Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6]([O:32][CH3:33])=[CH:7][C:8]2[C:9]([CH:31]=1)=[N:10][C:11]1[N:12]=[CH:13][C:14]([C:29]#[N:30])=[C:15]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=3[Cl:28])[C:16]=1[CH:17]=2.[I].[Na].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:28][C:20]1[CH:21]=[C:22]([Cl:27])[C:23]([O:25][CH3:26])=[CH:24][C:19]=1[NH:18][C:15]1[C:16]2[CH:17]=[C:8]3[CH:7]=[C:6]([O:32][CH3:33])[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][C:9]3=[N:10][C:11]=2[N:12]=[CH:13][C:14]=1[C:29]#[N:30]
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3nc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Agent: [I]
Agent: [Na]
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl
Yield: 47 %

Procedure:
A mixture of 8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile (202 mg, 0.40 mmol) and sodium iodine (70 mg, 0.47 mmol) in 4 mL of morpholine is heated at reflux for 2 hours. The reaction mixture is concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Ethyl acetate is added to the residue and the orange solid is collected by filtration to provide 105 mg (47%) of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile, mp 242–244° C. dec. MS 553.8, 555.8 (M+H)+ Analysis for C27H25Cl2N5O4 Calcd: C, 58.49; H, 4.54; N, 12.63. Found: C, 58.41; H, 4.23; N, 12.48.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:31][CH:32](Br)[CH2:33][CH3:34])(=[O:30])[CH2:28][CH3:29].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:32]([O:31][C:27](=[O:30])[CH2:28][CH3:29])[CH2:33][CH3:34])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(=O)OC(Br)CC
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Product: CCC(=O)OC(CC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer) was reacted with 1-bromopropyl propionate in the presence of sodium iodide to give 1-propionyloxypropyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 100°-108° C. (decompn.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[CH3:16])=[O:4].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[CH3:16])=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc2c(cc1C)[C@@H](N)CCS2
Product: COC(=O)c1cc2c(cc1C)[C@@H](NC(=O)OCc1ccccc1)CCS2

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using (S)-4-amino-6-methylthiochromane-7-carboxylic acid methyl ester (1.20 g) and benzyloxycarbonyl chloride (0.87 ml), the objective (S)-4-(benzyloxycarbonylamino)-6-methylthiochromane-7-carboxylic acid methyl ester (1.74 g) was obtained as colorless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:21])(=[O:20])=[O:19].[CH3:22][S-:23].[Na+]>O1CCOCC1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:23][CH3:22])=[C:3]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:4]=2)=[O:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(N)(=O)=O)c2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2ccc(SC)c(S(N)(=O)=O)c2)cc1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.15 g, 0.48 mmol) dissolved in dioxane (3 mL) is added sodium thiomethoxide (0.041 g, 0.57 mmol). The reaction mixture is heated at 90° C. for 4 h and then cooled to room temperature and concentrated in vacuo. The residue is partitioned between water and methylene chloride, and the aqueous phase is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) gives 0.11 g (68%) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.4 (d, J=2 Hz, 1H), 7.90 (dd, J=8, 2 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.50 (d, J=8 Hz, 1H), 7.00 (d, J=9 Hz, 2H), 5.20 (s, 2H), 3.90 (s, 3H), 2.65 (s, 31-1). Analytics calculated for C15H75NO4S2: C, 53.04; H, 4.48; N, 4.15. Found: C, 52.67; H, 4.57; N, 4.08. MS (m/z): 336 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[C:19](OS(C(F)(F)F)(=O)=O)=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][N:41]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[C:19]([C:37]4[S:38][CH:39]=[CH:40][N:41]=4)=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CCc2cccnc2OS(=O)(=O)C(F)(F)F)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ncccc1CN1CCC(CCc2cccnc2-c2nccs2)CC1
Yield: 30.3 %

Procedure:
150 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[2-[((trifluoromethyl)sulfonyl]oxy]-3-pyridyl]ethyl]piperidine, 180 mg of 2-(tributylstannyl)thiazole and 20 mg of tetrakis(triphenylphosphine)palladium were suspended in 4 ml of toluene, and the mixture was heated under reflux for 2 hours under nitrogen flow. The solvent was evaporated, and the residue was purified by NH form silica gel column chromatography (ethyl acetate:hexane=1:4), to give 39 mg of the title compound as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][O:18][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[CH:17][O:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: c1ccc(COc2ccc(-c3cocn3)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(-c2cocn2)cc1
Reaction time: 1.33 h
Yield: 45.5 %

