Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14](C(=O)C(F)(F)F)[CH2:15]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:12]12[CH2:21][CH2:20][CH:16]([CH2:15][NH:14][CH2:13]1)[C:17]1[C:11]2=[CH:10][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:19][CH:18]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.5 %

Procedure:
2-{5-Chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide (510 mg, 0.878 mmol) was dissolved in methanol (20 mL) and potassium carbonate (727 mg, 5.27 mmol, 6.0 eq) was added. The reaction was stirred at room temperature for 72 hours and then concentrated under reduced pressure. The residue was taken up in water (30 mL) and the product was extracted into EtOAc (3×30 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-5% MeOH/CH2Cl2 as the eluting solvent to obtain 2-[2-(10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as a white foam (300 mg, 70%). LCMS (m/e) 485 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.11 (bs, 1H), 8.49 (dd, 1H, J=1.0 and 8.4 Hz), 8.12 (s, 1H), 7.96 (dd, 1H, J=1.6 and 8.0 Hz), 7.60-7.52 (m, 1H), 7.33-7.19 (m, 3H), 7.00 (d, 1H, J=7.7 Hz), 6.95 (bs, 1H), 2.99-2.90 (m, 3H), 2.87-2.76 (m, 3H), 2.64 (s, 3H), 2.08-2.00 (m, 2H), 1.84-1.77 (m, 2H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17]CC2C=CC=CC=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[OH:17])[C:10]([O:12][CH3:13])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(O)c(OC2CCCC2)c1

Procedure:
A solution of methyl 3-cyclopentyloxy-4-benzyloxybenzoate (2.64 g; that is prepared as described in Reference Example 39) in methanol (120 mL) is treated with palladium on charcoal (5%,0.5 g) and ammonium formate (2.0 g) and heated at reflux for 45 minutes. The catalyst is filtered off through a pad of diatomaceous earth and washed with methanol. The filtrate and washings are evaporated under reduced pressure, and the resulting residue is subjected to flash chromatography on silica gel using a mixture of diethyl ether and pentane 1:1 v/v), to give methyl 3-cyclopentyloxy-4-hydroxybenzoate (1.8 g), in the form of a cream solid, m.p. 73-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14]2[CH:20]=[CH:19][CH:18]=[C:16]([NH2:17])[CH:15]=2)=[CH:5][C:4]=1[CH3:12]
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cccc(N)c2)cc1C
Temperature: 25 °C
Yield: 75 %

Procedure:
4-methoxy-3-methylphenyl boronic acid (0.115 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H2O and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.074 g in 75% yield.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C.[OH-].[Na+]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:26](=[O:28])[CH:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)C1C(=O)N(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of N,N′-dibenzylethylenediamine (14.12 mL, 60.2 mmol) in acetonitrile (100 mL) was added diethyl bromomalonate (5.14 mL, 30.1 mmol), and the mixture was heated with an oil bath at 90° C. (reflux) for 7 hours. The solvent was evaporated to provide a residue that was dissolved in 1M NaOH (aqueous), and the mixture was extracted with ethyl acetate twice, dried over Na2SO4, and the solvent was evaporated. The crude mixture was purified by silica gel chromatography (Analogix IntelliFlash 280, SF40-150) eluting with 15%-30% ethyl acetate/hexanes to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.38-7.20 (m, 100H), 4.54 (dd, J=15.0, 154.2, 2H), 4.20-4.10 (m, 2H), 4.03 (q, J=7.1, 1H), 3.96 (s, 1H), 3.61 (dd, J=13.5, 41.7, 2H), 3.27-3.14 (m, 2H), 3.05-2.95 (m, 1H), 2.60-2.52 (m, 1H), 1.23 (t, J=7.1, 3H); MS (ESI+) m/z 353.0 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:26])[C:23](=[NH:25])[NH2:24])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[S:34](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O>C(Cl)Cl>[NH2:25][C:23]1[C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:10][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[N:16]=2)=[N:26][S:34][N:24]=1
Reactant: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)n1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nsnc1NCCCOc1cccc(CN2CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the crude product prepared in Step B in 80 ml of CH2Cl2 and containing 7.69 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (7.35 g; 18.5 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 50 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 100 g of silica gel (230-400 mesh) using ethyl acetate-methanol (95:5) as the eluent to give 3.63 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate salt of the title compound, mp 125.5°-131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(N)cc1
Agent: [K+]
Agent: [OH-]
Product: C=Cc1ccc(N)cc1

