Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][NH:23]2>CN1C(=O)CCC1>[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][N:23]2[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: Fc1cccc2c1CCCN2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4c(F)cccc43)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, 4.19 mmol) in NMP (10.0 mL) was added 5-fluoro-1,2,3,4-tetrahydroquinoline (1.5 g, 9.92 mmol) with stifling for 1 h at 150° C. in an oil bath. The reaction mixture was cooled to room temperature, precipitated with water (100 mL). The solids were collected by filtration and dried in an oven under reduced pressure to afford methyl 3-(5-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (1.0 g, crude).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:22](=[O:23])[N:21]([CH3:24])[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)[CH:6]=[CH:7][CH:8]=1)#N.CC(O)=[O:27].[PH2]([O-])=O.[Na+]>[Ni].N1C=CC=CC=1>[CH3:24][N:21]1[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:27])[C:22]1=[O:23])=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3
Reactant: CC(=O)O
Reactant: Cc1ccc2[nH]c3c(cc(-c4cccc(C#N)c4)c(=O)n3C)c2c1
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc2[nH]c3c(cc(-c4cccc(C=O)c4)c(=O)n3C)c2c1
Temperature: 60 °C

Procedure:
450 mg of 3-(3-cyanophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one, 10 ml of AcOH, 20 ml of pyridine, 2.6 g of sodium hypophosphite and 434 mg of Raney Ni are mixed and then the mixture is heated at 60° C. for 4 hours. The reaction medium is filtered and the filtrate is evaporated; the residue is taken up in 50 ml of AcOEt/CH2Cl2 (1/1; v/v) and the organic phase is washed with water, dried and evaporated to produce the expected compound, M.p.=280° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][NH:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(CO)NCCCOc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Yield: 38.2 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.6 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with 2-amino-2-methyl-1-propanol (0.159 mL, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(1-hydroxy-2-methyl-2-propylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (37.7 mg, yield 38%).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(O)(=O)C>[Br:27][CH:1]([C:3]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1)[CH3:2]
Reactant: CCc1nc2cccc(C)c2c(=O)n1-c1ccc(F)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2nc(C(C)Br)n(-c3ccc(F)cc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a mixture of 1.969 g 2-ethyl-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one (IX) (6.974 mmol, 1.000 equiv) and 0.687 g sodium acetate (8.37 mmol, 1.20 equiv) in 28 mL glacial acetic acid at 40° C. (external temperature, oil bath) was added a solution of 0.372 mL bromine (7.32 mmol, 1.05 equiv) dissolved in 5 mL glacial acetic acid dropwise by addition funnel over 30 min. After 2 h the reaction solution was poured into 250 mL water. The resulting mixture was stirred vigorously at room temperature for 1 h, after which time the precipitate was collected by vacuum filtration, rinsing with warm (ca. 40° C.) water (3×50 mL). The solid was dried in vacuo over phosphorous pentoxide overnight, affording 2.19 g of a white solid. m.p. decomposes upon heating. 1H NMR (CDCl3)δ2.04 (d, 3H, J=6.8 Hz), 2.82 (s, 3H), 4.51 (q, 1H, J=6.8 Hz), 7.15 (ddd, 1H, J1=2.4 Hz, J2=4.4 Hz, J3=8.4 Hz), 7.23 (dd, 1H, J1=2.8 Hz, J2=10.8 Hz), 7.25-7.31 (m, 2H), 7.56 (ddd, J1=2.8 Hz, J2 4.8 Hz, J3 8.8 Hz), 7.64 (2×d, 2×1H, J=5.2 Hz) ppm. MS (ESI+) 361.1 [MH]+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1F)[NH2:21].[CH:26](O)(C)[CH3:27]>>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[C:2]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([C:26]#[CH:27])[CH:19]=3)=[N:3][C:4]3[C:9]([C:10]=2[CH:15]=1)=[CH:8][CH:7]=[CH:6][N:5]=3
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Clc1ccc2c(Cl)nc3ncccc3c2c1
Reactant: CC(C)O
Product: C#Cc1cccc(Nc2nc3ncccc3c3cc(Cl)ccc23)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
6,9-Dichloro-benzo[c][1,8]naphthyridine (20 mg, 0.08 mmol), and 3-chloro-4-fluoroaniline (24 mg, 0.16 mmol) were suspended in isopropanol (2 mL) and stirred overnight at 120° C. The reaction solution was cooled to room temperature, and the resulting precipitate was filtered, washed with isopropanol, and dried under vacuum to provide 57 (18 mg, 63% yield) as a yellow solid. LC-MS (M+H=358, obsd.=358). 1H NMR (400 MHz, d6-DMSO): δ 10.75 (s, 1H), 9.63 (dd, 1H), 9.07 (d, 1H), 8.99 (d, 1H), 8.86 (dd, 1H), 8.33 (dd, 1H), 8.09 (dd, 1H), 8.04 (m, 1H), 7.80 (dd, 1H), 7.52 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:13])=[O:12].O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:12])=[O:13]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-3-chlorosulfonyl-benzoic acid (6.90 g, 23.04 mmol, 1.00 Eq) in SOCl2 (27.41 g, 230.40 mmol, 10.00 Eq) was stirred at 80° C. for 3 hr. Then the solvent was evaporated. The residue was diluted in TOLUENE (50 mL), and MeOH (959.66 mg, 29.95 mmol, 1.30 Eq) was added, the formed mixture was stirred at 110° C. for 2 hr. Solid was formed, and the solvent was evaporated, the solid was washed with PE, and filtered to afford product methyl 4-bromo-3-chlorosulfonyl-benzoate (7.22 g, 23.03 mmol, 99.94% yield) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28]Cl>>[CH3:25][O:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Reactant: COCCCl
Product: COCCOc1ccc(CCc2ccc3cc(C(C)NC(C)=O)oc3c2)cc1
Yield: 25 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (32.3 mg, 0.100 mmol) obtained in Example 165 and 2-chloroethyl methyl ether (0.0189 mL, 0.200 mmol) and in the same manner as in Example 158, the title compound was obtained (9.4 mg, yield 25%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([O:7][C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[C:17]([F:20])([F:19])[F:18])[CH2:3]1.[H][H].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C.[Pt]>[CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([O:7][C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=2[C:17]([F:18])([F:19])[F:20])[CH2:3]1
Reactant: [H][H]
Reactant: CN1CC[C@@H](Oc2cc([N+](=O)[O-])ccc2C(F)(F)F)C1
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CN1CC[C@@H](Oc2cc(N)ccc2C(F)(F)F)C1

