Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[C:26]([O:28]C(C)(C)C)=[O:27])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].Cl>C1COCC1.O1CCOCC1>[CH2:1]([C:4]1([CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[C:26]([OH:28])=[O:27])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(CCN2CCCC2C(=O)OC(C)(C)C)c2ccccc2CCc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C=CCC1(CCN2CCCC2C(=O)O)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 38.3 %

Procedure:
Dissolved 1,1-dimethylethyl 1-[2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl]-2-pyrrolidinecarboxylate (2.40 g, 5.56 mmol) in 30 mL of dry THF. Added 25 mL of 4.0M HCl in dioxane, and refluxed for 16 hours on steam bath. Cooled to room temperature, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% MeOH-CH2Cl2. Combined appropriate fractions and evaporated to give 0.80 g (40% yield) of 1-[2-[10,11-dihydro-5-(2propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl]-2-pyrrolidinecarboxylic acid. Dissolved free base in dichloromethane, and added 3.4M HCl in ether to pH=2. Evaporated, and added ether to precipitate hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:16]3[C:17](=[C:19]([C:23](O)=[O:24])[CH:20]=[CH:21][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:28][C@H:29]1[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1>>[N:31]12[CH2:30][CH:29]([NH:28][C:23]([C:19]3[C:17]4[N:18]=[C:14]([N:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]5)[O:15][C:16]=4[CH:22]=[CH:21][CH:20]=3)=[O:24])[CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(C(=O)O)cccc3o2)CC1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCN(c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)CC1

Procedure:
Following general procedure GP-C1, A mixture of 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide tert-butyl 4-[4-(quinuclidine-8-ylcarbamoyl]benzoxazol-2-yl)piperazine-1-carboxylate (85 mg, 0.19 mmol) to which was added TFA (0.17 mL, 2.3 mmol). The reaction mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure. The TFA salt was converted to the dihydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36](O)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:36]([C:31]3[C:30]([C:27]4[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][CH:28]=4)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:37])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: O=C(O)c1ccccc1-c1ccc(Cl)cc1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CC(C)C[C@H]2CN1C(=O)c1ccccc1-c1ccc(Cl)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 4′-chloro-biphenyl-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:38]1[N:42]=[CH:41][S:40][N:39]=1)[C:12]([NH:14][CH:15]1[C:36](=[O:37])[N:17]2[C:18]([C:23]([O:25]CC3C=CC([N+]([O-])=O)=CC=3)=[O:24])=[C:19]([Cl:22])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:38]1[N:42]=[CH:41][S:40][N:39]=1)[C:12]([NH:14][CH:15]1[C:36](=[O:37])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([Cl:22])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1ncsn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ncsn1
Yield: 36.2 %

Procedure:
p-Nitrobenzyl 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (4.9 g) dissolved in a mixed solvent of methanol (30 ml), tetrahydrofuran (30 ml) and acetic acid (1 ml). After adding 10% palladium on carbon (2.5 g) thereto, the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the mixture was adjusted to pH 7.5 with 20% aqueous sodium carbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed by evaporation to give 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (1.4 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>O1CCCC1>[N:11]1([C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: COc1cc(C)nc(Cl)n1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: COc1cc(C)nc(-n2ccnc2)n1
Yield: 51.1 %

Procedure:
In anhydrous tetrahydrofuran, 159 mg of 2-chloro-4-methoxy-6-methylpyrimidine was substituted with 68 mg of imidazole. The reaction mixture was treated according to the Procedure of Example 5 to yield 97 mg of 2-(1-imidazolyl)-4-methoxy-6-methylpyrimidine, recrystallized from n-hexane, having a melting point of 53°-54° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20]CC=C)=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:24])=[C:10]1[CH3:25])=[O:4].N1CCOCC1>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:24])=[C:10]1[CH3:25])=[O:4]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: COC(=O)c1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of allyl 1-(3-(methoxycarbonyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (133 mg, 0.35 mmol) and morpholine (0.3 mL, 3.4 mmol) in THF (4 mL) was degassed and then Pd(PPh3)4 (41 mg, 0.035 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was dissolved in Methanol and acidified to pH 4. The precipitate was collected and washed with water to obtain the title compound.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>[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.C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:21][CH:20]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cc3ccccc3c3ccccc23)cc1
Reaction time: 24 h
Yield: 72 %

