Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)cccc1C(=O)Nc1ccccc1Cl
Yield: 78.8 %

Procedure:
Prepared according to Procedure A using 2-amino-3-chlorobenzoic acid (1.0 g, 5.82 mmol) and SOCl2 (1.1 mL, 14.6 mmol) in benzene (25 mL), followed by 2-chloroaniline (1.2 mL, 11.7 mmol) and CHCl3 (25 mL). The product was recrystallized from MeOH to provide 1.29 g of a yellow solid (78%). 1H NMR (CDCl3) δ: 8.43 (dd, J=1.4, 8.3 Hz, 1H); 8.30 (br s, 1H); 7.47 (dd, J=1.1, 8.0 Hz, 1H); 7.42 (d, J=8.0 Hz, 2H); 7.33 (dt, J=1.4, 7.9 Hz, 1H); 7.09 (dt, J=1.5, 7.7 Hz, 1H); 6.68 (t, J=7.9 Hz, 1H); 6.13 (br s, 2H). MS (ES): m/z 281.0 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:17]=[CH:18]/[Cl:19])[CH2:14][S:15](=O)[C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:21])=[C:13](/[CH:17]=[CH:18]/[Cl:19])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS(=O)[C@H]12
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of benzhydryl 7-t-butoxycarbonylamino-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate-1-oxide (7.3 g) in N,N-dimethylformamide (35 ml) was added phosphorus trichloride (1.76 ml) at -40° C. After stirring at the same temperature for 30 minutes, the mixture was poured into ice-water. The resulting precipitate was collected by filtration and dried to give benzhydryl 7-t-butoxycarbonylamino-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (6.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([NH2:31])(=[NH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]CC.[Na+]>C(O)C.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:30]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a suspension of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one (36 mg, 0.12 mmol) and benzamidine hydrochloride (25 mg, 0.16 mmol) in ethanol (500 μL) was added sodium ethoxide (52 μL, 3 M in ethanol, 0.16 mmol). The reaction mixture was stirred at room temperature 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:1 hexanes-ethyl acetate) provided 7-chloro-2-(4-fluorophenyl)-3-(2-phenylpyrimidin-4-yl)pyrazolo[1,5-α]pyridine (34 mg, 71%). Rf 0.36 (3:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 8.60–8.56 (m, 2H), 8.52–8.48 (m, 2H), 7.67 (m, 2H), 7.56–7.52 (m, 3H), 7.39 (m, 1H), 7.22–7.11 (m, 3H), 6.93 (d, 1H); 19F NMR (CDCl3) δ −112.30; MS m/z 401 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[Br-:1].[CH2:6]([O:5][C:3]([CH2:2][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: c1ccncc1
Solvent: CC(C)=O
Product: O=C(C[n+]1ccccc1)OCc1ccccc1
Product: [Br-]
Temperature: 60 °C

Procedure:
To a solution of benzyl bromoacetate (10 g, 43.7 mmol) in acetone (200 mL) was added a solution of pyridine (3.51 mL, 43.7 mmol) in acetone (20 mL) and the resulting mixture was stirred at 60° C. under nitrogen over the week-end. Then allowed to cool to RT and concentrated to give the desired material. MS (LC/MS): 228.1 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[N:13]1([CH2:18][CH2:19][CH2:20][Cl:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[ClH:21].[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[O:1][CH2:20][CH2:19][CH2:18][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COc1cc(C(=O)O)ccc1OCCCN1CCCC1
Product: Cl
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g), 3-(pyrrolidin-1-yl)propyl chloride (J. Amer. Chem. Soc., 1955, 77, 2272; 14.75 g), potassium carbonate (13.8 g), potassium iodide (1.66 g) and DMP (150 ml) was stirred and heated to 100° C. for 3 hours. The mixture was allowed to cool to ambient temperature, filtered and the filtrate was evaporated. The residue was dissolved in ethanol (75 ml), 2N aqueous sodium hydroxide solution (75 ml) was added and the mixture was heated to 90° C. for 2 hours. The mixture was concentrated by evaporation and acidified by the addition of concentrated aqueous hydrochloric acid. The resultant mixture was washed with diethyl ether and then purified by column chromatography using a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with a gradient of methanol (0 to 25%) in dilute hydrochloric acid (pH2.2). The methanol was removed by evaporation and the aqueous residue was freeze dried to give 3-methoxy-4-(3-pyrrolidin-1-ylpropoxy)benzoic acid hydrochloride (12.2 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.2 (m, 2H), 3.15 (t, 2H), 3.3 (t, 2H), 3.5 (d, 2H), 3.7 (t, 2H), 3.82 (s, 3H), 4.05 (d, 2H), 4.15 (t, 2H), 7.07 (d, 1H), 7.48 (s, 1H), 7.59 (d, 1H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>C(#N)C>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:3][CH:1]=[CH2:2])=[CH:9][CH:10]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCN
Solvent: O
Solvent: CC#N
Product: C=CNCc1ccc(Cl)nc1

