Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2)[CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[Cl:20])=O)(C)(C)C.C(OCC)(=O)C.[ClH:38]>>[ClH:16].[ClH:38].[Cl:20][C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][NH:8][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(N(Cc3c(Cl)ccc([N+](=O)[O-])c3Cl)C(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2cccc(NCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1

Procedure:
8-[N-tert-Butoxycarbonyl-N-(2,6-dichloro-3-nitrobenzyl)amino]-2-methylquinoline (100 mg) was treated with 4M hydrogen chloride -ethyl acetate (2 ml) at ambient temperature for 40 minutes. The precipitate was collected by vacuum filtration and washed with ethyl acetate to give 8-[(2,6-dichloro-3-nitrobenzyl)amino]-2-methylquinoline dihydrochloride (88 mg) as pale yellow crystals.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])=[C:16](OS(C)(=O)=O)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])=[C:16]([N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N3CCCCC3)CS[C@H]12

Procedure:
In a further example, p-nitrobenzyl 7-phenoxyacetamido-3-methylsulfonyloxy-3-cephem-4-carboxylate is reacted in DMF at 0° C. with 2-molar equivalents of piperidine to provide after isolation, p-nitrobenzyl 7-phenoxyacetamido-3-piperidino-3-cephem-4-carboxylate.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=C.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
3.51 g (0.025 mol) of benzoyl chloride, 3.125 g (0.03125 mol) of ethyl acrylate, 5.79 g (0.03125 mol) of tri-n-butylamine, 50 ml of toluene and 0.0561 g (0.00025 mol) of palladium acetate are introduced into a 100 ml glass flask and heated to 100° C., with stirring. A slight evolution of gas is observed. After the mixture has been stirred for 4 hours, it is cooled and the contents of the flask are extracted by shaking twice with 25 ml of 2 N hydrochloric acid at a time. The toluene phase is dried with magnesium sulfate and distilled. After the toluene has been distilled off, 2.9 g (0.0165 mol) of ethyl cinnamate are obtained, corresponding to a yield of 66% of theory; boiling point=135°-138° C./17×102Pa; nD20 =1.5592.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[C:24]3[N:23]=2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: CCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Product: CCOc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1C(F)(F)F
Yield: 68.5 %

Procedure:
Reaction of 1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (155 mg, 68%). MS (ISP) 453.5 [(M+H)+]; mp 178° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]3)=[CH:16][N:15]=2)=[CH:10][CH:11]=1)(=O)C.[OH-].[Na+].O.Cl>O1CCOCC1>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:9]3[S:8][C:7]([CH2:6][CH2:5][OH:4])=[CH:11][CH:10]=3)=[N:15][CH:16]=2)[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCCc1ccc(CCc2ccc(N3CCN(C(C)=O)CC3)cn2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCO)s3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 2-(5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)ethyl acetate (719.0 mg, 1.791 mmol) in dioxane (6.3 ml) were added 1M aqueous sodium hydroxide solution (6.27 ml, 6.27 mmol) and water (6.3 ml) at 0° C. After stirring at room temperature for 1 hr, the mixture was cooled to 0° C., and 1M hydrochloric acid (8.0 ml, 8.0 mmol) was added. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:acetone=7:3→5:5) to give 2-(5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)ethanol (608.7 mg, yield 94.5%) as a white solid.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Br[CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[N:18]=[CH:19][CH:20]=[CH:21][C:12]2=1)=O.C([OH:24])C>>[N:18]1[C:13]2[NH:14][C:15]3[C:11]([C:12]=2[CH:21]=[CH:20][CH:19]=1)=[CH:10][C:9]([C:7]1[NH:3][C:2](=[O:24])[S:1][CH:6]=1)=[CH:17][CH:16]=3
Reactant: CCO
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc2[nH]c3ncccc3c2c1
Agent: [K+]
Product: O=c1[nH]c(-c2ccc3[nH]c4ncccc4c3c2)cs1

