Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:19]1[CH:24]=[C:23]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=[O:17])=[CH:10][CH:9]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(-c3cccc(F)c3)cc21
Temperature: 80 °C
Yield: 81.1 %

Procedure:
Cesium carbonate (618 mg, 1.90 mmol) was added to a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (200 mg, 0.948 mmol), (3-fluorophenyl)boronic acid (265 mg, 1.90 mmol) and toluene (20 mL) in a 50 mL Schlenk tube at room temperature. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.001 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated in vacuo. The resulting crude residue was purified on a Teledyne-Isco combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 174 mg (81%) of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]#[CH:36].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]#[C:36][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Reactant: C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1ccc(C(F)(F)F)cc1Cl
Yield: 20.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.044 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.012 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.89 (s, 3H), 7.52 (t, J=9.0 Hz, 1H), 7.56-7.75 (m, 6H), 7.83 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 12.78 (s, 1H); MS (m/z): 522.00 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of t-butyl 3-methoxy-4-nitrophenylacetate (0.144 g, 0.539 mmol) and 10% Pd on carbon (0.155 g) in ethyl acetate (8 mL) and methanol (2 mL) was stirred under H2 (40–60 psi) for 2 h. The mixture was filtered through Celite and the filtrate concentrated to afford t-butyl 4-amino-3-methoxyphenylacetate (0.123 g, 96%) as a light yellow oil: 1H NMR (CDCl3, 300 MHz, ppm) 6.70 (m, 3H), 4.04 (bs, 2H), 3.84 (s, 3H), 3.42 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[C:10]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1oc2cccc(OC)c2c1C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3ccccc3)ccc(OC)c2c1C

Procedure:
To a solution of ethyl 3-methyl-4-methoxybenzofuran-2-carboxylate (1.00 g, 4.27 mmol) and benzoyl chloride (1.80 g, 12.81 mmol) in 1,2-dichloroethane (12 mL) was added aluminum chloride (1.71 g, 12.81 mmol) in portions. The mixture was heated to reflux for 1.5 hours then allowed to cool and poured into 2N HCl (50 mL). The resulting mixture was extracted with methylene chloride (3×30 mL) and the combined extracts washed with saturated NaHCO3 (3×25 mL), dried (Na2SO4), and concentrated. The crude product was purified by preparative HPLC, using 25% ethyl acetate in hexane as eluant, to afford ethyl 3-methyl-4-methoxy-7-benzoylbenzofuran-2-carboxylate mp. 137°-139° C.; 1H NMR d 1.27 (2H, t, J=6 Hz), 2.67 (3H, s), 3.95 (3H, s), 4.28 (2H, q, J=6 Hz), 6.66 (1H, d, J=8 Hz), 7.44 (3H, m), 7.72 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[C:21]([CH3:27])([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)[C:21]([CH3:27])([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cc(Br)c2occc2c1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Product: CC1(C)CN(Cc2ccccc2)CCC1(O)c1cc(F)cc2ccoc12
Yield: 546.6 %

Procedure:
Beginning with 0.28 gm (1.32 mMol) 5-fluoro-7-bromobenzofuran and 0.19 gm (0.088 mMol) 1-benzyl-3,3-dimethyl-4-oxo-piperidine, 0.17 gm (53%) of the desired compound were prepared essentially as described in EXAMPLE 3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:18][CH:17]=1)[CH3:15]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:18][CH:17]=2)[CH3:15])[CH2:11][CH2:12]1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3ccccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyridyl)piperazine instead of phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound can be obtained.
Reaction SMILES: [CH:1]([N:4]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[OH:15])([CH3:3])[CH3:2].O[CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]([O:39]CC)=[O:38])[CH:31]=[CH:30]2>>[CH:1]([N:4]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][C:6]=1[O:15][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]([OH:39])=[O:38])[CH:31]=[CH:30]2)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(CO)ccc2c1
Reactant: CC(C)N(c1ccc(C(F)(F)F)cc1O)S(=O)(=O)c1ccccc1
Product: CC(C)N(c1ccc(C(F)(F)F)cc1OCc1ccc2cc(C(=O)O)ccc2c1)S(=O)(=O)c1ccccc1

