Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C:18]2=[CH:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>N1C=CC=CC=1>[C:24]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C:18]2=[CH:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:26])[CH3:25]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@@H]1CC[C@]2(C)C3=CC[C@]4(C)[C@@H](C(C)=O)CC[C@H]4[C@@H]3CC[C@H]2C1
Reaction time: 66 h

Procedure:
3α-Hydroxy-5α-pregn-9(11)-en-20-one (3.7 g.) was dissolved in pyridine (37 ml.) and acetic anhydride (18.5 ml.) added; the reaction was allowed to stand at room temperature for 66 hr. It was then poured into water (4 l.) and stored at 2° for 2 hr., the white solid was filtered off and dried to give the title compound (3.8 g.) m.p. 163°-165°.
Reaction SMILES: [I-:1].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=1.O1CCOCC1.CNCCNC>[Cu]I.CN(C=O)C>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([I:1])=[CH:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=1
Reactant: [I-]
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Nc1nccc(Nc2cc(I)ccc2N)n1
Temperature: 115 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A pressure tube containing copper(I) iodide (61.2 mg, 0.32 mmol), sodium iodide (963.18 mg, 6.43 mmol) and 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (900 mg, 3.21 mmol) was flushed with nitrogen before the addition of 1,4-dioxane (4.0 mL), DMF (4.0 ml) and N,N′-dimethylethane-1,2-diamine (0.035 ml, 0.32 mmol). The vessel was sealed and stirred at 115° C. overnight. After cooling to RT, the reaction mixture was poured into ice water (7 ml) and the resulting solution extracted with DCM (2×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (Biotage, 3-14% methanol gradient in DCM) furnished the title compound (600 mg, 57% yield); 1H NMR (500 MHz, DMSO) delta 5.04 (2H, d, J=11.6 Hz), 5.78-5.73 (1H, m), 6.11-6.02 (2H, m), 6.57 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=8.4, 2.0 Hz), 7.47-7.38 (1H, m), 7.75 (1H, d, J=5.3 Hz), 8.20-8.12 (1H, m); LC-MS: m/z=+327.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:39]2[CH2:38][CH2:37][N:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)[CH2:41][CH2:40]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (538 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: O[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][N:5]1[C:6]2[CH:7]=[C:8]3[O:14][CH2:13][O:12][C:9]3=[CH:10][C:11]=2[CH:2]=[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4]1
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1O)OCO3
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1=Cc2cc3c(cc2N(Cl)C1)OCO3

