Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].Br[CH2:3][C:4]1[CH:5]=[NH+:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[CH3:10][C:11]1[N:16]=[C:15]([S:17][CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:14]=[C:13]([OH:18])[CH:12]=1
Reactant: BrCc1ccc[nH+]c1
Reactant: Cc1cc(O)nc(S)n1
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cccnc2)n1
Yield: 38.8 %

Procedure:
A mixture 3-(bromomethyl)pyridin-1-ium bromide (550 mg, 2.5 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (285 mg, 2.0 mmol), and triethylamine (1.1 mL, 8.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solid residue was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The solid product was suspended in acetone (50 mL). The solid material was removed by filtration. The filtrate was recovered and evaporated to dryness. The residue was suspended in water (50 mL). The product was recovered by filtration, washed with diethyl ether (2×20 mL), and dried in vacuo, affording 6-methyl-2-[(pyridin-3-ylmethyl)sulfanyl]pyrimidin-4-ol (181 mg, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.36 (s, 2H), 6.00 (s (br), 1H), 7.32 (td, 1H, J=0.8 Hz, 7.8 Hz), 7.82 (dd, 1H, J=0.8 Hz, 7.8 Hz), 8.42 (dd, 1H, J=0.8 Hz, 4.7 Hz), 8.61 (d, 1H, J=1.8 Hz); M+234; HPLC purity: 98.1%.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[K+].[CH2:23]1[O:33][C:32]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][C:25]=2[O:24]1>CN(C=O)C>[CH2:23]1[O:33][C:32]2[CH:31]=[CH:30][C:27]([CH2:28][N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:8]=[C:9]5[C:14](=[CH:15][CH:16]=4)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]5)[CH2:2][CH2:3]3)=[CH:26][C:25]=2[O:24]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(N3CCN(Cc4ccc5c(c4)OCO5)CC3)ccc2N1
Reaction time: 3.5 h
Yield: 11.9 %

Procedure:
To a mixture of 1.2 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium bicarbonate and 20 ml of DMF was added 785 mg of 3,4-methylenedioxybenzyl chloride and the mixture was stirred at 80°-90° C. for 3.5 hours. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography to give 0.2 g of 6-[4-(3,4-methylenedioxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1.[OH-].[Na+]>CC(C)=O.O>[Br:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][CH:18]=[N:17][C:16]=2[N:15]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methylbenzenesulfonyl chloride (5.21 g, 27.3 mmol) was added to a suspension of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (6.34 g, 27.3 mmol) in acetone (70 mL). After addition of an aqueous solution of sodium hydroxide (1.11 g, 27.8 mmol in 15 mL water), the reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (125 mL), stirred for 10 minutes, and filtered. The collected solids were washed with water to afford the product as a solid, Yield: 8.88 g, 23.0 mmol, 84%. LCMS m/z 385.9, 387.9, 389.8 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.42 (s, 1H), 8.06 (br d, J=8.4 Hz, 2H), 7.46-7.51 (m, 2H), 2.37 (br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([CH2:20][O:21][CH3:22])[NH:16][C:15]=3[CH:14]=[C:13]([N+:23]([O-])=O)[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1>CO.C1COCC1.[Pt]>[NH2:23][C:13]1[CH:12]=[C:11]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:26])=[O:10])[C:19]2[N:18]=[C:17]([CH2:20][O:21][CH3:22])[NH:16][C:15]=2[CH:14]=1
Reactant: COCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc([N+](=O)[O-])cc2[nH]1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(N)cc2[nH]1
Reaction time: 4 h
Yield: 77 %

