Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.Cl[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])=[O:19].[OH-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:9][C:8]1[C:7]2[CH:6]=[N:5][C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[N:3][C:2]=2[O:1][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])=[O:19]
Reactant: N#Cc1cnc(-c2ccccc2)nc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2nc(-c3ccccc3)ncc12
Temperature: 110 °C
Reaction time: 12 h
Yield: 9.5 %

Procedure:
To a stirred solution of 4-hydroxy-2-phenyl-pyrimidine-5-carbonitrile (12) (50 mg, 0.25 mmol, from step 1) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (85 mg, 0.38mmol, 1.5 equiv) in anhydrous N,N-dimethylformamide (1.0 mL) was added NaOH (30.4 mg, 0.76 mmol, 3.0 equiv). The dark brown reaction mixture was stirred at 110° C. for 12 h. The reaction was then poured into ethyl acetate (10 mL) and water (10 mL). Extracted with ethyl acetate (3×10 mL). The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. The crude product was purified by pre-HPLC to provide 9.1 mg (9.3%) of the desired compound as yellow solid. 1H-NMR (CD3CN) δ 9.36 (s, 1H), 8.50 (d, 2H), 7.66 (d, 1H), 7.55 (m, 5H); MS LC-MS (MH+=384/386).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=2[F:47])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=2[F:47])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2ccc(F)cc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(F)cc2F)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.00 g), sodium hydrogen carbonate (1.43 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,4-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.82 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (25 mL), N,N′-carbonyldiimidazole (0.41 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.85 g, 93%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:40])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:23]3=[O:36])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=[O:39].Cl>O1CCOCC1>[OH:1][C:2]1[C:3]([CH3:40])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]3=[O:36])=[CH:37][CH:38]=1)([CH3:14])[CH2:6][C:5]2=[O:39]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)O)C3=O)cc1)O2

Procedure:
A mixture of 350 mg of t-butyl α-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3yl}acetate (prepared as described in Example 49) and 4 ml of a 4N dioxane solution of hydrogen chloride was treated in the same manner described in Example 61, to give the title compound as a pale yellow powder, softening at 60°-70° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[OH2:18].[OH2:29].[CH2:1]([NH:8][C:9](=[O:23])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[C:30]2[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]2=[O:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)NCc2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)NCc2ccccc2)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.67 g of ethyl 2-(3-benzylureido)thiazol-4-ylglyoxylate, 0.95 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 25 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH:20]=O>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(Cl)ccc3[N+](=O)[O-])CC2)nc[nH]1

