Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:6]=[CH:5][N:4]=1.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([C:32](O)=[O:33])[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18]>>[CH3:1][N:2]([CH3:15])[C:3]1[N:4]=[CH:5][N:6]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:32]([C:22]3[CH:21]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:25]=[CH:24][C:23]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:33])[CH2:11][CH2:10]2)[N:8]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: CN(C)c1ncnc(N2CCNCC2)n1
Product: CN(C)c1ncnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3ccccc3)CC2)n1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from Dimethyl-(4-piperazin-1-yl-[1,3,5]triazin-2-yl)-amine (Example X) and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 467.4 MH+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Si:18](Cl)([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>CN(C=O)C>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:1][C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Yield: 557.3 %

Procedure:
To benzyl 4-oxopiperidine-1-carboxylate (152 g, 650 mmol) in DMF (650 mL) was added TMS-Cl (148 mL, 117 mmol) followed by triethylamine (326 mL, 234 mmol). The slurry was warmed to 80° C. for 16 hours, diluted with hexanes (1 L), washed 3 times with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to obtain benzyl 4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate, (199 g, 652 mmol) as a orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:47](Cl)([CH3:50])(=[O:49])=[O:48]>C(Cl)Cl>[O:27]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:3][CH:4]=1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 2 °C

Procedure:
2-[6-([2-(4-aminophenyl)ethyl]{2-[(4-aminophenyl)oxy]ethyl}amino)hexyl]-1H-isoindole-1,3(2H)-dione (108.3 mg) was dissolved in DCM (5 ml) and cooled to 0-4° C. in an ice-bath. Hunig's Base (0.227 ml) was added followed by the dropwise addition of mesylchloride (0.051 ml). The reaction was maintained at 0-4° C. for 0.5 h and then allowed to warm slowly to room temperature. After 3 h the reaction mixture was evaporated to dryness and used crude in next step.
Reaction SMILES: C([NH:8][C:9]([CH3:15])([CH2:12][CH2:13][OH:14])[CH2:10][OH:11])C1C=CC=CC=1.[ClH:16]>CCO.[Pd]>[ClH:16].[NH2:8][C:9]([CH3:15])([CH2:12][CH2:13][OH:14])[CH2:10][OH:11]
Reactant: CC(CO)(CCO)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(N)(CO)CCO
Reaction time: 37 h
Yield: 90.2 %

Procedure:
2-Benzylamino-2-methyl-1,4-butanediol (12E, 31.08 g, 0.149 mol) was dissolved in 95% EtOH (240 mL) containing conc. HCl (21 mL, 0.25 mol) and 5% Pd/C (10.0 g) and reduced in a Parr apparatus at 40 psi over 37 h at RT. The catalyst was then removed by filtration and the solvent removed by rotary evaporation (bath at 60°) to give 20.91 g of 2-amino-2-methyl-1,4-butanediol hydrochloride (90.2%) as a clear, thick, colorless oil with acceptable NMR and mass spectra. It was used without further purification. This compound has been reported as its acetate salt (G. Cardillo et al., Chem. Commun. 1308, 1982), but no data was given. Attempts to duplicate the latter procedure were unsuccessful.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].COC1C=CC(C[N:31]2[N:35]=[N:34][C:33]([C:36](Cl)=[O:37])=[N:32]2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C@H:3]([NH:2][C:36]([C:33]1[N:32]=[N:31][NH:35][N:34]=1)=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH3:9]
Reactant: COc1ccc(Cn2nnc(C(=O)Cl)n2)cc1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of intermediate 8-1 in DCM (8 ml) at room temperature is added 2-(4-methoxy-benzyl)-2H-tetrazole-5-carbonyl chloride and followed by TEA (Intermediate 22: 0.293 ml, 2.100 mmol). The reaction is stirred at room temperature for 5 min. The reaction is quenched by brine and is extracted with DCM. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (15% to 40% EtOAc/Heptane). The obtained residue in TFA (5 ml, 64.9 mmol) is heated at 80° C. for 0.5 hours. The reaction is concentrated under reduced pressure to give (R)-4-(3′-chloro-biphenyl-4-yl)-3-[(2H-tetrazole-5-carbonyl)-amino]-butyric acid ethyl ester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[P:11](Cl)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:11]([O:16][CH2:17][CH3:18])(=[O:12])[O:13][CH2:14][CH3:15]
Reactant: c1ccoc1
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1ccco1

