Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:14])[CH2:12]Cl)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][NH2:26])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:14])[CH2:12][NH:26][CH2:25][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COc1cc(Br)cc(NC(=O)CCl)c1
Product: COc1cc(Br)cc(NC(=O)CNCc2ccc(OC)c(OC)c2)c1

Procedure:
In a manner similar to Preparation 12, react N-(3-bromo-5-methoxyphenyl)-2-chloroacetamide with 3,4-dimethoxybenzenemethanamine to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cccc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 56.9 %

Procedure:
To a solution of methyl 3-(4-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.486 g, 1.30 mmol) in a mixture of methanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 21 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (0.266 g, yield 57%) as colorless needle crystals.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]([CH2:25][C:26](OCC)=[O:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)=O.CCOC(C)=O>[C:1]([N:5]1[C:9]2[NH:10][C:26](=[O:27])[CH:25]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(-c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(-c2ccccc2)c2c(-c3ccccc3)cc(=O)[nH]c21
Temperature: 110 °C
Yield: 15.7 %

Procedure:
To a stirring solution of crude 2-tert-butyl-5-phenyl-2H-pyrazol-3-ylamine (4.0 g, 18.6 mmol) in AcOH (25 mL) was added ethyl benzoylacetate (6.6 mL, 37.2 mmol). The reaction was then heated to 110° C. for 48 hr, at which time the reaction was cooled to room temperature, diluted with EtOAc, and quenched with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of this material was accomplished by flash chromatography, using an ISCO column (ISCO, Inc., Lincoln, Nebr.), eluting with 15% EtOAc/hexanes. The product-containing fractions were collected and concentrated under reduced pressure to give the title compound (1.0 g, 16% yield) as a tan solid. LRMS m/z (APCl) 344 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16](Cl)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]1[CH2:34][O:33][CH:32]2[CH:27]([CH2:28][CH2:29][NH:30][CH2:31]2)[O:26]1>C(OCC)(=O)C>[CH2:25]1[CH2:34][O:33][CH:32]2[CH:27]([CH2:28][CH2:29][N:30]([C:16]([CH:6]3[C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=4[CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]3=4)=[O:17])[CH2:31]2)[O:26]1
Reactant: O=C(Cl)C1c2ccccc2CCc2ccccc21
Reactant: C1CC2OCCOC2CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(C1c2ccccc2CCc2ccccc21)N1CCC2OCCOC2C1
Reaction time: 8 h