Procedure:
6-[4-(5-Chloro-2-nitro-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-chloro-2-nitrobenzaldehyde. Mass spectrum (ES) MH+=350.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.C([Sn](CCCC)(CCCC)[S:20][CH3:21])CCC>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[S:20][CH3:21]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reactant: CCCC[Sn](CCCC)(CCCC)SC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1nc(Cl)c(F)c(N)c1SC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (1.5 g, 4.6 mmol), tri-n-butylmethylthiostannane (2.5 g, 7.3 mmol), his (triphenylphosphine) palladium (II) chloride (320 mg, 0.46 mmol) and copper (I) iodide (90 mg, 0.46 mmol) were combined 15 ml dry, deaerated DMF and heated to 80° C. After 3 h another 2.5 g portion of the stannane were added and heating was continued for 18 h. After cooling, the mixture was stirred with 25 ml 10% potassium bifluoride solution for 20 ml. The heterogeneous mixture was stirred with 100 ml ethyl acetate and filtered through diatomaceous earth to remove curdy solids. The separated organic phase was washed twice with 15 ml water, 15 ml sat. NaCl, dried (Na2SO3) and evaporated. The product was purified by silica gel chromatography eluting with a 0-25% ethyl acetate-DCM gradient. The gummy residue was stirred with hexane to produce the written product as a white solid, 800 mg. Mp: 75-77° C. 1H NMR (400 MHz, CDCl3) δ 5.35 (s, 2H), 3.96 (s, 3H), 2.33 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −138.81. EIMS m/z 250.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][NH:33][C:3](=[O:28])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[N:14][O:15][C:16]=3[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=2)[CH2:31][CH2:30]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 87 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using cyclopropanemethylamine instead of methylamine, to the title compound (96 mg, 87%) which was obtained as an off white solid. MS: m/e=436.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:8])[CH2:3][CH2:2]1.O.O[Li].O>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(=O)C2CCOCC2)cc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC(=O)C2CCOCC2)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-(4-tetrahydropyranoyloxy)-2-methoxy-benzoate (369 mg, 1.38 mmol) in THF:H2O (2.5 mL: 0.5 mL) was added LiOH.H2O (116.4 mg, 2.77 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a small plug of silca gel packed in 80:20 hexanes:EtOAc and eluted with 50:50 hexanes:EtOAc. The solvent was removed under reduced pressure to afford 4-(4-tetrahydropyranoyloxy)-2-methoxy-benzoic acid as a foam.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH:21]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[CH:23]=[CH:22]1.[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([OH:5])([C:7]([F:8])([F:10])[F:9])[CH2:6][N:21]3[C:29]4[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=4[CH:23]=[CH:22]3)=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc2c1CCCC2=O)C(F)(F)F)c1cccc2c1OCC2
Temperature: 85 °C
Yield: 66 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (59.2 mg, 0.21 mmol) and 1,5,6,7-tetrahydroindol-4-one (56.0 mg, 0.41 mmol) in 0.4 mL of anhydrous ethanol was added 0.077 mL of sodium ethoxide solution (21 wt % in ethanol). The reaction mixture was then heated at 85° C. for 16 hours. The resulting mixture was poured into half-saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with 35% ethyl acetate-hexanes) to give 58.4 mg (66% yield) of the title compound as a white solid, m.p. 145° C.-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([OH:14])[CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[Cl:35])[N:28]([CH3:36])[N:27]=1>>[Cl:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([CH3:36])[N:27]=[C:26]([CH2:25][O:14][C:12]3[CH:13]=[C:8]([O:7][CH2:6][C:5]4[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=[CH:10][C:11]=3[CH3:15])[C:34]=12
Reactant: Cc1ccc(OCc2ccc(Cl)cc2)cc1O
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(OCc2ccc(Cl)cc2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(4-chloro-benzyloxy)-2-methyl-phenol (95.6 mg, 0.384 mmol) and potassium carbonate (58.2 mg, 0.421 mmole) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.1 mg, 0.344 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 4-chloro-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 38.0 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:32][C@:31]2([C:33](O)=[O:34])[C@@H:10]([CH2:11][C@H:12]3[CH:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:36])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:37][CH:38]1[CH2:42][CH2:41][O:40][C:39]1=[O:43]>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[O:43]=[C:39]1[CH:38]([S:37][C:33]([C@:31]23[C@@:13]4([CH3:36])[CH2:14][C@H:15]([OH:30])[C@@:16]5([F:29])[C@H:25]([C@@H:12]4[CH2:11][C@H:10]2[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:32]3)[CH2:24][C@H:23]([F:26])[C:22]2[C@:17]5([CH3:28])[CH:18]=[CH:19][C:20](=[O:27])[CH:21]=2)=[O:34])[CH2:42][CH2:41][O:40]1
Reactant: O=C1OCCC1S
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)CC1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)SC4CCOC4=O)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.14 %

