Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O-:10])=O)=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([NH:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[C:2]2=[N:3][C:4]([S:11][CH3:12])=[N:5][CH:6]=[C:7]2[C:8](=[O:10])[NH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNCc1ccccc1
Reactant: CSc1ncc(C(=O)[O-])c(Cl)n1
Product: CSc1ncc2c(=O)[nH]n(Cc3ccccc3)c2n1

Procedure:
Prepared as described above in Example 1 starting with 4-chloro-2-methylthio-5-pyrimidinecarboxylate and benzylhydrazine to give the intermediate pure 1-benzyl-6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one. The synthesis then follows as in Examples 2 and 3 to give 1-benzyl-3-bromo-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. To a solution of 1-benzyl-3-bromo-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (334 mg, 1 mmol) in chloroform (15 mL) was added 3-chloroperoxybenzoic acid (549 mg, 3 mmol, 3 eq) and the reaction mixture was allowed to stir for 5 hours at room temperature. To the reaction mixture were then added 10 mL of 1 M Na2CO3 solution and the layers were separated. The organic layer was washed with water, dried over MgSO4 and evaporated to give 1-benzyl-3-bromo-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-one (291 mg, 78% yield); LC/MS (m/e)=369.0 (MH+), Rt=1.95 min.
Reaction SMILES: Br[CH:2]1[CH2:28][C@@:27]2([CH3:29])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:26]2[CH2:25][C:24](=[O:30])[C@@:23]2([CH3:31])[C:9]3=[CH:10][C@@H:11]3[O:16][C@@:15]4([O:22][CH2:21][C@H:19]([CH3:20])[CH2:18][CH2:17]4)[C@@H:13]([CH3:14])[C@@H:12]32)[CH2:4][C:3]1=[O:32].[N-:33]=[N+]=[N-].[Na+].[I-].[Na+].O>CN(C)C=O>[NH:33]=[C:2]1[CH2:28][C@@:27]2([CH3:29])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:26]2[CH2:25][C:24](=[O:30])[C@@:23]2([CH3:31])[C:9]3=[CH:10][C@@H:11]3[O:16][C@@:15]4([O:22][CH2:21][C@H:19]([CH3:20])[CH2:18][CH2:17]4)[C@@H:13]([CH3:14])[C@@H:12]32)[CH2:4][C:3]1=[O:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C=C3[C@@H]4CC[C@H]5CC(=O)C(Br)C[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C=C3[C@@H]4CC[C@H]5CC(=O)C(=N)C[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
500 mg (0.99 mmol) of 2-bromo-(25R)-5α-spirost-14-ene-3,12-dione (II) is dissolved in 50 ml of dimethylformamide. After adding 700 mg of sodium azide and a few milligrams of sodium iodide, the solution is stirred for 2 hours at 50° C. The reaction mixture is brought to room temperature, poured into 20 ml of water and extracted with methyl-tert-butyl ether. This extract is washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. After crystallization, 407 mg (80%) of iminoketone III is obtained.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1.Cl>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[C@@H:15]([CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=1)[CH2:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -68 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a 3-necked 5 L RBF is added THF (2 L) and (4S)-4-benzyl-3-butanoyl-oxazolidin-2-one (270 g 1.09 moles) under N2. The resulting solution is cooled to −68° C. in an acetone-dry ice bath. To the cold solution is added sodium bis(trimethylsilyl)amide (1320 mL of 1M THF solution; 1.32 moles) dropwise over 1.5 h while the internal temperature is held between −68 to −60° C. Upon completion of the addition, the reaction is stirred at −68° C. for 30 min. To the cold solution is then added 4-trifluoromethylbenzyl bromide (278 g; 1.16 moles) in THF (1 L) over 30 min at −68° C. After 1.5 h, the reaction is poured into 1 M HCl. The mixture is extracted with ethyl acetate (3 L×1). The extracts are combined and washed with aq. NaHCO3 (2 L×1) and brine (2 L×1). The organic phase is dried over Na2SO4, filtered, and concentrated. The solid is triturated with EtOH (600 mL) at 15° C. Filtration provides the title compound as a solid (270 g, MS:[M+H]+=406 m/z).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][NH:30][CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N>[CH3:28][O:29][N:30]([CH3:31])[C:16](=[O:18])[C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CON(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