Procedure:
A mixture of 121 g of ethyl 8-hydroxy-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate (0.39 mol, prepared according to the procedure of J. Med. Chem., Vol. 11, 162 (1968)) and 500 ml of phosphorus oxychloride is refluxed for 7 to 8 hours. Three quarters of the excess phosphorus oxychloride is then removed, the residue is poured onto ice, alkalized with concentrated aqueous ammonia, and the solid product is filtered off, washed with water and dried at 60° C. Yield 108.2 g (99%), m.p. 103° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C@@H:21]([CH3:37])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=2)=[N:24]1>>[Cl:36][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:17]([C:15]3[N:16]=[C:10]4[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12][N:11]4[CH:14]=3)=[O:19])[CH3:37])[N:24]=2)[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)O)nc2C1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CN(C(=O)OC(C)(C)C)CC2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (0.044 g, 0.165 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.033 g, 0.127 mmol). The product was purified by flash chromatography. LC-MS: [M+1]=510.988.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[N:13]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[NH4+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:13])=[O:12]
Reactant: c1ccncc1
Reactant: COc1ccccc1CC(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methoxyphenylacetic acid (10.0 g, 60.1 mmol) was dissolved in acetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) and di-tert-butyl dicarbonate [Boc2O (19.6 g, 90.2 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 18 without purification.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:15][C:16]1[C:21]([N:22]([CH3:37])[C:23](=[O:36])[CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:20][CH:19]=[C:18]([Cl:38])[C:17]=1[CH2:39]OS(C)(=O)=O.O>CN(C)C=O>[Cl:15][C:16]1[C:21]([N:22]([C:23](=[O:36])[CH2:24][N:25]2[C:26](=[O:35])[C:27]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]3[C:29]2=[O:30])[CH3:37])=[CH:20][CH:19]=[C:18]([Cl:38])[C:17]=1[CH2:39][O:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(O)cccc2n1C
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)cccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a suspension of 4-hydroxy-1,2-dimethyl-1H-benzimidazole (250 mg) in N,N-dimethylformamide (2.5 ml) was added sodium hydride (60% in oil, 102 mg) under ice-cooling, and the mixture was stirred for 15 minutes at ambient temperature. To the mixture was added 2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)-amino]benzene (799 mg), and the mixture was stirred for 3 hours at ambient temperature. Water was dropwise added thereto, and the resulting precipitates were collected by filtration to give 4-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-1,2-dimethyl-1H-benzimidazole (418 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl-].[Li+].[Cl:32][C:33]1[N:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:36]=[CH:35][N:34]=1>O1CCOCC1.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.[Cu]I>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:36]=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
(S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (500 mg, 1.01 mmol), tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.15 mmol), lithium chloride (128 mg, 3.02 mmol), and copper(I) iodide (57.5 mg, 0.3 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added 2-chloro-4-(tributyl)stannyl pyrimidine (447 mg, 1.11 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated at 90° C. overnight, then cooled, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+ calc'd for C26H26Cl2N3O3S (M+H+): 530.1; Found: 529.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:26])[NH:14][C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:26])[N:14]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CCc2ccccc2)[nH]c1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
Using a similar procedure to that of Example 1.d., above, 3-benzyloxycarbonylamino-6-phenethylpyrid-2-one (1.64 g) was suspended in dry dimethylformamide (20 mL) and to this suspension was added NaH (0.22 g of a 60% mineral oil dispersion). The mixture was stirred for 1.5 h, at which point all solids were in solution. tert-Butyl bromoacetate (0.92 g) was added, and the mixture was stirred overnight. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (four times). The extracts were washed with brine, dried and evaporated. The residue was purified by chromatography, eluting with methanol:dichloromethane (0:100 then 3:97), to give tert-butyl (3-benzyloxycarbonylamino-2-oxo-6-phenethyl-1,2-dihydro-1-pyridyl)acetate (0.578 g); TLC: Rf =0.17, dichloromethane; MS: m/z=463(M+1).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]#[CH:18].[CH:23](=[O:25])[CH3:24]>C1COCC1.CCCCCC>[OH:25][CH:23]([CH3:24])[CH:18]=[CH:17][C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC=O
Reactant: C#CC(=O)OCC
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=CC(C)O
Temperature: -10 °C
Reaction time: 1.17 h

Procedure:
2,2,6,6-Tetramethylpiperidine (74.16 g, 0.525 mot) is dissolved in THF (600 ml) and cooled to −45° C. nBuLi is added (0.022 mol g−1 in hexane, 228.3 g, 0.500 mol) and is allowed to warm to −10° C. The reaction mixture is cooled to −70° C. Then ethyl propiolate (49.05 g, 0.500 mol) is added dropwise over 25 min at ≦−66° C. After additional stirring for 70 min at −72° C., acetaldehyde (23.35 g, 0.530 mol) in cold THF (30 ml) is added dropwise in 30 min at ≦−67° C. After stirring at −72° C. for 1 hour the reaction mixture is quenched with 2 M HCl (700 ml) and extracted with tBuOMe (650 and 400 ml). The organic phases are washed with saturated NaHCO3 (200 ml) and brine (3×125 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. Filtration over SO2 (150 g) with tBuOMe:heptane fraction (0.5 l) and tBuOMe (0.2 l) yields crude 20 (rac-Ethyl 4-hydroxypent-2-enoate) (6744 g, 90%, HPLC: ˜90 area %) as a brown oil. The crude product is used in the next step without further purification. 1H-NMR- and GC-analysis corresponded to an analogous synthesis of 20 (rac-Ethyl 4-hydroxypent-2-inoate) with LDA as base.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([NH2:14])[N:6]=1)=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(N)n1
Solvent: CO
Product: COC(=O)c1ccc(N)c(N)n1
Reaction time: 4 h
Yield: 79.8 %

