Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH:4]([CH3:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][CH2:11][C:12]1[C:13]([CH2:18]Cl)=[CH:14][CH:15]=[CH:16][CH:17]=1.Cl>C1COCC1.CS(C)=O.CCOCC>[Cl:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][N:6]1[CH:4]([CH3:5])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: CC1CCC(=O)N1
Reactant: ClCc1ccccc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CCC(=O)N1Cc1ccccc1CCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.4 %

Procedure:
A solution of γ-valerolactam (7 g, 70.5 mmol) in THF (150 mL) and DMSO (20 mL) was treated with NaH (2.83 g of a 60% oil dispersion) at 0° C. under nitrogen atmosphere. After a total of 15 min, α,α'-dichloro-o-xylene (25 g, 140 mmol) was added and the solution was allowed to warm and stir at room temperature. After 4 h, 100 mL of ether and 100 mL of 0.2 N HCl were added. The water was withdrawn, and the organic layer was washed 2× more with water, dried (MgSO4), filtered and concentrated. This material was purified on ca. 400 g of silica gel (flash chromatography; EtOAc/hexane 7:3) to yield N-[2-(chloromethyl)benzyl]-γ-valerolactam (6.6 g, 40%). 1H NMR and mass spectral analysis supported the assigned structure. A solution of this lactam (5.0 g, 21.09 mmol), 2-(isopropoxy)phenylpiperazine fumarate (6.38 g, 18.99 mmol), and triethylamine (8.82 mL, 62.37 mmol) in DMF (75 mL) was heated for 3 h at 50°-60° C. After 3 h, the solution was added to a 3:1 solution of ether/ethyl acetate (ca. 100 mL) and extracted 3X with water, dried (MgSO4), filtered and concentrated. The residual oil was purified on ca. 400 g of silica gel (flash chromatography, EtOAc/hexane, 6:4) to give 5.41 g of white semi-solid, pure by thin layer chromatography. It was then dissolved in iPrOH, filtered through a Millipore filter, treated with 2.44 mL of conc. aqueous HCl (ca. 26 mmol), and then triturated out of solution by the addition of ether. The resultant white solid was recrystallized in MeOH/ether to give 1-[[2-[[1-[2-(methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-one hydrochloride(3:2)as a white powder (5.50 g, 61%), m.p. 249.5°-252.5° C. 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][C:16]=2[N+:25]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36]>[Pt].C(O)C>[CH2:35]([O:37][CH2:38][C:39]1[N:14]([CH2:13][C:2]2([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:36]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Agent: [Pt]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OCC)CC1
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
A mixture of ethyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate (4.53 g, 12.1 mmol) and 5% platinum on carbon (0.50 g) in ethanol was hydrogenated on a Parr apparatus at 40 psi (2.8×105 Pa) for 2.5 h. The mixture was filtered through CELITE filter agent and the filtrate was concentrated. The residue was concentrated twice from toluene and once from chloroform to remove the ethanol, then was dissolved in dichloromethane (100 mL). To the solution at 0° C. was added triethylamine (1.86 mL, 13.3 mmol) and ethoxyacetyl chloride (88%, 1.77 g, 12.7 mmol). After 1 h at rt, the solution was concentrated to a yellow foam and ethanol (120 mL) and triethylamine (6 mL) were added. The resulting solution was heated at reflux for 16 h and then concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed twice with brine, dried over MgSO4, filtered, and concentrated to a crude yellow oil. The oil was purified by flash chromatography (silica gel, gradient elution with 2-7% methanol/dichloromethane) to provide ethyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate as a yellow foam (3.04 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[CH3:29][S:30]([OH:33])(=[O:32])=[O:31]>CC(C)=O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[S:30]([O-:33])(=[O:32])(=[O:31])[CH3:29]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)=O
Solvent: CCO
Product: CS(=O)(=O)[O-]

