Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O.[OH-].[K+]>[I:1][C:2]1[C:11]([N+:15]([O-:17])=[O:16])=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: O=c1[nH]c2cc(Cl)cc(I)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(I)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
The method of Cheeseman, G. W. H. (J. Chem. Soc. 1170 (1962)) was adapted. 5-Iodo-7-chloro-1,4-dihydro-2,3-quinoxalinedione (96 mg, 0.33 mMol) was dissolved in concentrated H2SO4 (1.0 mL) at 0° C. for 30 min and then KNO3 (36 mg, 0.36 mMol, Baker) was added into this solution. The mixture was stirred at 0° C. for 0.5 h and then at room temperature for 30 h. It was poured into ice water (5 g). A precipitate came out and was collected by filtration giving 101 mg of crude title compound. The sample was dissolved in 1N KOH (5 mL) and then red precipitate was removed by filtration. The filtrate was acidified to pH=2 with 4N HCl to give a brown precipitate which was collected by filtration and then dried in air at 50° C. for 4 h. The title compound (75 mg, 67%) was obtained as a brown powder. Crystallization from DMSO/H2O afforded pure compound (34 mg) as brown microcrystals, mp: 388°-90° C. IR (KBr, cm-1): 3462, 3200, 3050, 1712, 1587, 1537. NMR (1H, DMSO-d6): δ7.289 (s, 1H), 10.846 (s, 1H), 12.225 (s, 1H). HRMS: calcd for C8H3N3O4ClI (M+) m/z: 366.8855, found pending. Potency relative to DCK: partially active.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:18])[CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C1COCC1.O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:9](=[O:18])[C@@H:10]([OH:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:20]
Reactant: O=C(ON1C(=O)CCC1=O)C(O)c1ccccc1
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)[C@@H](O)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of the hydroxy-phenyl-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (0.70 g, 2.8 mmol) in THF/H2O (10 mL, 1:1) was added diethylamine (25% in H2O, 0.58 mL, 5.6 mmol). After stirring for 16 h, the reaction solvent was evaporated under reduced pressure. The resulting residue was diluted with H2O and extracted with EtOAc (3×50 mL). The organic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:5]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(Oc2ccccc2[N+](=O)[O-])(c2ccccc2)CC1
Reactant: [H][H]
Solvent: CO
Product: CN1CCC(Oc2ccccc2N)(c2ccccc2)CC1
Yield: 77.8 %

