Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:16]([OH:19])[CH2:17][Br:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C@@H:16]([OH:19])[CH2:17][Br:18])=[CH:3][C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromoethanol (Org. Process Research and Development, 1998, 2, 96)_(30.8 g, 95.6 mmol) in dichloromethane (300 ml) was treated with pyridine (9.3 ml, 115 mmol). The resulting solution was cooled to 5° C. and a solution of methanesulfonyl chloride (7.8 ml, 100.7 mmol) in dichloromethane (10 ml) added dropwise. The mixture was stirred at 5° C. for a further 30 minutes and then allowed to warm gradually to room temperature over a period of 16 hours. The reaction mixture was washed with 2N hydrochloric acid (110 ml) and the organic phase separated, dried (magnesium sulfate) and the solvent removed in vacuo to give an orange oil. The residue was crystallized from hot toluene (100 ml) to give the title compound as a pale pink solid (33.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:18])[N:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:7]=1)=[O:5])C.[CH2:29]([Mg]Br)[CH3:30]>C1COCC1.[Cu](I)I>[CH3:1][O:3][C:4]([CH:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:18])[N:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:7]1[CH2:29][CH3:30])=[O:5]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1cn(C(=O)OCc2ccccc2)c2c(C)nc(C)cc2c1=O
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CCC1C(C(=O)OC)C(=O)c2cc(C)nc(C)c2N1C(=O)OCc1ccccc1

Procedure:
This compound can be obtained by reacting a stirred suspension of 6,8-dimethyl-4-oxo-4H-[1,7]naphthyridine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester, prepared in step (iii) and CuI (copper iodide) in THF, with freshly prepared EtMgBr (ethyl magnesium bromide) at −78° C., followed by a typical workup.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:5]=1[C:6]([O:8]CC)=O.C[O-].[Na+].[OH-].[Na+]>CO>[NH2:3][C:4]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:5]=1[C:6]([NH:2][CH3:1])=[O:8]
Reactant: CN
Reactant: CCOC(=O)c1cc(C#N)cc(C)c1N
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Methylamine (117 g, 3.77 mol) is introduced into a solution of ethyl 2-amino-5-cyano-3-methylbenzoate (50 g, 0.251 mol) in methanol (175 mL), sodium methoxide (1.13 g, 30% strength in methanol, 6.28 mmol) is added and the reaction mixture is stirred overnight at room temperature. Thereafter, 100 ml of 22% strength NaOH are added and the batch is cooled down to 10° C. The suspension obtained is filtered and the solid obtained is washed once with 1:1 methanol:water and then with 50 mL of water. The solid is dried at 50° C. in a vacuum drying cabinet. 2-Amino-5-cyano-N,3-dimethylbenzamide is isolated as a slightly beige solid. Yield: 80.3% of theory, purity: 94.9% quantitative LC, 73 ppm Cu).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[N:11][C:4]=2[NH:3]1.CO[C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1)=O.[CH3:26][O:27][C:28]1[N:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]([OH:40])=[O:39])=[CH:31]2>>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([NH:25][C@H:22]3[CH2:23][CH2:24][C@H:19]([CH2:17][O:39][C:38]([C:32]4[CH:33]=[N:34][C:35]5[C:30]([CH:31]=4)=[N:29][C:28]([O:27][CH3:26])=[CH:37][CH:36]=5)=[O:40])[CH2:20][CH2:21]3)=[O:14])=[N:11][C:4]=2[NH:3]1
Reactant: COc1ccc2ncc(C(=O)O)cc2n1
Reactant: O=C1COc2ccc(C(=O)O)nc2N1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NC(=O)c4ccc5c(n4)NC(=O)CO5)CC3)cc2n1

