Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18](OS(C(F)(F)F)(=O)=O)=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.[F-].[K+].[Br-].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:32]1([C:18]2[C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11]=3[CH:17]=2)[CH2:34][CH2:33]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(C3CC3)cc12
Temperature: 100 °C

Procedure:
Methyl 2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylate (7.12 g, 15.37 mmol), cyclopropylboronic acid (2.19 g, 25.5 mmol), potassium fluoride (3.26 g, 56.1 mmol), sodium bromide (1.75 g, 17.01 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.85 g, 0.736 mmol) were stirred together under nitrogen in a mixture of toluene (90 mL) and water (2.25 mL) and heated at 100° C. for 18 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic phase was separated, dried by hydrophobic filter tube and evaporated under vacuum. The residue was purified by flash chromatography, eluting over silica gel with a gradient of 0-5% ethyl acetate in cyclohexane. Product containing fractions were evaporated under vacuum to give the methyl 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=728 (2M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.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:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccn1
Reactant: Brc1cc(-c2ccccc2)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccnc(Nc3ccccn3)c2)cc1
Reaction time: 17 h
Yield: 62.2 %

Procedure:
2-Bromo-4-phenylpyridine (280 mg, 1.19 mmol), 2-aminopyridine (124 mg, 1.31 mmol), potassium tert-butoxide (201 mg, 1.79 mmol), (±)-BINAP (3 mg, 0.05 mmol) and Pd2(dba)3 (2.7 mg, 0.03 mmol) were stirred in toluene (2.5 mL) at 90° C. under Ar(g). After 17 h stirring, the reaction mixture was diluted with CH2Cl2 (2.5 mL) and silica was added. The solvent was removed under reduced pressure and the resulting dry loaded material purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (100:2), to furnish I as a yellow solid (183 mg, 62%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C([Li])(C)(C)C.CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:23][CH2:24][CH2:25][C:26]([CH3:28])=[CH2:27]>CCOCC.[OH-].[Na+].CCOCC>[CH3:28][C:26](=[CH2:27])[CH2:25][CH2:24][CH2:23][C:3]#[C:2][C:1]([OH:5])=[O:4]
Reactant: C=C(C)CCCBr
Reactant: C#CC(=O)O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C)CCCC#CC(=O)O
Reaction time: 24 h

Procedure:
0.13 Gram (1.85 mmol) propiolic acid is dissolved in 20 ml ether, under nitrogen, and the solution is cooled to -70°. 3.3 Milliliters of 1.1 M t-butyllithium (3.63 mmol) is added over a period of 1 hr, and the mixture is stirred for an additional hour at -60°. HMPA (10 ml) is added, followed by 0.32 g (1.96 mmol) 1-bromo-4-methyl-4-pentene (prepared as in either Example 1 or Example 3), keeping the solution cold. After 24 hr, the mixture is heated to 40°-45°. After 3 days, the reaction is worked up in 5% NaOH/ether, and the aqueous layer is extracted with ether. The basic phase is acidified with HCl and extracted with ether (2×). The latter ether phases are washed with water and brine, dried over Na2SO4, filtered and the solvent is removed to yield 7-methyl-7-octen-2-ynoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=2[CH2:9][C@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][NH:7]2.C(=O)(O)[O-].[Na+].[CH3:23][C:24](=[CH2:27])[CH2:25]Cl>CN(C)C=O>[CH3:25][C:24](=[CH2:23])[CH2:27][N:7]1[C@@H:8]2[C@@H:3]([C:2]([CH3:17])([CH3:1])[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[CH2:9]2)[CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)c2cc(O)ccc2C[C@@H]2NCCC[C@@H]21
Reactant: C=C(C)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN1CCC[C@H]2[C@@H]1Cc1ccc(O)cc1C2(C)C

