Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[C:20]([C:21]4[CH:26]=[C:25]([S:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=4)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1.CO>C(Cl)Cl.CN(C=O)C.C([O-])(O)=O.[Na+].C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[C:20]([C:21]4[CH:26]=[C:25]([S:27]([CH3:28])=[O:38])[N:24]=[C:23]([CH3:29])[N:22]=4)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CSc1cc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)nc(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)cc(S(C)=O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
A 50 mL round-bottomed flask was charged with N-(1H-indazol-4-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)quinoxalin-2-amine (150 mg, 0.375 mmol) in DCM-DMF(5:1, 6 mL). mCPBA (130 mg, 0.751 mmol, Aldrich) was added to this solution at 0° C., the mixture was stirred at 0° C. for 2 h, then warmed to room temperature and diluted with saturated NaHCO3. The aqueous layer was extracted with DCM (3×), and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2M NH3.MeOH in DCM to give N-(1H-indazol-4-yl)-3-(2-methyl-6-(methylsulfinyl)pyrimidin-4-yl)quinoxalin-2-amine (36 mg, 0.087 mmol, 23% yield) as an orange solid. m/z (ESI, +ve ion) 416 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[CH3:11]O>>[CH3:11][O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(O)cc1
Reactant: CO
Product: COCCc1ccc(O)cc1
Temperature: 150 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A mixture of 80 grams of 4-hydroxyphenethyl alcohol (0.58 moles), methanol (100 ml), and 10 grams of Dowex 50 catalyst (H30 form, washed with methanol) was charged into a 300 cc autoclave. The autoclave was sealed, purged with nitrogen and then pressurized under nitrogen. The autoclave was heated to 150° C. overnight with stirring (about 16 hours). The reactor was then cooled, depressurized, and purged with nitrogen to remove by-product dimethyl ether. The catalyst was filtered off and a few drops of saturated aqueous sodium bicarbonate solution were added to neutralize acidity. The solvent was removed on a rotary evaporator. The product was isolated in 65% yield by distillation, with 33% of the 4-hydroxyphenethyl alcohol remaining unreacted.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)=[O:4].ClCC(C1C=CC(Br)=C(F)C=1)=O.[BH4-].[Na+].C[O-].[Na+]>C(O)C.O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][C:7]=1[F:12]
Reactant: O=C(CBr)c1ccc(Br)c(F)c1
Agent: C[O-]
Agent: O=C(CCl)c1ccc(Br)c(F)c1
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: Fc1cc(C2CO2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the mixture of 2-bromo-1-(4-bromo-3-fluoro-phenyl)-ethanone and 2-chloro-1-(4-bromo-3-fluoro-phenyl)-ethanone (6.16 g) in ethanol (100 ml) at 5° C. was added portionwise over 5 min NaBH4 (788 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (562 mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remaining and so the reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(4-bromo-3-fluoro-phenyl)-oxirane (4.69 g) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].[CH3:14]N(C)C=O>>[O:1]=[C:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CN(C)C=O
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Yield: 32 %

Procedure:
Example 9 was repeated except that 6 ml of N,N-dimethylformamide was used instead of t-butyl alcohol as the solvent. A mixture of 2-oxo-3-phenylbutanoic acid (39 %) and 2-oxo-3-methyl-3-phenylbutanoic acid (32 %) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=[CH2:13].C1(C(N)C2CCCCC2)CCCCC1>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].C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>[CH3:17][O:16][C:11](=[O:15])/[C:12](/[CH3:14])=[CH:13]/[C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: C=C(C)C(=O)OC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C/c1ccc(N(C)C)cc1
Yield: 86.7 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 1.000 g (5 mmol) of 4-dimethylaminobromobenzene, 1.001 g (10 mmol) of methyl methacrylate, 0.011 g (0.012 mmol) of tris (dibenzylideneacetone)dipalladium (0), 1.074 g (5.5mmol) of dicyclohexylmethylamine and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.026 g (0.05 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 25 hours. After the completion of the reaction, 5 ml of toluene and 10 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.951 g of (E)-3-(4-dimethylaminophenyl)-2-methylacrylic acid methyl ester (yield: 87 mol % based on 4-dimethylaminobromobenzene). The identification of the product was made by 1H-NMR and 13C-NMR.
Reaction SMILES: [C:1](=[O:15])([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:2][CH:3](Cl)[CH3:4].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:15])([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:2][CH:3]([O:21][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])[CH3:4]
Reactant: C=C(C)C(=O)[O-]
Reactant: C=C(C)C(=O)OCCOC(=O)OC(C)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOC(=O)OC(C)OC(=O)C(=C)C
Yield: 76.8 %

