Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][C:16]1[CH:17]=[C:18]([NH2:31])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].O>CN(C)C(=O)C>[CH3:15][C:16]1[CH:17]=[C:18]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Cc1cc(N)ccc1S(=O)(=O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.72 g, 4.5 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.54 g, 4.5 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 3-Methyl-4-(phenylsulfonyl)-benzeneamine (0.75 g, 3.0 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered to yield a brown solid which was purified by flash column chromatography (5% v/v ethyl acetate/methylene chloride). Trituration of the resulting solid with hexane yielded the title propanamide as a white solid (0.95 g, 82%); mp 141°-143° C. 1H-NMR (300 MHz, d6-DMSO): 1.58 (s, 3H, CH3) 2.32 (s, 3H, ArCH3) 7.55-7.70 (m, 4H, aromatic) 7.79-7.85 (m, 3H, aromatic) 7.92 (dd, 1H, J=8.8, 1.9 Hz, aromatic) 8.10 (d, 1H, J=8.8 Hz, aromatic) 10.30 (s, 1H, NH). MS (CI, CH4): 388 (M+1).
Reaction SMILES: Cl.[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(C)(C)C>C(OCC)(=O)C>[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -12.5 °C
Reaction time: 1.25 h

Procedure:
A cooled solution (-15° C.) of gaseous HCl (50.0 g, 1.37 mol) in ethyl acetate (250 g) was added to Boc-Leu-Leu-Lys(Z)-OBzl (50.0 g, 71.7 mmol) at -15 to -10° C. over 15 min. The mixture was stirred at -15 to -10° C. for 75 min and t-butyl methyl ether (310 g) was added over 25 min. The temperature was allowed to rise to about -8 to -5° C. and the excess HCl was removed under reduced pressure. Another portion of t-butyl methyl ether (310.0 g) was added over 15 min and the reaction temperature was maintained at -5° C. for approximately 2 h. The resulting solid product, H-Leu-Leu-Lys(Z)-OBzl·HCl was filtered and rinsed with t-butyl methyl ether then dried to give 41.8 g, 92.1%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=[C:20]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:30]=[C:24]12
Reactant: Cc1ccc(Oc2ccc(CO)cc2C#N)cn1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: Cc1ccc(Oc2ccc(COc3cc4n(c(=O)n3)CCCN4C)cc2C#N)cn1

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 5-(hydroxymethyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>C(#N)C.O>[C:1]1([C@@H:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)CN1CCN([C@@H](c2ccccc2)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazine (2.0 g, 6 mmol) in acetonitrile (20 mL) was added methyl bromoacetate (0.59 mL, 6 mmol) dropwise at rt. The reaction was stirred for 30 min. and triethylamine (3.6 mL, 26 mmol) was added. After stirring for 18 h at rt, the reaction mixture was diluted with water and extracted with CH2Cl2. The organic layers were combined, washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-40% ethyl acetate or 0-2% ethyl acetate in CH2Cl2 to give a mixture of enantiomers (2.0 g, 80%). The enantiomers were separated by chiral chromatography as described below and two peaks were collected with 100% ee.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:13]1[CH:22]2[CH:17]([CH:18]=[CH:19][CH:20]=[CH:21]2)[C:16](=[O:23])[CH2:15][CH2:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1.CC(=O)OCC>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:13]1[CH:22]2[CH:17]([CH:18]=[CH:19][CH:20]=[CH:21]2)[C:16](=[O:23])[CH2:15][CH2:14]1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: O=C1CCNC2C=CC=CC12
Agent: c1ccc2ncncc2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCN(c2ncnc3ccc(I)cc23)C2C=CC=CC12
Yield: 38.4 %

Procedure:
0.75 g of 4-chloro-6-iodoquinazoline, 0.51 g of 2,3,4a,8a-tetrahydro-1H-quinolin-4-one and 0.96 ml of triethylamine in 5 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 16 min.), giving 0.40 g of 1-(6-iodoquinazolin-4-yl)-2,3,4a,8a-tetrahydro-1H-quinolin-4-one as yellowish solid (yield 40%, content 91%); MS-FAB (M+H+)=402.0; Rf (polar method): 2.20 min.
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[O:34])[NH:14][C@H:15]([CH3:31])[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[N+:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=2)=[O:34])[NH:14][C@H:15]([CH3:31])[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1

