Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([NH:28]C(=O)C)=[CH:24][CH:23]=3)[C:20](=[O:32])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:33]>Cl>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]2[C:20](=[O:32])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:8]2[CH:7]=[C:6]([CH3:33])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:10]([CH3:11])[CH:9]=2)=[CH:23][CH:24]=1
Reactant: CC(=O)Nc1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccccc3c2=O)cc1
Agent: Cl
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cc(C)c1OCCO
Yield: 74.7 %

Procedure:
A solution of N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)acetamide (2.0 g, 4.50 mmol) in 2N HCl (50 mL) was stirred at reflux temperature for 30 minutes. Solids were filtered off and the aqueous filtrate was basified with NaOH. The filtrate was then extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 2% to 10% MeOH in CH2Cl2 afforded the title compound as an off-white solid (1.35 g, 75%). 1H-NMR (300 MHz, DMSO-d6): δ 8.14 (d, J=6.9 Hz, 1H), 7.76-7.93 (m, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.45-7.64 (m, 1H), 7.03 (s, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.44 (d, J=8.5 Hz, 2H), 5.21 (s, 2H), 4.84 (t, J=5.5 Hz, 1H), 3.49-3.72 (m, 4H), 2.11 (s, 6H). MS (APCI) m/z: 402 (M+H)+.
Reaction SMILES: Cl.C(O[C:7]([N:9]([C:11]1[C:12]([F:37])=[CH:13][C:14]([F:36])=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[CH3:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[CH:16]=1)C)=O)(C)(C)C>>[F:29][C:23]1[CH:22]=[C:21]2[C:26](=[C:25]([CH3:27])[C:24]=1[F:28])[N:17]([C:15]1[CH:16]=[C:11]([NH:9][CH3:7])[C:12]([F:37])=[CH:13][C:14]=1[F:36])[CH:18]=[C:19]([C:31]([OH:33])=[O:32])[C:20]2=[O:30]
Reactant: CCOC(=O)c1cn(-c2cc(N(C)C(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Agent: Cl
Product: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(C)c32)c(F)cc1F
Reaction time: 72 h
Yield: 80.2 %

Procedure:
12N Hydrochloric acid (4 ml) was added to ethyl 1-[5-(N-tert-butoxycarbonyl-N-methylamino)-2,4-difluorophenyl]-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (400 mg), and the mixture was stirred for 3 days while heating under reflux. After the reaction mixture was allowed to cool, solids were collected by filtration, washed with ethanol and dried to obtain the title compound (240 mg) as a colorless powder.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[C:1]1([C@@H:7]([CH3:10])[CH2:8][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](CO)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 112.4 %

Procedure:
An oven dried 250.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with (2R)-2-phenylpropan-1-ol (2.0 mL, 14.32 mmol), phthalimide (2.1 g, 14.32 mmol), triphenylphosphine (5.63 g, 21.48 mmol) and THF (70.0 mL). To this solution at room temperature was then added a solution of diethylazodicarboxylate (3.38 mL, 21.48 mmol) dissolved in THF (10.0 mL) over a period of 15-20 minutes (reaction exothermed slightly to 50° C. by the end of addition went from clear to reddish color). Stirred reaction to room temperature overnight). To the red solution was added water (50.0 mL) and the organic extracted with chloroform (140.0 mL). Dried the organic solution with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to an oil. To the oil was added heptane (150.0 mL) with stirring. Filtered of precipitates, then concentrated filtrate to an oil. Plug filtration of the oil over silica gel with 1:1 ethylacetate/hexane and concentrating product fractions afforded the intermediate title compound, 2((2R)-2-phenylpropyl)isoindoline-1,3-dione, (4.27 g, 96%) as an oil which solidified on equilibrating to room temperature; 1H nmr (CDCl3, 300 MHz) δ 1.3 (d, 3H), 3.3-4.0 (m, 1H), 3.7-3.9 (m, 2H), 7.1-7.3 (aromat. m, 2H), 7.63-7.7 (aromat. m, 2H), 7.8-7.85 (aromat. m, 4H).
Reaction SMILES: [C:1]([N:14]([CH2:16][C:17]([OH:19])=[O:18])[CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O.[CH2:25](O)[CH2:26][CH3:27]>>[CH2:25]([O:18][C:17](=[O:19])[CH2:16][N:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:15])[CH2:26][CH3:27]
Reactant: CCCO
Reactant: CCCCCCCCCCCC(=O)N(C)CC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCC(=O)N(C)CC(=O)OCCC

Procedure:
Sixty-one(61) grams of N-lauroylsarcosine (ex. Kawaken Fine Chemicals Co., Ltd.) and 200 ml of 1-propanol were charged into a 500-milliliter flask. Further, 1.45 g of conc. sulfuric acid were added as the catalyst. The mixture was heated under reflux for reaction for 7 hours.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C([N:21](CC)CC)C>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH2:21])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(N)=O)n2)s1
Temperature: 25 °C