Procedure:
The title compound is prepared as a light brown semisolid following Scheme 2 and in analogy to Example 28 using 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid, trans-4-amino-cyclohexanecarboxylic acid methyl ester and 6-methoxy-[1,5]naphthyridine-3-carboxylic acid as starting materials.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][C:43]#[C:44][C:45]([CH3:48])([OH:47])[CH3:46].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][C:43]#[C:44][C:45]([OH:47])([CH3:48])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(O)C#CCBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](SCC#CC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 73.2 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (59.4 mg, 0.102 mmol), 5-bromo-2-methyl-3-pentyn-2-ol (90.5 mg, 0.511 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=5:1, developed twice) to give the title compound as a colorless oil (41.6 mg, 73%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]cc(Cc3cccc(Cl)c3)c12
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a solution of commercially available methyl 1H-indole-4-carboxylate (5 g, 28.5 mmol) in 100 mL dichloromethane, at 0° C., was added 3-chlorobenzaldehyde (5 mL, 43.8 mmol), triethylsilane (15 mL, 93.9 mmol) and trifluoroacetic acid (5 mL, 64.9 mmol), and the resulting solution was stirred for ON as it warmed to rt. The reaction was then quenched with saturated aqueous sodium bicarbonate and the solution was extracted with dichloromethane. The organic phases were then combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resultant solid was washed with cold 10:1 hexanes:dichloromethane to yield 6 g of the title compound as a white solid. 1H NMR (500 MHz, d6-acetone): δ 8.5 (s, 1H), 8.0 (m, 2H), 7.4-7.1 (m, 5H), 5.7 (s, 2H), 4.0 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:14]Br>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:14])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Temperature: 45 °C
Yield: 48.2 %

Procedure:
A suspension of 2-amino-5-chloropyridine (5.14 g, 40 mmol) and anhydrous sodium acetate (3.29 g, 40 mmol) in acetic acid (25 mL) was mechanically stirred and warmed to a bath temperature of 45° C. A solution of bromine (2.1 mL, 40 mmol) in acetic acid (2 mL) was added over 1 hour. The resulting orange mixture was cooled to 15° C. and filtered. The solids were taken up in 400 mL of water, the suspension made basic by addition of 1 N NaOH and the suspension extracted with ethyl acetate (5×100 mL). The combined extracts were washed with 10% NaHSO3(1×100 mL) and were dried over MgSO4. Concentration afforded 2-amino-3-bromo-5-chloropyridine (4 g, 48%), mp 82-84° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[CH:19]=[N:18][NH:17][C:14]3=[CH:15][N:16]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[CH3:22]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[CH:19]=[N:18][N:17]([CH3:22])[C:14]3=[CH:15][N:16]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CI
Reactant: N#Cc1cc(F)ccc1Oc1cc2cn[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Oc3ccc(F)cc3C#N)ncc21
Temperature: 0 °C
Yield: 51.1 %

Procedure:
The intermediate (2u) (0.23 g) was dissolved in DMF (9 mL) and cooled to 0° C. Sodium hydride (60% in oil, 0.054 g, 1.36 mmol) and methyl iodide (0.28 mL, 642 mg, 4.52 mmol) were added to the solution at 0° C. and then the reaction mixture was stirred for an hour at 0° C. The mixture was quenched with 10 mL of water and extracted three times with 30 mL of ether. The combined organic layer was washed with 5 mL of water twice and brine once, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil residue was purified on silica gel with EtOAc/hexane (1:1) to afford colorless oil (3u) (0.124 g, 51% yield). 1HNMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.02 (s, 1H), 7.40-7.32 (m, 2H), 7.31-7.23 (m, 2H), 7.11-7.05 (m, 1H, 4.17 (s, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:3]([NH2:5])=[O:4].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C:6]2[C:11](=[CH:10][C:9]3[O:12][CH2:13][O:14][C:8]=3[CH:7]=2)[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:5][C:3]1=[O:4]
Reactant: CN(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3
Yield: 20 %