Procedure:
Methyl ester 3 (3.5 g, 18.0 mmol) was dissolved in methanol (300 mL) and EtOAc (300 mL) and the solution was degassed with Ar. After the addition of Pd/C (10 wt %, 0.7 g) the reaction mixture was stirred for 4 h under a hydrogen atmosphere. Filtration through a pad of Celite with EtOAc, evaporation of the solvent and purification by flash chromatography (EtOAc/MeOH 15:1) yielded 2.4 g (79%) of 4 as a deep red powder. Data of 4: Rf 0.42 (EtOAc/MeOH 15:1). 1H NMR (300 MHz, DMSO-d6): δ 3.68 (s, 3H), 5.51 (brs, 2H), 5.78 (brs, 2H), 6.67 (d, J1) 7.7 Hz, 1H), 7.21 (d, J1) 7.7 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 51.88, 116.32, 117.98, 132.40, 135.09, 147.93, 166.30. MS (ESI): m/z (rel intensity) 168 (100).
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:17][NH2:18].O>CCO>[NH2:6][C:5]1[NH:18][N:17]=[C:3]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:4]=1[C:7]#[N:8]
Reactant: NN
Reactant: CSC(Nc1cccnc1)=C(C#N)C#N
Solvent: CCO
Solvent: O
Product: N#Cc1c(Nc2cccnc2)n[nH]c1N
Temperature: 70 °C
Reaction time: 18 h

Procedure:
2-((methylthio)(pyridin-3-ylamino)methylene)malononitrile (0.4 g) was dissolved in EtOH (15 mL) and hydrazine hydrate (1.5 eq., 0.086 mL) was added. Reaction was stirred at 70° C. until complete by HPLC (absence of starting material, 18 hrs) and was brought to room temperature. 20 mL of H2O was then added and precipitate formed which was filtered to obtain 5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Br:13]N1C(C)(C)C(=O)N(Br)C1=O.C(O)(=O)C.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C1(Cl)C=CC=CC=1>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([O:11][CH3:12])=[CH:3][C:2]=1[CH2:1][Br:13])([O-:10])=[O:9]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: COc1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 3.2 %

Procedure:
3-Methyl-4-nitroanisole (41, 2.50 g, 15.0 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (5.00 g, 17.5 mmol) were combined in 250 mL of C6H5Cl, and acetic acid (75 μL, 1.31 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (VAZO 88, 150 mg, mmol) were added to the stirring solution. The solution was stirred at 40° C. for 72 h. The crude reaction mixture was washed three times with hot NaHCO3 solution (75 mL, 80° C.), and once with water (75 mL). The organic portion was dried over MgSO4 to give an orange solid after filtration and solvent removal. The solid was filtered through a plug of silica gel to yield a mixture of the brominated product and unbrominated starting material that was carried on to the next step without further purification. Pure material could be obtained from flash chromotography on silica (15:3:2 hexanes/EtOAc/C6H5CH3) to give a brown oil (117 mg, 3.19%). TLC Rf=0.34 (4:1 hexanes/EtOAc). 1H NMR (CDCl3, 500 MHz) δ 3.91 (3H, s), 4.85 (2H, s), 6.92 (1H, dd, J=4.5, 15.0 Hz), 7.02 (1H, d, J=5.0 Hz), 8.13 (1H, d, , J=15.5 Hz).). 13C NMR (CDCl3, 125 MHz) δ 30.19, 56.25, 114.11, 117.69, 127.61, 128.48, 135.72, 163.45. HRMS (ESI): Calcd for MH+, 245.9766; Found 245.9760.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:15](=[S:22])[N:16]([CH3:21])[CH2:17][C:18]([OH:20])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[OH:55][CH:56]1[O:64][C@H:63]([CH2:65][OH:66])[C@@H:61]([OH:62])[C@H:59]([OH:60])[C@H:57]1[NH2:58]>CN(C)C=O>[CH3:14][O:13][C:12]1[C:3]([C:2]([F:1])([F:23])[F:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:15]([N:16]([CH2:17][C:18]([NH:58][C@H:57]([C@H:59]([C@@H:61]([C@@H:63]([CH2:65][OH:66])[OH:64])[OH:62])[OH:60])[CH:56]=[O:55])=[O:20])[CH3:21])=[S:22])=[CH:7][CH:6]=[CH:5]2
Reactant: COc1ccc2c(C(=S)N(C)CC(=O)O)cccc2c1C(F)(F)F
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=S)N(C)CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO)cccc2c1C(F)(F)F
Reaction time: 1 h

