Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:34]=2)[C:29]([O:31]CC)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:35]>C(O)C>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:34]=2)[C:29]([NH2:35])=[O:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Solvent: CCO
Product: NC(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
A solution of ethyl 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinate (0.100 g, 0.222 mmol) in ethanol (10 mL) was purged with ammonia gas at −40° C. in a sealed tube for 15 min. The tube was sealed and the reaction mixture was stirred at ambient temperature for 14 h. The sealed tube was opened at −40° C. and allowed to rise to ambient temperature. The solvent was evaporated under reduced pressure to give a residue which was purified by preparative HPLC (Condition B-58 as described in general methods) to get 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinamide (80.0 mg, 86.0%) as a white solid. LCMS Condition B-26: retention time 2.28 min, [M+1]=421.2. HPLC Condition B-6: retention time 7.62 min, purity 99.33%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.84 (d, J=4.0 Hz, 2H), 6.68 (t, J=4.0 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 7.25-7.32 (m, 1H), 7.34-7.41 (m, 5H), 7.45-7.48 (m, 2H), 7.52-7.54 (m, 2H), 7.67 (s, 1H), 7.93 (d, J=4.0 Hz, 1H), 8.32 (s, 1H), 8.95 (t, J=4.0 Hz, 1H), 9.11 (d, J=2.4 Hz, 1H), 9.46 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]#[N:12].[S:13]([OH:17])(=[O:16])(=[O:15])[CH3:14].[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH3:19].ClC1C=CC=CC=1>>[NH2:10][C:11]([NH2:12])=[NH:23].[S:13]([OH:17])(=[O:16])(=[O:15])[CH3:14].[CH2:18]([C:20]1[CH:21]=[C:22]([NH:23][C:11]([NH:10][C:3]2[CH:4]=[C:5]([CH2:8][CH3:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[NH:12])[CH:24]=[CH:25][CH:26]=1)[CH3:19]
Reactant: CCc1ccc(Cl)c(NC#N)c1
Reactant: CCc1cccc(N)c1
Agent: CS(=O)(=O)O
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cc(CC)ccc2Cl)c1
Product: N=C(N)N

Procedure:
A mixture of 2-chloro-5-ethylphenylcyanamide (0.6 g, 3.08 mmol), 3-ethylaniline mesylate (0.64 g, 2.93 mmol), and chlorobenzene (12 mL) were combined in a dry round bottom flask equipped with a water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 3 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine mesylate, as a white solid (1.1 g, 91% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]=1[OH:16])#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:15]=2)=[CH:5][C:4]=1[O:16][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])#[N:2]
Reactant: CC(C)=CCBr
Reactant: N#Cc1ccc(Nc2ncccn2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ncccn2)ccc1C#N
Yield: 30 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-cyano-5-(pyrimidin-2-ylamino)phenol (10 mg, 0.047 mmol) and Cs2CO3 (16 mg, 0.049 mmol) in acetone (2.0 mL) was treated with 4-bromo-2-methyl-2-butene (5.5 μL, 0.14 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 30% yield (4 mg).
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]=1)(=[O:3])[CH3:2].[Se](=O)=[O:14].[OH2:16]>N1C=CC=CC=1>[S:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:4]([CH:1]([OH:3])[C:2]([OH:14])=[O:16])=[CH:5]1
Reactant: O
Reactant: CC(=O)c1csc2ccccc12
Reactant: O=[Se]=O
Solvent: c1ccncc1
Product: O=C(O)C(O)c1csc2ccccc12
Temperature: 60 °C

