Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C@H:4]1[O:6][CH2:5]1.[Br-:15].[Li+].P([O-])([O-])([O-])=O>O1CCCC1.[Ni](Br)Br>[Br:15][CH2:5][C@@H:4]([C:3]1[C:2]([F:1])=[C:10]([F:11])[C:9]([F:12])=[C:8]([F:13])[C:7]=1[F:14])[OH:6]
Reactant: [Br-]
Reactant: Fc1c(F)c(F)c([C@@H]2CO2)c(F)c1F
Agent: Br[Ni]Br
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.1 %

Procedure:
To an ice-cooled solution of 1.05 g of (R)-(+)-2,3,4,5,6-pentafluorostyrene oxide in 10 ml of tetrahydrofuran, was added dropwise a solution of Li2NiBr4, which was prepared by adding 2.19 g of nickel (II) bromide to a suspension of 1.74 g of lithium bromide in 20 ml of tetrahydrofuran. After completion of addition, the solution was stirred for 15 hours at room temperature. The resulted reaction mixture was poured into a 0.05 mol phosphate buffer, and was extracted with ether. The resultant extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 1.02 g of (R)-(-)-2-bromo-1-(pentafluorophenyl)ethanol containing 15% of (+)-2-bromo-2-(pentafluorophenyl)ethanol.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[Cl:15])[N:6]=1)(=[O:3])[CH3:2].[F:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[CH:20][C:18]=1[NH2:19]>C(O)(C)C>[ClH:15].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[NH:19][C:18]2[CH:20]=[C:21]([OH:25])[C:22]([CH3:24])=[CH:23][C:17]=2[F:16])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(Cl)ccnc2n1
Reactant: Cc1cc(F)c(N)cc1O
Solvent: CC(C)O
Product: CC(=O)Nc1ccc2c(Nc3cc(O)c(C)cc3F)ccnc2n1
Product: Cl
Yield: 55.1 %

Procedure:
A mixture of 2-acetamido-5-chloro-1,8-naphthyridine (357 mg, 1.6 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (200 mg, 1.4 mmol), (prepared as described for the starting material in Example 1), in isopropanol (20 ml) was heated at reflux for 5 hours. The mixture was allowed to cool and the precipitate was collected by filtration, washed with acetone and dried to give 2-acetamido-5-(2-fluoro-5-hydroxy-4-methylanilino)-1,8-naphthyridine hydrochloride (280 mg, 61%).
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8]CC)=O)=O.C1(C)C=CC=CC=1.Cl.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][NH2:31]>C(O)(=O)C>[OH:8][C:6]1[N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[N:31]=[C:3]([C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)n(-c2ccccc2C)n1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
To a mixture of diethyl oxalacetate sodium salt (10.5 g, 50 mmol), acetic acid (100 mL) and toluene (50 mL) was added an aqueous solution (50 mL) of (2-methylphenyl)hydrazine hydrochloride (7.93 g, 50 mmol) under stirring at room temperature, and the mixture was heated under reflux for 3 hr. After cooling, the reaction mixture was partitioned. The organic layer was washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give yellow crystals. This product was dissolved in acetic acid (36 mL), and the mixture was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and recrystallized from hexane-ethyl acetate to give the title compound (2.69 g, yield 22%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[C:19]([OH:23])(=[O:22])[CH:20]=O>C(O)(=O)C.O>[O:17]=[C:15](/[CH:14]=[CH:13]/[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:16]=[CH:20]/[C:19]([OH:23])=[O:22]
Reactant: COc1cc(/C=C/C(C)=O)cc(OC)c1OC
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(/C=C/C(=O)/C=C/C(=O)O)cc(OC)c1OC

