Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.[I-].[K+]>[CH2:14]([N:12]([CH2:9][CH2:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1cccc2c(N)cccc12
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCCCCCN(CCCCCCCC)c1cccc2c(N(CCCCCCCC)CCCCCCCC)cccc12
Temperature: 110 °C
Yield: 38.3 %

Procedure:
Naphthalene-1,5-diamine (3.14 g, 19.8 mmol), 1-bromooctane (25.25 g, 0.130 mol), potassium carbonate (11.79 g, 85.3 mmol), and potassium iodide (0.05 g, 0.30 mmol) was stirred in dry butanol (150 ml) and heated to 110° C. for 36 h. The reaction was quenched with water and extracted with ether three times. The combined organic phase was washed three times with water and evaporated to give black oil which was distilled under reduced pressure at 90° C. to yield a black tar. This was purified with flash chromatography using hexane as mobile phase to obtain colourless oil which crystallised to yield N1,N1,N5,N5-tetraoctylnaphthalene-1,5-diamine (2.3 g, 3.79 mmol) as white crystals. 1H-NMR (CDCl3, δ): 0.85 (t, 12H), 1.0-1.4 (m, 40H), 1.4-1.6 (m, 8H), 3.08 (t, 8H), 7.1 (d, 2H), 7.35 (t, 2H), 8.01 (d, 2H) MS MALDI-TOF (m/z): 606.574
Reaction SMILES: [C:1]1([S:7]([CH3:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[P:21](Cl)([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[CH2:24]([O:23][P:21]([CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])(=[O:22])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: CS(=O)(=O)c1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)c1ccccc1)OCC
Temperature: -78 °C
Yield: 47.8 %

Procedure:
A stirred solution of methyl phenyl sulfone (20 g, 0.128 mol) in dry THF (200 mL) was cooled at −78° C. in an acetone/dry ice bath. Lithium bis(trimethylsilyl)amide (Li HMDS; 134 mL, 1 M solution in THF, 0.134 mol) was added dropwise over 1 h. The resulting white suspension was stirred for an additional hour at −78° C. and diethyl chlorophosphate (18.5 mL, 128 mmol) in THF (20 mL) was added. The reaction mixture was stirred at −78° C. for 0.5 h, then allowed to slowly warm to room temperature and left stirring for 4 h. The reaction mixture was next concentrated under reduced pressure, the residue was dissolved in EA (500 mL), washed with brine (100 mL),dried over anhydrous Na2CO3 and concentrated under reduced pressure. The resultant crude material was purified by flash chromatography on silica gel (EA:H, 3:1 to 1:1) to afford the desired product as white solid (17.9 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:15][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1ccc(Cl)nn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 2-(6-chloropyridazin-3-yl)propanoate (2.8 g, 13.04 mmol) in THF (28 mL) was added lithium hexamethyldisilazide (1.0 molar in THF, 15.65 mL, 15.65 mmol) at −70° C. in dropwise fashion. The reaction was stirred at −70 for 30 min and then iodomethane (0.816 mL, 13.04 mmol) was added. The reaction was stirred for 2 hrs as allowed to warm to room temperature. The reaction was concentrated to dryness via rotary evaporation and the resulting material was purified by MPLC (98:2, DCM:MeOH) to provide the title compound, ethyl 2-(6-chloropyridazin-3-yl)-2-methylpropanoate (54B, 2.82 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.07 Hz, 3 H) 1.58 (s, 6 H) 4.08 (q, J=7.07 Hz, 2 H) 7.83-7.97 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])(=[O:14])=[O:13])[C:3]1=[O:25].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:3](=[O:25])[C:2]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[NH:1][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NS(C)(=O)=O)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reaction time: 18 h