Procedure:
Under an argon gas atmosphere, 39.25 g (177 mmol) of 9-phenanthreneboronic acid, 50.0 g (177 mmol) of 4-bromoiodobenzene, 4.10 g (3.54 mmol) of tetrakis(triphenylphosphine) palladium(0), 400 mL of toluene and 265 mL of 2M sodium carbonate solution were mixed, and stirred for 24 hours while being refluxed. After the reaction in the mixture was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 42.6 g of 9-(4-bromophenyl)phenanthrene was obtained with an yield of 72%.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7](=[O:8])[C:2]=1[C:35]1[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=1)[CH3:28]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc(OC(F)(F)F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 94.4 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 4-trifluoromethoxyphenylboronic acid (0.35 g) in 1,4-dioxane (15 mL) were added 2 M aqueous cesium carbonate solution (3 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.56 g, 95%) as a colorless amorphous solid.
Reaction SMILES: Cl.N[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[S:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].N([O-])=[O:16].[Na+]>O>[OH:16][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[S:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(SC)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(SC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
A stirred solution of concentrated hydrochloric acid (3.2 mL) in water (3.6 mL) at from 0° C. to 5° C. is treated with methyl 3-amino-4-(methylthio)benzoate (1.97 g), followed by a solution of sodium nitrite (0.82 g) in water (2 mL), at such a rate that the temperature remained from 0° C. to 5° C. The mixture is then allowed to warm to room temperature and it is stirred for a further period of 1 hour. The reaction mixture is treated with water (30 mL) and then heated to 55-60° C., until the evolution of nitrogen ceased (4 hours). The mixture is extracted with dichloromethane (2×100 mL) and the combined organic extracts are dried and concentrated. The resulting brown oil is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:4 v/v), to give methyl 3-hydroxy-4-(methylthio)benzoate (0.6 g) in the form of a yellow solid.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[C:5]([O:8][CH2:9][CH:10]=[CH2:11])(=[O:7])[CH3:6]>>[C:5]([O:8][CH2:9][CH2:10][CH2:11][Si:2]([Cl:4])([Cl:3])[Cl:1])(=[O:7])[CH3:6]
Reactant: C=CCOC(C)=O
Reactant: Cl[SiH](Cl)Cl
Product: CC(=O)OCCC[Si](Cl)(Cl)Cl

Procedure:
In a 4-liter flask with stirrer, reflux condenser, internal thermometer and 2 dropper funnels, one filled with 800 g of allyl acetate and the other with 1.355 kg of trichlorosilane, 200 ml of allyl acetate was heated to 65°C. Then the heat source was removed, 1 ml of an 0.01 molar solution of mesityl oxide-platinum dichloride complex in allyl acetate was added, and the reaction was allowed to complete itself within 8 minutes while stirring was performed and the two reactants were fed in simultaneously. During that period the temperature rose to 105°C due to self-heating. After that no more silane hydrogen was detected analytically. Distillation of the reaction product yielded 2.28 kg of 3-acetyloxypropyltrichlorosilane, BP20 : 98°-100°C; nD20 : 1.4359.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:27][C@H:26]([CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:40][NH:41][CH3:42]>CO.C1COCC1>[CH3:40][N:41]([CH2:28][C@H:26]1[CH2:27][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:25]1)[CH3:42]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C[C@H]1C[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Temperature: 60 °C