Procedure:
By using 2-(N-isopropyl-phenylsulfonylamino)-5-trifluoromethylphenol (prepared in Reference Example 24.) and ethyl 6-hydroxymethyl-2-naphthate, the title compound having the following physical data was obtained by the same procedure as Reference Example 18(b)→Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][C:12]1([O:15][CH2:14]1)[CH3:13]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][C:12]([CH3:14])([OH:15])[CH3:13])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CSc1ccc(Br)cc1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of 4-bromothiophenol (9.45 g, 50.0 mmol) in tetrahydrofuran (150 mL) was added sodium hydride (60% in oil, 2.20 g, 55.0 mmol) at 0° C. by small portions, and the resulting mixture was stirred for 1 hr. To this reaction mixture was added isobutylene oxide (4.91 mL, 55.0 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (11.6 g, yield 89%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:11]2=[O:12])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:11]2=[O:12])=[CH:8][CH:9]=1
Reactant: O=c1ccc2ccccc2n1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(-n2c(=O)ccc3ccccc32)cc1
Yield: 82.6 %

Procedure:
To 10% Pd-C (0.1 g) is added acetic acid (20 ml) and then 1-(4-nitrophenyl)carbostyril (0.9 g) and the mixture is subjected to catalytic reduction at 80° C. under normal pressure. After completion of the reaction, 10% Pd-C is removed by filtration and the resulting solution is concentrated under reduced pressure. To the concentrate is added water and the solution is made alkaline with an aqueous sodium hydroxide solution and then extracted with dichloromethane. The extract is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography and recrystallized from ethanol to give 1-(4-aminophenyl)carbostyril (0.66 g) as brown powders, m.p. 225°-230° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].Cl[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[C:23]([NH2:31])[N:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:7]=[CH:6][C:4]([NH:5][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:24]=[C:23]([NH2:31])[N:22]=3)=[CH:3][C:2]=2[F:1])[NH:16][CH:17]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
67 mg (0.24 mmol) of 3-fluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 47 mg (0.24 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 4 ml of water/ethanol 1:1. 25 μl (0.29 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21](Cl)=[CH:20][C:19]1=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([S:10][C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=2)=[CH:20][C:19]1=[O:29])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Sc1ccc(Br)cc1
Reactant: O=c1cc(Cl)c2cccnc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(Sc2ccc(Br)cc2)c2cccnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a suspension of NaH (24 mg, 1 mmol) in DMF (4 mL) was added 4-bromobenzenethiol (189 mg, 1 mmol) at 0° C. After being stirred at rt for 10 min, a solution of 1-benzyl-4-chloro-1H-[1,8]naphthyridin-2-one (135 mg, 0.5 mmol) in DMF (1 mL) was introduced at rt. The reaction was quenched by adding water followed by extracting with EtOAc. The organic layer was washed with brine and dried over Na2SO4. Column chromatography of the concentrated residue gave 210 mg of product (yield: 100%): 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=5.0 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 2H), 7.21 (dd, J=8.0, 5.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.10 (s, 1H), 5.70 (s, 2H); 13C NMR (125 MHz, CDCl3) 161.65, 150.77, 149.42, 148.87, 137.85, 137.46, 133.78, 132.97, 128.82, 128.47, 127.38, 126.81, 125.50, 118.09, 117.66, 114.65, 44.20; LCMS (EI) m/z 422.8 (M+), 424.8.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([N:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH:10]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(OCC)C>[C:19]1([CH:10]2[N:9]([NH2:7])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=NN1c2ccccc2OCC1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NN1c2ccccc2OCC1c1ccccc1
Reaction time: 18 h
Yield: 61 %

Procedure:
A slurry of lithium aluminum hydride (4.9 g, 130.5 mmol) in ethyl ether (100 mL) is stirred at ice bath temperature under an argon atmosphere. A solution of 4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine in ethyl ether (300 mL) is added dropwise over 1 h. The mixture is removed from the ice bath and allowed to stir for 18 h. Water (50 mL) is slowly added forming solids. The solids are collected by filtration and washed with ethyl ether. The resulting filtrates are combined and washed three times with water (200 mL), dried over magnesium sulfate, and concentrated to give 8.7g (61%) of 3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-ylamine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>>[F:24][C:23]([F:26])([F:25])[CH2:22][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: N#Cc1ccc2c(ccn2CC(F)(F)F)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2,2,2-trifluoroethyl trifluoromethanesulfonate: MS (ES) m/z 293 (M+1).
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20]([O:22]C)=[O:21])=[N:12]3)[C:4]=2[O:3]1.[OH-].[Na+]>C1COCC1.CO>[F:24][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20]([OH:22])=[O:21])=[N:12]3)[C:4]=2[O:3]1
Reactant: COC(=O)c1nn(-c2cccc3c2OC(F)(F)O3)cc(OC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of methyl 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.1 g, 12 mmol) in THF (100 mL) and MeOH (50 mL) was added 1 M NaOH aqueous solution (18 mL, 18 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and acidified with 1 M HCl aqueous solution. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.8 g, 97% yield) as a yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 4.06 (3H, s), 7.22-7.26 (1H, m), 7.34 (1H, t, J=8.3 Hz), 7.72 (1H, dd, J=8.3, 1.1 Hz), 8.29 (1H, s).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([Cl:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1c[nH]c2ncc(Br)nc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Cl)c2nc(Br)cnc21
Reaction time: 0.5 h
Yield: 79 %

