Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][C@@H:12]([CH3:33])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1.OO.[OH-:36].[Na+]>CO.ClCCl.O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:36]1[C:20]23[C@:25]([CH3:26])([CH2:24][CH2:23][C:22](=[O:32])[CH:21]12)[C@@H:27]1[C@H:17]([C@H:16]2[C@:30]([CH3:31])([CH2:29][CH2:28]1)[C@@H:13]([C@H:12]([CH3:33])[CH2:11][OH:10])[CH2:14][CH2:15]2)[CH2:18][CH2:19]3
Reactant: [OH-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(O)c1ccccc1
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
A solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one benzoate (8.9 g, 20.5 mmole) in methanol (80 mL) and dichloromethane (80mL) was cooled to 15° C. and treated sequentially with 30% hydrogen peroxide (5.0 mL) and sodium hydroxide (1.09 g) in water (6.7 mL). After 4 hours at room temperature, the product was isolated from the reaction mixture by the same procedure as described in Example 9 to give (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one benzoate (1.6 g, 17.3%). IR 1720, 1280 cm-1 ; MS (CI) 451 (95%, M+1), 329 (100%, M+1--PhCOOH); 1H NMR (CDCl3) δ 0.76 (3H, s, C18 --Me), 1.13 (d, C22 --Me), 1.16 (s, C19 --Me), 2.98+3.04 (1H, s +s, C4 --H), 4.04 (1H, dd, 1/2 C21 --CH2), 4.32 (1H, dd, 1/2 C21 --CH2), 7.46 (2H, t), 7.57 (1H, t), 8.04 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.[F:10][C:11]([F:23])([F:22])[C:12](=O)[CH2:13][C:14]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=O>CC(O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][C:12]([C:11]([F:23])([F:10])[F:22])=[N:9]2)[N:3]=1
Reactant: NNc1cccc(Cl)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: Cl
Solvent: CC(C)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(Cl)n2)n1
Yield: 89.7 %

Procedure:
To a stirred solution of 2-chloro-6-hydrazinopyridine (300 mg, 2.09 mmol) in 2-propanol (10.4 mL), was added 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (0.310 mL, 2.090 mmol) followed by 2 drops of conc HCl. The resulting mixture was heated to reflux overnight and then evaporated to dryness. A 2:1 mixture of regioisomeric products 45 (588 mg, 90% yield) were isolated as a pale yellow oil. LRMS (ESI): calc. 313.6; found 313.6 (M)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:51][CH2:52][O:53][CH2:54][CH2:55]Br.C(O)(C(F)(F)F)=O>ClCCCl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([N:1]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH2:3][CH2:4]3)[CH:10]=2)[CH2:39][CH2:40]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccnc(F)c1)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](N4CCOCC4)CC3)nn12
Temperature: 60 °C
Reaction time: 9 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.184 mmol) in 1,2-dichloroethane (2 mL) was added DIEA (0.128 mL, 0.734 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (42.6 mg, 0.184 mmol), and the reaction solution was stirred at 60° C. for 9 hrs. The reaction mixture was treated with TFA (0.849 mL, 11.02 mmol) at 65° C. for 1 hr, concentrated, diluted with methanol, and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to obtain 8-(cyclopropylamino)-N-(2-fluoropyridin-4-yl)-6-((trans)-4-morpholinocyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (36.3 mg, 0.073 mmol, 40.0% yield). LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.67 minutes. [M+H]=495.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (1H, s), 9.57-9.89 (1H, m), 8.26 (1H, d, J=5.77 Hz), 7.99 (1H, d, J=1.76 Hz), 7.67 (1H, s), 7.60 (1H, s), 7.44 (1H, d, J=4.77 Hz), 6.88-7.14 (1H, m), 5.98 (1H, s), 4.04 (2H, d, J=11.80 Hz), 3.58-3.83 (3H, m), 3.40 (2H, d, J=12.05 Hz), 2.98-3.23 (2H, m), 2.28 (2H, d, J=11.80 Hz), 2.17 (2H, d, J=11.29 Hz), 1.55 (2H, br. s.), 1.35 (2H, br. s.), 0.78 (2H, d, J=6.53 Hz), 0.63 (2H, br. s.)
Reaction SMILES: Cl.Cl.[CH2:3]1[CH:16]2[N:7]([CH2:8][C:9]3[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=3[CH2:15]2)[CH2:6][CH2:5][O:4]1.C[S:19](C)=O.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:3]1[CH:16]2[N:7]([CH2:8][C:9]3[CH:10]=[C:11]([NH:17][C:23]([C:24]4[S:19][CH:27]=[CH:26][CH:25]=4)=[NH:22])[CH:12]=[CH:13][C:14]=3[CH2:15]2)[CH2:6][CH2:5][O:4]1
Reactant: c1ccncc1
Reactant: CS(C)=O
Reactant: Nc1ccc2c(c1)CN1CCOCC1C2
Agent: Cl
Solvent: O
Product: N=C(Nc1ccc2c(c1)CN1CCOCC1C2)c1cccs1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 3,4,5,6,11,11a-hexahydro-1H-[1,4]oxazino[4,3-b]isoquinolin-8-amine dihydrochloride (0.461 g, 1.66 mmol) and methyl sulfoxide (5 ml) was added pyridine (0.28 ml) followed by S-methyl-2-thiophenethiocarboximide hydroiodide (0.612 g). The mixture was heated at 50° C., with stirring, for 4 h. The reaction mixture was then poured into water (50 ml) and, after stirring for 1 hour, the mixture was clarified by filtration. The filtrate was basified with concentrated ammonium hydroxide to precipitate the product as a solid. The product was isolated, washed with water and dried; yield 0.4917 g, m.p. 190-4° C., MS 314 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)=[CH:7][C:6]=1[N+:30]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CCO>[NH2:30][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)[CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The title compound was prepared from N-(4-tert-butyl-3-nitro-phenyl)-2-(1H-indazol-6-ylamino)-nicotinamide by dissolving in EtOH (20 ml) and adding Sn(II)Cl2 (12.58 g) and stirred at RT for 5 h and at 0° C. overnight. The mix was warmed to RT and quenched by pouring onto ice, neutralized with NaHCO3 and basified with 6N NAOH. An emulsion formed upon addition of EtOAc which was filtered through Celite and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O, brine and dried over MgSO4 then purified by flash chromatography (3-5% MeOH to afford the product as a orange-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH:8]=O)=[O:5].Cl.[NH2:17][OH:18].[C:19]([O-:22])(=O)C.[Na+]>CO>[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:17]([CH:19]=[O:22])[OH:18])=[O:5]
Reactant: O=CCNC(=O)c1cc(Cl)cc(Cl)c1Cl
Reactant: CC(=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=CN(O)CCNC(=O)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 18 h
Yield: 149.8 %