Procedure:
Eleven grams of the 3-acetylbenzothiophene from above was dissolved in 80 ml of pyridine and warmed to 60° C. To the reaction mixture were added portionwise 9.92 g of selenium dioxide. The reaction mixture was warmed to 120° C. and then cooled to 90° C. and stirred at that temperature for forty-five minutes. The mixture was next added to 80 ml of water, and the pyridine solvent was then removed by evaporation. The aqueous mixture was acidified to pH 2.0 with phosphoric acid, and the product was extracted into diethyl ether. Removal of the solvent by evaporation and crystallization of the product from benzene gave 3.85 g of 3-benzothienylglycolic acid. m.p. 89°-91° C.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][O:9][CH3:10])[NH:5][C:6]=1[I:7].[H-].[Na+].[C:13]([NH:20][CH2:21][CH2:22]Br)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][N:3]1[C:2]([I:1])=[C:6]([I:7])[N:5]=[C:4]1[CH2:8][O:9][CH3:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: COCc1nc(I)c(I)[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-diiodo-2-methoxymethyl-1H-imidazole (3.000 g; 8.244 mmol) in anhydrous DMF (35 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (395 mg; 9.895 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (2.032 g; 9.068 mmol) in anhydrous DMF (30 ml) was added dropwise, over 15 min., with an addition funnel. After completion of the addition, the resulting dark-orange homogeneous mixture was further heated at 100° C. for 1 h45. The reaction mixture was cooled to rt, and water (175 ml) was added slowly. This mixture was extracted with ether (4×120 ml). The combined organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=50/1) to give the pure product [2-(4,5-diiodo-2-methoxymethyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butylester as a pale yellow solid which was further dried under HV (3.050 g; 73%). LC-MS: tR=0.87 min.; [M+H]+=508.16 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:25][CH2:24]2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1ccc(OC2CCN(c3ccccn3)CC2)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OC3CCN(c4ccccn4)CC3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 2-[4-(4-chloromethylphenoxy)piperidine-1-yl]pyridine (404 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazol-4-yl]propionate (609 mg, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][O:17]C1CCCCO1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:5][CH:4]=1)[CH2:15][CH2:16][OH:17]
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCO)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
A mixture of N-methyl-(4-trifluoromethoxyphenyl)amine (4.83 g, 24.24 mmol), 2-(2-bromoethoxy)-tetrahydropyran (6.1 g, 29.03 mmol), and potassium carbonate (3.84 g, 27.76 mmol) in DMF (20 ml) was stirred at 100° C. for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford 2-[N-methyl-(4-trifluoromethoxyphenyl)-amino]ethanol (3.1 g, yield 53%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:1]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 145 °C
Reaction time: 22 h
Yield: 29.1 %

Procedure:
A mixture of methyl 3-cyanobenzoate (967 mg, 6.00 mmol), methyl thiosalicylate (1.51 g, 8.98 mmol), triethylamine (1.5 ml, 11 mmol) and xylene (6 mL) was stirred at 145° C. for 22 hours under a nitrogen flow. After the reaction mixture was allowed to cool, the crystals were taken by filtration and recrystallized from methanol to give the title compound (519 mg, 29%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=[O:16])[CH2:6][CH2:5]2.[CH3:17][CH:18](C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C[Si](C#C)(C)C>C(#N)C.C(OCC)(=O)C>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=[O:16])[CH2:6][CH2:5]2)#[CH:18]
Reactant: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C#C[Si](C)(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C#Cc1cc2c(cc1OC)C(C)(C)C(=O)CC2
Temperature: 85 °C
Reaction time: 2 h
Yield: 430.1 %

Procedure:
6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (1 g) was dissolved in acetonitrile (50 ml), added with PdCl2(CH3CN)2 (45 mg), X-phos (168 mg), CsCO3 (1.2 g) and trimethylsilylacetylene (0.9 ml), and the mixture was stirred at 85° C. for 2 hrs. The reaction mixture was diluted with ethyl acetate (100 ml). The organic layer was washed twice with 10% brine and concentrated under reduced pressure. The resulting residues were dissolved in THF (10 ml), added with the THF solution (4 ml) comprising tetrabutylammonium fluoride and stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 ml). The organic layer was washed twice with 10% brine and concentrated under reduced pressure. The resulting residues were purified by silica gel column (n-hexane/ethyl acetate=9/1) to obtain the title compound (346 mg, two step yield 43%).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(=[O:19])C.[K+].C(O)(=O)C>O>[CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:19])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(CCl)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCc1ccc(CO)cc1
Yield: 53.4 %