Procedure:
To a solution of the compound (1.087 g), which had been obtained in (1), in anhydrous dichloromethane (5 ml), trifluoroacetic acid (2 ml) was added dropwise under ice cooling. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation, Infrared absorption spectrum (KBr) νmax cm-1 : 3290, 1739, 1674, 1645, 1625, 1555, 1524.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([CH3:22])[CH:21]=2)[CH:18]=[C:17]([CH:23]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH:30][CH2:23][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[C:20]([CH3:22])[CH:21]=[C:12]([O:11][CH:8]3[CH2:7][CH2:6][CH:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1
Reactant: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccc(C=O)cc12
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)CNCc1ccc2cc(OC3CCC(C(C)(C)C)CC3)cc(C)c2c1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of 6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalene-2-carbaldehyde (50 mg, 0.15 mmol), glycine methyl ester, hydrochloride (27 mg, 0.22 mmol) and N,N-diisopropylethylamine (DIEA) (34 uL) in 1,2-dichloroethane (2 mL) was stirred for 1 hour at room temperature. Then sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added and stirred for 3 hrs. The reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate aqueous, dried over MgSO4, filtered, and concentrated. The crude was purified via silica gel column chromatography eluted 0-5% MeOH in methylene chloride to give the light brown solid (53 mg, yield: 86%). ESI-MS: 420.30 (M+23)+.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C@@:11]([O:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[O:19][C@@H:10]([C@@:11]([O:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][OH:8]
Reactant: C=CCC[C@@](C)(OC)[C@@H](COCc1ccccc1)OC1CCCCO1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC[C@@](C)(OC)[C@@H](CO)OC1CCCCO1

Procedure:
A mixture of (2R,3R)l-benzyloxy-2-tetrahydro-pyranyloxy-3-methoxy-3-methyl-6-heptene (1.78 mmol, 620 mg) and Pd(OH)2 on carbon (60 mg) in methanol (8 ml) is stirred 3 h under an hydrogen atmosphere whereby 82 ml of hydrogen is absorbed. The catalyst is filtered, washed with methanol and the methanol is removed in vacuo. The alcohol 12b is used as such in the next reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C(N(CC)CC)C.Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[BH4-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thiophene aldehyde (11.2 g) was dissolved in 100 mL of methanol, then 12.1 g of triethylamine and 16.1 g of ethyl 3-aminopropionate hydrochloride were added thereto in this order and the mixture was stirred overnight at room temperature. The reaction solution was cooled down to 0° C., 2.27 g of sodium borohydride was slowly added thereto little by little and the mixture was stirred at room temperature for 1 hour.
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[O:4][C:3]1([CH3:15])[CH3:14].[S:16]([O-])([O-])(=O)=S.C([N+](CC)(CC)CC)C.C([N+](CC)(CC)CC)C>C(O)C.C(OCC)C.C(Cl)Cl>[CH3:14][C:3]1([CH3:15])[C:2](=[S:16])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[O:4]1
Reactant: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1Br
Reactant: O=S([O-])([O-])=S
Agent: CC[N+](CC)(CC)CC
Solvent: CCOCC
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flask are placed 5.44 g (0.020 mole) of 3-bromo-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran (prepared by the method of Example 2, Step A) and 7.45 g (0.020 mole) of tetraethylammonium thiosulfate (prepared by the method of B. Hahn et al., Liebigs Ann. Chem. 1981, 10-19) in 100 mL of absolute ethanol. This mixture is heated at reflux for 24 hours after which the solvent is removed under reduced pressure, leaving a residue. This residue is taken up in 60 mL of diethyl ether which is then filtered to remove inorganic salts. Slowly, 20 mL of a 2N aqueous sodium hydroxide solution is added to the rapidly stirred filtrate. This mixture is stirred for 30 minutes at room temperature after which the aqueous phase is separated from the organic phase. The latter is washed with water, dried over anhydrous sodium sulfate, and filtered. The solvent is evaporated under reduced pressure, leaving a residue which is dissolved in methylene chloride. This solution is passed through a column of silica gel, eluting with methylene chloride. Product-containing fractions are combined, and the solvent is evaporated under reduced pressure, yielding 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-thione.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:15])([F:14])[C:10](Br)([F:12])[F:11].N1C=CC=CC=1C1C=CC=CN=1.CS(C)=O.Cl>CC1CCCCC1.[Cu]>[F:14][C:9]1([F:15])[C:10]([F:12])([F:11])[C:2]2[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)(F)Br)c(Cl)c1
Agent: [Cu]
Agent: Cl
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC1CCCCC1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)C(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 311.8 %