Procedure:
A solution of 2-((R)-1-Methyl-pyrrolidin-3-yloxy)-4-nitrobenzotrifluoride (7.8 g, 26.9 mmol) in ethyl acetate (50 ml) was treated with 10% platinum on carbon (200 mg) then subjected to 40 psi hydrogen pressure for 3 hrs. The slurry was treated with anhydrous magnesium sulfate (5 g) then filtered through a pad of Celite. The filter cake was rinsed with ethyl acetate (2×25 ml) then the filtrate was evaporated under reduced pressure to an oil. This oil was evaporated twice for dichloromethane (50 ml) to remove trapped ethyl acetate. This gave the product as a clear light brown oil that solidified on standing (6.9 g, 99%): LCMS 249 (M++H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[NH4+:28]>CO.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Yield: 26 %

Procedure:
A solution of the 9-[(phenyl)methyl]-4-hydroxy-5-Carbomethoxy carbazole (200 mg, 0.6 mM) in 4 mL MeOH and 40 mL concentrated aqueous ammonium hydroxide was sonicated for 30 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 50 mg (26%) of the 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=1 and 8 Hz), 7.5-7.1 (m, 9H), 6.6 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3428, 3198, 3063, 1631, 1599, 1579, 1562, 1496, 1442, 1330, 1261, 1215, 775, and 697. MS (ES) m/e 315, 317.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CS(C)=O.[H-].[Na+].S(OCC1CCC=CC1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=O)=O>O>[CH2:1]([O:11][CH2:25][CH:24]1[CH2:26][CH2:27][CH2:21][CH:22]=[CH:23]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCOCC1C=CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 23.7g (0.15 mol) decyl alcohol, and 150 mL of DMSO. Sodium hydride (4.22 g, 95% in purity; 0.167 mol) was slowly added to above mixture in an ice bath over 20 min. After the above mixture was reacted at room temperature for 3 hrs, the reaction mixture was cooled to room temperature. 3-Cyclohexene-1-methanol tosylate (39.9 g, 0.15 mol) was slowly added to the above mixture over 20 min. The reaction was carried at room temperature overnight, then 80° C. for 3 hrs. The reaction mixture was added to water (150 mL), and then extracted with chloroform (3×150 niL), washed to water (2×100 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: CCC(NC(=O)Cc1ccc(Cl)c(Cl)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above) the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20](C)[CH:19]=[CH:18]2.[NH3:24]>>[CH3:4][CH:3]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([NH2:24])[CH:19]=[CH:18]2)[CH2:2][CH2:11][CH2:10][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: N
Reactant: Oc1ccc2cccnc2c1
Product: CC(CCCOc1ccc2cccnc2c1)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 86 substituting 7-hydroxyquinoline for 8-hydroxyquinaldine. 1H NMR (500 MHz, CDCl3) δ ppm 8.99 (br d, 1H), 8.61 (d, 1H), 7.88 (d, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 7.65 (dd, 1H), 7.30 (m, 2H), 7.19 (m, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 4.73 (m, 1H), 4.22–4.42 (m, 2H), 2.19 (m, 2H), 2.00 (m, 2H), 1.48 (d, 3H); MS (DCI/NH3) m/z 373 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[N:15])[C:8]=2[CH3:13])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])N.[H][H]>[Ni].O.C(O)(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][NH:15][C:20]3[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:18]([O:17][CH3:16])[CH:19]=3)[C:8]=2[CH3:13])[N:3]=1
Reactant: [H][H]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Cc1c(C#N)ccc2nc(N)nc(N)c12
Agent: [Ni]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
Reaction time: 1.5 h
Yield: 27.1 %