Procedure:
A solution of 1-methyl-4-(2-nitrophenoxy)-4-phenylpiperidine (6.4 g) in methanol (200 ml) was hydrogenated at atmospheric pressure and ambient temperature until the theoretical uptake of hydrogen had occurred (about 2 hours). The catalyst was removed by filtration, the solvent removed under reduced pressure and the residue recrystallised twice from IPE to give the title compound (4.5 g) m.p. 129°-30°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[C:3]=1O.C(=O)([O-])[O-].[K+].[K+].ClCC([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=O.ClC1C=C(C)C=C(Cl)C=1OCC(NC1C=CC(C)=CC=1)=O.C[O-].[Na+]>CC(O)C.CO.CCCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1
Reactant: Cc1ccc(NC(=O)CCl)cc1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Agent: C[O-]
Agent: Cc1ccc(NC(=O)COc2c(Cl)cc(C)cc2Cl)cc1
Agent: O=C([O-])[O-]
Solvent: CCCCCCC
Solvent: CO
Solvent: CC(C)O
Product: Cc1ccc(Nc2c(Cl)cc(C)cc2Cl)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
12 g (67 mmol) of 2,6-dichloro-4-methylphenol are dissolved in 25 ml of 2-propanol followed by the addition of 10.5 g (76 mmol) of potassium carbonate and 12.8 g (70 mmol) of 2-chloro-N-(4-methylphenyl)acetamide. The mixture is refluxed for 4 h. At this time, the formation of A: 2-(2′,6′-dichloro-4′-methylphenoxy)-N-(4-methylphenyl)acetamide is completed. 13.6 ml of sodium methylate solution 30% in methanol are slowly added and the temperature is increased to about 85° C. by distilling 25 ml of solvent. The mixture is stirred 2 h more to complete the formation of B. 25 ml of water are added at 70° C. to obtain a 2 phases solution. The lower layer is discarded. The upper layer is diluted with 20 ml of heptane-fraction and washed with 2×20 ml of water. The organic phase is separated and concentrated in vacuo to obtain N-(2′,6′-dichloro-4′-methylphenyl)-4-methylaniline as a crude oil. GC/MS: 265 (100, M+), 195 (130).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:27]1CCOCC1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].CC1C=C(C)N=C(C)C=1>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=4)[S:16][C:12]=3[C:11](=[O:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: CC(=O)Nc1cc(-c2cc3c(s2)CCCC3c2ccc(Cl)cc2)ccn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CC(=O)Nc1cc(-c2cc3c(s2)C(=O)CCC3c2ccc(Cl)cc2)ccn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
In a 100 mL round bottomed flask was placed N-{4-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]pyridin-2-yl}acetamide (229.6 mg, 0.5996 mmol), 1,4-dioxane (15 mL) and acetonitrile (15 mL). To the mixture were added a solution of potassium persulfate (665.0 mg, 2.460 mmol) and copper (II) sulfate pentahydrate (68.9 mg, 0.276 mmol) in water (30 mL) and γ-collidine (320 uL, 2.4 mmol). The resulting blue-white suspension was stirred for 16 hr at 90° C. The mixture was allowed to cool to rt and then concentrated under reduced pressure to remove 1,4-dioxane and acetonitrile. The aqueous residue was extracted with EtOAc (50 mL×2). The combined organic phases were washed with 10% NaHSO3 aq (30 mL), saturated aqueous solution of NaHCO3 (30 mL), saturated aqueous solution of ammonium chloride (30 mL), and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by prepacked silica gel (24 g) column chromatography, eluting with 20% to 100% EtOA/hexane to yield the title compound (95 mg; 40%) as a colorless foam, which was recrystallized from EtOAc and ether to obtain a colorless crystalline solid. LCMS: (FA) ES+ 397, 399; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.64 (br s, 1H), 8.30-8.34 (m, 2H), 7.40-7.45 (m, 3H), 7.29 (d, 2H), 7.21 (s, 1H), 4.39 (dd, 1H), 2.59-2.75 (m, 1H), 2.20-2.52 (m, 3H), 2.09 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.[Br:20][C:21]1[C:22]([N+:26]([O-:28])=[O:27])=[N:23][NH:24][CH:25]=1>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:20][C:21]1[C:22]([N+:26]([O-:28])=[O:27])=[N:23][N:24]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:19])([F:18])[F:7])[CH:10]=2)[CH:25]=1
Reactant: O=[N+]([O-])c1n[nH]cc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1nn(-c2cccc(C(F)(F)F)c2)cc1Br
Reaction time: 42 h

Procedure:
Pyridine (99%, 0.512 mL, 6.27 mmol) and [3-(trifluoromethyl)phenyl]boronic acid (649 mg, 3.42 mmol) were added to a solution of 4-bromo-3-nitro-1H-pyrazole (596.6 mg, 3.108 mmol) in tetrahydrofuran (9 mL); copper(II) acetate (99%, 855 mg, 4.66 mmol) was then added, and the reaction was stirred for 42 hours. The reaction mixture was filtered through Celite and concentrated in vacuo, then partitioned between EtOAc (5 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3×5 mL), and the combined organic layers were washed with water (5 mL) and dried over sodium sulfate. After filtration and removal of solvent under reduced pressure, the residue was purified via silica gel chromatography (Gradient: 0% to 20% EtOAc in heptane) to provide C56. The regiochemistry of C56 was assigned based on NOE experiments. Yield: 779 mg, 2.32 mmol, 75%. GCMS m/z 335, 337 (M+). 1H NMR (400 MHz, CDCl3) δ 7.68-7.76 (m, 2H), 7.94-7.98 (m, 1H), 7.99-8.01 (m, 1H), 8.14 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]12[O:19][CH:15]([CH2:16][NH:17][CH2:18]1)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:7][N:6]1[C:2]([N:17]2[CH2:18][CH:11]3[O:19][CH:15]([CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]3)[CH2:16]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Yield: 65 %

Procedure:
To a microwave reaction vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (141 mg, 0.88 mmol), tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (200 mg, 0.88 mmol). Ethanol (8 mL) and diisopropylethylamine (0.92 mL, 5.25 mmol) were added and the mixture was irradiated with a microwave for 60 min at 130° C. The mixture was cooled, concentrated and purified via flash chromatography, ethyl acetate/heptane 0% to 100% to afford yellow oil tert-butyl 7-(2-methyl-4-nitro-pyrazol-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (202 mg, 65%).
Reaction SMILES: FC(F)(F)C([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]4[C:37](=[O:38])[N:36]([C:39]5[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[O:31])=[CH:25][C:24]=3[F:46])[NH:15][N:14]=2)[CH2:7]1)=O.Cl.CCOC(C)=O>[Li+].[OH-].C1COCC1.CO>[F:46][C:24]1[CH:25]=[C:26]([NH:29][C:30]([C:32]2[C:37](=[O:38])[N:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[N:35]=[CH:34][CH:33]=2)=[O:31])[CH:27]=[CH:28][C:23]=1[O:22][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[NH:15][N:14]=[C:13]([NH:12][CH:8]3[CH2:9][CH2:10][CH2:11][CH:6]([OH:5])[CH2:7]3)[C:21]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCCC(OC(=O)C(F)(F)F)C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCCC(O)C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 29.1 %

