Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cnccc2N2CCC(C(N)=O)CC2)cc1
Yield: 89 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (50 mg, 0.17 mmol), 4-methoxyphenylboronic acid (32 mg, 0.21 mmol), tetrakis (triphenylphosphine)palladium(0) (10 mg, 5 mol %), acetonitrile (1.2 mL) and 0.5 M sodium carbonate (0.49 mL, 0.25 mmol) for 50 min. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, gradient 97:3 to 95:5) to furnish the title compound as a white solid (49 mg, 89%), LC-MS (ESI) Rt 1.28 min, m/z 312 (100%, [M+H]+); m/z (ESI) C18H22N3O2 requires 312.1706 found [M+H]+ 312.1705.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[NH:22][CH2:21][CH2:20][O:19][CH3:18])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COCCN
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Starting from trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid and 2-methoxy-ethylamine the title compound is obtained as colorless solid.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][CH:8]=1)C>C1COCC1.CO.O>[C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:19])=[O:5])=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
LiOH (38 mg, 0.93 mmol) was added to a stirred solution of 6-phenyl-nicotinic acid ethyl ester (140 mg, 0.62 mmol) in THF:MeOH:H2O (3:1:1, 2.8 mL), and the resulting mixture was stirred at room temperature overnight. The methanol and THF were evaporated from the reaction mixture, which was then diluted with water (2 mL), acidified with citric acid solution and the product was extracted with EtOAc. The organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated in vacuo to afford 100 mg (81.9% yield) of 6-phenyl-nicotinic acid (100 mg). LCMS purity: 98.1%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:33]4[CH:34]=[CH:22][CH:23]=[C:24]([CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:32]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: Brc1cccc(CN2CCOCC2)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(CN5CCOCC5)c4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-morpholin-4-ylmethyl-phenyl)-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-(3-bromo-benzyl)-morpholine (54.0 mg, 0.211 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as an orange foam (0.021 g, 26%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 8.24 (d, J=7.4 Hz, 2H), 8.09 (d, J=7.3 Hz, 2H), 7.66 (d, J=7.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.35-7.29 (m, 1H), 7.05-6.97 (m, 2H), 6.87 (s, 1H), 3.75-3.70 (m, 4H), 3.54 (s, 2H), 3.11 (s, 3H), 2.52-2.45 (m, 4H). MS=464 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3](CC(O)=O)=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][Li].[CH2:24]1[CH2:28][O:27]CC1>>[CH3:22][C:28]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1)([OH:27])[CH3:24]
Reactant: O=C(O)Cc1c(F)cccc1-c1nccc2ccccc12
Reactant: [Li]C
Reactant: C1CCOC1
Product: CC(C)(O)c1c(F)cccc1-c1nccc2ccccc12
Reaction time: 18 h

