Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:3]=1.[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:29])=[C:4]([S:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])=[CH:14][CH:15]=2)[CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from step (iii) (0.3 g), tert-butylbromoacetate (0.15 ml) and potassium carbonate (0.13 g) in DMF (20 ml) was stirred at RT overnight. The mixture was partitioned between water and ethylacetate, the organics separated, dried, and evaporated under reduced pressure. Yield 0.55 g
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH2:28]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:23]([OH:26])([CH3:25])[CH3:24])[C:20]([NH:28][CH3:27])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C(C)(C)O)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 1.93 g (5.22 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]-3-(1-hydroxy-1-methylethyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 6) in 50 ml of methanol was saturated with gaseous methylamine by passing the gas through the solution whilst ice-cooling, and then the flask containing the reaction mixture was stoppered tightly and allowed to stand at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from hexane, to give 1.98 g (yield 95%) of the title compound as white crystals, melting at 174°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7]([OH:19])[CH:6]=1)=[O:4].[N+:20]([O-])([OH:22])=[O:21].CCCCCC>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:16])[F:17])=[N:12]2)=[C:7]([OH:19])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(O)c2ccc(C(F)(F)F)nc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 87.6 %

Procedure:
5-Hydroxy-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (46.0 g, 169.63 mmol) is dissolved in 200 ml of concentrated (97%) sulphuric acid at 0-5° C. To this cooled solution is added drop wise fuming (100%) nitric acid (7 ml, 10.69 g, 169.63 mmol). After the addition is complete, the reaction mixture is allowed to warm to room temperature. TLC analysis (4:1 hexane:ethyl acetate) after 30 min shows reaction completion. The reaction mixture is slowly poured onto an ice/water mixture (ca. 2 l), and the crystals then filtered at the pump, thoroughly washed with water, and dried in vacuo. This affords the title compound (47.0 g, 87.6%) as pale yellow crystals.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][O:16][CH2:15][C@H:14]2[OH:18])=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl.O>[CH3:4][S:1]([O:18][C@@H:14]1[C@@H:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[CH2:17][O:16][CH2:15]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1COC[C@@H]1c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)O[C@H]1COC[C@@H]1c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
Mesyl chloride (21.4 mL, 0.28 mol, 1.2 eq) was added dropwise to a mixture of compound (3S*,4S*)-4-(4-fluorophenyl)tetrahydrofuran-3-ol (Preparation 59, 42 g, 0.23 mol, 1 eq) and Et3N (79.6 mL, 0.55 mol, 2.0 eq) in DCM (250 mL) under stirring on an ice bath for 30 min. The mixture was stirred at room temperature for 1 h and diluted with water (500 mL). The layers were separated. The organic layer was subjected to chromatography on silica (1 L, carbon tetrachloride→25, 50, 75, 100% chloroform→MeOH) to give title compound (40 g, 0.15 mol, 67%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:20]=[C:21]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[C:28]([C:35](O)=[O:36])[CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:35]([C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[C:27]=2[N:26]=[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:39])([F:17])[F:38])[CH:20]=2)[CH:34]=[CH:33]3)=[O:36])=[CH:14][CH:15]=1
Reactant: O=C(O)c1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CC1(C)OCC(COc2ccc(N)cc2)O1
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: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccc(OCC(O)CO)cc1)c1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.2 %

Procedure:
To a mixture of 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)aniline (167 mg, 0.750 mmol), 2-(3-(trifluoromethyl)phenyl)quinoline-8-carboxylic acid (159 mg, 0.500 mmol), HATU (285 mg, 0.75 mmol) in NMP (5 mL) was added DIPEA (173 μL, 1.0 mmol). The reaction was stirred for 72 hours at room temperature, water (5 mL) was added and the resulting precipitates were collected by filtration and recrystallized from ethanol. The yellow solid was treated with a mixture of 1:3 6N HCl/Dioxane (8 mL) overnight. The mixture was concentrated to dryness, triturated with water, collected by filtration, washed with water and dried to obtain N-(4-(2,3-dihydroxypropoxy)phenyl)-2-(3-(trifluoromethyl)phenyl)quinoline-8-carboxamide (191 mg, 79% yield). MS (ESI) calcd for C26H21F3N2O4 (m/z): 482.15. found: 483 [M+1].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18]1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C[C@@H]1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Temperature: 140 °C
Yield: 68.5 %

