Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[NH2:40][C@@H:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:42]([NH:44][CH3:45])=[O:43]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:40][C@@H:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:42]([NH:44][CH3:45])=[O:43])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials, MS (EI): m/e=404.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:24])=[C:4]([CH3:23])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O-])=[O:19])[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:21]=1[CH3:22].[Na+].Cl.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[C:44]1([CH:50]([NH2:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[NH2:1][C:2]1[C:3]([CH3:24])=[C:4]([CH3:23])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([C:18]([NH:57][CH:50]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:19])[CH2:16][CH2:17]3)([CH3:10])[CH2:7][C:6]=2[C:21]=1[CH3:22]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(C(=O)[O-])CC1)O2
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(C(=O)NC(c3ccccc3)c3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
To a suspension of sodium 1-[(5-amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl)methyl]-4-piperidinecarboxylate (0.89 g) in N,N-dimethylformamide (10 mL) was added 0.35 g of triethylamine hydrochloride and the mixture was stirred at room temperature for 5 minutes. To this mixture were added 0.34 g of 1-hydroxybenzotriazole and 0.46 g of 1,1-diphenylmethylamine. Then, under ice-cooling, 0.48 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added. This mixture was stirred under nitrogen gas at room temperature for 23 hours. This reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to provide 0.71 g of the title compound. Yield 57%.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:24])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][O:19]C(C)=O.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:24])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][OH:19]
Reactant: CC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Retinol was prepared in a high degree of purity from commercial retinyl acetate for use as a reference retinoid in certain bioassays and as a precursor of retinyl ethers. A solution of 100 g of commercial all-trans-retinyl acetate in 1.5 L of a methanol solution of sodium hydroxide (2%) was stirred under a nitrogen atmosphere at room temperature. After 2 h, retinyl acetate was not observable by TLC. The orange solution was concentrated under reduced pressure, and at 30° C., to about 300 mL; the concentrated solution was poured, with stirring, into cold water (1.5 L); and hexane (1 L) was added to dissolve the precipitated retinol. The organic layer was separated and washed with three portions of water, saturated aqueous NaCl being added (as required) to separate emulsions. The organic solution was washed further with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to an orange syrup. A solution of the syrup in ethyl formate (100 mL) was cooled to −20° C., seeded with pure retinol, and stored (under a nitrogen atmosphere) at −20° C. The crystalline retinol was collected by filtration under nitrogen, washed with cold (−70° C.) ethyl formate, and dried in vacuo: yield, 47 g (54%); mp 60-62° C. [lit. Robeson et al., 1955), 62-64° C.]; HPLC, 99.4%: UV λmax 325 (ε 53 000) and 250 nm (ε 5000); 1H NMR in accord with the structure.
Reaction SMILES: F[C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O>C(#N)C>[N:14]1([C:2]2[C:3]([C:10]([F:13])([F:12])[F:11])=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: N#Cc1cccc(F)c1C(F)(F)F
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(N2CCNCC2)c1C(F)(F)F

Procedure:
A solution of 3-fluoro-2-(trifluoromethyl)benzonitrile (1.2 g, 6.3 mmol) and piperazine (0.72 g, 8.4 mmol) in acetonitrile (6 ml) was heated under microwave radiation at 150° C. for 15 minutes. The reaction mixture was poured into water (50 ml) and the aqueous phase was extracted with ethylacetate (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. Purification by flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound: 1.1 g. MS m/z (rel. intensity, 70 eV) 255 (M+, 16), 214 (11), 213 (bp), 171 (8), 151 (7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: C1CCNC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CN2CCCC2)cc1
Yield: 36.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(pyrrolidin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), pyrrolidine (0.076 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.028 g (36%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1.[CH:21](I)([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:7]([O:8][CH:21]([CH3:23])[CH3:22])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1
Reactant: CC(C)I
Reactant: Nc1c(O)c(Cl)cc(F)c1-n1nnn(CCCF)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1c(Cl)cc(F)c(-n2nnn(CCCF)c2=O)c1N

Procedure:
The mixture of 1-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazole (0.30 g), isopropyl iodide (1.2 ml), and potassium carbonate (0.14 g) in acetonitrile (5 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated and purified by a silica gel column, eluted with hexane-ethyl acetate (2:1) to give the desired product (0.29 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.B.C1COCC1>C1COCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A suspension of 4-bromomethylbenzoic acid (5.04 g, 23.3 mmol) in THF (30 mL) was cooled to 0° C. and treated with borane/THF (35 mmol). The ice bath was removed and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The excess borane was quenched first with MeOH, then with water. The reaction mixture was then concentrated in vacuo and redissolved in ethyl acetate. The ethyl acetate layer was washed with 5% HCl, water, NaHCO3, brine, dried (MgSO4), filtered, and evaporated in vacuo to afford 4.44 g (94%) of the titled product.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[C:21]([C:26](C)(C)[O:27][SiH2]C(C)(C)C)[CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[C:21]([CH2:26][OH:27])[CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4c(C(C)(C)O[SiH2]C(C)(C)C)cccc34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4c(CO)cccc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.2 %

