Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[CH:17][N:16]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)N3CCCCC3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2ccc(C(=O)N3CCCCC3)cn2)CC1

Procedure:
A solution of 0.475 g of 4-tert-butoxycarbonylamino-1-(5-piperid-1-ylcarbonyl-2-pyridyl)piperidine (1.24 mmol) and 5 ml of trifluoroacetic acid in 20 ml of dichloromethane is stirred for 1 hour. The reaction medium is concentrated under reduced pressure and then taken up in dichloromethane. The solution is basified (pH=9) using saturated aqueous sodium carbonate solution. The aqueous phase is extracted five times with dichloromethane. The organic phases are dried over magnesium sulfate and concentrated under reduced ressure. The 4-amino-1-(5-piperid-1-ylcarbonyl-2-pyridyl)piperidine is obtained in the form of an oil (0.310 g, 88%). [M+H+]=289.4
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH2:8][S:7][C:6](=[O:9])[N:5]=1)[CH3:2].[F:10][C:11]([F:32])([F:31])[C:12]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:32][C:11]([F:10])([F:31])[C:12]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18](/[CH:21]=[C:8]2/[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6](=[O:9])[S:7]/2)[CH2:17][CH2:16]1
Reactant: CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 75 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
To a solution of 4-(ethylamino)-1,3-thiazol-2(5H)-one (310 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (802 mg) in 2-propanol (10 mL) was added piperidinium acetate (312 mg). The reaction mixture was stirred at 75° C. for 4 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give the title compound (110 mg).
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:10](=[O:21])[NH:11][CH2:12][CH:13]=[C:14]([Sn](C)(C)C)[C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1Br.[F-].[Cs+]>CN(C=O)C.[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>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([C:14]2[C:15]3[N:16]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[S:8][C:9]=3[C:10](=[O:21])[NH:11][CH2:12][CH:13]=2)=[C:25]([CH:30]=1)[C:24]([O:23][CH3:22])=[O:33]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: C[Sn](C)(C)C1=CCNC(=O)c2sc(N3CCOCC3)nc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1C1=CCNC(=O)c2sc(N3CCOCC3)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A solution of 2-(morpholin-4-yl)-8-(trimethylstannyl)-5,6-dihydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one (0.160 g, 0.386 mmol) and methyl-2-bromo-5-chlorobenzoate (0.116 g, 0.464 mmol) in DMF (3.74 mL) was purged with Argon, then added cesium fluoride (0.205 g, 1.35 mmol), copper(I) iodide (0.0184 g, 0.0966 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0446 g, 0.0386 mmol). The mixture was stirred at 80° C. for 2 hours. The solution was cooled to room temperature, then evaporated some of the solvent. The residue was diluted with EA and water. The layers were separated and the aqueous layer was extracted twice more with EA. The combined organic layer was then washed with water and brine then dried over anhydrous sodium sulfate and concentrated. The residue was purified using column chromatography on silica gel (24 gr Analogix column, gradient DCM to 5% MeOH in DCM over 20 minutes) to give the product (0.129 g, 80%). LCMS: (AA) ES+ 420, 422. 1H NMR (300 MHz, d6-DMSO) δ: 7.95 (t, J=5.0 Hz, 1H), 7.71-7.67 (m, 1H), 7.66-7.59 (m, 1H), 7.39 (d, J=8.2 Hz, 1H), 6.28 (t, J=6.9 Hz, 1H), 3.66-3.57 (m, 6H), 3.47 (s, 3H), 3.30-3.25 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]1[CH2:19][CH:18]2[CH2:20][CH2:21][CH:15]([CH2:16][CH2:17]2)[CH2:14]1.[NH2-].[Na+].O>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH2:11][CH2:12][N:13]2[CH2:19][CH:18]3[CH2:20][CH2:21][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: N#CCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(CCN1CC2CCC(CC2)C1)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 20 parts of α-phenylacetonitrile in 300 parts by volume of toluene is added 94 parts of 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane dissolved in 500 parts by volume of toluene. The mixture is heated with stirring to about 80° C. and then 17 parts of sodium amide is added slowly over a period of 30 minutes. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether, the ether extract dried over calcium sulfate and distilled to afford 2-phenyl-4-(3-azabicyclo[3.2.2]non-3-yl)butyronitrile.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([N:20](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.CO>C(O)C.[OH-].[Pd+2].[OH-]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3C3=CCOCC3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: N[C@H]1CC[C@H](Oc2nccnc2C2CCOCC2)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Palladium hydroxide (0.040 g, 0.057 mmol, 20 weight % on carbon) was added to a stirred mixture of trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine (0.40 g, 0.77 mmol) in ethanol (4 mL). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at 50° C. for 18 h. Additional palladium hydroxide (0.040 g) and methanol (1 mL) were added, and the reaction mixture was stirred at 50° C. for an additional 5 h. The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was purified via silica gel chromatography to give trans-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexanamine as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13](Cl)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CC([O-])(C)C.[Na+].CC(O)=O>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc3nc(N4CCOCC4)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 160 °C
Yield: 19.2 %