Procedure:
A solution of furan (1 mmole) in diethyl ether was treated with TMEDA (N,N,N′N′-tetramethylethylenediamine) (1 mmole) and nBuLi (2 mmole) at −78° C. for 0.5 h. Diethyl chlorophosphate (1.2 mmole) was added to the reaction mixture and stirred for another hour. Extraction and distillation gave diethyl 2-furanphosphonate as a clear oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:51]=[CH:50][CH:49]=[C:48]3[C:44]=2[CH:45]=[N:46][NH:47]3)O1>>[C:24]([O:23][C:22](=[O:28])[NH:21][CH2:20][C:18](=[O:19])[NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:5]3[C:4]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:3][C:2]([C:43]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:44]=4[CH:45]=[N:46][NH:47]5)=[N:7][C:6]=3[CH:8]=2)[CH:12]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg) was reacted with Boc-glycine via General Procedure I to give tert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate. 70 mg of the crude tert-butyl (3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1>CN(C)C1C=CN=CC=1>[Cl:28][C:26]1[CH:25]=[C:24]([S:29]([NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[O:6])(=[O:30])=[O:31])[CH:23]=[C:22]([Cl:21])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Agent: CN(C)c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 98 %

Procedure:
Prepared according to the procedure described for Example 116 using 3-amino-4-methoxy-N-(3,4-dichlorophenyl)-benzamide from Example 4 (0.932 g, 3.00 mmol), 3,5-dichlorobenzenesulfonyl chloride (0.737 g, 3.00 mmol) and 4-dimethylaminopyridine to afford the product (1.53 g); m.p. >230° C. (dec).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]([CH3:23])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][NH2:10])(=[O:3])[CH3:2].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]([CH3:23])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][NH:10][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCN)O[C@@H](C)[C@H]1OC(C)=O
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCNCc2ccccc2)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminoethyl 2,3,4-tri-O-acetyl-α-L-fucopyranoside (8.56 g, 25.7 mmol) in CH2Cl2 (100 mL) was added benzaldehyde (2.197 ml, 21.67 mmol), acetic acid (372 μL, 6.50 mmol) and NaCNBH3 (3.40 g, 54.2 mmol). After stirring at rt for 16 hr, the reaction mixture was concentrated and the residue was partitioned between EtOAc (50 mL) and sat. NaHCO3 (50 mL). The organic phase separated, washed with sat'd NaHCO3 (2×100 mL), brine (100 mL), dried over MgSO4, and concentrated. The residue was purified by flash chromatography on C18 reverse phase silica gel (130 g), eluting with 0-100% AcCN in water to give the title compound. UPLC Method B: m/e=424.2089 [M+1]; Rt=3.42 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[C:12](OC)(=[O:15])[CH:13]=[CH2:14].C([O-])(=O)C>>[O:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:12]1=[O:15]
Reactant: Oc1ccccc1
Reactant: C=CC(=O)OC
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1ccc2ccccc2o1
Temperature: 90 °C

