Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([B:24]4[O:28]C(C)(C)C(C)(C)[O:25]4)=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:33])=[CH:11][CH:10]=1.Cl>C1COCC1.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([B:24]([OH:28])[OH:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:33])=[CH:34][CH:35]=1
Reactant: COc1ccc(Cn2c(=O)ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2c(=O)ccc3cc(B(O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Sodium periodate (5.9 g, 28 mmol) was added to a solution of 1-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2(1H)-one (3.6 g, 9.2 mmol) in THF/H2O (4/1, 40 mL). The reaction mixture was stirred at RT for 30 min, after which 2N HCl (9.2 mL) was added and the solution was then stirred at RT for 3 h. The solution was extracted with EtOAc (3×50 mL) and the organic layer was dried (MgSO4), and concentrated to yield crude 1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-ylboronic acid (2.6 g, 90% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (brs, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.88 (dd, J=1.6, and 8.8 Hz, 1H), 7.39 (d, J=9.2 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.69 (d, J=9.6 Hz, 1H), 5.45 (brs, 2H), 3.69 (s, 3H); LC-MS (EI) m/z: 310.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15](B(O)O)[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.C(COC)OC>[Cl:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[C:11]([Cl:10])[CH:16]=[CH:15][C:14]=2[CH3:20])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(Cl)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CC(C)=O
Product: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reaction time: 16 h
Yield: 40.3 %

Procedure:
To a mixture of 4,6-dichloro-2-amino-pyrimidine (0.481 g, 2.93 mmol), 5-chloro-2-methyl-phenyl boronic acid (0.5 g, 2.93 mmol), palladium (II) acetate (0.1 g, 0.44 mmol), and triphenylphosphine (0.23 g, 0.88 mmol) was added a solution of sodium carbonate (1.5 g, 14.6 mmol) in water (5.0 ml) followed by glyme (20 ml). The mixture was stirred under an argon atmosphere for 16 hours. After addition of acetone (15 ml), the mixture was filtered through a pad of celite under suction and the filtrate was concentrated under vacuum. The residual solid was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:9). After concentration under reduced pressure, the solid was dissolved in methanol and a solution of hydrogen chloride in dioxane (4.0 M, 5 ml) was added. After concentration under vacuum, the solid was treated with ethyl acetate (5 ml) and stirred for one hour. Filtration provided the hydrochloride salt of 4-chloro-6-(5-chloro-2-methyl-phenyl) pyrimidin-2-yl-amine (0.30 g, 35% yield) as a white powder.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:17]([O:16][C@@H:15]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:9][OH:8])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.5 g of 10% w/w palladium-on-activated carbon was added to a solution of 3.757 g of dl-trans-2-benzyloxymethyl-3-hexadecyloxytetrahydropyran (prepared as described in Preparation 7) in 150 ml of methanol, and the whole was mixed with hydrogen by shaking in a Paar's apparatus at room temperature under a pressure of 4 atmospheres (about 4 bars). After 20 hours, the catalyst was removed by filtration, and the solvent was then removed by distillation to give 2.749 g of the title compound as a solid, melting at 41°-42° C. (cold hexane).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([NH2:13])=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>>[CH2:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]#[N:13])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(N)=O)cc1C
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCn1nc(C#N)cc1C
Temperature: 90 °C
Yield: 106.1 %

Procedure:
A mixture of 1-butyl-5-methyl-1H-pyrazole-3-carboxamide (6.9 g, 38 mmol) and phosphorous oxychloride (34.0 mL) was heated at 90° C. under a nitrogen atmosphere for two hours and then allowed to cool to ambient temperature overnight. The reaction was poured into ice water (300 mL); concentrated ammonium hydroxide (115 mL) was added. The mixture was extracted with chloroform (3×), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 6.58 g of 1-butyl-5-methyl-1H-pyrazole-3-carbonitrile as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:28][C:26]2[S:27][C:23]([S:22][CH3:21])=[CH:24][N:25]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CSc1cnc(N)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cnc(NC(=O)c2ccc(OC(C)=O)cc2)s1
Yield: 84.1 %

Procedure:
Following the procedure for the synthesis of example 512, intermediate 510 (0.815 g, 4.10 mmol) dissolved in dry THF (25.0 mL), triethylamine (0.572 mL, 4.10 mmol), and 514 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL) gave 515 (0.887 g, 84%) as a tan solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 46.1 %

