Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NCCC1C=CC(O)=C([OH:22])C=1.CN(C1C=CC=CN=1)C>O1CCCC1.CCCCCC.C1C=CC=CC=1>[CH:10]1([NH:9][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
DHA is first converted to DHA anhydride in the presence of dicyclohexyl carbodiimide. This is then reacted with dopamine in the presence of dimethylaminopyridine as the acid acceptor in tetrahydrofuran. In a typical experiment 300 mg of DHA (0.009 M) was dissolved in a mixture of 3 ml hexane and 4 ml benzene and stirred under nitrogen. Next, a solution of 0.00615 M of dicyclohexyl carbodiimide in 4 ml benzene (0.1267 g) was stirred together with the DHA for 3 hr at room temperature. A white precipitate of dicyclohexyl urea formed as the reaction proceeded. The dicyclohexyl urea was filtered off to give a clear solution of the anhydride in benzene. This was concentrated down to 2 ml in a rotary evaporator and diluted with 10 ml of tetrahydrofuran (dry). The freshly prepared anhydride was then added to a solution of dopamine hydrobromide (0.1053 g) (or 0.005 M) in the presence of 0.009 M of diethylaminopyridine (0.098 g). The initially cloudy mixture after stirring for 30 min at room temperature gave a mixture of a clear liquid and a brown precipitate. At the end of the reaction, 0.2 ml of water was added to the mixture, and stirring was continued for an additional 30 min to completely hydrolyze any remaining unreacted anhydride. The liquid phase was isolated and evaporated to dryness to yield a brown viscous solid. This was then dissolved in 70% ethanol in water (25 ml), and the solution was then passed through a mixed-bed ion exchange resin containing a strong acidic resin based on polystyrene sulfonic acid and a strong basic resin based on quanternary ammonium substituents such as tetramethyl amonimum hydroxide (RG501, Fisher Scientific, Cambridge, Mass.) using 90% ethanol in water as the eluent. This resin removes from the mixture unreacted dopamine, dimethylaminopyridine, as well as the liberated DHA molecule. The effluent from the column (a pale yellow solution) was then evaporated in a rotary evaporator to give a solid. The product was recrystallized from aqueous ethanol (yield=75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[Cl:20]N1C(=O)CCC1=O>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[C:5]2[Cl:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCN(C(=O)c2cc3cc(Br)ccc3[nH]2)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CCN(C(=O)c2[nH]c3ccc(Br)cc3c2Cl)CC1
Reaction time: 18 h
Yield: 58.2 %

Procedure:
(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 3, 0.27 g) in dichloromethane (3 mL) at ambient temperature was treated with N-chlorosuccinimide (0.103 g) and stirred for 18 h. The reaction mixture was diluted with ether, washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.16 g). 1H NMR (400 MHz, CDCl3): δ 2.35 (3H), 2.52 (4H), 3.78 (4H), 7.23 (1H), 7.35 (1H), 7.74 (1H), 9.84 (1H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:12][C:13]([CH3:15])=[O:14].[OH-].[Na+].[C:18](O)(=O)C>C(O)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:12][C:13](=[O:14])[CH:15]=[CH2:18])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CC(=O)C=Cc1ccc(C(=O)O)cc1