Procedure:
4-(4-Benzyloxyphenyl)oxazole (360mg) was dissolved in methanol (10 ml). 5% Palladium on carbon (containing 50% water) (300 mg) was added to the solution, and the mixture was subjected to catalytic reduction for 80 minutes. The catalyst was filtered off from the reaction mixture, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel [eluting solvent: ethyl acetate-hexane (1:2)] to give 4-(4-hydroxyphenyl)oxazole (105 mg, 45.5%). The product was further purified by recrystallization from diethyl ether-hexane. m.p. 147.5°-148° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=2)([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Cl:20][C:16]1[N:15]=[C:14]([O:13][C:10]([CH3:12])([CH3:11])[C:9]([NH:8][C:3]2[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(Oc1cccc(Cl)n1)C(=O)Nc1ncccc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(Oc1cccc(Cl)n1)C(=O)Nc1ncccc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 4.2 %

Procedure:
To a solution of N-(3-Amino-pyridin-2-yl)-2-(6-chloro-pyridin-2-yloxy)-2-methyl-propionamide (0.15 g, 4.9 mmol) and pyridine (0.042 g, 5.3 mmol) in DCM (5 ml) at 0° C. was added Methane sulfonyl chloride (0.06 g, 0.04 ml, 5.3 mmol) drop wise over a period of 5 min. The reaction mixture was stirred for 1 h. The reaction mixture was quenched with water (2 ml) extracted in DCM (20 ml), washed with brine (5 ml), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude material thus obtained was purified by flash column affording 2-(6-Chloro-pyridin-2-yloxy)-N-(3-methanesulfonylamino-pyridin-2-yl)-2-methyl-propionamide (0.08 g, 5%). 1H NMR (400 MHz, CDCl3): δ 1.790 (s, 6H), 2.87 (s, 3H), 6.67 (t, 1H, J=8 Hz), 6.78 (d, 11-1, J=8 Hz), 6.91 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz), 7.57 (t, 1H, J=8 Hz), 8.69 (d, 1H, J=8 Hz), 9.11 (brs, 1H). MS (EI) m/z: 385 (M+1).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.N1CCCC(C(OCC)=O)C1.[S:31]1C=CC=C1C(Cl)=O>>[S:31]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:8]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(=O)c2cccs2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl nipecotate (202.9 mg; 1.29 mmol) and commercially available 2-thiophenecarbonyl chloride (138 μl; 1.29 mmol). The crude product was distilled at 225° C./0.1 torr, giving ethyl (2-thiophenecarbonyl)-3-piperidinecarboxylate (249.8 mg) as a yellow oil. MS m/z (positive ion) 290 (M+Na+; 40), 268 (MH+; 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11](N)=[CH:10][CH:9]=1.N(OC(C)(C)C)=[O:16].CCCCC>COCCOC.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=1
Reactant: Nc1ccc(-c2ccccc2F)nc1
Reactant: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCCCC
Product: Oc1ccc(-c2ccccc2F)nc1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
3.3 ml (26.6 mmol) of boron trifluoride diethylether complex were cooled to −15° C. Then 2.5 g (13.3 mmol) of 6-(2-fluoro-phenyl)-pyridin-3-ylamine in 5 ml of DME and, subsequently, 1.9 ml (15.9 mmol) of tert-butyl nitrite were added dropwise. Shortly after, a thick precipitate formed. The mixture was diluted with 8 ml of DME and 8 ml of dichloromethane and stirred in an ice bath for 2 h. After addition of 50 ml of pentane, the precipitate was filtered off, dried, and stirred in 50 ml of acetic anhydride at 100° C. for 1 h. After concentration, a sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated. The residue was purified by chromatography (silica gel, n-heptane/ethyl acetate 5:1). The obtained product was stirred with a 15% aqueous potassium hydroxide solution and few methanol in an ice bath and subsequently for 2 h at room temperature. After neutralization with 2 N hydrochloric acid, the mixture was extracted with ethyl acetate, and the combined extracts were dried and evaporated. Yield: 871 mg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]=1[O:26]C)[C:6]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=2[S:10](=[O:22])(=[O:21])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:28]([F:31])([F:29])[F:30])[C:25]=1[OH:26])[C:6]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=2[S:10](=[O:21])(=[O:22])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccc(C(F)(F)F)cc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccc(C(F)(F)F)cc32)cc(C(F)(F)F)c1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole (459 mg) was dissolved in N,N-dimethylformamide (4.5 mL), and lithium chloride (169 mg) was added to the solution, and then the mixture was stirred at 70° C. for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (411 mg) as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
A solution of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (compound 1.1; 1.0 mmol, prepared according to the procedure of Hah, J. M. et. al J. Med. Chem 46, 2003, 1661) and triethylamine (“TEA”; 3.0 equivalents) in anhydrous tetrahydrofuran (“THF”; 5.0 mL) is treated with the dropwise addition of benzoyl chloride (1.1 equivalents) at 0° C. After completion of the reaction, the mixture is partitioned between water and diethyl ether. The organic layer is separated, washed with 1.0 N HCl, saturated sodium bicarbonate, brine and dried. Purification by flash column chromatography on silica gel provides [2-(4-benzoylamino-phenyl)-ethyl]-carbamic acid tert-butyl ester (compound 1.2).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5]([C:20]([OH:22])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Cl)[C:13]=2[Cl:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CN(C=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5]([C:20]([OH:22])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1Cl
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1ccccc1Cl

