Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)=O)C.F[C:27]1C=CC(OC2C=CC(C3C=CN=C(C(O)=O)N=3)=CC=2)=CC=1.ICC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:4](=[O:3])[CH3:27])[N:11]=3)=[CH:13][CH:14]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: CCOC(=O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CC(=O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 62 %

Procedure:
4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid ethyl ester: A mixture of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid (3.15 g, 10.2 mmol), iodoethane (2.0 mL, 25 mmol), and cesium carbonate (7.00 g, 21.5 mmol) in DMF (100 mL) was maintained at 70°-80° C. for 16 hours. The mixture was then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed 3 times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give an oil. Purification by column chromatography (1:1 hexane/ethyl acetate) afforded the desired product (2.14 g, 62%) as an oil which solidified upon standing at room temperature overnight, mp 61°-63° C. 1H NMR (CDCl3): δ 8.88 (d, J=5.4 Hz, 1H), 8.16 (d, J=8.7 Hz, 2H), 7.77 (d, J=5.4 Hz, 1H), 7.12-7.05 (m, 6H), 4.55 (q, J=7.5 Hz, 2H), 1.49 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])[CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:28]6[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=6)[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1cccc(F)c1
Yield: 36 %

Procedure:
A solution (5 mL) of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol), 1-(3-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (120 mg, 0.48 mmol), HATU (180 mg, 0.48 mmol) and N,N-diisopropylethylamine (100 mg, 0.80 mmol) in N,N-dimethylformamide was stirred at room temperature for 5 hr. The reaction solution was divided into two layers with tetrahydrofuran (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) and the aqueous layer was subjected to extraction (3 times) with ethyl acetate (15 ml). The combined organic layer was washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (80 mg, 35%) as a brown solid.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([O:18]CC2C=CC=CC=2)[C@H:16]([O:26]CC2C=CC=CC=2)[C:12]2([CH2:15][O:14][CH2:13]2)[O:11][C@H:10]1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH3:50])=[CH:44][CH:43]=2)[CH:35]=1)C1C=CC=CC=1.C(O)=O>C1COCC1.CCO.[Pd]>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@H:10]2[C@H:9]([OH:8])[C@@H:17]([OH:18])[C@H:16]([OH:26])[C:12]3([CH2:13][O:14][CH2:15]3)[O:11]2)=[CH:35][C:36]=1[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH3:50])=[CH:44][CH:43]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC4(COC4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCO
Product: CCOc1ccc(Cc2cc([C@@H]3OC4(COC4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of (6S,7S,8R,9S)-7,8,9-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,5-dioxa-spiro[3.5]nonane (110 mg, 0.15 mmol) in THF:EtOH (1:1, 5 mL) was added 10% Pd/C (60 mg) followed by formic acid (0.46 mL, 12 mmol) and stirred under hydrogen atmosphere at room temperature for 8 hours. The reaction mixture was filtered through cetlie bed, neutralized with saturated aqueous NaHCO3 solution, extracted with EtOAc, concentrated and purified by preparative HPLC to furnish 31 mg of (6S,7R,8R,9S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,5-dioxa-spiro[3.5]nonane-7,8,9-triol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:35][N:36]([CH3:47])[CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>C(O)(C)C.Cl>[CH3:35][N:36]([CH3:47])[CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42]([NH:43][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]5[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=5[F:32])[CH:21]=[CH:22][CH:23]=4)=[N:10][N:11]4[CH:12]=[CH:13][CH:14]=[C:15]([F:17])[C:16]=34)[CH:5]=[CH:4][N:3]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: O=C(Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4cccc(F)c34)n2)c1
Yield: 94 %

Procedure:
To the solution of N-{3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (0.09 g) in isopropanol (5 mL) was added 3-{[2-(dimethylamino)ethyl]oxy}aniline (0.07 g) and 3 drops of concentrated hydrochloric acid. The reaction was microwaved in a sealed tube at 180° C. for 10 min. The isopropanol was removed by rotaevaporation and the residue was treated with sat. NaHCO3 (5 mL), extracted with EtOAc (2×5 mL), and dried (Na2SO4). Concentration and purification with column chromatography afforded the title compound as a yellow solid (0.11 g, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.30 (d, J=2.7 Hz, 6H), 2.70 (t, J=5.7 Hz, 2H), 4.01-4.07 (m, 2H), 6.58-6.68 (m, 2H), 6.95-7.03 (m, 2H), 7.10 (d, J=7.9 Hz, 1H), 7.17-7.30 (m, 4H), 7.37-7.50 (m, 4H), 7.80 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 8.20 (dd, J=5.2, 2.8 Hz, 1H), 8.39-8.48 (m, 2H); ESIMS (M+H)+=624.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc3c2Cl)cc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