Procedure:
To a solution of 2,3,5-trichloro-N-(2-oxo-ethyl)-benzamide (0.80 g, 3.0 mmol) in MeOH (100 mL) was added hydroxylamine hydrochloride (0.41 g, 6 mmol) and sodium acetate (0.49 g, 6 mmol). The mixture was stirred 18 h and the MeOH was removed in vacuo. The residue was dried in vacuo for 18 h and was used without further purification to yield the title compound (1.4 g) as a white solid. ESMS: M+H=281.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.Cl.Cl[CH2:24][CH2:25][N:26]([CH2:32][CH2:33]Cl)[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:33][CH2:32][N:26]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:25][CH2:24]1)=[O:20])[CH3:2]
Reactant: CCC(CC)N(CCCl)CCCl
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(C(CC)CC)CC2)cc1
Yield: 26 %

Procedure:
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-carboxylic acid ethyl ester was was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[4-(2-butynyloxy)phenyl]sulfonyl}acetate (8.8 g, 30.0 mmol) and bis-(2-chloro-ethyl)-(3-pentanyl)-amine dihydrochloride (7.4 g, 30 mmol), 3.5 g of product (brown oil) was isolated. Yield 26%; MS: 436 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH3:28])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:24])[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=2[C:14]([CH2:25][CH2:26][CH3:27])=[CH:13][CH:12]=1>C(O)C.O.Cl>[OH:7][CH:8]([CH3:28])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:24])[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=2[C:14]([CH2:25][CH2:26][CH3:27])=[CH:13][CH:12]=1
Reactant: CCCc1ccc(OCC(C)OC2CCCCO2)c2c(=O)cc(C(=O)O)oc12
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)O)oc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5-[2-(tetrahydropyran-2-yloxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid (0.12 g) in ethanol (3 ml), water (2 ml) and concentrated hydrochloric acid (1 drop) was stirred for 15 minutes at ambient temperature. The mixture was then extracted with chloroform (3×20 ml) and the chloroform extracts bulked, dried and evaporated in vacuo. The residue was crystallised from acetone giving 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid m.g. 134°-135° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:4]([NH2:16])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].Cl.N1C=CC=[CH:33][CH:32]=1.C(OCC)(OCC)(OCC)C>C1(C)C=CC=CC=1>[CH3:32][C:33]1[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[N:16]=1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCCc2cccnc2)c1C
Reactant: c1ccncc1
Agent: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCCCc3cccnc3)c2c1C
Temperature: 99 °C