Procedure:
A mixture of 6.92 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[g]-quinolin-7-ol, 2.52 g. of sodium bicarbonate, 2.98 g. of 2-methyl-2-propenyl chloride, and 60 ml. of N,N-dimethylformamide was stirred and refluxed for one hour. The reaction mixture was worked up in a manner similar to that described above in Example 11 to yield crude cis-1,2,3,4,4a,5,10,10a-octahydro-1-(2-methyl-2-propenyl)-5,5-dimethylbenzo[g]quinolin-7-ol. A 1.7 g. portion of the partially purified base was chromatographed on 170 g. of alumina (6% water) using diethyl ether as eluant, and the resulting syrupy product (1.3 g.) was recrystallized from hexane to yield 1.0 g. of the pure base as an off-white solid melting at 129°-131° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:28])[CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=O)[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[C:13]2[CH:33]=[CH:34][CH:35]=[CH:36][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:45])([C:41]([F:44])([F:43])[F:42])[CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:28])[CH:21]([O:25][CH2:26][CH3:27])[C:22]([NH:40][CH2:39][C:38]([F:45])([F:37])[C:41]([F:44])([F:43])[F:42])=[O:24])[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[C:13]2[CH:33]=[CH:34][CH:35]=[CH:36][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: CCOC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-ethoxy-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid. (82%). MS: m/e=620(M+H+).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:5][C:4]([CH3:9])([C:6](O)=[O:7])[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:1][C:2]1([F:10])[CH2:5][C:4]([CH2:6][OH:7])([CH3:9])[CH2:3]1
Reactant: CC1(C(=O)O)CC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(CO)CC(F)(F)C1
Temperature: -40 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of the 3,3-difluoro-1-methylcyclobutanecarboxylic acid (150 mg, 0.999 mmol) in diethyl ether (5 mL) was added to a suspension of LAH (2.198 mL, 2.198 mmol, 1M in THF) in diethyl ether (2 mL) at −40° C. The reaction mixture was stirred at −40° C. for 1 h and allowed to warm to RT and stirred for 15 h. The reaction mass cooled to −40° C. and quenched with sequential addition of water (10 mL), 10% aqueous solution of NaOH (10 mL) and water (10 mL). Diethyl ether (15 mL) was then added and the solution was stirred for 2 h. The organic layer was separated and the aqueous phase was extracted with diethyl ether (3×15 mL). The combined organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude sample was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in petroleum ether). Fractions containing the product were combined and evaporated to afford the Intermediate 229A as a pale yellow oil (100 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.92 (t, J=5.52 Hz, 1H) 3.27 (d, J=4.02 Hz, 2H), 2.55-2.45 (m, 2H), 2.07-2.21 (m, 2H), 1.07-1.17 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][NH:11]C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)=[O:4].[ClH:21]>>[ClH:21].[NH:10]([CH2:9][C:8]1[CH:19]=[CH:20][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[NH2:11]
Reactant: COC(=O)c1ccc(CNNC(=O)OC(C)(C)C)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNN)cc1

Procedure:
To the intermediate from step C (1.89 g, 6.75 mmol) was added HCl (4.0 M in dioxane, 100 mL). After stirring the reaction for 16 hours it was concentrated in vacuo to give a white powder. 1H NMR (CD3OD, 500 MHz): 8.09 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 4.21 (s, 2H), 3.93 (s, 3H). LC-MS=0.77; (M+H)=181.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:16][C:17]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH:33]1[CH2:35][O:34]1)([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>C1(C)C=CC=CC=1.CO>[CH3:21][O:20][C:18](=[O:19])[C:17]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH:33]([OH:34])[CH2:35][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:12]=[CH:13][C:14]([F:15])=[C:2]([F:1])[CH:3]=2)[CH2:7][CH2:8]1)([CH3:16])[CH3:22]
Reactant: Fc1ccc(OC2CCNCC2)cc1F
Reactant: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC1CO1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC(O)CN1CCC(Oc2ccc(F)c(F)c2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A toluene solution of 4-(3,4-difluorophenoxy)piperidine (0.03 ml, 0.5 M) was mixed with a toluene solution of methyl 2-methyl-2-{[2-(2-oxiranylmethoxy)benzoyl]amino}-propanoate (0.03 ml, 0.5 M). The mixture was diluted with 0.20 ml toluene and 0.05 ml methanol. The reaction mixture was stirred overnight at 100° C. in sealed vials. The product were concentrated in vacuo and used without any purification.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:10]3[S:9][CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([CH3:11])[C:3]=2[OH:12])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2ncsc2c(Br)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1O
Temperature: 110 °C