Procedure:
Prepared according to Method D step C from 1-cyclopentyl-7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.57 g, 1.83 mmol), boron tribromide (0.70 mL, 7.35 mmol) and 3 mL of cyclohexene to give the product (0.25 g) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[C:13]([NH:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:14]([NH2:34])[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:17]=1[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:18][C:17]1[N:16]=[C:15]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]2[N:34]=[C:36]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:35]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:13]=2[C:12]=1[CH3:11]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c(NCCc2ccccc2)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(Cc3ccccc3)n(CCc3ccccc3)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Phenylacetyl chloride (0.6 mL, 4.5 mmole) was added to a solution of 5,6-dimethyl-N4 -(2-phenylethyl)-N2,N2 -bis(phenylmethyl)pyridine-2,3,4-triamine (1.96 g, 4.5 mmole) in methylene chloride (100 mL) and the resulting mixture was stirred at ambient temperature overnight. A catalytic amount of p-toluenesulfonic acid was added and stirring was continued at ambient temperature over the weekend. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate then concentrated under vacuum to provide an oil. The oil was purified by silica gel column chromatography eluting with 5-10% ethyl acetate in hexane to provide 1.8 g of the desired product as a white solid, m.p. 139°-141° C. Analysis: Calculated for C37H36N4 : % C, 82.80; % H, 6.76; % N, 10.44; Found: % C, 82.86; % H, 6.78; % N, 10.36.
Reaction SMILES: C(OC([N:8]([C:24]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([CH2:36][CH2:37][C:38]2[S:39][C:40]([CH2:44][CH3:45])=[C:41]([CH3:43])[N:42]=2)[N:25]=1)[CH2:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:13]=[C:12]([Cl:23])[CH:11]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:23][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:13]=1)[CH2:9][NH:8][C:24]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([CH2:36][CH2:37][C:38]2[S:39][C:40]([CH2:44][CH3:45])=[C:41]([CH3:43])[N:42]=2)[N:25]=1
Reactant: C=CCOC(=O)Nc1cc(Cl)cc(CN(C(=O)OC(C)(C)C)c2cc(N3CCOCC3)cc(CCc3nc(C)c(CC)s3)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)Nc1cc(Cl)cc(CNc2cc(N3CCOCC3)cc(CCc3nc(C)c(CC)s3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-{N-tert-butoxycarbonyl-N-[3-chloro-5-(2-propenyloxycarbonylamino)benzyl]amino}-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine (470 mg) was dissolved in trifluoroacetic acid (5 ml), followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=50/1→20/1) to obtain the above identified compound (307 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:19])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:4].[Cl-].[NH4+]>CCO.O.C(Cl)Cl.[Fe]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:19])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:4]
Reactant: COC(=O)c1nc(C)sc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1nc(C)sc1-c1cccc(N)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Iron powder (53.7 mmol) is added to a suspension of 2-methyl-5-(3-nitro-phenyl)-thiazole-4-carboxylic acid methyl ester (44.1 mmol) and ammonium chloride (221 mmol) in a mixture of EtOH (100 mL) and water (50 mL). The mixture is stirred at 80° C. for 4 h, iron powder (53.7 mmol) is added and heating is continued for additional 3 h. After addition of a third portion of iron powder (26.8 mmol) the mixture is heated at 80° C. for additional 3 h, cooled to RT, diluted with DCM and filtered through Celite. The residue is washed with DCM and water and the filtrate is concentrated in vacuo. A sat. aqueous NaHCO3 solution and DCM are added and the layers are separated. The organic layer is washed with water, dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.67 min; [M+H]+=249.4.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH:14]=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1ccc2[nH]c(C=O)cc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCc1ccc2c(c1)cc(C=O)n2C
Temperature: 150 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a solution of 5-butyl-1H-indole-2-carbaldehyde (75 mg, 0.37 mmol) and methyl iodide (57 mg, 0.40 mmol) in 0.75 mL dimethylformamide was added potassium carbonate (57 mg, 0.41 mmol). The resulting suspension was stirred vigorously at 150° C. in a sealed vial under argon for 1 h. Solids were filtered and the liquor concentrated before being subjected to chromatography on silica gel (40% ethyl acetate in hexanes) to give 5-butyl-1-methyl-1H-indole-2-carbaldehyde (15 mg, 18%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[CH:17]1(B(O)O)[CH2:19][CH2:18]1>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][C:7]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c(C2CC2)nc1C(=O)O

