Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([Cl:49])=[C:44]([NH:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([Cl:49])=[C:44]([NH:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=3)[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: COc1ccc(CNc2nc(N)c(F)cc2Cl)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(Cl)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To 2 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.56 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.66 g of 2-amino-5-chloro-3-fluoro-6-(p-methoxybenzylamino)pyridine. The solution was concentrated under reduced pressure. To the residue were added 0.5 g of anhydrous potassium carbonate and 1.5 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 20 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The solution was allowed to stand after adding 4 ml of ethanol. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 0.56 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][CH3:19].[H-].[Na+].[CH2:22]1COC[CH2:23]1>>[CH2:22]([N:15]([CH2:18][CH3:19])[C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[CH3:23]
Reactant: C1CCOC1
Reactant: CCBr
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (100 mg, 0.45 mmol) and bromoethane (200 mg, 1.8 mmol), NaH (100 mg, 1.8 mmol) in THF was stirred at room temperature overnight, and concentrated in vacuo to give the crude title compound used for the next step. MS (m/z): 276 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][N:6]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]1[SH:14].[CH3:19]I.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][N:6]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]1[S:14][CH3:19]
Reactant: CI
Reactant: O=C(O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1ncc(C(=O)O)n1Cc1cc(F)cc(F)c1

Procedure:
Reaction of 1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxylic acid prepared as in Example 1 with methyl iodide and sodium methoxide in methanol by standard techniques yields 1-(3,5-diflurobenzyl)-2-methylmercaptoimidazole-5-carboxylic acid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:23]=[C:22]3[C:14]([N:15]4[C:20](=[CH:21]3)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]4)=[N:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.[H-].[Na+]>>[CH:27]1([CH2:26][N:18]2[CH2:17][CH2:16][N:15]3[C:20](=[CH:21][C:22]4[C:14]3=[N:13][CH:12]=[C:11]([O:10][CH:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)[CH:23]=4)[C:19]2=[O:24])[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCN(CC3CC3)C2=O)CC1
Yield: 85 %

Procedure:
The title compound was synthesized in analogy to example 17, from 7-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 84), 1-(bromomethyl)cyclopropane and sodium hydride, to give the desired product as a colorless solid (85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Al].Cl[CH:16](Cl)[CH2:17][Si:18]([Cl:21])([Cl:20])[Cl:19]>C(=S)=S.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:16]([CH2:17][Si:18]([Cl:21])([Cl:20])[Cl:19])[C:6]=2[CH:7]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Agent: [Al]
Solvent: CCCCCC
Solvent: S=C=S
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2ccc(Br)cc21
Yield: 15 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of 4-bromobiphenyl and 0.08 g (11.1 mmol) of aluminum foil were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)-trichlorosilane 6.68 g (21.7 mmol) for 24 hr. at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, the reaction products were vacuum distilled to give 1.28 g of 2-bromo-9-(trichlorosilyl)methylfluorene (yield; 15%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].O[C:13]1CCOCC=1C(OC)=O.[H-].[Na+].IC>CN(C=O)C.C(OCC)(=O)C>[CH3:13][C:3]1([C:8]([O:10][CH3:11])=[O:9])[C:2](=[O:1])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: COC(=O)C1=C(O)CCOC1
Reactant: COC(=O)C1COCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1(C)COCCC1=O
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Methyl 4-oxo-tetrahydro-2H-pyran-3-carboxylate and methyl 4-hydroxy-5,6-dihydro-2H-pyran-3-carboxylate (13.5 g, 85.5 mmol) were dissolved in DMF (70 mL). Sodium hydride (60%, 3.6 g, 1.05 eq) was added at 0° C. After 10 min, iodomethane (6.7 mL, 1.25 eq) was added. The reaction was stirred overnight, diluted with ethyl acetate (200 mL), and washed with water (5×100 mL). The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel eluting with 20% ethyl acetate/hexane to yield 8.2 g (61%) of methyl 3-methyl-4-oxo-tetrahydro-2H-pyran-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:5])[CH3:2].[NH2:17][NH2:18]>C(O)CCC>[CH2:1]([O:3][C:4]([NH:6][CH:7]([CH3:16])[C:8](=[N:17][NH2:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(C)C(=O)c1ccccc1
Reactant: NN
Solvent: CCCCO
Product: CCOC(=O)NC(C)C(=NN)c1ccccc1
Yield: 84.6 %