Procedure:
The reaction mixture of 7-bromo-5-methylbenzo[d]thiazol-6-ol (5D) (90 mg, 0.37 mmol), 4-chlorophenyl boronic acid (86 mg, 0.55 mmol), Pd(PPh3)4 (40 mg, 0.037 mmol), K2CO3 (153 mg, 1.11 mmol) in 1,2-dimethoxyethane (1 ml)/H2O(0.5 ml) was heated at 110° C. in the microwave for 10 min. Then the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-100% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C14H10ClNOS: 276.0 (M+H+). Found: 276.2 (M+H+).
Reaction SMILES: [O:1]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[O:1]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 735.5 %

Procedure:
To a solution of ethyl 2-phenoxypropanoate (1.8 g, 0.9 mmol) in EtOH (16 ml) was added a solution of NaOH (0.44 g, 1.1 mmol) in H2O (4 ml) at 25° C. The mixture was stirred for 30 min before being concentrated. The residue had water (20 mL) added and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 2N HCL until pH 3 and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (1.1 g, 73.3%) as a white solid which was used in next step without further purification.
Reaction SMILES: [K].[O:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:4][C:3]1=[S:12].[CH:13](I)([CH3:15])[CH3:14]>>[CH:13]([S:12][C:3]1[O:2][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][N:4]=1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: CCOC(=O)c1n[nH]c(=S)o1
Agent: [K]
Product: CCOC(=O)c1nnc(SC(C)C)o1

Procedure:
The title compound was prepared from ethyl 1,3,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate (11 g., 0.03 mole) and isopropyl iodide (5.6 g., 0.03 mole) analogously to the procedure described in Experiment A. The yield was 4.1 g. (63%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[CH:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[O:3]1.[OH-:23].[Na+].Cl>CS(C)=O.CN(C=O)C>[OH:23][C:4]1([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH2:11][CH:2]([CH3:1])[O:3]1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)OC(C)C2
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(O)(c1ccc([N+](=O)[O-])cc1)OC(C)C2
Reaction time: 5 h

Procedure:
A solution of 16 (1.3 g) in 4 ml of DMSO and 24 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over Na2SO4. Removal of the solvent afforded 17 as a syrup (1.6 g), which was used directly for the next step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]O)[N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>>[N:18]([CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:11]=1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CO)n1
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN=[N+]=[N-])n1
Reaction time: 25 h
Yield: 75.5 %

Procedure:
A mixture of 2-[(tert-butyldimethylsilyloxy)methyl]-6-hydroxymethylpyridine (1) (2.14 g, 8.42 mmol), sodium azide (2.73 g, 42.0 mmol), triphenylphosphine (2.65 g, 10.10 mmol), and carbon tetrabromide (3.07 g, 9.29 mmol) was dried in vacuo, and dissolved in DMF (64 mL). To the solution was added triethylamine (2.64 mL) and stirred for 25 hours under Ar atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, the mixture was subjected to extraction with EtOAc and water. The organic layer was washed with sat. NaCl aq., dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (Hex:EtOAc=50:1) to give 2-azidomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (2) (1.77 g, 76%) as a pale-yellow oil.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:46])[N:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37](C)(C)[O:38][SiH2]C(C)(C)C)[CH:31]=1)[CH2:26][CH2:27][F:28])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:46])[N:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH2:37][OH:38])[CH:31]=1)[CH2:26][CH2:27][F:28])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
TBAF (1M in THF, 8.84 mL, 8.84 mmol) was added to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (1.91 g, 4.42 mmol) in THF (44.2 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc (100 mL) was added, and the resulting mixture was washed with aq. sat. NH4Cl (2×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 30:70) yielded the title compound (901 mg, 64%). LC-MS: tR=0.64 min; ES+: 318.07.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](F)=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1.CN(C)C=O.O>O1CCOCC1.C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: COc1ccccc1N
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Nc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 2',5'-difluoro-4'-nitroacetanilide (20.0 g, 0.093 mol) and o-anisidine (17.1 g, 0.139 mol) in dioxane is refluxed overnight, treated with additional o-anisidine (5.7 g), refluxed for 5 hours, treated with additional o-anisidine (5.7 g), refluxed for 5 days, treated with N,N-dimethylformamide (50 mL), refluxed overnight, cooled to room temperature and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a red oil. Flash column chromatography of the oil using silica gel and a 5% ethyl acetate in methylene chloride solution gives the title product as a brown solid which is identified by NMR spectral analyses.
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: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
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: [Si:1]([O:8][O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Si:1]([O:8][O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH2:23][Br:32])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn([C@H]2CC[C@@H](COO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OOC[C@@H]1CC[C@H](n2cc(CBr)c(=O)[nH]c2=O)O1