Procedure:
A solution of 0.4 g of the compound obtained in EXAMPLE 3 in 5 ml of pyridine is cooled to 0° C. and 0.1 g of methanesulfonyl chloride is added. The mixture is stirred for 18 hours, the temperature being allowed to rise to RT, and evaporated under vacuum. The residue is extracted with AcOEt, washed with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue due is chromatographed on silica using a DCM/AcOEt mixture (98/2; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.22 g. M.p.=252° C.
Reaction SMILES: CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[C:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:45])[CH3:44].[OH-].[Na+]>CC(N(C)C)=O>[C:43]([N:46]1[CH2:51][CH2:50][N:49]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]5[N:34]([C:36]([C:39]([F:41])([F:40])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:48][CH2:47]1)(=[O:45])[CH3:44]
Reactant: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
DIPEA (107 mL, 613.00 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (99 g, 204.33 mmol) and N-acetylpiperazine (28.8 g, 224.77 mmol) in DMA (500 mL). The resulting solution was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature and the solvents were evaporated. The residue was dissolved in ethyl acetate (1 L) and the solution was washed with water (1 L). The aqueous was re-extracted with ethyl acetate (1 L) and the combined organics were washed with brine (1 L), dried over MgSO4, filtered and evaporated to give crude product. The aqueous layer was basified to pH 12 with 2M NaOH, then extracted with ethyl acetate (1 L), washed with brine (1 L), dried over MgSO4, filtered and evaporated to give further crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM then 5% MeOH in DCM. Pure fractions were evaporated to give 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (81 g, 77%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]([OH:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][C:25]=2[OH:40])[N:21]=[C:20]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([OH:56])[CH2:50][O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:43][C:42]=2[OH:57])[N:19]=1.[OH-].[K+].S(OC)(O[CH3:64])(=O)=O>COCCOCCOC>[OH:57][C:42]1[CH:43]=[C:44]([O:47][CH2:48][CH:49]([OH:56])[CH2:50][O:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:45]=[CH:46][C:41]=1[C:20]1[N:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]([OH:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][C:25]=2[OH:40])[N:23]=[C:18]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:2]=2[O:1][CH3:64])[N:19]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCCCC)cc3O)nc(-c3ccc(OCC(O)COCCCC)cc3O)n2)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCCCC)cc3O)nc(-c3ccc(OCC(O)COCCCC)cc3OC)n2)c(O)c1
Temperature: 80 °C

Procedure:
A mixture of 11.9 g (15.0 mmol) of 2,4,6-tris[2-hydroxy-4-(3-n-butoxy-2-hydroxypropoxy)phenyl]-1,3,5-triazine in 80 ml of diglyme (Fluka 99.5%) is heated under nitrogen to 80° C. To the solution there are added in succession 1.0 g (15.1 mmol) of pulverized KOH (Fluka, 85%) and 2.5 g (19.8 mmol) of dimethyl sulfate (Fluka, 99%), with stirring.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20](O)[CH3:21]>>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([O:17][CH2:20][CH3:21])=[O:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: Cl
Product: CCOC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 0 °C

Procedure:
A suspension of 5-(benzyloxy)-1,4-dihydro-4-oxo-2-pyridinecarboxylic acid (8.24 g, 33.6 mmole) in 120 ml of ethanol was cooled to 0° C. and treated with a stream of dry HCl for 15 minutes. The resulting mixture was heated at 50° C. for 5.5 hours. The volatiles were removed in vacuo and the residue was treated with water. While cooling, the pH was raised to 7 with saturated potassium bicarbonate and the resulting mixture was extracted with dichloromethane. The extracts were washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo produced 7.32 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:15]=3[N+:23]([O-:25])=[O:24])=[C:11]([C:27]([O:29]CC)=[O:28])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:15]=3[N+:23]([O-:25])=[O:24])=[C:11]([C:27]([OH:29])=[O:28])[N:10]=[N:9]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1cc(OC)c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(C)cc2[N+](=O)[O-])cc1

Procedure:
In the same manner as above, a solution of ethyl 1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate (b-2) (288 mg, 0.638 mmole) in tetrahydrofuran (7 ml) was hydrolyzed with a 1N aqueous sodium hydroxide solution (1.3 ml) at room temperature for 4.5 hours to give 1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylic acid (c-2': MP) (256 mg, 94%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[C:14]2=[CH:15][N:16]([CH2:24][CH2:25][S:26]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]2[C:12](=[O:46])[N:11]([CH3:47])[C:10]1=[O:48].C([SiH](CC)CC)C>C(Cl)Cl>[SH:26][CH2:25][CH2:24][N:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13]2[C:14]([N:9]([CH3:8])[C:10](=[O:48])[N:11]([CH3:47])[C:12]2=[O:46])=[CH:15]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCS)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TFA (5.975 ml, 78 mmol) was added to a solution of 1,3-dimethyl-5-phenyl-6-(2-tritylsulfanyl-ethyl)-1,6-dihydro-pyrrolo[3,4-d]pyrimidine-2,4-dione (step 1) (865 mg, 1.551 mmol) and triethylsilane (2.477 ml, 15.51 mmol) in DCM (20 ml) and the mixture stirred at RT for 3 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between DCM (10 mL) and sat. NaHCO3 (10 mL) and the phases separated. The organic phase was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was triturated with diethyl ether and the solid collected by filtration. The title compound was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CSc1ccccc1
Reaction time: 2 h