Procedure:
The starting material, 1,5-bis(p-carboxyphenyl-1,4-pentadien-3-one is prepared by the reaction of two moles of p-carboxybenzaldehyde and one mole of acetone in ethanol solution in the presence of 3 mols of 10 normal sodium hydroxide. Acidification with acetic acid gives the desired intermediate melting at 370°-375° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[O:40]1CCC[CH2:41]1>CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:41]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:40])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: C1CCOC1
Reactant: C1COCCN1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: CN(C)c1ccncc1
Product: COc1cc(OC(=O)N2CCOCC2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 153 mg, 0.340 mmol), 1,1′-carbonyldiimiazole (95.6 mg, 0.590 mmol), and 4-dimethylaminopyridine (5.2 mg, 0.043 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and stirred for 1 hour at room temperature. After morpholine (58.3 μL, 0.666 mmol) was added to the reaction mixture and the mixture was stirred for 2 hour, the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (61.2 mg) as a colorless solid. (Yield 32%)
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13]1[CH2:23]CN2C(=NCCC2)C[CH2:14]1.C(Br)C=C>CN(C=O)C>[CH2:23]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH:13]=[CH2:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCON1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a cooled solution (5 to 10° C.) of N-hydroxyphthalimide (53.80 g, 0.33 mol) in DMF (120 mL), was added DBU (46.36 mL, 0.31 mol) was added in one portion, with stirring. After 10 minutes, allyl bromide (25.96 mL, 0.30 mol) was added in portions. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour, until the color turned from dark burgundy to yellow. Ethyl acetate (300 mL) and water (150 mL) were added, the aqueous phase was separated, and the organic phase was washed with water (4×50 mL). The combined aqueous extracts were back-extracted with EtOAc (3×50 mL) and the total EtOAc solution was washed with saturated NaHCO3 (10×50 mL) until the aqueous phase was pale yellow, then with brine (2×75 mL) and dried over anhydrous MgSO4. Removal of the solvent afforded 58.83 g (96% yield) of the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: COc1ccc(B(O)O)cc1
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3)cccc2c1N
Yield: 70.2 %

Procedure:
Using method F, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.50 mmol) and 4-methoxyphenylboronic acid (303 mg, 2.00 mmol) were reacted (reflux 14 hours) to afford the title compound (118 mg, 70% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.58 (bm, 1H), 7.69-7.83 (m, 3H), 7.62 (d, J=8.9 Hz, 2H), 7.05 (d, J=8.9 Hz, 2H), 3.87 (s, 3 H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.65 (apparent sextet, J=7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=337 (M+H) HPLC 1.71 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:21]4[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)[C:19]#[N:20])[CH:16]=3)[N:11]=[C:10]([NH:28][NH2:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C1COCC1.[N:36]([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:21]4[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)[C:19]#[N:20])[CH:16]=3)[N:11]3[N:36]=[N:29][N:28]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(c1ccc(I)cc1)c1ccc2nc(NN)nc(-c3cccc(Cl)c3)c2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 5 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Intermediate (41) (0.0121 mol) was added at 5° C. to a mixture of HCl 1N (60 ml) and THF (60 ml). A solution of sodium nitrite (0.0133 mol) in water (20 ml) was added dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour then brought to room temperature, stirred at room temperature for 5 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc; 70/30; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 3.8 g (60%) which were crystallized from 2-propanone/CH3CN. The precipitate was filtered off and dried till dryness, yielding 3.5 g (55%) of 5-(3-chlorophenyl)-α-(4-iodophenyl)-tetrazolo[1,5-α]quinazoline-7-acetonitrile (intermediate 42).
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:32]>CO>[ClH:32].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-tetradecylpropane (1.25 g) was dissolved in 100 ml of methanol and 19.4 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane=1:1 in order to give 791 mg of 2-amino-2-tetradecyl-1,3-propanediol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[OH:25][C@@H:26]([CH2:30][C:31]1[NH:35][CH:34]=[N:33][CH:32]=1)[C:27](O)=[O:28].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[OH:25][C@@H:26]([CH2:30][C:31]1[NH:35][CH:34]=[N:33][CH:32]=1)[C:27]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:28]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: O=C(O)[C@@H](O)Cc1cnc[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)[C@@H](O)Cc4cnc[nH]4)CC3)nc(-c3ccccc3O)nc2c1

Procedure:
2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (87 mg, 0.27 mmol), (S)-2-hydroxy-3-(1H-imidazol-5-yl)propanoic acid (64 mg, 0.41 mmol), triethylamine (76 μL, 0.54 mmol), and BOP (180 mg, 0.41 mmol) in 1 mL of CH2Cl2 were stirred at room temperature for 1.5 h. The reaction mixture was diluted with H2O and CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification using 1-15% MeOH in CH2Cl2 gave (S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(1H-imidazol-5-yl)propan-1-one. LC/MS: m/z 459.3 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:29][NH2:30]>N1C=CC=CC=1>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH:25]([CH3:26])[CH3:27])=[CH:22][CH:21]=3)[NH:30][N:29]=2)[CH:11]=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[C:9]=1[OH:16])([CH3:18])([CH3:19])[CH3:20]
Reactant: NN
Reactant: CC(C)c1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)c1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1

