Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CO[C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O>C(Cl)Cl>[CH3:20][C:19]1([CH3:21])[N:11]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[C@H:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][C@H:2]2[O:1]1
Reactant: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Reactant: C=C(C)OC
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Reaction time: 0.33 h

Procedure:
N-(1S, 2R)-(2-Hydroxyindan-1-yl)-butyramide (XV, 2.2 g) and 2-methoxypropene (5 mL) were combined with CH2Cl2 (70 mL) at rt, and methanesulfonic acid (0.05 mL) was added. After 20 min at rt, the reaction mixture was partitioned between half-saturated NaHCO3 (30 mL) and CH2Cl2 (2×30 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give an oil as product: MH+ 260.1.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[N:5]([CH2:25][CH3:26])[C:6]([O:9][C:10]2[CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)=[N:7][N:8]=1)[CH3:3].Cl.C(N(CC)CC)C.[Cl:35][C:36]1[CH:37]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[Cl:42].C([O-])([O-])=O.[K+].[K+]>O>[C:22]([N:19]1[CH2:18][CH2:17][N:16]([C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[O:9][C:6]2[N:5]([CH2:25][CH3:26])[C:4]([C@H:2]([NH:1][S:43]([C:38]3[CH:39]=[CH:40][C:41]([Cl:42])=[C:36]([Cl:35])[CH:37]=3)(=[O:45])=[O:44])[CH3:3])=[N:8][N:7]=2)[CH2:21][CH2:20]1)(=[O:24])[CH3:23]
Reactant: CCn1c(Oc2cccc(N3CCN(C(C)=O)CC3)c2)nnc1[C@@H](C)N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1c(Oc2cccc(N3CCN(C(C)=O)CC3)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Water was added to a mixture (307 mg) of 1-(4-[3-[5-((R)-1-aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]-piperazin-1-yl)-ethanone obtained in Example 27-(2) and triethylamine hydrochloride, 3,4-dichlorobenzenesulfonyl chloride (0.13 ml), and K2CO3 (355 mg). The mixture was stirred at room temperature for 15 hours. The precipitated solid was filtered and purified by column chromatography (NH SiO2, MeOH/CHCl3=1/50) to give the titled compound (Compound 697) (117 mg, colorless syrup).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=O)[O:13]C(C)(C)C)=[CH:6][C:5]=2[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[N:20]=2)[CH2:3][CH2:2]1.Cl>>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:13])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:5]=2[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)[N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1cnc(C2CC2)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Agent: Cl
Product: CC(C)(C)C(=O)NCc1cnc(C2CC2)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
Stirred a solution of tert-butyl (6-cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methylcarbamate (0.100 g) in EtOC:HCl (5.0 mL) for 6 h at RT. Excess of solvent was removed and added DCM (5.0 mL), TEA (0.5 mL) and pivaloyl chloride (0.045 g) under nitrogen atmosphere o the reaction mixture. The reaction mass was stirred at RT for 4 h. Excess of solvent was removed under vacuum and the residue was diluted with water, extracted with EtOAC and concentrated to afford 0.020 g of the product. 1H NMR (300 MHz, DMSO d6): 0.98 (m, 4H), 1.12 (s, 9H), 2.73 (m, 1H), 4.27 (d, J=6.0 Hz, 2H), 7.78 (s, 1H), 7.85 (d, J=8.7 Hz, 2H), 8.13 (t, 1H), 8.19 (d, J=9.3 Hz, 2H), 8.40 (s, 1H), 12.75 (s, 1H); MS (m/z): 460.30 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([CH3:16])[C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>CO>[CH3:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:2]([CH3:1])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1c(C)cc(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(F)cc(C)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
To a solution of 318 mg (5.8 mmol) of ethyl 2,6-dimethyl-4-fluoro-phenoxyacetate in 50 mL of methanol was added 1 mL of 3N sodium hydroxide. After the reaction mixture was stirred at room temperature for 30 min, it was acidified with 3N HCl to pH=4 and partitioned between water and methylene chloride. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to give 248 mg (90%) of 2,6-dimethyl-4-fluoro-phenoxy acetic acid as a white solid.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[C:11]3([CH2:25][C:16]4=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]4[CH2:14]3)[N:10]([CH3:26])[C:9]2=[O:27])=CC=1.[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[CH3:26][N:10]1[C:11]2([CH2:25][C:16]3=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]3[CH2:14]2)[C:12](=[O:13])[NH:8][C:9]1=[O:27]
Reactant: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)NC(=O)N1C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 1′-(4-methoxybenzyl)-3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (100 mg, 0.25 mmol) in acetonitrile (8.4 mL) at ambient temperature was added eerie ammonium nitrate (4.1 g, 7.6 mmol) as a solution in H2O (5 mL). After 20 min, the reaction mixture was partitioned between H2O (50 mL) and 9:1—CH2Cl2:i-PrOH (50 mL). The aqueous was extracted further with 9:1—CH2Cl2:i-PrOH (5×50 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was washed with MTBE (3×10 mL) then partitioned between saturated aqueous sodium bicarbonate (5 mL) and EtOAc (10 mL). The aqueous layer was extracted further with EtOAc (10 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound in sufficient purity for use in the next step. MS: m/z 276.1 (M+1).
Reaction SMILES: ClS(O)(=O)=O.ClC1C=CC(OC)=CC=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22]([N:29]([CH3:28])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:24])=[O:23])[CH:21]=1
Reactant: CNc1ccccc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Agent: COc1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Product: COc1ccc(Cl)cc1S(=O)(=O)N(C)c1ccccc1
Temperature: 15 °C
Yield: 73.3 %