Procedure:
To (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (3.00 g) in methanol (100 ml) were added thiophenol (1.5 ml) and triethylamine (2.0 ml), followed by 2 hour' stirring under reflux. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give 4.14 g of (2S)-1-(t-butoxycarbonyl)-2-[1-hydroxy-2-(phenylthio)ethyl]pyrrolidine.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[CH:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH:14]1[CH2:15][N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(ON2C(=O)c3ccccc3C2=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (1.72 g, 10.541 mmol), di-tert-butyl 4-hydroxypyrazolidine-1,2-dicarboxylate 141 (Journal of Antibiotics, 1993, Vol 46, (12), 1866-1882, 1.52 g, 5.27 mmol) and triphenylphosphine (2.76 g, 10.54 mmol) in THF (50 mL) was added DIAD (2.24 mL, 11.59 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue, which was subjected to chromatography to give 142 (1.8 g, 79° A) as a white foam.
Reaction SMILES: [CH2:1]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:2]([C:4]([F:7])([F:6])[F:5])=O.Cl.[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:1]=[C:2]([C:4]([F:7])([F:6])[F:5])[N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[N:25]=1
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Product: O=[N+]([O-])c1cccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)c1
Yield: 94 %

Procedure:
Using hexafluoroacetylacetone and 3-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.
Reaction SMILES: C([O:8][CH2:9][CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])C1C=CC=CC=1.CC(O)=O>CO>[OH:8][CH2:9][CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)C(=O)N1CCOCC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(CO)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
tert-butyl-3-(benzyloxy)-1-morpholino-1-oxopropan-2-ylcarbamate (31) (1.4 g, 4.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by MeOH (40 mL). The reaction flask was flushed with N2 (g) and charged with 10% Pd/C (290 mg). The flask was equipped with 2H2 (g) balloons and stirred at rt for 30 min. AcOH (230 μL, 4.0 mmol, 1.0 equiv) was then added and the reaction was allowed to stir for 10 h. The solution was filtered through a pad of celite, washing with additional MeOH (200 mL). The solution was concentrated on a rotary evaporator, and dried under vacuum to give 1.2 g of crude material. The residue was purified by flash column chromatography (100% EtOAc) to give 970 mg (88%) of 32 as a colorless oil which crystallized to a white solid. Rf=0.26 (100% EtOAc); mp=45-47° C.; IR (film) 3418, 3315, 2972, 2927, 2859, 1706, 1631, 1444, 1166 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.87 (d, J=8.5 Hz, 1H, carbamate-NH), 4.67 (br d, J=4 Hz, 1H, Boc-NH—CH), 3.79 (br s, 2H, CH—CH2), 3.68-3.62 (m, 9H, morpholine CH2's & OH), 1.44 (s, 9H, t-butyl-CH3); 13C NMR (125 MHz, CDCl3) δ 169.7, 155.7, 80.2, 66.8, 66.7, 64.0, 51.4, 46.3, 42.6, 28.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].[Br:19]Br>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=[C:9]([Br:19])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc2c1OCC2(C)C
Reactant: BrBr
Solvent: CCO
Product: CCOC(=O)CCc1cc(Br)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A stirred, cooled (ice bath) solution of 3-(3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (Intermediate 75, 0.71 g, 2.86 mmol) in ethanol (14 mL) was treated with bromine (0.3 mL, 5.819 mmol) and the reaction mixture was allowed to gradually warm up to room temperature over 1.5 h. The volatiles were then evaporated in vacuo and the residue was dissolved in diethyl ether and washed with water (×1), aqueous sodium thiosulfate solution (×1) and brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound as an oil (0.875 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:9][OH:10])N)=[N:4][O:5][N:6]=1.[ClH:11].[Cl-].[Na+].N([O-])=O.[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:7]([Cl:11])=[N:9][OH:10])=[N:4][O:5][N:6]=1
Reactant: NC(=NO)c1nonc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nonc1C(Cl)=NO
Temperature: 43.5 °C
Yield: 53.4 %