Procedure:
To a stirred solution of 10.9 parts of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carboxylic acid chloride is added 4 parts of anhydrous sodium carbonate and then 6.1 parts of 4-(ethylenedioxy)piperidine. The mixture is stirred overnight and then diluted with ethyl acetate. Sodium carbonate is removed by filtration, the filtrate is washed with 1.2 N hydrochloric acid, 15% aqueous sodium hydroxide, and brine, dried with magnesium sulfate and concentrated to give 4-(ethylenedioxy)-1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carbonyl]piperidine, as a white solid melting at about 148.5°-149.5° C. after recrystallization from cyclohexane. This compound has the following structural formula ##STR23##
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:22])[CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].CC(C)=O>ClCCl>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:5]2[C:4](=[O:22])[CH2:3][C@H:2]([NH:1][C:23](=[O:25])[CH3:24])[CH2:6]2)=[CH:12][CH:11]=1
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
In the reaction flask, (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (7.0 g, 23.3 mmol), prepared as described in the previous example, was charged together with dichloromethane (70 mL). At 40° C., a solution of acetic anhydride (2.97 g, 29.1 mmol) in dichloromethane (10 mL) was added dropwise under stirring over 30 min. After a reaction time of 1.5 h, no starting material was left according to HPLC. Acetone (250 mL) was added and the mixture was concentrated in vacuo to a volume of ˜50 mL. The residue was dissolved in acetone (250 mL) at 60° C. The warm solution was treated with charcoal, the resulting suspension filtered and the charcoal washed with warm acetone. The filtrate was concentrated at 60° C. to a volume of ˜50 mL when the product started to crystallize. At room temperature, tert-butyl methyl ether (100 mL) was added and the suspension was kept at this temperature overnight. The crystals were collected by filtration, washed with tert-butyl methyl ether and dried in vacuo to afford (S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide (7.0 g, 88%) as an off-white powder. The purity of the material by HPLC was 99.4% (area) and the enantiomeric ratio (S):(R) was determined as >99.9:0.1. The result of the elemental analyses (C,H,N,F,O) corresponded to the expected values.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[C:28][C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(CC(C(=O)NC(CC#CC(=O)N(C)C)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound from Step A of Example 49 (0.389 g, 1 mmol) was dissolved in dry DMF (5 mL) with dichlorobis(diphenylphosphine)palladium (II) (0.02 eq), CuI (0.02 eq), Et3N (0.4 eq, 3 mL), and N,N-dimethylcarbamyl chloride (1.0 eq, 92 μL). The reaction mixture was stirred overnight at room temperature and then at 70° C. for 1 hour. The mixture was filtered through a pad of Celite and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:19][CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21].C(OC1C=CC(/C=C2/C(=O)N(CCCNC(=O)OC(C)(C)C)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:21][CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH3:19])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: CC(CBr)NC(=O)OC(C)(C)C
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCCNC(=O)OC(C)(C)C)C2=O)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(CC(C)NC(=O)OC(C)(C)C)C2=O)cc1
Yield: 22.5 %

Procedure:
The title compound 21b was prepared from compound 2 (260 mg, 1.04 mmol) and tert-butyl (1-bromopropan-2-yl)carbamate (247 mg, 1.04 mmol) in a manner similar to that described for 21a. Yield=22.5%, 95.0 mg.
Reaction SMILES: Br[C:2]([F:33])([F:32])[C:3](F)([F:30])[O:4][C:5]1[CH:29]=[CH:28][CH:27]=[C:7]2[C:8]([N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20](F)([F:25])[C:21]([F:24])([F:23])Br)=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=12)=[O:9]>C(#N)C.[Zn]>[F:30][C:3]([O:4][C:5]1[CH:29]=[CH:28][CH:27]=[C:7]2[C:8]([N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:25])=[C:21]([F:23])[F:24])=[CH:17][CH:18]=3)[C:11](=[O:12])[C:6]=12)=[O:9])=[C:2]([F:33])[F:32]
Reactant: O=C1c2cccc(OC(F)(F)C(F)(F)Br)c2C(=O)N1c1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: [Zn]
Solvent: CC#N
Product: O=C1c2cccc(OC(F)=C(F)F)c2C(=O)N1c1ccc(OC(F)=C(F)F)cc1
Yield: 83.3 %