Procedure:
A solution of 5 g (21 mmol) of (E)-4-(3,4,5-trimethoxyphenyl)but-3-en-2-one and 2 g (21.7 mmol) of glyoxylic acid monohydrate in 5.2 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether yielded (E,E)-4-oxo-6-(3,4,5-trimethoxyphenyl)-2,5-hexadienoic acid of melting point 152°-154°.
Reaction SMILES: CO.[C@@H:3]1([N:12]2[CH:19]=[CH:18][C:16]([NH2:17])=[N:15][C:13]2=[O:14])[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1O.C([Sn](=O)CCCC)CCC.C1(C)C=CC(S([Cl:39])(=O)=O)=CC=1>C(N(CC)CC)C>[CH:18]1[C:16](=[NH:17])[N:15]=[C:13]2[N:12]([C@@H:3]3[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@@H:4]3[O:14]2)[CH:19]=1.[ClH:39]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: CCN(CC)CC
Product: Cl
Product: N=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A 500 mL flask was charged with 50 mL methanol, 1.95 g cytidine and 2 g dibutyl tin oxide. The resulting suspension was refluxed for five hours and then stirred at room temperature for twelve hours. To the mixture was then added triethylamine (7.8 mL) followed by slow addition of p-toluenesulfonyl chloride (10.68 g). The resulting mixture was stirred for twelve hours at room temperature. Thereafter, the solvents were evaporated under vacuum and chloroform (100 mL) was added to the resulting white gum. The chloroform/white gum suspension was refluxed for fifteen minutes and then cooled to room temperature. The resulting white precipitate was filtered and washed with chloroform, and dried to yield 1 g of crude 2,2'-O-cyclocytidine hydrochloride. The crude cyclocytidine hydrochloride was suspended in 5 mL water and the mixture was heated to 60° C. This solution was filtered and the solvent reduced under vacuum to obtain a turbid oil. Ethanol (18 mL) was added and the mixture was stirred at 5° C. for twelve hours. The resulting precipitate was filtered and dried to provide 0.6 g of pure 2,2'-O-cyclocytidine hydrochloride (29% yield). The product was characterized by comparison of its melting point, and NMR and IR spectra with those previously reported for 2,2'-O-cyclocytidine.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)SC)#[N:2].[NH2:17][CH2:18][CH2:19]SCC1C=CSN=1.C(N)C>>[C:1]([NH:3][C:4]([NH:17][CH2:18][CH3:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)#[N:2]
Reactant: NCCSCc1ccsn1
Reactant: CSC(=NCCSCc1ccsn1)NC#N
Agent: CCN
Product: CCNC(=NCCSCc1ccsn1)NC#N

Procedure:
Reacting N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea, prepared from 3-[(2-aminoethyl)thiomethyl]isothiazole by the procedure of Example 3(c)(i), with ethylamine by the procedure of Example 4 gives N-cyano-N'-ethyl-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:25])[CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[F:26][C:27]([F:33])([F:32])[S:28](O)(=[O:30])=[O:29].O>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:25])[CH2:11][CH:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][S:28]([C:27]([F:33])([F:32])[F:26])(=[O:30])=[O:29])=[CH:22][CH:23]=2)[CH2:16][CH2:17]1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)CC1CCC(c2ccc(O)cc2)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Reaction time: 5 h
Yield: 91.1 %

Procedure:
Triethyl amine (8.1 mL, 57.99 mmol) was added dropwise to [4-(4-hydroxyphenyl)cyclohexyl]acetic acid methyl ester (9.6 g, 38.66 mmol) dissolved in CH2Cl2 and trifluoromethane sulphonic acid (8.1 mL, 48.32 mmol) solution at 0° C. The reaction mixture was warmed up to reach ambient temperature and stirred for 5 hours. The reaction mixture was poured into 200 mL water and extracted with CH2Cl2. The organic phase was washed with saturated sodium bicarbonate solution, brine and anhydrous Na2SO4. The solvent was reduced under reduced pressure, the residue was purified in silica gel using CH2Cl2 as an eluent to obtain [4-(4-trifluoromethanesulfonyloxyphenyl)cyclohexyl]acetic acid methyl ester (13.4 g, 91%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([NH:12]C(=O)C)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:16])[CH2:3]1>Cl.CCO>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:17])([CH3:1])[CH2:3][C:4](=[O:16])[NH:5]2)=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)CC2(C)C
Agent: Cl
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc(N)ccc21

Procedure:
N-(4,4-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-acetamide (1.50 g, 6.46 mmol) in 10 ml of HCl (concentrated, 37%) and 30 ml of EtOH was stirred at 75° C. for 4 h. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc/H2O, neutralized with NaHCO3, washed with brine, dried with Na2SO4, filtered, and condensed to give the titled compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[C:7]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)[CH:2]=[C:3]([Cl:9])[N:4]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Product: CN1CCN(c2cc(Cl)nc(N3CCN(C)CC3)n2)CC1
Temperature: 0 °C

