Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CN=C1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([Si:21]([CH3:23])([CH3:22])[O:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: O=[N+]([O-])c1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of compound 2 (4.7 g, 0.03 mol) and imidazole (2.71 g, 0.04 mol) in dry CH2Cl2 (30 mL) under N2 atmosphere at 0° C. was added a solution of TBDMS-Cl (5.08 g, 0.033 mol) in CH2Cl2 (15 mL) and allowed to stir at room temperature for 2 h. The precipitated solid was isolated by filtration and washed with CH2Cl2 (5×20 mL). The filtrate and combined CH2Cl2 fractions were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mass was purified by column chromatography (silica gel, eluant=3:7 mixture of ethyl acetate and hexane) to afford compound 3 (7.2 g, 90%) as a liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[F:17].O.[NH2:19][NH2:20]>CS(C)=O>[F:17][C:3]1[C:2](=[N:19][NH2:20])[N:7]=[C:6]([CH3:8])[NH:5][C:4]=1[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(NCc2ccccn2)n1
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(=NN)c(F)c(NCc2ccccn2)[nH]1
Reaction time: 8 h
Yield: 39 %

Procedure:
6-Chloro-5-fluoro-2-methyl-N-(2-pyridinylmethyl)-4-pyrimidinamine (0.2517 g, 0.999 mmol) was dissolved in 2 mL of DMSO and 1 mL of hydrazine monohydrate. The resulting reaction mixture was stirred overnight. Then the reaction mixture was purified by RP-HPLC to provide 5-fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4(1H)-pyrimidinone hydrazone as a beige solid (0.0954 g, 39%). LCMS: (M+H)+=249.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([O:24][CH3:25])[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCC(OC)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(OCC)(=O)C>C1COCC1.C[O-].[Na+].[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH:20]([O:24][CH3:25])[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC1CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: COC1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: C[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-(3-methoxycyclohexyl)pyrimidin-4-amine, 27b, (0.08 g, 0.15 mmol) in THF were added a few drops of NaOMe. The reaction mixture was stirred at room temperature for 20 min. To the reaction mixture was added ethyl acetate and brine. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in CH3CN/H2O and the mixture was purified by preparatory HPLC to afford 23 mg of the desired product, 552.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[CH:19]=[N:18][C:17]([SH:20])=[N:16]1.O1CCOCC1.Cl[CH:28]([F:30])[F:29]>C(OCC)(=O)C.O>[Cl:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:9]=[C:4]([Cl:3])[C:5]=1[N:15]1[CH:19]=[N:18][C:17]([S:20][CH:28]([F:30])[F:29])=[N:16]1
Reactant: FC(F)Cl
Reactant: FC(F)(F)c1cc(Cl)c(-n2cnc(S)n2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)Sc1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C

Procedure:
Sodium hydroxide (3.3 g) was added to a mixture of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-mercapto-1,2,4-triazole (0.32 g, 1 mmol), 1,4-dioxane (13 ml) and water (13 ml) at one time with blowing thereinto chlorodifluoromethane gas. The temperature rose to 60°-70° C. After the rise of temperature stopped, the mixture was cooled to room temperature and poured into water. Ethyl acetate was added and the organic layer was separated and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to give 0.29 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-difluoromethylsulfenyl-1,2,4-triazole.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1>>[Cl:12][C:8]1[C:9]([CH3:11])=[CH:10][C:4]2[N:3]=[C:2]([N:24]3[CH2:25][CH2:26][N:21]([C:16]4[C:15]([C:14]([F:28])([F:13])[F:27])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:22][CH2:23]3)[NH:6][C:5]=2[CH:7]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Cc1cc2[nH]c(Cl)nc2cc1Cl
Product: Cc1cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2cc1Cl