Procedure:
The product of the previous preparation, 3-(2-Bromotetrafluoroethoxy)-N-(4-(2-bromotetrafluoroethoxy)phenyl) phthalimide, (2.73 g, 0.00445 mole) is dissolved in 20 ml of warm acetonitrile (approximately 50° C.) and added to zinc metal (0.61 g, 0.0093 mole) in 5 ml of acetonitrile stirring at reflux. The reaction mixture is stirred at reflux for 12 hours, then filtered on a fine-pored fritted glass funnel to remove unreacted zinc and zinc halide salts. The precipitate is washed twice with 25 ml of dichloromethane, and the filtrates are combined with the acetonitrile flitrate and evaporated to dryness. The dry residue is dissolved in 15 ml of dichloromethane/hexane (1:1, v/v (volume/volume)) and subjected to column chromatography on neutral alumina using dichloromethane/hexane (1:4, v/v) to provide the product (1.54 g, 83.4 percent yield) as a light yellow solid with a melting point of 160°-160.5° C. IR (cm-1): 1721, 1708, 1322, 1121 (imide), 1289, 1282, 1273, 1213, 1191, 1166, 1146, 1110, 1096 (C-O, C-F), 1514, 808, 801,743 (aromatic).
Reaction SMILES: [NH:1]1[CH2:6]CC[CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[C:16](Cl)(=[O:18])[CH3:17].CS(Cl)(=O)=O>>[C:16]([N:1]1[CH2:2][CH2:3][C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:6]1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Agent: CS(=O)(=O)Cl
Product: CC(=O)N1CC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate and acetyl chloride for methanesulfonyl chloride in EXAMPLE 147A.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[N:6][CH2:7][CH3:8])[CH2:4][CH3:5].[Cl:9][CH:10]([Cl:14])[C:11](Cl)=[O:12].C(OCC)C>C(N(CC)CC)C>[CH2:7]([N:6]([C:3](=[CH:4][CH3:5])[CH2:2][CH3:1])[C:11](=[O:12])[CH:10]([Cl:14])[Cl:9])[CH3:8]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCN=C(CC)CC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC=C(CC)N(CC)C(=O)C(Cl)Cl

Procedure:
In a similar procedure as Example I, 5.9 g. (0.052 mole) N-3-pentylidene ethylamine was reacted with 4.8 ml. (0.05 mole) dichloroacetyl chloride in 100 ml. diethyl ether and 7.2 ml. triethylamine. There was obtained 7.7 g. of the title compound, an oil, nD30 = 1.4826.
Reaction SMILES: [C:1]([N:4]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][C:6](=[O:16])[C@@H:5]1[CH3:17])(=[O:3])[CH3:2].[C:18]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[C:18]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH:25][C:6](=[O:16])[C@H:5]([CH3:17])[N:4]([C:1](=[O:3])[CH3:2])[CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:7])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(=O)N1[C@@H](C)C(=O)OC[C@H]1c1ccccc1
Solvent: ClCCl
Product: CC(=O)N(C(CO)c1ccccc1)[C@@H](C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 33.7 %

Procedure:
(3S,5R)-4-N-acetyl-3-methyl-5-phenyl-3,4,5,6,-tetrahydro-2H-1,4-oxazin-2-one (68) (220 mg, 0.94 mmol) and L-alanine tert-butyl ester (66) (205 mg, 1.42 mmol, 1.5 equiv.) were dissolved in anhydrous dichloromethane (14 mL) in a doubly sealed PTFE cylinder and subjected to ultra-high pressure of 19 kbar for 48 hours. After releasing the pressure, the solution was filtered through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by flash column chromatography on silica eluting with diethyl ether and dichloromethane (4:1) to furnish the title product as fine colourless needles (120 mg, 34%); m.p. 38-40° C.; v(max)(KBr) 3411 (O—H), 2980 (C—H), 1735 (C═O, lactone), 1646 (C═O, amide) cm−1; δH (250 MHz, DMSO-d) 8.06 (0.5H, d, /6.95 Hz, NH×0.5), 7.55-7.24 (5H, m, Ph), 6.54 (0.5H, d, J 6.38 Hz, NH×0.5), 5.82 (0.5H, t, /4.88 Hz, OH×0.5), 5.14-5.06 (1H, m, PhCH), 4.83 (0.5H, t, J 6.56 Hz, OH×0.5), 4.35 (0.5H, q, J 6.99 Hz, CH3CH×0.5), 4.08-4.03 (2H, m, CH2OH), 3.98-3.76 (1.5H, m, CHCH3×0.5 and CHCH3×1), 2.23 (1.5H, s, COCH3), 2.14 (1.5H, s, COCH3), 1.46-1.39 (12H, m, CHCH3×3 and C(CH3)3×9), 1.19 (1.5H, d, /7.15 Hz, CHCH3×1.5), 0.97 (1.5H, d, J 7.23 Hz, CHCH3×1.5); δc (62.5 MHz, DMSO-d) 171.8, 171.7, 171.0, 170.8, 170.2, 140.0, 138.2, 129.1, 128.2, 128.0, 126.8, 80.7, 62.7, 62.5, 60.8, 56.3, 53.4, 48.8, 48.7, 27.9, 17.5, 16.9, 16.7, 15.2; m/z (CL, NH3), 379 (MH+, 70%), 361 (18%), 305 (20%), 249 (38%), 234 (100%), and 219 (40%); HRMS for C20H31N2O5 requires 379.2225 found 379.2240; [α]D20 −37.0 (c 1.06 CHCl3).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH:11]([CH3:15])[CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:18]=1[C:19](O)=[O:20]>>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH:11]([CH3:15])[CH2:12][CH2:13][NH:14][C:19](=[O:20])[C:18]3[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:17]=3[CH3:16])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC2(CC1)OCCO2
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC2(CC1)OCCO2
Yield: 83.9 %

