Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][N:20]=[N+:21]=[N-:22])[CH2:16][CH:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Yield: 73.3 %

Procedure:
The mesylate from step i (32.6 g, 110 mmol) was treated with sodium azide (21.45 g, 330 mmol) in DMF at 80° C. for 24 hrs. The solvent was evaporated, the residue was taken up in DCM, filtered and washed with saturated NaHCO3 (aq). The solution was dried with Na2SO4 and concentrated to a brown oil which was purified by flash chromatography using a gradient of ethyl acetate and hexane to afford the title compound as a white solid (19.55 g, 73%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]([OH:9])=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]([NH:10][C:11]2[N:16]=[N:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]3)=[CH:13][CH:12]=2)=[O:9])[CH2:2][CH2:3]1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)COCC1CC1
Product: O=C(COCC1CC1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use cyclopropylmethoxyacetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (41% yield). 1H NMR (300 MHz, CDCl3) δ 9.17, 8.32, 7.72, 7.61, 7.54, 7.35, 4.10, 4.01-3.88, 3.69-3.61, 3.57-3.55, 3.43, 3.33-3.30, 1.14-1.08, 0.61-0.57, 0.27-0.24. MS (ES+) m/z 464.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34](Cl)=[C:29]3[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34]([O:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][C:6]=4[F:11])=[C:29]3[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 160 °C
Yield: 36.9 %

Procedure:
A mixture of 3-fluoro-4-hydroxy-benzoic acid methyl ester (Combi-Blocks Inc, San Diego, Calif., USA; 31 mg, 0.178 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.391 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-[4-(2-fluoro-4-methoxycarbonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (31 mg, 37%) as a white solid. Mass spectrum MH+=472.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:41][C:42]([O:44][CH3:45])=[O:43]>[Cl-].[NH4+].O>[CH3:45][O:44][C:42](=[O:43])[CH2:41][O:28][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:11]2[C:6]=1[C:7]([CH3:27])=[C:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=1)[C:9]([CH:12]([CH3:13])[CH3:14])=[N:10]2
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(F)ccc(O)c12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(F)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 8-fluoro-2-isopropyl-4-methyl-3-(4-pyrazol-1-yl-benzyl)quinolin-5-ol (0.066 g), potassium carbonate (0.073 g) and N,N-dimethylformamide (0.35 mL) was treated with methyl bromoacetate (0.020 mL), and the resulting mixture was stirred at room temperature for 12 hours. The mixture was diluted with saturated aqueous ammonium chloride solution (3.0 mL) and water (20 mL), and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water (2.0 mL) and saturated aqueous sodium chloride solution (2.0 mL), and dried over magnesium sulfate. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume) gave title compound as a colourless oil (0.079 g).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10]>CC(C)=O>[CH3:12][O:11][C:9]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C@H:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)=[O:10]
Reactant: O=C1C=CCC1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C(C(=O)OC)[C@H]1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
Under an atmosphere of argon, 12.0 mg (0.02 mmol, S/C=50) of RuH[(R,R)-Tsdpen] (1,3,5-trimethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 114 μL (1.0 mmol) of dimethyl malonate, and 1 mL of acetone were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 213 mg (99% yield) of the title compound. The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.0 mL/min, detection at 210 nm) and it was found to be 89% ee.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[Br:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1.[Cl-].[Na+]>C(OCC)C.O1CCCC1>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:11]2[N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=3)(=[O:8])=[O:9])[CH:14]=[CH:13][N:12]=2)[OH:33])=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2)cc1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccccc2)c2ccc(Br)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 33.3 g. (0.15 mol) of 1-(toluene-p-sulphonyl)imidazole (H. A. Staab and K. Wendel, Ber. 93, (1960) 2902) in 300 ml. of anhydrous tetrahydrofuran and 150 ml. of anhydrous diethyl ether at a temperature of -40° to -50° C. under a nitrogen atmosphere were added drop-wise 91 ml. of a 20% solution of butyllithium in n-hexane (0.20 mol.) dissolved in 150 ml. of anhydrous diethyl ether. Upon completion of the addition, the mixture was kept at a temperature of -40° to -50° C. for one hour. Next and under identical conditions as to temperature 44.4 g. (0.17 mol) of 4-bromobenzophenone in 200 ml. of anhydrous tetrahydrofuran and 100 ml. of anhydrous diethyl ether were added drop-wise and the mixture was kept under the same conditions for another 3.5 hours. Cooling was stopped and the mixture was allowed to reach ambient temperature in 1/2 hour. It was then poured out into about 250 ml. of a sodium chloride solution. The aqueous layer was separated and discarded, the organic solvents layer was washed with 100 ml. of a sodium chloride solution, dried and concentrated. The residual oil was brought to crystallisation by addition of a very small amount of diethyl ether. Purification was brought about by crystallisation from warm ethanol to which some acetone was added. Melting point of the product was 138°-140° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:30]([C:41]([F:44])([F:43])[F:42])[CH:29]=1>CN(C=O)C>[CH:35]1([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][C:30]=2[C:41]([F:42])([F:43])[F:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: FC(F)(F)c1cc(CBr)ccc1CC1CCCCC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(CC4CCCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a stirred reaction mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (40 mg, 0.15 mmol) and cesium carbonate (75 mg, 0.23 mmol) in DMF (1 mL) was added 4-(bromomethyl)-1-(cyclohexylmethyl)-2-(trifluoromethyl)benzene (78 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h. The solid was filtered and washed with ethyl acetate. The combined filtrate was concentrated, and the residue was purified by preparative TLC to give the title compound (40 mg) as an oil. LCMS m/z=514.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.55-1.72 (m, 6H), 2.07-2.15 (m, 1H), 2.50 (dd, J=16.7 and 11.2 Hz, 1H), 2.66 (d, J=6.8 Hz, 2H), 2.70-2.86 (m, 4H), 3.52-3.58 (m, 1H), 4.18-4.25 (m, 2H), 5.08 (s, 2H), 6.85 (dd, J=8.8 and 2.4 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.31 (d, J=7.9 Hz and 1.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 8.46 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH3:16])[CH:9]=1)=O)C.[CH3:18][NH:19][NH2:20]>C1(C)C=CC=CC=1>[OH:3][C:4]1[N:19]([CH3:18])[N:20]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH3:16])[CH:9]=2)[CH:5]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(C)c1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(O)n(C)n2)cc1C
Yield: 68 %