Procedure:
Freshly distilled chlorosulfonic acid (b.p. 150° C.) 13.2 g (~0.1 mole) is placed in a 50 mL round-bottomed flask. The liquid is cooled to 15° C. in an ice-water bath, and 27 mL of 4-chloroanisole (95 w/w %) is carefully added to chlorosulfonic acid. The mixture is stirred between additions and the temperature of the mixture is kept below 50° C. When the addition is complete, the mixture is refluxed on a steam bath for 2 hours. A homogeneous, viscous liquid is formed. The reaction mixture is then carefully poured into a 250 mL beaker of ice water. A white, solid mass of 5-chloro-2-methoxybenzenesulfonyl chloride is precipitated, filtered and dried (m.p. 88-89° C.). The 5-chloro-2-methoxybenzenesulfonyl chloride (15.7 g, ~0.07 mole) is added to 7.0 g (~0.07 mole) of N-methyl aniline by the procedure for making sulfonanilides as described previously. A light brown oil, 5-chloro-2-methoxy-N-methylbenzenesulfonanilide, (16 g, 80% yield) is obtained. 1H NMR (deuterioacetone): δ6.3-7.9 (m, 8 ArH), 3.8 (s, 3H, OCH3), 3.2 (s, 3H, N--CH3); ms:m/z 311 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([CH2:26][CH3:27])=[C:22]([CH2:24][CH3:25])[CH:23]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH2:28][CH3:29].[C:31](O)(=[O:34])[CH2:32][OH:33].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[CH2:24]([C:22]1[CH:23]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH:3]([OH:30])[CH2:2][NH:1][C:32](=[O:33])[CH2:31][OH:34])=[C:7]([CH2:28][CH3:29])[CH:8]=3)[N:17]=2)[CH:19]=[N:20][C:21]=1[CH2:26][CH3:27])[CH3:25]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(CC)c3)no2)cnc1CC
Reactant: O=C(O)CO
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(CC)c3)no2)cnc1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of (RS)-1-amino-3-{4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propan-2-ol (99 mg, 0.24 mmol), glycolic acid (18.5 mg, 0.244 mmol) and Hünig's base (78 mg, 0.61 mmol) in DCM (5 mL) is added PyBOP (126.7 mg, 0.24 mmol) and the mixture is stirred at rt for 30 min. The mixture is diluted with EA, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on prep. TLC plates eluting with DCM:MeOH 10:1 to give N—((RS)-3-{4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (90 mg) as an oil; LC-MS: tR=0.88 min, [M+1]+=469.25.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](O)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=[C:2]([NH2:1])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c2c(n1)CCCC2
Solvent: Cc1ccccc1
Product: Nc1nc(Cl)c2c(n1)CCCC2
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a suspension of 2-amino-5,6,7,8-tetrahydroquinazoline-4-ol (20.0 g, 121 mmol) in toluene (150 ml) was dropped phosphorus oxychloride (55.7 g, 363 mmol) at 90° C. The mixture was stirred for 1 hour and the solvent was removed in vacuo. The residue was poured into 28% aqueous ammonia solution at 0° C. The solid was filtered and purified by silica gel column chromatography (3% MeOH/CHCl3) to give the object compound (13.5 g, 60%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:28][CH3:29])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:30]>CO.ClCCl.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>[CH2:28]([C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:30])[C:11]=2[N:12]=1)[CH3:29]
Reactant: CCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reactant: N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline (2.624 g, 6.451 mmol), 7 N ammonia in methanol (40 mL), and tetrakis(triphenylphosphine)palladium(0) were combined in a pressure vessel and heated at 120° C. for 16 hours. An analysis by HPLC indicated that the reaction was incomplete. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform. The solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting dark yellow solid was added to a pressure vessel with 7 N ammonia in methanol (60 mL), and the reaction was sealed and heated at 150° C. for 18 hours. The volatiles were removed under reduced pressure, and the residue was stirred with 0.5 N potassium hydroxide in methanol for 30 minutes. The resulting solid was isolated by filtration, diluted with dichloromethane, purified by column chromatography on silica gel (eluting with 5% to 10% CMA in chloroform), triturated with diethyl ether and filtered, and recrystallized from acetonitrile after a hot filtration. The crystals were isolated by filtration, washed with diethyl ether, and dried to provide 0.139 g of 2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 232.0-233.0° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH2:19][C:20]#[N:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH2:19][C:20]#[N:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile (0.020 g, 0.064 mmol) and ammonium acetate (49 mg, 0.64 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed tube for 30 min. The mixture was cooled to room temperature and sodium cyanoborohydride (8 mg, 0.13 mmol) was added. The reaction was heated at 65° C. for another 4 hours, cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step (20 mg, 100%). LCMS calculated for C17H14ClFN3 (M+H)+: m/z=314.1. found: 313.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.Cl.[CH3:10][O:11][C:12](=N)[NH:13][N+:14]([O-:16])=[O:15].[OH-].[Na+]>O>[CH3:10][O:11][C:12](=[N:13][N+:14]([O-:16])=[O:15])[NH:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1
Reactant: NCc1cnc(Cl)s1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
5-(Aminomethyl)-2-chlorothiazole (7.43 g, 50.0 mmol) was dissolved in water (96 ml), and concentrated hydrochloric acid (4.22 ml, 50.0 mmol) was added. To this reaction mixture was added O-methyl-N-nitroisourea (7.19 g, 60.0 mmol), and adjusted to pH 6.7 with aqueous sodium hydroxide solution (0.5 N) using PH meter. After 20 hours of stirring at room temperature, maintaining pH 6.7, the resulting white crystals were collecte by filtration under reduced pressure, and washed with water. The washed crystals were dried under reduced pressure (80° C., 2 hours) to provide 7.85 g, (62.6% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([OH:11])[C:6](=[CH2:10])[CH:7]([CH3:9])[CH3:8])=[CH2:3].[C:12](OC)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>>[C:12]([O:11][CH:5]([C:6](=[CH2:10])[CH:7]([CH3:9])[CH3:8])[CH2:4][C:2]([CH3:1])=[CH2:3])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]
Reactant: C=C(C)CC(O)C(=C)C(C)C
Reactant: COC(=O)CC(C)=O
Product: C=C(C)CC(OC(=O)CC(C)=O)C(=C)C(C)C