Procedure:
A microwave vial was charged with amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (0.5 g, 1.754 mmol), cyclopropylboronic acid (0.753 g, 8.77 mmol), and 1,1′Bis(diphenylphosphosphino)ferrocene palladium dichloride (0.143 g, 0.175 mmol). The mixture was taken up as a solution in THF (6 ml) and flushed with N2, sealed and heated using microwave radiation at 150° C. for 20 minutes. The reaction mixture was filtered through Celite® (filter material) and washed through with EtOAc (20 ml). The filtrate was partitioned between EtOAc (30 ml) and water (50 ml). The phases were separated and the organic portion was washed with brine (30 ml), dried over MgSO4, filtered and concentrated under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:21][CH2:22][C:23](Cl)=O>C(O)(=O)C>[Cl:21][CH2:22][C:23]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=2)[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1c2ccc([N+](=O)[O-])cc2nc(CCl)n1-c1ccccc1Cl
Yield: 56.4 %

Procedure:
Prepared according to Procedure B with 1o (500 mg, 1.71 mmol) and chloroacetyl chloride (0.41 mL, 5.14 mmol) in acetic acid (10 mL). Purified by extraction from aqueous K2CO3, followed by two chromatographies in CH2Cl2 to afford 338 mg of a yellow oil (56%). 1H NMR (CDCl3) δ: 8.64 (d, J=2.2 Hz, 1H); 8.48 (d, J=8.8 Hz, 1H); 8.32 (dd, J=2.2, 8.7 Hz, 1H); 7.66 (dd, J=2.5, 6.0 Hz, 1H); 7.52-7.59 (m, 3H); 4.41 (d, J=12 Hz, 1H), 4.10 (d, J=12 Hz, 1H). MS (ES): m/z 350.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30].CCN(CC)CC>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)OCc2ccccc2)ccc1N
Reactant: O=C=Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OCc2ccccc2)ccc1NC(=O)Nc1ccccc1F
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a stirred solution of benzyl 4-amino-3-methoxyphenylacetate (1.36 g, 5 mmol) in THF (20 mL) was added 2-fluorophenyl isocyanate (561 ul, 5 mmol) and a catalytic amount of Et3N. The resulting mixture was stirred for 3 hr. The mixture was quenched by the addition of H2O (10 mL) and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 as eluent to give 2.06 g (q.y.) benzyl 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetate as a green oil. 1H-NMR (CDCl)3 δ 3.63 (2H, s), 3.82 (3H, s), 5.14 (2H, s), 6.79–7.37 (12H, m), 8.01 (1H, d, J=7.8 Hz), 8.09–8.14 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])[N:9]=1.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([Cl:25])=[O:17])[N:9]=1
Reactant: O=C(O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
Compound 25 of the present invention may be prepared according to Scheme A as follows. A slurry of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid (Compound A1, 1.5.0 g; 52.8 mmol) and 100 μL of dimethylformamide catalyst in 250 mL of anhydrous dichloromethane is allowed to cool to 0° C. Oxalyl chloride (9.2 mL, 105.5 mmol, 2.0 eq.) is added to this slurry over 3 minutes. The reaction mixture is then allowed to warm to room temperature, and is stirred for 16 h. The resultant yellow solution is concentrated in vacuo, azeotroped several times with anhydrous dichloromethane (2×50 mL) and dried under high vacuum for 2 hrs to give 15.5 g of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl chloride (Compound A2) as a white solid (97%): 1H NMR (CDCl3) δ 7.23-7.38 (m, 2H), 7.58-7.71 (m, 2H), 8.22-8.29 (m, 2H), 8.50 (d, J=7.8 Hz, 1H), 8.91 (t, J=1.6 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Br.[K+].[Br-]>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Agent: Br
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Into a 1000 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, a nitrogen inlet, and a condenser, 2,3-bis(4-methoxyphenyl)-quinoxaline-6-carboxylic acid (34.7 g, 89.8 mmol) was dissolved in acetic acid (260 mL). Hydrobromic acid (48%, 500 mL) was then added to yellow clear mixture at room temperature. The reaction mixture was heated under reflux with vigorous stirring until the solution become homogeneous. It took about 6 h. After having been allowed to cool down to room temperature, the red-brown mixture was poured into distilled water. The resulting light brown precipitate was collected by suction filtration and dried under the reduced pressure to give 31.9 g (99% crude yield) of yellow solid, m.p. 315-317° C. (dec.). Anal. Calcd. for C21H14N2O4: C, 70.39%; H, 3.94%; N, 7.82%. Found: C, 66.70%; H, 3.98%; N, 7.20%. FT-IR (KBr, cm−1): 1698 (carbonyl), 3396 (hydroxy). Mass spectrum (m/e): 358 (M+, 100% relative abundance). 1H-NMR (DMSO-d6, δ in ppm): 6.76-6.79 (d, 4H, Ar), 7.35-7.39 (d, 4H, Ar), 8.09-8.12 (d, 1H, Ar), 8.20-8.24 (d, 1H, Ar), 9.87-9.89 (d, 1H, OH), 13.50 (s, 1H, COOH). 13C-NMR (DMSO-d6, δ in ppm): 114.93, 128.78, 129.21, 129.27, 130.39, 131.11, 131.23, 139.29, 142.06, 153.78, 154.38, 158.30, 158.44, 166.62.
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[N:4]1.S(Cl)([Cl:12])=O>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][Cl:12])[N:4]=1)#[N:9]
Reactant: N#Cc1ccn(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.89 g of 1-(hydroxymethyl)-3-cyano-1H-pyrazole was dissolved to 30 ml of dichloromethane. 1.6 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.00 g of 3-cyano-1-(chloromethyl)-1H-pyrazole.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]2[O:16][CH2:15][CH:14]([CH2:17][OH:18])[O:13][C:10]2=[N:11][CH:12]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:18][CH2:17][CH:14]1[O:13][C:10]2=[N:11][CH:12]=[C:7]([CH3:6])[CH:8]=[C:9]2[O:16][CH2:15]1)(=[O:4])=[O:3]
Reactant: Cc1cnc2c(c1)OCC(CO)O2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cnc2c(c1)OCC(COS(C)(=O)=O)O2
Temperature: 0 °C
Yield: 99 %