Procedure:
To a suspension of methyl 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylate (Example 11, Step 3) (4.8 g) in MeOH (120 mL), were added lithium hydroxide hydrate (4.56 g) and water (54 mL). The mixture was stirred at room temperature for 16 hours. Under ice-cooling, 1N hydrochloric acid was added slowly to the reaction mixture to adjust the pH to about 2. The precipitate was collected by filtration and dried to obtain 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g). To the solution of 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g) in DMF (90 mL), HBTU (8.23 g), triethylamine (2.19 g) and 3-chloro-2-methylaniline (3.07 g) were added sequentially, and the solution was stirred for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and stirred for 1 hour. The precipitate was collected by filtration and washed sequentially with water and ethyl acetate to obtain N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) as pale yellow powder. To the solution of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) in MeOH-THF (1:1, 120 mL), were added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (1.4 g). The mixture was stirred under hydrogen atmosphere (3 atm) for 4 hours. The catalyst was filtered off, and the mother liquid was concentrated. The residual solid was washed with ethyl acetate to obtain 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (5.1 g) as pale yellow powder.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.C(O[CH:18]=[C:19]([C:25]([CH3:27])=O)[C:20]([O:22]CC)=[O:21])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:27][C:25]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:13])([F:14])[F:2])=[CH:10][CH:9]=2)[N:12]=[CH:18][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ccc(OC(F)(F)F)cc1
Temperature: 76 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
4-Trifluoromethoxyphenylhydrazine hydrochloride (4.0 g) and ethyl 2-ethoxymethylene-acetoacetate (3.26 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), were added to a mixed solvent of water (10 ml) and ethanol (10 ml), and stirred at 76° C. for two hours. Sodium hydroxide (1.40 g) was added to the reaction solution and the mixture was further stirred at the same temperature for an hour. Ethanol was evaporated in vacuo, hydrochloric acid (1 mole/1) was added to the aqueous solution and the precipitated solid was recrystallized from ethyl acetate to give the titled compound (3.56 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([N:35]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]1)[CH3:34]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:40][CH:37]3[CH2:38][CH2:39][N:35]([CH2:33][CH3:34])[CH2:36]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: CCN1CCC(N)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCC(NC(=O)Cn2c(-c3ccc(Br)cc3)nc3cccnc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0151 mole), 1,1'-carbonyldiimidazole (2.45 g, 0.0151 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of 1-ethyl-3-aminopyrrolidine (1.89 g, 0.0166 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from isopropyl alcohol-isopropyl ether to give 4.64 g (72%) of white needles, mp 202.5°-204° C.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1N=CN(C2C=[C:20]3C(=CC=2)NC=[C:21]3[CH2:27][CH2:28][OH:29])C=1>CS(C)=O>[N:1]1([C:6]2[CH:12]=[C:11]3[C:9](=[CH:8][CH:7]=2)[NH:10][CH:20]=[C:21]3[CH2:27][CH2:28][OH:29])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCCc1c[nH]c2ccc(-n3cnnc3)cc12
Reactant: Nc1ccc(-n2cncn2)cc1
Solvent: CS(C)=O
Product: OCCc1c[nH]c2ccc(-n3cncn3)cc12

Procedure:
Prepared from 4-(1,2,4-triazol-1-yl)aniline (EP497512) as described for Intermediate 3, δ (250 MHz, D6 -DMSO) 2.89 (2H, t, J=7.2 Hz, CH2), 3.64-3.74 (2H, m, CH2), 4.67 (1H, t, J=5.3 Hz, OH), 7.29 (1H, d, J=2.3 Hz, Ar--H), 7.47 (1H, dd, J=8.7 and 1.5 Hz, Ar--H), 7.53 (1H, dd, J=8.7 and 2.3 Hz, Ar--H), 7.95 (1H, d, J=1.9 Hz, Ar--H), 8.19 (1H, s, Ar--H), 9.19 (1H, s, Ar--H), 11.10 (1H, s, NH).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:9]=[CH:8][O:7][N:6]=1.O.[NH2:12][NH2:13]>C(O)C>[O:7]1[CH:8]=[CH:9][C:5]([CH2:4][C:3]([NH:12][NH2:13])=[O:2])=[N:6]1
Reactant: NN
Reactant: COC(=O)Cc1ccon1
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1ccon1
Yield: 78 %

