Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1([C:21]([O-:23])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1>CO>[CH3:1][O:22][C:21]([C:9]1([NH2:8])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1)=[O:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)[O-])C1
Solvent: CO
Product: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
Added (Trimethylsilyl)-diazomethane (2M in hexanes: 15 ml, 30 mmol) to a solution of 3-Amino pyrrolidine 1,3 dicarboxylic acid, 1-tert-butyl ester (900 mg, 3.9 mmol) in MeOH (5 ml) at room temperature. Stirred 10 minutes then evaporated solvent yielding 1T as an oil (0.9 g, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[F:11][C:12]([F:25])([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)[CH:13]([F:15])[F:14].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:16][C:12]([F:11])([F:25])[CH:13]([F:14])[F:15])[CH:18]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.9 %

Procedure:
EX-528A) 3-nitroaniline (1.87 g, 13.51 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (3 g, 13.5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.9 mmol), then solid NaBH(OAc)3 (3.73 g 17.6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 3.25 g (70%) of the desired N-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethan-amine product as a brown oil. HRMS calcd. for C15H13F4N2O3: 345.0862 [M+H]+, found: 345.0864. 1H NMR (CDCl3) δ4.4 (s, 2H), 4.5 (s, 1H), 5.9 (tt, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 2H), 7.5 (d, 1H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[SH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[SH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:14]
Reactant: CCCCC(CC)CO
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)c1ccccc1S
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.4 %

Procedure:
2-Ethyl-1-hexanol (21.0 g, 0.161 mol), 2-mercaptobenzoic acid (25.0 g, 0.162 mol), toluene (200 mL), and concentrated sulfuric acid (0.2 mL) were placed in a 500-mL three-neck round-bottom flask equipped with a magnetic stirring bar, a water separator, and a reflux condenser. After the mixture had been heated under reflux with stirring for 6 h, the solid 2-mercaptobenzoic acid had disappeared, and 2.90 mL (0.161 mol) of water had been collected by the water separator. The mixture was allowed to cool to room temperature and washed in succession with 20 mL of saturated NaHCO3 solution and two 50-mL portions of brine. Then the organic layer was dried over anhydrous MgSO4 and freed of solvent by rotary evaporation under vacuum to give 40.9 g (95%) of residual 2-ethylhexyl 2-mercaptobenzoate as a mobile straw-colored oil; 1H NMR (400 MHz, in CDCl3 w/TMS, ppm) 0.88-0.97 (m, 6H, 2CH3), 1.3-1.5 (m, 8H, 4CH2), 1.68-1.78 (m, 1H, CH), 4.21-4.29 (m, 2H, OCH2), 4.73 (s, 1H, SH), 7.1-7.3 [m, 3H, H-4 and H-5 with d (J=3.2 Hz) for H-3 at 7.29], 8.01 (d, J=7.6 Hz, H-6); {1H}13C NMR (100 MHz, in CDCl3 w/TMS, ppm) 166.99 (C═O), 138.49 and 126.39 (C-1 and C-2), 132.53, 131.77, 131.12, and 124.82 (C-3, -4, -5, and -6), 67.86, 39.19, 30.92, 29.33, 24.34, 23.35, 14.44, and 11.46 (8 aliphatic Cs).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[Li].C1C=CC=CC=1.[C:17]([CH2:21][CH2:22][C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18].[Cl-].[NH4+]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:23]([CH2:22][CH2:21][C:17]([O:19][CH3:20])=[O:18])=[O:24]
Reactant: COC(=O)CCC(=O)Cl
Reactant: [Li]c1c(F)cccc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CCC(=O)c1c(F)cccc1OC

Procedure:
A cold solution of 2-fluoro-6-methoxylithiobenzene in ether was added to a cold dilute benzene solution of β-carbomethoxypropionyl chloride and the resulting complex was decomposed with ammonium chloride solution to give methyl 3-(2-fluoro-6-methoxybenzoyl)propionate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.CN1CCOCC1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:23]1[C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[C:19]([O:18][C:16]([O:1][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)=[O:17])[CH:24]=1
Reactant: OCc1cncs1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excess N-methyl morpholine in 100 ml of methylene chloride was cooled to 0° C. and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After being stirred for 1 h, the reaction mixture was diluted with CHCl3, washed successively with 1N HCl, saturated aqueous NaHCO3, and saturated brine, dried over NaSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, 1-2% MeOH/CHCl3, Rf=0.5 in 4% MeOH/CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid. NMR (CDCl3) δ 5.53 (s, 2H), 7.39 (dt, J=9,3 Hz, 2H), 8.01 (s, 1H), 8.29 (dt, J=9,3 Hz, 2H), 8.90 (s,1H). Mass spectrum: (M+H)+ =281.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([O:24][CH3:25])=[O:23].N1C=CC=CC=1>ClCCl>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([O:24][CH3:25])=[O:23])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1ccc(-n2cccn2)cc1
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.4 %