Procedure:
A suspension of 2-bromo-5-trifluoromethyl-pyridine (2.37 g; 10.0 mmol; 1.0 eq.), (R)-2-methylpiperazine (2.00 g; 20.0 mmol; 2.0 eq.) and DIEA (1.94 g; 15.0 mmol; 1.5 eq.) in 4 mL of DMA was heated at 140° C. for 14 h. The mixture was cooled to room temperature. After evaporation of the solvent under vacuum, the residue was dissolved in a 1/1 mixture of DCM/Et2O. A 4N solution of HCl was added (10 mL) then the resulting precipitate was collected and washed with Et2O. The solid was then poured to an aq. solution of NaOH (5N, 20 mL) and the resulting mixture was extracted with Et2O (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give the title compound as an orange solid (1680 mg, 69%) used without further purification for is the next steps. M+(ESI): 246.3. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 99.9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:10]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([N:1]2[CH2:16][CH2:17][CH2:18][C:19]2=[O:20])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1N
Reactant: O=C(Cl)CCCCl
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a mixture of 1-(3-amino-5-chloro-2-methoxy-4-methylphenyl)ethanone (100 mg, 0.5 mmol) and 4-dimethylaminopyridine (69 mg, 0.56 mmol) in tetrahydrofuran (1 mL) was added 4-chlorobutanoyl chloride (0.058 mL, 0.52 mmol). The reaction was stirred at room temperature for 1 hour. To the reaction mixture was added 1.0 M potassium tert-butoxide in tetrahydrofuran (1.03 mL, 1.03 mmol). The resulting mixture was stirred at room temperature for 2 hours, quenched with aq. ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the product (20 mg, 20%). LCMS calculated for C14H17ClNO3 (M+H)+: m/z=282.1. found: 282.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[S:18][C:19](Br)=[N:20][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:24]1[C:27]2([CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[CH2:26][NH:25]1>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[S:18][C:19]([N:25]2[CH2:24][C:27]3([CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)[CH2:26]2)=[N:20][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1-c1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(F)cc(Br)cc3OCc3ccccc3)s1)C2
Temperature: 120 °C
Yield: 44.9 %

Procedure:
To a stirred suspension of 2-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-5-bromo-1,3,4-thiadiazole (252 mg, 0.567 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (179 mg, 0.681 mmol) in dioxane (2.8 mL) was added TEA (237 μL, 1.702 mmol) and the mixture was heated at 120° C. for 3 hours. The reaction mixture was cooled to RT, diluted with water (20 mL), extracted with DCM (20 mL). The organic phase was concentrated in vacuo to afford the crude product as a yellow oily residue. The crude material was purified by flash chromatography using a 40 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a white solid (150 mg, 45% yield). LC-MS: Rt 1.62 min; MS m/z 591.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.47 (m, 7H), 5.31 (s, 2H), 3.83 (s, 4H), 3.17-3.30 (m, 4H), 1.65-1.77 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH2:5][C@@H:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[NH:3]1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[O:1]=[C:2]1[C@@H:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH2:5][C@@H:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:3]1[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: O=C1N[C@H](c2cccs2)CSC[C@@H]1N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)CSC[C@H]1c1cccs1