Procedure:
The benzoimidazole from step (b) above (201 mg, 1.0 mmol) reacted with 1-(3-trifluoromethylpyridin-2-yl)piperazine (231 mg, 1.0 mmol, Oakwood) under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 396.1 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[I-:12].[Na+].CN[C@@H]1CCCC[C@H]1NC.[Cl-].[NH4+]>C(OCC)(=O)C.[Cu]I>[I:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Brc1ccnc2cccnc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Ic1ccnc2cccnc12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
4-bromo-1,5-naphthyridine (99 mg, 0.47 mmol), copper(I) iodide (4.5 mg, 0.024 mmol) and sodium iodide (142 mg, 0.947 mmol) were combined into one vial fitted with a Teflon septum. The vial was flushed with nitrogen and 1,4-dioxane (4 ml) was added. After sparging with nitrogen for 5 minutes, rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (7.5 μl, 0.047 mmol) was added and the reaction was heated to 100° C. for 12 hours. The mixture was cooled to ambient temperature, and saturated aqueous ammonium chloride (2 ml) was added to quench the reaction. After stirring for 10 minutes, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was back extracted with ethyl acetate one more time. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane gradient) to afford 4-iodo-1,5-naphthyridine.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.C[Si](Cl)(C)C.[SH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH:5]([C:4]1[CH:3]=[C:2]([CH:1]([S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:9]=[CH:8][CH:7]=1)=[O:6]
Reactant: COC(=O)CCS
Reactant: O=Cc1cccc(C=O)c1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of isophthalaldehyde (5.4 g) in CHCl3 (50 ml) and methyl 3-mercaptopropanoate (9.2 ml) was added dropwise trimethylsilylchloride (6.5 ml). The reaction mixture was stirred 1 hour at room temperature, quenched with aqueous NH4OAc (25%), and extracted with ethylacetate. Flash chromatography of the residue using 1:1 ethylacetate hexane afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[O:11][CH2:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]([O:11][CH3:10])=[O:13])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CC(CCOC1CCCCO1)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C(C)CCOC2CCCCO2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 101.9 %

Procedure:
To the solution of 2-(3-(4-bromophenyl)butoxy)-tetrahydro-2H-pyran (1.05 mg, 3.37 mmol) in methanol (30 mL) was added 1,3-bis(diphenylphosphino) propane (278 mg, 0.67 mmol), palladium acetate (151 mg, 0.67 mmol), and triethylamine (1.7 g, 16.9 mmol), the mixture was stirred at 90° C. for 12 hours under an atmosphere of carbon monoxide in sealed tube. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(4-(tetrahydro-2H-pyran-2-yloxy)butan-2-yl)benzoate (501.8 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:14]([CH3:15])=[C:13]([S:16]C#N)[CH:12]=[C:11]([CH:19]([CH3:21])[CH3:20])[C:9]=2[N:10]=1)=[O:4].SC[C@H]([C@@H](CS)O)O.P([O-])([O-])([O-])=O>CCO>[CH3:1][O:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:14]([CH3:15])=[C:13]([SH:16])[CH:12]=[C:11]([CH:19]([CH3:21])[CH3:20])[C:9]=2[N:10]=1)=[O:4]
Reactant: COC(=O)Nc1nc2c(C(C)C)cc(SC#N)c(C)c2s1
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCO
Product: COC(=O)Nc1nc2c(C(C)C)cc(S)c(C)c2s1

Procedure:
The title compound was prepared according to General Method 14 using 2-(methyloxycarbonyl)amino-4-isopropyl-7-methyl-6-thiocyanato-benzothiazole (1.5 g, 4.7 mmol), dithiothreitol (2.9 g, 18.7 mmol), EtOH (50 mL), and phosphate buffer (15 mL). MS (APCI): 296 (M−H).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][C:18]([O:21][C:22]([N:24]1[CH2:31][C:30]2[O:29][C:28]([CH2:32][OH:33])=[N:27][C:26]=2[CH2:25]1)=[O:23])([CH3:20])[CH3:19].[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CO>[CH3:20][C:18]([O:21][C:22]([N:24]1[CH2:31][C:30]2[O:29][C:28]([CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:27][C:26]=2[CH2:25]1)=[O:23])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1Cc2nc(CO)oc2C1
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
Di-tert-butyl azodicarboxylate (0.079 g, 0.34 mmol) was added portionwise to a stirred solution of 4,6-dihydro-2-(hydroxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.055 g, 0.23 mmol), phenol (0.032 g, 0.34 mmol) and triphenylphosphine (0.090 g, 034 mmol) in THF (1 mL) at 0° C. The mixture was stirred at room temperature for 10 minutes, diluted with MeOH and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and evaporated in vacuo to yield 4,6-dihydro-2-(phenoxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.073 g, quantitative yield) as a clear oil that was used in the next step without further purification. C17H20N2O4 LCMS: Rt 3.06, m/z 317 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.CCCCCCC>[CH3:22][N:13]1[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]3[S:4][N:3]=[C:2]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:6]=3[CH:7]=2)[C:12]1=[O:23]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(Cl)c3c2)c1=O
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(N4CCOCC4)c3c2)c1=O
Yield: 61.4 %