Procedure:
A mixture of N-methyl-N-[3,4-(methylenedioxy)phenyl]urea (240 mg), benzaldehyde (140 μL) and methanesulfonic acid (50 μL) and toluene (60 mL) was refluxed for 2 h in a flask equipped with a Dean-Stark water separator. After cooling, the solution was washed with water thoroughly, dried over Na2SO4 and concentrated in vacuo. The resulting solid was recrystallized from chloroform/hexane to provided the title compound as a tan solid (70 mg, 20%), mp: 228-230° C. 1H NMR (CDCl3): 7.37-7.30 (m, 5H), 6.53 (s, 1H), 6.28 (s, 1H), 5.91 (d, 1H, J=1.4), 5.89 (d, 1H, J=1.4), 5.46 (s, 1H), 5.11(br s, 1H), 3.33 (s, 3H). Anal. calcd. for C16H14N2O3: C, 68.08; H, 5.00; N, 9.92. Found: C, 68.06; H, 4.91; N, 9.71.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[NH2:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:20][C:19]([Cl:29])=[CH:18][N:17]=1.O>CS(C)=O>[Cl:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:11]3[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][N:12]=3)=[CH:26][CH:27]=2)[C:16]([NH2:15])=[N:17][CH:18]=1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Reactant: Fc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2ccc(Cl)cn2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
A mixture of potassium carbonate (376 mg), 5-chloro-2-fluoropyridine (215 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (10 mL) was stirred at 120° C. for 5 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (450 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([O:24]C)[CH:19]=2)=[N:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([C:18]2[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=2)=[O:26])=[N:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)ccn1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(NC(=O)c2cc[nH]c(=O)c2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of N-benzyl-2-(2-methoxyisonicotinamido)-4-methylthiazole-5-carboxamide (0.26 g, 0.68 mmol) in anhydrous chloroform (15 mL) was added iodotrimethylsilane (1.37 g, 6.80 mmol) at 0° C. The mixture was refluxed for 16 hours and cooled down to ambient temperature. Methanol (3 mL) was added dropwise to quench the reaction. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated sodium bicarbonate solution (2×100 mL), and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo. The residue was recrystallized from ethyl acetate and methanol to yield a colorless solid in 55% yield (0.13 g); m.p. 290-292° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.74 (s, br, 2H), 8.63 (t, J=5.9 Hz, 1H), 7.48 (d, J=6.8 Hz, 1H), 7.35-7.17 (m, 5H), 6.95 (d, J=1.6 Hz, 1H), 6.66 (dd, J=1.6, 6.8 Hz, 1H), 4.37 (d, J=5.9 Hz, 2H), 2.49 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 165.5, 162.6, 163.1, 162.0, 144.1, 140.0, 136.8, 128.7, 127.6, 127.1, 120.3, 119.2, 103.3, 43.0, 17.0; MS (ES+) m/z 369.2 (M+1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11][N:12]1C(=O)C2=CC=CC=C2C1=O.[N+]([O-])=[O:24].ClC(Cl)C.O=O>>[N+:12]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)([O-:11])=[O:24].[C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=[N+][O-]
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])C12CC3CC(CC(C3)C1)C2
Product: OC12CC3CC(CC(C3)C1)C2
Yield: 12 %
Yield: 57 %

Procedure:
Into a flask, 1 mmole of adamantane, 0.05 mmole of N-hydroxyphthalimide, 15 mmole of nitrogen dioxide (NO2) and 3 ml of dichloroethane were added and stirred for 5 hours at 60° C. in an atmosphere of oxygen. The reaction products were analyzed by gas chromatography, and, as a result, the conversion of adamantane was 97%, and nitroadamantane (yield 57%), adamantanol (yield 12%) and adamantanone (yield 4%) were formed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14](O)=[O:15])[CH:7]=[CH:6]2.C(Cl)(=O)C([Cl:21])=O>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([Cl:21])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Reaction time: 0.05 h

Procedure:
A mixture of (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid (23.09 g) and THF (41 mL) is agitated until dissolution is achieved. Oxalyl chloride (17.5 mL) is added to the flask followed by DMF (3 drops) and heptanes (50 mL). The mixture is stirred for approximately 2 hours. The resulting slurry is filtered, washed with heptane (15 mL) and aspirated for 3 minutes and vacuum dried to give 17.44 g.
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[CH3:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([S:1][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH:11][C:10]2=[O:12]
Reactant: Cc1cccc2c(=O)[nH]c(S)nc12
Reactant: ClCc1ccncc1
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(SCc3ccncc3)nc12
Yield: 44 %