Procedure:
A mixture of 2-ethoxycarbonylaminopropiophenone (5 g) and hydrazine (3.5 g) in n-butanol (;b 40 ml) was refluxed for 4 hours. The reaction mixture was evaporated, and the residue was chromatographed on silica gel (400 g) using a mixture of chloroform and methanol (100:1) as an eluent. The first fraction was evaporated to give 2-ethoxycarbonylaminopropiophenone hydrazone (4.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:23]=[C:24]([CH3:26])[CH3:25].S(=O)(=O)(O)O.C(=O)([O-])O.[K+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24]([CH3:26])([CH3:25])[CH3:23])=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: C=C(C)C
Reactant: O=C(CCc1ccc(O)cc1)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(CCC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 72 h

Procedure:
4.51 g (15 mmol) of 3-(4-hydroxyphenyl)-propionic acid 4-nitrobenzyl ester in 200 ml of methylene chloride are carefully treated at 0° C. with 100 ml of isobutene and 0.5 ml of concentrated sulphuric acid. The mixture is stored at room temperature for 72 hours and then poured into 100 ml of 0.4-N potassium hydrogen carbonate solution. The organic solvent is almost completely evaporated in vacuo and the product extracted several times with diethyl ether. The combined organic phases are washed with 0.5-N sodium hydroxide and water, dried over sodium sulphate and then evaporated. The solid residue is dissolved in petroleum ether, insoluble material is filtered off and the filtrate evaporated to dryness in vacuo. There is obtained 3-(4-tert.butoxyphenyl)-propionic acid 4-nitrobenzyl ester in the form of a crystalline residue of melting point 30°-32° C. The product is chromatographically pure in cyclohexane/chloroform/acetic acid (45:45:10). The yield amounts to 4.5 g (83% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.[CH3:43][CH:44]([CH3:50])[CH2:45][CH2:46][C:47](Cl)=[O:48]>ClCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:47](=[O:48])[CH2:46][CH2:45][CH:44]([CH3:50])[CH3:43])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)CCC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a stirred mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 60 mg, 0.123 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.615 mmol) in dichloromethane (1.0 mL) at room temperature was added 4-methylvaleroyl chloride (Pfaltz & Bauer, Inc., Waterbury, Conn., USA; 20 mg; 0.15 mmol). After 1 h, the mixture was washed with 1 N HCl followed by water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was triturated with diethyl ether, filtered, washed with diethyl ether and allowed to air dry to provide 1-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-4-methyl-pentan-1-one (32 mg, 55%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.87 (d, 6H, J=6.6 Hz), 1.36-1.44 (m, 2H), 1.50-1.59 (m, 1H), 1.94-2.10 (m, 4H), 2.33-2.38 (m, 2H), 2.74-2.86 (m, 1H), 3.30 (water peak and SO2CH3), 3.98-4.08 (m, 1H), 4.46-4.57 (m, 1H), 5.00-5.14 (m, 1H), 7.62 (d, 2H, J=8.5 Hz), 8.04 (d, 2H, J=8.7 Hz), 8.38 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=472.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH:6]=1)=[N+]=[N-].Cl.[Cl:25]C(Cl)C.C(OCC)(=O)C>[Pt](=O)=O>[ClH:25].[NH2:1][CH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH:6]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Reactant: CC(Cl)Cl
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
In a 50 mL round bottom flask, 3-azidomethyl-7-fluoro-1-(2-fluoro-phenyl)-1H-quinolin-4-one (0.290 g, 0.929 mmol) was added platinum (IV) oxide (0.040 g, 0.176 mmol) and 4 N HCl (2 mL) in 1:1 dichloroethane-ethyl acetate (15 mL). The reaction was charged with 1 atm. H2 using a balloon and stirred at room temperature for 3 hr. The catalyst was filtered off and the filtrate evaporated to dryness to give 3-aminomethyl-7-fluoro-1-(2-fluoro-phenyl)-1H-quinolin-4-one hydrochloride salt (200 mg, 67% yield). The crude was used in subsequent steps without further purification.
Reaction SMILES: [N:1]1([CH:7]2[CH2:10][N:9]([C:11]([C:13]3[S:17][C:16]4[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=4[CH:14]=3)=[O:12])[CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[N:28]1[CH:29]=[CH:30][CH:31]=[N:32][C:27]=1[N:4]1[CH2:5][CH2:6][N:1]([CH:7]2[CH2:10][N:9]([C:11]([C:13]3[S:17][C:16]4[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:15]=4[CH:14]=3)=[O:12])[CH2:8]2)[CH2:2][CH2:3]1
Reactant: O=C(c1cc2ccc(C(F)(F)F)cc2s1)N1CC(N2CCNCC2)C1
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cc2ccc(C(F)(F)F)cc2s1)N1CC(N2CCN(c3ncccn3)CC2)C1

