Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:22][O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN>C(O)C>[C:24]([O:23][N:22]=[C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:10][NH2:11])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)ON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)ON=C(CN)c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To 162 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(tert-butoxyimino)ethyl]phthalimide in 10 ml of ethanol, 40 mg of hydrazine monohydrate was added, and the mixture was stirred at 80° C. for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and the reaction mixture was mixed with 30 ml of water and extracted with ethyl acetate (25 ml×2). The resulting organic layers were combined, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 89 mg of the desired crude product as a colorless oil. The oil was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C=Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=[N+]([O-])CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
A solution of 13.5 g (72 mmol) of 2-(3-Chlorophenyl)-1-nitroethene, from Step 2, in 200 mL of dioxane was added dropwise to a stirred suspension of 6 g (157 mmol) of sodium borohydride in a mixture of 140 mL of dioxane and 60 mL of ethanol. The reaction mixture was stirred at ambient temperature for 2 h and then the excess borohydride was quenched with acid. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and water (4:1). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel eluted with 20% methylene chloride in hexane to afford 6.3 g (48% yield) of the title compound; MS DCI-NH3M/Z: 203 (M+NH4)+ ; 1H NMR (CDCl3) δ3.3 (2H, t, J=7.5 Hz), 4.6 (2H, t, J=7.5 Hz), 7.05-7.3 (4H, m).
Reaction SMILES: [C:1]1([P:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18]O.O>CC(C)=O>[C:1]1([P:7](=[O:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([F:11])([F:9])[F:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)P(c1ccccc1)c1ccccc1
Reactant: OO
Solvent: O
Solvent: CC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)C(F)(F)F
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A solution of 1.0g (3.9 mmol) of diphenyltrifluoromethylphosphine (4) in 5 mL of acetone was treated with 0.5 mL (4.9 mmol) of 30% hydrogen peroxide. Within a few minutes an exothermic reaction occurred which caused the solution to reflux. After this had subsided, the solution was allowed to stand for 4 hours at room temperature and poured into 15 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of cichloromethane. The organic layers were combined, dried (MgSO4), and concentrated to give 0.85g (80% yield) of diphenyltrifluoromethylphosphine oxide as a colorless liquid: 19F NMR (CDCl3 relative to CF3CO2H) 5.86 ppm (d, JPF =89 Hz); mass spectrum (70 eV) m/z (relative intensity) 201 (100, M-CF3), 77 (23), 51 (16).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[C:21]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]>N1C=CC=CC=1>[C:21]([C:23]1[CH:24]=[C:25]([S:29]([NH:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[CH2:7][CH2:6]2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: N#Cc1cccc(S(=O)(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of (2-R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.200 g, 0.63 mmol) in 4 ml of pyridine at 0° C. was added 3-cyanobenzenesulfonyl chloride (0.127 g, 0.63 mmol). After 30 min, the reaction was allowed to warm to room temperature and was stirred for 2 h. The reaction was concentrated under vacuum, and the residue partitioned between 10% aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with water, then brine and dried over magnesium sulfate. The crude material was purified on silica gel (0 to 5% 7N ammonia in methanol/dichloromethane) to afford the title compound as a white foam (0.120 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:23]([O:25][CH3:26])=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH3:27][O-:28].[Na+].CO>[Cu]I.CN(C)C=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[N:11]1[C:8]2=[N:9][C:10]3[C:6](=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:4]=[CH:3][C:2]=3[O:28][CH3:27])[N:7]2[CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