Procedure:
The title compound was prepared in a yield of 44.0%, using 2-mercapto-8-methyl-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinoe and 4-chloromethylpyridine hydrochloride in place of 2-chloromethyl-4methylpyridine hydrochloride.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][C:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13]3)[CH2:4][CH2:3]1.[Cl:27]C(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>ClCCCl>[ClH:27].[C:21]1([S:18]([C:14]2[CH:15]=[N:16][C:17]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[N:5]2[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]2)(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A stirred solution of 8-(4-methyl-piperazin-1-yl)-3-phenylsulfonylquinoline (E1) (0.148 g, 0.4 mmol), 1-chloroethyl chloroformate (0.093 ml, 0.85 mmol) and N,N-diisopropylethylamine (0.148 ml, 0.85 mmol) in 1,2-dichloroethane (9 ml) was heated at reflux for 1.25 h under argon. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane, pooling fractions which contained the major component (Rf 0.9, methanol/dichloromethane 1:19). The purified material was redissolved in methanol (15 ml) and the solution was refluxed for 1 h under argon. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to a solid which was stirred with diethyl ether (5 ml) and filtered to afford the title compound (E2) (0.08 g, 0.21 mmol, 51%);
Reaction SMILES: C(O[C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:8]=[N:7]1)C.[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH2:30])[CH3:25].O>CCOCC>[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH:30][C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:8]=[N:7]1)[CH3:25]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccccn2)c1-c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccccn2)c1-c1ccccc1
Yield: 43.1 %

Procedure:
A solution of 10 g (0.032 mol) of ethyl 5-phenyl-4-(2-pyridinyl)pyrazole-1-acetate of example 1 in 15 mL (0.095 mol) of 3-(diethylamino)propanamine was heated at 100° for 3 hr. The excess amine was stripped in vacuo and the residue distributed between water and ether. The ether solution was dried over MgSO4, stripped and applied to 350 g of silica gel in a small amount of methylene chloride. The column was eluted with 20:1 acetone-triethylamine and a light yellow oil was obtained that crystallized upon triturating with cyclohexane to yield 5.4 g of product, mp 82°-83° C.
Reaction SMILES: [CH2:1]1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][C:33]([N:36]([CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH3:1])=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: C1CCOC1
Reactant: CCOC(=O)CCCNc1ccc(N2CCN(C(=O)c3cccc(-c4ccc(OC)c(OC)c4)n3)CC2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CCCN(C)c1ccc(N2CCN(C(=O)c3cccc(-c4ccc(OC)c(OC)c4)n3)CC2)cc1

Procedure:
To a THF solution of ethyl 4-[N-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)amino]butanoate were added a 36% aqueous formalin solution, acetic acid and sodium triacetoxyborohydride, followed by stirring. Then, post-treatment and purification were carried out in a usual way to obtain ethyl 4-[N-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)-N-methylamino]butanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:22]#[N:23])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
3-Nitro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester (89.7 g, 272 mmol), zinc cyanide (19.2 g, 163 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 g) were suspended in N,N-dimethylformamide (2500 ml). The reaction mixture was stirred for 3 hours at 100° C. under an inert atmosphere. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give 4-cyano-3-nitro-benzoic acid methyl ester (34.0 g, 60.7% yield). 1H-NMR (400 MHz, CDCl3): 8.92 (s, 1H), 8.48 (d, 1H), 8.04 (d, 1H), 4.03 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[F:15][C:16]([F:27])([F:26])[C:17](=O)[CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[NH2:28]/[C:29](/[CH3:33])=[CH:30]\[C:31]#[N:32]>CC(O)C.C(O)(=O)C>[C:31]([C:30]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:18]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[C:17]([C:16]([F:27])([F:26])[F:15])[NH:28][C:29]=1[CH3:33])#[N:32]
Reactant: C/C(N)=C/C#N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(C)OC(=O)CC(=O)C(F)(F)F
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OC(C)C)=C(C(F)(F)F)N1

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 105 mg (0.53 mmol) of isopropyl 4,4,4-trifluoro-3-oxobutanoate, 43.6 mg (0.53 mmol) of 3-aminocrotononitrile and 46 μl (0.79 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 4 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. The main product obtained in this way is stirred under reflux in acetic acid overnight. The solution is concentrated and the residue is recrystallized from diethyl ether. 75 mg (33% of theory) of the title compound are obtained as a white solid.