Procedure:
A solution of 5,6-dimethyl-2-phenoxy-N4-[2-(3-pyridin-3-ylpropoxy)ethyl]pyridine-3,4-diamine (12 g) in toluene (300 ml) from Part C was combined with pyridine HCl (0.08 g) and triethyl orthoacetate (8.4 ml). Under a nitrogen atmosphere, the reaction mixture was heated to reflux (99° C.) for 1.5 hours. TLC and HPLC analysis indicated that the reaction was complete. The solvent was removed under reduced pressure. The resulting yellow oil was dissolved in dichloromethane and washed once with saturated potassium carbonate, 3 times with water, and 3 times with brine. The combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting yellow oil darkened slightly after being dried under vacuum at 70° C. overnight. The product was purified by column chromatography over silica using 95/5 ethyl acetate/methanol as the eluant. The product was dried and then triturated with diethyl ether to yield a white solid that was dried under vacuum at 80° C. overnight. NMR analysis of the dried solid indicated a pure product.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][CH2:28][CH2:29][O:30][CH3:31])(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:15]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[S:24](=[O:25])(=[O:26])[NH:27][CH2:28][CH2:29][O:30][CH3:31])[CH:10]=1
Reactant: COCCNS(=O)(=O)c1ccc(F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCCNS(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Product: Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(Step 2) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.4 g), 2-(aminomethyl)-4-fluoro-N-(2-methoxyethyl)benzenesulfonamide obtained in Step 1 (0.61% g) and potassium carbonate (0.71 g) in ethanol (10 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.29 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([N+:16]#[C-:17])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1>Cl(O)(=O)(=O)=O>[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:1]=[C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]3[C:17]=2[NH:16][C:9]([CH3:15])([CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:20][CH:19]=1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: Nc1cnccn1
Reactant: O=Cc1ccncc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccncc2)nc2cnccn12

Procedure:
Compound (8) was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide (0.2 M, MC), 0.500 ml pyridine-4-carbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11](=[O:27])[N:12]([C@@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](O)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:41])[CH2:34][CH:35]([NH2:40])[CH:36]([OH:39])[CH2:37][F:38])([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:28]([O:32][C:33](=[O:41])[CH2:34][CH:35]([NH:40][C:17](=[O:18])[C@@H:16]([N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11]1=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:36]([OH:39])[CH2:37][F:38])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: O=C(Nc1cccn([C@@H](Cc2ccccc2)C(=O)O)c1=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(O)CF
Temperature: 0 °C
Yield: 36.7 %

Procedure:
A stirred mixture of (S)-2-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid (2.20 g, 6.07 mmol), 3(R,S)-Amino-5-fluoro-4(R,S)-hydroxy-pentanoic acid tert-butyl ester (1.39 g, 6.68 mmol), HOBt (902 mg, 6.68 mmol), DMAP (853 mg, 6.98 mmol) and THF (20 mL) was cooled to 0° C. then EDC (1.28 mg, 6.68 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (30-70 to 55-45% ethyl acetate/hexane) to afford the title compound as a white foam (1.23 g, 32%); 1H NMR (400 MHz, CDCl3) δ 0.88-0.93 (3H, m), 1.35-1.42 (9H, 2s), 2.50-2.65 (2H, m), 3.20-3.35 (2H, m), 3.60 (1H, m), 3.98 (1H, m), 4.10-4.32 (3H, m), 5.62-5.70 (1H, m), 6.44 (1H, m), 6.80-6.98 (1H, m), 7.21-7.41 (5H, m), 7.55-7.62 (3H, m), 7.95 (2H, m), 8.58 (1H, t), 9.18 (1H, br s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3](/[C:7](/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:8]\[OH:9])=[N:2]1.[C:17](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.Cl>CN(C)C=O>[CH3:17][O:9]/[N:8]=[C:7](\[C:3]1[O:4][CH2:5][CH2:6][O:1][N:2]=1)/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: O=C([O-])[O-]
Reactant: O/N=C(\C1=NOCCO1)c1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CO/N=C(\C1=NOCCO1)c1ccccc1O
Reaction time: 16 h
Yield: 62.7 %

