Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:24]B1OBOBO1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reactant: CB1OBOBO1
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: C1COCCO1
Product: COC(=O)c1nc(C)c2cc(Sc3ccccc3)ccc2c1O
Yield: 28.2 %

Procedure:
1-Bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (0.2 g), tetrakis(triphenylphosphine)palladium (60 mg), methyl boroxine (65 mg), and potassium carbonate in 1,4-dioxane (4 ml) were heated in a microwave reactor (sealed tube) for 10 min at 140° C. After cooling reaction mixture was concentrated and partitioned between 1 N hydrochloric acid and ethyl acetate. Organic layer dried over magnesium sulfate and filtered. Filtrate concentrated and separated by silica gel chromatography (eluting with 2% ethyl acetate in methylene chloride) to give the title compound (47 mg). MS-(+)-ion M+1=326.1.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][S:17][CH:16]3[N:13]([C:14](=[O:27])[CH:15]3[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]=2[C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:9][N:10]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][S:17][CH:16]3[N:13]([C:14](=[O:27])[CH:15]3[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]=2[C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (1.51 cc) in dry tetrahydrofuran (10 cc) is added dropwise, in 5 minutes, to a solution, cooled to 0° C., of 3-(2-aminothiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (10 g) in dry tetrahydrofuran (150 cc), and a solution of triethylamine (2.8 cc) in dry tetrahydrofuran (5 cc) is then added. The reaction mixture is stirred for 1 hour 30 minutes at about 0°-5° C. and is then treated with further acetyl chloride (1.51 cc) in tetrahydrofuran (10 cc). After 1 hour 50 minutes at 5° C., the reaction mixture is filtered and the filtrate is concentrated to 50 cc and diluted with ethyl acetate (250 cc). The organic phase is washed with a saturated sodium bicarbonate solution (100 cc), with distilled water (100 cc) and with a half-saturated sodium chloride solution (100 cc) and is then dried over magnesium sulphate and concentrated to dryness. Crude 3-(2-acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicylo[4.2.0]oct-2-ene (10 g) is obtained in the form of a brown froth. Crystallisation from acetonitrile (25 cc) gives pure 3-(2-acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.9 g) in the form of a whitish crystalline powder whose characteristics are identical to those of the product obtained in variant (A).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2I.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]>C1COCC1>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]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]
Reactant: Cn1nc(I)c2cc(OC(F)F)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC(F)F)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
5-(Difluoromethoxy)-3-iodo-1-methyl-1H-indazole (0.265 g, 818 μmol) was dissolved in THF (3.00 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath) then isopropylmagnesium chloride (2M in THF, 458 μL, 916 μmol) added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (306 mg, 255 μL, 940 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum and taken into next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:14])[NH:10][NH:11][C:12]=1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(O)(=O)C>CN(C)C=O.O>[C:21]([N:11]1[C:12]([CH3:13])=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:14])[NH:10]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
4-Benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.00 g) was suspended in N,N-dimethylformamide (5 mL) at room temperature. In addition, potassium carbonate (0.441 g) was added to the suspension, and the mixture was stirred for 30 minutes. Acetic anhydride (0.570 g) was added to the mixture in a dropwise manner at room temperature. The mixture was stirred at room temperature overnight and at 50° C. for 2 hours. In addition, the mixed solution of glacial acetic acid (0.191 g) and water (5.0 g) was added to the reaction mixture under stirring at room temperature. After confirming the precipitation of the crystals, water (25 g) was added to the mixture under stirring. The crystals were collected by filtration, washed with water and dried under reduced pressure to give a white solid of 1-acetyl-4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.92 g).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11](O)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH2:52])[CH2:47][O:46]1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH:52][C:11]([C:4]2[C:3]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])=[C:2]([F:1])[C:7]3[N:8]=[CH:9][S:10][C:6]=3[CH:5]=2)=[O:12])[CH2:47][O:46]1
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reactant: CC1(C)OCC(CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)OCC(CONC(=O)c2cc3scnc3c(F)c2Nc2ccc(I)cc2F)O1
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid (519 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added HOBt (254 mg, 1.63 mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts was washed by water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (475 mg) was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1.[CH3:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:29]=[CH:30][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Solvent: O
Product: COC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2C)cc1

Procedure:
In analogy to example 203, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1-methyl-1H-pyridin-2-one (example 323, step 3) was reacted with 4-(methoxycarbonyl)phenyl-boronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a orange solid, MS (ESI+): m/z=424.1 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccccc1OCCCCl

