Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O>CN1C(=O)N(C)CCC1>[CH3:14][N:13]([CH3:15])[C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:3]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCOCC1
Temperature: 150 °C
Yield: 93.6 %

Procedure:
A mixture of methyl {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.094 g, 0.19 mmol) and morpholine (0.048 mL, 0.55 mmol) in DMPU (2 mL) was heated at 150° C. in a sealed tube for 15 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts was washed sequentially with 1N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed over silica gel eluting with 5% EtOAc in CH2Cl2 to give methyl {4-(dimethylamino)-6-morpholin-4-yl-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.096 g, 95% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)[N:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH2:31]2>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH:31]2[C:12](=[O:14])[C:9]1[S:10][CH:11]=[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)[CH:8]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: Cc1nc(-c2csc(C(=O)O)c2)cs1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc(-c2csc(C(=O)C3C(=O)N(C(N)=O)c4ccc(Cl)cc43)c2)cs1

Procedure:
The title compound was prepared according to the procedure of Example 55. A 1.25 g (5.55 mmoles) sample of 4-(2-methyl-4-thiazolyl)-2-thiophenecarboxylic acid (prepared as described in Example 18) was converted to the acyl imidazole by reaction with 0.98 g (6.05 mmoles) of 1,1'-carbonyldiimidazole in 15 ml of N,N-dimethylformamide. After complete reaction this solution was transferred to an addition funnel and slowly added 1.06 g (5.04 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 1.66 g (13.59 mmoles) of 4-(N,N-dimethylamino)pyridine in 50 ml of N,N-dimethylformamide. Acidic workup followed by filtration and trituration with 2-butanone gave 0.50 g (1.20 mmoles) of title compound as a yellow solid, m.p. 238°-241° C.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>CN(C)C=O>[C:26]1([S:32][C:2]2[CH:25]=[CH:24][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=4[OH:23])[N:8]=[C:4]3[CH:3]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Into a two-liter three-necked flask equipped with stirrer, thermometer, distillation set-up and nitrogen supply are charged 268.4 g (0.75 mole) of 5-chloro-2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole, 93.7 g (0.825 mole) of thiophenol and 400 mL of N,N-dimethylformamide (DMF). The reactor is evacuated and filled with nitrogen three times to establish an inert atmosphere. To the slurry is added 66.0 g (0.825 mole) of 50% aqueous sodium hydroxide solution and the mixture heated to reflux. At this point water distills off as an azeotrope until the head-temperature reaches 132° C. and a reaction temperature of 150° C. After 18 hours there is no residual starting benzotriazole compound observed (TLC). At reduced pressure most of the DMF is distilled off at 80° C. To the residue is then charged 500 mL of toluene and 200 mL of water. After slow stirring for a few minutes at 80° C. the lower aqueous phase is drained off. The addition of 200 mL of water is repeated twice more, the second time with addition of 1 mL of acetic acid. Any residual water is azeotroped off until a clear solution is obtained. Approximately 300 mL of toluene is removed under partial vacuum at 90° C. and to the concentrate is added 800 mL of isopropanol, resulting in rapid crystallization. The reaction mixture is cooled to 20° C. and filtered. The light yellow crystals are washed with 250 ml of isopropanol and dried to give 317 g (97.9% of theory) of the title compound, mp. 132°-134° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([CH3:31])[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=1)(=[O:23])=[O:22]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([S:21]([N:20]([CH3:31])[CH3:19])(=[O:22])=[O:23])[CH:29]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CN(C)S(=O)(=O)c1cccc(Br)c1
Product: CN(C)S(=O)(=O)c1cccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N,N-dimethyl 3-bromobenzenesulfonamide (Combiblocks), the title compound was obtained as a yellow oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([S:18][C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(S)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2cccc(F)c2C#N)cc1
Reaction time: 24 h
Yield: 36.9 %