Procedure:
A solution of potassium thiocyanate (73 mg, 0.73 mmol, 2 equiv.) in Ethanol (1 mL), was added dropwise a solution of compound 2-Bromo-1-(9H-pyrido[2,3-b]indol-6-yl)ethanone (150 mg, 0.366 mmol) in ethanol (1 mL). The mixture was stirred at reflux for 1 hour. The resulting mixture was then cautiously quenched at 0° C. with H2O. It was extracted with EtOAc. The resulting organic layer was washed with NaCl saturated aqueous solution, dried over MgSO4, and filtered. Solvent was removed under reduced pressure The crude product was triturated and filtered. The resulting product (82 mg, 0276 mmol) was dissolved in glacial acetic acid (1 mL), 50% sulfuric acid (200 μL) was added, and then the mixture was heated to reflux for 1 hour. The resulting mixture was quenched at 0° C. with H2O. The aqueous layer is treated with Na2CO3 until pH=6 and then extracted with AcOEt (3×20 ml). The organic layers was washed with NaCl saturated aqueous solution, dried over MgSO4, and filtered. Solvent was removed under reduced pressure. A white powder was obtained in 23% yield after trituration of the crude product in MeOH and filtration; 1H NMR (300 MHz, DMSO-d6): δ 11.96 (bs, 1H), 11.78 (bs, 1H), 8.48-8.43 (m, 3H), 7.74 (dd, 1H, J=1.9, 8.5 Hz), 7.52 (d, 1H, J=8.5 Hz), 7.25 (dd, 1H, J=5.5, 7.2 Hz), 6.69 (d, 1H, J=1.9 Hz), 4.75 (bs, 1H); MS (ESI) m/z 268.1 [M+H+]
Reaction SMILES: [CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:30]#[N:31])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:30]([C:11]1[N:10]=[C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=1)#[N:31]
Reactant: C[Si](C)(C)C#N
Reactant: CCOC(=O)C(C)Cc1ccccn1
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.5 %

Procedure:
Ethyl 2-methyl-3-(2-pyridyl)propionate (1.0 g, 5.2 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 1.2 g, 5.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 14 hrs and subjected to a silica gel (50 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (10 ml), and trimethylsilyl cyanide (0.95 g, 9.6 mmol) and N,N-dimethylcarbamoyl chloride (0.77 g, 7.2 mmol) were added thereto. The reaction mixture was stirred at room temperature for 16 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.80 g, 76%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][S:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:16][CH2:15][CH2:14][S:13][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CSCCN
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCCNc1ccc(S(C)(=O)=O)cc1
Temperature: 65 °C
Reaction time: 12 h
Yield: 47.4 %