Procedure:
1-(3-Chloro-propoxy)-2-nitro-benzene (˜60 mmol) is dissolved in ethanol (200 ml) and platinum dioxide (0.5 g) is added. The stirred mixture is treated with hydrogen under normal pressure until the hydrogen uptake stopped. The catalyst is filtered off and the filtrate is evaporated. A pale yellow oil with Rf=0.3 (CH2Cl2) is obtained, which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)[C:10]([O:12][C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[OH:35][C:23]1[CH:22]=[C:21]([CH2:20][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([O:12][C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:11])[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of (1R)-2-acetyloxy-1-methylethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (18) (12.7 g, 22.1 mmol) in 100 mL of methanol, 10% Pd—C (200 mg) pre-mixed with 10 mL of methanol was added under a nitrogen atmosphere. The nitrogen was exchanged with hydrogen using the evacuation refill cycle method. The mixture was stirred under hydrogen at room temperature for 4 hours. After filtration and washing with methanol, the filtrate was concentrated to afford 8.8 g (100% yield) of the title compound (19). 1H NMR (400 MHz, CDCl3): δ 1.21 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.07 (s, 3H), 2.95 (m, 2H), 4.05 (dd, J=12.0, 6.4 Hz, 1H), 4.12 (dd, J=12.0, 3.2 Hz, 1H), 4.48 (dd, J=14, 6.4 Hz, 1H), 5.04 (d, 1H, NH), 5.15 (m, 1H), 6.53 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.74 (d, J=8.0 Hz, 1H). MS (ESI) m/z 420.0 (M+Na)+ and 396.0 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CSC>>[C:9]([CH:8]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: CSC
Product: O=C(c1ccccc1)C1C(c2ccccc2)C1c1ccccc1

Procedure:
The same method was applied for the cyclopropanation of chalcone using a stoichiometric amount of dimethyl sulphide (36.5 μl; 0.5 mmol). Column chromatography over silica afforded the title compound as a 5:1 mixture of trans; cis cyclopropanes as a yellowy solid (54 mg; 36.2%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][N:41]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N-methyl-isobutyramide (Example 88) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 173. NMR 400 MHz (CDCl3): 2.56 (6H, b, CH3), 2.80 (3H, d (J=4.93), CH3), 3.83 (2H, s, CH2), 3.88 (4H, m, CH2), 4.03 (4H, m, CH2), 5.19 (2H, s, NH), 7.26 (1H, s, ar), 9.28 (2H, s, ar). MH+512.37
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>C(=O)([O-])[O-].[Ag+2].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>[C:18]1([CH3:17])[CH:23]=[CH:22][C:21]([C:5]2[S:1][C:2]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=3)=[N:3][CH:4]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(I)cc1
Reactant: CCOC(=O)c1ccc(-c2nccs2)cc1
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1ccc(-c2ncc(-c3ccc(C)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
In a sealed tub was added ethyl 4-(thiazol-2-yl)benzoate (100 mg, 0.43 mmol), 4-methyliodobenzene (111 mg, 0.51 mmol), silver carbonate (236 mg, 0.86 mmol) and tetrakis(triphenylphosphine)palladium (0) (11.2 mg, 0.86 mmol). The flask was purged with nitrogen three times and then was added acetonitrile (1.8 mL). The mixture was stirred under Ar atmosphere for 12 h at 60° C. When the reaction completed, the inorganic solids were filtered on (Celite®) and the residue was washed several times with dichloromethane, then filtered and evaporated. Flash chromatography of the residue on silica gel (SiO2, hexane:ethyl acetate, 9:1) afforded 115.8 mg of ethyl 4-(5-(p-tolyl)thiazol-2-yl)benzoate as a white crystalline solid (84% yield). EM (IE): m/z (%): 323.1; (M+, 100). HRMS (ESI): calculated for C19H18NO2S: 324.1053. found: 324.1055.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][CH:29]=3)[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:37]=[O:38]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[CH:37]=[O:38])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(COc2ccc(-c3cnc4ccnn4c3C3CCCCC3)cc2)cc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice cold solution of 300 mg (0.78 mmol) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine in 2 mL of dimethylformamide (DMF) and 1 mL of dichloromethane (DCM) was added 0.085 mL (0.9 mmol) of phosphorus oxychloride (POCl3) and the resulting mixture was allowed to warm up to rt and stirred at rt for 4 h when analysis by thin layer chromatography (TLC) indicated complete conversion of starting material to product. The reaction mixture poured into ice-water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 335 mg of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (436) as a beige solid as indicated by 1H NMR; LC-MS—calcd for C26H25N3O2 [M++H]+: 412.19, found: 412.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH:15]=[CH:14][CH:13]=[C:12]2[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:17])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]([C:12]2[N:11]([CH2:10]/[CH:9]=[CH:8]/[C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[O:1][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:15]=[CH:14][CH:13]=2)=[O:17])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(O)c2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 461.2 %