Procedure:
To a solution of aqueous ethylamine, an appropriate amount of acetonitrile is, added. Then 2-chloro-5-(chloromethyl)pyridine in acetonitrile is added dropwise in ice bath. The reaction is monitored by TLC. After completion, the mixture is added large amount of water, extracted by DCM, dried, filtered and evaporated to obtain N-((6-chloropyridin-3-yl)methyl)ethenamine as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]([C:17](=O)[CH3:18])[C:15]#[N:16].Cl.Cl.[NH2:22][NH2:23].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:18][C:17]1[C:14]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=2[O:2][CH3:1])=[C:15]([NH2:16])[NH:23][N:22]=1
Reactant: NN
Reactant: COCCOc1cccc(C(C#N)C(C)=O)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCCOc1cccc(-c2c(C)n[nH]c2N)c1OC
Yield: 64.6 %

Procedure:
To a solution of 2-(2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.17 g, 0.65 mmol) in ethanol (5 mL) was added hydrazine dihydrochloride (99 mg, 0.94 mmol). The resulting mixture was heated at reflux for 1 hour. It was cooled, poured into a saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 5% methanol in dichloromethane) to provide 3-methyl-4-(2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)-1H-pyrazol-5-amine (115 mg, 0.42 mmol, 65% yield). MS (EI) for C14H19N3O3: 278 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[CH:23]=5)[C:19]([CH3:30])=[C:18]([CH3:31])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:31])[C:19]([CH3:30])=[C:20]([C:22]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)ccn1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2cc[nH]c(=O)c2)c1C
Temperature: 55 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (96 mg, 0.23 mmol) in CH3CN (4.8 mL) was added TMSI (65.6 μL, 0.46 mmol) drop wise. The suspension became a clear solution on TMSI addition. The reaction was stirred at 55° C. for 5 hours. The reaction was allowed to cool down to room temperature. Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (50 mg, 54%). ESI-MS m/z calc. 401.5. found 402.5 (M+1)+. Retention time 1.41 minutes.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1>[C:1]([O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nicotinic chloride (1.78 g, 10 mmoL) was added to phenol (1.29 g, 12 mmoL) in 10 mL of tetrahydrofuran (THF). Triethylamine (5 mL) and pyridine (5 mL) were then added to the mixture, which was then stirred at room temperature overnight. After THF was evaporated, the mixture was washed with ethyl acetate in water for three times. The ethyl acetate (EtOAC) layer was then purified with silica column (Hexane: EtOAC=4:1) to give pure product. 1H NMR (400 MHz, CDCl3): δ=9.40 (s, 1H), 8.86 (d, 1H), 8.46 (d, 1H), 7.45 (m, 3H), 7.32 (d, 1H), 7.24 (m, 2H). 2′,3′,5′-Triacetyl ethyl nicotinate riboside (2):
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:36]=[C:4]2[N:3]=1.[OH:46]C(C)(C)C>>[OH:46][C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:36]=[C:4]2[N:3]=1
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc(=O)c2c(Cl)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Reactant: CC(C)(C)O
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc(=O)c2c(O)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Temperature: 95 °C

