Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)=[CH:4][CH:3]=1.Br[C:24]1[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Br:30])[CH:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:30][C:28]1[CH:29]=[C:24]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH:9]4[CH2:15][CH2:14][CH:13]3[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]4)=[CH:4][CH:3]=2)[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3C4CCC3CN(C(=O)OC(C)(C)C)C4)cn2)c1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 152b (1.3 g, 4.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.2 g, 4.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (394 mg, 0.43 mmol), XantPhos (497 mg, 0.86 mmol), Cs2CO3 (2.8 g, 8.6 mmol), and 1,4-dioxane (15 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 120° C. for 2 h. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 152c as a yellow solid (900 mg, 43%). MS-ESI: [M+H]+ 490.3.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:25]1([C@@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:33][C@H:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:32])[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: C[C@H](N)c1ccccc1
Agent: Cl
Product: Cc1nc(N[C@@H](C)c2ccccc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(1S)-1-phenylethyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.87 (m, 16H), 2.13 (s, 3H), 3.80 (s, 1H), 4.95-5.02 (m, 1H), 6.73 (s, 1H), 7.14-7.41 (m, 5H), 8.38 (s, 1H); MS (ESI) m/z 325.8 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([O-])(=[O:12])=[O:11].[Na+].P(Cl)(Cl)([Cl:19])=O>CCOCC>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([Cl:19])(=[O:12])=[O:11]
Reactant: Cc1cccc(C(F)(F)F)c1S(=O)(=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C(F)(F)F)c1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 290 g of sodium 2-trifluoromethyl-6-methylbenzenesulfonate and 500 mL of phosphorous oxychloride was heated to reflux for 5 hours. The mixture was then cooled to 0° C. and poured into a large flask containing 2000 g of ice and 2 L of ether. After stirring for 30 minutes, the phases were separated and the organic phase washed with cold water, cold saturated aqueous sodium carbonate, and then brine. The solvent was removed in vacuo to yield 2-trifluoromethyl-6-methylbenzenesulfonyl chloride as a brown oil.
Reaction SMILES: C([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])=[CH:13][C:8]=2[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[C:38]#[N:39])=[CH:27][CH:26]=2)[CH2:6]1)CCC.[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>>[CH2:13]([C:6]1[N:7]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[C:38]3[NH:39][N:42]=[N:41][N:40]=3)=[CH:29][CH:30]=2)[C:8]2[CH:13]=[C:12]([NH:14][C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])[CH:11]=[CH:10][C:9]=2[N:5]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN1CN(Cc2ccc(-c3cc(Cl)ccc3C#N)cc2)c2cc(NC(=O)NC3CCCCC3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCCc1nc2ccc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2cc(Cl)ccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 59 from 4'-[(3-n-butyl-6-(N-cyclohexylaminocarbonylamino)-benzimidazol-1-yl)-methyl]-5-chloro-2-cyano-biphenyl and sodium azide/ammonium chloride.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([O:10]C)=[C:5]([CH3:12])[C:4]=1[CH3:13])[CH3:2].Br>O>[CH2:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([OH:10])=[C:5]([CH3:12])[C:4]=1[CH3:13])[CH3:2]
Reactant: CCc1c(C)cc(OC)c(C)c1C
Agent: Br
Solvent: O
Product: CCc1c(C)cc(O)c(C)c1C
Yield: 50.1 %

Procedure:
To 4-ethyl-2,3,5-trimethylanisole (7.8 g) was added 47% aqueous hydrogen bromide solution and the mixture was refluxed for 17 hours. Water was added to the solution and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate, water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane to obtain 4-ethyl-2,3,5-trimethylphenol (3.6 g) (Compound A-17). The physical properties and NMR spectrum data thereof are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH2:21]([NH:23][CH2:24][CH:25]1[CH:29]([CH3:30])[CH2:28][NH:27][CH2:26]1)[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[C:3]([N:27]2[CH2:28][CH:29]([CH3:30])[CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CCNCC1CNCC1C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-ethylaminomethyl-4-methylpyrrolidine (0.36 g) and DBU (0.25 g) was refluxed for 2 hours and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.56 g) as pale yellow powder, mp 254°-257° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>ClCCl.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>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH:12]([OH:15])[C:13]#[CH:14])[CH:7]=[CH:8][N:9]=1
Reactant: C#CCO
Reactant: Brc1cccc2ccncc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(O)c1cccc2ccncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an inert atmosphere. 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of 8-bromoisoquinoline, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of -(8-isoquinolinyl)-2-propyne-1-ol, mp 138°-139° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:9]1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(CCc2ccccc2OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OCC2CCCNC2)c1
Reaction time: 3 h
Yield: 76 %