Procedure:
In another example, 282 grams (3.0 moles) of phenol, 182 grams (3.04 moles) of acetic acid, 52.0 grams (0.604 moles) of methyl acrylate, 2.4 grams (0.012 moles) of cupric acetate monohydrate, 1.4 grams (0.0062 moles) of pallidium acetate, and 6 grams of a finely divided inert diatomaceous earth known in the trade as Celite were placed in a stainless steel autoclave. The autoclave was sealed and pressured to 250 pounds per square inch with air; this pressure being maintained as the mixture was stirred and air was bubbled through it at a rate of two cubic feet per hour (measured at atmospheric pressure). The mixture was heated to 90°C. for 3.5 hours while maintaining the stirring and the air flow, hereinbefore described. The catalyst did not precipitate out on the walls of the autoclave, while the methyl esters of o- and p-hydroxycinnamic acids and coumarin were obtained in a good yield.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23]O)[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][S:33]([CH3:32])(=[O:35])=[O:34])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1O[C@H](CS(C)(=O)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
In a 100 mL round bottom flask containing 50 mL dichloromethane at 0° C. was placed 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose (4.62 g, 13.26 mmol). To this solution was added triethylamine (2.77 mL, 19.90 mmol) followed by dropwise addition of methanesulfonyl chloride (1.23 mL, 15.9 mmol). The reaction was then warmed to room temperature and stirred for 3 hours at which time the reaction was diluted with 100 mL dichloromethane. The organic layer was then washed two times each with 50 mL of water, 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield 4.45 g of crude title compound as a white solid which was used directly in Preparation 2. (79%).
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[C:34]([C:36]2[C:41]([I:42])=[CH:40][C:39]([I:43])=[C:38]([CH2:44][CH3:45])[C:37]=2[I:46])[CH:33]=[CH:32][C:5]=1[C:6]([C:8]1([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:13]1[NH2:14])[O:9]C(=O)C)=[O:7])([O-])=O.Cl>>[NH2:1][C:4]1[CH:35]=[C:34]([C:36]2[C:41]([I:42])=[CH:40][C:39]([I:43])=[C:38]([CH2:44][CH3:45])[C:37]=2[I:46])[CH:33]=[CH:32][C:5]=1[C:6]([C:8]1([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:13]1[NH2:14])[OH:9])=[O:7]
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)C3(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3N)c([N+](=O)[O-])c2)c1I
Agent: Cl
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)C3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)c(N)c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12). C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → C ⁢   ⁢ H 3 ⁢   ⁢ C ⁢   ⁢ O ⁢   ⁢ Cl Al ⁢   ⁢ Cl 3 ⁢ C 15 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 5 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12) is then reacted with a zinc mercury amalgam and hydrochloric acid and heated to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13). C 15 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 5 ⁢ → Δ Zn ( Hg ) ,   ⁢ H ⁢   ⁢ Cl ⁢ C 15 ⁢ H 10 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14). C 15 ⁢   ⁢ H 10 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → S ⁢   ⁢ O ⁢   ⁢ Cl 2 ⁢ C 15 ⁢   ⁢ H 9 ⁢ Cl ⁢ I 3 ⁢ N ⁢   ⁢ O 3 1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14) to yield 2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15). C14H21NO9+C15H9ClI3NO3→C29H29I3N2O12 2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15) is treated with stannous chloride and hydrochloric acid to yield 2-amino-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (16). C 29 ⁢   ⁢ H 29 ⁢ I 3 ⁢ N 2 ⁢ O 12 ⁢ → Sn ⁢   ⁢ Cl 2 ,   ⁢ H ⁢   ⁢ Cl ⁢ C 21 ⁢   ⁢ H 23 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 6 Example 2 is similar in general structure to Example 1, with the additional presence of a short alkyl chain attached to the radio-opaque tri-iodophenyl moiety at the C-3′ position to further increase lipophilicity of the molecule and enhance cell membrane permeability. The computed logP of Example 2 is 5.31.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1C(=O)c1cccc(Br)n1
Solvent: CC#N
Product: Nc1ncc(Br)cc1C(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a suspension of (2-aminopyridin-3-yl)(6-bromopyridin-2-yl)methanone (5.76 g, 20.7 mmol) in acetonitrile (120 ml) was added N-bromosuccinimide (4.05 g, 22.77 mmol). The resulting mixture was stirred at room temperature for 1 hour before mixture was concentrated in vacuo to approximately 20 ml. The solid was then collected by filtration and washed with minimal acetonitrile and dried to leave title compound as a brown solid (4.23 g, 57%). 1H NMR (DMSO-d6) 7.93-7.89 (4H, m), 8.03-7.99 (1H, m), 8.22 (1H, d), 8.36 (1H, d). ES+ 357.99.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([N:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[C:8]([CH3:26])[N:7]=[C:6]1[O:27]C)=[O:4].Cl>O1CCCC1.CO>[CH3:29][N:2]([CH3:1])[C:3]([N:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])=[C:8]([CH3:26])[NH:7][C:6]1=[O:27])=[O:4]
Reactant: COC1=NC(C)=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N1C(=O)N(C)C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A solution of crude 1-[(dimethylamino)carbonyl]-1,6-dihydro-2-methoxy-4-methyl-6-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (2.27 g), in tetrahydrofuran/methanol (20 ml each) was treated with 5N hydrochloric acid (3.0 ml, pH1) and stirred at room temperature for 1.0 hour. The reaction was then evaporated and partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium chloride, dried (magnesium sulfate), and evaporated. The residue was crystallized from dichloromethane/isopropyl ether to give the title compound as colorless crystals (1.55 g), melting point 165°-166° C.
Reaction SMILES: [NH2:1][C:2](=[O:12])[CH2:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>>[NH2:18][C:17]1[N:10]([C:6]2[CH:5]=[C:4]([CH2:3][C:2]([NH2:1])=[O:12])[CH:9]=[CH:8][CH:7]=2)[N:11]=[C:15]([C:14]([CH3:21])([CH3:20])[CH3:13])[CH:16]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cccc(CC(N)=O)c1
Product: CC(C)(C)c1cc(N)n(-c2cccc(CC(N)=O)c2)n1

Procedure:
3-(2-amino-2-oxoethyl)phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 2-(3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl)acetamide. See WO 2006/071940.
Reaction SMILES: [F:1][C:2]1([F:12])[CH2:4][CH:3]1[CH2:5][S:6][CH2:7][CH2:8][C:9](O)=[O:10].S(Cl)([Cl:15])=O>ClCCl>[F:1][C:2]1([F:12])[CH2:4][CH:3]1[CH2:5][S:6][CH2:7][CH2:8][C:9]([Cl:15])=[O:10]
Reactant: O=C(O)CCSCC1CC1(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCSCC1CC1(F)F
Temperature: 40 °C
Yield: 96.4 %