Procedure:
Into a pressure bottle was placed 10.0 g (0.028 mole) 3-chloro-4-(2-bromo-1,1,2,2-tetrafluoroethoxy)nitrobenzene, 9.0 g (0.14 mole) copper powder (200 mesh), 0.45 g (0.0028 mole) 2,2'-bipyridyl, and 40 mL of dimethylsulfoxide. The pressure bottle was sealed and the reaction mixture stirred at 190°-195° C. for two hours. The pressure bottle was cooled to room temperature, opened, and the contents poured into a separatory funnel. Approximately 200 mL of a 2N hydrochloric acid solution was added to the separatory funnel. The mixture was extracted with three 150 mL portions of diethyl ether. The extracts were combined and washed in succession with 200 mL of a 2N hydrochloric acid solution, 200 mL of a saturated aqueous sodium chloride solution, and 200 mL of a 2N sodium hydroxide solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure leaving an oil. The reaction described above was repeated six additional times. The residual oils from the seven experiments were combined and subjected to column chromatography on silica gel, eluting with toluene, to yield a yellow oil. This oil was dissolved in 125 mL methylcyclohexane and the solution placed in a freezer for approximately 18 hours. Crystals had formed and were collected by filtration to yield 20.7 g 2,3-dihydro-2,2,3,3-tetrafluoro-5-nitrobenzofuran. The filtrate was evaporated under reduced pressure leaving an oil. Distillation of this oil under reduced pressure provided an additional 3.0 g of product (bp 75° C./0.2 mm). Hydrogenation of 2.15 g (0.011 mole) 2,3-dihydro-2,2,3,3-tetrafluoro-5-nitrobenzofuran with a catalytic amount (0.25 g) of platinum oxide in 150 mL of methanol produced 2.15 g of 5-amino-2,3-dihydro-2,2,3,3-tetrafluorobenzofuran.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:19]([C:20]([O:22]C)=[O:21])=[C:18]([C:24]4[CH:32]=[CH:31][C:27]5[O:28][CH2:29][O:30][C:26]=5[CH:25]=4)[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:33][CH:34]([CH3:36])[CH3:35])[CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:24]4[CH:32]=[CH:31][C:27]5[O:28][CH2:29][O:30][C:26]=5[CH:25]=4)[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:33][CH:34]([CH3:36])[CH3:35])[CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)C1=C(c2ccc3c(c2)OCO3)c2cc(OC(C)C)ccc2OC1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc2c(c1)C(c1ccc3c(c1)OCO3)=C(C(=O)O)C(c1ccc3c(c1)OCO3)O2

Procedure:
A mixture of compound (Ia-3) (57 mg, 0.117 mmol) and 1 M aqueous solution of sodium hydroxide (1.2 ml) in THF (2 ml) and methanol (2 ml) were refluxed for 1 h. The solvent was removed under reduced pressure, acidified with hydrochloric acid and extracted with ether three times. The ether layers were combined, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone-isopropylether to give compound (I-1) (37 mg, 66%) as yellow crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8](=[CH:11]Cl)[CH:9]=O.[NH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.C(C=C)=O>C(Cl)Cl.CN(C)C=O>[Cl:7][C:8]1[CH:9]=[N:13][C:14]2[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[C:15]=2[CH:11]=1
Reactant: O=CC(Cl)=CCl
Reactant: NC1CCCC(=O)C1
Agent: C=CC=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCc2ncc(Cl)cc21