A mixture of methyl 9-bromo-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (200 mg, 0.439 mmol), sodium methoxide (237 mg, 4.39 mmol), copper(I) iodide (100 mg, 0.525 mmol), Methanol (1.8 mL) and N,N-dimethylformamide (2.6 mL) was stirred at 100° C. for 4 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (54.4 mg, 0.134 mmol, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([O:19]C)=O)=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1.[NH3:33]>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([NH2:33])=[O:19])=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3nc(OC)ccc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: COc1ccc2c(ncn2-c2cc(OCc3ccccc3C(F)(F)F)c(C(N)=O)s2)n1

Procedure:
In a similar manner as described for example 22, 1.5 g of methyl 5-(5-methoxy-1H-imidazo[4,5-b]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thio-phene-2-carboxylate (compound B7a) and 200 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>C(OCC)(=O)C.CCCCCC.O1CCCC1>[C:20]1([C:8]2([C:9]3[CH:10]=[C:11]([B:32]([OH:35])[OH:33])[CH:12]=[CH:13][CH:14]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:3]3[C:4]2=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1cccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
In a 100 mL three-neck flask was put 1.4 g (3.6 mmol) of 9-(3-bromophenyl)-9-phenyl-9H-fluorene. The air in the flask was replaced with nitrogen. Then, 36.0 mL of tetrahydrofuran was added to the mixture, and the mixture was stirred at 80° C. for 30 minutes. After the stirring, 2.4 mL (4.0 mmol) of a 1.65 mol/L hexane solution of n-butyllithium was dripped with a syringe, followed by stirring at −80° C. for 2 hours. Then, 0.6 mL (4.8 mmol) of trimethyl borate was added, and the mixture was stirred overnight while the temperature thereof was gradually increased from −80° C. to room temperature. After the stirring, an aqueous solution of hydrochloric acid (1 mol/L) was added to this mixture, and it was then stirred at room temperature for 30 minutes. Then, ethyl acetate was added to separate the organic layer and the aqueous layer of this mixture, and the aqueous layer was extracted with ethyl acetate three times. This ethyl acetate layer and the organic layer were combined, washed with saturated brine, and dried with magnesium sulfate. The obtained mixture was gravity filtered so that magnesium sulfate was removed, and the obtained filtrate was concentrated to give a white solid. Recrystallization of the obtained white solid from a mixed solvent of ethyl acetate and hexane gave 1.2 g of a white solid in 90% yield, which was the substance to be produced. The synthesis scheme of this Step 1 is shown in (E18-1) given below.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][OH:8])[CH2:4][CH3:5].[H-].[Na+].Br[C:12]1[N:17]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:2]([N:3]([CH2:6][CH2:7][O:8][C:12]1[N:17]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCN(CC)CCO
Reactant: CC(C)(C)OC(=O)c1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc(C(=O)OC(C)(C)C)n1
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
1.03 g of diethylaminoethanol were introduced into 25 ml of dimethylformamide. At room temp., 0.22 g (9.26 mmol) of sodium hydride (60% suspension in white oil) was added. After stirring at room temp. for 30 minutes, a solution of 2.03 g (8.882 mmol) of tert-butyl 6-bromopicolinate in 20 ml of dimethylformamide was added dropwise. The reaction mixture was stirred at room temp. for 16 hours. After decomposition of excess sodium hydride with water, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (toluene/tetrahydrofuran/methanol, 4/1/1+2.5% triethylamine). 0.67 g of a pale brown oil was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])(C)[CH2:5]C(C)=C1.[OH:11]O.[OH-].[Na+].[CH:15]([OH:18])([CH3:17])[CH3:16]>>[CH3:5][C:6]([CH3:8])([CH2:16][C:15](=[O:18])[CH3:17])[CH2:9][C:2]([OH:1])=[O:11]
Reactant: OO
Reactant: CC(C)O
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC(C)(C)CC(=O)O
Temperature: 15 °C
Reaction time: 16 h

Procedure:
Isophorone (138 g) and 30% hydrogen peroxide (730 g) are dissolved in isopropanol (500 ml), and the solution is cooled to 15° C. 3N Sodium hydroxide solution (800 ml) is added slowly over a three-hour period to maintain the temperature of the reaction below 20° C. by adjusting the addition rate of sodium hydroxide solution and cooling with an ice-water bath. The reaction is allowed to warm to ambient temperature while stirring for 16 hours. The reaction mixture is extracted once with isopropyl ether (200 ml) then treated with sodium bisulfite (40 g) and acidified to pH 2 with concentrated hydrochloric acid (225 ml). The solution is extracted twice with methylene chloride (200 ml) and the resulting methylene chloride solution stripped under vacuum at 40° C., 10 mm Hg to give 3,3-dimethyl-5-ketohexanoic acid as a residue product.