Procedure:
240 mg of 1-t-butoxycarbonyl-3-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}piperidine [prepared as described in step (a) above] were dissolved in 4 ml of a 4N solution of hydrogen chloride in dioxane. The solution was allowed to stand at room temperature for 3 hours, after which it was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration, to give 183 mg (yield 76%) of the title compound as colorless crystals, melting at 155°-157° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:25])=[N:4][CH:3]=1>[Pd].CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:25])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(/C=C/c3nc(N4CCCCC4)nn3C)nc12
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(N4CCCCC4)nn3C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.2 %

Procedure:
A mixture of (E)-5,8-dimethyl-2-(2-(1-methyl-3-(piperidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrazine (52 mg, 154 μmol, Eq: 1.00) and palladium on carbon 10% (16.4 mg, 15.4 μmol, Eq: 0.1) in methanol (20 ml) was stirred for 24 hours at 25° C. under a hydrogen atmosphere. The catalyst was filtered off, the filtrate was evaporated affording 5,8-dimethyl-2-[2-(2-methyl-5-piperidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine (30 mg, 57.4%) as a yellow oil. MS: m/z=341.5 (M+H+)
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Cl)nc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-chloropyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-chloropyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[NH2:33][C:34]1[NH:39][C:38]2=[N:40][CH:41]=[C:42]([CH3:43])[C:37]2=[C:36]([Cl:44])[N:35]=1.C(#N)C>C(Cl)Cl>[NH2:33][C:34]1[N:35]=[C:36]([Cl:44])[C:37]2[C:42]([CH3:43])=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:38]=2[N:39]=1
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: Cc1cnc2[nH]c(N)nc(Cl)c1-2
Agent: Br
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2nc(N)nc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product from Step C of Example 62 (1.57 g, 3.16 mmol) in CH2Cl2 (50 mL) was added HBr (5.7 M in acetic acid; 3.3 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×20 mL). The resulting oil was dissolved in MeCN (20 mL) and added dropwise to a solution of the sodium salt of 2-amino-4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine in acetonitrile [generated in situ from 2-amino-4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see Liebigs Ann. Chem. 1984: 708–721] (1.13 g, 6.2 mmol) in anhydrous acetonitrile (150 mL), and NaH (60% in mineral oil, 248 mg, 6.2 mmol), after 2 h of vigorous stirring at rt]. The combined mixture was stirred at rt for 24 h and then evaporated to dryness. The residue was suspended in water (100 mL) and extracted with EtOAc (300+150 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (5×7 cm) using ethyl acetate/hexane (0 to 30% EtOAc in 5% step gradient) as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.96 g) as a colorless foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)=[O:1]
Reactant: CC(=O)NC1CCN(c2ccc(CO)cc2)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)NC1CCN(c2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 74.3 %

Procedure:
A mixture of N-(1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)acetamide (0.380 g, 1.53 mmol), TPAP (0.026 g, 0.08 mmol), NMO (0.268 g, 2.30 mmol), and molecular sieves (3 Angstrom, 0.300 g) in CH2Cl2 was stirred at room temperature for 19 hours. The mixture was filtered through Celite, concentrated, and purified by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% MeOH/ethyl acetate, to afford N-(1-(4-formylphenyl)piperidin-4-yl)acetamide as a white solid (0.280 g, 74%).
Reaction SMILES: C1(NC(C2C3C=C(C4C(F)=CN=C(NCCCC5CCNCC5)N=4)SC=3C=CC=2)=O)CC1.[ClH:33].Cl.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55](F)=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][CH:61]5[CH2:66][CH2:65][N:64]([CH3:67])[CH2:63][CH2:62]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])CC1.CNC(C1C2C=C(C3C([Cl:87])=CN=C(Cl)N=3)SC=2C=CC=1)=O>>[ClH:87].[ClH:33].[CH3:35][NH:38][C:39]([C:41]1[C:49]2[CH:48]=[C:47]([C:50]3[C:55]([Cl:87])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][CH:61]4[CH2:66][CH2:65][N:64]([CH3:67])[CH2:63][CH2:62]4)[N:51]=3)[S:46][C:45]=2[CH:44]=[CH:43][CH:42]=1)=[O:40]
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CN1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: Cl
Agent: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3F)cc12
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCN(C)CC4)ncc3Cl)cc12

Procedure:
Using the methods of 2-[5-fluoro-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 2-{5-fluoro-2-[3-(1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 458 (35Cl) and 460 (37Cl) [M(free base)+H].
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:3]=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:5][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:1])[CH2:3][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C=O)s1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CN2CCCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (22 mg), pyrrolidine (0.02 ml), acetic acid (0.01 ml) in methylene chloride (1 ml) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (28 mg) was added. The mixture was stirred at room temperature for at least two days. The mixture was quenched with diluted NaOH and extracted with methylene chloride. The organic layer was separated, concentrated to dryness and the residue was purified by silica gel column chromatography using 35% to 65% ethyl acetate in hexane as eluent to give the title compound. The title compound was prepared as the corresponding HCl salt by adding HCl/doxane, followed by concentration to give a solid. LC_MS retention time 2.0 min M+1=480.0.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.OS(O)(=O)=O.[OH-].[Na+]>OCC(CO)O>[F:9][C:8]1[C:2]([F:1])=[C:3]2[C:5]([CH:19]=[CH:14][CH:15]=[N:4]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Nc1cccc(F)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: Fc1ccc2cccnc2c1F
Temperature: 135 °C