Procedure:
In reaction 3 of Scheme 1, a solution of oxalyl chloride in methylene chloride is added dropwise to a solution of chloromalondialdehyde III in methyene chloride and a phase transfer catalyst, such as dimethylformamide, under inert reaction conditions. The reaction mixture is stirred at room temperature until conversion to the corresponding 2,3-dichloroacrolein is complete. In reaction 4 of Scheme 1, a solution of 1-amino-cyclohexan-3-one VI in dimethylformamide is added dropwise to the above acrolein to form the corresponding 3-chloro-5,6,7,8-tetrahydroquinolin-5-one VII. The reaction, generally carried out overnight, will be in the temperature range between about 60° C. to about 80° C., preferably about 70° C.
Reaction SMILES: [Si:1]([CH:8]1[C:12](=[CH:13][O:14][Si](C(C)(C)C)(C)C)[C:11]2[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:26][CH:27]([CH3:29])[CH3:28])[C:10]=2[O:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl>CO>[Si:1]([C:8]1[O:9][C:10]2[C:25]([O:26][CH:27]([CH3:28])[CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=[CH:22][C:11]=2[C:12]=1[CH:13]=[O:14])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1OC(C)C)OC([Si](C)(C)C(C)(C)C)C2=CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc2c(C=O)c([Si](C)(C)C(C)(C)C)oc2c1OC(C)C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 2-t-butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy-7-isopropoxybenzofuran (2.69 mmol) in methanol (100 mL) was added concentrated hydrochloric acid (200 μL) and the reaction was stirred for 30 minutes (monitored by tlc), quenched with triethylamine (2 mL) and the solvent removed by distillation under vacuum. The residue was dissolved in dichloromethane (20 mL), washed with water (10 mL), dried over magnesium sulfate, concentrated under vacuum and co-distilled with toluene (20 mL). The crude product was dissolved in dry dichloromethane (4 mL) and added to a stirred solution of Collin's reagent (chromium trioxide (1.01 g), pyridine (1.65 mL) in dry dichloromethane (30 mL)). The suspension was stirred for 10 minutes, filtered and the residue washed with diethyl ether (20 mL). The filtrate was concentrated onto silica (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl-ether/triethylamine (90:9:1) to afford the title compound as a light yellow oil (503 mg, 48%); 1H NMR (300 MHz, CDCl3) δ 10.25 (s, 1H, CHO), 7.79 (d, 1H, J=8.45 Hz), 6.98 (d, 1H, J=8.46 Hz), 4.65 (m, 1H), 3.89 (s, 3H, OMe), 1.35 (d, 6H, J=6.17 Hz), 0.97 (s, 9H), 0.45 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CO[C:11](OC)([CH3:13])[CH3:12]>C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH3:12][C:11]1([CH3:13])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: COC(C)(C)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CC1(C)OC[C@H]2CCC(=O)N21
Temperature: 88 °C
Reaction time: 0.08 h
Yield: 45.3 %

Procedure:
To a mixture consisting of (R)-5-hydroxymethyl-2-pyrrolidinone (50.0 g, 434 mmol) in 2,2-dimethoxypropane (533 mL, 4300 mmol) was added camphorsulfonic acid (2.85 g, 10.8 mmol). The stirring mixture was brought to reflux at 88° C. for 1.5 hours, while removing methanol by distillation. The reaction mixture was subsequently heated to 95° C. for one hour, cooled to room temperature, treated with triethylamine (5 mL), and stirred for 5 minutes. The mixture was then diluted with hexanes-ethyl acetate (500 mL, 1:3 v/v) and washed sequentially with a 50% aqueous solution of sodium chloride and a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by crystallization from hexanes to afford the title compound as white crystalline solid (30.48 g, 45%); TLC Rf 0.4 (solvent system: 5:95 v/v methanol:dichloromethane) MS (ESI+) m/z 156.1 (M+H)+, 178.1 (M+Na)+; 1H-NMR (CDCl3) δ 4.3-4.2 (m, 1H), 4.1 (dd, 1H), 3.5 (t, 1H), 2.9-2.7 (m, 1H), 2.6-2.5 (m, 1H), 2.2-2.1 (m, 1H), 1.9-1.7 (m, 1H), 1.7 (s, 3H), 1.5 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[NH:7][CH:8]=[CH:9][C:10]=2[C:11]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][CH3:23])[N:16]=[CH:15]2.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][CH3:23])[N:16]=[CH:15]2
Reactant: CNc1ncc2cc(-c3c(C)cnc4c(=O)[nH]ccc34)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CNc1ncc2cc(-c3c(C)cnc4c(Cl)nccc34)ccc2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 3-methyl-4-(2-(methylamino)quinazolin-6-yl)-1,7-naphthyridin-8(7H)-one (0.400 g, 1.26 mmol) and phosphorous oxychloride (5.00 ml, 1.26 mmol) was heated to 100° C. After 3 hours, the volatiles were removed under vacuum. Residual phosphorous oxychloride was azeotroped with toluene. The resulting residue was dissolved in chloroform and washed with cold water. The organic layer was then washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 50 to 100% EtOAc in hexanes to give 6-(8-chloro-3-methyl-1,7-naphthyridin-4-yl)-N-methylquinazolin-2-amine as a yellow solid. MS(M+H)+ 336.