Procedure:
N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine (3.57 g, 0.010 mol), 1-hydroxybenzotriazole (2 g, 0.015 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g, 0.012 mol) and triethylamine (3.5 mol, 0.025 mol) were dissolved in dimethylformamide (25 ml). The mixture was cooled in ice and stirred for 1 hour. D-Glucosamine hydrochloride (2.38 g, 0.011 mol), and additional triethylamine (2.0 mol) were added to the cold reaction mixture. The reaction mixture was stirred at 0° C. for 1 hour, and at room temperature over night and evaporated. The residue was triturated with water and filtered. The solids were washed with H2O, 1NHCl, 5% NaHCO3, H2O and crystallized from 8/5 H2O/MeOH to yield 3.63 g, 67.7%. The product was further purified by recrystallization from boiling methanol (3.1 g), m.p. 166°-169° C. (dec.) as yellow crystals.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[OH:27].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:26][C:22]1[C:21]([OH:27])=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(F)c1O
Yield: 50.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 357 mg of 2-amino-6-fluorophenol, and 600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 4 ml of pyridine and 4 ml of N,N-dimethylformamide. 335 mg of N-(3-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[C:17]([O:20][CH2:21][C:22](Cl)=[O:23])(=[O:19])[CH3:18]>CC(N(C)C)=O>[Cl:9][C:7]([C:6]1[C:10]([I:11])=[C:2]([NH:1][C:22]([CH2:21][O:20][C:17](=[O:19])[CH3:18])=[O:23])[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]=1[I:12])=[O:8]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Amino-2,4,6-triiodo-isophthaloyl dichloride was dissolved in dimethyl acetamide (DAMC) and a solution of acetoxyacetylchloride (2 eq) in DMAc was slowly added with efficient stirring. The reaction mixture was stirred overnight and the following day, the mixture was slowly poured into stirred ice water. The precipitate was filtered off and dried to give the desired material. The structure was confirmed by 1H NMR (CDCl3, 300 MHz): 10.43 (brs, 1H); 4.71 (s, 2H); 2.11 (s, 3H)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[ClH:22]>O1CCOCC1>[C:9]1([C:8]2[CH2:7][CH2:6][NH:5][CH2:4][C:3]=2[CH2:2][OH:1])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[ClH:22]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)=C(CO)C1
Agent: Cl
Solvent: C1COCCO1
Product: OCC1=C(c2ccccc2)CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 3-(hydroxymethyl)-4-phenyl-5,6-dihydropyridine-1(2H)-carboxylate (510 mg, 1.76 mmol) was added 4N HCl in Dioxane (3 ml), after stirring at room temperature for 1 h, it was concentrated to give (4-phenyl-1,2,5,6-tetrahydropyridin-3-yl)methanol as HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(OC)C(=CC=CC=1)OC.ClS(O)(=O)=O.[CH:30]([N:33]([CH:40]([CH3:42])[CH3:41])[CH2:34][CH2:35][NH:36][CH:37]([CH3:39])[CH3:38])([CH3:32])[CH3:31]>>[CH3:42][CH:40]([N:33]([CH:30]([CH3:32])[CH3:31])[CH2:34][CH2:35][N:36]([CH:37]([CH3:39])[CH3:38])[S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH3:41]
Reactant: CC(C)NCCN(C(C)C)C(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: O=S(=O)(O)Cl
Solvent: COc1ccccc1OC
Product: COc1ccc(S(=O)(=O)N(CCN(C(C)C)C(C)C)C(C)C)cc1OC

Procedure:
3,4-Dimethoxybenzene sulfonyl chloride, prepared from veratrole and chlorosulfonic acid was reacted with N,N,N'-triisopropyl ethylene diamine following the procedure of Example 1. The reaction was worked up and the crude product chromatographed on alumina with ethyl acetate. The pure product was obtained, m.r. 69°-71° C.