Procedure:
A solution of 4-(2-chloro-6-isopropylnicotinoyl)-2,6-di-tertiary butylphenol and hydrazine hydrate in pyridine is refluxed. After the pyridine is distilled off, to the residue is added water. The resulting crystals are recrystallized from ethanol to give 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-6-isopropyl-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>O>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:15][C:12]1[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: Oc1ccc(OCc2ccccc2)nc1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To an ice-cold solution of 0.5 g (2.48 mmol) 6-benzyloxy-3-hydroxypyridine (commercially available) in 5 mL tetrahydrofuran 0.12 g (2.7 mmol) sodium hydride (55% dispersion in mineral oil) was added in portions. After the vigorous gas evolution had ceased the reaction mixture was stirred for another 20 min., then 0.44 mL (3.0 mmol) ethyl-alpha-bromoisobutyrate (commercially available) were added dropwise. The light brown suspension was stirred for 23 h at room temperature and then poured into water. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and filtered. Silica gel was added to the filtrate and the slurry evaporated. The resulting solid is purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 70:30) to give the product as a colorless oil (38%). MS (Turbo Spray): m/z=316.1 [M+H].
Reaction SMILES: [CH3:1][C:2]([S:9][S:10][CH3:11])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[N:32]1([CH2:38][CH2:39][O:40][C:41]2[CH:46]=[C:45]([CH2:47][OH:48])[N:44]=[C:43]([CH2:49][OH:50])[CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C=O)C>[CH3:8][C:2]([S:9][S:10][CH3:11])([CH3:1])[CH2:3][CH2:4][C:5]([N:35]1[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][O:40][C:41]2[CH:46]=[C:45]([CH2:47][OH:48])[N:44]=[C:43]([CH2:49][OH:50])[CH:42]=2)[CH2:33][CH2:34]1)=[O:7]
Reactant: CSSC(C)(C)CCC(=O)O
Reactant: OCc1cc(OCCN2CCNCC2)cc(CO)n1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CSSC(C)(C)CCC(=O)N1CCN(CCOc2cc(CO)nc(CO)c2)CC1
Reaction time: 15 h
Yield: 39.2 %

Procedure:
344 μL of TEA and then, after stirring for 10 min, 748 mg of 4-methyl-4-(methyldisulphanyl)pentanoic acid, 417 μl of diisopropylcarbodiimide and 69 mg of 1-hydroxybenzotriazole hydrate are added to 600 mg of 4-[2-(piperazin-1-yl)ethoxy]-2,6-bis(hydroxymethyl)pyridine in solution in 12 ml of DMF. After 15 h at AT, the mixture is concentrated under RP, 15 ml of water are added and extraction is carried out 2× with AcOEt. The combined organic phases are dried over MgSO4 and concentrated under RP, and the residue is purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-80 g) using a gradient from 2 to 10% of MeOH in DCM. 390 mg of 4-(2-[4-(4-methyl-4-(methyldisulphanyl)pentanoyl)piperazin-1-yl]ethoxy)-2,6-bis(hydroxymethyl)pyridine are thus obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Reaction time: 0.25 h
Yield: 192.2 %

Procedure:
Bis(4-bromophenyl)amine (4.0 g, 12.3 mmol) and phenylboronic acid (4.0 g, 32.7 mmol) were mixed in 250 mL of toluene and 60 mL of ethanol. The solution was bubbled with nitrogen while stirring for 15 minutes. Pd(PPh3)4 (1.4 g, 1.23 mmol) and K3PO4 (13.5 g, 64 mmol) were added in sequence. The mixture was heated to reflux overnight under nitrogen. After cooling, the reaction mixture was filtered through filter paper and the solvent was then evaporated. The solid was redissolved in nitrogen-purged hot toluene and was filtered through a Celite®/silica pad when the solution was still hot. The solvent was then evaporated. The white crystalline solid was washed by hexane and air dried to obtain 3.8 g of product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:32]([F:42])[CH:31]=3)[O:27][N:26]=2)=[CH:21][CH:20]=1>CN(C)C=O>[F:42][C:32]1[CH:31]=[C:30]([C:28]2[O:27][N:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])=[CH:20][CH:21]=3)[N:29]=2)[CH:35]=[CH:34][C:33]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OCCNCCO
Reactant: Fc1cc(-c2nc(-c3ccc(CCl)cc3)no2)ccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCCN(CCO)Cc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Temperature: 90 °C