Procedure:
At room temperature, to a mixture of 3-(4-methoxy-3-methyl-phenyl)-3-oxo-propionic acid ethyl ester (described in Reference Preparation example 89) 14.8 g and toluene 100 ml was added N-methyl hydrazine 29 g, and the resulting mixture was stirred for twelve hours. The toluene was distilled off. At room temperature, to the reaction mixture was added water 100 ml and the resulting mixture was acidified with 10% aqueous hydrochloric acid solution and was stirred for three hours. The precipitates were filtered and were washed with water 400 ml and ethyl acetate 500 ml, and then were dried under reduced pressure to give 5-hydroxy-3-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 9.3 g.
Reaction SMILES: CN.C([Li])CCC.[OH:8][C:9]1([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([N:29](C(C)C)[CH:30](C)C)=[O:28])[CH:21]=[CH:20]3)[C:16]2[N:12]([CH:13]=[N:14][CH:15]=2)[CH2:11][CH2:10]1.O>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[OH:8][C:9]1([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([NH:29][CH3:30])=[O:28])[CH:21]=[CH:20]3)[C:16]2[N:12]([CH:13]=[N:14][CH:15]=2)[CH2:11][CH2:10]1
Reactant: CC(C)N(C(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1)C(C)C
Agent: CN
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Reaction time: 0.33 h
Yield: 72 %

