Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)=[O:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:23][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:21][N:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazine-carbonyl)piperazine-1-carboxylate (903 mg, 1.8 mmol) in DCM (200 mL) was added pyridine (2.8 mL, 36.0 mmol). (CF3SO2)2O (2.8 ml, 9.0 mmol) was then slowly added at −10° C. The reaction mixture was stirred at rt for 3 hrs. Sat. NaHCO3 was added at −10° C. very slowly. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (2:1 EtOAc/hexanes) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate (723 mg, 83%) as a slight yellow solid. ESI-MS (EI+, m/z): 485.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:21][CH2:20][N:19]3[C:12](=[CH:13][C:14]4[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]=43)[C:11]2=[O:24])[CH:5]=[CH:4][N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43](B4OC(C)(C)C(C)(C)O4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1.O>[CH3:22][C:16]1([CH3:23])[CH2:15][C:14]2[CH:13]=[C:12]3[N:19]([CH2:20][CH2:21][N:10]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:43]5[CH:44]=[C:39]([NH:38][C:36]6[CH:37]=[C:31]7[CH2:30][N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH2:34][CH2:33][N:32]7[N:35]=6)[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=5)[C:7]=4[CH:8]=[O:9])[C:11]3=[O:24])[C:18]=2[CH2:17]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1ccnc(Cl)c1C=O)C3=O
Reactant: COCCN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: COCCN1CCn2nc(Nc3cc(-c4nccc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 329a (100 mg, 0.30 mmol), 3-(5-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 328a (257 mg, 0.60 mmol), Pd(dppf)Cl2 (25 mg, 0.030 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate (49 mg, 0.60 mmol), water (0.50 mL), and THF (10 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at reflux for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 329b as a brown solid (60 mg, 34%). MS-ESI: [M+H]+ 611.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:6](N[C@@H]1CCN(C)C1)=[O:7].[CH2:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:6](=[O:7])[C:5]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:25][CH2:24]1)[CH3:22]
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Reactant: CCN1CCC(N)CC1
Product: CCN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising 1-ethylpiperidin-4-amine (Fluorochem; 1.19 g, 9.28 mmol), as a brown solid (3.3 g, 100%)
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].C(N(CC)CC)C.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>CCOCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:16][CH:17]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CNS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNS(=O)(=O)Nc1ccc(C(C)=O)cc1
Temperature: -50 °C

Procedure:
Methylsulfamoyl chloride (42.5 g., 0.33 mole) is added dropwise to a mixture of triethylamine (33.4 g., 0.33 mole) and p-aminoacetophenone (40.5 g., 0.30 mole )in ether (1.5 1.) at -50° C. The mixture is stirred at -50° C. and then allowed to warm to -10° C. The mixture is filtered to give a mixture of product and triethylamine hydrochloride. Washing with water and recrystallization from isopropanol furnishes 30.6 g. (40%) of the above pure intermediate, m.p. 159°-159.5° C. (dec.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1.[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[Cl-].[NH4+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([O:15][C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([OH:30])[CH3:29])=[CH:24][CH:23]=3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:14]1
Reactant: CC(=O)c1ccc(-c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)c1ccc(-c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
1-(4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)phenyl)ethanone (see EXAMPLE 10.26; 99 mg, 0.25 mmol) was dissolved in 10 ml of methanol. This solution was cooled down to 0° C. using an ice bath and sodium tetraborohydride (19 mg, 0.50 mmol) was added in portions. The reaction mixture was stirred for 4 hours at ambient temperature, and then saturated aqueous solution of ammonium chloride (5 mL) was added. The methanol was evaporated off under reduced pressure then the reaction mixture was taken up in ethyl acetate. The organic layer was separated from the aqueous layer. This extraction was repeated one more time and then the organic layers were combined and dried over magnesium sulphate, followed by concentrating under reduced pressure. The residue was purified by column chromatography on silica gel to give (racemic mixture) 1-(4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)phenyl)ethanol (75 mg, 0.19 mmol, 75% yield). ESI-MS (M+1): 399 calc. for C24H22N4O2 398.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[Na].[C:16]1([PH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[P:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: BrCCCCCCCCCCCCBr
Agent: [Na]
Product: c1ccc(P(CCCCCCCCCCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
In a like manner to Examples 3 and 4, one-half molar equivalent of 1,12-dibromododecane is reacted with one molar equivalent of the sodium salt of diphenylphosphine to produce (C6H5)2P(CH2)12P(C6H5)2, a waxy colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:24][C:25]3[C:30]([C:31]=2[CH:32]=O)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[NH:24][C:25]3[C:30]([C:31]=2/[CH:32]=[CH:14]/[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:15])=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:22]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c(-c2ccc(Cl)cc2)[nH]c2ccccc12
Product: COc1cc(C(=O)/C=C/c2c(-c3ccc(Cl)cc3)[nH]c3ccccc23)cc(OC)c1OC
Yield: 169.9 %