Procedure:
A solution of 5′-O-TBDMS-3′-deoxythymidine (2) (700 mg, 2.055 mmol) in CCl4 (50 mL) was treated with NBS (702 mg, 4.11 mmol), followed by irradiation from a flood lamp (150 W) under reflux for 3 h to give (3). After filtering the solid, the filtrate was evaporated to dryness, followed by coevaporating with THF (20 mL×3). To a stirred solution of the 3-(trifluoroacetamido)prop-1-yne (620 mg, 4.11 mmol), DBU (0.61 mL, 4.11 mmol) and CuI (782 mg, 4.11 mmol) in THF (20 mL) was added a solution of 3 (Need conc. and solvent), followed by stirring at r.t for 15 h. After evaporating solvent, the residue was purified by silica gel column chromatography with MeOH:CH2Cl2 (0-4%) to afford 17 (170 mg, 0.35 mmol, 17%) over two steps. 1H NMR (CDCl3), 300 MHz) δ 9.55 (br s, 1H, NH), 7.74 (s, 1H, H6), 7.18 (br s, 1H, NH), 6.04 (dd, 1H, H1′, J=3.9 and 6.3 Hz), 4.23-4.10 (m, 3H, H4′ and CH2), 3.94 (dd, 1H, H5′, J=3.3 and 11.4 Hz), 3.75 (dd, 1H, H5′, J=3.6 and 11.4 Hz), 3.26-3.22 (m, 2H, 2 CH2), 2.45-2.35 (m, 1H, H2′), 2.09-1.85 (m, 3H, H2′, 2H3′), 0.90 (d, 9H, 3 CH3), 0.09 (s, 6H, 2 CH3). 19F NMR (CDCl3, 282.2 MHz) δ −76.22 (s, CF3).
Reaction SMILES: O=[C:2]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:10].C(=O)([O-])[O-:30].[K+].[K+].CS(C)=O.OO>CO.O>[NH:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([C:2]3[NH:10][C:9](=[O:30])[C:5]4[N:4]([CH:8]=[CH:7][CH:6]=4)[CH:3]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: N#Cc1cccn1CC(=O)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2ccc(C3CCNCC3)cc2)cn2cccc12
Reaction time: 8 h

Procedure:
1-(2-Oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carbonitrile (1.40 g; 3.60 mmol) is slurried in methanol (10 ml). Potassium carbonate (2.49 g; 17.98 mmol), dry dimethylsulfoxide (0.77 ml; 10.79 mmol) and hydrogen peroxide (1.10 ml; 10.79 mmol) are added (caution: strong exothermic reaction after the addition of hydrogen peroxide). The yellow suspension is stirred overnight. The reaction mixture is diluted with water, the precipitate is filtered off by suction, washed with water and dried under vacuum at 50° C. The crude product is purified by flash chromatography. The combined fractions are evaporated to dryness. The residue is triturated with diethylether, filtered off by suction and dried under vacuum at 50° C. to afford 3-(4-piperidin-4-yl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as off-white solid;