Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][S:8][C:9]2[C:19]3[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])[S:5][CH:6]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][C:19]2[C:9]([S:8][CH2:7][C:4]3[S:5][CH:6]=[C:2]([C:28]#[N:29])[CH:3]=3)=[C:10]([Cl:27])[CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3cc(Br)cs3)c2CC1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3cc(C#N)cs3)c2CC1
Temperature: 120 °C
Yield: 52 %

Procedure:
Degas a stirred solution of 6-(4-bromothiophen-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (183 mg, 0.37 mmol), zinc cyanide (50 mg, 0.42 mmol) and tetrakistriphenylphosphine palladium(0) (30 mg, 0.026 mmol) in dry DMF. Purge with dry nitrogen, and heat at 120° C. for 6 h. Dilute with water, extract three times with EtOAc, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-cyanothiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (85 mg, 52%). MS (APCI+) m/z: 335 (M+H−Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (APCI+) m/z: 335 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:9])[CH3:8].Br[Mg][C:12]#[CH:13]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])([C:12]#[CH:13])[CH3:8]
Reactant: CC(=O)c1ccccn1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(pyridin-2-yl)ethan-1-one (6.0 g, 49.53 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of bromo(ethynyl)magnesium (0.5 M in THF, 250 mL, 2.50 equiv) dropwise with stiffing at 0° C. The resulting solution was stirred for 30 min at 0° C. The resulting solution was allowed to react, with stirring, for an additional 18 h at room temperature. The reaction was then quenched by the addition of 50 mL of saturated aqueous NH4Cl. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/hexane (1/10). This resulted in 0.8 g (11%) of 2-(pyridin-2-yl)but-3-yn-2-ol as a off-white solid. 1H-NMR (300 MHz, CDCl3, ppm) δ: 8.534 (d, 1H), 7.800-7.744 (t, 1H), 7.620 (d, 1H), 7.295-7.263 (m, 1H), 5.481-5.300 (br s, 1H), 2.546 (s, 1H), 1.797 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39]C(C)(C)C)[N:34]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(O)=O>O>[O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([C:33]3[NH:34][C:35](=[O:39])[CH:36]=[CH:37][CH:38]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(OC(C)(C)C)n2)cc2cn[nH]c12
Solvent: O=CO
Solvent: O
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(=O)[nH]2)cc2cn[nH]c12
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Solid (±)-1-(6-tert-butoxypyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (previous example) (20.6 mg) was treated with 1 mL formic acid (90%). After 2 h, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water, saturated sodium bicarbonate solution, dried and concentrated. Further drying under high vacuum afforded the product (11.8 mg, 63.4%) as an off-white powder. MS (ESI) [M+H]+=527. HPLC tR=1.68 min.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]1([CH3:15])[CH2:14][CH:13]=[CH:12][O:11]1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].[OH-].[K+]>CCO>[C:1]([NH:4][CH:5]([C:10]1([CH3:15])[CH2:14][CH:13]=[CH:12][O:11]1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(NC(C)=O)C1(C)CC=CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)NC(C(=O)O)C1(C)CC=CO1
Yield: 61.7 %