Procedure:
Using general procedure E with 3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butylamine (2.30 g, 10.7 mmol) and 2,6-dimethylbenzoic acid (1.77 g, 11.8 mmol) followed by purification by column chromatography on silica gel (1-5% MeOH/CH2Cl2) gave N-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-2,6-dimethyl-benzamide (3.11 g, 83%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1cccc(CBr)c1F
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(F)c1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,3-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
A suspension of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid (3.00 g, 11.53 mmol), N,O-dimethylhydroxyamine hydrochloride (2.25 g, 23.06 mmol), triethylamine (4.0 mL, 28.83 mmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (3.32 g, 17.30 mmol) and 1-hydroxybenzotriazole (2.34 g, 17.30 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water, aqueous sodium hydroxide solution, hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (2.75 g, yield 79%) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:6][CH:5]=1.Cl>O1CCCC1.[OH-].[Na+].C(OCC)C.O>[Br:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:26])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Yield: 89.7 %

Procedure:
Racemic 4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid methyl ester (7.80 g, 18.1 mmol) is dissolved in the tetrahydrofuran (75 mL) and sodium hydroxide (25 mL, 5N) is added. The reaction is heated to reflux under nitrogen. The reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized with hydrochloric acid (25 mL, 5N) and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated. The title compound (7.46 g, 16.24 mmol) is used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18].CN1CCOCC1>C(Cl)Cl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:16]([N:11]2[C:12]3[C:8](=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.59 mL, 20.4 mmol) was added to a stirred solution of 3b (6.67 g, 19.5 mmol) and 4-methylmorpholine (2.78 mL, 25.3 mmol) in DCM (100 mL) at 0° C. After 30 min, an additional portion of methanesulfonyl chloride (0.80 mL, 10.2 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-50% EtOAc/hexanes as eluent) to afford the title compound 25. m/z (ES) 421 (MH)+; IP=A rating
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[ClH:34].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=2)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cc(Cl)cc(Cl)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cc(Cl)cc(Cl)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 180.2 %

Procedure:
Compound 35-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (590 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl

Procedure:
The preparation of 2N,N-trimethyl-5-nitrobenzamide utilized the procedure described in U.S. Pat. No. 4,942,163. The reaction mixture of 2-methyl-5-nitrobenzoic acid (5 g, 27.6 mmol) and thionyl chloride (16.4 g, 138 mmol) was refluxed overnight. The excess thionyl chloride was removed by vacuum distillation to afford 2-methyl-5-nitro-benzoyl chloride as a solid residue. This material was dissolved in methylene chloride (30 mL) and added dropwise with stirring to a commercial 40% dimethylamine solution (30 g, 270 mmol) maintaining the temperature at 0 to 12° C. After complete addition, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried and concentrated. The residue was purified by column chromatography with n-hexane-ethyl acetate (3:1) to afford amide as a solid (5.46 g, 95%). The identity was verified by 1H NMR