Procedure:
1-Chloroethyl 2-methacryloyloxyethyl carbonate (1.183 g, 5.00 mmol) prepared as described in Preparation 8 is added to a suspension of freeze dried potassium methacrylate (0.683 g, 5.50 mmol) and 18-crown-6 (0.066 g, 0.25. mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.10 g (77%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.63 (3 H, d, J=5 Hz, CH3 --CH), 1.98 (6 H, s, 2×CH3), 4.42 (4 H, s, O--CH2 --CH2 --O), 5.62 (2 H, m, CH=), 6.15 (2 H, m, CH=), 6.84 (1 H, k, J=5 Hz, CH--CH3).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19]([S:22][CH3:23])=[N:20]2)=[CH:15][CH:14]=1)[S:3]([CH3:6])(=[O:5])=[O:4].CO.[Br:26]N1C(=O)CCC1=O>>[Br:26][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])[N:21]2[C:16]=1[CH:17]=[N:18][C:19]([S:22][CH3:23])=[N:20]2
Reactant: CSc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: CSc1ncc2c(Br)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1-Neck round-bottom flask, N-Methyl-N-[2-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (0.710 g, 2.04 mmol) Tetrahydrofuran (20.0 mL, 246 mmol), and Methanol (10 mL, 200 mmol) were added under an atmosphere of Nitrogen at room temperature . Recrystallized N-Bromosuccinimide (0.381 g, 2.14 mmol) was added portion wise over 10 minutes. The reaction was stirred at room temperature for 2 hours. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 5% methanol). The collected fractions afforded N-[2-(5-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide a yellow solid (0.72 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13]1>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13]2)=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nn1cnc2ccccc2c1=O
Solvent: ClCCCl
Product: O=c1c2ccccc2ncn1NC(=S)Nc1ccc(Br)cc1

Procedure:
4-Bromophenyl isothiocyanate (2.51 g, 11.72 mmol) is added to a mixture of 3-amino-4(3H)quinazolinone (1.72 g, 10.66 mmol) in 1,2-dichloroethane at reflux under a nitrogen atmosphere. The reaction mixture is heated at reflux for 2 days, cooled, washed with ether and filtered. The filter cake is dried to give the title product as a white solid, 2.44 g, mp 189°-190° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:34]=[CH:33][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:30]([CH3:32])[CH3:31])[N:26]=[C:27]([CH3:29])[N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O.C(OCC)(=O)C>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([C:12]2[CH:34]=[CH:33][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:30]([CH3:32])[CH3:31])[N:26]=[C:27]([CH3:29])[N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(C(=O)OC(C)(C)C)C4)ccc2-3)n(C(C)C)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester (4.11 g, 0.01234 mol) in methylene chloride (42 mL) was added trifluoroacetic acid (20 mL) dropwise. The reaction was stirred at room temperature for 1 hour. Water and ethyl acetate were added and the mixture was extracted with 1N HCl. The aqueous phase was basified to pH 13 with 1N NaOH. The aqueous phase was filtered and rinsed with cold water to afford 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as an off-white solid (3.2 g). MS(ESI+) 382.2
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[CH2:29]([O:36][C:37]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[O:50][CH3:51])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([O:36][C:37]1[C:45]([C:46]([F:47])([F:48])[F:49])=[CH:44][C:40]([C:41]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:42])=[CH:39][C:38]=1[O:50][CH3:51])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1cc(C(=O)Cl)cc(C(F)(F)F)c1OCc1ccccc1
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CSc3ccccc32)cc(C(F)(F)F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and diisopropylethylamine (0.63 mL) and 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl chloride (657 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (578 mg) as a yellow oily substance.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:17][CH:18]=2)=[CH:27][CH:26]=1)([CH3:30])([CH3:31])[CH3:29]
Reactant: COC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1

Procedure:
To a solution of racemic 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (300 mg, 1.35 mmol) in toluene (14 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 512 mg, 2.03 mmol) at 0° C., followed by the addition of tributylphosphine (0.5 mL, 2.03 mmol) and 4′-tert butyl-biphenyl-4-ol (367 mg, 1.62 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid methyl ester. The ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1 mL), extract with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (400 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[N:26]=[C:25]([NH:27][C@@H:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]3)[N:24]=[C:23]([CH3:37])[N:22]=2)[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C@@H:28]1([NH:27][C:25]2[N:24]=[C:23]([CH3:37])[N:22]=[C:21]([NH:20][C@H:12]3[C@@H:13]4[O:17][C:16]([CH3:19])([CH3:18])[O:15][C@@H:14]4[C@@H:10]([CH2:9][OH:8])[CH2:11]3)[N:26]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: Cc1nc(N[C@H]2CCc3ccccc32)nc(N[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H]3OC(C)(C)O[C@H]32)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(N[C@H]2CCc3ccccc32)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)n1
Reaction time: 0.5 h
Yield: 116 %