Procedure:
Substantially the same procedure as in Example 12 was repeated using 3',4',5'-trimethoxyacetophenone (0.84 g) and 2-(4-chlorophenyl)indole-3-carboxaldehyde (2.56 g) to give Compound 14 (3.04 g).
Reaction SMILES: C(Br)Br.[CH2:4](N(CC)CC)C.[C:11]1([S:17][CH2:18][NH:19][C:20](=[S:22])[S-:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].S1CCS1>O.CN(C)C=O>[C:11]1([S:17][CH2:18][N:19]=[C:20]2[S:21][CH2:4][S:22]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: S=C([S-])NCSc1ccccc1
Agent: C1CSS1
Agent: [K+]
Solvent: O
Solvent: BrCBr
Solvent: CN(C)C=O
Product: c1ccc(SCN=C2SCS2)cc1
Reaction time: 2 h

Procedure:
To a mixture of 28.2 g. of methylene bromide and 10.9 g. of triethylamine in 250 ml. of dimethylformamide was added, in portions, 27.3 g. of potassium phenylthiomethyldithiocarbamate keeping the reaction temperature below 30° C. by cooling. After another two hours, the mixture was poured into water and extracted with ethylene chloride. The ethylene chloride mixture was washed with water, dried, and saturated with dry hydrogen chloride. The resulting salt was collected by filtration and washed with acetone. The salt, on stirring with a mixture of 100 ml. of water and 300 ml. of chloroform, dissolved and removal and concentration of the chloroform layer gave 8.5 g. of the dithietane as a white solid, m.p. 50-52° C.
Reaction SMILES: [C:1]([O:4][CH:5]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=O)(=O)[CH3:2].C([O-])(=O)C.[NH4+:30]>C(O)(=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:30]=[C:1]([CH3:2])[O:4][C:5]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=2)=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: CC(=O)OC(C(=O)c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)c(F)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(Br)cc2)c(-c2ccc(S(C)(=O)=O)c(F)c2)o1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
The mixture of 2-acetoxy-1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone (743.7 mg, 1.733 mmol) and ammonium acetate (333.9 mg, 4.333 mmol) in acetic acid (15 mL) was heated at reflux temperature for 2.5 hours, and cooled down to room temperature. The mixture was evaporated, diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution (100 mL×2), water (50 mL), brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to provide the subtitle compound (447.1 mg, 63% yield) as a solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:19]1[CH:23]=[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:26]=3[N:27]=[CH:28][N:29]=2)[CH:21]=[N:20]1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)#[N:2].[ClH:41].O1CCOCC1>>[ClH:41].[NH:9]1[CH2:8][CH2:7][CH:6]([CH2:5][CH:4]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:3][C:1]#[N:2])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC4CCNCC4)c3)ncnc21

Procedure:
tert-Butyl 4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidine-1-carboxylate (second peak from chiral purification, 1.12 g, 0.00198 mol) was stirred with 4.0 M of hydrogen chloride in p-dioxane (5 mL, 0.02 mol) at RT for 30 min. After being concentrated to dryness under reduced pressure, the resultant HCl salt was used directly in next step. LCMS calculated for C24H36N7OSi(M+H)+: m/z=466.3; Found: 466.2.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][NH2:13])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Cl:14][C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][C:29]([CH3:34])([C:31](O)=[O:32])[C:28](=[O:35])[NH:27][C:26]=3[CH:36]=2)[C:18]([F:37])=[CH:17][N:16]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:14][C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][C:29]([CH3:34])([C:31]([NH:13][CH2:12][CH2:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=4)=[O:32])[C:28](=[O:35])[NH:27][C:26]=3[CH:36]=2)[C:18]([F:37])=[CH:17][N:16]=1
Reactant: NCCc1cccc([N+](=O)[O-])c1
Reactant: CC1(C(=O)O)Oc2ccc(Nc3nc(Cl)ncc3F)cc2NC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)NCCc2cccc([N+](=O)[O-])c2)Oc2ccc(Nc3nc(Cl)ncc3F)cc2NC1=O
Reaction time: 16 h
Yield: 91.8 %