To a 1-liter round bottom flask were added (R)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanoic acid (10 g, 27 mmol), N-methoxy-N-methylamine-HCl (5.3 g, 55 mmol), PyBOP (21 g, 41 mmol), and MeCN (400 mL). DIEA (19 mL, 110 mmol) was added and the reaction was allowed to stir at room temperature for 12 hours. The solvent was removed under reduced pressure and the residue was suspended in EtOAc and washed with 1N NaOH (aq) (×3) then 2N HCl (aq) (×2), then saturated NaHCO3 (aq) (×1), then brine (×1). The product was then purified by column chromatography (EtOAc/hexanes) to give N-methoxy-N-methyl-(R)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanamide (305) (10.9 g, 26.7 mmol, 99% yield) as a clear oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[C:20]([CH3:21])=[C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=2)[CH:12]=1)=O>C1COCC1>[CH2:23]([O:22][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=2)[CH:12]=[C:11]([CH2:9][OH:8])[C:20]=1[CH3:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CO)cc2ccc(F)cc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a suspension of LiAlH4 (8.8 g, 235 mmol) in dry THF (120 mL) was added a solution of 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (25.4 g, 78.3 mmol) in THF (180 mL) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was cooled to 0° C. and quenched carefully by addition of cold water (10 mL) followed by 15% NaOH solution (10 mL) and additional water. The resulting solution was stirred for one hour, then filtered through a sintered glass funnel. The filter pad was washed with THF (50 mL). The combined filtrates were dried over Na2SO4, filtered, and concentrated to afford (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-methanol (21.5 g, 92%, crude) as a white solid. The crude product was used in the next step without further purification. MS calcd. for C19H16FO2 [(M−H)−] 295, obsd. 294.9.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:21]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])(=[O:13])=[O:12])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Reactant: C1CNCCN1
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(N3CCNCC3)cccc21

Procedure:
The title compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and piperazine according to Method 1 to give 25 mg (12%) of a white solid: 1HNMR (CD3OD) δ 7.91–6.79 (m, 9H), 3.49–3.30 (m, 8H), 2.48 (s, 3H); MS (ESI) 356.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:4]([C:19](O)=[O:20])=[C:3]1[CH3:22].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[F:33])[NH:29][N:28]=[CH:27]2>>[F:33][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[N:28][NH:29]2)=[CH:25][C:24]=1[NH:23][C:19]([C:4]1[CH:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=2)[CH2:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]=1[CH3:22])=[O:20]
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1C
Reactant: Nc1cc2cn[nH]c2cc1F
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1C

Procedure:
The title compound was prepared from the product of Example 41, Step 2 and 5-amino-6-fluoroindazole using the method described in Example 56, Step 3. MS (ES+) m/e 447 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.[NH:16]1[CH2:19][CH:18]([C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[N:21]=2)[CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[N:5]=[C:4]([CH3:15])[N:3]=[C:2]([N:16]3[CH2:19][CH:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)[CH2:17]3)[CH:7]=2)[N:9]=1
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Reactant: Cn1c(C2CNC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CC(c3nc4ccccc4n3C)C2)cc(-n2nc(C)nc2C)n1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
Intermediate 2 (0.15 g, 0.67 mmol), Intermediate 1 (0.13 g, 0.67 mmol), and Cs2CO3 (0.66 g, 2.01 mmol) were suspended in DMF (6.7 mL) in a microwave vial. The vial was then capped and heated in the microwave at 100° C. for 30 min. After cooling to room temperature, the reaction was filtered and the filtrate was purified by reverse phase chromatography (acetonitrile/water/0.1% TFA). The fractions containing the product were partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated to provide Example 1 (0.17 g, 78%) as a white solid. 1H NMR: (500 MHz, CD3OD) δ 7.63 (d, J=8 Hz, 1H), 7.5 (d, J=8 Hz, 1H), 7.28 (m, 2H), 6.66 (s, 1H), 4.66 (m, 2H), 4.53 (m, 3H), 3.83 (s, 3H), 2.84 (s, 3H), 2.51 (s, 3H), 2.36 (s, 3H). MS: m/z=375.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=2[CH2:17][CH2:16][C:15]2[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:14]1=2>>[F:24][C:23]1[C:18]2[CH2:17][CH2:16][C:15]3[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:14]=3[C:13](=[CH:12][C:4]3[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=3)[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Fc1cccc2c1CCc1c(F)cccc1C2=CBr
Product: Oc1cccc(C=C2c3cccc(F)c3CCc3c(F)cccc32)c1