Procedure:
Trichloropyrimidine is added in portions to an ice cool solution of N-methylpiperazine (40 g) in ethanol (200 ml). The mixture is then heated at 60° for 2 h. The mixture is concentrated and chromatographed on silica gel with 2-5% methanol and methylene chloride to give 2,4-bis[4-methylpiperazino]-6-chloropyrimidine. This material is heated at 130° in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 h. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give the title compound, TLC (methylene chloride/methanol/ammonium hydroxide-91.5/8/0.5) Rf =0.3.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[C:4]([Cl:17])[CH:3]=1.Cl.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[ClH:17].[Cl:17][C:4]1[CH:3]=[C:2]([CH:16]=[CH:15][C:5]=1[C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:1][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1
Reactant: Nc1ccc(C(=O)Nc2ccccc2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(C(=O)Nc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 71 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-amino-2-chlorobenzanilide was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(N-phenylcarbamoyl)anilino]-6,7-dimethoxyquinazoline hydrochloride salt in 71% yield, m.p. >260° C.;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:18])[CH3:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].COCCO.Cl.C(=O)([O-])[O-]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:18])[CH3:17])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(C)=O)n3)cc2CC1
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 68.7 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide (170.0 mg, 0.5607 mmol) was added into a Vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (103.0 mg, 0.5413 mmol) in 2-Methoxyethanol (7 mL, 90 mmol). 4 M of Hydrogen chloride in 1,4-Dioxane (0.20 mL) was added and the reaction was heated at 120° C. After 4.5 h, the reaction was cooled to room temperature, Macroporous carbonate resin (3.16 mmol/g loading; 530 mg, 1.68 mmol) was added and stirred 30 min. The polymer was filtered off, and the solvent removed in vacuo. The residue was dissolved in DCM, concentrated onto Celite, then chromatographed (2×12 g SiO2, ISCO, 0-10% (5% NH4OH:MeOH):DCM) to afford N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-acetamide as a beige solid (170 mg, 69%). m.p.=248-250° C.; LCMS (m/e) 457 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.28 (m, 2H), 7.04 (d, 1H, J=7.5 Hz), 6.77 (s, 1H), 6.02 (s, 1H), 5.73 (s, 1H), 3.81 (m, 2H), 2.81-2.91 (m, 4H), 2.5-2.6 (m, 6H), 2.26 (m, 1H), 2.13 (m, 1H), 1.81 (m, 2H), 1.71 (s, 3H), 1.2-1.4 (m, 4H), 1.10 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)C=O.N.CC1C=CC(S(C[N+]#[C-])(=O)=O)=CC=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28]C1>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:4]([C:30]2[NH:29][CH:28]=[N:26][CH:31]=2)[C:3]=1[OH:11]
Reactant: C1CNCCN1
Reactant: O=Cc1cc(F)cc(Cl)c1O
Agent: N
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: Oc1c(Cl)cc(F)cc1-c1cnc[nH]1
Yield: 65 %