Procedure:
A mixture of 16.2 g (68 mMols) of 4-octylbenzyl chloride, 41,8 g (0.43 mols) of potassium acetate and 200 ml of glacial acetic acid was heated for 20 h to 130° C. After cooling, the mixture was poured into approximately 1 liter of water and the aqueous phase was extracted with tert.-butyl methyl ether. The organic phase was washed twice with water, repeatedly with potassium hydrogen carbonate solution (2N) and then with saturated sodium chloride solution. After the solvent had been distilled off, the residue was taken up in 160 ml of 1,2-dimethoxyethane and, after the addition of 64 g of sodium hydroxide in 130 ml of water, the solution was heated for 45 h to boiling point. After the solvent had been distilled off, the residue was extracted with tert.-butyl methyl ether, the ether phase was washed with water, the solvent was distilled off, the residue was taken up in petroleum ether and the solution was reconcentrated by evaporation after treatment with active carbon and fuller's earth. Fractionation under reduced pressure produced 8 g (54% of theoretical) of 4-octylbenzyl alcohol boiling at 128° C./0.11 mbar and having a refractive index n of 1.5033.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 80.1 %

Procedure:
A solution of 4-trifluoromethylphenylacetic acid (784 mg, 3.84 mmol) in tetrahydrofuran (3 mL) was cooled to 0° C. and treated dropwise with a solution of borane in tetrahydrofuran (1.0 M, 5.4 mL, 5.4 mmol). The mixture was stirred at room temperature for 2.75 hours, then was treated slowly with 50% water in tetrahydrofuran (2 mL), followed by water (2 mL). The mixture was stirred for 5 minutes, and solid potassium carbonate was added to saturate the aqueous phase. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide a colorless liquid (585 mg, 80%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.59 (d, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 2H), 3.92 (t, J=7 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 1.53 (s, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([Cl:16])[N:6]=1>C(OC)(C)(C)C>[Cl:16][C:7]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][C:10]([Cl:11])=[C:5]([O:2][CH3:1])[N:6]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cc(Cl)c(Cl)nc1Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1nc(Cl)c(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
10.8 g (0.06 mol) of 30% strength sodium methoxide solution were added to 15 g (0.06 mol) of 2,3,6-trichloro-5-trifluoromethylpyridine in 200 ml of methyl tert-butyl ether at 0-5° C. with stirring in the course of 20 minutes and the mixture was subsequently stirred at the same temperature for 30 minutes. After warming to 20° C., the resulting fine precipitate was filtered off with suction and washed with methyl tert-butyl ether. The organic filtrate was washed with water, dried and concentrated, 14.3 g (97% of theory) of the title compound of n25D =1.4890 being obtained.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:33]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])#[N:34].C(O)(=O)C.N1CCCCC1>C(O)C>[C:33]([C:35](=[CH:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=2)=[CH:22][N:21]=1)[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])#[N:34]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)nc3)nc12
Reactant: CN(C)C(=O)CC#N
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Yield: 75 %

Procedure:
In a 50 ml three necked round bottom flask, 5-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)picolinaldehyde (0.17 g, 0.00037 mole) and 2-cyano-N,N-dimethylacetamide (0.084 g, 0.00075 mole) was taken in ethanol (5 ml). Piperidine acetate (3.3 M solution in water) (0.2 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed for 4 hrs and after completion of the reaction, the ethanol was distilled out and water was added to residue. Aqueous layer was extracted with ethyl acetate, organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was triturated with n-pentane, the pentane layer was decanted and solid was dried under vacuum to yield 0.152 g of 2-cyano-N,N-dimethyl-3-(5-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl-amino)pyridin-2-yl)acrylamide which was converted to the title compound as described in Example 8 above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](Cl)=[O:31].C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])[C@H:13]([CH3:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1C(=O)c1ccccn1
Temperature: 85 °C
Yield: 45.5 %

Procedure:
To a solution of (3R)-1-[(4-chlorophenyl)sulfonyl]-3-methylpiperazine (0.15 g, 0.55 mmol) in dry acetonitrile (5 mL) was added potassium carbonate (90 mg, 0.66 mmol) and 2-pyridinecarbonyl chloride (106 mg, 0.60 mmol) and the reaction mixture heated at 85° C. for 24 h. To the mixture was added ethyl acetate (30 mL) and the organic phase washed with 10% aqueous sodium bicarbonate (50 mL) before it was dried (MgSO4), filtered and the solvent evaporated. The crude product was purified by Biotage SP4 (12+M silica column) eluting 0-4% MeOH in DCM to give the title compound as an off-white solid (95 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:13][CH2:12]2)[C:5]([O:8]C)=[N:6][CH:7]=1.S(Cl)(Cl)=[O:31].[C:34](=[O:37])([O-:36])[O-].[Na+].[Na+]>C(O)C>[C:26]([OH:25])(=[O:31])[C:34]([OH:36])=[O:37].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:15][CH2:16]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1CN1CCC(CCc2ccccc2OCC(C)C)CC1
Reactant: O=S(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)COc1ccccc1CCC1CCN(Cc2cc(Cl)c[nH]c2=O)CC1
Product: O=C(O)C(=O)O

