Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6](=[CH2:9])[C:7]#[N:8]>O1CCCC1>[ClH:5].[ClH:5].[C:7]([CH:6]1[CH2:9][NH:4][CH2:1][CH2:2][NH:3]1)#[N:8]
Reactant: NCCN
Reactant: C=C(Cl)C#N
Solvent: C1CCOC1
Product: Cl
Product: N#CC1CNCCN1
Temperature: 30 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Into 300 ml of tetrahydrofuran was added 54.1 g (0.9 mole) of ethylenediamine and the mixture was heated to 30° C. To the mixture was added dropwise 52.5 g (0.6 mole) of 2-chloroacrylonitrile over a period of 2 hours with stirring and further stirring was continued for 6 hours. During stirring, the temperature was kept at about 30° C. The reaction mixture formed was cooled to 20° C. and precipitates formed were removed by filtration. After adding 35% hydrochloric acid to the filtrate formed to adjust pH of the mixture to 4, precipitates formed were collected by filtration. The precipitates were dissolved in 20% hydrochloric acid and the solution thus formed was added dropwise to tetrahydrofuran. Precipitates formed were collected by filtration and the solvent attaching the precipitates was removed under reduced pressure to provide 55.2 g (yield 50%) of 2-cyanopiperazine-di-hydrochloride. The analytical values of the product were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=2)=[CH:18][CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=3)=[CH:32][CH:33]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
A solution of 494 mg (2.23 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 10 ml THF was added within 15 min. to a solution of 580 mg (2.23 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 10 ml THF and stirring continued overnight. The reaction mixture was evaporated and purified by HPLC/MS (Reprosil 100 C18, 10 μm, methanol/water 80:20) to give 500 mg oil that solidified by treatment with a small amount of ether. The precipitate was filtered and dried to yield 400 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3cccc(Cl)c3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Product: CN1C(=O)C2(CC(c3cccc(Cl)c3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 3.2 %

Procedure:
Pd(PPh3)4 (27 mg, 0.072 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-2-(3-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.072 mmol) in toluene (5 mL), Na2CO3 (2 N, 2 mL), and 4-cyanophenylboronic acid (12.9 mg, 0.088 mmol). The mixture was refluxed under Ar overnight. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-2-(3-chlorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (1.03 mg, 3%). 1H-NMR (MeOD): 2.63 (m, 2H), 3.22 (s, 3H), 5.34 (m, 1H), 7.18 (m, 1H), 7.41 (m, 3H), 7.54 (m, 2H), 7.10 (m, 1H), 7.17 (m, 2H), 7.89 (m, 1H), 7.98 (m, 1H).
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[O:9]([CH2:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:30][CH:29]=1)[Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:54]([N:58]([CH2:69][CH2:70][CH2:71][CH3:72])[C:59]1[CH:66]=[CH:65][C:62]([CH:63]=O)=[C:61]([O:67][CH3:68])[CH:60]=1)[CH2:55][CH2:56][CH3:57].O>O1CCCC1.C(OCC)(=O)C>[CH2:54]([N:58]([CH2:69][CH2:70][CH2:71][CH3:72])[C:59]1[CH:66]=[CH:65][C:62]([CH:63]=[CH:32][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:53][CH:52]=2)=[C:61]([O:67][CH3:68])[CH:60]=1)[CH2:55][CH2:56][CH3:57]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: CC(C)(C)[Si](OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)c(OC)c1
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
In a stream of argon, to 35 ml of tetrahydrofuran was added 3.33 g of phenyllithium (19% solution in dibutylether) (7.53 mmol), and 4.8 g (6.84 mmol) of 4-(tert-butyldiphenylsiloxymethyl)benzyltriphenylphosphonium bromide was added thereto under ice cooling. Next, 1.8 g (6.838 mmol) of 4-dibutylamino-2-methoxybenzaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. Ethyl acetate/hexane (5/1) was added to the residue and the precipitate was filtered off. The filtrate was reconcentrated and the residue was purified by silica gel column chromatography to give 3.92 g of a yellow liquid (yield: 94.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36]([OH:38])=O)[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH:54]C(C2(C3C=CC=CC=3)CCNCC2)=O)[CH2:48][CH2:47]1>CO.ClCCl>[ClH:1].[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH:54][C:36]([C:33]2([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:10]3)[CH2:35][CH2:34]2)=[O:38])[CH2:48][CH2:47]1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(NCCN1CCOCC1)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)NCCN4CCOCC4)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 26FH.5 using 1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid (0.16 g, 0.625 mmol) and 4-phenyl-piperidine-4-carboxylic acid (2-morpholino-ethyl)-amide hydrochloride (0.07 mL, 0.5 mmol). Chromatograph on silica gel eluting with 6% methanol/dichloromethane to give the title compound: Rf =0.34 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2=[N:12][C:13]([C:15](OCC)=[O:16])=[N:14][N:4]2[C:3]1=[O:20].[NH3:21]>CN(C)C=O>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2=[N:12][C:13]([C:15]([NH2:21])=[O:16])=[N:14][N:4]2[C:3]1=[O:20]
Reactant: N
Reactant: CCOC(=O)c1nc2c3ccccc3n(C)c(=O)n2n1
Solvent: CN(C)C=O
Product: Cn1c(=O)n2nc(C(N)=O)nc2c2ccccc21
Reaction time: 48 h