To a stirred solution of 8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.39 mmol) in acetone (10 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (91 mg, 0.46 mmol), followed by K2CO3 (107 mg, 0.77 mmol). The resulting suspension was heated at reflux overnight. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. Water (15 mL) and EtOAc (15 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to obtain 96 mg of the title compound as an off-white solid. HPLC/MS: retention time=3.71 min, [M+H]+=419.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:26][CH2:25][CH2:24][C:19]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].[OH-].[Na+].Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.CO.O1CCCC1>[CH2:20]1[C:19]2([CH2:24][CH2:25][CH2:26][C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C@@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:27])=[O:2])=[CH:14][CH:13]=3)=[CH:18]2)[CH2:23][CH2:22][CH2:21]1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=CC3(CCCC3)CCC2)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCC2=CC3(CCCC3)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (1.33 g) obtained in Step 7 in a mixed solvent of tetrahydrofuran (13 mL)-methanol (13 mL) was added 2N aqueous sodium hydroxide solution (4.6 mL), followed by stirring the reaction mixture at room temperature overnight. Then, to the reaction mixture were added successively 2N aqueous hydrochloric acid solution (5.1 mL), ethyl acetate (100 mL) and sodium sulfate (50 g), followed by stirring for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=20:80) to give (S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (895 mg) as the desired compound.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[C:13]([NH:19][CH2:20][C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:14][C:15](F)=[CH:16][CH:17]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:15]1[N:14]=[C:13]([NH:19][CH2:20][C:21]2([C:27]#[N:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:12]([F:11])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#CC1(CNc2nc(F)ccc2F)CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(CNc2nc(OCc3ccccc3)ccc2F)CCOCC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
Benzyl alcohol (352 mg, 3.26 mmol) was dissolved in anhydrous DMF (2 ml) and placed under argon. This was then treated with a 60% dispersion in oil of SODIUM HYDRIDE (78.7 mg, 3.26 mmol). This resultant suspension was then stirred at room temperature for 15 min. At this time it was treated with a solution of 4-((3,6-difluoropyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (275 mg, 1.09 mmol) dissolved in anhydrous DMF (2 ml). Once the addition was complete the reaction was stirred at 90° C. for 5 hours. The reaction was allowed to cool to room temperature. It was then poured into brine (20 ml). This was extracted with EtOAc (3×15 ml). The combined extracts were washed with H2O (3×10 ml) followed by brine (1×10 ml). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo to give the crude material which was purified using the ISCO and a 12 g SiO2 column. Eluted using 100 hexanes to 30 EtOAc/70 hexanes over 20 min. 245 mg (66% yield) of the desired product was obtained as a viscous liquid. LCMS (m/z): 342.1 [M+H]+; retention time=1.017 min.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH:18]([C:20]1[C:29]([O:30][CH3:31])=[CH:28][C:27]2[C:26]([CH3:33])([CH3:32])[CH2:25][CH2:24][C:23]([CH3:35])([CH3:34])[C:22]=2[CH:21]=1)=O>CS(C)=O>[CH3:31][O:30][C:29]1[C:20]([C:18]#[C:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)=[CH:21][C:22]2[C:23]([CH3:35])([CH3:34])[CH2:24][CH2:25][C:26]([CH3:32])([CH3:33])[C:27]=2[CH:28]=1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Reactant: COc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Solvent: CS(C)=O
Product: COc1cc2c(cc1C#Cc1ccc(C)cc1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A solution of 20.2 g (0.18 mole) of potassium tert.-butylate in 45 ml of dimethyl sulfoxide was added dropwise to a solution of 23.2 g (0.09 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate and 22.1 g (0.09 mole) of 2-formyl-5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethylnaphthalene in 270 ml of dry dimethyl sulfoxide at room temperature. The mixture was stirred for 30 minutes, poured onto 1 liter of ice water and extracted three times with ether. The ether phase was washed twice with water, dried over sodium sulfate and evaporated down to give 22.6 g (76%) of a slightly impure product. Recrystallization from methanol gave 15.2 g (51%) of the pure title compound of melting point 127° C.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH2:7][CH3:8].[CH3:16][C:17](C)([CH3:21])[C:18](O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].N>O.[N+]([O-])([O-])=O.[Ag+]>[C:17]([C:13]1[N:12]=[CH:11][C:10]([C:6](=[O:9])[CH2:7][CH3:8])=[CH:15][CH:14]=1)([CH3:21])([CH3:18])[CH3:16]
Reactant: CCC(=O)c1cccnc1
Reactant: CC(C)(C)C(=O)O
Agent: [Ag+]