Procedure:
reaction of 2,6-dimethyl-5-methylene-1-hepten-4-ol with methyl aceto acetate in order to form 2,6-dimethyl-5-methylene-1-hepten-4-yl aceto acetate or, directly, 5-isopropyl-8-methyl-5,8-nonadiene-2-one;
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])=[N:6][C:5]=12.Br[C:16]1[N:21]=[C:20]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([C:10]([C:7]1[CH:8]=[CH:9][N:4]2[C:3]([C:16]3[N:21]=[C:20]([C:22]4[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=4[C:24]#[N:25])[CH:19]=[CH:18][CH:17]=3)=[CH:2][N:1]=[C:5]2[N:6]=1)([CH3:14])[CH3:13])#[N:12]
Reactant: N#Cc1ccccc1-c1cccc(Br)n1
Reactant: CC(C)(C#N)c1ccn2ccnc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C#N)c1ccn2c(-c3cccc(-c4ccccc4C#N)n3)cnc2n1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
2-(Imidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionitrile (100 mg, 0.51 mmol), 2-(6-bromopyridin-2-yl)benzonitrile (159 mg, 0.61 mmol) and cesium carbonate (332 mg, 1.02 mmol) were suspended in 1,4-dioxane and degassed with nitrogen for 20 min. Tetrakis(triphenylphosphine)-palladium(0) (29 mg, 0.025 mmol) was added and the mixture was heated at 80° C. for 3 h. The reaction was cooled to ambient temperature then diluted with water (60 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with brine (70 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a pale yellow oil. The oil was purified by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-1%). Collecting appropriate fractions followed by recrystallisation from ethyl acetate/isohexane gave 2-{6-[7-(1-cyano-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile (70 mg, 38%) as a white solid: δH (360 MHz, CDCl3) 1.86 (6H, s), 7.43 (1H, d, J 7), 7.59-7.63 (2H, m), 7.80 (2H, m), 7.86-7.97 (3H, m), 8.42 (1H, s), 10.44 (1H, d, J 7); m/z (ES+) 365 (M++H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].Cl.[OH:24][NH2:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:20][C:19](=[N:25][OH:24])[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[CH2:12][CH2:11]2)[N:18]=1
Reactant: NO
Reactant: CC(C)(C)CCC(=O)N1CCN(c2nccc(C#N)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)CCC(=O)N1CCN(c2nccc(C(N)=NO)n2)CC1
Yield: 79.4 %