Procedure:
Methanesulfonyl chloride (0.00103 mol) was added to a mixture of intermediate (39) (0.00081 mol) and triethylamine (0.0019 mol) in DCM, stirred at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. Water was added. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 0.208 g of 2,3-dihydro-7-methyl-[1,4]dioxino[2,3-b]pyridine-3-methanol methanesulfonate (ester) (intermediate (40).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[CH3:26][C:27]1[N:31]=[CH:30][NH:29][N:28]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:29]2[CH:30]=[N:31][C:27]([CH3:26])=[N:28]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: Cc1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-n2cnc(C)n2)n(C)c(=O)c1OCc1ccccc1
Temperature: 24 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
A solution of 5-benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (1.00 g, 2.73 mmol) and 3-methyl-1H-[1,2,4]triazole (0.272 g, 3.27 mmol) in dry N,N-dimethylformamide (10 ml) at 0° C. was treated with sodium hydride (0.16 g of a 60% dispersion in mineral oil, 4.0 mmol) and the resulting mixture was stirred at 0° C. for 30 min and at 24° C. for another 30 min. The reaction mixture was then quenched with acetic acid (0.2 ml) and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography on silica gel (elution toluene-acetone 90:10 to 85:15) first gave 0.358 g (35% yield) of 5-benzyloxy-1-methyl-2-(3-methyl-[1,2,4]triazol-1-yl)-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (3H, t, J=7.1 Hz, CH3), 2.51 (3H, s, CH3), 3.73 (3H, s, NCH3), 4.37 (2H, q, J=7.1 Hz, CH2), 5.37 (2H, s, OCH2), 7.40 (3H, m, aromatics), 7.50 (2H, m, aromatics), 8.71 (1H, s, CH). HRMS (FAB POS) calculated for C18H20N5O4 [M+H+]: 370.14. found: 370.14. The following fractions then gave 0.395 g (39% yield) of 5-benzyloxy-1-methyl-2-(5-methyl-[1,2,4]triazol-1-yl)-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, t, J=7.0 Hz, CH3), 2.67 (3H, s, CH3), 3.52 (3H, s, NCH3), 4.37 (2H, q, J=7.0 Hz, CH2), 5.41 (2H, s, OCH2), 7.40 (3H, m, aromatics), 7.51 (2H, m, aromatics), 8.00 (1H, s, CH). HRMS (FAB POS) calculated for C18H20N5O4 [M+H+]: 370.14. found: 370.14.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=1>>[F:19][C:18]([F:21])([F:20])[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[N:17]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: OCCc1ccc(O)cc1
Product: OCCc1ccc(Oc2nccc(C(F)(F)F)n2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 4-(2-hydroxyethyl)phenol and 2-chloro-4-(trifluoromethyl)pyrimidine. LC-MS (ESI): m/z 285 [M+H]+; 2.66 min (ret time).