Procedure:
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(chloro)imidazo[4,5-b]pyridine (100 mg; 0.25 mmol), R-(+)-BINAP (10 mg; 0.016 mmol), Pd2(dba)3 (22 mg; 0.024 mmol) are suspended in xylene (16 ml), morpholine (0.43 ml; 4.9 mmol) is added, followed by NaOtBu (47 mg; 0.49 mmol) and heated to 160° C. for 10 min. under argon. The reaction mixture is poured on water (100 ml) containing HOAc (2 ml) and extracted with TBME three times. The combined organic phases are washed with 2N Na2CO3, dried over Na2SO4 and evaporated to dryness. Purification via SiO2 chromatography (TBME/hexane 7:3 to 10:0) and recrystallisation from TBME yields the title compound as colorless crystals (22 mg: 19%).
Reaction SMILES: [Si]([O:8][CH:9]([C:15]1[S:16][C:17]([C:20]2[N:25]=[C:24]([NH:26][C:27]3[CH:31]=[C:30]([CH:32]4[CH2:34][CH2:33]4)[NH:29][N:28]=3)[C:23]([Cl:35])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(C(C)(C)C)(C)C.CCN(CC)CC>O1CCCC1.C(OCC)(=O)C>[Cl:35][C:23]1[C:24]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)=[N:25][C:20]([C:17]2[S:16][C:15]([CH:9]([OH:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:19][CH:18]=2)=[N:21][CH:22]=1
Reactant: CCOC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of ethyl 2-(tert-butyldimethylsilyloxy)-2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)acetate (200 mg, 0.37 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added Et3N.3HF (0.2 mL, 1.11 mmol, 3.0 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE:EA=1:1) to give Ethyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-hydroxyacetate (Compound 191) (123 mg, 78.6%). LC-MS (m/z): 420.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.73-0.77 (m, 2H), 0.96-1.01 (m, 2H), 1.21 (t, J=7.0 Hz, 3H), 1.91-1.98 (m, 1H), 4.14-4.19 (m, 2H), 5.42 (d, J=4.8 Hz, 1H), 6.44 (s, 1H), 6.52 (d, J=5.6 Hz, 1H), 7.13 (d, J=4.0 Hz, 1H), 7.67 (d, J=4.0 Hz, 1H), 8.40 (s, 1H), 9.29 (s, 1H), 12.30 (bs, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:10]2[S:11][C:12]([CH2:14][OH:15])=[CH:13][C:9]=2[CH:8]=1)C>C(O)C.Cl.O>[Cl:18][C:17]1[C:7]([O:6][CH2:5][C:4]([OH:20])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][OH:15])[S:11][C:10]=2[C:16]=1[Cl:19]
Reactant: CCOC(=O)COc1cc2cc(CO)sc2c(Cl)c1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cc2cc(CO)sc2c(Cl)c1Cl
Yield: 9 %