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (110 mg; 0.36 mmol; 1 eq.), is dissolved in anhydrous THF (10 ml). Under nitrogen, triethylamine (0.08 ml; 0.55 mmol; 1.5 eq) is added. Ammonia (gas) is bubbled during 10 minutes. The flask is closed and the reaction mixture is stirred for 20 additional minutes at RT. The solvents are removed and the crude product is directly purified by preparative HPLC, affording Compound (62) as a white-off solid (25.6 mg; 22%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:27]([CH3:28])=[C:26]([CH:29]=O)[NH:25][C:24]=2[CH3:31])=[O:22])[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:27]([CH3:28])=[C:26]([CH:29]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:25][C:24]=2[CH3:31])=[O:22])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCn1ccnc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCCCn1ccnc1
Yield: 58.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.09 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (0.1 g) to give 0.1 g (59%) of the title compound as an orange solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:25][C:13]([F:12])([F:24])[C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cn(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 4-(trifluoromethyl)phenylsulfonyl chloride (0.587 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-[4′ (trifluoromethyl)phenylsulfonyl]-1H-indole-3-carboxaldehyde (0.650 g, 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]O.Cl.[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15]([O:30][CH3:31])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)OC21CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)C(OC)(c1ccccc1)OC21CCN(Cc2ccccc2)CC1

Procedure:
A solution of 1'-benzyl-1,3-dihydro-3-hydroxy-5-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] (prepared by method of Example 1), methanol, and a catalytic amount of methanolic hydrogen chloride is heated under reflux, cooled, made basic with sodium hydroxide, and diluted with water. The mixture is extracted with ethyl acetate, and the ethyl acetate solution is dried over sodium sulfate and concentrated to a solid. Recrystallization from acetone-water provides colorless crystals, m.p. 129°-133°.
Reaction SMILES: Cl.N([O-])=O.[Na+].[CH2:6]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1N)[CH3:7].[OH:16]S(O)(=O)=O>O.CCO>[CH2:6]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[OH:16])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CCc1cccc(C)c1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cccc(C)c1O
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
19.4 mL (0.23 mmol) concentrated HCl and a solution of 16.1 g (0.23 mmol) sodium nitrite in water (approx. 70 mL) were added at 0° C. to a solution of 30 g (222 mmol) 2-ethyl-6-methyl-aniline in 135 mL EtOH and stirred for 15 min. This mixture was added at 45° C. to a solution of 10.5 mL of concentrated H2SO4 in 300 mL water and at the end of the addition heated to 70° C. The aqueous phase was cooled to RT and exhaustively extracted with EtOAc. The combined organic phases were extracted with 1 M NaOH solution. The aqueous phase was washed with DCM, acidified to pH 1 with 4 N HCl solution and extracted with DCM. The organic phase was washed with saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation i. vac. The crude product was used in the subsequent reaction step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][CH:6]2[CH:4]([CH2:5]2)[C:3]=1[CH:8]=O.[CH2:10]([O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14])[CH3:11]>>[Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([CH2:5]2)[C:3]=1/[CH:8]=[CH:15]/[C:13]([O:12][CH2:10][CH3:11])=[O:14]
Reactant: O=CC1=C(Cl)CC2CC12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/C1=C(Cl)C[C@@H]2C[C@H]12