Procedure:
45.27 g (0.161 mol) of 1-[3-fluoro-2-(carboxymethyl)phenyl]isoquinoline were dissolved in 950 ml of THF and admixed dropwise at −78° C. with 185.12 ml (0.370 mol, 2.3 eq.) of methyllithium (2 M in diethyl ether). After the addition, the mixture was stirred at from −78° C. to −20° C. for 18 h. The reaction mixture was subsequently quenched with MeOH with ice cooling and admixed with 500 ml of dichloromethane. The mixture was subsequently washed three times with 100 ml of NaHCO3 solution and water, dried over MgSO4 and concentrated under reduced pressure. The resulting solid was crystallized from 600 ml of heptane. 29.72 g of a white solid were obtained, corresponding to 65.8% of theory, with a purity of 97.5%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O.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>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:5]2[C:10]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: OB(O)c1cccnc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2cccnc2)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a vial was added 2-chloro-5-iodo-4-(3-nitrophenoxy)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (333.7 mg, 0.61 mmol), pyridin-3-ylboronic acid (79 mg, 0.64 mmol, 1.05 mol eq), 1,4-dioxane (4 mL), water (1 mL), Na2CO3 (78 mg, 0.73 mmol, 1.2 mol eq) and Pd(PPh3)2Cl2 (21 mg, 0.05 mol eq). The reaction vial was capped, stirred at rt for 1 hr and was then heated to 60° C. (block temperature) for 2 days (note: the reaction progress was monitored by LCMS after couple hours and more pyridin-3-ylboronic acid was added as needed). The reaction was diluted with ethyl acetate (100 mL) and water (20 mL) and the organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated to give crude product (TLC: Rf 0.3 in 50% ethyl acetate-50% heptane). The crude product was purified on silica gel to give the title compound as a light yellow solid (266 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (d, J=2.01 Hz, 1H) 8.54 (dd, J=4.78, 1.51 Hz, 1H) 8.38 (t, J=2.14 Hz, 1H) 8.23 (dd, J=8.06, 2.01 Hz, 2H) 8.15 (s, 1H) 7.86-7.93 (m, 1H) 7.77-7.85 (m, 1H) 7.50 (dd, J=7.93, 4.66 Hz, 1H) 5.68 (s, 2H) 3.58-3.74 (m, 2H) 0.83-1.02 (m, 2H) 0.00 (s, 9H). m/z (APCI+) for C23H24ClN5O4Si 498.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](C(O)=O)[CH:8]=2)[CH:3]=[CH:2]1.C1C[O:16][CH2:15]C1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O.CO>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:15][OH:16])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
1H-Indole-6-carboxylic acid (1.00 g, 6.23 mmol) was dissolved into anhydrous THF (20 ml) under argon. The solution was cooled in an ice bath and lithium aluminum hydride (13.1 ml of 1M solution in THF, 13.1 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was cooled to 0° C. and ethyl acetate (10 ml) was carefully added, followed by methanol (5 ml) and water (5 ml). The mixture was stirred for 30 min and filtered through celite. The solution was concentrated and dissolved in ethyl acetate (200 ml) and washed with brine (2×100 ml), dried over MgSO4, filtered and concentrated to yield (1H-indol-4-yl)-methanol (471 mg, 52%) as an orange oil: 1H NMR (400 MHz, DMSO-d6) δ 11.04 (bs, 1H), 7.30-7.26 (m, 2H), 7.05-6.98 (m, 2H), 6.48-6.47 (m, 1H), 5.04 (t, J=4.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[O:35]1[CH2:40][CH2:39]C(O)[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH:29]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[CH:18][CH:17]=1
Reactant: OC1CCOCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCOCC4)cc3)c2cc1OC
Yield: 53.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, tetrahydro-2H-4-pyranol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (38 mg, yield 53%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.Cl.[CH3:26][O:27][C:28]1[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([O:35][CH3:36])[N:29]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:34][C:33]3[C:28]([O:27][CH3:26])=[N:29][C:30]([O:35][CH3:36])=[CH:31][CH:32]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: COc1ccc(N)c(OC)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2ccc(OC)nc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 20.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 500 mg, 1.35 mmol) and 2,6-dimethoxypyridin-3-amine monohydrochloride (768 mg, 4.04 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 15 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (133 mg, 0.272 mmol, 20%) as a colorless amorphous.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C#N)cc2)CC1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
To 4-fluorobenzonitrile (11.56 g) in DMSO (200 ml) was added piperidine-4carboxylic acid ethyl ester (15 g) and potassium carbonate (14.4 g) and the reaction was heated to 120° C. for 4 h. After cooling solvent was evaporated and the residue taken up into EtOAc (150 ml) and washed with HCl (1M, 2×100 ml), sodium hydrogen carbonate solution (2×100 ml) and brine (100mI). Evaporation of the organic layer provided the subtitled compound (22.6 g). LCMS electrospray(+ve) 259 (MH+).
Reaction SMILES: [C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:13][CH2:12]5)[O:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:35](S(CCCC)=O)[CH2:36][CH2:37]C>>[C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:32][CH2:33]2)[CH2:13][CH2:12]5)[O:8][CH:7]([CH2:35][CH2:36][CH3:37])[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCS(=O)CCCC
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Product: CCCC1O[C@]23CC[C@@]4(C[C@@H]2[C@@](C)(C(C)(C)C)O1)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5

Procedure:
The title compound 5 was synthesized similar to the procedure described in Example 1 for compound 3 using dibutyl sulfoxide instead of DMSO. After column chromatography, 227 mg (86.3% yield, 99.4 purity) of compound 5 was isolated as an off-white solid as a mixture of two epimers in a 95.4:4.6 ratio.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH:51]([O:53][CH3:54])[CH3:52])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].C(O)(=O)C.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH:51]([O:53][CH3:54])[CH3:52])[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3]
Reactant: COC(=O)c1c(C(C)(C)O)nc(C(C)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C(C)(C)O)nc(C(C)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 83.2 %

