Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6](=[O:10])[C:7](=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.[H][H]>C(O)C.[Pt]=O>[C:1]([N:5]1[CH2:11][CH2:12][CH2:13][NH:14][CH:7]([CH3:8])[C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(=O)N(CCC#N)C(C)(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC1NCCCN(C(C)(C)C)C1=O

Procedure:
N-(tert-butyl)-N-(2-cyanoethyl)-2-oxopropanamide obtained in Step A (440 mg) and platinum oxide (60 mg) were suspended in ethyl alcohol (40 mL) containing chloroform (0.3 mL) and mixed on a Parr shaker over an atmosphere of hydrogen at 40 psi for 16 h. The mixture was filtered, the catalyst was washed with methanol/dichloromethane (10:90) and the combined filtrate was evaporated and purified by Biotage® flash chromatography (silica gel, 5–10% methanol/dichloromethane) to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:52])[NH:40][CH2:41][CH2:42][CH:43]([NH2:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:51][CH:43]([C:44]5[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=5)[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:52])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and [3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester (from Example 3 supra) (722 mg, 2.6 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude [4-(3-{2-[3-tert-butoxycarbonylamino-1-(3-chloro-phenyl)-propylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester. (Yield 135 mg, 30.6%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:8]([NH:14][C:1](=[O:7])[CH:2]=[CH:3][C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CCCCCCNC(=O)C=CC(=O)O
Reaction time: 2 h

Procedure:
Maleic anhydride (39.4 g, 0.40 mol) was partly dissolved in toluene (1 l) to form a milky suspension. N-hexylamine (53 ml, 0.40 mol) was diluted with toluene (500 ml) and added dropwise over a period of 1.5 h. After 2 h, the reaction mixture was filtered and the title compound was obtained as a Nvhite solid (76.4 g, 96%) after drying for 16 h in a vacuum oven at 40° C.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].O[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>>[C:13]([C:9]1[C:8]([C:15]([F:18])([F:16])[F:17])=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][CH:2]([O:1][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)[CH3:20])[C:5]([CH3:19])=[CH:6]2)#[N:14]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O
Product: CC(=O)Nc1ccc(OC(C)Cn2c(C)cc3c(C(F)(F)F)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 139C using 1-(2-hydroxypropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 335) and N-(4-hydroxyphenyl)acetamide: MS (ES) m/z 414 (M−1).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][N:19]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]2=[O:3])=[CH:22][CH:23]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)nc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred ice-cooled suspension of sodium hydride, (60% dispersion in mineral oil, 0.83 g, 21 mmol) in DMF (15 mL) was added a suspension of tert-butyl 3-oxopiperazine-1-carboxylate (2.5 g, 12 mmol) in DMF (45 mL) through a syringe. The ice-H2O bath was removed and the resulting mixture, which was a suspension, was stirred at ambient temperature for 30 min. Complete dissolution was observed. 2-chloro-5-(chloromethyl)pyridine (2.0 g, 12 mmol) was added in one portion as a solid. The resulting mixture was stirred at ambient temperature for 18 h then poured into ice and saturated NaHCO3 aqueous solution. It was extracted with ethyl acetate (2×). The combined organics were washed with saturated NaHCO3 aqueous solution (3×), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM) to give compound 358 (3.65 g, 91% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.31 (1 H, d, J=2.2 Hz), 7.65 (1 H, dd, J=8.3, 2.4 Hz), 7.33 (1 H, d, J=8.1 Hz), 4.59 (2 H, s), 4.15 (2 H, s), 3.62 (2 H, t, J=5.4 Hz), 3.29 (2 H, t, J=5.1 Hz), 1.46 (9 H, s). LCMS-ESI (POS), M/Z, M+1: Found 326.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:32]=[C:31]([I:33])[CH:30]=[CH:29][C:27]=1[NH2:28]>O1CCOCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:28][C:27]2[CH:29]=[CH:30][C:31]([I:33])=[CH:32][C:26]=2[F:25])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(I)cc1F
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Nc1ccc(I)cc1F
Yield: 54.9 %