Procedure:
In a round-bottomed flask, 2-[7-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (85 mg, 0.14 mmol) was dissolved in THF (0.7 ml) and tetrabutylammonium fluoride (1.0 M in THF, 1.4 ml, 1.4 mmol) was added dropwise. The light brown solution was stirred at room temperature for 10 min then heated at 70° C. for 2.5 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient: 0-10% MeOH). The appropriate fractions were combined and concentrated and the residue was triturated with ethyl acetate containing a few drops of methanol to afford 21 mg (41%) of 2-(7-hydroxymethyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white powder. MS: (M+Na)'=387; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 13.49 (s, 1H), 12.77 (s, 1H), 9.15 (s, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.36 (d, J=3.0 Hz, 1H), 8.01 (s, 1H), 7.38-7.46 (m, 1H), 7.16-7.25 (m, 1H), 5.37 (t, J=5.6 Hz, 1H), 4.88 (d, J=5.6 Hz, 2H), 1.53 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Cl[C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=2)[C:3]1=[O:14]
Reactant: COc1ccnc(Cl)n1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)n1
Temperature: 25 °C
Yield: 13 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (500 mg, 2.497 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-4-(methyloxy)pyrimidine (361 mg, 2.497 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1220 mg, 3.75 mmol), Xantphos™ (108 mg, 0.187 mmol) and tris(dibenzylideneacetone)dipalladium(0) (57.2 mg, 0.062 mmol) and the mixture was heated at reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (×2, 20 ml). The organic layers were combined, washed with water (20 ml) and brine (20 ml), dried over magnesium sulphate and then evaporated in vacuo. The residue was purified by flash-silica gel chromatography eluting with 0-10% methanol in dichloromethane. The fractions containing product were combined and solvent evaporated in vacuo to give a yellow oil. The residue was purified again by flash-silica gel chromatography, eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylate as a yellow oil (100 mg, 13% yield). LC/MS [M+H]+309. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylate (100 mg, 0.324 mmol) in dichloromethane (0.6 ml)/trifluoroacetic acid (0.300 ml) was stirred at room temperature for 24 hours. The solution was evaporated and the residue was co-evaporated with toluene (×3) and then dichloromethane (×4). The product was then dried in a vacuum oven (50° C.) to give crude 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylic acid as a yellow gum (95 mg, ˜0.3 mmol) which was used in the next reaction. LC/MS [M+H]+253.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH2:21][CH:22]([F:24])[F:23])=[N:13][C:12]=2OCC(F)F)[CH2:5][CH2:4]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH2:21][CH:22]([F:24])[F:23])=[N:13][C:12]=2[N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:5][CH2:4]1
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1OCC(F)F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1N1CCOCC1

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-(2,2-difluoroethylamino)-5-nitro-2-(2,2-difluoroethoxy)-nicotinic acid amide (0.40 g, 0.83 mmol), morpholine (87 mg, 1.0 mmol), K2CO3 (170 mg, 1.24 mmol) and 2.5 mL DMSO is irradiated in a microwave apparatus at 100° C. for 30 min. The mixture is poured into water and the precipitate is collected by filtration and dried. Yield 0.34 g
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2].[Na+:22].[Na].[Br:24]Br>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl.C(Cl)(Cl)(Cl)Cl>[C:1]([NH:4][CH:5]=[C:6]([Br:24])[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2].[Na+:22]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)[O-])N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Reactant: BrBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC=C(Br)SC1=C(C(=O)[O-])N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Temperature: 25 °C

Procedure:
Sodium (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg of 52.6% pure material) in water (10 ml) was treated with Aliquat 336 (500 mg) in dichloromethane (10 ml). After separation the aqueous solution was re-extracted with dichloromethane (10 ml) containing Aliquat 336 (500 mg). The dichloromethane extracts were combined, dried (MgSO4) and evaporated in vacuo to leave a mixture of Aliquat 336 and the quaternary ammonium salt corresponding to the starting sodium salt. This mixture was redissolved in dichloromethane (8 ml) cooled to -70° and bromine in carbon tetrachloride (0.50 ml; 100 mg/ml) was added, followed by tiethylamine in dichloromethane (0.30 ml; 100 mg/ml). The mixture was allowed to warm to room temperature, the dichloromethane solution was washed with water (3.5 ml) and extracted with a saturated aqueous solution of NaCl(2×3.5 ml). The sodium chloride extracts were combined and loaded onto a DIAION HP20 column (8×1 cm) and the column eluted with saturated aqueous sodium chloride (10 ml) followed by deionised water. Fractions of the aqueous eluate were monitored by u.v. spectroscopy, and those containing a maximum in absorption at ca 300 nm were combined and evaporated in vacuo to low volume. Ethanol (ca 20 ml) was added and evaporated in vacuo to low volume (5×), on the last evaporation all the solvent was removed. Toluene was added to the residue and evaporated in vacuo (2×) to leave the title compound as a solid (24 mg):λmax (H2O)246(11,300), and 297(8,800 nm). λmax(KBr) 1755, 1680, 1620 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:18])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Product: COc1cc(C(=O)Cl)cc(OC)c1OC

