Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1.[O:13]1[C:18]2[CH:19]=[CH:20][C:21](B(O)O)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.CC(N(C)C)=O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=3)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc([N+](=O)[O-])nc1-c1ccc2c(c1)OCCO2
Temperature: 150 °C

Procedure:
2-Bromo-3-methoxy-6-nitro-pyridine (0.5 g, 2.14 mmol), 1,4-benzodioxane-6-boronic acid (0.5 g, 2.79 mmol) and a mixture of dimethylacetamide/water (10 mL/3 mL) were added to a microwave tube containing potassium phosphate (0.91 g, 4.29 mmol) and palladium tetrakistriphenylphosphine (0.4 g, 0.2 mmol) and the reaction was heated to 150° C. for 10 min. The solution was added in a separating funnel and water and ethyl acetate were added. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organics were washed with water (*2) then brine, dried over magnesium sulphate and concentrated in vacuo. The crude was used without further purification (0.48 g, 77%). LCMS Method: 2: RT: 4.41 min, MI: 289 [M+1].
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].CN(C=O)C.[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C1COCC1>[CH2:13]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCO
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of 50.0 g (0.657 mol) of 1,3-propandiol 11 in 500 mL of cosolvent (DMF:THF=3:1) in an ice bath was carefully added 26.3g (0.657 mol) of 60% sodium hydride and stirred for 1 hour, followed by slow addition of 80.5 g (0.636 mol) of benzyl chloride at 0° C. and stirring at room temperature overnight. After adding 50 mL of water to quench the reaction, the mixture was extracted with, ether (2×600 mL). The organic layer was washed with water (50 mL) and Brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Distillation at 118-120° C./5 mmHg gave 54.8 g of a liquid in 50.2% yield. 1H NMR (CDCl3): δ 7.35-7.28 (m, 5H, ArH), 4.51 (s, 2H, ArCH2O), 3.76 (m, 2H, CH2O), 3.65 (t, J=6.0 Hz, 2H, CH2O), 2.58 (m, 1H, OH), 1.85 (p, J=6.0 Hz, 2H, CH2). 13C NMR (CDCl3): δ 131.93, 128.34, 127.60, 127.54, 73.15, 69.15, 61.58, 32.04.
Reaction SMILES: [NH3:1].[O:2]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH:16]3[O:18][CH2:17]3)[CH:11]=2)[CH:6]=[CH:5][C:3]1=[O:4]>C(O)C>[NH2:1][CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][C:3](=[O:4])[O:2]2)=[CH:8][CH:9]=1
Reactant: N
Reactant: O=c1ccc2ccc(OCCC3CO3)cc2o1
Solvent: CCO
Product: NCC(O)CCOc1ccc2ccc(=O)oc2c1
Temperature: 65 °C
Yield: 50 %

Procedure:
5 ml of 30% aqueous ammonia and Gd (OTf3) (0.039 g, 0.065 mmol) are added to a solution of racemic 4-(7-coumarinyloxy)-1,2-epoxybutane (0.150 g, 0.65 mmol) in 2 ml of ethanol. It is heated at 65° C. for 15 hours, the solvent is evaporated, the residue is diluted in ethyl acetate, and it is washed with an NaCl-saturated solution. The residue provides the crude amine (0.081 g, yield 50%) that is used without purification for the next stage.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(=NNc1ccc(Br)cc1)Sc1ccc(Cl)cc1

Procedure:
1-chloro-1-[(4-bromophenyl)hydrazono]-2-propanone is reacted with 4-chlorothiophenol and triethyl amine in ethanol as Example 11 to yield 1-[(4-chlorophenyl)thio]-1-[(4-bromophenyl)hydrazono]-2-propanone.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([F:31])[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([F:31])[N:10]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=[O:40])[CH3:2]
Reactant: CCSCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 0.17 h