Procedure:
In ethanol (10 ml) was dissolved 443 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(isobutyloxy)phenyl]ethyl]piperidine. To the mixture was added 0.5 ml of thionyl chloride, followed by heating under reflux for 3 hours. An aqueous sodium carbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting oil was dissolved in ethanol, 99 mg of oxalic acid was added thereto, and then the resulting precipitates were collected by filtration, to give 382 mg of the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[CH:20](=[O:23])[CH2:21][CH3:22]>C1COCC1>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH:20]([OH:23])[CH2:21][CH3:22]
Reactant: CCC=O
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Br)c2C)c(C)c1
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)pyridine in dry THF was added nBuli and stirred at that temperature for 20 minutes. Excess propionaldehyde was added and stirred for 2 hours at −78° C. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. After column chromatography, an off-white solid was obtained, mp. 119-120° C. 1H NMR(CDCl3) d 6.86(s,3H), 4.90(m,1H), 2.281(s,3H), 2.28(s,3H), 2.21(s,3H), 2.02(s,6H), 1.65-1.8(m,2H), 1.00(t,3H) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:21]=[CH:20][C:12]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])(O)=O.[Na+].CI>CN(C=O)C>[CH3:22][N:13]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]1[CH:20]=[CH:21][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)CCCNc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CCCC(=O)O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.41 g (0.05 mole) of 4-(4-benzoylanilino)butyric acid are dissolved in 15 ml of DMF, and 0.84 g of NaHCO3 (0.01 mole) and 1.42 g (0.01 mole) of methyl iodide are added, and the mixture is stirred at 80° C. for about 3 h. It is then poured onto ice-water, the mixture is extracted with ethyl acetate, the organic phase is dried with MgSO4, and the solvent is evaporated off in vacuo. The residue is chromatographed on silica gel using n-hexane/ethyl acetate as eluent. The oily product is immediately hydrolyzed with 2 N LiOH. The title compound is obtained and has the melting point 111°-113° C.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=1.[NH2:23][C@@H:24]([C:28]([OH:30])=[O:29])[C@H:25]([CH3:27])[OH:26].CCN(CC)CC>CN(C=O)C.O>[OH:26][C@@H:25]([CH3:27])[C@@H:24]([NH:23][C:6]([O:20][CH2:19][CH2:18][C:17]1[CH:21]=[CH:22][C:14]([CH3:13])=[CH:15][CH:16]=1)=[O:7])[C:28]([OH:30])=[O:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: Cc1ccc(CCO)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(CCOC(=O)N[C@@H](C(=O)O)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
In a four necked round bottom flask, CDI (9.32 g, 57.4 mmol) was added to a solution of 4-methylphenethyl alcohol (4 mL, 28.7 mmol) in anhydrous DMF (60 mL) under argon. After stirring 2 h at rt, D-threonine (3.42 g, 28.7 mmol) dissolved in water (60 mL) and Et3N (6 mL, 43.1 mmol) were added. The mixture was heated at 50° C. for 16 h, then allowed to cool. Water (600 mL) was added and the mixture washed with Et2O (2×300 mL). The aqueous phase was acidified with 2M HCl solution then extracted with AcOEt (3×500 mL). The collected organic phases were washed with brine and then dried over Na2SO4, filtered and the solvent removed under vacuum. The crude was further co-evaporated with toluene, to yield a pale yellow oil (3.72 g, 46%), which was used in the next step without further purification. Rf=0.4 (Cy/AcOEt 2:8+1% CH3COOH). FTIR (cm−1): 3419(br), 2977, 2932, 1716, 1661, 1517, 1388, 1255, 1226, 1099, 1077, 665.