Procedure:
A suspension of 6.05 g of ethyl[(6,7-dichloro-2-hydroxymethylbenzo[b]thien-5-yl)oxy]acetate in 40 ml of 95% ethanol and 56 ml of 3N hydrochloric acid is stirred under a reflux for 1 hr. The cooled mixture is diluted with 200 ml of water and made acidic with concentrated hydrochloric acid until pH=2. The precipitate is extracted into ethyl acetate (3×200 ml) and the combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Recrystallization of the residue from acetone-hexane gives 0.5 g of [(6,7-dichloro-2-hydroxymethylbenzo[b]thien-5-yl)oxy]acetic acid, mp 187.5°-188.5°.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:13])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1.C(N(CC)CC)C.[C:27]1([N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[F:19][C:2]([F:18])([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:13][C:34]([N:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:35])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1c(OC(=O)N(c2ccccc2)c2ccccc2)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2 g (0.0069 mol) of methyl 2,6-bis(trifluoromethyl)-4-hydroxy-3-pyridinecarboxylate (example 4 of U.S. Pat. No. 4,655,816) in 20 mL of acetonitrile was added 0.7 g of triethylamine. A solution of 1.6 g (0.0069 mol) of diphenylcarbamyl chloride in 20 mL of acetonitrile was added to the above mixture and the resulting mixture was stirred at room temperature over the weekend. The precipitate formed was filtered off and the filtrate was concentrated in vacuo. The residue was slurried with ether. The insoluble material was filtered. The ether filtrate was concentrated and the residue was recrystallized from cyclohexane to give a white solid, mp 114-116° C.
Reaction SMILES: F[B-](F)(F)F.[FH:6].[FH:7].F.C(N(CC)CC)C.[C:16]([CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17]>>[C:16]([CH:21]1[CH2:26][CH2:25][C:24]([F:7])([F:6])[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: F
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(F)(F)CC1
Reaction time: 23 h

Procedure:
Procedure for the fluorination of carbonyls in various solvents (examples 68-69): To a mixture of the diethylaminodifluorosulfinium tetrafluoroborate (458 mg, 2.0 mmol) and triethylamine trihydrofluoride (163 μL, 1.0 mmol) in the solvent (2.0 mL), at room temperature and under nitrogen, is added 4-carboethoxycyclohexanone (159 μl, 1.0 mmol). The reaction mixture is stirred for 23 h, then quenched with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture was extracted using pentane. The organic phases were combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents were evaporated to provide 4-carbethoxy-1,1-difluorocyclohexane admixed with 4-carbethoxy-1-fluorocyclohex-1-ene as a clear oil (refer to the following table for yields and product distribution).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.C(N[C:29]([C:31]1N=CN2[C:40]3[CH:41]=CC(F)=C[C:39]=3[C:38](=O)[N:37](C)[CH2:36][C:35]=12)=O)C#C.IN1C(=O)CCC1=O.C(NCCCC)CCC>C1COCC1>[CH2:36]([N:37]([CH2:20][C:17]1[O:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=23)=[N:19][CH:18]=1)[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:35][CH2:31][CH3:29]
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Agent: O=C1CCC(=O)N1I
Solvent: CCCCNCCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 42 h
Yield: 15 %

Procedure:
125 ml of a crude THF solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one (prepared from 15.6 g (0.050 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide and 16.9 g (0.075 mol) of N-iodosuccinimide, subsequently completely freed from the solvents, dried azeotropically several times with toluene and dissolved in 500 ml of THF) were treated with 18.5 ml (0.109 mol) of dibutylamine and stirred at room temperature for 42 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the orange product was chromatographed over silica gel with dichloromethane/methanol 39:1 as the eluent. There was obtained 0.83 g (15%) of 3-(5-dibutylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 100-103° (dec.).
Reaction SMILES: [OH-:1].[Na+:2].[CH:3]1([C:8]2[C:9](=[O:21])[O:10][C:11](=[O:20])[C:12]=2[C@H:13]2[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6][CH2:5][CH2:4]1>O1CCOCC1>[CH:3]1(/[C:8](=[C:12](\[C@H:13]2[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15][CH2:14]2)/[C:11]([O-:10])=[O:20])/[C:9]([O-:21])=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=C1OC(=O)C([C@H]2CC[C@@H](O)CC2)=C1C1CCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C([O-])/C(=C(\C(=O)[O-])[C@H]1CC[C@@H](O)CC1)C1CCCC1
Reaction time: 3 h

Procedure:
A 1 M NaOH (0.3 ml, 0.30 mmol) was added to a solution of 3-cyclopentyl-4-(cis-4-hydroxycyclohexyl)furan-2,5-dione (40 mg, 0.15 mmol) in 1,4-dioxane (1.0 ml) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, and the residue was dried in vacuo to give the title compound as a colorless solid (50 mg, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[O:6])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccc(C)cc2)cc1N
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(C)cc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 48 h
Yield: 33 %