Procedure:
A solution of ethanethiol in DMF was treated with sodium hydride, and then with 2-fluoro-4-(3-methanesulphonyloxypropyl)-1-triphenylmethylimidazole. After stirring at ambient temperature for 16 hours, the mixture was worked up by extraction and chromatography to give 4-(3-ethylthiopropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.2 (t, 3H); 1.85 (quintet, 2H); 2.48 (q, 6H); 6.24 (s, 1H); 7.0-7.4 (m, 15H). This thioether was dissolved in CH2Cl2, cooled to 0°, and treated in portions with one equivalent of 3-chloroperbenzoic acid, having the reaction closely by HPLC. Complete conversion to product occurred 10 minutes after the final addition of peracid. The solution was extracted with aqueous sodium bicarbonate, dried and evaporated to give 4-(3-ethanesulphinylpropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.28 (t, 3H); 2.02 (quintet, 2H); 2.66 (m, 6H); 6.27 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C(O)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(CNCc1cccs1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Thiophene-2-carboxaldehyde (22.4g, 200 mmol) was dissolved in anhydrous ethanol (200 mL) and treated with 2,2-dimethoxyethanamine (26.6 g, 200 mmol) and para-toluenesulfonic acid hydrate (0.1 g, catalytic) and the mixture heated to reflux for 4 h. The reaction was allowed to cool down to room temperature and sodium borohydride (7.6 g, 200 mmol) was added in small portions to the reaction. Following complete addition, the reaction was stirred at room temperature for 15 min, then at reflux for 2 h. The reaction was allowed to cool down to room temperature and all the volatiles removed in vacuo. The residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, passed through a pad of silica gel, concentrated and placed on a vacuum line to afford an off-white solid. Yield=40.1 g. MS (M+H)+ 202.
Reaction SMILES: [CH3:1][C:2]([C:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:18])([CH3:7])[CH2:3][C:4]([OH:6])=O.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][OH:33])=[CH:30][CH:29]=1>C1COCC1>[OH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([C:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=2[CH3:18])[CH3:7])=[CH:29][CH:30]=1
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Reactant: Nc1ccc(CO)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CO)cc2)=C(C)C1=O
Yield: 74 %

Procedure:
To a solution of 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanoic acid (1.75 g, 7.46 mmol) and isobutyl chloroformate (1.11 g, 8.12 mmol) in 20 ml of dry THF, N-methyl morphorline (0.82 ml) was added at 0° C. The resultant mixture was stirred for 30 minutes at 0° C., 4-aminobenzylalcohol (1.38 g, 11.2 mmol) added, and the resultant mixture stirred overnight. After removal of the solid by filtration, the compound was directly purified with silica chromatography using heptane and ethyl acetate as eluent to give a yield of 74%. 1H NMR (300 MHz, CD2Cl2) δ 7.40 (d, J=9, 2H), 7.28 (d, J=9, 2H), 7.19 (s, br, 1H, NH), 4.61 (s, 2H, CH2O), 2.99 (s, 2H, CH2), 2.14 (s, 3H, CH3), 1.97 (s, 6H, CH3), 1.55 (s, 3H, CH3), 1.48 (s, 3H, CH3). MS (m/e): 356 (M+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=CC=[C:6](C(N=C=O)(C)C)[CH:5]=1)=C.[C:16]([O:20]CC)(=O)[CH:17]=[CH2:18].[C:23](OC)(=O)C(C)=C.C(OOC(C)(C)C)(=O)C1C=CC=CC=1.CC(O[Hg]C1C=CC=CC=1)=O.N#N>>[CH3:1][CH2:2][CH:4]([CH2:5][CH2:6][C:16]([OH:20])([CH2:17][CH3:18])[CH3:23])[CH3:9]
Reactant: C=C(C)C(=O)OC
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: C=CC(=O)OCC
Agent: CC(=O)O[Hg]c1ccccc1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Agent: N#N
Product: CCC(C)CCC(C)(O)CC
Temperature: 40 °C

Procedure:
30 g of M-TMI (M-TMI is 1-(1-isocyanato-1-methyl)ethyl-3-(1-methyl)ethenyl benzene, from Cytec industries), 5 g of ethyl acrylate, 15 g of methyl methacrylate and 8 g of t-butyl peroxybenzoate were heated to 120° C. in 232 g of Arcosolve PMAcetate (propylene glycol methyl ether acetate from Arco Chemicals) in a N2 purge. Then a mixture of 90 g of m-TMI, 15 g of ethyl acrylate, 45 g of methyl methacrylate, 16 g of t-butyl peroxybenzoate (Aldrich Chemicals) was added over 2 hours. After the addition was complete, an additional 8 g of t-butyl peroxybenzoate was added in two equal portions. The reaction was completed to theoretical % non-volatiles (50%) in 7 hrs. Then a partial batch of this solution (164.54 g), containing free —NCO groups of m-TMI, was further reacted with p-aminophenol (22.25 g) at 1:1 equivalent ratio. The reaction was monitored by IR-spectroscopy for disappearance of —NCO group at 2275 cm−1 and was completed by heating to 40° C. The product (AR-1), terpolymer of ethyl acrylate, methyl methacrylate and the urea adduct of m-TMI/p-aminophenol, was precipitated in powder form using water/ice, filtered and dried at room temperature. The product terpolymer AR-1 had the following structure:
Reaction SMILES: [OH:1][C@@:2]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:3](O)=[O:4].[Cl:11][C:12]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C1(C2C=CC=C(C3C=CC=CC=3)N=2)C=CC=CC=1>>[N+:19]([C:18]1[C:12]([Cl:11])=[C:13]([NH:14][C:3](=[O:4])[C@:2]([OH:1])([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: Nc1cccc([N+](=O)[O-])c1Cl
Agent: c1ccc(-c2cccc(-c3ccccc3)n2)cc1
Product: C[C@@](O)(C(=O)Nc1cccc([N+](=O)[O-])c1Cl)C(F)(F)F