Procedure:
(--2,6-dimethyl-3-carbomethoxy-4-(2,3-dichlorophenyl)-5-carboxy-1,4-dihydropyridine, mp=225° C., [α]D20 =-28.5°, c=5, DMF;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][C:22]3[CH:27]=[C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=[CH:24][C:23]=3[NH:33]C(=O)OC(C)(C)C)=[O:20])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:33][C:23]1[CH:24]=[CH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:27][C:22]=1[NH:21][C:19](=[O:20])/[CH:18]=[CH:17]/[C:14]1[CH:15]=[N:16][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ccc(/C=C/C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cn2)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(/C=C/C(=O)Nc3cc(-c4cccs4)ccc3N)cn2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a solution of compound 41 (85.2 mg, 0.15 mmol) in DCM (2 mL) was added neat trifluoroacetic acid (0.7 mL). The reaction was allowed to stir at room temperature for 2 h then concentrated, diluted with AcOEt, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated to give title compound 42 (38 mg, 54% yield).
Reaction SMILES: [C:1]1([CH2:13][C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]3[N:31]=[C:30]([N:32]4[CH2:37][CH2:36][CH:35]([C:38]([O:40]CC)=[O:39])[CH2:34][CH2:33]4)[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:17]2)=[O:15])(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1.[OH-].[Na+].Cl>CO>[C:2]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH2:17]1)=[O:15]
Reactant: CCOC(=O)C1CCN(c2nc(N[C@H]3CCN(C(=O)CC4(c5ccccc5)C=CC=CC4)C3)nc3ccccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.4 %

Procedure:
Ethyl 1-(2-((S)-1-(2-biphenyl-1-ylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperidine-4-carboxylate (0.59 g) synthesized in the same manner as the method described in Example 1 was dissolved in methanol (4.5 mL), followed by addition of 2.2 M aqueous sodium hydroxide (1.3 mL), and the mixture was stirred at room temperature for 1 day. 1 M hydrochloric acid was added until the reaction solution became pH 7, the mixture was stirred at room temperature for 2 days, and then the precipitated solids were collected by filtration to obtain 1-(2-((S)-1-(2-biphenyl-2-ylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperidine-4-carboxylic acid (0.30 g). (2) To a mixture of 1-(2-((S)-1-(2-biphenyl-2-ylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperidine-4-carboxylic acid (0.17 g) and DMF (5.0 mL) were added EDC.HCl (85 mg) and HOBt.H2O (77 mg), followed by addition of 28% aqueous NH3 (0.023 mL), and the mixture was stirred at room temperature for 17 h. The reaction solution was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate, water, and saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, then the residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol=10:1), and then the resulting compound was crystallized in diethyl ether to obtain 1-(2-((S)-1-(2-biphenyl-2-ylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperidine-4-carboxylic acid amide (160 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].Cl[C:17]1[C:26]2[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:11][CH:12]=1)([CH3:3])([CH3:5])[CH3:6]
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: CC(C)(C)c1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CCOc2ccnc3c(F)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a mixture of 1.1 g of sodium hydride in 50 mL of DMF was added 4.0 g of 2-[4-(1,1-dimethylethyl)phenyl]ethyl alcohol, and the mixture was stirred for one hour at room temperature. Then 4.0 g of 4-chloro-8fluoroquinoline in 20 mL of DMF were added, and the mixture was stirred at room temperature overnight. Then the mixture was poured into an ice/water mixture, and the solid was collected and recrystallized from ethyl acetate/pentane to give 2.3 g of the title product. Yield 32.4%. M.P. 81°-82° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:10]=1[C:11]([NH:13][CH3:14])=[O:12])C1C=CC=CC=1>[Pd].CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH:15]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(N)ccc1O
Reaction time: 8 h