Procedure:
A 95% EtOH solution (150 mL) of 17 (5.00 g, 23.6 mmol) and KOH (3.00 g, 53.5 mmol) was stirred at room temperature (48 h). The solvent was removed and the residue was dissolved in H2O (50 mL). The aqueous solution was washed with Et2O (3×50 mL) and then acidified to pH 1.5 with 10% H3PO4. The acidified solution was extracted with EtOAc (3×200 mL) and the combined extracts were dried (Na2SO4), and concentrated in vacuo to give 2.90 g (62%) of 18: mp 178°-180° C. (d) (recrystallized from CH3CN); IR (KBr) 3400 (br), 1700 (br) cm-1 ; 1H NMR (DMSO-d6) δ 1.67 (s, CH3), 1.83 (s, C(O)CH3), 6.39 (m, C3H, C4H), 7.59 (s, C5H), 8.34 (s, NH), 12.63 (s, C(O)OH); 13C NMR (DMSO-d6) 22.20 (C(O)CH3), 22.59 (CH3), 57.65 (C(CH3)), 107.09 (C4), 110.49 (C3), 142.33 (C5), 153.36 (C2), 168.86 (C(O)NH), 171.78 (C(O)OH) ppm; mass spectrum, m/e (relative intensity) 198 (M+ +1, 4), 143 (97), 152 (63), 140 (23), 111 (73), 110 (100), 94 (24). Anal. (C9H11NO4) C, H, N.
Reaction SMILES: N.[Li].[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C1C=CC=CC=1.[Na+]>O1CCCC1.C(O)(C)(C)C>[CH2:14]1[C:10]2[CH2:11][CH2:12][C:13]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH2:8][C:9]=2[CH2:17][CH:16]=[CH:15]1
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Agent: N
Agent: O=C([O-])c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C1=CCC2=C(C1)CCc1ccccc1C2
Reaction time: 0.03 h

Procedure:
A mixture, stirred at -40°, of 1.28 l of dry tetrahydrofuran and 2.1 l of dry liquid ammonia is treated with 8.6 g of lithium wire. The mixture is stirred for 2 minutes and subsequently there is added thereto over a period of 6 minutes a solution, pre-cooled to -40°, of 80.0 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 1.44 l of dry tetrahydrofuran and 280 g of t-butanol. After a color change from blue to colorless, the mixture is treated with 6.0 g of sodium benzoate and the ammonia is evaporated. The mixture is washed three times with 500 ml of water each time. The combined aqueous washings are extracted twice with 1.0 l of ether each time. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The oily residue is purified by fractional crystallization from petroleum ether (low-boiling) at -25°. There is obtained 1,4,10,11-tetrahydro-5H-dibenzo[a,d]cycloheptene as white crystals of melting point 42.5-43°.
Reaction SMILES: [NH2:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](F)=[O:34])=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1.C(OCC)(=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[C:33](=[O:34])[NH:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)F
Reactant: CCOC1OC(=O)C=C1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
To a solution of 4-amino-5-ethoxy-5H-furan-2-one (0.08 g, 0.58 mmol) in tetrahydrofuran (10 mL) at −78° C. under nitrogen was dropwise added a solution of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.64 mL, 0.64 mmol). The reaction was stirred 3 h at 0° C. A solution of 2-fluorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.77 mmol) in tetrahydrofuran (3 mL) was added dropwise. The reaction was stirred for 16 h at room temperature. The mixture was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 35:65 ethyl acetate:hexanes afforded (R )-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.05 g, 26% yield). Also isolated was starting 4-amino-5-ethoxy-5H-furan-2-one (0.03 g, 36% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[CH3:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCc2ccccc2)ccc([N+](=O)[O-])c1F
Temperature: 100 °C
Yield: 33.3 %