Procedure:
The title compound was prepared by the method of Example 6 using (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 3) and 2-chloro-3-nitroaniline (Tetrahedron, 1999, 56 (2), 165-173) except that 2,6-diphenylpyridine was used instead of 2,6-di-t-butylpyridine. NMR (CDCl3) 1.77 (s, 3H), 3.58 (s, 1H), 7.44 (t, 1H), 7.63 (d, 1H), 8.66 (d, 1H), 9.27 (s, 1H); m/z 311.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH3:24][NH2:25].C(O)(=O)C.O>CCO>[CH3:24][NH:25][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C
Yield: 72.1 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol) and methylamine (0.65 mL, 1.3 mmol, 2 M in THF) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., acetic acid (0.3 mL) and water (3 mL) were added. The resulting suspension was filtered and the solid isolated was washed with water and dried under high vacuum to afford 29 mg of the title compound. MS: (+) m/z 309.97 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:31][C:30]3[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:29]=3[F:28])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C(F)(F)F)ccc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 33.1 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2-fluoro-5-(trifluoromethyl)aniline (0.064 g, 0.357 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.10 (s, 2H), 7.30 (s, 1H), 7.53-7.63 (m, 2H), 8.45 (s, 2H), 8.87 (d, J=6.6 Hz, 1H), 10.20 (s, 1H), 11.02 (br s, 1H), 11.59 (br s, 1H); MS [M+H]+: 551.97.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH:13]=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Clc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc2c(Cl)cccc2c1
Yield: 113.6 %

Procedure:
1-chloronaphthalene (183 mg), acryloyl chloride (120 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (277 mg).
Reaction SMILES: [CH2:1](I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([N:22]([S:31]([NH:34][CH3:35])(=[O:33])=[O:32])[C@H:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C=O)C>[CH2:15]([N:22]([S:31]([NH:34][CH2:35][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])=[O:32])[C@H:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNS(=O)(=O)N(Cc1ccccc1)[C@@H](C(=O)OC)C(C)C
Reactant: ICc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C(C)C)N(Cc1ccccc1)S(=O)(=O)NCCc1ccccc1
Reaction time: 96 h
Yield: 60 %

Procedure:
Benzyl iodide (280 mg, 1.28 mmol) and anhydrous potassium carbonate (440 mg, 3.2 mmol) were added to a solution of methyl 2-(R)-[benzyl-(methylaminosulfonyl)amino]-3-methylbutyrate (200 mg, 0.64 mmol), [prepared as described in Step 1 above] in DMF (3 ml) at RT. After 96 h, 1 M HCl was added and the product was extracted into ethyl acetate. The organic layer was washed with dilute sodium thiosulfate and brine and dried over MgSO4. The organics were removed in vacuo and the residue was chromatographed (PTLC, SiO2, 20% ethyl acetate/hexane) to give methyl 2-(R)-[benzyl-(benzylmethylaminosulfonyl)amino]-3-methylbutyrate as a colorless oil (60%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.N([O-])=O.[Na+].[Cu]C#N.[ClH:20]>C(O)(=O)C.O>[Cl:20][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([CH3:1])=[CH:8][C:7]=1[CH3:9]
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: Cl
Agent: N#C[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethylbenzamide (0.42 g, 95%).
Reaction SMILES: CC(OC1C=CC=C(OC(C)C)C=1[C:15]1[C:20](P(C2CCCCC2)C2CCCCC2)=[CH:19][CH:18]=[CH:17][CH:16]=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.ClC1C=CC=C2C=1[CH:47]=[C:48]1[CH2:70][C:62]3([CH2:67][O:66][C:65]([CH3:69])([CH3:68])[O:64][CH2:63]3)[CH2:61][C:49]1=[C:50]2[C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57].CCCCCC.CCOC(C)=O.[CH3:83][NH:84][CH3:85]>C1COCC1>[CH3:83][N:84]([CH3:85])[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:20]=1[CH:47]=[C:48]1[CH2:70][C:62]3([CH2:63][O:64][C:65]([CH3:69])([CH3:68])[O:66][CH2:67]3)[CH2:61][C:49]1=[C:50]2[C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC1(C)OCC2(CO1)Cc1cc3c(Cl)cccc3c(C(=O)C(C)(C)C)c1C2
Reactant: CNC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(C)c1cccc2c(C(=O)C(C)(C)C)c3c(cc12)CC1(COC(C)(C)OC1)C3
Yield: 58 %