Procedure:
A mixture of 3-(3-chloro-1,2-benzisothiazol-5-yl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.300 g), morpholine (2.00 g) and triethylamine (5.00 g) in tetrahydrofuran is refluxed for 18 hours and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and 25% and 50% ethyl acetate in heptane solutions gives the title product as a yellow solid (0.210 g, mp 200-205° C.).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[C:18](=[O:19])[CH:17]=[C:16]2[C:7](=[N:8][C:9]3[C:14]([S:15]2)=[CH:13][C:12]([O:20][CH3:21])=[CH:11][CH:10]=3)[CH:6]=1.CO>C(O)(=O)C>[Br:1][C:17]1[C:18](=[O:19])[C:5]([O:4][CH3:3])=[CH:6][C:7]2[C:16]=1[S:15][C:14]1[C:9](=[CH:10][CH:11]=[C:12]([O:20][CH3:21])[CH:13]=1)[N:8]=2
Reactant: COc1ccc2nc3cc(OC)c(=O)cc-3sc2c1
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2nc3cc(OC)c(=O)c(Br)c-3sc2c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A solution of bromine (280 g) in acetic acid (2.8 l) was added over a period of 30 minutes to a suspension of 2,7-dimethoxy-3H-phenothiazin-3-one (250 g) (Step 3) in acetic acid (7.5 l) and stirred for 2 hours. Methanol (12 l) was added and the mixture was stirred until the black suspension became an orange suspension. Then, the precipitate was filtered, washed with methanol and air-dried to afford the desired compound (312 g), m.p. 260°-261° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([C:16](=[C:33](OS(F)(=O)=O)[CH3:34])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:40])[C@H:13]1[NH:41][C:42](=[O:50])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)CC)C.[Na+].[Cl-]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([C:16](=[C:33]=[CH2:34])[C:17]([O:19][CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:18])[C:14](=[O:40])[C@H:13]1[NH:41][C:42](=[O:50])[CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(OS(=O)(=O)F)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Under a stream of dry nitrogen, the flask was charged with 500 mg (0.65 mmol) of diphenylmethyl 2-[(3R, 4R)-4-[(benzothiazol-2-yl)dithio]-3-phenylacetamido-2-oxo-azetidin-1-yl]-3-fluorosulfonyloxy-2-butenoate (XVf) and 5.0 mL of dry THF. After stirring the solution for 15 min at 0°-5° C., 92.0 μL (0.65 mmol) of triethylamine was added dropwise. Stirring at 0°-5° C. under a blanket of dry nitrogen was continued for 2 h. The solution was diluted with THF (10 mL) and poured into an aqueous saturated NaCl solution (30 mL). The phases were separated and the organic phase was dried 15 min over anhydrous MgSO4, filtered and concentrated to a small volume (ca. 6 mL). The solution was added dropwise into 36 mL of hexanes with vigorous stirring. After 30 min, the solid was collected by suction filtration and dried in vacuo for 3 h at 22° C. to yield 387 mg (92%) of the title product as a beige powder.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:1][C:2]=12)#[N:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: CC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A mixture of 540 mg of 3-aminopyrazole-4-carbonitrile, 1.23 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylacetamide and 50 ml of glacial acetic acid was heated at reflux for 8 hours then the solvent was removed: The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried, passed through a pad of hydrous magnesium silicate and hexane was added to the refluxing filtrate to crystallize the product. The mixture was cooled and the solid collected, giving the desired product, mp 195°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([OH:18])=O)[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][CH2:70][N:71]1[CH2:76][CH2:75][O:74][CH2:73][CH2:72]1>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:67][CH2:68][CH2:69][CH2:70][N:71]3[CH2:76][CH2:75][O:74][CH2:73][CH2:72]3)=[O:18])[CH:12]=2)[CH:6]=1
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCN5CCOCC5)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)morpholine (48 mg, 0.33 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 122 mg, 95%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1.[H-].[Na+].Cl.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:15])[CH2:7][N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=2[O-:26])[C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc2O1
Reactant: [O-][n+]1ccccc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 2.66 g of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine followed by addition of 1.02 g of sodium hydride (60% in oil) and the mixture was stirred at room temperature for 30 minutes. Then, 2.77 g of 2-bromopyridine N-oxide hydrochloride was added with ice-cooling and, after the evolution of heat had subsided, the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured in water and extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on a silica gel column using chloroform as the eluent to give crude 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide.
Reaction SMILES: C[C@@H:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:27])[N:3]1[C@H:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1)[CH3:29].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(Cl)Cl.O>[OH:40][C:37]([CH3:38])([CH3:39])[CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:28]([N:3]2[CH2:2][CH2:7][C@:6]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:5][C:4]2=[O:27])[CH3:29])=[CH:31][CH:32]=1
Reactant: COc1ccc(COCCCC2(c3ccccc3)C[C@@H](C)N([C@@H](C)c3ccc(CC(C)(C)O)cc3)C(=O)O2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CC(C)(C)O)cc3)C(=O)O2)cc1
Reaction time: 3 h
Yield: 0.8 %

