Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CCOC(C)=O>[F:26][C:23]([F:25])([F:24])[C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH2:13][C:11]3[CH:10]=[CH:9][C:7]4[N:8]=[C:4]([NH:27][C@@H:28]5[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]5[OH:34])[S:5][C:6]=4[CH:12]=3)[CH:15]=[N:16][C:17]=2[CH:22]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Temperature: 130 °C
Yield: 24.2 %

Procedure:
A stirred mixture of 2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (0.20 g, 0.50 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol (0.17 g, 1.5 mmol), DIEA (0.59 g, 4.6 mmol) and NMP (2 mL) was heated at 130° C. for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), and washed with water (10 mL×2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)-2-((6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (54 mg, 23%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 5.54 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.39 (m, 1H), 2.01 (m, 1H), 1.80 (m, 1H), 1.59-1.62 (m, 2H), 1.17-1.23 (m, 4H); LCMS (ESI) m/z 447 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]1.C(Cl)[Cl:65]>>[ClH:65].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: CN1CCN(CCO)CC1
Reactant: ClCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCN1CCN(C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0.4 mmol), triphenylphosphine (314 mg, 1.2 mmol) and 1-(2-hydroxyethyl)4-methylpiperazine (86 mg, 0.6 mmol), (prepared as described for the starting material in Example 17), in methylene chloride (5 ml). The mixture was stirred for 1 hour at ambient temperature and the mixture was purified by column chrormatography eluting with methylene chloride/methanol (90/10 followed by 80/20). The purified product was triturated with ether, collected by filtration and dried under vacuum. The solid was dissolved in methylene chloride and 3M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation and the resulting oil was triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline hydrochloride (100 mg, 41%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.Cl.[CH2:27]([O:29][C:30](=[O:40])[CH2:31][C@H:32]([NH2:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)C.C[O-].[Na+].CO>>[CH3:27][O:29][C:30](=[O:40])[CH2:31][C@H:32]([NH:39][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CCOC(=O)C[C@H](N)c1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1cccnc1
Temperature: 140 °C
Yield: 56.1 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in a CEM microwave tube (10 mL) with (S)-3-amino-3-pyridin-3-yl-propionic acid ethyl ester dihydrochloride (134 mg, 0.5 mmol) (commercially available from AstaTech 46247) and a solution of sodium methoxide in methanol (2 mL, 0.5M, 1 mmol) was added with stirring. The reaction was heated to 140° C. in the CEM microwave apparatus for approximately 90 minutes. The reaction was cooled, concentrated under vacuum and filtered through silica to provide 41 mg of the desired product which was used without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCc1ccccc1C(F)(F)F
Yield: 92.4 %

Procedure:
A solution of 2.42 g (19.47 mmol) of 2-hydroxybenzyl alcohol in 100 ml of dry acetonitrile is mixed with 3.91 g (19.47 mmol) of 2-trifluoromethylbenzyl bromide and 2.96 g (21.42 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 5.08 g (87% yield) of a solid are obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].[C:34](=[O:37])(O)[OH:35].[CH3:38]Cl.O>CN(C=O)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[C:34]([O:35][CH3:38])=[O:37])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)O
Reactant: CCl
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)n1ccc2c(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{5-[3-(Trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (100 mg) was dissolved in DMF (1.0 ml), followed by addition of 60% NaH (10.9 mg) at 0° C., and stirring at room temperature for 0.5 hour. Methyl chloride carbonate (26.3 μl) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml), the organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 98:2) to obtain methyl 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole-1-carboxylate (98.6 mg) as a white solid.
Reaction SMILES: [C:1]([O:11]CC)(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[Na+]>C(O)C.O1CCOCC1>[C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC/C=C/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCC/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-ethyl 2-nonenoate in ethanol and 1,4-dioxane was added a 1N aqueous solution of sodium hydroxide. After being stirred at room temperature for 3 hours, the reaction mixture was concentrated and acidified with diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give the object compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][NH:16][C:15]2=O)([CH3:9])([CH3:8])[CH3:7].N>C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>[Cl:3][C:15]1[C:14]2[C:19](=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=[CH:12][CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cccc2c(=O)[nH]cnc12
Agent: N
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc2c(Cl)ncnc12
Temperature: 0 °C

Procedure:
18.6 ml (200 mmol) of phosphoryl chloride are added dropwise at room temperature to a suspension of 10.2 g (50 mmol) of 8-tert-butyl-4(3H)-quinazolinone in 100 ml of toluene. After addition of 5 drops of N,N-dimethylaniline, the reaction mixture is heated under reflux for 5 h. After cooling, the reaction mixture is diluted with 300 ml of toluene, poured onto 1000 g of ice and rendered alkaline (pH about 9) by addition of conc. ammonia solution. The organic phase is separated off, washed once with 300 ml of sat. sodium chloride solution, dried over magnesium sulfat e, and the toluene is removed in vacuo. The residue is chromatographed on silica gel (n-heptane:ethyl acetate 3:1 v:v). Yield: 9.3 g (42 mmol), 84%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]=[C:6]([NH2:8])[S:5][N:4]=1.[C:9](Cl)(=[O:17])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>ClCCl>[C:11]1([O:10][C:9](=[O:17])[NH:8][C:6]2[S:5][N:4]=[C:3]([O:2][CH3:1])[N:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1nsc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nsc(NC(=O)Oc2ccccc2)n1
Reaction time: 16 h