Procedure:
To a solution of the compound (180 mg, 0.567 mmol) of Example 6-2 in N,N-dimethylformamide (3.0 ml) was added potassium carbonate (100 mg, 0.724 mmol) and ethyl 4-bromo-n-bytyrate (105 mg, 0.538 mmol), and the mixture was stirred for 2 hours at 45° C. To the reaction mixture was further added ethyl 4-bromo-n-butyrate (20.0 mg, 0.100 mmol) and the mixture was stirred for additional 9 hours at 50° C. Thereto was added an aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (hexane:ethyl acetate=4:1) to give the subject compound (199 mg, 81%).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18].O>>[OH:1][CH:2]([CH2:16][NH:20][CH:17]([CH3:19])[CH3:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: O
Product: COC(=O)Cc1ccc(OCC(O)CNC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-[(2,3-epoxy)propoxy]phenylacetate (2.00 g, 9.00 mmol), isopropylamine (23 ml, 0.27 mol) and water (1.35 ml, 74.7 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated (rotavapor) and the oily residue was dissolved in chloroform and dried (Na2SO4). Filtration and concentration gave quantitative yield of a yellow oil that was used in the next step without further purification. The structure was verified by 1H and 13C NMR analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:28]1[NH:33][C:32](=[O:34])[N:31]([CH:35]([CH3:37])[CH3:36])[C:30](=[O:38])[CH:29]=1>CN1C(=O)CCC1.CS(C)=O>[CH:35]([N:31]1[C:30](=[O:38])[CH:29]=[C:28]([NH:10][C@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH3:9])[NH:33][C:32]1=[O:34])([CH3:37])[CH3:36]
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Reactant: Cc1ccccc1[C@H](C)N
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccccc1[C@H](C)Nc1cc(=O)n(C(C)C)c(=O)[nH]1
Temperature: 130 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
To a stirred solution of (1S)-1-(2-methylphenyl)ethan-1-amine (310 mg, 2.29 mmol, 1.50 equiv) in NMP (1 mL) was added proton sponge (491.4 mg, 2.30 mmol, 1.50 equiv) and 1.3 (288 mg, 1.53 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 130° C. in an oil bath, cooled to room temperature, and then diluted with DMSO (2 mL). The solids were filtered and the filtrate was purified by Flash-Prep-HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: H2O/0.05% TFA, Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min. This afforded 50 mg of crude product which was subsequently separated by chiral preparative HPLC with the following conditions: Column, Chiralpak IC, 2*25 cm, Sum; mobile phase, hexanes and ethanol (9:1, 15 min). This resulted in 35.6 mg (8%) of the title compound as a white solid. LC/MS: m/z (ES+) 288 (M+H)+. 1H-NMR (300 MHz, DMSO-d6): δ ppm 9.76 (br s, 1H), 7.28 (d, J=7.2 Hz, 1H) 7.24-7.14 (m, 3H), 6.48 (d, J=6.3 Hz, 1H), 4.95-4.86 (m, 1H), 4.60 (quin, J=6.9 Hz, 1H), 4.19 (s, 1H), 2.34 (s, 3H), 1.37 (d, J=6.6 Hz, 3H), 1.27 (d, J=6.9 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:21]2[CH:20]=[CH:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:17]=3)[CH:22]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: OB(O)c1ccc2cc(-c3ccccc3)ccc2c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(-c2ccc3cc(-c4ccccc4)ccc3c2)c(C)n1
Yield: 82 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were placed 0.24 g of 2-chloro-3,5-dimethylpyrazine, 0.41 g of 6-phenylnaphthalene-2-boronic acid, 0.18 g of sodium carbonate, 0.008 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was irradiated with microwaves (2.45 GHz, 100 W) for 30 minutes, so that heating was performed. Then, the reaction container was cooled to 50° C. or less. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled, whereby Hdm6p2npr, which is the pyrazine derivative to be produced, was obtained (as a white powder in 82% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 4 is illustrated in the following (d-4).