Procedure:
To 8.28 g (47.52 mmol) of 4-fluorophenyl methyl sulfone dissloved in 20 mL DMF was added 5.20 g (57.03 mmol) of 2-(methylthio)ethyl amine (1.2 eq.), followed by 13.13 g (95.04 mmol, 2 eq.) potassium carbonate. The mixture was heated to 65° C. and stirred for 12 h. Upon cooling to room temperature, the mixture was partitioned between EtOAc and brine, dried over MgSO4 and concentrated. Column chromatography, eluting with ethyl acetate/hexane, provided 5.53 g of 4-[2-(methylthio)ethylamino]phenyl methyl sulfone, pure by 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH2:16])[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH:6]3[CH3:17].Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH:16][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][NH:23]4)[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH:6]3[CH3:17]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC1CCc2c(F)ccc3nc([C@H](C)N)n1c23
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCc2c(F)ccc3nc([C@H](C)Nc4ncnc5[nH]cnc45)n1c23
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A mixture of (S)-1-(7-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethylamine (15.8 mg, 0.0677 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (17.8 mg, 0.0745 mmol), and DIPEA (0.0346 mL, 0.20 mmol) in n-butanol (0.5 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (1.5 mL) and cooled in an ice bath. HCl in isopropanol (1.25 M, 1 mL) was added and the mixture stirred at 0° C. for 90 min and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) afforded 407 as a white solid (8 mg, 34%). Analytical data shows the product to be a mixture of diastereomers (ratio ˜1:1) which could be separated. LCMS (Method K): RT 2.59 & 2.62 min [M+H]+ 352. 1H NMR (CD3OD, 400 MHz): 8.25 & 8.24 (1H, 2 s), 8.10 & 8.08 (1H, 2 s), 7.39-7.35 (1H, m), 6.96-6.91 (1H, m), 5.93 & 5.82 (1H, 2 bs), 5.26-5.21 & 4.93-4.87 (1H, 2 m), 3.09-3.03 (1H, m), 2.97-2.88 (1H, m), 2.27-2.21 (1H, m), 2.15-2.03 (1H, m), 1.83 & 1.78 (3H, 2 d, J=6.9 Hz), 1.45 & 1.41 (3H, 2 d, J=6.7 Hz)
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([O:13][Si](C)(C)C)[C:4]1=[O:18].C(N(CC)CC)C.C(OCC)(=O)C>CO.C[Si](C)(C)Cl>[OH:13][C@H:5]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][C:4]1=[O:18]
Reactant: C[Si](C)(C)OC1C(=O)N([Si](C)(C)C)C1c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1N[C@H](c2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a heterogeneous solution of N-trimethylsilyl-3-trimethylsiloxy-4 -phenyl-azetidin-2-one (150 g, 0.49 mol) in methanol (500 mL) was added a catalytic amount of trimethylchlorosilane (1.08 g, 1 mmol) and the mixture was stirred at ambient temperature to give a clear solution. Thin layer chromatography (TLC) monitoring of the reaction eluting with ethyl acetate and hexanes (3:1) indicated that complete conversion was achieved after 15 minutes. The reaction mixture was quenched with triethylamine (10.1 g, 0.1 mol) and the methanol was removed under rotary evaporation at 40° C. until crystals formed. Ethyl acetate (300 mL) was added and the evaporation was continued to remove the remaining methanol to give a thick slurry before cooling to 0 to 5° C. for 20 minutes. The white crystals were collected via vacuum filtration following by washing with cold 0° C. ethyl acetate (75 mL) and dried to constant weight of 75 g (94% yield) of the desire product described previously.
Reaction SMILES: [C:1]1(S(C(F)(F)F)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[K])(C)(C)C.C(OC)(=O)C1C=CC=CC=1.[F:30][C:31]([F:41])([F:40])C(C1C=CC=CC=1)=O.IC1C=CC=CC=1>[Cu](I)I>[F:30][C:31]([F:41])([F:40])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)C(F)(F)F
Agent: I[Cu]I
Agent: CC(C)(C)O[K]
Solvent: COC(=O)c1ccccc1
Solvent: Ic1ccccc1
Product: FC(F)(F)c1ccccc1
Yield: 26 %

Procedure:
The trifluoromethyl phenyl sulfone/tBuOK trifluoromethylation method can also be applied to other systems. For instance, methyl benzoate can be trifluoromethylated to generate 2,2,2-trifluoroacetophenone in 30% yield at about −50° C. to about −20° C. CF3Cu can be in situ generated with trifluoromethyl phenyl sulfone/tBuOK and copper iodide (CuI), and then further react with iodobenzene at 80° C. for 20 h to give α,α,α-trifluorotoluene in 26% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]3[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:21]=2)[C:15]([O:17]C)=[O:16])=[N:9][CH:10]=1)=[O:4].CO.[OH-].[Li+].O>C1COCC1>[CH3:1][N:2]([CH3:30])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]3[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:21]=2)[C:15]([OH:17])=[O:16])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1cnc(Oc2cc(O[C@H]3CCN(C)C3=O)cc(C(=O)O)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
The methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 46) (772 mg, 1.86 mmol) was dissolved in THF (9 mL) and methanol (3 mL) and lithium hydroxide solution (1N, 2.2 mL) was added followed by water (25 mL). The resulting mixture was stirred for 1 hour at room temperature. The majority of the organic solvent was removed by distillation under reduced pressure. The remaining aqueous solution was extracted with ethyl acetate (10 mL) then acidified with 2N citric acid and re-extracted with ethyl acetate (5×25 mL), the combined organic extracts were washed with water (10 mL) and brine (20 mL), dried (MgSO4) and evaporated to afford the product (716 mg, 96%). 1H NMR δ (300 MHz, CDCl3) 2.13-2.27 (m, 1H), 2.55-2.69 (m, 1H), 2.96 (s, 3H), 3.17 (d, 6H), 3.35-3.58 (m, 2H), 4.98 (t, 1H), 7.10 (s, 1H), 7.45 (s, 1H), 7.63 (s, 1H), 8.36 (s, 1H), 8.53 (s, 1H); m/z 401 (M+H+).
Reaction SMILES: [C:1]([C@H:3]1[CH2:6][C@H:5]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH3:8])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([C@H:3]1[CH2:6][C@H:5]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH3:8])[CH2:4]1)#[N:2]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-cyano-cyclobutyl)-ethyl]-amide (44 mg, 0.08 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and extracted with 5% MeOH/CH2Cl2 (2×). The combined organics were concentrated and the residue was triturated with EtOAc to afford 19 mg (57%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-cyanocyclobutyl)-ethyl]-amide as a light yellow solid. MS: (M+H)+=418; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.08 (s, 1H), 8.43 (s, 1H), 8.40 (dd, J=8.9, 5.5 Hz, 1H), 7.96 (d, J=9.1 Hz, 1H), 7.70 (dd, J=9.8, 2.3 Hz, 1H), 7.29 (td, J=9.1, 1.9 Hz, 1H), 4.19-4.31 (m, 1H), 4.14 (s, 3H), 2.64-2.77 (m, 2H), 2.34-2.45 (m, 1H), 2.22-2.33 (m, 3H), 1.18 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[S:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([CH:25]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])(O)=O.N1CCCCC1.N1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[S:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)[C:7](/[CH:10]=[C:25](\[CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(Cc1cccs1)C(=O)O
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)s1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OCC)n1Cc1ccc(C(=O)OC)s1
Yield: 60.4 %