Procedure:
1-(4,4-Dimethylpentanoyl)-4-(4-cyanopyrimidin-2-yl)piperazine (540 mg) obtained in Example 54 was dissolved in ethanol (5 mL), and hydroxyamine hydrochloride (386 mg) and potassium carbonate (995 mg) were added thereto and heated under reflux for 2 hours. Then, the solvent was evaporated away, and the resulting residue was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away to obtain 476 mg of the entitled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9].[C:10]([OH:13])(=O)[CH3:11]>C1COCC1.O>[CH3:1][C:2]1[C:6]([CH2:5][N:4]2[CH2:11][CH2:10][O:13][CH2:2][CH2:3]2)=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9]
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1CN1CCOCC1
Temperature: 92.5 °C
Yield: 36 %

Procedure:
A mixture of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (1.85 g, 15 mmol), dimorpholine-methane (5 mL, 27 mL) in THF (40 mL), water (15 mL) and acetic acid (4 mL) was heated to reflux (oil bath 90-95° C.) for 6 hours. The reaction was concentrated to a volume of 20 mL, basified with Na2CO3 and extracted with ethyl acetate (3×75 mL). The combined extracts were dried, concentrated and the residue was purified on a silica gel column to give 2 g (36%) of 3,5-dimethyl-4-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)(=[O:19])=[O:18].OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[NH4+].[OH-].CCOC(C)=O.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:23]2[CH:24]=[CH:25][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:21][CH:22]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Temperature: 145 °C
Yield: 66 %

Procedure:
A mixture of 4-benzyloxy-2(1H)-pyridone (6.87 g, 34.1 mmol, Aldrich), 4-bromophenyl methyl sulphone (8.01 g, 34.1 mmol, Combi-Blocks Inc.), copper(I) iodide (1.30 g, 6.82 mmol, Aldrich), 8-hydroxyquinoline (0.99 g, 6.82 mmol, Alfa Aesar) and potassium carbonate (6.12 g, 44.3 mmol, EMD) in DMSO (100 mL) was heated at 145° C. for 6 h, cooled to room temperature and then diluted with 10% NH4OH aqueous solution (50 mL) and EtOAc (100 mL). The resulting mixture was filtered and the solid was washed with H2O and EtOAc to give 8.0 g crude product as a greenish solid. MS (ESI) 356 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].O=[C:12]([CH2:19][CH3:20])[CH2:13][C:14](OCC)=[O:15].C[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:14](=[O:15])[CH:13]=[C:12]([CH2:19][CH3:20])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(=O)[nH]c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A 1-L round bottomed flask was charged with 3-chlorobenzimidamide (23.9 g, 154 mmol, 1 eq.), ethyl 3-oxopentanoate (27.8 g, 193 mmol, 1.25 eq.), and ethanol (500 mL). To the mixture was added sodium methoxide (10.0 g, 185 mmol, 1.20 eq.). The resulting mixture was stirred under reflux for 20 hr. After cooling to room temperature, the mixture was evaporated under reduced pressure to 50 mL. The residual slurry was cautiously treated with 2N HCl (219 mL). Solid was collected by filtration and washed with water followed by ether to afford 2-(3-chlorophenyl)-6-ethylpyrimidin-4(3H)-one (9.3 g, 39% yield), which was carried forward into the next step without further purification. 1H NMR (CD3OD, 500 MHz) δ 8.07 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.52 (t, J=8.0, Hz, 1H), 6.27 (s, 1H), 2.66 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>ClC(Cl)C.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: COc1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Product: COc1ccc(Br)c(CBr)c1
Yield: 64 %

Procedure:
To a solution of 2-bromo-5-methoxytoluene (50 g, 0.25 mol) in dichloroethane (375 ml), N-bromosuccinimide (48.8 g, 0.275 mol) and AIBN (1.36 g) were added and the reaction was refluxed for 4 h. The cooled solution was filtered and the solvent was evaporated to give a weight of 44.8 g crude 1-Bromo-2-bromomethyl-4-methoxy-benzene (64% yield). This compound was used in next step without further purification.