Procedure:
4-Chloro-1-(4-methoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1.8 g, 5.2 mmol) and 2-fluoro-4-iodoaniline (1.5 g, 6.3 mmol) were dissolved in dioxane (20 mL) and the resultant mixture stirred at reflux for 16 hours. The reaction mixture was diluted with water (50 mL) and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic fractions were filtered through a hydrophobic frit and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-30% ethyl acetate in cyclohexane) to yield the title compound as a white solid (1.56 g, 56%). LCMS (Method B): RT=4.78 min, [M+H]+=547.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:17])[O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:7]=1[C:8](=[N:10][OH:11])[NH2:9].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([CH2:19][O:11][N:10]=[C:8]([NH2:9])[C:7]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:6]=2[O:5][CH:4]([F:3])[F:17])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: NC(=NO)c1c(F)cccc1OC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=NOCC1CC1)c1c(F)cccc1OC(F)F
Reaction time: 3 h
Yield: 52 %

Procedure:
0.4 g of 80% pure sodium hydride was added to a solution of 3.0 g of 2-difluoromethoxy-6-fluorobenzamidoxime in 30 ml of dimethylformamide (DMF) at 0 to 5° C. and the mixture was stirred at this temperature for 3 hours. 1.8 g of bromocyclopropylmethane were subsequently added at the same temperature, and stirring was subsequently continued for 2 hours at 5° C. and overnight at room temperature. The batch was stirred into 300 ml of water and extracted three times with in each case 70 ml of cyclohexane. After the cyclohexane had been evaporated, 1.9 g of the desired product were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1)=[O:5])[CH3:2].[CH3:13][C:14](OC(C)=O)=[O:15]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([O:12][C:14](=[O:15])[CH3:13])[CH:10]=[CH:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@@H]1OCC=C[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1OCC=C[C@H]1OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (70 mg, 0.41 mmol) and DMAP (24 mg, 0.2 mmol) in CH2Cl2-Et3N (9:1, 5 mL) was added Ac2O (54 mg, 0.53 mmol). The resulting solution was stirred at ambient temperature for 2 H. The solution was diluted with CH2C12 (40 mL), washed with H2O (20 mL×2), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>C(O)CCC>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COCCN
Solvent: CCCCO
Product: COCCNc1ccccc1[N+](=O)[O-]

Procedure:
To 28.2g of 2-fluoronitrobenzene in 70ml of n-butanol 30.0g of 2-methoxyethylamine were added and the mixture refluxed overnight to give a dark red solution. After cooling the n-butanol was evaporated off and the product extracted into diethyl ether. The diethyl ether was then washed twice with dilute (aqueous) hydrochloric acid, once with dilute (aqueous) sodium carbonate and once with brine. The ether was then dried using magnesium sulphate and evaporated off to give 35g of 2-(2-methoxyethylamino)nitrobenzene as a red liquid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][NH2:26]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NNc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: Clc1ccc(NNc2nc(Cl)nc3c2ncn3C2CCCC2)c(Cl)c1

Procedure:
2-Chloro-6-(2,4-dichlorophenyl hydrazino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-dichlorophenyl hydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH3:17][C:18]([C:20]1[CH:28]=[CH:27][C:25]([OH:26])=[C:22]([O:23][CH3:24])[CH:21]=1)=[O:19].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5][O:26][C:25]1[CH:27]=[CH:28][C:20]([C:18](=[O:19])[CH3:17])=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(C)=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a N2 purged flask was added 2,4-bis-trifluoromethyl benzyl bromide (2.21 g, 7.20 mmol), acetovanillone (1.32 g, 7.92 mmol), and DMF (15 mL). To the reaction solution was added fine mesh K2CO3 (3 equiv, 21.6 mmol). The reaction was allowed to stir at 70° C. for 1 h, then at 60° C. for 14 h. The reaction solution was then diluted with EtOAc (150 mL), filtered through a Buchner funnel, washed with sat'd NH4Cl (70 mL×2) washed with sat NaCl (50 mL), dried over Na2SO4, and then filtered and concentrated in vacuo to provide a crude product (2.8 g, 99% yield).
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][CH:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1([F:15])[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:7]1
Reactant: CCOC(=O)/C=C/C1CCC(F)(F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Ethyl(E)-3-(4,4-difluorocyclohexyl)acrylate (520 mg, 2.39 mmol) obtained in step 1 was dissolved in ethanol (8.0 mL), and 10% palladium/carbon (containing water) (200 mg) was added. After displacing inside of the reaction vessel with hydrogen gas, the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure to give ethyl 3-(4,4-difluorocyclohexyl)propionate (522 mg, yield 99%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[N:14][CH:15]=1>>[Br:9][C:10]1[CH:11]=[N:12][C:13]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14][CH:15]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: Clc1ncc(Br)cn1
Product: Clc1ccc(Oc2ncc(Br)cn2)cn1