Procedure:
Dehydration of 9.2 g of p-aminophenylethanol (Chem. Abs., vol. 59:3797f) was done by heating with 8.8 g of KOH in the flame of a Bunsen burner under a nitrogen atmosphere (about 6 mm pressure). The product was collected by cooling with a Dry Ice-acetone bath. The solution was extracted with ether, dried over KOH and filtered. Evaporation of the ether gave p-aminostyrene, which was characterized by IR and NMR; the yield was 6.4 g.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53]([O:55][C:56](=[O:77])[C@H:57]([O:59][C:60]1[CH:65]=[C:64](Cl)[N:63]=[C:62]([S:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=2[F:76])[N:61]=1)[CH3:58])[CH3:54]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:76][C:70]1[C:71]([F:75])=[CH:72][CH:73]=[CH:74][C:69]=1[CH2:68][S:67][C:62]1[N:61]=[C:60]([O:59][C@H:57]([CH3:58])[C:56]([O:55][CH2:53][CH3:54])=[O:77])[CH:65]=[C:64]([NH:12][S:9]([N:6]2[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]2)(=[O:10])=[O:11])[N:63]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CCN1CCN(S(N)(=O)=O)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCN(CC)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
To a solution of 1-Ethylpiperazine (1 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield 4-Ethylpiperazine-1-sulfonamide as a white solid. A mixture of 4-ethylpiperazine-1-sulfonamide (0.289 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.50 g) in dioxane (10 mL) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.720 g
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1>CO.[Pd]>[F:26][C:2]([F:1])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
4-{1-[3-(Trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (obtained as described in Example 5.2, preparation of starting materials) (30 g, 82.57 mmol) and 5% Pd on carbon (50% wet, JM Type 87L) (35.1 g, 8.26 mmol) in MeOH (50 mL) were stirred under an atmosphere of hydrogen at 5 bar and 50° C. for 5 days. The mixture was cooled to room temperature and the catalyst removed by filtration. The solvent was evaporated to give 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (20.54 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1)=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1ccc(N)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.98 mL, 19.72 mmol) in dichloromethane (22.3 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (3.0 g, 19.72 mmol), pyridine (4.80 mL, 59.16 mmol) and dichloromethane (89.4 mL) at 0° C. The mixture was removed from the ice bath after 1.5 hours and was stirred at room temperature for 0.5 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration rinsing with hexanes to yield methyl 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (5.16 g, 76%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.38 (dd, J=8.6, 2.5 Hz, 1H), 8.16 (dd, J=6.1, 2.4 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.09-7.98 (m, 1H), 7.67 (t, J=9.2 Hz, 1H), 3.88 (s, 3H) ppm. ESI-MS m/z calc. 342.06, found 343.2 (M+1)+; Retention time: 1.54 minutes (3 minutes run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH2:15]([SH:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([S:17][CH2:15][CH3:16])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCSc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 5 g, 18.21 mmol), ethanethiol (1.482 mL, 20.04 mmol) and potassium carbonate (5.03 g, 36.4 mmol) in NMP (volume: 60 mL) was stirred at rt for 18 hr. Water (500 ml) was added and the resulting suspension was stirred at rt for 1 hr. The suspension was filtered and the filter cake was air dried. The solid obtained was then washed with hexane and dried to afford a dark yellow solid. This solid was dissolved in warm EtOAc (200 ml) and decolorizing carbon was added. The mixture was allowed to stand for 10 minutes. The mixture was filtered through celite and the filter cake was washed thoroughly with warm EtOAc. The filtrate was concentrated and dried under high vacuum to afford the title compound (3.56 g, 11.86 mmol, 65.1% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.5 Hz, 3 H) 3.11 (q, J=7.4 Hz, 2 H) 5.98 (brs, 1 H) 7.03 (d, J=1.8 Hz, 1 H) 7.83 (d, J=1.8 Hz, 1 H) 7.95 (brs, 1 H) 8.66 (s, 1 H). LCMS (M+H)=299.95/301.95.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[CH:12]=1.[NH2:16][NH2:17]>CO>[F:1][C:2]1[CH:12]=[C:6]2[C:5]([N:10]3[C:9]([CH2:8][O:7]2)=[N:17][NH:16][C:6](=[O:7])[CH:5]3[CH3:4])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc2c(cc1F)OCC(=S)N2
Reactant: NN
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(F)c([N+](=O)[O-])cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 7-fluoro-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (Example #56, Step D, 1.0 g, 3.05 mmol) in MeOH (10 mL) was added hydrazine (55% wt, 0.2 mL, 3.4 mmol) at ambient temperature and the reaction mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration to give 7-fluoro-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.63 g, 74%) as an orange solid. LC/MS (Table 1, Method 2) Rt=0.884 min; MS m/z: 281 [M+H]+
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[C:11]([N:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[NH:26][CH2:25][CH2:24]2)[N:10]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[ClH:1].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[C:11]([N:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[N:26]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:25][CH2:24]2)[N:10]=1