Procedure:
A solution of 2,6-difluorobenzonitrile (5.18 g, 37.26 mmol) in dimethylformamide (100 mL) was treated with p-thiocresol (4.628 g, 37.26 mmol) and potassium carbonate (10.28 g, 74.52 mmol). The reaction mixture was stirred for 24 h under a nitrogen atmosphere. Water (150 mL) and ethyl acetate (250 mL) were added to the reaction mixture. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were washed with water (1 L), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting 7:1 heptane:ethyl acetate. The column afforded 3.341 g (37%) of 2-fluoro-6-[(4-methylphenyl)sulfanyl]benzonitrile. 1H NMR (DMSO-d6, 400 MHz) δ 7.66-7.61 (m, 1H), 7.47-7.45 (m, 2H), 7.36-7.32 (m, 3H), 6.83-6.79 (m, 1H), 2.36 (s, 3H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 8.04 min (93%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:20][CH2:19]1)=[O:4]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
To a solution of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (2.33 g, 10 mmol) in THF (2.0 mL) was added benzyl 4-oxopiperidine-1-carboxylate (2.33 g, 10 mmol), dibutyltin chloride (302 mg, 1.0 mmol) and phenylsilane (1.36 ml, 11 mmol) at room temperature. The reaction mixture was stirred for two days at room temperature and quenched with saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate and washed with brine. Dried and concentrated, the crude was purified on silica gel column to give the title compound (4.23 g, 94%).
Reaction SMILES: [C:1]1([C@H:7](O)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C([OH:32])CCC2C=CC=CC=2)C=CC=CC=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]1([CH2:7][C:8](=[O:32])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCc1ccccc1)c1ccccc1
Reactant: O[C@H](CCc1ccccc1)c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
General procedure for conversion of racemic 1-substituted alkanols to optically active 1-substituted alkanols via prochiral ketones. Exemplified for (1 R)-1,3-diphenyl-1-propanol. A solution of racemic 1,3-diphenyl-1-propanol (1.26 g; 5.94 mmol) was dissolved in 10 mL of acetone, and Jones reagent was added until persistence of the orange color. After stirring for 30 min, the reaction was quenched by adding 2 mL of 2-propanol. The solvent was decanted away from the precipitated solids, which were washed with ethyl acetate. The combined organic fractions were washed with 2×20 mL of water, dried and concentrated. The crude product was filtered through a plug of silica gel, eluting with 25% ethyl acetate/hexane, to obtain 1.07 g (86%) of 1,3-diphenylpropanone as a white crystalline solid, 1H NMR (360 Mhz; CDCl3): d 3.09 (t, 2H, 1=8.1); 3.33 (t, 2H, 1=8.1); 7.29 (m, 5H); 7.49 (m, 3H); 7.98 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([OH:12])=[O:11])[CH:5]=1)([OH:3])=[O:2].C([O-])(=O)C.[Zn+2:17].C([O-])(=O)C>C(O)C.O>[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O-:12])=[O:11])[CH:5]=1)([OH:3])=[O:2].[Zn+2:17].[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O-:12])=[O:11])[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccnc(C(=O)[O-])c1
Reaction time: 0.25 h
Yield: 108.1 %

Procedure:
To a solution of 3.34 g (0.02 mol) of 4-carboxypicolinic acid dissolved in 150 ml of ethanol under heating was dropwise added a solution of 2.20 g (0.01 mol) of zinc acetate.dihydrate in 10 ml of water under stirring. After the dropwise addition, the mixture was stirred at the same temperature for 15 minutes. The solid obtained after leaving the mixture to stand for 2 days was collected by filtration, and recrystallized from water to obtain 4.30 g of crystals (yield 99.3%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)N(c2cccc(C#N)c2)C2CCCCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Yield: 93.8 %

Procedure:
N-(3-Cyanophenyl)-N′-(1-(t-butoxycarbonyl)piperidin-4-yl)cycloheptylurea (3.2 g, 7.76 mmol) was stirred in dichloromethane (40 ml) and trifluoroacetic acid (40 ml) at ambient temperature for 1.5 h. The reaction mixture was evaporated and the residue taken up in water. The aqueous suspension was made basic (pH 11) by the dropwise addition of aqueous sodium hydroxide solution (50%). The basic aqueous suspension was extracted with ethyl acetate (2×); the ethyl acetate extracts were washed with brine, dried (Na2SO4), and evaporated to give N-(3-cyanophenyl)-N′-(piperidin-4-yl)cycloheptylurea (2.17 g, 7.28 mmol, 94%). This sample was in all respects identical to the sample of N-(3-cyanophenyl)-N′-(piperidin-4-yl)cycloheptylurea prepared in Example 5.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12](=[O:15])[CH2:13]Br)=[O:6])[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:52])[C@@H:28]([NH:38][C:39]([C:41]2[CH:50]=[C:49]([OH:51])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)=[O:40])[CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:52])[C@@H:28]([NH:38][C:39]([C:41]2[CH:50]=[C:49]([O:51][CH2:13][C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:7]3[C:5](=[O:6])[NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:15])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)=[O:40])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3c2)CC1
Reactant: O=C(NC1CC1)[C@@H]1CCCN1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CC3)c3ccccc3c2)CC1
Temperature: 80 °C