Procedure:
A mixture of trans-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (30.0 mg, 0.0555 mmol), dimethylamine in MeOH (2 M, 2 mL) and THF (5 mL) was heated to 60° C. overnight in a sealed tube. The material was concentrated in vacuo, purified by prep TLC (eluting with 5% MeOH in DCM). MS (ES+): m/z 414.19 (100) [MH+]. HPLC: tR=0.65 min (polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:10]=1[CH3:11])[C:5]([NH2:7])=[O:6].Br[C:22]1[C:27](=[O:28])[N:26]([CH3:29])[C:25]2[N:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[N:31]=[CH:32][C:24]=2[CH:23]=1.[OH-].[Na+]>O1CCOCC1.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.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[N:30]1[C:25]2[N:26]([CH3:29])[C:27](=[O:28])[C:22]([C:9]3[CH:8]=[C:4]([CH:3]=[C:2]([F:1])[C:10]=3[CH3:11])[C:5]([NH2:7])=[O:6])=[CH:23][C:24]=2[CH:32]=[N:31]1
Reactant: Cc1c(F)cc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3ccccc3Cl)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(N)=O)cc1-c1cc2cnn(-c3ccccc3Cl)c2n(C)c1=O
Temperature: 125 °C
Yield: 88.7 %

Procedure:
A mixture of 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (118 mg, 422 μmol), 5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (130 mg, 384 μmol), Pd(PPh3)4 (0.016 mmol, 19 mg), and sodium carbonate (2 M) (0.576 ml, 1.15 μmol) in 2.0 mL of dioxane in a sealed tube was heated in a microwave at 125° C. for 25 min. The mixture was treated with 2 mL of 1 N NaOH solution, extracted with 2×5 mL of EtOAc. The combined organic phases were washed with 2 mL of brine, dried and concentrated. The brown residue was loaded on an ISCO 12 g column (eluting with a gradient of 1-6% MeOH in DCM) to provide the title compound (140 mg) as an off white crystalline solid. MS (ESI, pos.ion) m/z: 411.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([NH:13]/[C:14](/[CH3:21])=[CH:15]\[C:16]([O:18]CC)=O)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:18]=[C:16]1[CH:15]=[C:14]([CH3:21])[NH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][NH:10][C:11]1=2
Reactant: CCOC(=O)/C=C(/C)Nc1c[nH]nc1-c1ccc(Cl)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(=O)c2[nH]nc(-c3ccc(Cl)cc3)c2[nH]1
Yield: 76.5 %

Procedure:
Ethyl 3-[3-(4-chlorophenyl)-pyrazol-4-ylamino]crotonate (D14) (0.6 g) was added to refluxing Dowtherm A (20 ml) under nitrogen and heated for 20 min. The cooled solution was diluted with petroleum ether (40°-60°; 100 ml) and the resulting solid was collected and washed well with petroleum ether to afford the title compound (0.39 g) m.p. 324°-327° C. (Found: C, 60.06; H, 3.74; N, 16.14% C13H10N3OCl requires C, 60.13; H, 3.88; N, 16.18%)
Reaction SMILES: O.[ClH:2].[C:3]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][C:31]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:34]#[N:35])[CH2:30][CH2:29]2)([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CCO.[Ni]>[OH2:10].[ClH:23].[ClH:2].[NH2:35][CH2:34][C:31]1([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][C:13]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:14][CH2:15][CH2:16][N:11]([C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)[CH2:29][CH2:30]1.[NH2:35][CH2:34][C:31]1([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][C:13]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:14][CH2:15][CH2:16][N:11]([C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)[CH2:29][CH2:30]1.[ClH:23].[ClH:23]
Reactant: N#CC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CCO
Product: NCC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Reaction time: 72 h
Yield: 111.8 %