Procedure:
A mixture of (3-(piperazin-1-yl)azetidin-1-yl)(6-(trifluoromethyl)benzo[b]thiophen-2-yl)methanone (0.14 mmol, 50 mg), 2-bromopyrimidine (0.23 mmol, 37 mg), and K2CO3 (0.34 mmol, 47 mg) in THF (3 mL) and water (1.5 mL) was refluxed for 8 h. Following workup and extraction, the residue was purified by flash column chromatography (silica gel, 3% methanol/CH2Cl2) to yield (3-(4-(pyrimidin-2-yl)piperazin-1-yl)azetidin-1-yl)(6-(trifluoromethyl)benzo[b]thiophen-2-yl)methanone as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]1[C:14](=O)[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:12][S:11][CH2:10]1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:27]([CH2:24][CH2:25][CH3:26])[N:28]=[C:14]2[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:12][S:11][CH2:10][CH:9]12
Reactant: CCCNN
Reactant: Cc1ccccc1C=C1CSCC(=Cc2ccccc2C)C1=O
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccccc3C)CSCC2C1c1ccccc1C
Temperature: 25 °C
Yield: 20.3 %

Procedure:
A mixture of 6.7g of tetrahydro-3,5-bis-[(2-methylphenyl)methylene]-4H-thiopyran-4-one and 1.6g of n-propyl hydrazine in 250ml of methanol is heated at reflux temperature for 4 hours and allowed to cool to room temperature over a 16hour period. The precipitate that forms is collected by filtration and chromatographed on a neutral alumina column (Activity I). The fractions eluted with 10-20 % ether/hexane are combined and recrystallized from methanol/water to give 1.6g of the title compound, melting point 110°-112.5°C.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:46])[CH2:18][N:19]2[C:24](=[O:25])[CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH3:29])[N:21]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)[C:20]2=[O:45])=[CH:13][CH:12]=1.[N:47]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:46])[CH2:18][N:19]2[C:24](=[O:25])[CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH3:29])[N:21]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:47][C:4](=[O:7])[O:5][N:44]=4)=[CH:35][CH:36]=3)[C:20]2=[O:45])=[CH:13][CH:12]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Reactant: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogencarbonate (1.38 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.7 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.2 g, 26%).
Reaction SMILES: [C:1]([C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:9][CH:10]=[CH2:11])[CH2:4][C:5]([O:7]C)=[O:6])#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH2:9][CH:10]=[CH2:11])[CH2:4][C:5]([OH:7])=[O:6])#[N:2]
Reactant: C=CCC(C#N)(CC(=O)OC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(C#N)(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-cyano-3-phenylhex-5-enoate (6.03 g, 26.3 mmol) in methanol (90 mL) was added 1M aqueous NaOH (29 mL, 29 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under vacuum. The residue was partitioned between EtOAc and water and the pH of the aqueous phase was adjust to pH 4 using 3N aqueous HCl. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 12.45 (br, 1H), 7.50 (d, J=1.6 Hz, 2H), 7.45 (t, J=1.9 Hz, 2H) 7.42 (t, J=1.7 Hz, 1H), 5.51 (m, 1H), 5.11 (m, 2H), 3.17 (s, 2H), 2.77 (m, 2H), 2.51 (s, 2H) ppm. ES MS M+1=216.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:15][CH:14]3[C:10]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)([N:11](CC4C=CC(OC)=CC=4)[O:12][CH2:13]3)[CH2:9]2)=[N:6][CH:7]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:15][CH:14]3[C:10]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)([NH:11][O:12][CH2:13]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: COc1ccc(CN2OCC3CN(c4ncc(F)cn4)CC32c2cccnc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cnc(N2CC3CONC3(c3cccnc3)C2)nc1
Yield: 96 %