Procedure:
1.3 g of 5-oxo-6(R)-phthalimido-3(S)-(2-thienyl)perhydro-1,4-thiazepine [prepared as described in step (e) above] was treated with t-butyl bromoacetate in the manner described in Example 1(f), to give 0.99 g of the title compound as crystals, melting at 211°-212° C.
Reaction SMILES: [OH:1][CH:2]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10]C)=[O:8])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][CH:14]([C:2]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:12][CH:13]=2)=[O:1])[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1ccc(C(O)C2CCOCC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To a solution of methyl 4-iodobenzoate (1.21 mL, 7.24 mmol) in THF (12 ml) at −40° C. was added TurboGrignard (1.3 M in THF, 6.13 ml, 7.97 mmol) dropwise. The mixture was stirred for approximately 60 minutes whereupon, tetrahydro-2H-pyran-4-carbaldehyde (0.761 ml, 0.724 mmol) was added dropwise. The mixture was stirred for 15 minutes and slowly warmed to rt over 12 hours. The reaction was quenched with HCl (1 N, aq.) and the aq. layer was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide ethyl 4-(hydroxy(tetrahydro-2H-pyran-4-yl)methyl)benzoate. Crude mixture used into the next step without any further purification. Step B: A round bottom flask was charged with ethyl 4-(hydroxy(tetrahydro-2H-pyran-4-yl)methyl)benzoate (1.9 g, 7.2 mmol), the Dess-Martin reagent (3.66 g, 8.63 mmol) and DCM (15 mL). The reaction was stirred at room temperature overnight. Reaction diluted with DCM and solid filtered off. The mother liquor concentrated and loaded onto a silica gel column. Purification by silica gel flash chromatography (ethyl acetate/DCM) provide methyl 4-(tetrahydro-2H-pyran-4-carbonyl)benzoate (290 mg, mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.75-1.96 (m, 4H) 3.45-3.62 (m, 3H) 3.97 (s, 3H) 4.07 (dt, J=11.88, 3.25 Hz, 2H) 7.98-8.02 (m, 2H) 8.12-8.17 (m, 2H); MS (M−1): 246.8.
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C@H:30]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:31]([OH:33])=O)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Si](ON)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C@H:30]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:31]([NH:2][OH:1])=[O:33])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CC(C)(C)[Si](C)(C)ON
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NO)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Reaction time: 0.33 h
Yield: 34.6 %

Procedure:
150 mg (1.1 mmol) of 1-hydroxybenzotriazole and 210 mg (1.1 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride are added to a solution of 420 mg (1.0 mmol) of (S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-ylpropanoic acid in 15 ml of dimethylformamide. The reaction medium is stirred for 20 min and then a solution of 160 mg (1.1 mmol) of O-tert-butyldimethylsilylhydroxylamine in 3 ml of dimethylformamide is added. The reaction medium is then stirred at ambient temperature for 18 h and then hydrolyzed with 2 ml of a saturated aqueous solution of sodium hydrogen carbonate and 2 ml of water. After stirring for 20 min in order to complete the deprotection of the hydroxamate, the product is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is crystallized from isopropyl ether under hot conditions, and then filtered off. The resulting solid is recrystallized from a 1/1 heptane/ethyl acetate mixture, filtered and then oven-dried under vacuum for 4 h. 150 mg of (S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-piperidin-1-ylpropionamide are obtained in the form of a beige solid with a melting point of 126° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[C:18]([O:22][C:23](=[O:26])[NH:24][NH2:25])([CH3:21])([CH3:20])[CH3:19]>C(O)CCC>[C:18]([O:22][C:23](=[O:26])[NH:24][NH:25][C:4]1[N:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[C:2]([CH3:1])[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1cccc([N+](=O)[O-])c1
Solvent: CCCCO
Product: Cc1cc(NNC(=O)OC(C)(C)C)nnc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 5.49 g. of 5-methyl-6-(m-nitrophenyl)-3-chloropyridazine and 8.71 g. of t-butylcarbazate in 100 ml. of butanol is heated at reflux for 3 hours and then allowed to cool to room temperature overnight. The butanol is removed on a rotating evaporator leaving a heavy liquid residue. The final product is obtained after crystallization from a minimum amount of methanol on standing, washing with methanol, water and drying, m.p. 160°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:19]1([C:25]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[PH2:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:28]1([C:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([PH2:26]=[O:27])[N:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:4](=[O:5])[C:3]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=2[F:1])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CNC([PH2]=O)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(F)c(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)c2cc(OC)ccc2F)C([PH2]=O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a mixture of 2-fluoro-5-methoxy-benzoyl chloride (4.77 g, 25.0 mmol) and sodium carbonate (13.4 g, 126.7 mmol) in dichloromethane (100 mL) cooled to 0° C. a solution of (diphenyl-phosphinoylmethyl)-(4-methoxy-benzyl)-amine (8.9 g, 25.3 mmol) in dichloromethane (50 mL) was added and the resulting mixture allowed to warm up to RT overnight. Then the mixture was filtered and evaporated and the residue was purified by chromatography (SiO2, Hexane:Acetone 1:1) to afford the title product (7.3 g, 57%) as a light yellow solid. MS m/e=504.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: N#Cc1ccc(O)cc1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccc(C#N)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-hydroxy-benzonitrile and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 342(MH+).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH:30]([CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: Nc1ccccc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: -10 °C
Yield: 74.7 %