Procedure:
3.79 g of Donepezil is dissolved in 80 ml of acetone, and 10 ml of a solution of methanesulfonic acid in absolute ethanol is slowly added. The solid precipitated is filtered to give the title compound, which is dried at 55° C. under vacuum. Melting point: 181.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH3:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Br)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2cc(Br)ccc2c1=O
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A suspension of 4.04 g of ethyl 7-bromo-4-hydroxy-quinoline-3-carboxylate (J. Am. Chem. Soc. 71,3226, (1949)) and 4.71 g of potassium carbonate in 30 ml of dimethylformamide is treated with 9.68 g of methyl iodide at room temperature. The reaction mixture is heated to 90° and stirred at this temperature for 3 hrs. The reaction mixture is concentrated in a high vacuum. The residue is suspended in 50 ml of water, filtered off under suction and washed with 50 ml of water. Recrystallization of the crude product from ethanol/diethyl ether yields 3.67 g (86%) of ethyl 7-bromo-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate as a colourless solid. M.p. 189°-191°.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20](=[CH2:22])[CH3:21])[CH3:15].Cl>>[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20]([C:10]1[CH:11]=[C:6]([Br:5])[CH:7]=[CH:8][C:9]=1[O:12][CH3:13])([CH3:22])[CH3:21])[CH3:15]
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)ccc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
34.45 g (258.91 mmol) of aluminum trichloride is introduced into 354.35 g (237.02 mmol) of 4-bromoanisole. 38.95 g (172.19 mmol) of 2-hydroxy-4-methylene-2-(trifluoromethyl)pentanoic acid ethyl ester is added in drops to this mixture within one hour. After stirring overnight at room temperature, the batch is added to ice water and made acidic with 10% hydrochloric acid. After 3× extraction with ethyl acetate, the combined organic extracts are washed with 1N hydrochloric acid and brine. After drying on magnesium sulfate, the solvent is spun off. Most of the excess 4-bromoanisole is distilled off (10 mbar; bath temperature 110° C.). After chromatography on silica gel (mobile solvent ethyl acetate/hexane), 36.87 g (51.8%) of the desired compound is obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:20]=[C:19]2[C:21]3[CH:15]([N:16]([CH3:22])[CH2:17][CH2:18]2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:24]C(C)C)[CH:12]=2)[C:7]=3[C:6]=1[O:30][CH3:31])([CH3:3])[CH3:2]>C(O)(=O)C.S(=O)(=O)(O)O>[OH:24][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:28][CH3:29])[C:7]1=[C:21]3[CH:15]([N:16]([CH3:22])[CH2:17][CH2:18][C:19]3=[CH:20][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]1[O:30][CH3:31])[C:14]2=[O:23]
Reactant: COc1cc2c(cc1OC(C)C)C(=O)C1c3c(cc(OC(C)C)c(OC)c3-2)CCN1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)C(=O)C1c3c(cc(OC(C)C)c(OC)c3-2)CCN1C
Temperature: 25 °C
Yield: 22.2 %

Procedure:
The solution of compound (3) (50 mg) in acetic acid-sulfuric acid solution (96:4, 5 ml) was refluxed for 1 hour under nitrogen. After cooling to room temperature, the solution was evaporated under vacuum. The residue was neutralized with ammonia water and extracted with chloroform (100 ml ×2). The combined chloroform layers were washed with water (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue obtained was purified on a silica gel column and eluted with chloroform-methanol (99:3) to obtain a brown solid, 9-hydroxy-2-isopropyloxy-1,10-dimethoxy-7-oxoaporphine (4) (10 mg, 22% yield): m.p. 240–242° C.; IR(KBr) νmax 3422, 3008, 2977, 2932, 1728, 1651, 1593, 1513, 1461, 1417, 1380, 1351, 1280, 1247, 1213, 1149, 1116, 1059, 1013, 932, 894, 866, 822 cm−1; 1H NMR (200 MHz, CD3OD) δ 1.51 (6H, d, J=6.0 Hz, 2×CH3), 4.01 (3H, s, OCH3), 4.02 (3H, s, OCH3), 4.87 (1H, m, OCH), 7.25 (1H, s, H-3), 7.74 (1H, s, H-8), 7.83 (1H, d, J=4.8 Hz, H-4), 8.63 (1H, d, J=4.8 Hz, H-5), 8.68 (1H, s, H-11); ESI MS (positive): [M+H]+ 366.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C@@H:22]1([C:31]([OH:33])=[O:32])[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[C:28]([OH:30])=[O:29]>>[C:31]([C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[C:28]([O-:30])=[O:29])([OH:33])=[O:32].[NH2+:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)O
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C([O-])[C@@H]1CCCC[C@H]1C(=O)O
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CC[NH2+]CC1)O2

Procedure:
Compound 15 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, trans-cyclohexane-1,2-dicarboxylic acid and conditions outlined for compound 14. M.p.=208-211° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90-7.87 (m, 1H), 7.82-7.73 (m, 2H), 7.58-7.53 (m, 1H), 3.06 (s, 2H), 2.96-2.86 (m, 4H), 2.29-2.26 (m, 2H), 1.98-1.91 (m, 4H), 1.77-1.65 (m, 4H), 1.23-1.17 (m, 4H); LCMS: 302 [M+H].
Reaction SMILES: [F:1][C:2]1[C:3]([O:20]C)=[CH:4][C:5]2[CH2:6][CH2:7][C@H:8]3[C@H:16]4[C@@H:12]([C@@H:13]([OH:17])[CH2:14][CH2:15]4)[CH2:11][CH2:10][C@@H:9]3[C:18]=2[CH:19]=1.CC(C[AlH]CC(C)C)C.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[CH2:6][CH2:7][C@H:8]3[C@H:16]4[C@@H:12]([CH:13]([OH:17])[CH2:14][CH2:15]4)[CH2:11][CH2:10][C@@H:9]3[C:18]=2[CH:19]=1
Reactant: COc1cc2c(cc1F)[C@H]1CC[C@H]3[C@@H](CC[C@@H]3O)[C@@H]1CC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1cc2c(cc1F)[C@H]1CC[C@@H]3C(O)CC[C@H]3[C@@H]1CC2