Procedure:
A solution of 5-(5-fluoropyrimidin-2-yl)-1-[(4-methoxyphenyl)methyl]-6a-(3-pyridyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole (1.11 g, 2.32 mmol) in trifluoroacetic acid (9.3 mL) is stirred at 60° C. for 1 hour. The solvent is evaporated and the resulting residue is partitioned between dichloromethane (100 mL) and saturated aqueous sodium carbonate solution (25 mL). The organic phase is separated and the aqueous phase is re-extracted twice with dichloromethane (100 mL). The combined organic extracts are dried over magnesium sulfate, filtered, and the solvent evaporated under vacuum to give a residue that is purified by silica gel chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (0.64 g, 96%). ES/MS (m/e): 288 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:30]=[O:31])C.C(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([CH:30]=[O:31])[O:4][C:3]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:8]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(-c2noc(-c3occc3Br)n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(-c2nc(-c3ccc(Cl)cc3)no2)o1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A solution of 5-(3-bromo-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole (599 mg, 1.84 mmol) in tetrahydrofuran (10 mL) was added under argon over 20 min to a stirred solution of 1.5 M lithium diisopropylamide (1.3 mL, 1.95 mmol) and tetrahydrofuran (10 mL) in a dry ice/acetone bath, and it was stirred for 1 h. To the solution was then added dry DMF (1.5 mL, 19.4 mmol) dropwise and the solution was stirred for 30 min. The dry ice bath was replaced by an ice bath and the solution was stirred for 20 min. The ice bath was removed and the solution was quenched with methanol (10 mL) and then saturated sodium bicarbonate (3 mL). To the solution was added 1 N hydrochloric acid until the solution reach pH 3. The solution was extracted with dichloromethane (2×100 mL). The extracts were dried over sodium sulfate, filtered, and concentrated. The product was purified twice by column chromatography (dichloromethane) to yield 393 mg (60%) of the title compound as a light yellow solid. 1H NMR (DMSO-d6): 9.79 (s, 1H), 8.11 (dd, J=8.52, 2.13 Hz, 2H), 8.05 (s, 1H), 7.70 (dd, J=8.24, 2.06 Hz, 2H).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:9]1[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]2[N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:2]=[CH:3][CH:4]=2)=[N:8]1
Reactant: COc1ccccc1-n1ccc(=O)c(C(=O)C=CN(C)C)n1
Reactant: NNc1ccccc1
Solvent: CO
Product: COc1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Yield: 5 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(2-methoxyphenyl)pyridazin-4(1H)-one (crude 639 mg, 2.14 mmol) in 20 mL of methanol was added phenylhydrazine (347 mg, 3.21 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(2-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (35 mg, 5% for two steps) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]([C@H:20]3[CH2:25][CH2:24][C@H:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)[N:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=23)[CH:7]=[CH:6][C:4]=1[NH2:5].B(Br)(Br)Br>ClCCl>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([C:10]2[N:11]=[C:12]([C@H:20]3[CH2:25][CH2:24][C@H:23]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH2:22][CH2:21]3)[N:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=23)=[CH:9][C:3]=1[OH:2]
Reactant: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nccn2c1c(-c1ccc(N)c(O)c1)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)aniline (0.152 mmol, 66 mg) in dichloromethane (1.4 ml) at 0-5° C. was added boron tribromide (0.758 mmol, 73 μl) under a nitrogen atmosphere. Then the reaction mixture was stirred for three hours at room temperature. Then additional boron tribromide (0.758 mmol, 73 μl) was added. After 30 minutes the reaction mixture was quenched with methanol and stirred during the night. The solid formed was removed by filtration and the filtrate was concentrated in vacuo. Water was added and the mixture was coevaporated with toluene twice. The crude product was dissolved in methanol; sillica gel added, concentrated in vacuo and the residue charged on a silica gel column for purification (gradient of dichloromethane to dichloromethane/methanol 5/1) to give impure 2-amino-5-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenol (116 mg content approximately 20%) which was used without further purification.