Procedure:
3-Chlorobicyclo[3.1.0]hex-2-ene-2-carbaldehyde (142 mg, 0.67 mmol) was olefinated according to General Procedure 1.1.B with ethoxycarbonylmethylene triphenylphosphorane ((487 mg, 1.4 mmol). The material was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 10% EtOAc to afford the title compound. 142 mg. 1H NMR (CHLOROFORM-d) δ: 7.57 (d, J=15.8 Hz, 1H), 6.11 (d, J=15.7 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 3.01 (dd, J=19.1, 7.3 Hz, 1H), 2.65 (dd, J=19.1, 2.9 Hz, 1H), 1.93-2.03 (m, 1H), 1.61 (qd, J=7.3, 4.3 Hz, 1H), 1.33 (t, J=7.1 Hz, 3H), 1.00 (td, J=7.5, 4.7 Hz, 1H), 0.13-0.21 (m, 1H).
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](OCC)=[O:6])(=O)[CH3:2].[F:16][C:17]1[C:23]([OH:24])=[C:22]([F:25])[CH:21]=[CH:20][C:18]=1[OH:19]>CS(O)(=O)=O>[F:25][C:22]1[CH:21]=[C:20]2[C:18](=[C:17]([F:16])[C:23]=1[OH:24])[O:19][C:5](=[O:6])[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:1]2[CH3:2]
Reactant: Oc1ccc(F)c(O)c1F
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: CS(=O)(=O)O
Product: CCOC(=O)Cc1c(C)c2cc(F)c(O)c(F)c2oc1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
Diethyl acetylsuccinate (2.4 g, 11.1 mmol) is added to a solution of Compound 4 (1.3 g, 8.9 mmol) in 20 mL methanesulfonic acid at 20° C. The reaction is stirred for 16 hours and poured into 200 mL ice water. The product is extracted with EtOAc (80 mL×2), washed with brine (40 mL), dried over anhydrous MgSO4, and concentrated in vacuo to yield a brown oil. The crude oil is purified by column chromatography on silica gel eluted with CHCl3 /MeOH (95:5 to 90:10) to yield 1.06 g (40%) of Compound 10 as an off-white solid. 1H-NMR (DMSO-d6) δ 7.56 (d, 1H), 4.08 (q, 2H), 3.67 (s, 2H), 2.34 (s, 3H), 1.19 (t, 3H). 19F-NMR (DMSO-d6) Φ 130.13 (t, 1F), 148.87 (d, 1F). Also isolated from the column is 0.50 g (20%) of 6,8-difluoro-7-hydroxy-4-methylcoumarin 3-acetic acid (Compound 11).
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].C1C2C(=CC(C(C=2)=O)=O)NC1C(O)=O>>[CH:8]1[C:7]([CH2:6][CH:4]([NH2:5])[C:2]([OH:3])=[O:1])=[CH:14][C:12]([OH:13])=[C:10]([OH:11])[CH:9]=1
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=C1C=C2CC(C(=O)O)NC2=CC1=O
Product: NC(Cc1ccc(O)c(O)c1)C(=O)O

Procedure:
The autoxidation of dopa, i.e. a dopachrome formation without enzyme participation, is not found at pH=6.5 in the observed period.
Reaction SMILES: [C:1]1([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[C:14]1([S:20]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Fe].C(Cl)(Cl)(Cl)Cl>[C:14]1([S:20][C:11]2[S:10][C:9]([C:1]3[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=3)=[CH:13][CH:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClSc1ccccc1
Reactant: Cc1ccc(-c2cccs2)cc1C
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccc(Sc3ccccc3)s2)cc1C
Reaction time: 48 h
Yield: 29.1 %

Procedure:
A mixture of 37 g (0.197 mole) of 2-(3,4-xylyl)thiophene, 200 ml of reagent carbon tetrachloride, 29 ml (36 g, 0.259 mole) of benzenesulfenyl chloride and 0.05 g of iron powder was allowed to stand two days at room temperature. A vapor phase chromatogram of the mixture showed that all the 2-(3,4-xylyl)thiophene had been consumed. The carbon tetrachloride was removed by distillation and the residue recrystallized from ethanol to give a first crop of 17 g (29%) of 2-phenylthio-5-(3,4-xylyl)thiophene, m.p. 77°-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(CC(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 4.7 %

Procedure:
To a solution of piperidine-4-carboxylic acid methyl ester (10 g, 70 mmol, 1 eq.) and Et3N (19.5 mL, 140 mmol, 2 eq.) in 150 mL of THF was added bromo-acetic acid tert-butyl ester (13.6 g, 70 mmol, 1 eq.) in 150 mL of THF. The resulting mixture was heated at reflux overnight. After 18 h, the resulting mixture was concentrated and purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH) to give the title compound as a yellow oil (0.84 g). Exact mass calculated for C13H24N1O4 258.2. MS (ESI) m/z 258.6 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([Cl:12])[N:3]=1.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=[O:35])C>C1COCC1>[Cl:12][C:4]1[NH:3][C:2](=[O:35])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(=O)O
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)nc2ccccc12
Yield: 86 %

Procedure:
A solution of 3 g (11 mmol) of the dichloroquinazoline (1A) in 50 mL THF was stirred with 30 mL of 40% aqueous KOH and 3 mL of 40% aqueous tetrabutylammonium hydroxide for 3 days. The layers were allowed to separate and the upper layer was concentrated to give a white solid. This was treated with dilute acetic acid and the solid was collected and washed with water, then dried at 65° C. in vacuo to afford 2.4 g (86%) of the 2-chloroquinazolin-4-one (1). Mp 251–251.7° C.; MS (ES+) m/z 255 (M+H)+. Anal. (C11H11ClN2O3) Calcd.: C, 51.88; H, 4.35; N, 11.00. Found: C, 51.94; H, 4.34; N, 10.95.
Reaction SMILES: Br[CH:2]([CH2:12][Br:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[OH:11].C([O-])(O)=O.[Na+]>C(O)C>[Br:13][CH2:12][CH:2]1[O:11][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Oc1cnccc1OCC(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: BrCC1COc2ccncc2O1
Yield: 67.7 %