Procedure:
3-Methoxy-1,2,4-thiadiazol-5-amine a (500 mg, 3.82 mmol) and phenyl carbonochloridate b (600 mg, 3.82 mmol) were dissolved in 20 mL of dichloromethane, followed by addition of triethylamine (0.8 mL, 5.73 mmol). After reacting for 16 hours, 30 mL of H2O were added into the reaction mixture to dilute the solution. The aqueous phase and organic phase were separated, the aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate c (200 mg, yield 20.8%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C[Mg+].[Br-].[CH:16](Cl)(Cl)Cl>C1COCC1>[CH3:16][C:5]1[C:6]2[S:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Reactant: ClC(Cl)Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])ccc2ncsc12
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of 6-nitrobenzothiazole (1.4 g, 7.7 mmol) in 50 mL of THF was added 5.1 mL of MeMgBr (15.3 mmol) dropwise in 0.5 h period at 0° C. The reaction mixture was then stirred for additional 2 h. It was quenched by adding THF solution of 2,3-dichloro-5,6-dicyanobenzoquinone until the color of the solution turns to dark green. The reaction mixture was concentrated in vacuo to yield a dark solid which was subjected to column chromatography (CHCl3, neat) to provide 0.68 g (3.5 mmol, 46%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.[Si](C#N)(C)(C)C.[N:27]1([C:32](N2C=CN=C2)=[O:33])C=CN=[CH:28]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:15]([C:14]4[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=4[O:12][CH3:11])[CH2:28][NH:27][C:32]3=[O:33])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccccc1C=O
Reactant: Nc1ccc2nc[nH]c2c1
Agent: C[Si](C)(C)C#N
Product: COc1ccccc1C1CNC(=O)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2-methoxybenzaldehyde (0.484 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.05 mL, 7.55 mmol), di-(imidazol-1-yl)methanone (0.667, 4.12 mmol) as described in method 2.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[OH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=O>>[OH:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: Cc1ccc(C(=O)O)cc1O
Product: Cc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1O

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-hydroxy-4-methylbenzoic acid: MS (APCl): m/z 399 (M+1).
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])[CH2:3][CH2:4][CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:13].[CH3:17][I:18]>C1C=CC=CC=1>[I-:18].[CH3:1][CH:2]([N+:14]([CH3:17])([CH3:15])[CH3:16])[CH2:3][CH2:4][CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:13]
Reactant: CI
Reactant: CC1CCCC(C)(C)C1CCC(C)N(C)C
Solvent: c1ccccc1
Product: CC1CCCC(C)(C)C1CCC(C)[N+](C)(C)C
Product: [I-]
Yield: 90 %

Procedure:
To a solution of [1-methyl-3-(2,6,6-trimethylcyclohexyl)propyl]dimethylamine (3.0 g) in benzene (20 cc) was added methyliodide (10.0 g), and the mixture was allowed to stand over night. Precipitated crystals were gathered by filtration, and recrystallized from a mixed solvent of benzene and ether to give colorless crystals (4.4 g) of [1-methyl-3-(2,6,6-trimethylcyclohexyl)propyl]trimethylammonium iodide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][NH:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:16][O:17][N:18]([CH3:19])[C:10](=[O:12])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 79.2 %

Procedure:
2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (6.62 g, 32.6 mmol), O,N-dimethylhydroxylamine hydrochloride (3.50 g, 35.8 mmol), and HATU (14.86 g, 39.1 mmol) were combined in DMF (100 mL). To this solution was added Hunig's Base (17.07 mL, 98 mmol). The reaction was stirred for overnight (17 hours). The reaction was then concentrated under vacuum and the residue was diluted with EtOAc (300 mL) and washed with water (2×80 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50 percent EtOAc-Hexanes) to afford the desired product as a white solid (6.36 g). LCMS m/z 247.2 (M+H)+, Rt 0.61 min.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.[Br:30][C:31]1[N:36]=[C:35]([CH:37](O)[CH2:38][CH2:39][O:40][CH3:41])[CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:30][C:31]1[N:36]=[C:35]([CH:37]([O:15][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:38][CH2:39][O:40][CH3:41])[CH:34]=[CH:33][CH:32]=1
Reactant: COCCC(O)c1cccc(Br)n1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC(CCOC)c2cccc(Br)n2)cc1C
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A solution of diisopropylazodicarboxylate (1.44 mL, 7.31 mmol) in dry THF (50 mL) was added drop-wise, under nitrogen, over 1.5 h (using a syringe pump) to a solution ethyl (4-hydroxy-2-methylphenoxy)acetate (1.10 g, 5.21 mmol), 1-(6-bromo-2-pyridinyl)-3-(methyloxy)-1-propanol (1.29 g, 5.24 mmol) and triphenylphosphine (1.92 g, 7.32 mmol) in dry THF (50 mL) at 0° C. The resulting mixture was stirred under nitrogen and gradually allowed to warm to room temperature over 19 h. The solvent was then removed in vacuo and the residue purified by Biotage (silica, 90 g cartridge), eluting with cyclohexane:EtOAc 85:15 to afford the title compound as a pale yellow oil (1.32 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[CH:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:49])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([NH:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[CH:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:49])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24]1)=[O:21])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@H](COCc5ccccc5)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.4 %