Procedure:
12.0 g of ethyl 6-methyl-1,2,4-triazolo[1,5-c]quinazolin-5-one-2-carboxylate were suspended in 600 ml of absolute dimethylformamide, and 200 ml of a 7% strength methanolic NH3 solution were added. The mixture was stirred for 48 hours, after which the precipitate was filtered off under suction, washed with dimethylformamide and water, and dried. Yield: 4.8 g (42%), mp. 286°-287° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[Cl-].[OH:15][NH3+:16].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[N:16][OH:15]
Reactant: Cc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
49.5 g (0.263 mol) of 2,2,2-trifluoro-1-(4-methylphenyl)-ethanone are dissolved in 250 ml of ethanol at 80° C. To the solution are added dropwise 19.2 g (0.276 mol) of hydroxylammonium chloride and 36.7 g (0.447 mol) of sodium acetate dissolved in 125 ml of water. The reaction mixture is refluxed for 3.5 hours. The mixture is poured into ice water, affording a white solid. The filtration yields 39.2 g of 2,2,2-trifluoro-1-(4-methylphenyl)-ethanone oxime as a white solid, mp. 54-68° C. The crude product is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.ClC(OCC(C)C)=O>CN(C=O)C.O>[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1nc2cnccc2s1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1nc2cnccc2s1
Temperature: 60 °C
Yield: 16.2 %

Procedure:
A mixture of 2-aminothiazolo[4,5-c]pyridine (530 mg, 3.5 mmole), 2.0 ml of N,O-bistrimethylsilylacetamide (BSA) and 7 ml of dimethylformamide was heated at 60° C. with stirring. The resulting clear solution was added to the chilled mixed anhydride solution which was prepared from N-t-butyloxycarbonyl glycine (700 mg, 4 mmoles), triethylamine (404 mg, 4 mmoles) and isobutyl chloroformate (546 mg, 4 mmoles) in 10 ml of dry DMF at -10° C. The reaction mixture was stirred 2 days at room temperature and then diluted with water and extracted with 450 ml of ethyl acetate. The extracts were combined, evaporated and triturated with chloroform to give 175 mg of the title compound. Additional product (155 mg) was obtained from the mother liquor. Total yield was 330 mg (30%), which was recrystallized from CH3OH. Mp. 204°~208° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH:11]([NH:14][CH2:15][C:16](O)=[O:17])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[CH2:15][N:14]([CH:11]([CH3:13])[CH3:12])[C:9]2=[S:10])=[CH:4][CH:3]=1
Reactant: CC(C)NCC(=O)O
Reactant: Fc1ccc(N=C=S)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 50 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 15.3 g of 4-fluorophenyl-isothiocyanate,. 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (12.6 g) as a peach solid, m.p. 184°-186° C. Anal. Calcd. for. C12H13F N2O S: C, 57.12; H, 5.19; N, 11.10. Found: C, 56.98; H, 5.09; N, 11.06. Mass spectrum (+FAB, [M+H]+) m/z 253.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH2:18])[N:12]=1.[N:19]([O-])=[O:20].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH2:18])[C:14]([N:19]=[O:20])=[C:15]([NH2:17])[N:16]=1
Reactant: O=N[O-]
Reactant: Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 153.7 %

Procedure:
The product of step (a) (2.5 g) was dissolved in acetic acid (150 ml) and the solution cooled to 5° C. A solution of sodium nitrite (625 mg) in water (50 ml) was added dropwise resulting in a dark blue colouration. The reaction was stirred at room temperature for 30 minutes during which time a pink solid precipitated from solution. This was isolated by filtration and washed with water, then dried at 50° C. to give the sub-titled product as a blue solid (4.14 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31]C(NC(=O)CC2C=CC=CC=2)=S)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:25][CH3:26])=[C:12]([C:15](NCCCOC(C)C)=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.NC1C=CC([O:49]C2C3C(=CC(OC)=C(C([NH:62][CH2:63][C:64]([OH:67])([CH3:66])[CH3:65])=O)C=3)N=CC=2)=C(F)C=1>>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:25][CH3:26])=[C:12]([C:15]([OH:49])=[O:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:30]=1.[NH2:62][CH2:63][C:64]([CH3:66])([OH:67])[CH3:65]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)NCC(C)(C)O
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NCCCOC(C)C
Product: CC(C)(O)CN
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)O