Procedure:
Paraformaldehyde (0.35 g) was added in portions to a mixture of phenol (487.8 mg, 3.33 mmol), triethylamine (1.3 mL, 9.33 mmol), and anhydrous MgCl2 (0.98 g, 10.3 mmol) in acetonitrile (30 mL). The mixture was refluxed for 48 h, cooled to room temperature, acidified with aqueous 3 N HCl solution, and extracted with ether. The ether layer was washed with water, and brine, and dried (MgSO4). Removal of solvent yielded a crude material which was purified by column chromatography (SiO2) to yield 3-chloro-5-fluoro-2-hydroxybenzaldehyde. To this aldehyde (0.25 mmol) in at room temperature was added 3 mL of NH3 (2.0 M solution in EtOH) solution and the solution was stirred overnite (upon addition of NH3 in ethanol, the solution changed to yellow). TosMIC (0.30 mmol equiv) and piperazine (0.38 mmol) were then added directly to the solution at room temperature in solid form. The solution were stirred at room temperature for 3 h until completion confirmed by TLC monitor. The solvent was evaporated mostly under reduced pressure and the crude was purified by column chromatography using 1:1 Hexanes and Ethyl acetate mixtures to afford the desired product as a light yellow solid. Yield=65%. 1H NMR (MeOH-d4): 6.95-6.99 (m, 1H), 7.29-7.33 (m 1H), 7.61 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[O:45][CH3:46])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:33][C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:38][C:37]=1[O:45][CH3:46])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B(O)O)ccc1C(=O)NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)NCCc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (154 mg, 0.349 mmol), 4-[(phenethylamino)carbonyl]-3-methoxyphenylboronic acid (115 mg, 0.384 mmol), palladium tetrakistriphenyphosphine (24 mg, 0.021 mmol) and sodium carbonate (89 mg, 0.839 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (64 mg, 32%). 1H NMR (CDCl3-d) δ 1.62 (m, 4H), 2.16 (m, 16H), 2.87 (m, 2H), 3.57 (m, 2H), 3.90 (s, 3H), 4.83 (m, 1H), 7.31 (m, 7H), 7.95 (m, 1H), 8.22 (m, 2H); LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=569.3, Rt=2.50 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([C:21](=O)[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccccc1)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(CCc1ccccc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1,3-diphenyl-propan-1-one.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[OH:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][C:41]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:41]5[CH:42]=[C:43]([CH3:46])[CH:44]=[CH:45][C:40]=5[OH:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: Cc1ccc(O)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O)c4)cn23)CC1
Temperature: 90 °C
Yield: 57.9 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (84 mg, 0.144 mmol, 1 equiv) and (2-hydroxy-5-methylphenyl)boronic acid (33 mg, 0.216 mmol, 1.5 equiv) in DMF (1.4 mL, sparged with nitrogen for 10 min) was added Pd(PPh3)4 (17 mg, 0.014 mmol, 0.1 equiv) and 2 M Na2CO3 (0.144 mL, 0.287 mmol, 2 equiv). The reaction was heated at 90° C. for 3 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (51 mg, 58%) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.13 (br. s., 1H), 8.08-8.01 (m, J=7.0 Hz, 1H), 7.95 (br. s., 1H), 7.62-7.56 (m, 1H), 7.51 (br. s., 1H), 7.14 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.01 (s, 1H), 6.96 (d, J=7.5 Hz, 1H), 6.10-5.94 (m, 2H), 5.40 (d, J=17.1 Hz, 1H), 5.03 (d, J=9.5 Hz, 1H), 3.99 (d, J=5.0 Hz, 2H), 3.90 (br. s., 1H), 3.79-3.75 (m, 1H), 3.71 (s, 3H), 3.08 (br. s., 1H), 2.79-2.70 (m, 1H), 2.56 (br. s., 3H), 2.35 (s, 3H), 2.00 (d, J=13.6 Hz, 2H), 1.88-1.77 (m, 2H), 1.34 (s, 3H), 1.26 (s, 9H); LCMS (ESI, M+1): 612.4.
Reaction SMILES: N[CH:2]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].CC[N:12](CC)CC.[Cl:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[S:22][C:21]([S:23]([NH2:12])(=[O:25])=[O:24])=[C:20]([CH:2]([CH2:3][OH:4])[CH2:5][C:6]([F:9])([F:8])[F:7])[CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCN(CC)CC
Reactant: NC(CO)CC(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1sc(Cl)cc1C(CO)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-4,4,4-trifluoro-butan-1-ol (0.161 g, 1. 12 mmol) in dry CH2Cl2 (4 mL) at 25° C. under nitrogen was added dropwise Et3N (0.17 mL, 1.23 mmol) followed also by dropwise addition of 5-chlorothiophene-2-sulfonyl chloride (0.243 g, 1.12 mmol) as a solution in dichloromethane (1 mL). The reaction was stirred for 18 h at 25° C. The reaction was then quenched by pouring it into a separatory funnel containing saturated NaHCO3 solution. Additional CH2Cl2 (15 mL) was added. After extraction, the organic layer was washed with 1N HCl solution, distilled water and brine. The organic phase was then dried over MgSO4 and concentrated to a crude solid. After concentration, the crude product was purified by flash chromatography, eluent:hexane:EtOAc, 4:1 to 2:1, to obtain 5-chloro-(3,3,3-trifluoro-1-hydroxymethyl-propyl)-thiophene-2-sulfonamide as a clear oil that crystallized under vacuum (0.191 g, 53%).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:12](O)(=O)[CH2:13][C:14]([CH2:19][C:20](O)=O)([C:16]([OH:18])=O)O>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1](=[O:10])[CH:1]([CH2:2][CH3:3])[C:16]([C:14]2[CH:13]=[CH:12][C:5]([O:8][CH3:9])=[CH:20][CH:19]=2)=[O:18])=[CH:3][CH:4]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCC(C(=O)c1ccc(OC)cc1)C(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-methoxybutyrylphenone (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C. followed by addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,3-bis(4-methoxyphenyl)-2-ethylpropane-1,3-dione.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N:7][C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][N:4]=1)[NH2:2].[C:19](OCC)(=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:9]([C:8]1[C:3]2[N:4]([C:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:2][N:1]=2)[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)Cc1nc(-c2cccnc2)cnc1NN
Product: CCOC(=O)Cc1nnc2c(CC(C)C)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 2-hydrazino-3-isobutyl-5-(3-pyridyl)pyrazine with diethyl malonate there is obtained ethyl 8-isobutyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 339 (M)+, which is converted by saponification into the above acid: MS 267 (M-CO2)+.