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)c1ccc(C(C)(C)C)nc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a 10% sulphuric acid aqueous solution (22 ml) of 3-propionylpyridine (Lancaster, 2.70 g, 20 mmol), trimethylacetic acid (10.21 g, 0.1 mol), silver nitrate (0.68 g, 4 mmol) and ammonium persulfate in water (36 ml) were added and the mixture was stirred for 1.5 hours at 70° C. Then, the mixture was basified with 25% ammonia solution (pH=9-10) and extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave a residue, which was purified by column chromatography, eluting with hexane/EtOAc (5:1), to give the title compound (3.75 g, 98%) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([O:27][CH2:28][CH3:29])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[O:19][C:20]=2[CH3:21])=[CH:8][C:7]=1[CH3:26].[Li+].[OH-]>>[C:22]([C:18]1[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:9]2[CH:10]=[C:11]([CH3:12])[C:6]([CH2:5][C@H:4]([O:27][CH2:28][CH3:29])[C:3]([OH:30])=[O:2])=[C:7]([CH3:26])[CH:8]=2)[N:17]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: CCO[C@@H](Cc1c(C)cc(OCCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 46 d], (S)-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: [C:1]([C:3](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:28]=[C:29]3[C:35]([C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:34][N:33](COCC[Si](C)(C)C)[C:30]3=[N:31][CH:32]=2)=[CH:22][CH:21]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:6]1([C:4]([C:3](=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]3[N:28]=[C:29]4[C:35]([C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:34][NH:33][C:30]4=[N:31][CH:32]=3)=[CH:22][CH:21]=2)[C:1]#[N:2])=[O:5])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(C#N)=Cc2ccc(Nc3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCNCC4)cc3)nc12
Reaction time: 8 h
Yield: 38.2 %

Procedure:
Tert-butyl 4-[2-cyano-3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxy-methyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]prop-2-enoyl]piperazine-1-carboxylate (80 mg, 0.12 mmol) was dissolved in DCM (3 mL), cooled in an ice bath, and TFA (3 mL, 0.12 mmol) was added. The reaction mixture was stirred overnight, and then most of the solvent was removed in vacuo. The mixture was neutralized by Na2HCO3 to pH 7-8, extracted by EtOAc, combined organic layer was evaporated. The residue was dissolved in methanol (15 mL), adding HCl (0.05 mL, 0.12 mmol, and a few of drops water, and the mixtured was stirred overnight. When the reaction was deemed complete by LCMS analysis, the solvent was removed, and the product precipitated from EtOAc/MeOH to get 21 mg of 2-(piperazine-1-carbonyl)-3-(4-((7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)phenyl)acrylonitrile.
Reaction SMILES: O[CH2:2][CH:3]1[CH:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][CH:7]2[CH:6]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:5][C:4]1=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CS(Cl)(=O)=O>N1C=CC=CC=1>[CH2:2]=[C:3]1[CH:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][CH:7]2[CH:6]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:5][C:4]1=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C=C1CC(OC(C)OCC)C2OC(C)(C)OC2C1CO
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C=C1C(=CC(=O)OCC)CC(OC(C)OCC)C2OC(C)(C)OC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The obtained ethyl (2-hydroxymethyl-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexylidene)acetate was dissolved in 5 ml of pyridine, and 0.12 g of methanesulfonyl chloride was added, followed by stirring the mixture overnight at room temperature. The reaction liquid was concentrated under reduced pressure, diluted with diethyl ether, washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence, dried over anhydrous magnesium sulfate, and then concentrated conducted under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.282 g of ethyl (2-methylene-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexylidene)acetate having the following property.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][CH:14]1[CH2:19][NH:18][CH2:17][CH:16]([CH3:20])[NH:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([N:18]2[CH2:17][C@H:16]([CH3:20])[NH:15][C@H:14]([CH3:13])[CH2:19]2)[CH:7]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1Cl
Reactant: CC1CNCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2cc(Cl)c(C(F)(F)F)cn2)C[C@H](C)N1
Temperature: 140 °C

Procedure:
2,4-dichloro-5-(trifluoromethyl)pyridine (800 mg, 3.70 mmol), 2,6-dimethylpiperazine (800 mg, 7.14 mmol), and K2CO3 (1.0 g, 7.25 mmol) were added to dimethylformamide (15 mL). The resulting solution was heated for 2 h at 140° C. The reaction mixture was then quenched by the adding 50 mL of ice-water and extracted with EtOAc (50 mL). The organic layers were combined and dried over MgSO4. The solvent was concentrated and the residue was purified using silica gel column chromatography to 0.2 g (18%) of 1-(4-chloro-5-(trifluoromethyl)pyridine-2-yl)-cis-3,5-dimethylpiperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:15](=[O:17])[NH:1][C:2]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
2-Amino-4-nitro-benzoic acid (1.00 g, 0.00549 mol) was dissolved in THF. Triphosgene (1.63 g, 0.00549 mol) was dissolved in THF and added. The reaction mixture was stirred at rt for 2 h, concentrated, triturated with H2O, filtered, and taken up in acetone to afford a pale yellow solid (1.14 g, 99.8%).