Procedure:
impure 2-Bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine was dissolved in DMF (30 mL). NaH (60%, 436 mg, 10.9 mmol) was added slowly. After the addition was complete stirring was continued for 30 minutes at RT. (2-Chloromethoxy-ethyl)-trimethyl-silane (1.9 mL, 10.9 mmol) was added and the reaction mixture was allowed to warm up overnight. The reaction was quenched with H2O. The aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (24 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 2.62 g of 2-bromo-7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine as a yellow liquid (79% yield for 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.C([Li])CCC.CCCCCC.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:31]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:19])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1Cc1ccccc1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (130 mg, 0.50 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96 mmol) with stirring. The reaction mixture was stirred at 0° C. for 2 hours, followed by addition of a second portion of 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96 mmol), and the mixture stirred for another 2 hours. To this mixture was added slowly a solution of benzyl bromide (855 mg, 5.00 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C., stirred overnight, and allowed to warm to room temperature. The reaction was followed by LCMS and stirring was continued until all of the starting material was consumed. The reaction mixture was quenched by slow addition of saturated aqueous ammonium chloride (10 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (20 mL) and dilute aqueous ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase successively washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture, which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 1-benzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (62 mg, 0.18 mmol, 35%). LCMS mz 350.0 (M+H), 372.0 (M+Na), anal HPLC>98% in purity. 1H NMR (400 MHz; CDCl3) δ7.10-7.40 (m, 8H); 6.80-7.00 (m, 3H); 5.22 (s, 2H); 3.05 (m, 2H); 2.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:10][CH:11]1[CH2:14][NH:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:13]2[CH2:14][CH:11]([F:10])[CH2:12]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: FC1CNC1
Agent: Cl
Product: FC1CN(c2ncc(Br)cn2)C1

Procedure:
The title compound was prepared following a procedure analogous to that described for Intermediate 27 using 5-bromo-2-chloropyrimidine and 3-fluoroazetidine hydrogen chloride salt. LC (method 5): tR=1.33 min; Mass spectrum (ESI+): m/z=232/234 (Br) [M+H]+.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:12]1([C:18]2([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:27]([O:34][C:35](ON1C(=O)CCC1=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:27]([O:34][C:35]([N:21]1[CH2:20][CH2:19][C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of commercially available 4-phenyl-4-carboxypiperidine toluenesulfonate (7.55 g, 20 mmol), N-(benzyloxycarbonyloxy)succinimide (5.0 g, 20 mmol) and TEA (5 mL, 36 mmol) in CHCl3 (100 mL) is stirred at r.t. for 48 h. The mixture is diluted with CH2Cl2 (100 mL) and extracted with 1 M aq. NaOH (3×50 mL). The aq. phase is extracted with Et2O (2×50 mL), acidified (pH 2) with 6N aq. HCl and extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([C:14]#[N:15])[N:10](CC=C)[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]>C1COCC1.CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([C:14]#[N:15])[NH:10][C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C#N)nc2c1c(=O)n(C)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(C)c(=O)c2[nH]c(C#N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A solution of 3-butyl-1-methyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile (230 mg, 0.80 mmol) in anhydrous THF (5 ml) and anhydrous DMSO (0.5 ml) was treated with Pd(PPh3)4 (185 mg, 0.16 mmol). The mixture was degassed under gentle vacuum, morpholine (698 uL) added, and left to stir at rt under nitrogen for 2 hours. The yellow solution was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down and amino-propyl SPE (5 g), eluting with MeOH followed by 5% AcOH then 10%, 20% and 30% AcOH/MeOH mixtures. The product fractions were combined and concentrated to afford a pale yellow solid (116 mg). This was washed with MeOH and the title compound a white solid was collected by filtration and dried under vacuum (55 mg, 28%). NMR; δH (400 MHz, d6-DMSO) 0.90 (t, 3H, J=7.5 Hz), 1.25-1.35 (m, 2H), 1.59-1.68 (m, 2H), 3.24 (s, 3H), 3.96 (t, 2H, J=7 Hz), NH not observed to δH 15; m/z 248.2[MH+].