Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.BrC1C=CC=CC=1.[CH3:17][C:18]([O:22][Si](C)(C)C)([CH3:21])[C:19]#N.Cl.C(=O)(O)[O-:29].[Na+]>BrCCBr.C1COCC1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:19](=[O:29])[C:18]([OH:22])([CH3:17])[CH3:21])=[CH:4][CH:5]=1
Reactant: O=C([O-])O
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)(C#N)O[Si](C)(C)C
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: Brc1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
In a dry 250 ml three necked flask was placed magnesium turnings (2.46 g, 101.2 mmol), 5 ml dry THF and two drops of 1,2-dibromoethane, stirred under N2 at room temperature. Subsequently 1,4-dibromobenzene (19.8 g, 84 mmol) in 15 ml dry THF was added dropwise over 30 min. An ice water bath was occasionally used to moderate the reaction. After addition was complete the reaction was stirred for 2 hrs to complete conversion of bromobenzene. A solution of 2-methyl-2-trimethylsilanyloxy-propionitrile (13.25 g, 85 mmol) in 15 ml dry THF was added dropwise to the Grignard reagent and the mixture was stirred for 20 hrs. By this time a large quantity of white precipitate was formed. The intermediate produced was hydrolyzed by cautious addition of 80 ml 6N HCl with ice cooling and vigorous stirring as the solution warmed to room temperature and then kept stirring at this temperature for 4 hrs. Solid sodium bicarbonate was added cautiously to neutralize the excess acid and the solid in the mixture was removed by vacuum filtration through a pad of Celite and the Celite pad was washed three more times with ethyl acetate. The filtrate was extracted three times with ethyl acetate, dried over anhydrous MgSO4. The solvent was removed by rotary evaporation and the product obtained as liquid, which was suitable for direct use in the next step. For further characterization one gram of the crude product was purified by silica gel column chromatography using EtOAc/hexane 1/4 as eluent. Calculated yield: (77%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 4.01 (s, 1H), 1.51 (s, 6H). 13C NMR (100 MHz, (100 MHz, CDCl3) δ 203.21, 134.46, 132.63, 131.28, 127.68, 76.66, 28.11.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:24][OH:25])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=NO)cc2)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
3.52 g (11 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate was dissolved in 150 ml ethanol. 2.29 g (33 mmole) hydroxylamine hydrochloride and 3.6 g (44 mmole) sodium acetate in 30 ml water were added. The reaction mixture was stirred at 50° C. for 1 h 45 minutes. The solvent was evaporated in vacuo and water was added to give a white precipitate, which was filtered off and washed with hexane to give 3.3 g (yield 89%) of 4-{2-[4-(hydroxyiminomethyl)phenoxy]ethyl}phenyl methanesulfonate.
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:20][C:21]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].F[C:31](F)(F)[C:32](O)=O>ClCCl>[Cl:20][C:21]1[CH:28]=[C:27]([N:18]([CH2:23][CH2:22][CH2:21][CH2:28][CH2:27][CH2:31][CH3:32])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 2-chloro-4-fluorobenzonitrile as starting materials and by operations similar to those of Example 265-1 and Example 265-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: [P:1]([OH:39])([OH:38])([O:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]2[C:7]([C:21](=[O:37])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=2[F:36])=[CH:6]1)=[O:2].[OH-].[Na+:41]>C1COCC1.O>[P:1]([O-:38])([O-:39])([O:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]2[C:7]([C:21](=[O:37])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=2[F:36])=[CH:6]1)=[O:2].[Na+:41].[Na+:41]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COP(=O)(O)O)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COP(=O)([O-])[O-])c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl dihydrogen phosphate (396 mg, 0.66 mmol) in THF (20 mL) was added dropwise a solution of NaOH (58 mg, 1.45 mmol) in 0.3 mL of H2O and 4 mL of THF at rt. The reaction was stirred at rt for 4 h, and then filtered to give the title compound as a white solid (401 mg, 94.4%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22])=[CH:7]2)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([C:21]([NH:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:22])=[CH:7]2
Reactant: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2n1CCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CCc1ccccc1

Procedure:
50 mg (0.13 mmol) of 5-nitro-N-phenyl-1-(2-phenylethyl)-1H-indole-2-carboxamide from Example XLIX are initially charged in 7 ml of ethyl acetate and 7 ml of ethanol. 49 mg (0.78 mmol) of ammonium formate and 14 mg of palladium on activated carbon are added. The mixture is heated to reflux, and at 50° C. gas evolves. After 4 hours at reflux, the mixture is cooled and filtered through kieselguhr, which is then washed with 500 ml of ethanol. The solvent is removed under reduced pressure and the residue is dried. This gives 115 mg of a white solid which still contains inorganic salts and which is reacted further without purification.