Procedure:
To a solution of methyl (R)-3-((S)-1-(4-(2-hydroxy-2-methylpropyl)phenyl)ethyl)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 0.188 mmol) in DCM/H2O (10:1, 2 mL) was added CAN (100 mg). The formed mixture was stirred for 3 h. The reaction was washed with water and extracted with CH2Cl2. The combined organic phase was concentrated to provide the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-(2-hydroxy-2-methylpropyl)phenyl)ethyl)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-1,3-oxazinan-2-one (0.8 mg, 10%). LC-MS Method 2 tR=1.191 min, m/z=411.24; 1H NMR (CDCl3): δ=0.81 (m, 4H), 1.09 (d, 6H), 1.43 (d, 3H), 1.64 (m, 3H), 1.92 (m, 3H), 2.16-2.26 (m, 4H), 2.59 (s, 2H), 2.83 (m, 1H), 3.52 (t, 2H), 5.62 (q, 1H), 6.78 (m, 2H), 6.86 (m, 2H), 6.94 (m, 1H), 7.26 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]1.[CH2:13]([O:15][C:16](=[O:30])[C:17](=[CH:26]OCC)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:30])[C:17](=[CH:26][NH:12][C:11]1[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9][CH:10]=1)[C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Reactant: Nc1ccnn1Cc1ccco1
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)c1ccccc1

Procedure:
163 g. of 1-(2-furyl)methyl-5-aminopyrazole (1 mol.) and 248 g. of ethoxymethylene benzoyl acetic acid ethyl ester (1 mol.) are heated at 130° until no more alcohol distils off (approximately 1 hour). The oily residue crystallizes and yields on cooling and recrystallization from hexane 310 g. of [[[1-(2-furyl)methyl-5-pyrazolyl]-amino]methylene]benzoyl acetic acid ethyl ester (85%), m.p. 75°-77°.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].C(N(CC)CC)C.[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14]>C(O)C>[CH3:1][N:2]([O:3][CH3:4])[C:13](=[O:14])[C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:17]
Reactant: CNOC
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON(C)C(=O)c1ccccc1N
Yield: 99.1 %

Procedure:
N,O-Dimethylhydroxylamine (102.5 g) was dissolved in 90% ethanol (40 ml). To the solution were added triethylamine (106 g) and isatoic anhydride (74 g). The mixture was heated for 1.5 hour under reflux. The reaction mixture was concentrated, to which was added a saturated aqueous saline solution, followed by extraction with ethyl acetate (500 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave N-methyl-N-methyloxy-2-aminobenzamide (81 g) as a yellow oily product. This compound (6.8 g) and 1-[(tert-butoxycarbonylamino-1-methyl)ethyl]-3-bromobenzene (10 g) were dissolved in tetrahydrofuran (200 ml). The solution was cooled to −80° C. or below, to which was added dropwise, while stirring, n-butyl lithium (1.6 mol/L) (128 ml) over 1.5 hour. To the reaction mixture was added water (200 ml), which was subjected to extraction with ethyl acetate (300 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-amino-3′-(1-tert-butoxycarbonylamino-1-methyl)ethyl-benzophenone (2.2 g) as a yellow oily product.