Procedure:
Methylamine (2M in THF, 200 ml) was dissolved in dry THF (300 ml) and the mixture was cooled to −70° C. n-Butyl lithium (1.6 M; 250 ml) was added dropwise and the mixture was stirred at the same temperature for 20 min. The above-mentioned solution was added to a suspension (600 ml) of 6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N,N-diisopropyl-2-naphthamide (37.7 g) in dry THF with a Teflon needle while stirring the mixture under ice-cooling, and the mixture was stirred at room temperature for 16 h. The saturated brine and water were added to the reaction mixture, and the mixture was diluted with ethyl acetate. The mixture was stirred for 10 min and the precipitated crystals were filtrated. The organic layer of the filtrate was separated and the aqueous layer was extracted with THF/ethyl acetate (1:1) mixture. The organic layers were combined and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in THF-ethyl acetate (1:1). The precipitated crystals were collected by filtration to give colorless powder crystals. The obtained crystals were combined and recrystallized from ethanol-ethyl acetate to give the title compound (22.1 g) as colorless powder crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[C:25]([O:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1)(=[O:27])[CH3:26]
Reactant: O=C1Cc2nnc(CO)n2-c2ccc(Cl)cc2N1c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.4 g of 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 1.0 g of acetic anhydride in 10 ml of pyridine are warmed in a steam bath for 0.2 hour and stirred at room temperature for 10 hours. The reaction mixture is cooled, diluted with 100 ml methylene chloride and washed with 100 ml water containing 0.84 g sodium bicarbonate. The organic phase is washed four times with water, dried and evaporated. The residue is triturated with a minimum amount of ether and the title compound filtered off, dried and recrystallized from methylene chloride and ether.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][CH:12]=[C:11]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:13][CH:12]=[C:11]([CH2:14][N:15]3[N:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cc(Cn3ncc([N+](=O)[O-])n3)cs2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2cc(Cn3ncc(N)n3)cs2)OCCO1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-ylmethyl]-4-nitro-2H-[1,2,3]triazole (50 mg, 0.17 mmol), iron powder (29 mg, 0.51 mmol) and NH4Cl (46 mg, 0.84 mmol) in a mixture of EtOH (1.0 mL) and water (0.5 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a light yellow oil. LC-MS-conditions 02: tR=0.78 min; [M+H]+=267.28.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O.[NH2:48][C:49]1[NH:53][N:52]=[N:51][N:50]=1>CN(C=O)C.O>[CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=3)[N:9]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:48][C:49]4[NH:53][N:52]=[N:51][N:50]=4)=[O:30])=[CH:31][CH:32]=3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of 70 mg product from Step A above, 38.1 mg EDC, 26.9 mg HOBt in 1 mL DMF was stirred at room temperature for 30 minutes. 5-Aminotetrazole monohydrate (20.5 mg) was added and the mixture stirred for additional 16 hours. Precipitate the product by adding 1 mL water to the reaction mixture. Collect the product by filtration, wash it with 1:1 DMF and water, water, and MeCN, and dry to give the title compound as a white solid. 1H NMR (CD3OD, 600 MHz) δ 7.92 (d, J=8.4 Hz, 2H), 7.42˜7.45 (m, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 6.32 (s, 1H), 5.42 (s, 2H), 2.67 (tt, J=3.5 & 11.5 Hz, 1H), 1.97˜2.01 (m, 2H), 1.81˜1.85 (m, 2H), 1.72˜1.76 (m, 1H), 1.46˜1.53 (m, 2H), 1.38˜1.47 (m, 2H), 1.26˜1.35 (m, 1H). LC-MS: 2.30 min. (M+H=512.3).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:23]/[O:24][C:25](=[CH2:42])[C:26]([O:28]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:27])/[C:8]([NH:10][CH:11]2[C:14]([CH3:16])([CH3:15])[N:13]([O:17][S:18]([OH:21])(=[O:20])=[O:19])[C:12]2=[O:22])=[O:9])[N:6]=1.C(Cl)Cl.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:23]/[O:24][C:25](=[CH2:42])[C:26]([OH:28])=[O:27])/[C:8]([NH:10][CH:11]2[C:14]([CH3:15])([CH3:16])[N:13]([O:17][S:18]([OH:21])(=[O:19])=[O:20])[C:12]2=[O:22])=[O:9])[N:6]=1
Reactant: C=C(O/N=C(\C(=O)NC1C(=O)N(OS(=O)(=O)O)C1(C)C)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: ClCCl
Product: C=C(O/N=C(\C(=O)NC1C(=O)N(OS(=O)(=O)O)C1(C)C)c1csc(N)n1)C(=O)O
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
To the flask containing (±)-(Z)-2-[[[1-(2-amino-4-thiazolyl)-2-[[4,4-dimethyl-2-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-propenoic acid, diphenylmethyl ester was added methylene chloride (10 ml) and anisole (10 ml). After cooling to -5° C., trifluoroacetic acid (8 ml) was added and the reaction mixture was stirred at -5 to 0° C. under argon for 45 minutes. Toluene was added, and the reaction mixture was evaporated to a residue. Water and hexane were added to the residue and the layers were separated. The aqueous layer was adjusted to pH 2.5 with 10% potassium bicarbonate. An HP20 column was run eluting first with water and then an acetone/water gradient. The appropriate fractions were combined and lyophilized to give the title compound as a white solid. 1H-NMR (1:1 D2O/CD3CN) δ1.57 (s, 3H); 1.75 (s, 3H); 5.09 (s, 1H); 5.75 (d, J =2.3 Hz, 1H); 5.86 (d, J2.3 Hz, lH); 7.42 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:7]2[O:8][C@@H:6]2[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2OC(C)(C)[C@H](O)[C@@H:23]([N:30](CC(OCC)=O)C3C=CC=CC=3)[C:22]=2C=1)#[N:17].NCCC1C=CC=CN=1>>[N:17]1[CH:16]=[CH:18][CH:19]=[CH:20][C:21]=1[CH2:22][CH2:23][NH:30][C@H:6]1[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:15])([CH3:1])[C@@H:7]1[OH:8]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Agent: NCCc1ccccn1
Product: CC1(C)Oc2ccc(C#N)cc2[C@H](NCCc2ccccn2)[C@H]1O
Temperature: 25 °C