Procedure:
A suspension of 3-amino-4-methoxy-N-p-tolyl-benzamide from Example 7 (0.515 g, 2.01 mmol) in methylene chloride (75 mL) was heated to the boiling point, then 3,5-dichlorophenyl isothiocyanate (0.411 g, 2.01 mmol) was added, and the reaction was allowed to stand at room temperature. After 2 days, the mixture was stripped of solvent at 40° C. and the residue triturated in warm methylene chloride. The solid was filtered off, redissolved in methylene chloride/methanol, and filtered to clarity. Evaporation of the solvent afforded the product (0.305 g); m.p. 178-180° C.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:15])[C@H:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:14])[NH2:13])[NH2:7].[OH-].[Na+]>CO>[NH2:7][C@H:6]([C:5]([OH:15])=[O:4])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:13])[NH2:14]
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)NCCC[C@H](N)C(=O)O
Temperature: 110 °C

Procedure:
1.31 Gram (5 mmol) of L-arginine methyl ester dihydrochloride was dissolved in 4 ml of methanol, and 2.5 ml of 2 N aqueous sodium hydroxide solution was added thereto to prepare a treating agent solution. An untreated cotton cloth (160 mm×170 mm, 5.0 g) was allowed to uniformly absorb the total amount of the above treating agent solution and then air-dried for an hour at room temperature. The dried cloth was heat-treated for 20 minutes at 140° C. in a batch type hot air oven (“IPHH-2000”, an inert oven manufactured by Tabaiesbeck Co., Ltd.) and then washed with water. It was further washed with 5% aqueous sodium bicarbonate solution and rinsed three times with water and subsequently washed with 10% aqueous citric acid solution and rinsed three times with water, and finally washed with a JAFET standard detergent solution for household washing machine, rinsed with water and air-dried. A part of this cloth was cut and a solution of ninhydrin in butanol was sprayed on it. Thereafter, it was heated for 10 minutes in an oven of 110° C. to cause coloring thereby the presence of the amino acid was confirmed. As a result of determination for the amount of the bonded L-arginine, it was 0.08 mmol based on 1 g of the cloth. The degree of esterfication was 0.013.
Reaction SMILES: FC1C(N[C@@H](C(C)(C)C)CO)=NC(C2C3C(=NC=C(F)C=3)NC=2)=NC=1.[F:26][C:27]1[C:28]([NH:55][C@@H:56]([C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:57][OH:58])=[N:29][C:30]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([F:44])[CH:42]=3)[N:37](S(C3C=CC(C)=CC=3)(=O)=O)[CH:36]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]>>[F:26][C:27]1[C:28]([NH:55][C@@H:56]([C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:57][OH:58])=[N:29][C:30]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([F:44])[CH:42]=3)[NH:37][CH:36]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CO)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Agent: CC(C)(C)[C@@H](CO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Product: CC(C)(C)[C@@H](CO)Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F

Procedure:
Alcohol, 24, was synthesized in a manner similar to compound 32 utilizing the same deprotection procedure, starting with compound 98a: 1H NMR (400 MHz, CDCl3) δ 10.27 (brs, 1H), 8.25 (d, J=9.4 Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.23 (d, J=10.3 Hz, 1H), 5.20 (d, J=9.6 Hz, 1H), 4.41 (t, J=7.4 Hz, 1H), 4.09 (d, J=11.3 Hz, 1H), 3.82-3.58 (m, 1H), 0.99 (d, J=19.5 Hz, 9H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:16][CH:15]=1)[CH3:12]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCOc1ccc(C(=O)C2CC2)cc1

Procedure:
Alternatively, the substituted-phenyl cyclopropyl ketones may be prepared by reacting cyclopropanecarboxylic acid chloride with an appropriately substituted-phenyl compound in the presence of a Friedel-Crafts catalyst, e.g., aluminum chloride. In Example 6, Step A, cyclopropanecarboxylic acid chloride is reacted with ethoxybenzene in the presence of aluminum chloride, yielding cyclopropyl (4-ethoxyphenyl) ketone.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([NH:44][NH2:45])=[O:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH2:46][C:47](=[O:51])[C:48](O)=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([NH:44][NH:45][C:48](=[O:49])[C:47]([NH2:46])=[O:51])=[O:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NC(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
HATU (0.95 g, 2.5 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (1.00 g, 2.5 mmol), 2-amino-2-oxoacetic acid (0.18 g, 2.1 mmol) and DIPEA (1.08 g, 8.4 mmol) in DMF (10 mL). The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The aqueous layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (1:1 EtOAc/hexane) to give 2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoacetamide (0.57 g, 64%). ESI-MS (EI+, m/z): 362 [M+H]+.