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)benzene-1-sulfonyl chloride (0.5 g; 2.0 mmol) in dichloromethane (4.5 mL) at room temperature, was added methyl 3-aminothiophene-2-carboxylate (0.27 g; 1.7 mmol) followed by pyridine (0.27 g; 3.4 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (50 mL) and washed with water. The aqueous layer separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was recrystallized from ethyl acetate/hexanes (1:9, v/v) to yield the title product as a tan/yellow solid (404 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:15]1[CH:20]=[N:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[N:16]=1)(C)(C)C.[OH-].[NH4+]>ClCCl>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=3)[N:16]=2)=[CH:33][CH:32]=1
Reactant: Cc1cccc(-c2cncc(N(C(=O)OC(C)(C)C)c3ccc(Cl)cc3)n2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2cncc(Nc3ccc(Cl)cc3)n2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.5 %

Procedure:
Trifluoroacetic acid (1.0 mL, 13.4 mmol) in dichloromethane (3 mL) was added to an ice cooled solution of (4-chloro-phenyl)-[6-(6-methyl-pyridin-2-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester (70 mg, 0.18 mmol) in dichloromethane (4 mL) and stirred for 2.5 hour at room temperature. The reaction mixture was cooled on an ice bath and aqueous ammonium hydroxide was added followed by evaporation of dichloromethane. The formed precipitate was filtered off. The crude product was purified by flash chromatography (ethyl acetate/heptane as eluent) to give (4-chloro-phenyl)-[6-(6-methyl-pyridin-2-yl)-pyrazin-2-yl]-amine (51 mg, 98%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]2[CH:10]=[N:9]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(I)ccnc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1ccccc1C(F)(F)F

Procedure:
To a 48 mL pressure bottle containing Intermediate 76A (535 mg, 1.32 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (500 mg, 1.97 mmol), potassium acetate (520 mg, 5.30 mmol), and anhydrous DMSO (10 mL). The reaction mixture was flushed with argon, treated with PdCl2(dppf).CH2Cl2 (60 mg, 0.082 mmol), and heated to 105° C. for 1.25 h to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([SH:21])[CH:17]=[C:18]([Cl:20])[CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1nc(Sc2cc(Cl)cc(Cl)c2)ccc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 6-chloro-3-nitropicolinonitrile (3.70 g, 0.02 mol), 3,5-dichlorobenzenethiol (3.60 g, 0.02 mol) and K2CO3 (5.6 g, 0.04 mol) in 100 ml of acetonitrile is carried at 70° C. for 16 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using an aqueous phase. The organic phase is dried with sodium sulfate and the residue is purified by silica gel chromatography (AcOEt/petroleum ether) to yield 5.4 g (80%) of a yellow solid.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:13])=[O:12].[OH-].[K+]>CCO>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=C1CCc2ccccc21
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C=C2Cc3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a suspension of indanone (2.00 g, 15.1 mmol) and 4-carboxybenzaldehyde (1.89 g, 12.6 mmol) in EtOH (10 ml) was added KOH (1.77 g, 31.5 mmol) at 0° C. The reaction mixture was stirred 30 min at 0° C. then at room temperature for 16 h. The solvent was evaporated and the residue was dissolved in water, acidified to pH 5 with HCl 1 M. The precipitate was filtered and rinsed with water to afford the title compound 273 (2.27 g, 57%) as a yellow solid. LPMS: 264.1 (Calc.); 265.0 (found).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].[CH:22](O)=O>>[C:12]([NH:11][CH2:10][CH2:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:15]3[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:3][C:2]=2[N:1]=[CH:22]1)(=[O:14])[CH3:13]
Reactant: O=CO
Reactant: CC(=O)NCCNc1ccc(-c2ccc(=O)[nH]n2)cc1N
Product: CC(=O)NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21