Procedure:
Diisopropylethylamine (23.5 mL, 0.136 mol) and diethanolamine (14.2 g, 0.135 mol) are added to a stirred solution of 3-(4-chloromethylphenyl)-5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole (33 g, 0.090 mol) in N,N-dimethyl-formamide (200 mL). The reaction mixture is heated at 90° C. for 2.5 hrs, the solvent is removed under reduced pressure and the residue is treated with demineralized water (200 mL) to get a solid which is filtered and washed with n-hexane (150 mL) and diethyl ether (100 mL) to furnish 2-[{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}(2-hydroxyethyl)amino]ethanol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)=O.[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:34][CH2:35][OH:36])[CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[S:33])[NH2:32])[CH2:27][CH2:26]1>>[OH:36][CH2:35][CH2:34][N:24]([CH:25]1[CH2:26][CH2:27][N:28]([C:31]2[S:33][CH:2]=[C:3]([C:5]3[CH:14]=[CH:13][C:12]4[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=4[CH:6]=3)[N:32]=2)[CH2:29][CH2:30]1)[CH2:23][CH2:22][CH2:21][CH2:20][OH:19]
Reactant: NC(=S)N1CCC(N(CCO)CCCCO)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N(CCO)CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 800 mg (1.01 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 452 mg (1.01 mmol) of 4-[(4-hydroxybutyl)-(2-hydroxyethyl)amino]-piperidine-1-carbothioic acid amide from step d. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:8][C:7]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ncccc2Br)cc1
Temperature: 80 °C

Procedure:
In a 2-5 mL Smith Process Vial, 2,3-dibromopyridine (300.0 mg, 1.266 mmol), 4-fluorophenyl boronic acid (177.2 mg, 1.266 mmol, 1 equiv) and Pd(PPh3)4 (73.2 mg, 0.063 mmol, 0.05 equiv) were placed. The mixture was suspended in 1,4-dioxane (3 mL) and 2M-Na2CO3 (1 mL) under a nitrogen atmosphere. The mixture was heated at 80° C. for 10 min using the microwave reactor. To the mixture were added EtOAc (70 mL) and water (30 mL). The whole was filtered through Celite (3 g) and the filtrate was washed with brine (30 mL), dried over Na2SO4 and concentrated under a reduced pressure. Obtained crude material was purified by Gilson preparative HPLC to give 3-bromo-2-(4-fluorophenyl)pyridine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17](I)[C:16]([Cl:20])=[C:15]([O:21][CH2:22][CH3:23])[N:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(OC(C)(C)C)(=O)C=C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:16]1[CH:17]=[CH:18][C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:24]=2)=[O:12])=[N:14][C:15]=1[O:21][CH2:22][CH3:23]
Reactant: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(I)c1Cl
Agent: [Pd+2]
Agent: C=CC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)ccc1Cl
Temperature: 100 °C
Yield: 10.8 %

Procedure:
This material obtained from step A (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (0.1 mL) followed by addition of t-butyl acrylate (25 mg, 0.2 mmol), (Tol)3P (6 mg, 0.02 mmol), palladium(II) acetate (2 mg, 0.01 mmol), and triethylamine (20 mg, 0.2 mmol). The mixture was heated to 100° C. for 2 h, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, drived over Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% ethyl acetate to provide the title compound (4 mg, 10%). 1H NMR (500 MHz, DMSO-d6) δ 9.29 (t, J=6.0 Hz, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 4.60 (d, J=7.0 Hz, 2H), 4.59 (q, J=7.0 Hz, 2H), 3.18 (s, 3H), and 1.38 (d, J=7.0, 3H). MS (m/e) positive mode: 369, 71 (3:1, M+H)+.