Procedure:
To a solution of 100 mg of (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclopropylamide and 93 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 118 mg of cesium carbonate was added and the reaction mixture was heated to 80° C. for 5 h. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM and 0.2 ml of TFA. After 16 h at RT 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 40 mg MS (ES+): m/e=652.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[C:7]([C:9](=[NH:13])OCC)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.Cl.N[C:26]1[C:31]([NH2:32])=[CH:30][N:29]=[C:28]([N:33]2[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:40])[CH2:34]2)[N:27]=1.C(O)(=O)C>C(O)C>[N:41]1([C:39]([C@@H:35]2[CH2:36][CH2:37][CH2:38][N:33]([C:28]3[N:27]=[C:26]4[C:31]([N:32]=[C:9]([C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[N:8]=5)[NH:13]4)=[CH:30][N:29]=3)[CH2:34]2)=[O:40])[CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)c1cccc(C(F)(F)F)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ncc3nc(-c4cccc(C(F)(F)F)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
To a solution of ethyl 6-(trifluoromethyl)picolinimidate (291 mg, 1.3 mmol) and triethylamine (0.6 mL, 4.4 mmol) in ethanol (5 mL) was added dropwise a solution of (R)-(1-(4,5-diaminopyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (400 mg, 1.1 mmol) and acetic acid (0.3 mL, 6.6 mmol) in ethanol (10 mL) at room temperature over a period of 10 min. The reaction mixture was stirred for 16 h at 120° C. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (110 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.32 (m, 1H), 1.48 (d, 1H), 1.71 (t, 2H), 1.76-1.83 (m, 2H), 1.89 (dt, 3H), 2.55-2.64 (m, 2H), 2.85-3.03 (m, 2H), 3.42-3.50 (m, 1H), 3.51-3.63 (m, 1H), 4.76 (d, 2H), 8.00 (d, 1H), 8.22-8.32 (m, 1H), 8.49 (d, 1H), 8.83 (br s, 1H), 13.41 (br s, 1H). MS (ES+) (M+H) 446.33; LCMS retention time 3.34 min (Method S).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[CH3:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=1
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2ccccc2)nc(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 313 mg of 4-chloro-2-methyl-6-phenylpyrimidine and 118 mg of 2-butyn-1-ol, to which 67 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 260 mg of 2-methyl-4-phenyl-6-(2-butynyloxy)pyrimidine (the present compound (78)).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:16][C:17]1([CH2:23]Br)[CH2:22][O:21][CH2:20][O:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:7][O:6][C:4]([C:3]1[C:2]2[O:1][CH2:23][C:17]3([CH2:22][O:21][CH2:20][O:19][CH2:18]3)[CH2:16][O:12][C:11]=2[C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: BrCC1(CBr)COCOC1
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c2c1OCC1(COCOC1)CO2

Procedure:
Following the general procedure, dialkylation of compound 513 (198 mg, 1 mmol) with compound 523 (301 mg, 1.1 mmol) in DMSO (5 mL) in the presence of K2CO3 (345 mg, 2.5 mmol) afforded compound 524 as a white solid material after purification by column chromatography (50-65% EtOAc in light petroleum). LC-MS: RT=2.65 min.; m/z 311.23 (M+H)+. 1H NMR (DMSO-d6): 7.37 (1H, d, J 8.8), 6.81 (1H, d, J 8.8), 4.80 (1H, d, J 6.4), 4.78 (1H, d, J 6.4), 4.07 (2H, s), 4.01 (2H, s), 3.81 (7H, s), 3.76 (3H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
148 (510 mg, 1.7 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (82 mg, 3.4 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]#[N:21])[C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:19]=1.Cl>B(Br)(Br)Br>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]#[N:21])[C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[N:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(C#N)c3s2)cc1
Agent: BrB(Br)Br
Agent: Cl
Product: COc1cc(C#N)c2sc(-c3ccc(O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.4 %

Procedure:
5-Methoxy-2-(4-methoxy-phenyl)-benzothiazole-7-carbonitrile (0.04 g, 0.135 mmol) was suspended in boron tribromide (1M in methylene chloride, 5.0 mL) and stirred at room temp under nitrogen for 48 hr. Reaction was poured into aqueous hydrochloric acid (1M) and extracted with ethyl acetate. Ethyl acetate extracts were washed with: 1) hydrochloric acid (1.0M), 2) saturated NaHCO3, 3) saturated brine and concentrated in vacuo. This material was further purified by chromatography on silica yielding the title compound (14 mg, 39%) as a tan solid. Mass spec: MH+=296 5-Methoxy-2-(4-hydroxy-phenyl)-benzothiazole-7-carbonitrile (7 mg, 18%) was also obtained as a white solid from this chromatography. The starting 7-Cyano-5-Methoxy-2-(4-methoxy-phenyl)-benzothiazole was prepared as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:17][NH:16][C:15](=[O:18])[N:14]1[CH3:19])=[O:12].Br[C:21]1[C:22]([C:27]#[N:28])=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(=O)([O-])O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:27]([C:22]1[C:21]([N:16]2[CH2:17][CH:13]([C:11]([NH:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:12])[N:14]([CH3:19])[C:15]2=[O:18])=[CH:26][CH:25]=[CH:24][N:23]=1)#[N:28]
Reactant: N#Cc1ncccc1Br
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1C(=O)N(c2cccnc2C#N)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A suspension of N-[(2,4-dichlorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (200 mg, 0.662 mmol) (prepared as described in Example 30) and 3-bromo-2-pyridinecarbonitrile (121 mg, 0.662 mmol) in 1,4-dioxane (5 ml) was treated with cesium carbonate (323 mg, 0.993 mmol), Xantphos™ (28.7 mg, 0.050 mmol) and tris(dibenzylideneacetone)dipalladium(0) (15.15 mg, 0.017 mmol) and the mixture was heated at reflux under argon for overnight. After cooling to room temperature, the reaction mixture was diluted with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1-(2-cyano-3-pyridinyl)-N-[(2,4-dichlorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (212 mg, 78% yield). LC/MS [M+H]+=404, retention time=2.32 minutes.