Procedure:
14.2 g (49.4 mmol) of 6-(3-amino-4-acetylaminoethylaminophenyl)-3(2H)-pyridazinone are refluxed for one hour in 60 ml of formic acid. Then the excess formic acid is distilled off in vacuo, the residue is mixed with 50 ml of ice water and then adjusted to pH 8-9 with concentrated ammonia solution. The product precipitated is suction filtered, washed with about 50 ml of cold water, then with 50 ml of ether and dried.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.9 %

Procedure:
3-Hydroxy-2-nitrobenzoic acid (2.00 g) was dissolved in 110 ml of N,N-dimethylformamide, then 1.53 g of 4-chloroaniline, 3.15 g of 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide hydrochloride and 2.21 g of 1-hydroxybenzotriazole were added thereto and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated in vacuo, a saturated saline was added to the concentrate and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by means of a silica gel column chromatography using chloroform:methanol (100:1) as an eluate to give 2.97 g of 4′-chloro-3-hydroxy-2-nitrobenzanilide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:18])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.CC1CC=CCC=1>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:18])[CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)/C=C/c2cccc(O)c2)CC1
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: CN1CCN(C(=O)CCc2cccc(O)c2)CC1

Procedure:
To a solution the product of Example 17, Step 1 (300 mg, 1.22 mmol) in EtOH (15 mL), was added 10% palladium on carbon (50 mg), followed with 1-methyl-1,4-cyclohexadiene (1.5 mL). This suspension was then heated to reflux for 45 min. The reaction mixture was filtered and concentrated to afford the title compound, as a white solid (291 mg, 96%). MS (ES+) m/e 249 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH2:12][NH2:13])=[CH:6][CH:5]=1.[S-:15][C:16]#[N:17].[K+]>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[N:17]=[C:16]([SH:15])[NH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(CC(=O)CN)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cc2c[nH]c(S)n2)cc1

Procedure:
A solution of 3-(4-methoxyphenyl)-2-oxo-1-aminopropane, hydrochloride (3.0 g, 14 mmole) and potassium thiocyanate (1.36 g, 14 mmole) in acetic acid (60 ml) was heated under reflux for 15 minutes. The reaction was cooled, diluted with water and the product was filtered and recrystallized from ethyl alcohol and dried to give the product was a solid (1.6 g, 52%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:33])[C:8]1=[O:34])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:34])[N:9]([CH3:33])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:31][CH:30]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccnc3)cnc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(pyridin-3-yloxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (10.3 mg, 0.021 mmol) in THF (5 mL) and water (5 mL), was added LiOH.H2O (1.80 mg, 0.042 mmol) The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(pyridin-3-yloxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6 mg, 61.8% yield) as a white solid. 1H NMR (CDCl3) δ: 8.39 (d, J=4.6 Hz, 1H), 8.33 (d, J=4.5 Hz, 2H), 7.24 (d, J=4.7 Hz, 1H), 7.17 (s, 4H), 7.10 (dd, J=8.4, 1.6 Hz, 1H), 4.75 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 3.71 (s, 3H), 3.62-3.49 (m, 2H), 2.99 (t, J=6.8 Hz, 1H), 2.00-1.84 (m, 2H). LCMS: MH+ 453 and TR=1.963 min.
Reaction SMILES: [C:1](#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.CC[O:23]CC>O>[C:2]1([C:1]([CH2:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([CH3:16])[CH:14]=2)=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CBr)c1
Reactant: N#Cc1ccccc1
Reactant: CCOCC
Agent: II
Agent: [Mg]
Solvent: O
Product: Cc1cccc(CC(=O)c2ccccc2)c1

Procedure:
A solution of benzonitrile (58.5 g) in anhydrous ether (150 ml) is added dropwise with stirring to Grignard reagent which is prepared from magnesium turnings (14.6 g), a small amount of iodine and m-methylbenzylbromide (100 g) in anhydrous ether (800 ml) at moisture-free atmosphere. The mixture is refluxed for 6 hours. The reaction mixture is decomposed by adding water thereto, and the ether layer is separated and distilled to remove the solvent. The residue is mixed with 10% hydrochloric acid and the mixture is refluxed for 1.5 hours. After cooling, the mixture is extracted with ether. The ether layer is dried over anhydrous sodium sulfate and the solvent is distilled off to give crude m-methylbenzyl phenyl ketone (82 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH2:18][CH:19]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:40]>C(O)(=O)C.C(OCC)(=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[NH:40][C:17]([CH:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][CH2:13]3)=[CH:18][C:19]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:23][CH:24]=1
Reactant: O=C(CC(C(=O)c1ccc(F)cc1)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1