Procedure:
In a 3 L 3 neck round bottomed-flask equipped with an overhead stirrer, a temperature probe, and addition funnel and an nitrogen inlet was charged with 3-(((2,2-difluorocyclopropyl)methyl)thio)propanoic acid (90.0 g, 459 mmol) that was immediately taken up in dichloromethane (140 mL) with stirring. At room temperature, thionyl chloride (170 mL, 2293 mmol) in dichloromethane (100 mL) was added drop-wise with stirring. The reaction mixture was heated to 40° C. and heated for 2 hours. The reaction was determined to be complete by 1H NMR (An aliquot of the reaction mixture was taken, and concentrated down via rotary evaporator). The reaction was allowed to cool to room temperature and the mixture was transferred to a dry 3 L round-bottom and concentrated via the rotary evaporator. This resulted in 95 g of a honey-colored oil. The contents were gravity filtered through paper and the paper rinsed with diethyl ether (10 mL). The rinse was added to the flask. This gave a clear yellow liquid. The liquid was placed on a rotary evaporator to remove the ether. This gave 92.4 g of a yellow oil. The oil was Kugelrohr distilled (bp 100-110° C./0.8-0.9 mm Hg) to provide the title compound as a colorless oil (81.4 g, 81%): 1H NMR (400 MHz, CDCl3) δ 3.27-3.12 (m, 2H), 2.89 (t, J=7.1 Hz, 2H), 2.67 (ddd, J=6.8, 2.6, 1.0 Hz, 2H), 1.78 (ddq, J=13.0, 11.3, 7.4 Hz, 1H), 1.64-1.46 (m, 1H), 1.09 (dtd, J=13.2, 7.7, 3.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]([S:20]([C:23]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=1[NH2:25])(=[O:22])=[O:21])[CH3:19]>>[CH2:18]([S:20]([C:23]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)(=[O:22])=[O:21])[CH3:19]
Reactant: CCS(=O)(=O)c1ccc(O)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: CCS(=O)(=O)c1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-ethylsulfonyl-5-hydroxyaniline (46 mg, 0.231 mmol) similar to Example 186 and was isolated as a yellow solid (35 mg, 54%). 1H NMR (CDCl3): 8.88 (s, 1H), 8.60 (brt, 2H), 8.01 (t, 1H), 7.52 (m, 2H), 7.01 (m, 2H), 3.02 (q, 2H), 1.22 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.Cl.Cl.[N:20]1([CH2:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:32][C@H:29]1[CH2:28][CH2:27][C@H:26]([CH2:25][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:31][CH2:30]1
Reactant: N[C@H]1CC[C@H](CN2CCCC2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Agent: Cl
Product: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (466 mg, 1.5 mmol) was reacted with trans-4-(pyrrolidin-1-ylmethyl)cyclohexanamine dihydrochloride (847 mg, 3.0 mmol) to afford the desired product (180 mg, 52%) as an off-white solid. ESI MS m/z 456 [C24H30BrN3O+H]+
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].CCO.Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>O>[Br:15][C:12]1[CH:11]=[N:10][C:9]([O:3][CH2:2][CH3:1])=[CH:14][CH:13]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
A solution of NaOEt in EtOH (21%; 157 mL, 422 mmol) was added to 2,5-dibromopyridine (4-1) (20 g; 84.4 mmol) and the mixture heated to 80° C. for 16 hours. After cooling, the mixture was poured into water, extracted twice with EtOAc, washed with water then brine, dried (MgSO4) and concentrated under reduced pressure to give crude product 4-2 as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH2:25]>ClCCl>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:25][NH:24][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:9])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cnc(C(=O)O)s1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cnc(C(=O)NNC(=O)OC(C)(C)C)s1
Reaction time: 0.25 h

Procedure:
A solution of 5-methyl-1,3-thiazole-2-carboxylic acid (500 mg, 3.49 mmol) in dry dichloromethane (DCM) (17.500 ml) was stirred at room temperature under an atmosphere of argon. EDC (803 mg, 4.19 mmol) and HOBT (267 mg, 1.746 mmol) were added to the stirred solution. After 15 minutes, 1,1-dimethylethyl hydrazinecarboxylate (554 mg, 4.19 mmol) was added to the stirred solution. The resulting solution was stirred for 18 hours. After this time, the solution was diluted with DCM (approx. 50 ml) and washed with water (2× approx. 20 ml). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oil of desired product in 451 mg.