Reaction SMILES: [P:1](Cl)(Cl)(Cl)=[O:2].[CH:6](NC(C)C)([CH3:8])[CH3:7].P(Cl)(O)O.C(NC(C)C)(C)C.C(NC(C)C)(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][CH2:38][CH2:39]O.N1C=NN=N1>C1C=CC=CC=1>[CH:6]([P:1]1[N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[CH2:38][CH2:39][O:2]1)([CH3:8])[CH3:7]
Reactant: CC(C)NC(C)C
Reactant: OCCNc1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Agent: OP(O)Cl
Agent: c1nnn[nH]1
Solvent: c1ccccc1
Product: CC(C)P1OCCN1c1ccccn1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
50 mL of anhydrous benzene was placed in a flask under argon. The flask was then closed tightly, followed by an addition of a freshly distilled phosphoric chloride (III) (876λ 1; 10 mmole). The flask was then cooled down to a temperature of 5° C., and the anhydrous N,N-diisopropylamine (7.7 ml; 55 mmole) was added. The reaction mixture was stirred for 30 minutes, and then slowly heated to 25° C. The temperature was then maintained until the bis(N,N-diisopropylamine) chlorophosphite was formed. After the reaction was completed in 98% (about 3 days), 2-(2-pyridyl)aminoethanol (1.38 mg; 10 mmole) was added to entire content of the flask. Then, after about 2 hours, 1-H-tetrazole (700 mg; 10 mmole) dissolved in anhydrous benzene (5 mL) was added. After the entire content of the flask reacted, 1 μl of diisopropylamine was added. The product of the reaction was then eluted on the column filled with silica gel with 200-mesh molecules. The eluent phase used a mixture of solvents: benzene and triethylamine, with a benzene volume fraction of 90%. As a result of the reaction, 2-isopropyl-3-(pyrid-2-yl)-[1,3,2]oxazaphospholidine was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[C:5]([C:8](OC)=O)=[N:6][CH:7]=1.[NH2:16][C@:17]([CH3:24])([CH:21]([CH3:23])[CH3:22])[C:18]([NH2:20])=[O:19].CC([O-])(C)C.[K+].O>C1(C)C=CC=CC=1>[CH:21]([C@:17]1([CH3:24])[C:18](=[O:19])[NH:20][C:8]([C:5]2[N:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[C:12]([OH:14])=[O:13])=[N:16]1)([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(C)cnc1C(=O)OC
Reactant: CC(C)[C@@](C)(N)C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(C2=N[C@](C)(C(C)C)C(=O)N2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
A stirred mixture of dimethyl 5-methylpyridine-2,3-dicarboxylate (52.25 g, 0.25 mol) and (R)2-amino-2,3-dimethylbutyramide (33.43 g, 0.2563 mol, 96.2% R isomer) in dry toluene is treated with KOt-Bu (29.4 g, 0.2625 mol) at 35° C., stirred at ambient temperatures for 10 minutes, treated with a second portion of KOt-Bu (29.4 g, 0.2625 mol) at 40° C., heated at 80°-85° C. for 1.5-2.0 hr, cooled to room temperature, treated with water and stirred until dissolution of solids is complete. The phases are separated. The aqueous phase is acidified to pH 3 with concentrated HCl, stirred at pH 3 for 10-15 min., and filtered. The aqueous filtrate is extracted with methylene chloride. The filtercake is dispersed in methylene chloride and the dispersion is filtered. The methylene chloride extracts and the methylene chloride filtrate are combined, dried over MgSO4 and concentrated to dryness in vacuo to give the title product as a white solid, 47.3 g, 68.6% yield, 98.1% pure, 97% R isomer by quantitative NMR analysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@H:5]([OH:23])[CH2:6][C@H:7]([NH2:22])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].C(O)[C:26]1[CH:31]=[CH:30]C=[CH:28][CH:27]=1.Cl.O1CCOCC1.[OH:40][C:41]1[N:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[N:44]=[C:43]([C:52]([OH:54])=O)[CH:42]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4](=[O:24])[C@H:5]([OH:23])[CH2:6][C@H:7]([NH:22][C:52]([C:43]1[CH:42]=[C:41]([OH:40])[N:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[N:44]=1)=[O:54])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cc(O)n(-c2ccccn2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCc1ccccc1)c1cc(O)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