Reaction SMILES: COC(N[C@@H](C(C)C)C(N1CC(=O)C[C@H]1C(OCC1C=CC=CC=1)=O)=O)=O.[CH3:28][O:29][C:30]([NH:32][C@@H:33]([CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:34]([OH:36])=O)=[O:31].[F:43][C:44]1([F:99])[C:56]2[CH:55]=[C:54]([C:57]3[CH:58]=[CH:59][C:60]4[N:64]=[C:63]([C@@H:65]5[CH2:73][C:68]6([O:72][CH2:71][CH2:70][O:69]6)[CH2:67][N:66]5[C:74](=[O:87])[C@H:75]([NH:82][C:83](=[O:86])[O:84][CH3:85])[C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[NH:62][C:61]=4[CH:88]=3)[CH:53]=[CH:52][C:51]=2[C:50]2[C:45]1=[CH:46][C:47]([C:89]1[NH:93][C:92]([C@@H:94]3[CH2:98][CH2:97][CH2:96][NH:95]3)=[N:91][CH:90]=1)=[CH:48][CH:49]=2.Cl.O=C1CN[C@H](C(OCC2C=CC=CC=2)=O)C1.COC(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:85][O:84][C:83](=[O:86])[NH:82][C@H:75]([C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1)[C:74]([N:66]1[C@H:65]([C:63]2[NH:62][C:61]3[CH:88]=[C:57]([C:54]4[CH:53]=[CH:52][C:51]5[C:50]6[C:45](=[CH:46][C:47]([C:89]7[NH:93][C:92]([C@@H:94]8[CH2:98][CH2:97][CH2:96][N:95]8[C:34](=[O:36])[C@@H:33]([NH:32][C:30]([O:29][CH3:28])=[O:31])[CH:37]8[CH2:42][CH2:41][O:40][CH2:39][CH2:38]8)=[N:91][CH:90]=7)=[CH:48][CH:49]=6)[C:44]([F:43])([F:99])[C:56]=5[CH:55]=4)[CH:58]=[CH:59][C:60]=3[N:64]=2)[CH2:73][C:68]2([O:69][CH2:70][CH2:71][O:72]2)[CH2:67]1)=[O:87]
Reactant: COC(=O)N[C@@H](C(=O)N1CC2(C[C@H]1c1nc3ccc(-c4ccc5c(c4)C(F)(F)c4cc(-c6cnc([C@@H]7CCCN7)[nH]6)ccc4-5)cc3[nH]1)OCCO2)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CC7(CN6C(=O)[C@H](NC(=O)OC)c6ccccc6)OCCO7)[nH]c5c4)ccc2-3)[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate, except that (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid and methyl (R)-2-((S)-8-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-2-oxo-1-phenylethylcarbamate as 3HCl salt and (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid were used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS (ESI) m/z 972.29 [M+H]+. (27.6 mg, 53%).
Reaction SMILES: O=[O+][O-].[C:4]1([CH2:10][O:11][C:12](=[O:18])[CH:13]([CH3:17])[CH2:14][CH:15]=C)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=O.C(O)(=[O:23])C>CO.[Zn]>[C:4]1([CH2:10][O:11][C:12](=[O:18])[CH:13]([CH3:17])[CH2:14][CH:15]=[O:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: C=CCC(C)C(=O)OCc1ccccc1
Agent: O=O
Agent: O=[O+][O-]
Agent: [Zn]
Solvent: CO
Product: CC(CC=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A stream of ozone is passed through a -78° C. solution of 1.0 g of racemic 2-methyl-4-pentenoic acid phenylmethyl ester in 110 ml of methyl alcohol until the blue color persists. The excess ozone is discharged by a stream of oxygen, followed by argon. One gram of zinc dust and 1.0 g of acetic acid is added and the resulting mixture allowed to warm to room temperature; followed by stirring for 1 hour. The excess zinc is removed by filtration and the filtrate is concentrated in vacuo. The residue is extracted with diethyl ether, filtered and the filtrate concentrated in vacuo. The residue is purified by pad filtration (silica gel, 50% diethyl ether/petroleum ether) to give 1.01 g of racemic 2-methyl-4-oxobutanoic acid phenylmethyl ester.