Procedure:
To the uncyclized intermediate from example 3 (30 mg) under nitrogen was added K—OtBu (1M, 0.05 mL) and HOtBu (2 mL). The mixture was then heated at 95° C. for 1 h. After cooling to rt, the mixture was subjected to preparative HPLC to give the titled compound (4.5 mg). LC: 3.54′ (Gradient 1); MH+: 634.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].C(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
In a 500 mL three-necked flask were placed 30 g (82 mmol) of 4,4′-dibromobenzil, 9.3 g (86 mmol) of 1,2-phenylenediamine, and 300 mL of chloroform, which were refluxed under nitrogen stream at 80° C. for 5 hours. After a predetermined time, the solution was cooled to room temperature, and there was added water. The aqueous layer was extracted with chloroform, and the extract and the organic layer were dried together over magnesium sulfate. After drying, the mixture was subjected to suction filtration, and the filtrate was condensed. The obtained solid was dissolved in toluene, and the solution was subjected to suction filtration through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and alumina. The filtrate was condensed; thus, 30 g of target white powder of 2,3-bis(4-bromophenyl)quinoxaline was obtained with a yield of 99%.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.[OH-].[K+]>O1CCOCC1.C(OCC)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:16]1[CH2:15][CH2:14][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:12]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCN(Cc3ccccn3)CC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](O)c1nccc(N2CCN(Cc3ccccn3)CC2)n1
Reaction time: 3 h

Procedure:
To a solution of (R)-1-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 182, Step A, 0.14 g, 0.33 mmol) in dioxane (6 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (0.5 mL). After stirring for 3 h the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white solid, 0.09 g (69%). 1H NMR (CDCl3, 300 MHz) δ 1.52 (d, 3H), 2.38-2.59 (m, 4H), 3.72-3.77 (m, 6H), 4.69 (q, 1H), 6.37 (d, 1H), 7.22 (d, 1H), 7.41 (d, 1H), 7.69 (m, 1H), 8.21 (d, 1H) 8.58, (d, 1H); mp: 68-70° C.; MS (CI) 300 (MH+); [α]D +16.2 (c 1.0, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10][CH2:11]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1cccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
126.1 mg of the target compound (0.35 mmol, 42.9%) was obtained using 1-(3-methoxyphenyl)piperazine (315 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C:29](=[O:34])C(C)(C)C)=[C:4]([CH:8](O)[CH:9]([CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)C(OC)=O)[CH:5]=[CH:6][CH:7]=1.O.[ClH:36]>CO>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:28][C:29](=[O:34])[C:9]([CH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[CH:8]2
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccc(F)c1NC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reaction time: 2.5 h
Yield: 83 %

Procedure:
tert-Butyl 4-(1-(3-fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate (16.4 mmol, 7.86 g) was dissolved in methanol (20 mL). Water (45 mL) was added to the mixture followed by concentrated hydrochloric acid (183 mmol, 15 mL). Reaction was heated to reflux and held for 2.5 hours. Reaction mixture was concentrated in vacuo. Residue was dissolved in ethanol (50 mL) then concentrated in vacuo. Residue was crystallized from ethanol. Solids were filtered off, washed with cold ethanol then dried in vacuo. Title compound was obtained as white solid in 83% yield. 1H NMR (500 MHz, DMSO-d6): δ=11.85 (s, 1H), 8.98 (m, 1H), 8.85 (m, 1H), 7.75 (s, 1H), 7.54 (d, J=7.63, 1H), 7.36 (dd, J1=10.22, J2=8.09, 1H), 7.21-7.11 (m, 1H), 3.41-3.29 (m, 2H), 3.14-2.94 (m, 3H), 2.02 (d, J=13.43, 2H), 1.88-1.71 (m, 2H). MS m/e (M+H)+=247.2.
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.C(OCC)(=O)C>[CH2:10]([O:12][C:13](=[O:18])[C:14]([O:9][C:6]1[CH:7]=[N:8][C:3]([NH2:2])=[CH:4][CH:5]=1)([CH3:16])[CH3:15])[CH3:11]
Reactant: Nc1ccc(O)cn1
Reactant: CCOC(=O)C(C)(C)Br
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(N)nc1
Reaction time: 16 h
Yield: 69.1 %

