Anal. Calcd. for C22H20F2N2O6: C, 59.19; H, 4.52; N, 6.28. Found: C, 58.98; H, 4.41; N, 6.16.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[C:27]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH3:30])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]S(C(F)(F)F)(=O)=O)[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Br[CH2:50][CH2:51][CH2:52][F:53]>C(#N)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:50][CH2:51][CH2:52][F:53])[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[C:27]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH3:30])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1
Reactant: C[C@@H]1CN([C@@H](c2cccc(OS(=O)(=O)C(F)(F)F)c2)c2cccc(C(=O)N(C)c3cccc(F)c3)c2)[C@@H](C)CN1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(C)c3cccc(F)c3)c2)[C@@H](C)CN1CCCF
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.2 %

Procedure:
3-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-(trifluoromethylsulfonyloxy)-benzyl)-N-(3-fluorophenyl)-N-methylbenzamide (from Example 5, 0.70 g, 1.2 mmol) was combined with anhydrous sodium carbonate powder (0.65 g, 6.1 mmol), 10 mL anhydrous acetonitrile, sodium iodide (0.03 g, 0.2 mmol), and 1-bromo-3-fluoropropane (0.12 mL, 1.3 mmol). The reaction was stirred for three days at room temperature under nitrogen, and then concentrated under reduced pressure. The residue was suspended in 15 mL ethanol, 10 mL of 10% w/v aqueous NaOH solution was added, and the reaction was stirred 2 hours at room temperature. The ethanol was removed under vacuum and the residue was partitioned between water and dichloromethane. The solution was adjusted to pH 8.5 using 3 N HCl, separated and extracted again with dichloromethane (2×15 mL). The solution was dried (Na2SO4/MgSO4) and concentrated under reduced pressure. The residual oil was purified by chromatography on silica gel (EtOAc+2% NH4OH/CH2Cl2) to give 0.39 g (0.77 mmol) of the desired product as an off-white foam. 1H NMR (600 MHz, d6-DMSO): δ 9.28 (s, 1H), 7.17-7.24 (m, 5H), 7.04-7.07 (m, 2H), 6.97 (dt, J=2.2, 8.4 Hz, 1H), 6.88 (dd, J=1.2, 8.0 Hz, 1H), 6.61 (dd, J=1.8, 8.0 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.4 Hz, 1H), 4.74 (br s, 1H), 4.42 (dt, J=47.5, 6.0 Hz, 2H), 3.30 (s, 3H), 2.70 (dd, J=2.9, 11.0 Hz, 1H), 2.55-2.61 (m, 1H), 2.48-2.52 (m, 1H—partially obscured by DMSO peak), 2.38-2.42 (m, 1H), 2.26 (br d, J˜9.2 Hz, 1H), 2.19-2.24 (m, 1H), 2.00 (dd, J=7.3, 10.8 Hz, 1H), 1.70-1.75 (m, 1H), 1.64-1.70 (m, 2H), 0.95 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.2, Hz, 3H). Calculated for C30H35F2N3O2: C, 70.98; H, 6.95; N, 8.28; F, 7.48%. Found: C, 70.78; H, 7.23; N, 8.19; F, 7.24%.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC=CC1CC(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1CC(=O)N1
Yield: 97.9 %

Procedure:
A solution of 4-(2-acetoxyvinyl)-2-azetidinone (10.0 g, 0.065 mole) in 200 ml ethyl acetate containing 100 mg of 10% Pd/C is hydrogenated on a Parr shaker at 25° C. under 40 psi hydrogen for 15 minutes. The mixture is filtered through a bed of Supercel and washed with additional ethyl acetate. The combined filtrate is evaporated in vacuo to give 4-(2-acetoxyethyl)-2-azetidinone (10.0 g) as a crystalline solid. Recrystallization from ether affords white crystals: M.P. 44°-7°; ir (CHCl3) μ 5.66, 5.74; nmr (CDCl3) τ 3.44 (broad s, 1, NH), 5.82 (m, 2, CH2OCOCH3), 6.29 (m, 1, C-4H), 6.87 (1/2 AB pattern further split in four by C-4H and NH, 1, Jgem =12.8 Hz, J=4.5 H JNH =1.9 Hz, 7.38 (1/2 AB pattern further split in four by C-4H and NH, 1, Jgem =12.8 Hz, J=2.3 Hz, JNH =1.0 Hz), 7.93 and 8.02 (s on m, total 5, OCOCH3 and CH2CH2OCOCH3, respectively).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH:18]3[CH2:20][CH2:19]3)=O)=[CH:12][CH:11]=2)[N:3]=[CH:2]1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=2)[N:3]=[CH:2]1
Reactant: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCCCc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
0.8 mmol of cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl ketone (Example 61), 4 mmol of hydrazine hydrate and 3.2 mmol of KOH in 30 ml of triethylene glycol are brought to reflux for 2 hours. The solvent is evaporated off under reduced pressure, and the crude product is extracted with dichloromethane and purified by rotatory chromatography (eluent:dichloromethane/methanol (99:1)-(90:10), ammoniacal atmosphere). The product is crystallized in the form of hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16](Cl)=[O:17]>O1CCCC1.O>[CH2:10]([O:9][C:1]1[O:8][CH2:15][C:16](=[O:17])[C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(OCC)OCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl malonate (8.0 mL, 0.052 mol) was added dropwise to a solution of sodium hydride (60% w/w in oil, 4.2 g, 0.11 mol) in anhydrous tetrahydrofuran (130 mL) that cooled with ice bath. The mixture was refluxed for 7 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (4.2 mL, 0.052 mol) was added dropwise to the reaction mixture and stirred for 1 h then stirred at 45° C. for 1 h. Cooled to ambient temperature, the reaction mixture was diluted with water, and extracted with chloroform for 4 times. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel(chloroform/methanol) to afford ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (5.0 g, y. 48%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-pyridyl)piperazine (9.78 g), ethyl 4-fluorobenzoate (9.7 ml) and powdered potassium carbonate (9.9 g) in dried dimethylsulphoxide (60 ml) was heated at 95° C. for 18 hours. The mixture was poured into water (1200 ml) and stirred for 30 minutes. The precipitate was filtered off, washed with water and dried. The solid was purified by flash column chromatography on alumina (ICN alumina N32-63) using 1% methanol/dichloromethane as eluent, to give ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (4.85 g) as a cream solid, mp 162-164° C.