Procedure:
A mixture of 1.1 grams (0.005 mole) of 2,4-diamino-6-cyano-5-methylquinazoline, 4.6 grams (0.025 mole) 3,4,5-trimethoxyaniline and 2.0 grams (catalyst) of Raney nickel (50% slurry in water) in 30 mL of water and 70 mL of acetic acid was hydrogenated at 50 psi of hydrogen for 6 hours using a Parr hydrogenator. After this time the reaction mixture was filtered. The filter cake was slurried with a boiling mixture of 15 mL of water and 35 mL of acetic acid and was then filtered. The filtrates were combined and subjected to thin layer chromatography (TLC). The TLC analysis indicated that a small amount of the starting quinazoline remained unreacted. The filtrate was combined with 1.0 gram of Raney nickel and the mixture was again hydrogenated for an additional 1.5 hours using the Parr hydrogenator. After this time the reaction mixture was filtered and concentrated under reduced pressure to a residual oil. The residual oil was subjected to column chromatography on silica gel. Elution was accomplished initially using 25% N,N-dimethylformamide in ethyl acetate and, finally 40% N,N-dimethylformamide in ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure to a residual solid. The solid was recrystallized from water, yielding 0.5 gram of 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylamino)methyl]quinazoline, mp 95°-210° C. The NMR analysis was consistent with the proposed structure; however, it indicated that the compound was a complex with acetic acid and water.
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:11][C@@H:10]1[C@@H:12]([O:13][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:14]([O:15][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:16]([CH2:18][O:19][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][C@H:9]1[O:8][C@@H:7]1[C@@H:20]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:21][CH:2]([O:1][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]([O:4][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:5]1[O:6][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)C(OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lactose (1.0 g, 2.92 mmol) was dissolved in dry pyridine (20 mL) at 0° C. DMAP (cat.) was added. Benzoyl chloride (2.5 equiv., 58 mmol, 6.8 mL) was added dropwise and the solution stirred at room temperature overnight. The solution was poured onto a mixture of ice-water and DCM. The organic layer was washed with NaHCO3(sat.) (×7), brine, H2SO4 (5%) (×2), followed by brine. The solution was dried (Na2SO4) and the solvent evaporated. The product was passed through a short silica plug to remove the remaining benzoyl chloride and the solvent was evaporated to yield 3.67 g (quantitative) of the white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[F:9][C:10]1[CH:18]=[C:17]([C:19](O)=[O:20])[C:16]([CH3:22])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].O.CN([CH:27]=[O:28])C>>[F:9][C:10]1[CH:18]=[C:17]([C:19]([O:28][CH3:27])=[O:20])[C:16]([CH3:22])=[CH:15][C:11]=1[C:12]([O:14][CH3:1])=[O:13]
Reactant: Cc1cc(C(=O)O)c(F)cc1C(=O)O
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(F)c(C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.2 g) and iodomethane (0.7 ml) were added to a solution of 2-fluoro-5-methylterephthalic acid (755 mg) in DMF (5 ml), followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was further washed with water and then saturated brine, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10), and the solvent was evaporated under reduced pressure to obtain, as a colorless solid, dimethyl 2-fluoro-5-methylterephthalate (708 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])[CH2:31][CH2:30]1>C(#N)C.O>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH2:33][CH2:34]2)[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 79.9 %

Procedure:
Pulverized potassium carbonate (0.76 g, 5.5 mmole) and potassium iodide (0.97 g, 5.5 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-ylmethyl)piperidine (1.16 g, 5.0 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (1.27 g, 5.0 mmole) in 25 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 5 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (1.8 g, 80%). Treatment with an excess of 1M etheral hydrochloric acid gave the acid addition salt, which was recrystallized from methanol.
Reaction SMILES: CC1(C)CO[C:5]2([CH:7]=[C:6]2[CH:8]([OH:22])[C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13])[O:4]C1.S(=O)(=O)(O)O.O>C(OCC)C.O1CCCC1>[C:18]([O:17][C:15]([NH:14][C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]([C:6]1[C:5](=[O:4])[CH:7]=1)[OH:22])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)C1=CC12OCC(C)(C)CO2
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)c1cc1=O
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of 8.80 g of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone 2,2-dimethyl-1.3-propanediyl acetal obtained in Example 5 in 100 ml of diethyl ether and 20 ml of tetrahydrofuran were added 0.2 ml of 2 N sulfuric acid and 1 ml of water, and the mixture was stirred for 30 minutes. After subsequent addition of 300 ml of ether, the resulting product was washed sequentially in 50 ml of an aqueous 0.01 N sodium hydroxide solution and an aqueous saturated brine. After drying over magnesium sulfate, the product was filtered and concentrated, followed by purification by silica gel column chromatography (eluent; hexane: ethyl acetate =1:2) to produce the objective product (3.15 g).