Procedure:
A solution of intermediate (9) (0.0097 mol) in ethanol (50 ml) was stirred and refluxed overnight. NaHCO3 (0.0097 mol) was added and the resulting reaction mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was washed with water and extracted with DCM. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by open column chromatography (eluent: hexane/ethyl acetate (3/2)). The pure fractions were collected and the solvent was evaporated, yielding 1.51 g of (±)-3-(bromomethyl)-2,3-dihydro-1,4-dioxino[2,3-c]pyridine (intermediate 10).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH:17](O)[C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH2:14]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1.C(N(S(F)(F)[F:36])CC)C>ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH:17]([F:36])[C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH2:14]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(Cl)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)C(F)C2)ncn1Cc1ccc(Cl)cc1
Yield: 42.2 %

Procedure:
To a dichloromethane solution (1.0 mL) of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (15 mg, 0.04 mmol) synthesized in Synthesis Example 90, (diethylamino)sulfur trifluoride (10 μL, 0.04 mmol) was added at 0° C. and the resultant mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, dichloromethane was added to the reaction solution and the resultant reaction solution was washed with saturated sodium bicarbonate water and brine. The resultant organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. To the resultant residue, silica gel was added and the mixture was filtered, followed by washing the mixture with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the title compound (7 mg, yield: 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12](=[O:23])[NH:13][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15].[CH:24]([O-])([O-])OCC.O>CN(C=O)C>[O:23]=[C:12]1[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[N:1]=[CH:24][N:13]1[C:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]
Reactant: CCOC([O-])[O-]
Reactant: COC(=O)c1ccc(N)c(C(=O)NC(C)(C)c2ccccc2)c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2ncn(C(C)(C)c3ccccc3)c(=O)c2c1
Temperature: 150 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
To a solution of methyl 4-amino-3-[(2-phenylpropan-2-yl)carbamoyl]benzoate (0.13 g, 0.42 mmol) in DMF (2.5 mL) was added ethyl orthoformate (3.0 mL, 18 mmol) followed by one scoop of 3 Å molecular sieves. The reaction mixture was heated to 150° C. and stirred for 1 d. The mixture was cooled to rt, water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (50% to 100% EtOAc/hexanes) to afford methyl 4-oxo-3-(2-phenylpropan-2-yl)-3,4-dihydroquinazoline-6-carboxylate (0.11 g, 84%). LC-MS: (FA) ES+ 323.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]4[CH:30]=[N:29][C:28](=[O:31])[NH:27][C:26]=4[N:32]=3)[CH2:13][CH2:12]2)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl.CCOCC>C1COCC1.CO>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]4[CH2:30][NH:29][C:28](=[O:31])[NH:27][C:26]=4[N:32]=3)[CH2:15][CH2:16]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=c1ncc2ccc(OCCCCN3CCN(c4cccc5c4OCCC5)CC3)nc2[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1NCc2ccc(OCCCCN3CCN(c4cccc5c4OCCC5)CC3)nc2N1
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of 7-[4-(4-chroman-8-yl-piperazin-1-yl)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one (320 mg) in THF (6 mL) and MeOH (2 mL) was added NaBH4 (54 mg) in portions. After the addition was over, the mixture was kept stirring overnight. The reaction was quenched with H2O. The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel to give a semi-solid which was converted to its HCl salt by treating with 1 equivalent of 1 N HCl in a mixed solvent of THF and Et2O to give the title compound (147 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.40 (d, 1H), 6.98 (s, 1H), 7.70 (m, 3H), 6.25 (d, 1H), 4.30–4.06 (m, 6H), 3.60–3.30 (m, 4H), 3.15 (m, 4H), 3.00–2.70 (, 4H), 2.00–1.60 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[Li+].[CH3:21]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[CH3:21]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
A solution of bis-(4-chloro-phenyl)-acetic acid methyl ester (1.19 g, 4.0 mmol) in THF (20 ml) was cooled to −78° C. under nitrogen. A solution of LDA (3.0 mL, 6.0 mmol, 2M in heptane/THF/ethylbenzene) was added over 5 minutes, then after a further 20 minutes, iodomethane (0.63 ml, 10.1 mmol) was added. After 4 hours the reaction was quenched by the addition of saturated ammonium chloride solution and allowed to warm to room temperature then concentrated in vacuo to remove organic solvents. The mixture was diluted with ethyl acetate/petrol 1:4 and washed with saturated ammonium chloride solution then brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with an ethyl acetate/petrol gradient (1% to 2%), to afford the title compound as a colourless oil (210 mg, 17%); LCMS (PS-B3) Rt 4.01 min, No Ionisation. 1H NMR (CDCl3) δ 1.88 (3H, s), 3.73 (3H, s), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).