Procedure:
To a flask charged with 2-(benzyloxy)-N-methyl-5-nitrobenzamide (176 mg, 1.061 mmol) was added MeOH (4 mL). The resulting suspension was thoroughly purged with nitrogen prior to the addition of 10% Pd/C (12 mg, 0.046 mmol). The reaction mixture was purged with H2 gas, and then stirred under at atmosphere of hydrogen overnight. The reaction mixture was filtered through Celite® (diatomaceous earth) and the filtrate dried under reduced pressure. The resulting 5-amino-2-hydroxy-N-methylbenzamide (90 mg, 99% crude yield) was used in next step without further purification.
Reaction SMILES: [C:1]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23]Cl)=[O:20])([O:3][CH2:4][CH3:5])=[O:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][N:36]1[CH2:35][CH2:34][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])[CH2:38][CH2:37]1)=[O:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)c1c(NC(=O)NCCCl)sc(C)c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(NC(=O)NCCN2CCN(c3ccccc3OC)CC2)sc(C)c1-c1ccccc1
Yield: 63.4 %

Procedure:
A solution of Example 2A (0.60 g, 1.6 mmol), 1-(2-methoxyphenyl)piperazine (0.84 g, 6.5 mmol) and diisopropylethylamine (0.35 mL) in acetonitrile (25 mL) was processed as in Example 1B. Purification of the crude product on silica gel with 2% triethylamine 50% ethyl acetate/hexane provided 0.53 g of the title compound.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5].C(=O)=O.CC(C)=O.[CH2:30]([Mg]Br)[CH2:31][CH:32]=[CH2:33]>C1COCC1>[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH2:33][CH2:32][CH:31]=[CH2:30]
Reactant: C=CCC[Mg]Br
Reactant: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=CCCC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
While under an argon atmosphere, a solution of benzyl 4-(methoxy(methyl) carbamoyl)piperidine-1-carboxylate (15.0 g, 49.0 mmol) in THF (100 mL) was cooled to −78° C. (dry ice/acetone bath) and treated with 3-butenylmagnesium bromide (250 mL, 0.5 M sol. in THF, 125 mmol, Aldrich) via canula. After the addition was complete, the cooling bath was removed allowing the solution to slowly warm to room temperature. After stirring overnight (16 h), the reaction mixture was quenched with 0.1N HCl (200 mL) and diluted with ethyl acetate (300 mL). After stirring an additional 5 min, the organic phase was separated, washed with saturated sodium bicarbonate (200 mL), dried over MgSO4, filtered and concentrated. Purification by MPLC (100 g column, 20-50% ethyl acetate in heptane) gave benzyl 4-pent-4-enoylpiperidine-1-carboxylate (14.5, 98%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.38-7.32 (m, 5H), 5.79 (dddd, J1=17.1 Hz, J2=10.2 Hz, J3=6.9 Hz, J4=6.6 Hz, 1H), 5.12 (s, 2H), 5.02 (dd, J1=17.1 Hz, J2=1.5 Hz, 1H), 4.97 (dd, J1=10.2 Hz, J2=1.5 Hz, 1H), 4.28-4.10 (m, 2H), 2.86 (br t, J=12 Hz, 2H), 2.58-2.43 (m, 3H), 2.35-2.28 (m, 2H), 1.9-1.74 (m, 2H), 1.62-1.48 (m, 2H). ESI MS found for C18H23NO3 m/z [302.3 (M+1), 324.1 (M+23)].