Procedure:
6-Chloropyridin-3-ol (670 mg, 5.17 mmol) and 5-bromo-2-chloropyrimidine (1.0 g, 5.17 mmol) were reacted in analogy to example 2c. Yield: 1.02 g (69%), M+H+: 285.95.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([S:20][CH:21]([NH:28][C:29](=[O:32])[CH2:30]Cl)[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([S:20][CH:21]([NH:28][C:29](=[O:32])[CH2:30][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2SC(NC(=O)CCl)c2ccncc2)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2SC(NC(=O)CN2CCOCC2)c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N-(4-tert-Butylphenyl)-2-(2-chloroacetylaminopyridin-4-ylmethylthio)pyridine-3-carboxamide (Compound No. 16-1, 50 mg, 0.11 mmol) was suspended in morpholine (1.0 mL), and the mixture was stirred for 2 hours at 80° C. in the sealed tube. Ethyl acetate (50 mL) was added to the reaction mixture, the whole was washed with water (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting solid was filtered off with diethyl ether and dried under reduced pressure to give 17 mg of the target compound as a pale yellow solid. (Yield 32%)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11](OCC)(=[O:13])[CH3:12]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[N:1]1[CH:2]=[CH:3][CH:4]=[C:5](/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:12][CH2:11][OH:13])[CH:10]=1
Reactant: c1ccc2ncccc2c1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: OCCCC/C=C\c1cccnc1
Yield: 73 %

Procedure:
A solution of 45 ml (0.47 mol) of 3-bromopyridine and 52 g (0.53 mol) of 5-hexyn-l-ol in 150 ml of triethylamine and 500 ml of dichloromethane is degassed for 15 minutes with argon, and 3 g (4,3 mmol) of bis(triphenylphosphine)palladium(II)chloride and 450 mg of cuprous iodide is added. The mixture is heated at reflux for 3 h. The cooled reaction mixture is diluted with 1 liter of dichloromethane and is washed with water and brine, dried (K2CO3), concentrated and bulb-to-bulb distilled (b.p. 120°-130° C./0.05 mbar), to give 63 g of 6-(3-pyridyl)hex-5-ynol as a yellow oil, which is dissolved in 500 ml of ethyl acetate and af ter addition of 15 ml of quinoline is hydrogenated f or 5 h over 6 g Lindlar catalyst (Pb-poisoned Pd catalyst) in a Parrhydrogenator. The crude product is evaporatively distilled (b.p. 120°-130° C./0.05 mbar), yielding 61 g (73%) of (Z)-6-(3-pyridyl)hex-5-enol as a colourless viscous liquid. (C11H15NO; F.W. 177.3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([NH:17]C(=O)C)[NH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].OS(O)(=O)=O.[K]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([NH2:17])[NH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Temperature: 25 °C

Procedure:
To a stirred solution of Step 1 intermediate (1.1 g, 3.829 mmol) in a mixture of methanol (20 ml) and water (20 ml) was added conc. H2SO4 (2 ml) and the resulting mixture was refluxed for 24 h. The reaction mixture was cooled to room temperature, saturated solution of potassium carnonate was added and extracted with ethyl acetate (2×50 ml). The organic layers were combined and dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5% methanol in chloroform to obtain 290 mg of the product as a yellow solid; 1H NMR (300 MHz, DMSO-d6): δ 5.55 (br s, 2H), 7.32 (s, 1H), 7.59-7.67 (m, 3H), 11.30 (br s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:6]=[CH:7][C:8]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[C:15]([C:17]2[C:18](=[O:25])[NH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:14]=[C:13]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]=1[O:30][CH3:31].[CH3:37][O-:38].[Na+]>CO>[C:26]([C:13]1[C:12]([O:30][CH3:31])=[C:11](/[CH:10]=[CH:9]/[C:8]2[CH:7]=[CH:6][C:5]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])=[CH:4][C:3]=2[CH2:2][O:38][CH3:37])[CH:16]=[C:15]([C:17]2[C:18](=[O:25])[NH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:14]=1)([CH3:28])([CH3:29])[CH3:27]
Reactant: COc1ccc(-c2cc(/C=C/c3ccc(NS(C)(=O)=O)cc3CBr)c(OC)c(C(C)(C)C)c2)c(=O)[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(OC)[nH]c2=O)cc(C(C)(C)C)c1OC