Procedure:
Follows general procedure [RuPhos Palladacyle] (0.0023 g, 0.0032 mmol), LHMDS (0.26 mL of a 1.0 M solution in THF, 0.26 mmol), 5b (0.050 g, 0.13 mmol) in THF (0.3 mL), dimethylamine (0.098 mL of a 2.0 M solution in THF, 0.19 mmol). The title compound was isolated (n-hexane/AcOEt 7:3, 0.030 g, 58% yield) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([NH:13][C:14]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][OH:16])=[O:12])=[C:9]([I:21])[C:8]([NH:22][C:23](=[O:27])[CH2:24][O:25][CH3:26])=[C:7]([I:28])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+:30]>>[I:1][C:2]1[C:10]([C:11]([NH:13][C:14]([CH2:15][OH:16])([CH2:19][OH:20])[CH2:17][OH:18])=[O:12])=[C:9]([I:21])[C:8]([NH:22][C:23](=[O:27])[CH2:24][O:25][CH3:26])=[C:7]([I:28])[C:3]=1[C:4]([O-:6])=[O:5].[Na+:30]
Reactant: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(CO)(CO)CO)c1I
Agent: [Na+]
Agent: [OH-]
Product: COCC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(C(=O)NC(CO)(CO)CO)c1I

Procedure:
2,4,6-Triiodo-5-methoxyacetamido-N-[tris(hydroxymethyl)methyl] isophthalamic acid (2.03 g.) was dissolved in a stoichiometric quantity of 0.1032 N NaOH. The solution was evaporated under reduced pressure at 60° C. and the residual sodium salt was dried at 45° C. overnight. The solubility of this sodium salt in water at 25° C. is approximately 67.4% (w/v). The following examples illustrate the use of certain compounds of the invention in the preparation of X-ray contrast media.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3C=CC(C(N4CCN(C/C=C/C5C=CC=CC=5)CC4)=O)=CC=3)[N:30]=2)=[CH:20][CH:19]=1>>[ClH:15].[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([C:29]2[C@H:38]3[C@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([CH2:40][C:36]3[CH:37]=[CH:38][C:33]([C:32]([N:4]4[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][N:9]5[CH2:10][CH2:11][O:12][CH2:13][CH2:14]5)[CH2:6][CH2:5]4)=[O:39])=[CH:34][CH:35]=3)[N:30]=2)=[CH:20][CH:19]=1
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)N4CCN(CCN5CCOCC5)CC4)cc3)C(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A11 and 4-(2-piperazin-1-yl-ethyl)-morpholine as described for compound 8. M.p. 210–211° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OCCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccc(OCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
4-Phenethyloxybenzoic acid methyl ester 10 (7.66 g, 29.89 mmol) was dissolved in diethyl ether and chilled to 0° C. LiAlH4 was slowly added and allowed to stir at 0° C. for 3 hours. The mixture was quenched with H2O. After addition of 3N NaOH the mixture was allowed to stir for 30 min. The mixture was then acidified with 4.5N HCl, extracted, dried, and concentrated in vacuo to give about 6.7 g of a crystalline (4-phenethyloxyphenyl)methanol 11.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][OH:17]>>[CH3:10][N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][O:17][C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CN1CCC[C@H]1CO
Reactant: [O-][n+]1cc(Br)cc(Br)c1
Product: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1

Procedure:
A sample of 3,5-dibromopyridine-N-oxide (prepared according to the method of Y. Tamura et al., Heterocycles, 15:871-874 (1981)) is reacted with (S)-(-)-1-methyl-2-pyrrolidinemethanol according to the procedure of Example 3a, and the product is purified by chromatography on silica gel.