Procedure:
1,3-Difluoro-2-methyl-4-nitro-benzene (16 g, 0.092 mol), benzyl alcohol (10 g, 0.092 mol) and K2CO3 (25.3 g, 0.18 mol), were combined in DMF (300 mL) and heated to 100° C. overnight. The mixture was poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography to give 1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.04 (t, J=8.8 Hz, 1 H), 7.30-7.46 (m, 5 H), 7.08 (d, J=9.2 Hz, 1 H), 5.28 (s, 2 H), 2.13 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:24])([F:25])[F:23])(=[O:21])=[O:20])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)sulfonyl]phenyl}propan-1-ol (260 mg, 0.69 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (130 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxybenzotriazdle hydrate (105 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (252 mg, 67%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][C:6]1([CH3:12])[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1>C1COCC1>[CH3:5][C:6]1([CH3:12])[CH2:10][CH2:9][C:8]([CH:1]=[CH2:2])([OH:11])[CH2:7]1
Reactant: CC1(C)CCC(=O)C1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC1(O)CCC(C)(C)C1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
The reactor was charged with vinylmagnesium bromide (0.6M in THF, 245 ml, 147 mmol) and the solution was cooled to 5-10° C. 3,3-Dimethylcyclopentanone (2a, 15.0 g, 134 mmol) in THF (50 ml) was added over 10 minutes while keeping the temperature of the reaction mixture between 5-10° C. by means of an ice bath. The mixture was stirred for 30 minutes, then quenched with 10% AcOH (150 ml) and extracted with hexane (2×100 ml). The combined organic phases were washed with water, dried (MgSO4), concentrated and distilled bulb-to-bulb to afford 3a (14.3 g, 76% yield) as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([O:31]COC)=[CH:27][CH:26]=2)=[C:16](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)\[CH2:17][CH3:18])=[CH:9][CH:8]=1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O.O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:35])/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:16](/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)\[CH2:17][CH3:18])=[CH:11][CH:12]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(OCCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC/C(=C(\C(=O)Nc1ccc(OCCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 6b (55 mg, 0.113 mmol) in MeOH (0.5 ml) was added 3N HCl in AcOEt (0.5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 h. A solution of NaHCO3 (139 mg) in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt and a little MeOH. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 7b (76%). 7b: colorless powder; 1H-NMR (CD3OD) δ 0.97 (3H, t, J=7.4 Hz), 1.99 (2H, m), 2.35 (6H, s), 2.59-2.66 (4H, m), 4.02 (2H, t, J=6.1 Hz), 6.51 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=9.2 Hz), 6.92 (2H, d, J=8.8 Hz), 7.12-7.23 (5H, m), 7.50 (2H, d, J=9.2 Hz). HRMS calcd for C28H33N2O3 [M+H]+: 445.2491. Found: 445.2507.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:32]#[N:33])=[C:25]([CH:31]=1)[O:26][CH2:27][CH:28]1[O:30][CH2:29]1>C(O)(C)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:32]#[N:33])=[C:25]([CH:31]=1)[O:26][CH2:27][CH:28]([OH:30])[CH2:29][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(N)CNc1ccc(C2=NNC(=O)CC2)cc1
Reactant: N#Cc1ccc(Cl)cc1OCC1CO1
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)COc1cc(Cl)ccc1C#N
Reaction time: 20 h
Yield: 87.4 %

Procedure:
5.2 g of 6-[4-(2-amino-2-methylpropylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone obtained in Example 1, (3) and 4.4 g of 1-(5-chloro-2-cyanophenoxy)2,3-epoxypropane were dissolved in 30 ml of isopropyl alcohol, and the solution was heated with stirring for 20 hours. The solution was then worked up as in Example 1, (5) to give 8.2 g of 6-[4-[2-[3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropylamino]pheyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([O:26]C)=O)=[CH:23][C:17]=4[N:16]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[CH3:34][NH2:35]>CCO>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH:35][CH3:34])=[O:26])=[CH:23][C:17]=4[N:16]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2[nH]c(C3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)nc2c1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1ccc2[nH]c(C3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)nc2c1

Procedure:
A solution of methyl 2-[1-(biphenyl-4-ylcarbonyl)piperidin-4-yl]-1H-benzimidazole-5-carboxylate (30 mg, 0.068 mmol) in 2M methylamine in EtOH (1 mL) is heated in at 50° C. for 18 h. The reaction is concentrated under reduced pressure and purified by preparative HPLC to give 13 mg of 2-[1-(biphenyl-4-ylcarbonyl)piperidin-4-yl]-N-methyl-1H-benzimidazole-5-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8].C(N(CC)CC)C.[C:22]1([CH3:31])[C:23]([C:28](Cl)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:31])=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8]
Reactant: CCCOC(=O)c1cc(N)ccc1Cl
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)c1cc(NC(=O)c2ccccc2C)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A solution of propyl 5-amino-2-chlorobenzoate (10.7 g, 0.050 mole) and triethylamine (6 g, 0.059 mole) in methylene chloride (50 ml) was added dropwise over 1 hour to an ice-cooled solution of o-toluoyl chloride (7.8 g, 0.50 mole) in methylene chloride (50 ml). The mixture was then stirred at room temperature for 3 hours and worked up by washing sequentially with water, dilute hydrochloric acid, water, 2% aqueous sodium hydroxide and water. The residue from evaporation of the methylene chloride was recrystallized from ethanol (100 ml) to give the title compound, m.p. 103°-105° C. (7.5 g, 45% yield).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[NH2:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1ccco1
Reaction time: 2 h