Procedure:
Similar to the synthesis of compound 1, from compound 39c (103 mg), DMTMM•n-hydrate (104 mg), and 1-amino-2-methylpropan-2-ol (42 mg), compound 42a was yielded (66.3 mg, yield: 53%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:35][C:33](=[O:34])[NH:32][CH:23]([C:22]3[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]([OH:28])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)c1ccc(Br)cc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(Br)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 34 %

Procedure:
A mixture of 1-(4-bromophenyl)-2-phenylethanone (100 mg, 0.36 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (64 mg, 0.30 mmol), urea (55 mg, 0.91 mmol), and concentrated HCl solution (0.03 mL, 0.36 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and purified by preparative HPLC to give Compound 33 (52.12 mg, yield 34%). 1H NMR (DMSO-d6 400 MHz): δ 10.29 (s, 1H), 8.78 (s, 1H), 7.56 (s, 1H), 7.46-7.42 (m, 3H), 7.15-7.13 (m, 3H), 7.09-7.03 (m, 3H), 6.84 (d, J=6.8 Hz, 2H), 5.21 (d, J=2.0 Hz, 1H), 4.07-3.99 (m, 2H), 2.23 (s, 3H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 511.9 [M+1]+.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].CO[C:9]([C:11]1[CH2:12][NH2+:13][CH2:14][CH:15]([CH3:17])[CH:16]=1)=[O:10].CO[C:20]([C:22]1[CH2:23][NH2+:24][CH2:25][CH:26]([CH3:28])[CH:27]=1)=[O:21].[C:29](=[N:33]O)([NH2:32])[CH2:30][CH3:31].Br.[CH:36]([C:39](=[N:41]O)[NH2:40])(C)[CH3:37]>>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[CH3:17][CH:15]1[CH2:14][NH2+:13][CH2:12][C:11]([C:9]2[O:10][N:33]=[C:29]([CH2:30][CH3:31])[N:32]=2)=[CH:16]1.[CH3:28][CH:26]1[CH2:25][NH2+:24][CH2:23][C:22]([C:20]2[O:21][N:41]=[C:39]([CH2:36][CH3:37])[N:40]=2)=[CH:27]1
Reactant: CCC(N)=NO
Reactant: COC(=O)C1=CC(C)C[NH2+]C1
Reactant: CC(C)C(N)=NO
Agent: Br
Agent: O=C([O-])C(=O)[O-]
Product: CCc1noc(C2=CC(C)C[NH2+]C2)n1