Procedure:
The solution of 0.53 g of 2-fluoro-3-methoxy-gona-1,3,5(10)-trien-17β-ol in 50 ml of toluene is mixed with 5 ml of 20% solution of DIBAH in toluene and heated for 2 hours to 80° C. After cooling, water is added drop by drop until the reaction has run its course, then it is dispersed between water and ethyl acetate, the ethyl acetate phase is washed with concentrated common salt solution and dried with sodium sulfate. After evaporation, a residue remains that is chromatographed on silica gel with hexane-ethyl acetate, and the yield is 0.32 g (63% of theory).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][C:26]2[C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[S:29][CH:30]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[S:29]1[CH:30]=[C:26]([O:25][CH:23]2[CH2:24][NH:21][CH2:22]2)[C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]1=2
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(Oc3csc4ccccc34)C2)cc1
Solvent: CCO
Solvent: ClCCl
Product: Cl
Product: c1ccc2c(OC3CNC3)csc2c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
1-Chloroethyl chloroformate (67.3 μL, 0.621 mmol) was added to a solution of 1-benzhydryl-3-(benzo[b]thiophen-3-yloxy)azetidine (220 mg, 0.592 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred for 2 hours at 0° C. and for 5 hours at room temperature. Ethanol (5 mL) was added and the reaction mixture was stirred for 1 hour at 40° C. After concentration to dryness, the crude mixture was precipitated from a mixture dichloromethane/pentane to afford a pale orange solid (140 mg, quantitative) which was used without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][NH2:23])[N:17]=1>CO>[Br:15][C:16]1[N:17]=[C:18]([NH:22][N:23]=[C:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NNc1cccc(Br)n1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=NNc2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
N-Boc piperidinone (13.8 g, 69.1 mmol) was added to a solution of 2-bromo-6-hydrazinylpyridine (13.0 g, 69.1 mmol) in MeOH (240 mL). The resulting solution was stirred at ambient temperature for 2 h. The solution was concentrated and dried to provide the title compound (25.4 g, 99%) as a white foam: 1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.49 (overlapping dd, J=7.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 3.52-3.38 (m, 4H), 2.59-2.40 (m, 2H overlaps with solvent), 2.38 (t, J=5.7 Hz, 2H), 1.41 (s, 9H); ESI MS m/z 369 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=O)C.I.[CH2:12]=[O:13].[C:14](O)(=[O:16])[CH3:15]>>[CH3:1][C:2]1[NH:3][C:4]([C:12]([O:16][CH2:14][CH3:15])=[O:13])=[C:5]([CH3:10])[C:6]=1[CH3:7]
Reactant: CC(=O)O
Reactant: C=O
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Product: CCOC(=O)c1[nH]c(C)c(C)c1C

Procedure:
2,4-Dimethyl-3-acetyl-pyrrole (0.68 g), acetic acid (15 ml), aq. hydriodic acid (15 ml) and paraformaldehyde (0.6 g) were stirred for three hours under nitrogen at room temperature. The crude product was isolated as in Example 4 (2,3,4-trimethyl-5-carbethoxy-pyrrole) then crystallized from benzene to yield 0.55 g (73%) of colourless elongated prisms, m.p. 204°-207° C. (lit. 207° H. Fischer and W. Zerweck, Berichte 56, 523 (1923)). Anal. Calc. for C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.29; H, 8.68; N, 9.38.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][CH:28]=[C:29](C(O)=O)[C:22]=3[N:21]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@H:34]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].N1([O:65][C:66](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][C:28]([C:66]([NH:33][CH:34]([C:46]([O:48][CH2:49][C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[O:47])[CH2:35][C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])=[O:65])=[CH:29][C:22]=3[N:21]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cn1c(-c2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)nc2c(C(=O)O)cccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)nc2cc(C(=O)NC(CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)ccc21