Procedure:
1.2 g (0.0054 mol) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone oxime (V-1) in 5 ml of dimethylformamide are stirred at 20° C. together with 0.66 g (0.0062 mol) of sodium carbonate initially for 30 minutes. 0.83 g (0.00658 mol) of dimethyl sulphate is then added and stirring is continued at 20° C. for a further 16 hours. The reaction mixture is adjusted to a slightly acidic pH using 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 0.8 g (50.35% of theory) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) of a purity of 80.3% (HPLC) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][O:41][CH3:42]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:39][CH2:40][O:41][CH3:42])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COCCBr
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCC(n2cc(-c3ccc4nnc(C(C)C)n4n3)c(-c3ccc(F)cc3F)n2)CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
The 6-(3-(2,4-difluorophenyl)-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.15 g, 0.35 mmol; Example #Q.1.2) was dissolved in DMF (4 mL) and then the K2CO3 (0.10 g, 0.71 mmol) and 1-bromo-2-methoxyethane (0.075 g, 0.53 mmol) were added. The mixture was heated at about 65° C. in an oil bath for about 1 h then another portion of 1-bromo-2-methoxyethane (0.075 g, 0.53 mmol) was added. After about 1 h, a third portion of 1-bromo-2-methoxyethane (0.075 g, 0.53 mmol) was added. The mixture was heated for about 1 h longer then cooled and concentrated under reduced pressure. The material was purified by RP-HPLC (Table 1, Method d). The appropriate fractions were concentrated and then basified with 2N NaOH and then extracted with EtOAc. Drying over MgSO4 and evaporating gave an oil which was purified further by flash chromatography on silica with DCM/MeOH (9:1) as an eluent. Concentration of the appropriate fractions followed by trituration with Et2O/heptane resulted in a solid which was collected by filtration to provide the title compound (0.086 g, 50%): LC/MS (Table 1, Method a) Rt=1.90 min; MS m/z: 482.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=CN([C:19]([N:21]2C=N[CH:23]=[CH:22]2)=O)C=1.C(N(CC)CC)C.Cl.N1CCC1>C1COCC1>[N:21]1([C:11](=[O:13])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:19][CH2:23][CH2:22]1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (1 g, 5.52 mmol) and CDI (1.34 g, 8.28 mmol), the mixture was stirred for 2 hrs at 0° C. followed by addition of triethylamine (2.308 ml, 16.56 mmol) and azetidine hydrochloride (1.033 g, 11.04 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title product (0.53 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:25][OH:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(O)C>O>[NH2:8][C@H:9]([CH2:25][OH:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCCNC(=O)OCc1ccccc1
Solvent: O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CO)CCCCNC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 4 g of benzyl (5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate, 30 cm3 of trifluoroacetic acid and 20 cm3 of ethanol is stirred at a temperature in the region of 20° C. for 2 hours. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 50 cm3 of water and washed with twice 100 cm3 of diethyl ether. The aqueous phase is separated out after settling has taken place, basified with sodium carbonate to pH 9-10 and then extracted with 3 times 100 cm3 of dichloromethane. The combined extracts are washed with aqueous sodium chloride solution and then dried on magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.0 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamate are obtained in the form of a white solid melting at 82° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:9]>ClCCCl>[Cl-:3].[Cl:3][CH2:6][CH2:7][NH+:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:9]
Reactant: CCCCCCCCCCCCCCCCCCN(C)CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCCCCC[NH+](C)CCCl
Product: [Cl-]
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.45 mL) was dissolved in 1,2-dichloroethane (3.0 mL). The solution of N-(2-hydroxyethyl)-N-methyl-octadecylamine (1.0 g) in 1,2-dichloroethane (7.0 mL) was added thereto at 0° C., followed by stirring at 50° C. for 30 minutes. The reaction solution was concentrated under reduced pressure and azeotrope was carried out with toluene twice to obtain the title compound (1.2 g) having the following physical property values.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([NH2:33])[CH2:29][CH2:30][CH2:31][CH3:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:33][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCN
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCCCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.41 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.58 mmol), and n-pentylamine (0.19 mL, 1.65 mmol) are treated according to method E yielding the title product.