Procedure:
As described for example 112a, isoxazol-3-yl-acetic acid methyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) at rt for 16 h. After evaporation of the solvent the residue was chromatographed (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) to afford the title compound as a white solid (yield: 78%). MS: m/e=142.1 [M+H]+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])=[CH:10][S:9][C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[CH3:24][C:25]1[C:30]([CH3:31])=[C:29](O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:29]3[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([CH3:24])[C:30]=3[CH3:31])=[C:8]([C:20]([F:23])([F:22])[F:21])[S:9][CH:10]=2)=[C:13]([F:19])[CH:14]=1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2F)csc1C(F)(F)F
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(Cl)cc3F)csc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(2-fluoro-4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(2-fluoro-4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl) propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.30 (dd, J=11.5, 5.5 Hz, 2H), 7.14 (dd, J=10.7, 4.5 Hz, 2H), 6.92 (d, J=6.5 Hz, 1H), 6.57 (d, J=6.5 Hz, 1H), 4.92 (s, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.58 (t, J=7.0 Hz, 2H), 2.15 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C:11]1[O:12][CH2:13][C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:25]=[CH:24][C:9]=2[N:10]=1
Reactant: COc1ccccc1CNC1=Nc2ccc(NC(=O)CCl)cc2CO1
Reactant: CN1CCNCC1
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)CN3CCN(C)CC3)cc2CO1
Yield: 225.1 %

Procedure:
Prepared from the above described 2-chloro-N-[2-(2-methoxy-benzylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (50 mg, 0.129 mmol, HPLC 0.889 min 81%) and N-methylpiperazine (900 ul, 8 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (123 mg, 73%, HPLC 0.531 min 100%), MS (ISP) m/e=424.4 [(M+H)+].
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[CH:21])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:25])[CH2:2][CH3:3].I[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[O:25]=[C:5]1[N:6]([CH2:22][CH2:23][CH3:24])[C:7]2[N:8]=[C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[C:21][C:27]4[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=4)[CH:18]=3)[NH:10][C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: NS(=O)(=O)c1ccc(I)cc1
Reactant: C#CCn1cc(-c2nc3c([nH]2)c(=O)n(CCC)c(=O)n3CCC)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC#Cc4ccc(S(N)(=O)=O)cc4)c3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.4 %