Procedure:
A solution of (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile ((1.0 g, 5.0 mmol, the title A compound of Example 3) and 2-aminoethylpyridine (1.1 g, 9.0 mmol) was heated in a sealed tube at 75° C. for 18 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography to afford an oil, which solidified upon standing (1.4 g, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:19]([Cl:34])=[CH:18][N:17]=1>>[Cl:34][C:19]1[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CC1(C)CCCOc2c(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cccc21

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 179. Product was isolated as a tan foam (51 mg, 50%). LCMS (m/e) 494 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.22 (d, 1H, J=7.8 Hz), 7.96 (s, 1H), 7.72 (s, 1H), 7.01 (dd, 1H, J=7.8, 7.58 Hz), 6.93 (d, 1H, J=8 Hz), 5.42 (m, 1H), 5.24 (m, 1H), 4.02 (m, 2H), 3.93 (m, 1H), 3.27 (m, 1H), 2.80 (s, 3H), 2.24 (m, 2H), 2.08 (m, 2H), 1.84 (m, 2H), 1.69 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][NH:17]3)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ncc(OC[C@@H]2CCN2)cc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To 5-phenyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 67a (380 mg) was added TFA in CH2Cl2 at 0° C., and the mixture was stirred for 30 minutes. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO3 to pH 8, then extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH:NH4OH 10:1:0.1 to afford to give the free base of the title compound. MS (CI/NH3) m/z 275 (M+H)+, 277 (M+2H)+. 1H NMR (CDCl3, 300 MHz) δ 2.21-2.46 (m, 2H), 3.41-3.50 (m, 1H), 3.73 (dd, J=7.5, 8.0 Hz, 1H), 4.0-4.12 (m, 2H), 4.25-4.35 (m, 1H), 7.26 (d, J=3 Hz, 1H), 7.41-7.48 (m, 5H), 8.09 (d, J=3 Hz, 1H). The base was converted to the salt by treatment with hydrogen chloride saturated EtOH to give the title compound (256 mg). mp 148-150° C. MS (CI/NH3) m/z 275 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.66-274 (m, 2H), 4.06-4.21 (m, 3H), 4.46 (d, J=4.1, 2H), 4.92-5.01 (m, 1H), 7.50-7.59 (m, 5H), 7.60 (d, J=3.0, 1H), 8.20 (d, J=3.0, 1H). Anal. Calcd for C15H15N2OCl.2 HCl: C, 51.82; H, 4.93; N, 8.06. Found: C, 52.10; H, 5.29; N, 7.70. [α]25D=+7.5° (c 0.16, MeOH).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:12])OC)[CH:6]=[CH:7][CH:8]=1.[CH:13]([NH:15][NH2:16])=O.O>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([C:9]2[N:12]=[CH:13][NH:15][N:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNC=O
Reactant: COC(=N)c1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Brc1cccc(-c2nc[nH]n2)c1
Temperature: 25 °C

Procedure:
To a slurry of methyl 3-bromobenzenecarboximidoate hydrochloride (example IV-21 Step 1; 0.541 g; 2.18 mmol) in pyridine (3 mL) at 0° C. was added a solution of formic hydrazide (0.157 g; 2.62 mmol). The flask was stoppered and gradually warmed to room temperature (overnight) and poured into water (˜20 mL). Precipitated solid was collected by filtration and the filtrate was extracted with EtOAc (×3). Combined extracts were washed (water, brine), dried over Na2SO4, concentrated in vacuo. The residue obtained was combined with the above precipitate, and the whole was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid. LC/MS (method A) tR 2.49 min, m/z 224, 226 (M+H, Br isotopes).