Procedure:
To a solution of N-[(3aS,4R,6S,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-N′-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-1,3,5-triazine-2,4-diamine (0.23 g, 0.00044 mol) in THF (1 mL) was added 1.00 M of TBAF in THF (1.31 mL). The reaction was stirred for 30 minutes. The solution was concentrated and the residue purified by flash chromatography (0 to 4% MeOH/EtOAc) to afford 210 mg (>99%) of the title compound. LC/MS: Rt=1.24 min, ES+ 412 (FA standard).
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:18](I)=[CH:17][N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.COB(OC)OC>O1CCOCC1.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]>[CH:1]1([C:7]2[N:11]3[C:12]4[C:18]([CH3:28])=[CH:17][N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c1ncc1ncc(C3CCCCC3)n12
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: COB(OC)OC
Solvent: C1COCCO1
Product: Cc1cn(COCC[Si](C)(C)C)c2ncc3ncc(C4CCCCC4)n3c12
Temperature: 85 °C
Yield: 41.4 %

Procedure:
To the solution of 8-cyclohexyl-1-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.100 g, 0.201 mmol, prepared using GGG with 8-cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine [WO2009152133A1], KK) in 1,4-dioxane (1 mL) was added cesium carbonate (0.131 g, 0.403 mmol), tricyclohexylphosphine (20 wt % solution in toluene, 0.045 g, 0.032 mmol), Pd2(dba)3 (0.018 g, 0.020 mmol) and trimethylborate (0.033 g, 0.262 mmol). The mixture was degassed and heated at about 85° C. for about 2 h. The catalyst was filtered off. The filtrate was concentrated and purified by RP-HPLC (Table 1, Method s) to give 8-cyclohexyl-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.032 g, 41%) as a clear oil: LC/MS (Table 1, Method b) Rt=3.41 min; MS m/z: 385 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][N:31]2[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:30][N:31]3[CH2:32][CH2:33][S:34](=[O:38])(=[O:37])[CH2:35][CH2:36]3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1CN1CCS(=O)(=O)CC1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1CN1CCS(=O)(=O)CC1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 4-[(6-chloro-2-methylpyridin-3-yl)methyl]thiomorpholine 1,1-dioxide (132 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C:6]([C:10]([OH:12])=O)=[C:7]([CH3:9])[N:8]=1)[CH3:2].C(NC1SC(C(Cl)=O)=C(C)N=1)C.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:32][CH:33]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:34]#[N:35]>C(N(CC)CC)C>[C:34]([CH:33]([NH:32][C:10]([C:6]1[S:5][C:4]([NH:3][CH2:1][CH3:2])=[N:8][C:7]=1[CH3:9])=[O:12])[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)#[N:35]
Reactant: N#CC(N)c1cccs1
Reactant: CCNc1nc(C)c(C(=O)O)s1
Agent: CCNc1nc(C)c(C(=O)Cl)s1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNc1nc(C)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 29.5 %

Procedure:
1.2g of 2-ethylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-ethylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.3g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.1g of amino-thiophen-2-yl-acetonitrile hydrochloride and 2.5ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.57g (Yield 32%) of the title compound.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])(=[O:4])=[O:3])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CS(=O)(=O)N1CCN(Cc2ccccc2)CC1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with magnetic stirring bar and N2 inlet was charged with 2.5 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate in 25 mL CH2Cl2. The solution was cooled to 0° C. and charged with 1.57 mL (1.0 eq.) 4-benzylpiperazine and 1.26 mL NEt3. The reaction was stirred for 1 hour then concentrated in vacuo and partitioned between ethyl acetate and saturated sodium bicarbonate. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to yield 3.4 g crude product. Flash chromatography (80:20 ethyl acetate/hexane) yielded 3.0 g pure product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([C:21]4[S:22][CH:23]=[CH:24][N:25]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>>[O:29]1[CH2:28][CH2:27][N:26]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([S:18]([C:21]5[S:22][CH:23]=[CH:24][N:25]=5)(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: O=S(=O)(c1nccs1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(S(=O)(=O)c5nccs5)CC4)cc3n2)cn1

Procedure:
2-Chloro-4-morpholin-4-yl-6-[4(thiazole-2-sulfonyl)-piperidin-1-ylmethyl]-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 310. NMR (CDCl3): 2.03-2.18 (4H, m), 2.18-2.22 (2H, m), 3.12-3.16 (2H, m), 3.39-3.46 (1H, m), 3.84 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 5.20 (2H, br), 7.26 (1H, s), 7.79 (1H, d, J=3.0), 8.11 (1H, d, J=3.0), 9.29 (2H, s). MS (ESI+): MH+ 559.13 (100%)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][C:19]=1[CH3:27].[B][B][B][B][B][B][B][B][B][B]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([CH3:27])[CH:20]=3)[CH3:25])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: CC(=O)c1ccc(Cl)c(C)c1
Reactant: COC(=O)C1CN(Cc2cccc(N)c2)C1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)C1CN(Cc2cccc(NC(C)c3ccc(Cl)c(C)c3)c2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of INT 3 (220 mg, 0.99 mmol) and 1-(4-chloro-3-methyl-phenyl)-ethanone (202 mg, 1.20 mmol) in MeOH (10 mL) was added decaborane (85 mg, 0.70 mmol). The mixture was stirred at 60° C. overnight. More decaborane (85 mg, 0.70 mmol) was added and the mixture was stirred at 60° C. for an additional 3 hours. The mixture was concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH) to afford INT 4.