Procedure:
By using N-tert-butyloxycarbonyl-O-benzyl-L-serine (2.28 g, 7.72 mmol) and 3α-aminocholestane (3.00 g, 7.74 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (4.64 g, yield; 90.4%).
Reaction SMILES: [OH:1]C(COC1C=CC(C(O)=O)=CC=1)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1.[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>N1C=CC=CC=1.C(N)=O>[C:46]([NH:45][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)([NH:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:1]
Reactant: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(C(=O)O)cc2)CCN(CC(=O)O)CC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: NC=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A solution of the gadolinium complex of 10-(2-hydroxy-3-(4-carboxyphenoxy)-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (500 mg, 0.72 mmol) in pyridine/formamide (1:1, 10 mL) was cooled to 0° C. with stirring. Dicyclohexylcarbodiimide (DCC, 149 mg, 0.72 mmol) and N,N-dimethylaminopyridine (DMAP, 20 mg, 0.16 mmol) were added. The resulting solution was stirred for 30 min at 0° C. A solution of dextran (MW 40,000; 1.0 g, 0.025 mmol) in formamide/pyridine (1:1, 30 mL) was prepared by gently warming a suspension of the polysaccharide. The dextran solution was added to the activated chelate and the mixture was stirred at 25° C. for 4 days. During this time a precipitate of dicyclohexylurea formed. The suspension was filtered and the polysaccharide was precipitated by dropwise addition of the filtrate into ethanol/ether (1:2, 300 mL). The suspension was stirred for 30 min then allowed to settle. The solvent was decanted off and the solid was isolated by filtration. The product was purified by GPC on a column of Sephadex G-25 eluted with distilled H2O. Fractions corresponding to the macromolecular component were collected, pooled and lyophilized. To ensure there were no small molecular components unremoved by GPC an analytical sample was prepared by ultrafiltration (Centrex MWCO 10,000) of an aqueous solution (500 μL) containing the product (300 mg). The retentate was collected and lyophilized giving a white pad (296 mg). The UV spectrum of an aqueous solution of this product (0.175 mg/mL) had an absorbance at 258 nm which confirmed the presence of the benzoic acid ester. The analytical sample contained 0.92% gadolinium, corresponding to approximately 3 mol Gd/mol dextran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][C@@H:14]([N:16]=[N+]=[N-])[CH2:13][C@@H:12]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C:29]3=[O:34])=[CH:24][CH:23]=2)=[O:20])=[O:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@@H:12]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C:29]3=[O:34])=[CH:24][CH:23]=2)=[O:20])=[O:10])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
9.4 A solution of 25 mg (0.052 mmol) of “A9” and 20.46 mg (0.08 mmol) of triphenylphosphine in a mixture of 0.5 ml of tetrahydrofuran and 0.5 ml of water is stirred at room temperature for 12 hours. After the precipitated triphenylphosphine oxide has been filtered off, the filtrate is evaporated to dryness, and the residue is purified by preparative HPLC (acetonitrile/water/0.1% trifluoroacetic acid), giving 12 mg (40%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-aminopyrrolidine-1,2-dicarboxamide (“10”) as colourless crystals, ESI 458.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH:11](NC)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:32][C:33]([OH:35])=O)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:20].[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.OS([O-])(=O)=O.[K+]>ClCCl>[CH2:19]([N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:32][C:33]([NH:37][CH2:36][CH:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=2)[CH2:10]1)=[O:35])[CH3:20]
Reactant: CCN(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: CNC1CCCN(c2ccc(C(F)(F)F)cc2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC(=O)NCC1CCCN(c2ccc(C(F)(F)F)cc2)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 16.9 %

Procedure:
A solution of crude [1-(4-trifluoromethyl-phenyl)-piperidin-3-yl]-methylamine (30.0 mg, 0.12 mmol, crude) and [ethyl-(4-fluoro-benzenesulfonyl)-amino]-acetic acid (30.0 mg, 0.12 mmol) in dichloromethane (5 mL) at 25° C. was treated with HATU (43.7 mg, 0.12 mmol). N,N-Diisopropylethylamine (29.7 mg, 0.23 mmol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2 M aqueous KHSO4 solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (50/50 hexanes/ethyl acetate) afforded 2-[ethyl-(4-fluoro-benzenesulfonyl)-amino]-N-[1-(4-trifluoromethyl-phenyl)-piperidin-3-ylmethyl]-acetamide (10.2 mg, 18%) as a white solid. [MH]+=502.0.