Procedure:
0.082 mL of triethylamine, 44 mg of 2-furoyl chloride and 2.0 mL of methylene chloride were added to 1.0 mL of methylene chloride solution containing 50 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 2 hours. 380 mg of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(furan-2-carboxamido)-4-phenethylbenzoate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[N-:11]=[N+:12]=[N-:13].[Na+]>>[N:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCBr
Agent: [Na+]
Product: COC(=O)CCCCCN=[N+]=[N-]

Procedure:
Methyl 6-bromohexanoate was reacted with sodium azide to give methyl 6-azidohexanoate, then converted to the corresponding hydrazide using hydrazine hydrate. The linker compound 6-azidohexanehydrazide was conjugated with DOX hydrochloride in dry methanol, with a drop of acetic acid, forming the desired DOX-azide compound. The one-pot method polymerization/click method shown in the scheme was used to synthesize the new DOX-polyMPC copolymer. The polymer was characterized with NMR spectroscopy and GPC, while drug weight percent was measured using a UV method.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.II.CN([CH:16]=[O:17])C.Cl>C1COCC1.O>[CH:16]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)=[O:17]
Reactant: CN(C)C=O
Reactant: Brc1ccc2occc2c1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2occc2c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 539.3 %

Procedure:
A mixture of 5-bromo-1-benzofuran (0.5 g), Mg (0.92 g, 0.038 mol), I2 (1 crystal) in dry THF (2.5 mL) under N2 atmosphere was refluxed for 30 min. To this was added a solution of 5-bromo-1-benzofuran (4.5 g) in 25 mL of dry THF) as soon as the 12 color disappear and refluxed for another 2 h. The reaction mixture was then cooled to −40° C. and added dry DMF (3.6 g) drop-wise and slowly warmed to RT for a period of 12 h. The reaction mixture was then cooled to 0° C. and acidified with 3N HCl to pH=2 and stirred for 30 min. The reaction mixture was then diluted with water (500 mL), extracted with ethylacetate (2×200 mL), washed with brine and dried. The solvent was removed under vacuum and purified by column chromatography over silica gel (pet. ether/CH2Cl2) to give 5-formyl-1-benzofuran (2 g, 54%) as a liquid. LC-MS: M/Z ESI: 1.47 min, 147.34 (M+1).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1.[CH:19]([O-])=[O:20].[Na+].[C]=O>CN(C)C=O.O>[CH:19]([C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1)=[O:20]
Reactant: O=C[O-]
Reactant: Cc1cc(Br)ccc1C(=O)NCc1ccccn1
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=O)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C
Yield: 30 %

Procedure:
In a solution of 2.0 g of 4-bromo-2-methyl-N-(2-pyridylmethyl) benzoic acid amide in 20 ml of N,N-dimethylformamide in an autoclave, 0.67 g of sodium formate and 0.10 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under 1.05 MPa carbon monoxide atmosphere at 110° C. for 3 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and poured in 100 ml of water, and extracted with ethyl acetate (50 ml ×2). The organic phases together were dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (9:1), and 0.50 g of the aimed product was obtained as pale yellow crystal.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:19][CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:11].[SH:21][C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[S:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:19][CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:11]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1ncccc1NC(=O)CCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncccc1NC(=O)CCCCCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a DMF (5 ml) solution of this amide (90 mg, 0.25 mmol) and 2-mercaptobenzoxazole (38 mg, 0.25 mmol) were added potassium carbonate (42 mg, 0.30 mmol) and 18-crown-6 (7 mg, 0.03 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was recrystallized from a mixture of ethyl acetate-hexane to obtain 83 mg (yield 77%) of the desired compound as a colorless powdery crystal.