Yield: 113.1 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-hydroxyphenyl boronic acid (380 mg, 2.75 mmol) and 5-bromomethylene-1,9-difluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (803 mg, 2.75 mmol), provides to 1.04 g of the title compound as crude product. The crude product is purified using column chromatography eluting with 15% EtOAc/hexane to 30% EtOAc/hexane to give 500 mg (60%) product as a light yellow foam, mp 129.5° C. MS (ES) 333 (M−1). HPLC (ISO90-10M) shows 98% at t=2.90 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CS[C:21]1[NH:26][C:25](=[O:27])[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:23][N:22]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:21]1[NH:26][C:25](=[O:27])[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:23][N:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCN(Cc1ccccc1)c1ccccn1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Product: O=c1[nH]c(NCCCN(Cc2ccccc2)c2ccccn2)ncc1Cc1ccc(Cl)cc1

Procedure:
2-[N-(3-aminopropyl)-N-benzylamino]pyridine (1.45 g) and 2-methylthio-5-(4-chlorobenzyl)pyrimid-4-one (1.33 g) were fused together on an oil bath at 160° C. for 3 hr. On cooling, the residue was crystallised from ethanol and then chromatographed (silica gel, chloroform). Fractions containing the required product were stripped and the residue recrystallised from ethanol to give 2-[3-(N-benzyl-N-pyrid-2-ylamino) propylamino]-5-(4-chlorobenzyl)pyrimid-4-one 0.25H2O, 0.9 g (39%) mp 80°-86° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:24]1[C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=[CH:22][CH:23]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2c(Cl)cccc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2c(Cl)cccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
To a solution of [(S)-1-(4-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (1.40 g, 3.76 mmol) in DCM (20 mL) was added TFA (20 mL) and the resulting mixture was stirred at RT for 20 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous layer was further extracted with DCM and the combined organic layers were then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) affording (S)-1-(4-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a white solid (680 mg, 67%). LCMS: RT 2.23 min [M+H]+ 272.1
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]=[O:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.[CH3:44][O:45][CH2:46][CH2:47][NH2:48]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([C:31]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:32])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COCCN
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COCCNC(=O)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N)n2)c1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 151 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinecarbaldehyde and 2-methoxyethylamine (Sigma-Aldrich, St. Louis, Mo.), and the desired product 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(2-methoxyethyl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinecarboxamide was isolated as a yellow solid (8% for two steps). 1H NMR (400 MHz, CDCl3) δ 12.08 (s, 1H); 9.19 (d, J=2.54 Hz, 1H); 8.78 (d, J=2.54 Hz, 1H); 8.35 (d, J=2.54 Hz, 1H); 8.12 (dd, J=8.80, 2.74 Hz, 1H); 6.79 (d, J=8.80 Hz, 1H); 6.72-6.76 (m, 1H); 3.95 (s, 3H); 3.66-3.72 (m, 2H); 3.63 (q, J=4.56 Hz, 2H); 3.38 (s, 3H); 2.55 (s, 3H). m/z (ESI, +ve ion) 411.0 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[N:5]([CH:18]=[N:19][CH:20]=2)[C:6]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[N:5]3[CH:18]=[N:19][CH:20]=[C:4]3[C:3]([Cl:2])=[CH:8][C:7]=2[C:9](=[O:11])[CH3:10])[CH2:13][CH2:14]1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(C)=O)CC1
Reaction time: 0.08 h
Yield: 77 %

Procedure:
1-(8-Chloro-5-piperazin-1-ylimidazo[1,5-a]pyridin-6-yl)ethanone hydrochloride was dissolved in methylene chloride (1.0 mL) and N,N-diisopropylethylamine (45 μL, 0.26 mmol) was added. To the reaction mixture, acetyl chloride (5.5 μL, 0.077 mmol) was added and the mixture was stirred for 5 minutes. Evaporation and purification by preparative LCMS (pH 10) gave the desired compound (13 mg, 77%). LCMS calculated for C15H18ClN4O2 (M+H)+: m/z=321.1. found: 320.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1C(O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC1C(OC(=O)C)=C(I=O)C=CC=1)(=[O:21])C.II.CO>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[O:21][CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1cccc(I=O)c1OC(C)=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: II
Solvent: CO
Solvent: ClCCl