Procedure:
LiOH (2M solution, 2 drops) was added into a solution of 3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)cyclohexyl 2,2,2-trifluoroacetate (10 mg, 0.015 mmol, obtained from Example 131, Step C) in THF (0.5 mL) and MeOH (0.1 mL). HCl (5M, 0.1 mL). EtOAc was added to dilute the reaction mixture. The organic layer was separated, washed with brine, dried with Na2SO4, filtered and concentrated to afford the product (2.5 mg, 29% yield) as a yellow solid. LRMS (APCI pos) m/e 574.2 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ 8.38 (d, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.05 (dd, 1H), 7.66-7.70 (m, 2H), 7.56-7.62 (m, 1H), 7.48-7.54 (m, 1H), 7.38-7.44 (m, 2H), 6.80-7.00 (m, 1H), 6.00-6.05 (m, 1H), 3.80-4.00 (m, 2H), 3.50-3.80 (m, 1H), 1.80-2.00 (m, 1H), 1.60-1.80 (m, 2H), 1.40-1.60 (m, 1H), 1.10-1.30 (m, 2H), 0.80-0.90 (m, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.Cl.[CH3:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:20]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CCCN1C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
5-Fluoro-2-nitrotoluene (1.55 g, 10 mmol) was dissolved in anhydrous DMSO. To this solution was added 2-(2R)-methyl-[1,3′]bipyrrolidinyl hydrochloride (2.30 g, 15 mmol), followed by powdered potassium carbonate. The suspension was heated on an oil bath to 85° C. for 3 h when the starting material was consumed as determined by TLC (5% MeOH/DCM) and LC/MS. To the suspension were added 20 mL of water and 50 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with sodium bicarbonate (20 mL), and brine (15 mL×2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5% MeOH in DCM to get the title compound as a yellow solid after drying, 2.70 g (93%). MS: 290 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:49]>C(Cl)Cl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N+:37]([O-:49])([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)cc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cn1nc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CC[N+](C)([O-])C3)c1=O
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To a solution of 6-tert-butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)phthalazin-1(2H)-one (500 mg, 854 μmol, 1 equiv.) in DCM (10 ml) was added 3-chlorobenzoperoxoic acid (191 mg, 854 μmol, 1 equiv.). The reaction mixture was stirred for 18 h. The reaction mixture was diluted with methylene chloride and washed with 1.0 N NaOH (aq). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford a liquid that gradually hardened to a low melting, yellow solid under vacuum, overnight. The solid was dissolved in a minimum of methanol, diluted with methylene chloride and loaded onto a column. The crude material was purified by flash chromatography (silica gel, 40 g, 50% 60:10:1 DCM:MeOH:NH4 OH in DCM) to give 2-(6-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H) -yl)-3-(hydroxymethyl)pyridin-4-yl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 5-oxide (158.5 mg, 263 μmol, 30.9% yield) as a yellow solid. (M+H)+=602 m/e. 1H NMR (300 MHz, METHANOL-d4) d ppm 1.47 (s, 9 H) 3.45 (s, 3 H) 3.74 (dt, J=12.46, 2.46 Hz, 1 H) 3.89 (s, 3 H) 4.07 (td, J=11.80, 4.72 Hz, 1 H) 4.25-4.43 (m, 1 H) 4.45-4.62 (m, 2 H) 4.61-4.85 (m, 3 H) 6.13 (s, 1 H) 7.54-7.79 (m, 2 H) 7.87 (d, J=1.51 Hz, 1 H) 8.07 (s, 1 H) 8.50 (d, J=2.64 Hz, 1 H) 8.66 (d, J=5.29 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[C:7]([F:32])[CH2:6]1)[CH3:3].N1CC[CH2:35][CH2:34]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[O:16])=[C:7]([F:32])[CH2:6]2)[CH2:1][CH2:35][CH2:34][CH2:3]1
Reactant: C1CCNC1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2)=C(F)C1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=C(F)CC(=NN2CCCC2)C=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.284 mmol) from EXAMPLE 33, a pre-mixed pyrrolidine (0.119 mL, 1.43 mmol) and HOAc (0.122 mL, 2.14 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (17 mg). MS 494.1 and 496.2 (M+H, Cl pattern).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[ClH:32]>CCO>[ClH:32].[C:1]([O:5][C:6](=[O:31])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 99 %