Procedure:
A solution of 600 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-(1-methoxyethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of a 25% v/v aqueous solution of acetic acid was stirred at 60° C. for 1.5 hours. The solution was then mixed with 10 ml of water and cooled with ice. The trityl alcohol which appeared as crystals was filtered off. The filtrate was concentrated by distillation under reduced pressure, and then acetic acid and water were distilled off as azeotropic mixtures with toluene, to give 331 mg of the title compound as an amorphous powder.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Li])CCC.[C:22]([O:26][C:27](=[O:36])[CH:28]=[CH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:36])[CH2:28][CH:29]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:17])[CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: [Li]CCCC
Reactant: CN(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)C=CC1CCCCC1
Solvent: C1CCOC1
Product: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)OC(C)(C)C)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of N-benzyl-(+)-methyl-benzylamine (8.5 mL, 40.4 mmol) in THF (100 mL) was cooled to 0° C., then n-butyl lithium (16 mL, [2.5 M], 40.4 mmol) was added and the resulting mixture stirred for 1 hour. The reaction mixture was cooled to −78° C., then a solution of 3-cyclohexyl-acrylic acid tert-butyl ester (7.71 g, 36.7 mmol) in THF (20 mL) was added dropwise for 30 min and the resulting mixture was stirred an additional 1 hour at −78° C. The reaction was quenched with NH4CT (s), and extracted with EtOAc, the organic layer was dried with MgSO4, filtered and evaporated under reduced pressure to yield a residue. The residue was purified by column chromatography (10%-70% EtOAc/heptane) to yield a residue.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[I-].[CH3:16][S+](C)(C)=O.CC(C)([O-])C.[Na+]>C1COCC1.COCCOC>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.50 g, 2.51 mmol) in THF/DME (2:1, 6 mL) at 60° C. was added trimethylsulfoxonium iodide (0.58 g, 2.63 mmol) and sodium t-butoxide (0.25 g, 2.63 mmol). The reaction mixture was stirred at 60° C. for 30 min, cooled to rt and concentrated. Water was added and the mixture was extract with EtOAc twice. The combined organics were dried over Na2SO4, filtered and concentrated. Purification on silica gel (3:1, hexanes:EtOAc) gave tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate as a clear oil that solidified upon standing.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)C(C)C)(C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([C:41](O)=[O:42])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:41]([CH:37]3[CH2:38][CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36]3)=[O:42])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)piperazine-1-carboxamide hydrochloride (1.0 g) in dichloromethane (100 mL) was added N,N-di-iso-propylethylamine (0.56 mL) at room temperature. After 10 minutes N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide (617 mg) was added followed by 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (671 mg) and 1-hydroxybenzotriazole (435 mg). The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexane to give the title compound as a white foam (1.4 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([OH:16])[CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[K+].Cl>C1COCC1.CN(C=O)C.O>[CH2:12]([O:16][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCO
Reactant: O=C(O)c1cc(F)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(Cl)c(C(=O)O)c1

Procedure:
To a solution of 2-chloro-5-fluorobenzoic acid (50 mg) and 1-butanol (263 μL) in THF (0.5 mL) and DMF (3 mL) was added potassium t-butoxide (329 mg) and the solution was reacted at 120° C. for 10 minutes in a microwave synthesizer (Biotage, Initiator). The reaction mixture was cooled and acidified by addition of water and 2M hydrochloric acid, extracted with diethyl ether, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified on column chromatography to obtain the titled compound (17 mg) as white powder.
Reaction SMILES: NC1C=C(N)C=C(N)C=1C1C=CC(C)=CC=1.[C:17]([O:20][CH:21]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:22]1[NH2:23])(=[O:19])[CH3:18].[I:41][C:42]1[C:47]([CH2:48][CH3:49])=[C:46]([I:50])[CH:45]=[C:44]([I:51])[C:43]=1[C:52]1[CH:57]=[CH:56][C:55]([C:58](Cl)=[O:59])=[C:54]([N+:61]([O-:63])=[O:62])[CH:53]=1>>[N+:61]([C:54]1[CH:53]=[C:52]([C:43]2[C:44]([I:51])=[CH:45][C:46]([I:50])=[C:47]([CH2:48][CH3:49])[C:42]=2[I:41])[CH:57]=[CH:56][C:55]=1[C:58]([C:21]1([O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:22]1[NH2:23])[O:20][C:17](=[O:19])[CH3:18])=[O:59])([O-:63])=[O:62]
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccc(-c2c(N)cc(N)cc2N)cc1
Product: 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

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.