Procedure:
step 3—A solution of 324 (93 mg, 0.162 mmol) in MeOH (10 mL) and sodium methoxide (10 mL, 5 mmol, 0.5 M methanol solution) was stirred at RT overnight. The reaction mixture was concentrated, diluted with EtOAc and acidified with 6N HCl (1 mL). The organic extract was dried (Na2SO4), filtered and concentrated. The crude product was purified on a preparative TLC plate developed with 2:1 EtOAc/hexane to afford 26 mg (31%) of I-209 as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:6]2[N:15]=[CH:16][CH:17]=[C:5]2[N:4]=1.[C:18](Cl)(=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH2:13][CH2:14]2)[N:6]2[N:15]=[CH:16][CH:17]=[C:5]2[N:4]=1
Reactant: CC/C=C/C(=O)Cl
Reactant: COc1cc(N2CCNCC2)n2nccc2n1
Solvent: ClCCl
Product: CC/C=C/C(=O)N1CCN(c2cc(OC)nc3ccnn23)CC1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
5-Methoxy-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine (23.3 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (1 ml), TEA (17.4 μl, 1.25 mmol) followed by (E)-pent-2-enoyl chloride (14.8 mg, 0.125 mmol) were added, the mixture was shaken for 10 minutes, diluted with dichloromethane, washed with 10% sodium bicarbonate solution, water and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 16.1 mg of a solid (0.05 mmol, 51%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](=O)[CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH4+].[OH-]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH2:13][CH3:14])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1CC
Temperature: 25 °C
Yield: 103.8 %

Procedure:
To a refluxing solution of thiourea (2.6 g, 34.3 mmol) in absolute ethanol (30 mL) was added ethyl 2-bromo-3-oxopentanoate (7.3 g, 32.7 mmol) always keeping the mixture at reflux. The solution was stirred at reflux for another 1.5 hours. After cooling to room temperature, the solution was poured in ice/water (150 mL). The mixture was neutralized with concentrated NH4OH. The solid material was recovered by filtration, washed with water (2×50 mL) and hexanes (3×50 mL), and dried in vacuo, affording ethyl 2-amino-4-ethyl-1,3-thiazole-5-carboxylate (6.8 g, 94% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][O-].[Na+].CI.[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2>CN(C)C=O>[CH3:1][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: C[O-]
Reactant: Cc1ccc(-c2cc3ccccc3[nH]2)c(O)c1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1-c1cc2ccccc2[nH]1
Reaction time: 2 h
Yield: 70 %

Procedure:
At a temperature of 25° C. 54 g (1 mol) of sodium methylate and 170 g (1.2 mol) of methyl iodide were added to a solution of 223 g (1 mol) of 2-(2'-hydroxy-4'-methyl-phenyl)-indole, prepared as in Example 1, in 1200 ml of N,N-dimethylformamide. The solution was then stirred for 2 hours and the crude product was precipitated by adding water. After recrystallization from benzene, 166 g of 2-(2'-methoxy-4'-methyl-phenyl)-indole were obtained. M.P.: 125° C. Yield: 70%.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[Cl:33][C:34]1[CH:39]=[C:38]([C:15]2[N:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)[N:17]([CH3:18])[C:16]=2[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])[CH:37]=[CH:36][N:35]=1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CCCCCCc1cccc(-c2nc(-c3ccnc(Cl)c3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 2-chloro-pyridin-4-yl-boronic acid to give the title compound as light yellow gum. MS: 534.3 (MH+, 1Cl).