Procedure:
Nα -BOC-Nε -CBZ-L-lysine tert-butyl ester (2) (34.51 g, 79.15 mmol) was dissolved in a mixture of 300 ml absolute EtOH and 1 N HCl (88 ml). Prior to the introduction of H2 gas, 10% Pd--C (2.95 g) was added. After 7 hours, additional catalyst (1.0 g) was added. After 5 hours, the black suspension was filtered through a bed of Celite and washed with EtOH. The filtrate was concentrated and the residue dried under high vacuum to give the Nα -BOC-L-lysine tert-butyl ester as its hydrochloride salt (3) (26.59 g, 99%). 1H NMR (CD3OD) δ3.95 (dd, 1H, J=8.8, 5.0 Hz), 2.93 (t, 2H, J=7.7 Hz), 1.84-1.60 (m, 6H), 1.45 (s, 9H), 1.43 (s, 9H); 13C NMR (CD3OD) δ173.5, 158.2, 82.7, 80.5, 79.5, 55.5, 40.6, 32.1, 28.7, 28.3, 23.9. HRMS m/z calcd. for C15H31N2O4 303.2284, found 303.2272. [α]26D -10.1° (c=1.00, CH3OH).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl:5][C:6]1([C:9](=[O:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:8][CH2:7]1.II>O1CCCC1.[Zn]>[Cl:5][C:6]1([C:9]([OH:16])([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:3][CH:2]=[CH2:1])[CH2:8][CH2:7]1
Reactant: C=CCBr
Reactant: O=C(Cn1cncn1)C1(Cl)CC1
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCC(O)(Cn1cncn1)C1(Cl)CC1
Reaction time: 24 h

Procedure:
A solution of 12. 1 g (0.1 mol) of allyl bromide and 16.65 g (0.09 mol) of 1-(1-chlorocyclopropyl)-2-(1,2,4-triazol-1-yl)-ethan-1-one in 50 ml of tetrahydrofuran are added dropwise at 20° C. under nitrogen atmosphere in the course of 0.5 hours to a stirred mixture of 7.2 g (0.11 mol) of zinc dust, 0.1 g of iodine and 50 ml of absolute tetrahydrofuran. When the addition has ended, stirring is continued for 24 hours at room temperature, the mixture is then concentrated by stripping off the solvent and treated with aqueous ammonium chloride solution. The resulting mixture is extracted several times using dichloromethane. The combined organic phases are dried over sodium sulphate and then concentrated by stripping off the solvent under reduced pressure. In this manner, 10.2 g (50% of theory) of (4-(1-chloro-cyclopropyl)-4-hydroxy-5-(1,2,4-triazol1-yl)-pent-1-ene are obtained in the form of a solid substance of melting point 75° to 76° C. ##STR40##
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(#N)C>[N:19]1([S:2]([C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]3=[O:15])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Reactant: C1CNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)N3CCC3)ccc12
Reaction time: 72 h

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g) was added to azetidine (0.7 ml) and diisopropylethylamine (0.4 ml) in tetrahydrofuran (5 ml) and acetonitrile (5 ml) and the mixture was stirred for 72 h then evaporated. The solid was crystallised from methanol then hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-(azetidin-1-ylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:12]([F:13])=[C:11]([NH:14][C:15](=[O:30])[C:16]([F:29])([F:28])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([F:27])=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:8]=1[NH2:31])(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:31][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:30])[C:16]([F:29])([F:28])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([F:27])=[CH:19][CH:18]=2)=[C:12]([F:13])[C:7]=1[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCc1c(N)ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c(F)c1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 2-{2-amino-5-[2,2-difluoro-2-(4-fluoronaphthyl)acetylamino]-6-fluorophenyl}ethyl acetate (3.8 g, 8.8 mmol), as prepared in the preceding step, in MeOH (40 mL) and THF (20 mL) was added a solution of K2CO3 (1.68 g, 12 mmol) in water (30 mL). The mixture was stirred at room temperature for 3 hours. Additional water (50 mL) was added, and the resulting mixture was extracted with EtOAc (3×50 mL). The extracts were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound (3.3 g, 96%) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.4 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.13 (s, 1H), 7.81 (m, 2H), 7.64 (m, 2H), 7.19 (t, J=8.7 Hz, 1H), 6.47 (d, J=8.7 Hz, 1H), 4.07 (s, 2H), 3.89 (t, J=5.6 Hz, 2H), 2.85 (t, J=5.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccccc1CN
Solvent: COCCOC
Product: Cc1ccccc1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-methylbenzylamine in DME. ES-MS m/e (%:306 (M+H+, 100).