Procedure:
2-(3-nitrophenyl)ethanamine hydrochloride (100.00 mg; 0.49 mmol; 1.00 eq.), 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (SYN5052A) (174.06 mg; 0.49 mmol; 1.00 eq.), o-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetra-methyluronium hexafluorophosphate (375.28 mg; 0.99 mmol; 2.00 eq.) and N-ethyl-N-isopropylpropan-2-amine (0.32 ml; 1.97 mmol; 4.00 eq.) are placed into a scintillation vial equipped with a stir bar. The mixture is taken up in DMF (3.00 ml). The reaction mixture is stirred for 16 hours. Upon completion, the reaction mixture is diluted with ethyl acetate (100 mL) and extracted with brine solution. The organic layer is then dried over magnesium sulfate, filtered, concentrated and purified via Prep HPLC using a gradient of 10-50% acetonitrile in water with 0.1% trifluoroacetic acid modifier to give 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2-methyl-N-[2-(3-nitrophenyl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (10) (226.4 mg; 0.45 mmol; 91.6%);
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH2:27]([O:29][C:30](=[O:36])[CH2:31][C:32](=O)[CH2:33]Cl)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:36])[CH2:31][C:32]1[N:14]=[C:9]2[C:8]([O:7][C@@H:6]3[S:15][CH2:16][C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:5]3[O:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=[CH:11][N:10]2[CH:33]=1)[CH3:28]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1N
Product: CCOC(=O)Cc1cn2cccc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Yield: 54 %

Procedure:
By carrying out the process in a manner similar to process A of example 1, starting from 2-amino-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-chloro-3-oxobutanoic acid ethyl ester, the desired product is obtained in the form of a white solid with a yield of 54%.
Reaction SMILES: O1C=CCCC1.O1C=CCC1.C(OCC)=C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[H-].[Na+].[Br-].[C:41]([CH2:44][CH2:45][CH2:46][CH2:47][P+:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([OH:43])=[O:42]>C1(C)C=CC=CC=1.CS(C)=O.C(Cl)Cl>[C:41]([CH2:44][CH2:45][CH2:46][CH:47]=[P:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([OH:43])=[O:42]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1=COCC1
Agent: C1=COCCC1
Agent: C=COCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(O)CCCC=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Compounds of formula XX may be prepared by hydrolysis under alkaline conditions of compounds of formula XIX. Compounds of formula XXI may be obtained by the acetylation of compounds of formula XX under mild conditions and may be converted into compounds of formula XXII by reaction with a dihydropyran, dihydrofuran or ethyl vinyl ether in an inert solvent, e.g. methylene chloride, in the presence of a condensing agent, e.g. p-toluenesulphonic acid. Compounds of formula XXIII may be prepared by reducing compounds of formula XXII with diisobutylaluminium hydride in toluene for about 15 minutes at -60° C. Dimsyl anion, previously prepared from sodium hydride and dimethyl sulphoxide, is reacted with (4-carboxybutyl)triphenylphosphonium bromide to form (4-carboxybutylidene)triphenylphosphorane. To that compound is added a compound of formula XXIII and the mixture in dimethyl sulphoxide is made to react for 2 hours at room temperature to yield a compound of formula XVA.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:26](=[O:28])[CH3:27])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 1 h
Yield: 78 %