Procedure:
To a mixture of 2,3-difluoroaniline (commercially available, 3.57 g), glycerol (5.55 g) and m-nitrobenzene sulfonic acid sodium salt (10.12 g) was added dropwise 70% H2SO4 (20 mL). The reaction was heated at 135° C. for 3.5 hours and then cooled to room temperature. It was poured over ice, made basic with 50% aqueous NaOH and extracted with Et2O. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated on a rotary evaporator to give 4.13 g of the desired product as a light brown solid; MS (ES) m/z (relative intensity); 166 (M+H)+ (100).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:23]=C)=[N:8]1.[O:27]1CCOCC1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[N:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:12]([C:9]3[N:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:25])[CH3:1])[N:8]=3)=[C:13]([CH:23]=[O:27])[N:14]=2)=[CH:18][CH:19]=1
Reactant: C=Cc1nc(-c2ccncc2)sc1-c1ncn(COCC[Si](C)(C)C)n1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1cccc(C)n1
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)nc2C=O)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of 4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-4-vinyl-1,3-thiazol-2-yl]pyridine (1.43 g, 2.60 mmol) in a 3:1 mixture of 1,4-dioxane (17.5 mL, 224.6 mmol) and water (5.8 mL, 324.25 mmol) was added 2,6-lutidine (1.50 mL, 12.98 mmol) and the mixture was cooled to 0° C. Sodium metaperiodate (2.80 g, 12.98 mmol) was added followed by the addition of 4% osmium tetroxide in water (0.50 mL, 0.080 mmol) and the reaction mixture was slowly warmed to ambient temperature and allowed to stir overnight. Water (10 mL) was added. The resulting yellow precipitate was collected by filtration, washed with water, ether and MeOH. The filtrate was concentrated under reduced pressure and dried on the high vac to give the title compound (1.0 g, yield 99%). LCMS: (FA) ES+, 388. 1H NMR (400 MHz, d6-DMSO) δ: 10.70 (s, 1H), δ:9.05 (s, 1H), 8.79-8.80 (dd, J=1.5 Hz, 2H), 7.98-8.0 (dd, J=1.5 Hz, J=1.7 Hz, 2H), 5.64-5.66 (s, br, 2H), 3.64-3.68 (m, 2H), 0.870-0.90 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH:23]([NH2:37])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Na].CC([O-])(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=2)[CH:23]([NH:37][C:2]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#Cc1ccc(Br)c2cccnc12
Reactant: CC(C)(C)OC(=O)N1CC(N)C(c2cccc(OC(F)(F)F)c2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(C#N)c3ncccc23)C(c2cccc(OC(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A reaction mixture of 5-Bromo-quinoline-8-carbonitrile (200.00 mg; 0.86 mmol; 1.00 eq), (3-amino-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.41 ml; 1.03 mmol; 1.20 eq.) (trans_racemic), sodium; 2-methyl-propan-2-olate (181.43 mg; 1.89 mmol; 2.20 eq.), and dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (122.73 mg; 0.26 mmol; 0.30 eq.) in toluene (5 ml) in microwave tube was degas, followed by adding Pd2(dba)3 (74.02 mg; 0.13 mmol; 0.15 eq.). The resulting mixture was stirred for 10 min at RT, placed in microwave at 100° C. for 20 min. The reaction mixture was concentrated and re-dissolved in DMSO, purified by prep HPLC (Basic condition, 70-75% acetonitrile in water) to give 3-(8-cyano-quinolin-5-ylamino)-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (trans_racemic) (150 mg, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:18]([CH3:20])[CH3:19].[Br:24]Br.N.CO>O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([Br:24])[N:12]2[CH:18]([CH3:20])[CH3:19]
Reactant: COc1cccc(CNc2nc(Cl)nc3c2ncn3C(C)C)c1
Reactant: BrBr
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc(CNc2nc(Cl)nc3c2nc(Br)n3C(C)C)c1
Yield: 88 %

Procedure:
1 mmol of 6-(3-methoxybenzylamino)-2-chloro-9-isopropylpurine was brominated with 1.1 mmol of bromine as described in Example 1. The crude 2,8-dihalogeno derivative prepared was alkalinized with NH3/MeOH and extacted between water-EtOAc. The product crystallizes after partial evaporation of ethylacetate. M.p.123-125° C., yield 88%. MS-ESI(+)m/z 409.5, 411.4, 413.3 [M+H]+