Procedure:
A solution of compound 93 and 1,1-carbonyldiimidazole (74.3 mg, 0.458 mmol) in dry DMF (3 ml) is stirred under nitrogen at RT for 1 hour and at 65° C. for 1 hour 30 minutes. The mixture is cooled to RT and 4-dimethylaminopyridine (46.7 mg, 0.382 mmol) and a solution of 3-mercaptodihydrofuran-2(3H)-one (54.1 mg, 0.458 mmol) in dry DMF (1.2 ml) are added. The mixture is stirred at RT for 1 hour then at 70° C. for 48 hours. The mixture is diluted with AcOEt and washed with brine. The organic phase is dried over Na2SO4 and filtered. The solvent is evaporated to give a brown oil which is purified by silica gel chromatography (AcOEt/petroleum ether 45/55) to afford the title compound (30 mg, 0.050 mmol, 13.14% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:15]2[CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cc(F)cc(Oc2ccc(F)cc2)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: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(Oc3ccc(F)cc3)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 3.0 grams (0.012 mole) of 3-fluoro-5-(4-fluorophenoxy)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-fluoro-5-(4-fluorophenoxy)phenyl]pyridine.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH2:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[CH3:15].[O-][CH2:24][CH3:25].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:18]2[CH2:17][CH:16]([CH2:14][CH3:15])[CH2:21][C:20](=[CH:8][C:7]3[CH:10]=[CH:11][C:4]([N:3]([CH2:24][CH3:25])[CH2:1][CH3:2])=[CH:5][CH:6]=3)[C:19]2=[O:22])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CC[O-]
Reactant: CCC1CCC(=O)CC1
Agent: [Na+]
Solvent: CCO
Product: CCC1CC(=Cc2ccc(N(CC)CC)cc2)C(=O)C(=Cc2ccc(N(CC)CC)cc2)C1

Procedure:
In 50 ml of anhydrous ethanol were dissolved 35.4 g of p-diethylaminobenzaldehyde and 12.6 g of 4-ethylcyclohexanone, and 20 ml of 10% ethanolic solution of sodium ethoxide was added dropwise to the resulting solution, and the resulting mixture was subjected to reaction under reflux for 12 hours. The reaction mixture was cooled, and the crystals thus precipitated were collected by filtration and then recrystallized from toluene, to obtain 15.8 g of 2,6-bis(4'-diethylaminobenzal)-4-ethylcyclohexanone (m.p. 141° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#C[Si](C)(C)C)cc2NC(=O)C3)cc1OC
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) (300 mg, 0.614 mmol) in 4 mL DMF at 22° C. was added dichlorobis(triphenylphosphine)palladium (15 mg, 0.02 mmol), copper iodide (9 mg, 0.05 mmol), and triethylamine (0.34 mL, 2.45 mmol). The solution was degassed with argon, and stirred at 22° C. for 1 h. (Trimethylsilyl)acetylene (120 mg, 1.22 mmol) was added and the solution was stirred at 22° C. for 2 h. Water was added to the reaction mixture, and the resulting precipitate was filtered and purified by silica gel chromatography (ISCO, elution with 30-100% ethyl acetate in hexanes) to give I-33-a (180 mg, 64%): MS m/z═459 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[O-:12][C:13]#[N:14].[K+].[CH:16](O)([CH3:18])[CH3:17].C(O)(=O)C>O>[CH:16]([O:11][CH:8]([CH3:5])[CH3:9])([CH3:18])[CH3:17].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:14][C:13](=[O:12])[O:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: CC(C)O
Reactant: O=C(CO)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)OC(C)C
Product: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Temperature: 50 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
To a mixture of 4′-chloro-2-hydroxyacetophenone (3.41 g), potassium cyanate (3.25 g) and isopropanol (15 mL) was added dropwise acetic acid (2.88 g) at 50° C. The obtained mixture was stirred at 50° C. for 5 h and water (34 mL) was added. The precipitated crystals were collected by filtration, and washed with water and then with isopropyl ether to give 4-(4-chlorophenyl)-2-oxo-4-oxazoline (3.33 g; yield 85.1%).
Reaction SMILES: C[NH:2]N.CC([Si](C)(C)[O:9][C:10]1[CH:11]=[C:12]([C:16](=O)[C:17](=[CH:35][N:36]([CH3:38])C)[C:18]2O[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH:13]=[CH:14][CH:15]=1)(C)C.[OH2:42]>>[C:23]1([C:21]2[N:22]=[C:18]([C:17]3[C:16]([C:12]4[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][CH:13]=4)=[N:2][N:36]([CH3:38])[CH:35]=3)[O:42][C:20]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O
Reactant: CNN
Reactant: CN(C)C=C(C(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: Cn1cc(-c2nc(-c3ccccc3)c(-c3ccccc3)o2)c(-c2cccc(O)c2)n1
Reaction time: 1 h