Procedure:
The product of Step 2 was heated in 5 ml of acetic acid in the presence of 2.0 g ammonium acetate at 110° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water. The combined organic phases were washed with brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by MPLC over silica gel eluting with 2% MeOH/CH2Cl2 to give the desired product. H1-NMR (CDCl3, 300 MHz):1.67 (m, 2H); 2.02 (bd, 2h); 2.75-3.0 (m, 3H); 4.29 bd, 2H); 5.12 (s, 2H); 6.19 (d, 1H); 7.03 (t, 2H); 7.18 (dd, 2H); 7.25-7.39 (m, 6H); 8.39 (dd, 2H); 8.52 (bs, 1H). FAB ms: C28H26N3O2F:455; Observed: 456 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH3:21])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1.[C:23](#N)C>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1
Reactant: CC#N
Reactant: CC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
This residual partially resolved [(5,6-dichloro-9a-methyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid (2.86 gm., 0.0118 mole) is treated with 1(-)cinchonidine (3.47 gm., 0.0118 mole) and the mixture dissolved in the minimum quantity of acetonitrile. After cooling for 48 hours, the salt that separates is removed by filtration and recrystallized twice from the minimum volume of acetonitrile. The pure salt is suspended in water (50 ml), treated with 6 normal hydrochloric acid (5 ml) and the precipitate that separates is removed by filtration and dried. This solid is recrystallized from a miture of tetrahydrofuran and ethyl ether to give the (-) enantiomer of [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid, m.p. 239°-241° C.,
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(N[C:26](=[O:38])[C:27]5[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=5[F:37])C=4C(C4C=CC=CC=4)(C4C=CC=CC=4)O[SiH2]C(C)(C)C)C=3C=2)CC1)=O.[O:60]1[CH2:65][CH:64]=[C:63]([C:66]2[NH:83][C:69]3[N:70]=[CH:71][N:72]=[C:73]([C:74]4[C:75]([CH3:82])=[C:76]([NH2:81])[CH:77]=[C:78]([F:80])[CH:79]=4)[C:68]=3[CH:67]=2)[CH2:62][CH2:61]1>>[O:60]1[CH2:61][CH:62]=[C:63]([C:66]2[NH:83][C:69]3[N:70]=[CH:71][N:72]=[C:73]([C:74]4[C:75]([CH3:82])=[C:76]([NH:81][C:26](=[O:38])[C:27]5[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=5[F:37])[CH:77]=[C:78]([F:80])[CH:79]=4)[C:68]=3[CH:67]=2)[CH2:64][CH2:65]1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCOCC3)cc12
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)O)cc2F)cc(F)cc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Example 22 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 12.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].C[C:6](=O)[CH2:7][C:8](=[O:10])C.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>[Na].C(O)(=O)C>[C:1]([CH:7]([CH3:6])[C:8](=[O:10])[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])(=[O:3])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCO
Reactant: CC(=O)CC(C)=O
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)CCC(=O)C(C)C(C)=O
Temperature: 25 °C

Procedure:
Sodium metal (1.5 g) was placed in a 3 L 3-neck round bottom flask equipped with a thermometer, a reflux condenser, and mechanical stirring, and placed in an oil bath. Absolute ethanol (1 L) was added with stirring. When the sodium had dissolved, 350 g of pentan-2,4-dione was added all at once, and then 310 g of ethyl acrylate was added over 30 min. The mixture was refluxed for 2.5 hrs and then allowed to cool to room temperature overnight. Glacial acetic acid (3 mL) was added and the solvent removed by rotary evaporation. The residue was filtered through a pad of diatomaceous earth and distilled through a wiped film still at 0.1 mm. The distillate was redistilled through a 10 inch vacuum jacketed Vigreux column to give 518 g of ethyl 5-acetyl-4-oxohexanoate, BP 84-92° C. at 0.2-0.7 mm.