Procedure:
A mixture of 2-n-butyl-1-[(5-carbomethoxy-2-thienyl)methyl]imidazol-5-carboxaldehyde (0.5 g, 1.66 mmol), ethyl 2-carboxy-3-(2-thienyl)propionate (1.14 g, 4.99 mmol), piperidine (0.155 g, 1.83 mmol), 0.5 ml of pyridine in 50 ml of benzene were refluxed for 18 hours under argon in the presence of a Dean-Stark trap. The crude product was flash chromatographed over silica gel eluting with ethyl acetate/hexane (1:1) to give 0.474 g (49%) of ethyl (E)-3-[2-n-butyl-1-{(5-carbomethoxy-2-thienyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2propenoate.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([O:17]CC)=[O:16])[C:11]=2[CH3:20])=[CH:6][CH2:5]1)([CH3:3])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([OH:17])=[O:16])[C:11]=2[CH3:20])=[CH:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1noc(C2=CCC(C(C)C)CC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)noc1C1=CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [ethyl 5-(4-isopropylcyclohex-1-en-1-yl)-4-methylisoxazole-3-carboxylate] (92 mg, 0.332 mmol) in THF (5 mL) and MeOH (3 mL) was added 2M sodium hydroxide (aq) (0.166 mL, 0.332 mmol) and the mixture was stirred at room temperature for 2 hrs. The resulting mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was washed with EtOAc, acidified with 2M HCl (aq) and extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].CO[C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:10]>>[OH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:10]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CNCCCO
Product: CN(CCCO)C(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 39 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-methylamino-propan-1-ol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (39%) as amorphous yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH2:15].C(N(CC)CC)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>ClCCl.C(OCC)(=O)C>[Si:23]([O:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH2:15])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCc1cc(C(=O)OC)cc(C)c1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1cc(C(=O)OC)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of methyl 4-hydroxy-3-allyl-5-methylbenzoate (157 mg, 0.762 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.21 mL, 2 equivalents) and tert-butyldimethylsilyl chloride (172 mg, 1.5 equivalents). The reaction was stirred at room temperature under a nitrogen atmosphere for 3 days by which time TLC analysis showed complete conversion. The reaction was diluted with ethyl acetate (30 mL) and washed with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford the product as a brown oil. Yield=0.239 g (98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:26]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1

Procedure:
67 mg (0.24 mmol) of 3-fluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 40 mg (0.24 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 4 ml of water/ethanol 1:1. 25 μl (0.29 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7 and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue is purified by preparative HPLC.