Reactant: COc1cc2nc(N3CCN[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nc(N3CCN(C(=O)CCl)[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of 0.26 g of chloroacetyl chloride in 6 ml of methylene chloride was added dropwise over 15 minutes at 0° C. to a stirred mixture of 0.5 g of the above intermediate 4A and 0.21 g of diisopropylethylamine in 15 ml of methylene chloride. After 4-hour stirring at room temperature and 72-hour resting in a refrigerator, the solid was collected by suction and purified by crystallisation from chloroform to give 0.12 g (33%) of the desired product; m.p. >270° C.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[ClH:22].[CH2:2]([NH:9][C:17](=[O:19])[CH2:16][O:15][CH:12]1[CH2:11][CH2:10][N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)[CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)COC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
2-(1-Benzylpiperidin-4-oxy)acetic acid, hydrochloride, (7.0 g) and thionyl chloride (5 ml) in dry chloroform (100 ml) were heated under reflux for 21/2 hours. The solvent was evaporated in vacuo and the resulting acid chloride taken up in chloroform (50 ml) and added dropwise to a solution of n-butylamine (5 ml) in chloroform (50 ml) with stirring at 0°. The solution was stirred at 0° for 4 hours then left at room temperature overnight. The chloroform solution was washed with water (3×50 ml), sodium hydroxide solution (3×50 ml, 2 N) and hydrochloric acid solution (3×50 ml, 2 N). The aqueous acid solution was basified to pH 12 and extracted with chloroform (3×100 ml). The chloroform extract was dried and the solvent evaporated in vacuo. The residue in ether was treated with ethereal hydrogen chloride, the resulting solid collected, washed with ether and dried to give N-n-butyl-2-(1-benzylpiperidin-4-oxy)acetamide, hydrochloride (3.5 g) identified by n.m.r. spectroscopy.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH3:4].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][NH2:13].C(O)(=O)C>CO.N1C=CC=CC=1>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][N:13]=[C:3]([CH3:4])[CH2:2][OH:1]
Reactant: CC(=O)CO
Reactant: NOC1CCCCO1
Solvent: CC(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: CC(CO)=NOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A mixture of 1-hydroxypropan-2-one (1 g, 13.5 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.9 g, 16.2 mmol) in methanol (20 mL) and pyridine (7 mL) was treated with acetic acid (0.23 mL, 4 mmol) and stirred at room temperature for 12 hours. The mixture was then concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extract was concentrated and purified by chromatography (SiO2, eluted with EtOAc-hexane-2:1) to afford 1.8 g of the title compound. MS (DCI/NH3) m/z 174 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH:2]=[CH2:3].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>C1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[C:6]([NH:7][C:14](=[O:15])[CH2:13][CH2:12][Cl:11])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCCl
Reactant: C=CCc1cccc(N)c1
Solvent: c1ccccc1
Product: C=CCc1cccc(NC(=O)CCCl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Allylaniline (0.3 moles), β-chloropropionyl chloride (0.35 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 4 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(3-allylphenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[NH2:10][C:11]1[S:12][C:13]([CH2:17][CH2:18]O)=[C:14]([CH3:16])[N:15]=1.[OH-].[Na+]>CCCCCC.O>[CH3:16][C:14]1[N:15]=[C:11]([NH2:10])[S:12][C:13]=1[CH2:17][CH2:18][O:2][N+:1]([O-:4])=[O:3]
Reactant: Cc1nc(N)sc1CCO
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: Cc1nc(N)sc1CCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Subsequently, 4-methyl-5-(2-nitrooxy-ethyl)-thiazole-2-ylamine was prepared by drop-wise addition of 1.59 grams of nitric acid (70%) to 2.48 grams of cooled sulfuric acid (95-98%) at 0-5° C. over a time period of 20 minutes. Following, 4 grams (0.025 moles) of 2-(2-Amino-4-methyl-thiazol-5-yl)-ethanol were added over a time period of 45 minutes at 0-5° C. After the addition was completed, the reaction mixture was stirred for 3 hours at 25° C., and was then added carefully to 50 ml of cold water. The water solution was turned basic with an aqueous solution of 20% sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. Chromatography of the crude product on silica gel (using a mixture of 8:2 ethyl acetate:hexane as eluent) gave 1.8 grams (35% yield) of the product as orange oil having a purity of 98.5% as determined by gas chromatography.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].COC1C=C(OC)C=CC=1C[N:18]1[C@H:21]([C@@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[CH2:20][C:19]1=[O:29].C(=O)([O-])O.[Na+]>O.C(#N)C>[CH3:27][C:24]1([CH3:28])[O:23][C@H:22]([C@H:21]2[NH:18][C:19](=[O:29])[CH2:20]2)[CH2:26][O:25]1
Reactant: COc1ccc(CN2C(=O)C[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)OC[C@@H]([C@@H]2CC(=O)N2)O1
Reaction time: 1 h

Procedure:
A solution of 1.47 g (5.45 mmol) of potassium persulphate in 25 ml of water is added dropwise within 30 minutes to a suspension, heated to 80°, of 0.964 g (3 mmol) of (S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone in a mixture of 10 ml of water and 10 ml of acetonitrile, whereby the pH of the reaction mixture is held at 5 by the addition of saturated sodium hydrogen carbonate solution. The reaction mixture is stirred for a further 1 hour at pH 5, then cooled and extracted three times with 50 ml of methylene chloride each time. The organic phases are washed with 20 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel with ethyl acetate/hexane (3:1 by volume) as the eluent. By crystallization of the resulting material from ethyl acetate/hexane there is obtained (S)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl] -2-azetidinone as white crystals of melting point 91°-92°; [α]D20 =+13.6° (c=1, ethyl acetate).