Procedure:
A mixture of 2.3 g of the compound obtained in EXAMPLE 8 and 0.3 g of Raney® nickel in 100 ml of EtOH is hydrogenated for 72 hours at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (85/15; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.08 g of the expected product.
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]2[C:20](=[O:29])[C:21]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[N:22][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([B:38]2[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([C:8]1[C:9]2[N:10]([C:20]([O:29][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([B:38]4[O:39][C:40]([CH3:46])([CH3:45])[C:41]([CH3:44])([CH3:43])[O:42]4)=[CH:36][CH:37]=3)=[C:21]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[N:22]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: O=c1c(Cc2ccco2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC1(C)OB(c2ccc(COc3c(Cc4ccco4)nc4c(Cc5ccccc5)nc(-c5ccccc5)cn34)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a solution of 8-benzyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one (50 mg, 0.13 mmol) was added 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (47 mg, 0.16 mmol), potassium carbonate (27 mg, 0.20 mmol) and potassium iodide (33 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 h and heat to 40° C. until HPLC shows the completion of the reaction. After cooling down, the reaction mixture was extracted with ethyl acetate/water. The organic layer was collected and dried over magnesium sulfate. After evaporation, the residue was purified with flash chromatography to give the product as yellow solid (30 mg, 49%). 1H NMR (300 MHz, CD2Cl2, δ): 7.79-7.23 (m, 18H), 7.32 (d, J=6.0 Hz, 2H), 5.11 (s, 2H), 4.53 (s, 2H), 4.15 (s, 2H), 1.53 (s, 12H); MS (ESI) m/z 597.41.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=O>C1COCC1.O>[F:1][C:2]([F:12])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH2:5]
Reactant: NC(=O)C(F)(F)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: NCC(F)(F)c1ccccc1
Temperature: 0 °C
Yield: 59.3 %

Procedure:
Following the procedures described in Middleton and Bingham J. Org. Chem., 1980, 45, 2883, 500 mg portion of 7-5 (4.826 mmol) was dissolved in 25 ml of THF and cooled to 0° C. via ice bath. To this stirred solution was added 30 ml (30 mmol) of 1M Borane·THF complex dropwise over ten mintes via syringe. The reaction mixture was aged until the ice bath expired. Upon expiration of the ice bath, the reaction mixture was heated to 70° C. overnight. The reaction mixture was diluted with water and concentrated in vacuo. The residue was diluted with chloroform and washed with 10% sodium carbonate. Three chloroform extractions were performed on the aqueous layer. The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to give 450 mg of a yellow oil. The oil was purified using a 30mm column, 5 inches of silica gel, and a 1:1 ethyl acetate to hexane solvent system to give 7-6 (Wade and Kheribet J. Org. Chem, 1980, 45, 5333) as a yellow oil: H1NMR CDCl3): δ 3.15 (t, 2H, 14.6 Hz), 7.4-7.49 (m, 5H).
Reaction SMILES: C1C(O)=CC=C(C)C=1.C(Cl)(=O)CCCCC.[CH3:17][CH:18]([CH3:31])[CH2:19][CH2:20][CH:21]([OH:30])[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:17][CH:18]([CH3:31])[CH2:19][CH2:20][CH:21]([OH:30])[C:22](=[N:33][OH:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NO
Reactant: CC(C)CCC(O)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: CCCCCC(=O)Cl
Agent: Cc1ccc(O)cc1
Solvent: CCO
Solvent: O
Product: CC(C)CCC(O)C(=NO)c1ccccc1

Procedure:
p-cresol and caproylchloride are converted in a well-known mode to ester which, according to Fries, is rearranged to 5-methyl-2-hydroxy-caprophenone, 155° in b.p.65 (cf. P.P.T. Sah and H. H. Anderson, J. Am. Chem. Soc. 63, 3164 (1941). 20 g (0.1 Mol) of ketone are solved in 45 ml ethanol and heated 30 minutes to boiling level under reflux cooling together with a concentrated aqueous solution of 7.5 g of hydroxylamine hydrochloride and 15 g of crystalline sodium acetate. Water is then added to the mixture, and the separated oxime recrystallised from ethanol/water, the flash point being between 83° C. and 85° C.