Procedure:
10 g of (0.047 mole) of 3,4,5-trimethoxybenzoic acid are suspended in 120 ml of thionyl chloride and refluxed for 2 hours. The solution is concentrated under reduced pressure. The residual oil crystallizes immediately after the addition of petroleum ether. The crystals are spun and washed with petroleum ether.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:3][CH2:4][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.) suspension of ethyl-benzimidazole-5-carboxylate (4.76 g, 25 mmol) in CH2Cl2 (100 mL) was added a 1 M solution of DIBAL in CH2Cl2 (100 mL) and the mixture was stirred for 4 h. The reaction was quenched by the sequential addition of MeOH (8 mL), 1 M NaOH (16 mL), and 30% sodium potassium tartrate (40 mL). The mixture was warmed to RT and filtered, and the solid residue was washed with CH2Cl2. The filtrate was concentrated in vacuo to afford the title compound as a brown solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:37][C:22]3=[CH:23][C:24]4[C:25](=O)[N:26]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27](=[O:30])[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1.[C:38](O)(=O)C>[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:37][C:22]3=[CH:23][C:24]4[CH2:25][N:26]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27](=[O:30])[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1
Reactant: CC(Cc1cccc(F)c1)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Reactant: CC(=O)O
Agent: [Zn]
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(CCN(C)C)C3=O
Yield: 74 %

Procedure:
Compound 2-(4-(1-(5-fluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.32 g, 2.56 mmol) and zinc powder (4.01 g, 61.32 mmol) were suspended in acetic acid (60 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.85 g, 74% yield. MS: 503.1 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.07 (s, 1H), 11.17 (s, 1H), 11.09-11.05 (m, 1H), 7.97 (s, 0.5H), 7.86 (s, 0.51-1), 7.80 (s, 0.5H), 7.70 (s, 0.5H), 7.30-7.10 (m, 3H), 6.92-6.84 (m, 1H), 6.15-6.11 (m, 1H), 4.54 (s, 2H), 4.18-4.14 (m, 1H), 3.64 (t, 2H, J=6.0 Hz), 3.02-2.97 (m, 2H), 2.53-2.49 (m, 2H), 2.36 (d, 3H, J=3.9 Hz), 2.20 (s, 6H), 1.35-1.33 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]([Cl:19])=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:19].[Cl:19][C:18]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][S:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nsnc1N1CCNCC1
Reaction time: 8 h
Yield: 191.2 %

Procedure:
4-(4-Chloro-[1,2,5]thiadiazol-3-yl)piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 3.28 mmol) was suspended in 10 mL of 4 M HCl in dioxane. The suspension was stirred overnight and the solid material was removed by filtration. The solid was washed three times with 15 mL ethyl acetate and dried under vacuum. 756 mg of white powder was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[C:34]([CH2:35][CH2:36][CH2:37]O)=[C:33]([CH:39]([CH3:41])[CH3:40])[O:32][N:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[C:24]=1[C:30]1[C:34]([CH2:35][CH2:36][CH2:37][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:33]([CH:39]([CH3:40])[CH3:41])[O:32][N:31]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCCCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 90 °C
Yield: 22.1 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (31 mg, 0.11 mmol), 3-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]-1-propanol (35 mg, 0.11 mmol) and triphenylphosphine (29 mg, 0.11 mmol) in dichloromethane (1 mL) was added diisopropyl azodicarboxylate (0.020 mL, 0.11 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes and was then adsorbed onto silica gel and purified by chromatography (silica gel, 0-35% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({3-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]propyl}oxy)phenyl]-2-quinolinecarboxylate (14 mg, 22%). 1H-NMR (400 MHz, CDCl3) δ 8.33 (m, 2H), 8.21 (d, J=8 Hz, 1H), 8.03-7.99 (m, 2H), 7.63 (d, J=9 Hz, 2H), 7.40-7.28 (m, 3H), 6.91 (d, J=9 Hz, 2H), 4.09 (s, 3H), 3.89 (t, J=6 Hz, 2H), 3.19 (septet, J=7 Hz, 1H), 2.51 (t, J=6 Hz, 2H), 1.82-1.76 (m, 2H), 1.33 (d, J=7 Hz, 6H).