Product: COC1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a mixture of (S)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (purchased at Fluka, Ref 97090, 6 g, 1.0 eq.) in dichloromethane (300 mL) was added diacetoxyiodosobenzene (15.8 g, 2 eq.) and iodine (3.0 eq., 0.5 eq.). The mixture was stirred 5 h at room temperature. Methanol (12 mL) was added and the reaction mixture was stirred for an additional 1.5 h at room temperature, partitioned between an aqueous solution of sodium sulfite and dichloromethane. The organic layer was washed with an aqueous solution of sodium sulfite, brine, evaporated in vacuo and purified on silica eluting with 9:1 cyclohexane/ethyl acetate to yield 5.0 g (88%) of the desired product as light yellow oil. MS (m/e): 235.5 (MH+, 100%)
Reaction SMILES: C([O-])(=O)C.[Na+].O.Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[NH:28][NH2:29]>C(OCC)C>[Cl:23][C:21]1[C:20]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:19][C:18]([NH:28][N:29]=[CH:8][C:9](=[O:10])[C:11]([F:14])([F:13])[F:12])=[C:17]([F:16])[CH:22]=1
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixed solution of 5.3 g (53.5 mmol) of sodium acetate and about 100 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the reaction was allowed to proceed at 70° C. for 20 minutes. Then, the reaction mixture was cooled to room temperature, to which a solution of 5.8 g (21.5 mmol) of 2-fluoro-4-chloro-5-isopropoxyphenylhydrazine dissolved in about 20 ml of diethyl ether was added, and the reaction mixture was stirred at room temperature for 1 hour. The ether layer was separated, washed once with 10 ml of saturated sodium chloride solution, and dried with magnesium sulfate. The diethyl ether was distilled out, which afforded 6.5 g (20.0 mmol) of 3,3,3-trifluoro-2-oxo-propanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][Si:2]([CH3:12])([CH3:1])[CH3:13])=[O:18]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: C[Si](C)(C)CCc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CCc1ccccc1NC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
425 mg of 2-(2-trimethylsilylethyl)phenylamine (2.2 mmol) and 438 mg (2.0 mmol) of 2-bromo-benzoyl chloride were dissolved in 20 ml of acetonitrile, and 332 mg (2.4 mmol) of potassium carbonate were added. The reaction mixture was stirred at room temperature for 18 h, 20 ml of water were then added, the mixture was extracted with ethyl acetate and the extract was dried over sodium sulphate. Removal of the solvent and column-chromatographic purification on silica gel 60 (mobile phase: methylene chloride) gave 405 mg (54% of theory) of 2-bromo-N-[2-(2-trimethylsilyl-ethyl)phenyl]benzamide [log P (pH 2.3)=4.32].
Reaction SMILES: [Na+].[P:2]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[C@H:14]([OH:27])[C@@H:13]1[OH:28])([O:5][P:6]([O-:9])([O-:8])=[O:7])(=[O:4])[O-:3].[Na+].[Na+].N1C=CC=CC=1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>ClCCl>[P:2]([O:10][CH2:11][C@H:12]1[O:16][C@@:15]([Si:38]([CH3:40])([CH3:39])[CH3:37])([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[C@H:14]([OH:27])[C@@H:13]1[OH:28])([O:5][P:6]([OH:8])([OH:9])=[O:7])(=[O:3])[OH:4]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)([O-])OP(=O)([O-])[O-])[C@@H](O)[C@H]1O
Reactant: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)[C@@]1(n2cnc3c(N)ncnc32)O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a 500 mL round-bottomed flask was added 3 g (21.7 mmol) adenosine-5′-diphosphate sodium salt and 200 mL pyridine. After the salt had dissolved. the solution was cooled to 0° C. under nitrogen atmosphere. Trimethylsilyl chloride (85 g, 800 mmol) in 200 mL dichloromethane was added slowly to the solution. After this addition was complete, the reaction was stirred at 35° C. for 8 hr. The pyridine hydrochloride salt was removed by filtration and excess pyridine and dichloromethane removed under high vacuum for 24 hr to yield 19.3 g (21.3 mmol) of TMS-ADP. The product was used without further purification. This synthesis is illustrated in FIG. 4E.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NS(C)(=O)=O)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 36 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 23 mg (0.2 mmol) methyl sulfonyl chloride. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 45 mg (50%) N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-methanesulfonamide as a light yellow solid. MS ISP (m/e): 450.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.40 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.54 (d, 1H), 7.24 (d, 1H), 7.06 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 4.36 (q, 1H), 3.84 (s, 3H), 2.14 (s, 3H), 1.65 (m, 3H), 0.89 (m, 6H).