Procedure:
Prepared from 2-(4-benzyloxycarbonylamidino-phenyl)-1-methyl-benzimidazole-4-carboxylic acid and dibenzyl aspartate with the addition of 2-(1H-benztriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate in tetrahydrofuran.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:13]=1.CC1(C)C(C)(C)OB([C:28]2[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:11][N:10]1[C:9](=[O:12])[CH2:8][O:7][C:6]2[N:13]=[C:2]([C:28]3[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:30][CH:29]=3)[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:5]1=2
Reactant: CN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)COc2nc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Yield: 71.8 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.125 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (50 mg, 0.150 mmol) in 1,4-dioxane (2 ml), followed by a solution of sodium carbonate (40 mg, 0.3 mmol) in water (0.5 ml) to give a white suspension. This was degassed by bubbling nitrogen for 10 minutes, followed by the addition of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (9 mg, 0.013 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with brine (4 ml) and extracted into ethyl acetate (3×4 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a white solid (40 mg, 72% yield). 1H-NMR (500 MHz, CDCl3) δ 7.27-7.32 (5H, m), 7.25 (1H, s), 7.16-7.20 (2H, m), 7.10 (2H, d), 4.89 (2H, s), 4.81 (1H, br s), 4.26 (2H, br s), 3.39 (3H, s), 1.23 (9H, br s). LCMS (Method D): RT=1.40 min, M+H+=446.20.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>>[ClH:1].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Product: COc1cc2ncnc(Nc3ccc(F)c([N+](=O)[O-])c3)c2cc1OC
Product: Cl

Procedure:
Using analogous procedures to those described in the portion of Example 2 which is concerned with the preparation of starting materials, 4-chloro-6,7-dimethoxyquinazoline was reacted with 4-fluoro-3-nitroaniline to give 4-(4-fluoro-3-nitroanilino)-6,7-dimethoxyquinazoline hydrochloride; NMR: 3.98 (s, 3H), 4.03 (s, 3H), 7.39 (m, 1H), 7.7 (m, 1H), 8.25 (m, 1H), 8.44 (m, 1H), 8.62 (m, 1H), 8.9 (m, 1H), 11.85 (s, 1H); Mass: M+H+ 345 and that material was reduced during 1.5 hours to give 4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline; NMR: 3.9 (s, 3H), 3.92 (s, 3H), 5.11 (s, 2H), 6.84 (m, 1H), 6.96 (m, 1H), 7.12 (s, 1H), 7.18 (s, 1H), 7.79 (s, 1H), 8.39 (s, 1H); 9.22 (s, 1H); Mass: M+H+ 315.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([S:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[CH2:21][CH2:20][CH2:19]3)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:28](C)[C:29]([O:31][CH2:32]C)=[O:30]>O.[Zn]>[CH3:32][O:31][C:29](=[O:30])[CH2:28][C:22]1([OH:26])[C:23]2[C:18](=[CH:17][C:16]([S:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:15])=[O:14])=[CH:25][CH:24]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [Zn]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)CC1(O)CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution/suspension of anhydrous benzene (25 mL), powdered Zinc metal (0.505 g, 7.72 mmol), 12 (0.01 g) and 6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one was stirred for 10 minutes at room temperature. Ethyl bromopropionate (0.784 mL, 1.18 g, 7.07 mmol) was added and the reaction mixture was heated to reflux for 2.5 hours. The reaction mixture was allowed to cool, diluted with 300 mL of water and extracted twice with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield (6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester. MS: 375 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:8]([S:9][CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCc1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(CSCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of phenylethyl mercaptan (0.66 g, 4.80 mmol) and methyl 3-(bromomethyl)benzoate (1.0 g, 4.37 mmol) in DMF (10 mL) was added Cs2CO3 (2.84 g, 8.73 mmol). The suspension was stirred at rt for 3 h. The reaction mixture was then diluted with ethyl acetate and water. The organic layer was separated, washed with brine three times, dried over MgSO4. The filtrate was concentrated in vacuo to give a light yellow oil. The crude product was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane to give the desired product (1.2 g, 96%) as a colorless oil. 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.96-7.94 (m, 1H), 7.55-7.53 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.33-7.28 (m, 2H), 7.25-7.17 (m, 3H), 3.95 (s, 3H), 3.76 (s, 2H), 2.89-2.85 (m, 2H), 2.69-2.65 (m, 2H). MS (ESI): 287.1 (M+H)−.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-diphenylaminophenyl boronic acid (2.57 g, 8.9 mmol), 4-bromo-iodobenzene (5.03 g, 17.8 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and K2CO3 (3.0 g, 22 mmol) in dioxane/water (80 mL/15 mL) was degassed and heated at about 80° C. for about 20 hours. The whole was mixed with water/dichloromethane, the organic phase was collected and washed with brine, dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 30:1). The desired fraction was collected, and concentrated to give a white solid (Compound 12), which was filtered and washed with methanol (2.70 g, in 76% yield).