Procedure:
4-Nitro-3-piperidin-1-yl-phenylamine (64 mg, 0.28 mmol, as prepared in the previous step) and DIEA (122 μL, 0.700 mmol) in 4 mL of CH2Cl2 was treated with acetyl chloride (28 μL, 0.40 mmol). The reaction was stirred for 1 h, diluted with CH2Cl2 (25 mL), washed with water (50 mL), and dried (Na2SO4). Concentration of the solvent in vacuo afforded 51 mg (78%) of N-(4-nitro-3-piperidin-1-yl-phenyl)-acetamide. Using a procedure similar to Example 3, step (c), 4-nitro-3-piperidin-1-yl-phenylamine (51 mg, 0.21 mmol) was stirred with 5% Pd—C (35 mg) under H2 to afford 40 mg (61%) of the title compound as a dark semi-solid. Mass spectrum (ESI, m/z): Calcd. for C13H19N3O, 234.1 (M+H), found 234.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]4[N:27]=[CH:26][N:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[N:24]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>COCCOC.O.CCOC(C)=O>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:12]4[S:13][C:14]([C:23]5[N:27]=[CH:26][N:25]([CH:28]6[CH2:33][CH2:32][CH2:31][CH2:30][O:29]6)[N:24]=5)=[C:15]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:16]=4)=[C:9]([CH3:11])[N:10]=3)[CH:7]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]
Reactant: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc3nc(C)c(-c4nc(-c5ccccc5)c(-c5ncn(C6CCCCO6)n5)s4)n3c2)cc1OC
Temperature: 95 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a suspension of 6-bromo-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine (157 mg, 0.3 mmol) obtained above in DME (10 mL) and water (2 mL), were added (3,4-dimethoxyphenyl)boronic acid (81.9 mg, 0.45 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (24.5 mg, 0.03 mmol) and cesium carbonate (293 mg, 0.9 mmol) under a nitrogen atmosphere, and the mixture was stirred at 95° C. for 1 h. The reaction mixture was allowed to cool to rt, and then were added saturated aqueous solution of sodium bicarbonate (30 mL) and EtOAc (50 mL). The resulting precipitate was collected by filtration and washed with THF and diethyl ether to give the title compound (142 mg, 81%) as a white solid.
Reaction SMILES: [C:1]([O:6]CCCC)(=O)[C:2]([CH3:4])=[CH2:3].[CH3:11][N:12]([CH3:19])[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH2:16].OP(O)(O)=O.C1(C=CC(O)=CC=1)O>>[CH3:11][N:12]([CH3:19])[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:16][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCCC
Reactant: CN(C)CC(C)(C)CN
Agent: O=P(O)(O)O
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)NCC(C)(C)CN(C)C
Yield: 60 %

Procedure:
426 g (3 mols) of butyl methacrylate, 390 g (3 mols) of N,N,2,2-tetramethylpropane-1,3-diamine, 29.4 g (0.3 mol) of H3PO4, and 2 g of hydroquinone were warmed for 2 hours at 220° C. N-(3-dimethylamino-2,2-dimethylpropyl)-methacrylic acid amide was formed in this way. Yield: 60% (selectivity: 94% calculated on the reacted butyl methacrylate).
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1.[N+:14]([C:17]1[CH:21]=[N:20][NH:19][N:18]=1)([O-:16])=[O:15].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[N+:14]([C:17]1[CH:21]=[N:20][N:19]([CH2:4][C:5]2[O:6][CH:7]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=2)[N:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC(C)(O)c1coc(CCl)n1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)c1coc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(2-(chloromethyl)oxazol-4-yl)propan-2-ol (1.32 g, 7.51 mmol) in DMF (22.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (12.84 g of a 8% solution in DMF, 9.01 mmol) in DMF (22.0 mL) pre-treated for 30 min with DIPEA (2.57 mL, 15.01 mmol) and the reaction mixture was stirred overnight at 50° C. Water (60 mL), followed by EA (60 mL) were added. The layers were separated and the org. layer was washed with water (3×60 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as an orange oil: TLC: rf (4:6 hept-EA)=0.30. LC-MS-conditions 06: tR=0.55 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@H:19]1[CH2:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@H:19]2[CH2:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: N[C@H]1CCCNC(=O)C1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CCCNC(=O)C1

Procedure:
Following General Procedure B above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-(S)-amino-ε-caprolactam (Aldrich), the title compound was prepared as a solid having a melting point>225° C. The reaction was monitored by tlc on silica gel (Rf=0.36 in 1:9 methanol/dichloromethane).