Procedure:
To a flask containing 6-aminopyridin-3-ol hydrobromide (2 g, 10.5 mmol) and ethyl-2-bromo-2-methylpropanate (2.04 g, 10.5 mmol) in anhydrous acetonitrile (25 ml) was added cesium carbonate (10.7 g, 33 mmol) and the material was stirred for 16 hours under argon atmosphere. Water (60 ml) and ethyl acetate (60 ml) were added and the material was shaken in a reparatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to provide a golden brown solid (1.626 g)(M+H)+=225 m/e.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([N:22]([CH2:23][CH:24]=[CH2:25])[CH2:19][CH:20]=[CH2:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: C=CCNCC=C
Solvent: O
Product: C=CCNc1nc(N(CC=C)CC=C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A mixture of 300 mg (1.13 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.18 g (12.15 mmol) of diallylamine for 2 hours was stirred at room temperature, and then at 60° C. for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 325 mg (yield: 88.5%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N[S:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[O:30])(=[O:19])=[O:18])CC>>[O:29]=[C:24]1[C:23](=[O:30])[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([S:17]([NH:1][C@@H:2]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([NH2:12])=[O:11])(=[O:19])=[O:18])[CH:21]=2)[NH:25]1
Reactant: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Product: NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2

Procedure:
The title compound was prepared from L-Phe-NH2 following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=O.[Si]([N:37]=[C:38]=[O:39])(C)(C)C.[OH-].[Na+]>C1COCC1.CC(O)=O.CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([CH:4]3[C:3]4[C:2](=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:32])[NH:1][C:38](=[O:39])[NH:37]3)=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:14])=[O:15])=[CH:17][C:18]=1[C:23]([F:26])([F:25])[F:24]
Reactant: Nc1cccc(Cl)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2cccc(Cl)c2C(c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)N1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
N-(2-(2-Amino-6-chlorobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl) benzenesulfonamide (26 mg, 0.05 mmol) in THF (2 mL) was treated with TMS-isocyanate (100 mg) and AcOH (0.5 mL) and then stirred at 75° C. for 12 h. To the mixture was added MeOH (0.5 mL), followed by NaOH (5 N, 1 mL), and the resultant mixture stirred at 75° C. for another 2 h. To the mixture was added AcOH (0.5 mL), and the mixture was purified through HPLC and dried (lyophilizer) to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 2H), 8.34 (d, 1 H), 8.14 (d, 1 H), 7.90 (dd, 1 H), 7.66 (d, 1 H), 7.46 (s, 1 H), 7.16 (t, 1 H), 6.90 (d, 2H), 6.81 (d, 1 H), 6.14 (d, 1 H); MS (ES) (M+H)+ expected 550.9, found 550.9.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][SH:14].[CH2:15]=O>C(N(CC)CC)C.C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:13][S:14][CH3:15]
Reactant: C=O
Reactant: Cc1cccc2c(O)ccnc12
Reactant: CS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSCc1cnc2c(C)cccc2c1O

Procedure:
To a stirred suspension of 4-hydroxy-8-methylquinoline (10.0 g.) in triethylamine (8.8 ml.) and industrial methylated spirit (15 ml.) at 0°-5° was added methanethiol (10.4 ml.) followed by aqueous formaldehyde (40%, 14.2 ml.). The mixture was stirred and boiled under reflux for 30 hours. Aqueous formaldehyde (40%, 14.2 ml.) was added dropwise to a stirred solution of triethylamine (8.8 ml.) and methanethiol (10.4 ml.) in ethanol (15 ml.), maintaining the temperature below 10°. The resulting solution was added to the above reaction mixture and the mixture was stirred and boiled under reflux for 20 hours. The mixture was left to cool overnight. The resulting crystalline solid was collected by filtration to give the novel compound 4-hydroxy-8-methyl-3-methylthiomethylquinoline, m.p. 226°-228°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1cc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4cc3OC)CC2)c1
Yield: 74.5 %

Procedure:
Phenyl N-(2-methoxynaphth-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 86 to obtain the titled compound.