A mixture of (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (150.0 mg, 431 μmol), benzyl alcohol (446.2 μL, 4.3 mmol), and 4.0 M HCl in 1,4-dioxane (431 μL, 1.7 mmol) was stirred at room temperature overnight, then at 50° C. for 1 hour. The mixture was then concentrated under reduced pressure. 5-Hydroxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid (44.2 mg, 216 μmol) and HATU (98.4 mg, 259 mol) were stirred in DMF (0.5 mL, 5 mmol) for 10 minutes, then added to the concentrated mixture, along with DIPEA (113 μL, 647 μmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in 50% AcOH-water (5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (19.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]12
Reactant: COc1cccc(C=O)c1OC
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc(OC)c2OC)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,3-dimethoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][CH:4]=5)=[O:9])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1nc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
A mixture of 2-methyl-1,3-thiazole-4-carboxylic acid (120 mg, 0.84 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol), 1-hydroxybenzotriazole (110 mg, 0.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.84 mmol), triethylamine (85 mg, 0.84 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0) to give the title compound (180 mg, 62%) as a white solid.
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.Cl[CH2:13][C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=1>CO.CN(C=O)C>[F:21][C:20]([F:22])([F:23])[C:16]1[CH:15]=[C:14]([CH2:13][S:2][C:3]2[NH:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: Sc1nc2cnccc2[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cccc(CSc2nc3cnccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.15 g (0.0065 g atom) of sodium in 35 mL of methanol was added 1.0 g (0.0066 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine. After stirring for 15 minutes at room temperature, the methanol was removed in a rotary evaporator. The residue was dissolved in 20 mL of DMF and 1.28 g (0.0066 mol) of α'-chloro-α,α,α-trifluoro-m-xylene in 2 mL of DMF was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature overnight and was then poured into 150 mL of ice water. The product which crystallized was collected and amounted to 1.61 g. An analytical sample (m.p. 148°-150° C.) was obtained by recrystallization from acetonitrile.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][NH:23][CH3:24].[CH:25](O)(C)C>O>[CH3:22][N:23]([CH3:24])[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([O:14][CH:15]([CH3:25])[CH3:16])=[O:13])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CC(C)O
Reactant: CCOC(=O)Cn1cnc2c(-c3ccco3)nc(Cl)nc21
Reactant: CNC
Solvent: O
Product: CC(C)OC(=O)Cn1cnc2c(-c3ccco3)nc(N(C)C)nc21
Yield: 19 %

Procedure:
A solution of ethyl 2-chloro-6-(2-furyl)-9H-purine-9-acetate (100 mg, 0.33 mol) in isopropanol (1 mL) was treated with 40% dimethylamine in water, refluxed for 2 h, cooled, poured into water, extracted with EtOAc and the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; Heptane:EtOAc, (1:1)] to give the title compound (20 mg, 19%) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[C:8]([C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9].C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[Br:7][C:5]1[CH:6]=[C:2]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH:11]=2)[C:8]#[N:9])[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: CC(C)Oc1ccc(B(O)O)cc1C#N
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2cc(Br)cs2)cc1C#N

Procedure:
A 2 mL microwave vial was charged with 2,4-dibromothiophene (20 mg, 0.08 mmol), (3-cyano-4-isopropoxyphenyl)boronic acid (17 mg, 0.08 mmol), potassium carbonate (35 mg, 0.25 mmol) and 3:1 mixture of DME/H2O (4 mL). The reaction mixture was degassed by bubbling N2 through the stirred solution for 10 min. Pd(PPh3)4 (7 mg, 0.006 mmol) was added and the solution degassed for an additional 2 min. The vial was subjected to microwave irradiation at 70° C. for 30 min or until starting material consumed. 5-(4-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-3 was used in the next experiment without purification. LCMS-ESI (m/z) calculated for C14H12BrNOS: 320.9; no M+ observed, tR=4.15 min.