Reaction SMILES: [C:1]1([C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:25])C.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2([CH:11]=[O:25])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccccc2)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=CC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 1-phenyl-cyclobutanecarbonitrile, dissolved in 70 ml of toluene, is mixed with 56 ml of diisobutylaluminum hydride in toluene (1.2 molar) at −72 to −69° C. After 4 hours at −75° C., 30 ml of ethyl acetate is added in drops. After heating to room temperature, additional ethyl acetate and water are added. It is filtered on diatomaceous earth, the organic phase is separated, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane with 0-10% ethyl acetate), 7.6 g of 1-phenyl-cyclobutanecarbalde-hyde is obtained. 3 g of it is dissolved in 10 ml of tetrahydrofuran and added in drops at 0° C., to a solution, in which previously 5 g of triethyl-2-ethoxyphosphonoacetate in 70 ml of tetrahydrofuran was mixed at 0° C. with 10.3 ml of a 2 molar solution of lithium diisopropylamide in tetrahydro-furan/heptane/ethylbenzene. After 20 hours at room tempera-ture, water is added, it is extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. 2 g of this crude product is saponified with 28 ml of 1N sodium hydroxide solution. 1.32 g of the acid, which is heated for 20 hours to 90° C. with 25 ml of 1 molar sulfuric acid while being stirred vigorously, is obtained. After extraction with ether, drying (Na2SO4) and concentration by evaporation, 0.89 g of 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid is obtained as a yellowish oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:13]1([C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: c1ccc(CN2CC[C@@H](N3CCCC3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CCN([C@@H]2CCNC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-1′-benzyl-[1,3′]bipyrrolidinyl (0.517 g, 2.24 mmol) in methanol (25 ml) under an atmosphere of argon is treated with palladium hydroxide on carbon (0.1 g). The reaction mixture is placed under an atmosphere of hydrogen, stirred at room temperature overnight and then filtered through Celite™ filter material. The filtrate is concentrated in vacuo to yield the title compound as a dark orange oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]([NH:34][NH2:35])=[O:33])[CH2:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C1COCC1>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:35][NH:34][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:33])=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CN1CCC(C(=O)NN)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)NNC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g, 1.0 eq.) was dissolved in EtOAc:THF (15 mL; 2:1) and cooled to −60° C. where 1-methylpiperidine-4-carbohydrazide (0.123 g, 1.1 eq.) was introduced. T3P (50% in EtOAc) (0.85 mL, 2 eq.) was added dropwise followed by DIPEA (0.31 mL, 2.5 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (35° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)—N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-1-methylpiperidine-4-carbohydrazide (0.016 g, yield: 4.5%).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH2:8]([NH:10][C:11]1[C:16]([C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=O)=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:9].O>O1CCCC1>[CH2:8]([N:10]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[N:5][C:6]1=[O:7])[CH3:9]
Reactant: CCNc1ncccc1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)nc(-c2cccs2)c2cccnc21
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
Chlorosulfonyl isocyanate (0.5 ml, 5.6 mmol) was added to a solution of 2-ethylamino-3-(2-thiophenecarbonyl)pyridine (1.01 g, 4.35 mmol) in tetrahydrofuran (50 ml) under ice-cooling, followed by stirring for 30 minutes. The reaction solution was mixed with water and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the resulting filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-ethyl acetate) and recrystallized from ethyl acetate to give 1-ethyl-4-(2-thienyl)pyrido[2,3-d]pyrimidin-2(1H)-one (613 mg, 2.38 mmol, 55%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24].[NH4+].[Cl-]>O1CCCC1>[CH3:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)[C:2]([Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2ccc(C(F)(F)F)cc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 132.7 %

Procedure:
To a solution of 3-iodo-1-methyl-6-(trifluoromethyl)-1H-indazole (491 mg, 1.51 mmol) in dry tetrahydrofuran (20 mL) was added drop-wise isopropylmagnesium chloride (1.66 mL, 2M in THF, 3.31 mmol) at −16° C. under N2 atmosphere. After stirring for 20 minutes, tributylchlorostannane (0.49 mL, 1.81 mmol) was added drop-wise at −16° C., then it was warmed to room temperature for 2 h. NH4Cl solution (2 mL) was added and product was extracted with dichloromethane (150 mL), then washed with water (3×20 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford 1-methyl-3-(tributylstannyl)-6-(trifluoromethyl)-1H-indazole (0.98 g, crude) as yellow oil which was used to next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.79 (d, 1H, J=11.4 Hz), 7.70 (s, 1H), 7.32 (d, 1H, J=8.4 Hz), 1.48-1.32 (m, 6H), 1.25-1.18 (m, 12H), 0.92-0.79 (m, 9H).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[N:3][C:2]=1[CH2:14][OH:15])=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH2:14][OH:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: OCc1cn2c(n1)CNc1ccccc1-2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: OCc1cn2c(cnc3ccccc32)n1
Reaction time: 6 h
Yield: 90.2 %

Procedure:
A solution of 3 g of 4,5-dihydro-imidazo-[1,2-a]-quinoxaline-2-methanol in 500 ml of chloroform and 9 g of manganese dioxide was refluxed with stirring for 6 hours and the mixture was filtered hot and concentrated. The mixture was cooled and filtered to obtain 2.68 g of a imidazo-[1,2-a]quinoxaline-2-methanol and imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde mixture and the latter was chromatographed over silica gel. Elution with a 97.5% chloroform-2.5% methanol mixture yielded first 0.23 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde and then 1.42 g of imidazo-[1,2-a]quinoxaline-2-methanol melting at 217°-220° C. Evaporation of the filtrate yielded 0.43 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde for a total yield of 0.66 g melting at 214°-215° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+]>CN(C=O)C.O>[CH3:22][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Cc2cccc(C(F)(F)F)c2)cc1
Reaction time: 18 h

Procedure:
3-Trifluoromethylbenzyl bromide (50 mmole) and sodium p-toluenesulfinate (65 mmole) were dissolved in 100 mL of dry DMF. The mixture was stirred at about 23° for about 18 hours then diluted with water. The sulfone crystallized from the aqueous mixture and was filtered. The compound was purified by recrystallization (EtOH). Colorless plates, mp 139°-140°: IR (KBr) 2954, 1614, 1598, 1450, 1332, 1312, 1288, 1164, 1142, 1116, 1074 cm-1 ; 1H NMR (CDCl3) δ 2.44 (s, 3H), 4.34 (s, 2H), 7.16 (s, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.42 (m, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.58 (d, J=7.5 Hz, 1H); MS m/e 315 (MH+).
Reaction SMILES: Cl.Cl.Cl.N1C=C(C[N:10]2[C:16]3[CH:17]=[CH:18][C:19](C4C=NC=CC=4)=[CH:20][C:15]=3C[N:13](C(=O)C(F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)N=C1.[H][H].C(OCC)(=[O:44])C>[OH-].[OH-].[Pd+2]>[O:44]=[C:11]1[NH:10][C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:15]=2)[NH:13][CH:12]1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: [H][H]
Reactant: CCOC(C)=O
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: O=C1Nc2ccccc2NC1Cc1ccccc1
Reaction time: 5 h

Procedure:
To a solution of Compound B (720 mg, 2.34 mmol) in ethyl acetate (5 mL) at rt was added 20% Pd(OH)2 /C (40 mg). The flask was filled with hydrogen gas via a balloon. After 5 hr, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The colorless solid was chromatographed (silica, flash, 30% EtOAc/hexanes) to afford Compund C (550 mg, 98%) as a solid. MS (M+H)+ 239.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(N)n(C)n1
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)C(C)(C)C)n(C)n1
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To 15.0 g (131 mmol) N-(2,5-dimethyl-2H-pyrazol-3-yl)-amine in 150 mL pyridine at 0° C. was added 19.3 mL (18.9 g, 158 mmol) of pivaloyl chloride. After stirring at 23° C. for 3.5 hours, the reaction solvent was evaporated, and the residue was evaporated with 2×200 mL toluene. The remaining solid was dissolved in 500 mL EtOAc/200 mL H2O and extracted. The aqueous layer was extracted with 2×100 mL EtOAc, and the combined organics were washed with 1×200 mL brine, dried over MgSO4, filtered and evaporated to an orange solid. Recrystallization from hot hexanes/EtOAc gave 24.45 g (125 mmol, a 96% yield) of the title compound as an off-white, crystalline solid: mp: 86-88° C.; 1H NMR (300 MHz, CDCl3): δ1.32 (s, 9H), 2.22 (s, 3H), 3.63 (s, 3H), 5.98 (s, 1H), 7.12 (brs, 1H); IR (KBr, cm−1): 3316s, 3274s, 2967m, 2935m, 1673s, 1655m, 1570s, 1514m, 1492m, 1457m; MS (ES) m/z (relative intensity): (196, M+, 100).