Procedure:
N-Methyl hydrazine (2.5 mL, 46.6 mmol) was added dropwise to 1-[3-[(1,1-dimethylethyl)dimethylsiloxy]phenyl]-2-[(dimethylamino) methylene]-2-(4,5-diphenyl-2-oxazolyl)ethanone (20) (12 g, 22.8 mmol) and the mixture stirred for about 1 hour, diluted with water, and extracted with dichloromethane. The organic phase was concentrated, and the residue was taken up in THF (150 mL), and tetra-n-butylammonium fluoride (27.84 mL of 1M solution) added. The reaction mixture was stirred about 5 minutes, concentrated, diluted with 1N HCl, and extracted with dichloromethane. Separation by SiO2 chromatography, (elution with 75% ether/hexanes) and recyrstallization from dichloromethane/ether/hexanes gave 3-methyl 2.3 g, (25%), mp 186°-188° C. and 5-methyl 2.85 g (50%), mp 213°-215° C. both as white solids.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)(C)c1ccn2c(Br)cnc2n1
Product: CC(C)(C)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-tert-butylimidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-tert-butylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white powder: δH (360 MHz, CDCl3) 1.43 (9H, s), 7.05 (1H, d, J 7), 7.37-7.73 (6H, m), 7.81 (1H, s), 7.85 (1H, dd, J 8 and 1), 8.75 (1H, d, J 7); m/z (ES+) 371 (M++H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH:20]=[CH:21][C:22]2[C:30]3[C:25](=[CH:26][C:27]([NH:31][C:32]4[N:40]=[CH:39][CH:38]=[CH:37][C:33]=4[C:34](O)=[O:35])=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:14]=1.[CH:41]1([C:44]#[C:45][CH2:46][NH2:47])[CH2:43][CH2:42]1>>[CH:41]1([C:44]#[C:45][CH2:46][NH:47][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[N:40][C:32]=2[NH:31][C:27]2[CH:26]=[C:25]3[C:30]([C:22](/[CH:21]=[CH:20]/[C:15]4[CH:14]=[C:13]([CH3:12])[CH:18]=[C:17]([CH3:19])[N:16]=4)=[N:23][NH:24]3)=[CH:29][CH:28]=2)[CH2:43][CH2:42]1
Reactant: Cc1cc(C)nc(C=Cc2n[nH]c3cc(Nc4ncccc4C(=O)O)ccc23)c1
Reactant: NCC#CC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C)nc(/C=C/c2n[nH]c3cc(Nc4ncccc4C(=O)NCC#CC4CC4)ccc23)c1

Procedure:
Prepared-in a similar manner to that described for Example 6 above, except using 2-{3-[2-(4,6-Dimethyl-pyridin-2-yl)-vinyl]-1H-indazol-6-ylamino}-nicotinic acid p-toluene sulfonate and 3-Cyclopropyl-prop-2-ynylamine. 1H NMR (DMSO-d6): δ 13.01 (1H, s), 11.20 (1H, s), 9.19 (1H, bt), 8.51 (1H, s), 8.40 (1H, d, J=4.9 Hz), 8.15 (1H, d, J=7.5 Hz), 8.05 (1H, d, J=8.7 Hz), 7.83 (1H, d, J=16.4 Hz), 7.42 (1H, d, J=16.4 Hz), 7.31 (1H, s), 7.05 (1H, d, J=8.3 Hz), 6.96 (1H, s), 6.92 (1H, dd, J=7.5, 4.9 Hz), 4.06 (2H, d, J=4.14 Hz), 2.46 (3H, s), 2.29 (3H, s), 1.33–1.28 (1H, m), 0.77–0.72 (2H, m), 0.60–0.55 (2H, m).