Procedure:
4-Amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (422 g, 2.95 mol) was added to a mixture of water (5.9 L), acetic acid (3 L) and 6 N hydrochloric acid (1.475 L, 3 eq.) and this suspension was stirred at 42-45° C. until complete solution was achieved. Sodium chloride (518 g, 3 eq.) was added and this solution was stirred in an ice/water/methanol bath. A solution of sodium nitrite (199.5 g, 0.98 eq.) in water (700 mL) was added over 3.5 hrs while maintaining the temperature below 0° C. After complete addition stirring was continued in the ice bath for 1.5 hrs and then the reaction mixture was allowed to warm to 15° C. The precipitate was collected by filtration, washed well with water, taken in ethyl acetate (3.4 L), treated with anhydrous sodium sulfate (500 g) and stirred for 1 hr. This suspension was filtered through sodium sulfate (200 g) and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in methyl t-butyl ether (5.5 L), treated with charcoal (40 g), stirred for 40 min and filtered through Celite. The solvent was removed in a rotary evaporator and the resulting product was dried in a vacuum oven (45° C.) to give the desired product (256 g, 53.4%). LCMS for C3H4ClN4O2 (M+H)+: m/z=162.9. 13C NMR (100 MHz, CD3OD): δ 155.8, 143.4, 129.7.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.S(O)(=O)(=O)C.S(O)(=O)(=O)C.[NH2:29][NH:30][C:31]([NH2:33])=[NH:32]>C(O)C>[NH2:33][C:31]1[N:30]=[N:29][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:32]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: N=C(N)NN
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1ccc(-c2nnc(N)nc2-c2ccc(C)cc2)cc1

Procedure:
A stirred mixture of 4,4′-dimethylbenzil (2.38 g; 0.01 mol), aminoguanidine bismesylate (3.33 g; 0.0125 mol) and ethanol (10 cm3) was heated under reflux until no starting material remained (4 hrs) when a cream solid was deposited. The mixture was evaporated to half volume and basified with 880 ammonia+water (1:1; 4 cm3). On standing, bight yellow prisms were deposited. The product was filtered off, washed with ethanol+water (1:1) and dried in vacuo at 450.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(C)cc2)cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccc(C)cc2)cc1
Yield: 72 %

Procedure:
As before in Example 134, a solution of (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (2.5 g) and 3-pyridinebutanamine (1.08 g) in tetrahydrofuran (25 mL) was stirred overnight at room temperature and then worked up in the usual way. The amide was purified by HPLC (ethyl acetate) and then was crystallized two times from ether to give 1.85 g of (E)-5,5-bis(4-methylphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 144.5°-145.5° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[OH:10].[Na+].OO>C(Cl)Cl.O>[CH2:1]1[O:10][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: C=Cc1ccccc1
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1ccc(C2CO2)cc1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
0.0178 g (0.02 mmol) of the complex salt as described in Preparative Example 1 was added to a mixture of 0.208 g (2 mmol) of styrene in 20 ml of CH2Cl2 and 1.68 g (20 mmol) of sodium hydrogen carbonate in 20 ml of water. After a reaction time at room temperature of 10 minutes, 20 ml of H2O2 (30% strength) was added slowly over a period of 2.5 hours, with the temperature rising to 28° C. After a further 22 hours, the reaction was complete. The layers were separated and the organic phase was evaporated under reduced pressure. The product obtained was purified by column chromatography giving styrene oxide in a yield of 54% based on styrene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][CH3:18])[CH3:14]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:18]=[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:19])[N:10]=[N:9]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: CCOC(=O)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of para-methoxy benzyl azide (125.0 g, 0.77 mol) in anhydrous DMF (300 mL) was added dropwise propionic acid ethyl ester-(166 g, 1.77 mol) at 0° C. After the addition, the mixture was stirred at RT overnight. The mixture was evaporated in vacuo to yield crude title compound (190.0 g, 95.0%) as yellow oil that was used without further purification.