Procedure:
The compound was synthesized as described in Example 17 using (RS)-3-methoxycarbonyl-5-methyl-1,2,5,6-tetrahydropyridinium oxalate and propionamide oxime instead of arecoline, HBr and isopropylcarboxamide oxime, respectively. M.P. 188°-189° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C@H:3]2[CH2:7][CH:8]=[CH:9][CH2:10][C@@H:2]12.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([N:5]1[C:1](=[O:11])[C@H:2]2[CH2:10][CH:9]=[CH:8][CH2:7][C@H:3]2[C:4]1=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1[C@H]2CC=CC[C@H]2C(=O)N1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
30.2 g of cis-1,2,3,6-tetrahydrophthalimide was dissolved in 200 ml of N,N-dimethylformamide. After adding 38.7 g of potassium carbonate and 30.4 g of benzyl chloride, the resulting mixture was stirred at 50° C. for 3 hours and further at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure. The crude crystals thus obtained were ground and washed with diisopropyl ether and n-hexane followed by filtration. Thus 39.1 g of the title compound was obtained as pale yellow crystals.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18](=O)[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH:22]([CH2:27][O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH2:21]2)=[N:14][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH:22]([CH2:27][O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH2:21]3)=[N:17][N:16]=2)[CH:15]=1
Reactant: CC(C)[Si](OCC1CN(CC(=O)NNc2ccc(F)cn2)CCN1C)(C(C)C)C(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCC1CN(Cc2nnc3ccc(F)cn23)CCN1C)(C(C)C)C(C)C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
Hexachloroethane (426 mg, 1.80 mmol) was added portion-wise to a stirred mixture of Intermediate 56c (410 mg, 0.90 mmol), Ph3P (472 mg, 1.80 mmol) and Et3N (500 μL, 3.60 mmol) in THF (15 mL) at RT. The reaction mixture was stirred for 18 h, then filtered and concentrated in vacuo. The resulting residue was purified by FCC, using 0-25% MeOH in EtOAc, to give the title compound (237 mg, 60%). LCMS (Method 3): Rt 2.95 min, m/z 436 [MH+].
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:12])[C@@H:6]([OH:11])[CH2:7][CH2:8][CH:9]=O)=[N+:2]=[N-:3].[BrH:13].[C:14]([O:17]C(=O)C)(=O)[CH3:15]>Cl(O)(=O)(=O)=O>[C:14]([O:11][C@@H:6]1[C@@H:5]([CH2:4][N:1]=[N+:2]=[N-:3])[O:12][CH:9]([Br:13])[CH2:8][CH2:7]1)(=[O:17])[CH3:15]
Reactant: [N-]=[N+]=NC[C@@H](O)[C@@H](O)CCC=O
Reactant: Br
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)O[C@H]1CCC(Br)O[C@@H]1CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6-Azido-2,3,6-trideoxy-D-erythro-hexose (1.73 g, 10 mmol) was acetylated in acetic anhydride (8 ml) with a few drops of 70% perchloric acid as catalyst. After 1 h at room temperature the solution was saturated with dry hydrogen bromide and the mixture was allowed to stand for 2 h. It was then poured into ice-water and extracted with ice-water, ice-cold saturated sodium bicarbonate solution and water. Finally the extracts were dried (Na2SO4) and concentrated to yield 4-O-acetyl-6-azido-2,3,6-trideoxy-D-erythro-hexopyranosyl bromide as a colourless syrup (2.2 g), which was used immediately for the next step.
Reaction SMILES: N1C=CN=C1.[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[CH:11]=1.ClCCl.[C:22]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([O:17][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:11]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(O)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
Imidazole (230 mg, 3.38 mmol) was added to a solution of 3,5-dihydroxyphenylacetic acid methyl ester (530 mg, 2.91 mmol) in tetrahydrofuran (6.7 mL)-dichloromethane (6.7 mL) at room temperature. t-Butylchlorodiphenylsilane (0.75 mL, 2.9 mmol) was added under cooling with ice. Then, the ice bath was removed, and the mixture was stirred at room temperature for three hours. The reaction mixture was diluted with diethyl ether. 50% saturated aqueous ammonium chloride was added, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (470 mg, 33%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:16][C:17]1[C:18](=[O:37])[N:19]([CH2:24][CH2:25][C@@:26]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1I.O>O1CCOCC1.[Pd]>[F:16][C:17]1[C:18](=[O:37])[N:19]([CH2:24][CH2:25][C@@:26]([CH3:36])([S:32]([CH3:35])(=[O:33])=[O:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)[C@@](C)(CCn1ccc(I)c(F)c1=O)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@](C)(CCn1ccc(-c2ccccc2)c(F)c1=O)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
Pd EnCat™ (172 mg, 0.067 mmol) was added to a mixture of potassium carbonate (298 mg, 2.16 mmol), phenylboronic acid (132 mg, 1.08 mmol), and ethyl (2R)-4-(3-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (288 mg, 0.647 mmol) in 1,4-dioxane:water (10 ml, 4:1) in a 20 ml vial. The vial was sealed and the reaction was heated to 80° C. and allowed to stir overnight at that temperature. The reaction was allowed to cool to RT, filtered and the catalyst was washed with methanol (20 mL) and dichloromethane (20 mL). The combined filtrates were concentrated and the crude product was purified via flash chromatography using an Analogix SF15-12g column and an eluant of ethyl acetate in heptane (60-100%) to afford the title compound as a white solid (131 mg, 51.2%). LC-MS m/z 396.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.12 Hz, 3 H) 1.79 (s, 3 H) 2.46-2.67 (m, 2 H) 3.14 (s, 3 H) 3.99-4.16 (m, 1 H) 4.22-4.44 (m, 3 H) 6.24-6.39 (m, 1 H) 7.10-7.22 (m, 1 H) 7.38-7.55 (m, 3 H) 7.54-7.63 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:14]([O-:16])=[O:15])[C:7]2[O:11][CH:10]([CH3:12])[CH2:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[CH3:17][NH2:18]>C(O)C>[CH3:17][NH:18][C:7]1[C:6]([N+:14]([O-:16])=[O:15])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=1[CH2:9][CH:10]([OH:11])[CH3:12]
Reactant: CN
Reactant: CC1Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2O1
Solvent: CCO
Product: CNc1c(CC(C)O)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
0.056 Mole (12.5 g) of 2,3-dihydro-5,7-dinitro-2-methyl-benzofuran is suspended in 100 ml of a 33% strength solution of methylamine in ethanol. After 10 hours' stirring at room temperature in a sealed Erlenmeyer, the reaction mixture is brought for 30 minutes to the refluxing temperature of the alcohol. After the mixture is cooled, the expected product precipitates. It is drained, washed with alcohol and then recrystallized from 50 ml of 96° strength ethanol. After being dried, 0.047 mole (12 g) is obtained of a product which melts at 132° C.