Procedure:
A mixture of 1,3-dipropyl-8-(1-prop-2-ynyl-1H-pyrazol-4-yl)-3,7-dihydro-purine-2,6-dione (200 mg, 0.59 mmol), 4-iodo-benzenesulfonamide (166 mg, 0.59 mmol), copper iodide (10 mg, 0.059 mmol), dichlorobis (triphenylphosphine)-palladium (II) (21 mg, 0.03 mmol), triethylamine (2 ml), DMF (2 ml) was degassed for 10 min. and stirred for 20 hrs at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×10 ml). Organic layer was washed with brine (2×15 ml) and dried over Na2SO4. The organic volatile solvent was evaporated and the crude product was purified using HPLC to obtain pure 4-{3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzenesulfonamide (4.2 mg, 2%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH2:40])=[O:39])#[CH:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:38]([C:37]1[CH:36]=[C:35]([C:33]#[C:34][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:32]=[CH:31][C:16]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:15][CH:14]=3)[N:3]=2)[CH:43]=[CH:42][CH:41]=1)(=[O:39])[NH2:40]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1cccc(C(N)=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4cccc(C(N)=O)c4)n3)cc2)CC1
Temperature: 120 °C
Yield: 29 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.30 g, 0.64 mmol), 3-ethynylbenzamide (I144) (102 mg, 0.70 mmol), copper(I) iodide (12 mg, 10 mol %), triphenylphosphine (17 mg, 10 mol %), bis(triphenylphosphine)palladium(II) chloride (22 mg, 5 mol %), DMF (3 mL) and triethylamine (0.443 mL, 3.18 mmol) were loaded into a microwave tube and degassed with nitrogen for five minutes. The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes then cooled to room temperature. The cooled mixture was added to 5% aqueous potassium carbonate (150 mL) and the resulting mixture extracted with ethyl acetate (3×150 mL). The combined ethyl acetate phases were washed with water (200 mL), brine (200 mL), dried then evaporated. The residue was chromatographed (Biotage Isolera: 12 g silica cartridge, 20-100% ethyl acetate/petroleum benzine 40-60° C. then 0-10% methanol/ethyl acetate) to give the title compound (I145) (107 mg, 29% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.46 (s, 1H), 8.84 (s, 1H), 8.17 (s, 1H), 8.09 (t, J=1.7 Hz, 1H), 8.04 (dt, J=7.9, 1.4 Hz, 1H), 7.77 (dt, J=7.8, 1.3 Hz, 1H), 7.71-7.66 (m, 2H), 7.66-7.52 (m), 7.27 (d, J=8.6 Hz, 2H), 3.44 (s, 2H), 2.33-2.26 (m, 4H), 1.38 (s, 9H). LCMS Method C: rt 5.06 min; m/z 581.1 [M+H]+, 525.1 [M-tBu+2H]+; m/z 579.2 [M−H]−.
Reaction SMILES: [OH-].[Li+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[CH:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>C1COCC1.O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (25 mg, 1.0 mmol) was added to mixture of methyl 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylate (90 mg, 0.2 mmol) in 10 mL of THF-H2O (7:3) at 0° C. The reaction mixture was stirred overnight at room temperature and acidified to pH=1. Upon evaporation and dried in vacuo, the residue was dissolved in DMF (10 mL) and then used directly for step A. Purity:>80% (checked by LCMS). MS (ESI) (M+H)+=445.99.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C>[Cl:31][C:27]1[CH:28]=[C:29]([CH3:30])[C:21]2[N:20]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:23](=[O:24])[C:22]=2[CH:26]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a solution of 3.1 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride in 100 ml of acetonitrile, 1.9 g of 2-amino-5-chloro-3-methylbenzoic acid was added. The mixture was stirred at room temperature for 10 minutes and then, 1.0 g of triethylamine was added thereto. The mixture was stirred at room temperature for 20 minutes and then, 2.0 g of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 1.2 g of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were poured into the residue to separate layers. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressured. The resulting residue was subjected to silica gel column chromatography to obtain 4.2 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1.S(Cl)([Cl:26])=O>[Zn]>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([Cl:26])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Reactant: O=S(Cl)Cl
Agent: [Zn]
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])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: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH3:16])=[CH:11][C:12](=O)[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:12]1[N:13]=[N:14][C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[C:10]([CH3:16])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(Cl)c(Cl)c1
Product: Cc1cc(Cl)nnc1-c1ccc(Cl)c(Cl)c1
Temperature: 100 °C

Procedure:
6-(3,4-dichlorophenyl)-5-methylpyridazin-3(2H)-one (500 mg) is added stepwise to phosphoryl trichloride (1.8 ml). The reaction mixture is heated to 100° C. for 1 hour, then cooled to room temperature and poured onto ice water. The formed precipitate is separated, washed with water and dried to give 3-chloro-6-(3,4-dichlorophenyl)-5-methylpyridazine (509 mg).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[C:1]([N:5]([CH2:6][CH2:7][C:8](=[O:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:23](=[O:24])[O:25][CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCCC(=O)c1ccccc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N(CCC(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 3-(tert-butylamino)-1-phenylpropan-1-one (5.80 g, 0.028 mol) and K2CO3 (7.73 g, 0.056 mol) in CH2Cl2 (100 mL) was added dropwise methyl chloroformate (7.98 g, 0.085 mol) at 0° C., and the reaction mixture was stirred at rt overnight. The solution was filtered. The filtrate was concentrated to give the crude product, which was purified by chromatography to afford methyl tert-butyl(3-oxo-3-phenylpropyl)carbamate (5.09 g, 69%). 1H NMR (CDCl3): 1.43 (s, 9H), 3.16-3.21 (m, 2H), 3.62 (s, 3H), 3.60-3.72 (m, 2H), 7.2-7.49 (m, 2H), 7.51-7.59 (m, 1H), 7.93-7.98 (m, 2H).