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[O-])=[CH:6]/[C:7]([O:9]CC)=[O:8])C.[Na+].C(O)(=O)C.[CH:19](=[NH:21])[NH2:20].[OH-].[Na+]>O>[OH:3][C:4]1[N:21]=[CH:19][N:20]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: CCOC(=O)/C=C(\[O-])C(=O)OCC
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
To a solution of sodium (Z)-1,4-diethoxy-1,4-dioxobut-2-en-2-olate (55.0 g, 262 mmol) in H2O (500 mL) was added formimidamide acetate (27.3 g, 262 mmol) and NaOH (10.5 g). After addition, the resulting mixture was stirred at 25° C. for 16 h then concentrated and then acidified by added aqueous HCl (1N) until pH=1. The resulting solid was collected by filtration, washed with H2O and ether to give 6-hydroxypyrimidine-4-carboxylic acid (6.0 g, yield: 16.3%). 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.24 (s, 1H), 6.83 (s, 1H).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][C:21]1[N:26]=[C:25]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]2[CH3:37])[C:24]([CH3:38])=[C:23]([CH3:39])[N:22]=1>CN(C)C=O>[ClH:20].[CH3:38][C:24]1[C:25]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]2[CH3:37])=[N:26][C:21]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[N:22][C:23]=1[CH3:39]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: NCc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NCc2cccc3ccccc23)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 81.4 %

Procedure:
After 1-naphthylmethylamine(0.38 ml, 2.61 mmol) and triethylamine (0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 630 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:52]1([C:58]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C=O)C.O>[O:29]=[C:27]([N:55]1[CH2:56][CH2:57][N:52]([C:58](=[O:59])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:67])[F:68])[CH2:53][CH2:54]1)[CH2:26][NH:25][C:23]([C:20]1[CH:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH3:10])[NH:22][N:21]=1)=[O:24]
Reactant: COc1ccccc1-c1cc(C(=O)NCC(=O)O)n[nH]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)n[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 37 %

Procedure:
DIPEA (99 mg, 0.13 mL, 0.76 mmol) was added to a stirred solution of {[5-(2-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (60 mg, 0.21 mmol) in DMF (2 mL). HOBT (34 mg, 0.25 mmol) and EDCI (49 mg, 0.25 mmol) were then added at room temperature. After 2 minutes, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride salt (64.3 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to afford 40 mg (35.7% yield) of 5-(2-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 97.45%. 1H NMR (DMSO-d6): δ 13.5 (s, 1H), 8.0 (m, 1H), 7.62 (m, 4H), 7.5 (m, 1H), 7.3 (m, 1H), 7.16 (m, 1H), 7.01 (m, 2H), 4.1 (d, 2H), 3.84 (s, 3H), 3.6 (m, 2H), 3.56 (m, 2H), 3.36 (m, 2H), 3.1 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].C1([O-])C=CC=CC=1.[Br:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[Br:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: O=Cc1cccc(CBr)c1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1cccc(COc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.4 g of 3-bromomethylbenzaldehyde was dissolved in 3 ml of dimethylformamide, and the solution was added to 5 ml of a tetrahydrofuran solution of phenolate, prepared from 1.5 g of 3-bromophenol and 0.36 g of 60% oily sodium hydride. The mixture was stirred for 2 hours at room temperature. The solvent was evaporated, and water and ethyl acetate were added to the residue to extract it. The extract was worked up in a customary manner to give crude 3-(3-bromophenoxymethyl)benzaldehyde. When the same reaction as in Referential Example 12 was performed using 440 mg of the resulting aldehyde compound, 747 mg of tributyl(3-thienyl)stannane and 10 mg of tetrakis(triphenylphosphine)palladium, 341 mg (yield 77%) of 3-[3-(3-thienyl)phenoxymethyl)benzaldehyde was obtained.