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.10 g) dissolved in methylene chloride (15 ml). To this solution was added aniline (0.28 g) under cooling at -10°C and then silver fluoroborate (0.43 g), after which the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was washed with a dilute phosphoric acid aqueous solution and then with water, dried over magnesium sulfate, after which the solvent was distilled off. The residue was subjected to column chromatography on silica gel (20 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml. The second to seventh fractions were collected and the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.84 g), mp 148° to 149°C. Infrared Absorption Spectrum (CHCl3) 3400, 1780, 1765, 1680 cm-1.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(NC[C@H]1CCNC1)c1cc2cc(Cl)ccc2s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2cc(Cl)ccc2s1

Procedure:
66.3 Using general method H, 5-chloro-benzo[b]thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 523.0 ([M−H]−)
Reaction SMILES: [N+](C1C=C[C:7]([O:8][C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15](/[C:18](/[C:28]3[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38]C(C)(C)C)=[O:37])=[CH:30][CH:29]=3)=[C:19](\[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)/[CH2:20][CH3:21])=[CH:14][CH:13]=2)=[O:10])=[CH:6]C=1)([O-])=O.CCO.CCN(CC)CC>C(Cl)Cl>[CH2:7]([O:8][C:9]([O:11][C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)=[C:19](\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[CH2:20][CH3:21])=[CH:16][CH:17]=1)=[O:10])[CH3:6]
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
To a solution of 38 (0.050 g, 0.084 mmol) in CH2Cl2 (2 mL) was added EtOH (0.050 g, 1.08 mmol) and Et3N (0.016 g, 0.16 mmol). The mixture was stirred at ambient temperature for 18 h, diluted with CH2Cl2, washed with water and 0.1 N hydrochloric acid, dried (Na2SO4), and concentrated. The residue was separated by preparative RP-HPLC (C-18 Luna column, 85% MeCN/H2O/0.1% TFA) and the corresponding fractions were concentrated. The residue was dissolved in CH2Cl2 (0.3 mL) and cooled to 0° C. TFA (0.3 mL) was added and the mixture stirred at 0° C. for 1 h. The solvent was evaporated and co-evaporated with CH2Cl2 (2×10 mL) and the residue crystallized from a small amount of EtOAC to provide 37 (0.010 g) as an off-white solid; mp 135-136° C.; 1HNMR (DMSO-d6): δ 0.85 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 2.39 (q, J=7.2 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 6.5 (d, J=16 Hz, 1H), 6.85 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 7.08-7.22 (m, 5H), 7.24 (d, J=7.9 Hz, 2H), 7.58 (d, J=16 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 12.45 (br s, 1H); MS, m/z 465 (M+Na)+; Anal. calculated for C28H26O5.0.13H2O: C, 75.60; H, 5.95; Found: C, 75.61; H, 5.93.